Allergen-Induced Dermatitis Causes Alterations in Cutaneous Retinoid-Mediated Signaling in Mice

PubMed Central

Gericke, Janine; Ittensohn, Jan; Mihály, Johanna; Dubrac, Sandrine; Rühl, Ralph

2013-01-01

Nuclear receptor-mediated signaling via RARs and PPARδ is involved in the regulation of skin homeostasis. Moreover, activation of both RAR and PPARδ was shown to alter skin inflammation. Endogenous all-trans retinoic acid (ATRA) can activate both receptors depending on specific transport proteins: Fabp5 initiates PPARδ signaling whereas Crabp2 promotes RAR signaling. Repetitive topical applications of ovalbumin (OVA) in combination with intraperitoneal injections of OVA or only intraperitoneal OVA applications were used to induce allergic dermatitis. In our mouse model, expression of IL-4, and Hbegf increased whereas expression of involucrin, Abca12 and Spink5 decreased in inflamed skin, demonstrating altered immune response and epidermal barrier homeostasis. Comprehensive gene expression analysis showed alterations of the cutaneous retinoid metabolism and retinoid-mediated signaling in allergic skin immune response. Notably, ATRA synthesis was increased as indicated by the elevated expression of retinaldehyde dehydrogenases and increased levels of ATRA. Consequently, the expression pattern of genes downstream to RAR was altered. Furthermore, the increased ratio of Fabp5 vs. Crabp2 may indicate an up-regulation of the PPARδ pathway in allergen-induced dermatitis in addition to the altered RAR signaling. Thus, our findings suggest that ATRA levels, RAR-mediated signaling and signaling involved in PPARδ pathways are mainly increased in allergen-induced dermatitis and may contribute to the development and/or maintenance of allergic skin diseases. PMID:23977003

Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington's Disease and Other Neurodegenerative Disorders.

PubMed

Niewiadomska-Cimicka, Anna; Krzyżosiak, Agnieszka; Ye, Tao; Podleśny-Drabiniok, Anna; Dembélé, Doulaye; Dollé, Pascal; Krężel, Wojciech

2017-07-01

Retinoic acid (RA) signaling through retinoic acid receptors (RARs), known for its multiple developmental functions, emerged more recently as an important regulator of adult brain physiology. How RAR-mediated regulation is achieved is poorly known, partly due to the paucity of information on critical target genes in the brain. Also, it is not clear how reduced RA signaling may contribute to pathophysiology of diverse neuropsychiatric disorders. We report the first genome-wide analysis of RAR transcriptional targets in the brain. Using chromatin immunoprecipitation followed by high-throughput sequencing and transcriptomic analysis of RARβ-null mutant mice, we identified genomic targets of RARβ in the striatum. Characterization of RARβ transcriptional targets in the mouse striatum points to mechanisms through which RAR may control brain functions and display neuroprotective activity. Namely, our data indicate with statistical significance (FDR 0.1) a strong contribution of RARβ in controlling neurotransmission, energy metabolism, and transcription, with a particular involvement of G-protein coupled receptor (p = 5.0e -5 ), cAMP (p = 4.5e -4 ), and calcium signaling (p = 3.4e -3 ). Many identified RARβ target genes related to these pathways have been implicated in Alzheimer's, Parkinson's, and Huntington's disease (HD), raising the possibility that compromised RA signaling in the striatum may be a mechanistic link explaining the similar affective and cognitive symptoms in these diseases. The RARβ transcriptional targets were particularly enriched for transcripts affected in HD. Using the R6/2 transgenic mouse model of HD, we show that partial sequestration of RARβ in huntingtin protein aggregates may account for reduced RA signaling reported in HD.

Deflation-activated receptors, not classical inflation-activated receptors, mediate the Hering-Breuer deflation reflex.

PubMed

Yu, Jerry

2016-11-01

Many airway sensory units respond to both lung inflation and deflation. Whether those responses to opposite stimuli come from one sensor (one-sensor theory) or more than one sensor (multiple-sensor theory) is debatable. One-sensor theory is commonly presumed in the literature. This article proposes a multiple-sensor theory in which a sensory unit contains different sensors for sensing different forces. Two major types of mechanical sensors operate in the lung: inflation- and deflation-activated receptors (DARs). Inflation-activated sensors can be further divided into slowly adapting receptors (SARs) and rapidly adapting receptors (RARs). Many SAR and RAR units also respond to lung deflation because they contain DARs. Pure DARs, which respond to lung deflation only, are rare in large animals but are easily identified in small animals. Lung deflation-induced reflex effects previously attributed to RARs should be assigned to DARs (including pure DARs and DARs associated with SARs and RARs) if the multiple-sensor theory is accepted. Thus, based on the information, it is proposed that activation of DARs can attenuate lung deflation, shorten expiratory time, increase respiratory rate, evoke inspiration, and cause airway secretion and dyspnea.

Stimulation of pulmonary rapidly adapting receptors by inhaled wood smoke in rats

PubMed Central

Lai, C J; Kou, Y R

1998-01-01

The stimulation of pulmonary rapidly adapting receptors (RARs) by wood smoke was investigated. Impulses from seventy RARs were recorded in fifty-nine anaesthetized, open-chest and artificially ventilated rats; responses to delivery of 6 ml of wood smoke into the lungs were studied in sixty-one receptors whereas responses to histamine (10 or 100 μg kg−1, i.v.) were studied in the other nine. Delivery of wood smoke stimulated fifty-two of the sixty-one RARs studied. When stimulated, an intense burst of discharge was evoked within 1 or 2 s of smoke delivery. This increased activity quickly peaked in 1-3 s (Δ= 15.8 ± 1.6 impulses s−1; n = 61; mean ± s.e.m.), then declined and yet remained at a level higher than the baseline activity. The mean duration of the stimulation was 25.1 ± 2.7 s. In contrast, smoke delivery did not affect tracheal pressure. Peak responses of RARs to wood smoke were partially reduced by removal of smoke particulates and were largely attenuated by pretreatment with dimethylthiourea (DMTU, a hydroxyl radical scavenger), indomethacin (Indo, a cyclo-oxygenase inhibitor), or both DMTU and Indo (DMTU + Indo). Conversely, the peak responses of RARs were not significantly affected by pretreatment with isoprenaline (a bronchodilator) or vehicle for these chemicals. Additionally, pretreatment with DMTU, Indo, or DMTU + Indo did not significantly alter the RAR sensitivity to mechanical stimulation (constant-pressure lung inflation; 20 cmH2O). Of the nine RARs tested, six were stimulated by histamine and their sensitivity to this chemical irritant was not altered by pretreatment with DMTU + Indo. The results suggest that both the particulates and gas phases are responsible for, and both the hydroxyl radical and cyclo-oxygenase products are involved in, the stimulation of RARs by wood smoke. Furthermore, changes in lung mechanics following smoke delivery are not the cause of this afferent stimulation. PMID:9508820

REACTIVITY PROFILE OF CONFORMATIONALLY-FLEXIBLE RETINOID RECEPTOR LIGANDS

EPA Science Inventory

Retinoids and associated derivatives represent a class of endogenousr hormones that bind to and activate different families of retinoic acid receptors (RARs, RXRs), and control many aspects of normal vertebrate development. Identification of potential RAR and RXRs ligands is of i...

Dysregulation of retinoic acid receptor diminishes hepatocyte permissiveness to hepatitis B virus infection through modulation of sodium taurocholate cotransporting polypeptide (NTCP) expression.

PubMed

Tsukuda, Senko; Watashi, Koichi; Iwamoto, Masashi; Suzuki, Ryosuke; Aizaki, Hideki; Okada, Maiko; Sugiyama, Masaya; Kojima, Soichi; Tanaka, Yasuhito; Mizokami, Masashi; Li, Jisu; Tong, Shuping; Wakita, Takaji

2015-02-27

Sodium taurocholate cotransporting polypeptide (NTCP) is an entry receptor for hepatitis B virus (HBV) and is regarded as one of the determinants that confer HBV permissiveness to host cells. However, how host factors regulate the ability of NTCP to support HBV infection is largely unknown. We aimed to identify the host signaling that regulated NTCP expression and thereby permissiveness to HBV. Here, a cell-based chemical screening method identified that Ro41-5253 decreased host susceptibility to HBV infection. Pretreatment with Ro41-5253 inhibited the viral entry process without affecting HBV replication. Intriguingly, Ro41-5253 reduced expression of both NTCP mRNA and protein. We found that retinoic acid receptor (RAR) regulated the promoter activity of the human NTCP (hNTCP) gene and that Ro41-5253 repressed the hNTCP promoter by antagonizing RAR. RAR recruited to the hNTCP promoter region, and nucleotides -112 to -96 of the hNTCP was suggested to be critical for RAR-mediated transcriptional activation. HBV susceptibility was decreased in pharmacologically RAR-inactivated cells. CD2665 showed a stronger anti-HBV potential and disrupted the spread of HBV infection that was achieved by continuous reproduction of the whole HBV life cycle. In addition, this mechanism was significant for drug development, as antagonization of RAR blocked infection of multiple HBV genotypes and also a clinically relevant HBV mutant that was resistant to nucleoside analogs. Thus, RAR is crucial for regulating NTCP expression that determines permissiveness to HBV infection. This is the first demonstration showing host regulation of NTCP to support HBV infection. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Dysregulation of Retinoic Acid Receptor Diminishes Hepatocyte Permissiveness to Hepatitis B Virus Infection through Modulation of Sodium Taurocholate Cotransporting Polypeptide (NTCP) Expression*

PubMed Central

Tsukuda, Senko; Watashi, Koichi; Iwamoto, Masashi; Suzuki, Ryosuke; Aizaki, Hideki; Okada, Maiko; Sugiyama, Masaya; Kojima, Soichi; Tanaka, Yasuhito; Mizokami, Masashi; Li, Jisu; Tong, Shuping; Wakita, Takaji

2015-01-01

Sodium taurocholate cotransporting polypeptide (NTCP) is an entry receptor for hepatitis B virus (HBV) and is regarded as one of the determinants that confer HBV permissiveness to host cells. However, how host factors regulate the ability of NTCP to support HBV infection is largely unknown. We aimed to identify the host signaling that regulated NTCP expression and thereby permissiveness to HBV. Here, a cell-based chemical screening method identified that Ro41-5253 decreased host susceptibility to HBV infection. Pretreatment with Ro41-5253 inhibited the viral entry process without affecting HBV replication. Intriguingly, Ro41-5253 reduced expression of both NTCP mRNA and protein. We found that retinoic acid receptor (RAR) regulated the promoter activity of the human NTCP (hNTCP) gene and that Ro41-5253 repressed the hNTCP promoter by antagonizing RAR. RAR recruited to the hNTCP promoter region, and nucleotides −112 to −96 of the hNTCP was suggested to be critical for RAR-mediated transcriptional activation. HBV susceptibility was decreased in pharmacologically RAR-inactivated cells. CD2665 showed a stronger anti-HBV potential and disrupted the spread of HBV infection that was achieved by continuous reproduction of the whole HBV life cycle. In addition, this mechanism was significant for drug development, as antagonization of RAR blocked infection of multiple HBV genotypes and also a clinically relevant HBV mutant that was resistant to nucleoside analogs. Thus, RAR is crucial for regulating NTCP expression that determines permissiveness to HBV infection. This is the first demonstration showing host regulation of NTCP to support HBV infection. PMID:25550158

Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes

PubMed Central

2013-01-01

Background Increased adipose thermogenesis is being considered as a strategy aimed at preventing or reversing obesity. Thus, regulation of the uncoupling protein 1 (UCP1) gene in human adipocytes is of significant interest. Retinoic acid (RA), the carboxylic acid form of vitamin A, displays agonist activity toward several nuclear hormone receptors, including RA receptors (RARs) and peroxisome proliferator-activated receptor δ (PPARδ). Moreover, RA is a potent positive regulator of UCP1 expression in mouse adipocytes. Results The effects of all-trans RA (ATRA) on UCP1 gene expression in models of mouse and human adipocyte differentiation were investigated. ATRA induced UCP1 expression in all mouse white and brown adipocytes, but inhibited or had no effect on UCP1 expression in human adipocyte cell lines and primary human white adipocytes. Experiments with various RAR agonists and a RAR antagonist in mouse cells demonstrated that the stimulatory effect of ATRA on UCP1 gene expression was indeed mediated by RARs. Consistently, a PPARδ agonist was without effect. Moreover, the ATRA-mediated induction of UCP1 expression in mouse adipocytes was independent of PPARγ coactivator-1α. Conclusions UCP1 expression is differently affected by ATRA in mouse and human adipocytes. ATRA induces UCP1 expression in mouse adipocytes through activation of RARs, whereas expression of UCP1 in human adipocytes is not increased by exposure to ATRA. PMID:24059847

Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice.

PubMed Central

Colbert, M C; Hall, D G; Kimball, T R; Witt, S A; Lorenz, J N; Kirby, M L; Hewett, T E; Klevitsky, R; Robbins, J

1997-01-01

Retinoids play a critical role in cardiac morphogenesis. To examine the effects of excessive retinoid signaling on myocardial development, transgenic mice that overexpress a constitutively active retinoic acid receptor (RAR) controlled by either the alpha- or beta-myosin heavy chain (MyHC) promoter were generated. Animals carrying the alpha-MyHC-RAR transgene expressed RARs in embryonic atria and in adult atria and ventricles, but developed no signs of either malformations or disease. In contrast, beta-MyHC-RAR animals, where expression was activated in fetal ventricles, developed a dilated cardiomyopathy that varied in severity with transgene copy number. Characteristic postmortem lesions included biventricular chamber dilation and left atrial thrombosis; the incidence and severity of these lesions increased with increasing copy number. Transcript analyses showed that molecular markers of hypertrophy, alpha-skeletal actin, atrial natriuretic factor and beta-MyHC, were upregulated. Cardiac performance of transgenic hearts was evaluated using the isolated perfused working heart model as well as in vivo, by transthoracic M-mode echocardiography. Both analyses showed moderate to severe impairment of left ventricular function and reduced cardiac contractility. Thus, expression of a constitutively active RAR in developing atria and/ or in postnatal ventricles is relatively benign, while ventricular expression during gestation can lead to significant cardiac dysfunction. PMID:9329959

Retinoic acid signaling and mouse embryonic stem cell differentiation: Cross talk between genomic and non-genomic effects of RA.

PubMed

Rochette-Egly, Cécile

2015-01-01

Retinoic acid (RA), the active derivative of vitamin A, a fat-soluble vitamin, plays key roles in cell growth and differentiation by activating nuclear receptors, RARs (α, β and γ), which are ligand dependent regulators of transcription. The past years highlighted several novelties in the field that increased the complexity of RA effects. Indeed, in addition to its classical genomic effects, RA also has extranuclear and non-transcriptional effects. RA induces the rapid and transient activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of RARs at a conserved serine residue located in the N-terminal domain and their coregulators. In order to investigate the relevance of RARs' phosphorylation in cell differentiation, mouse embryonic stem (mES) cells were used as a model. When treated with RA, these pluripotent cells give rise to neuronal cells. Cells invalidated for each RAR were generated as well as stable rescue lines expressing RARs mutated in phosphor acceptor sites. Such a strategy revealed that RA-induced neuronal differentiation involves the RARγ2 subtype and requires RARγ2 phosphorylation. Moreover, in gene expression profiling experiments, the phosphorylated form of RARγ2 was found to regulate a small subset of genes through binding a novel RA response element consisting of two direct repeats with a 7 base pair spacer. These new findings suggest an important role for RAR phosphorylation during cell differentiation, and pave the way for further investigations with other cell types and during embryonic development. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. Copyright © 2014 Elsevier B.V. All rights reserved.

Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity

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

Whelan, Jarrett T.; Wang, Lei; Chen, Jianming

2014-11-28

Highlights: • Transcription and translation are required for retinoid-induced lymphocyte adhesion. • RAR activation is sufficient to induced lymphocyte cell adhesion. • Vitamin D derivatives inhibit RAR-prompted lymphocyte adhesion. • Adhesion occurs through a novel binding site within ADAM disintegrin domains. • RARα is a key nuclear receptor for retinoid-dependent lymphocyte cell adhesion. - Abstract: Oxidative metabolites of vitamin A, in particular all-trans-retinoic acid (atRA), have emerged as key factors in immunity by specifying the localization of immune cells to the gut. Although it is appreciated that isomers of retinoic acid activate the retinoic acid receptor (RAR) and retinoid Xmore » receptor (RXR) family of nuclear receptors to elicit cellular changes, the molecular details of retinoic acid action remain poorly defined in immune processes. Here we employ a battery of agonists and antagonists to delineate the specific nuclear receptors utilized by retinoids to evoke lymphocyte cell adhesion to ADAM (adisintegrin and metalloprotease) protein family members. We report that RAR agonism is sufficient to promote immune cell adhesion in both immortal and primary immune cells. Interestingly, adhesion occurs independent of integrin function, and mutant studies demonstrate that atRA-induced adhesion to ADAM members required a distinct binding interface(s) as compared to integrin recognition. Anti-inflammatory corticosteroids as well as 1,25-(OH){sub 2}D{sub 3}, a vitamin D metabolite that prompts immune cell trafficking to the skin, potently inhibited the observed adhesion. Finally, our data establish that induced adhesion was specifically attributable to the RAR-α receptor isotype. The current study provides novel molecular resolution as to which nuclear receptors transduce retinoid exposure into immune cell adhesion.« less

REACTIVITY PROFILE OF LIGANDS OF MAMMALIAN RETINOIC ACID RECEPTORS: A PRELIMINARY COREPA ANALYSIS

EPA Science Inventory

Retinoic acid and associated derivatives comprise a class of endogenous hormones that bind to and activate different families of retinoic acid receptors (RARs, RXRs), and control many aspects of vertebrate development. Identification of potential RAR and RXR ligands is of interes...

Utilization of DR1 as true RARE in regulating the Ssm, a novel retinoic acid-target gene in the mouse testis.

PubMed

Han, Kyuyong; Song, Haengseok; Moon, Irene; Augustin, Robert; Moley, Kelle; Rogers, Melissa; Lim, Hyunjung

2007-03-01

Various nuclear receptors form dimers to activate target genes via specific response elements located within promoters or enhancers. Retinoid X receptor (RXR) serves as a dimerization partner for many nuclear receptors including retinoic acid receptor (RAR) and peroxisome proliferator-activated receptor (PPAR). Dimers show differential preference towards directly repeated response elements with 1-5 nucleotide spacing, and direct repeat 1 (DR1) is a promiscuous element which recruits RAR/RXR, RXR/RXR, and PPAR/RXR in vitro. In the present investigation, we report identification of a novel RAR/RXR target gene which is regulated by DR1s in the promoter region. This gene, namely spermatocyte-specific marker (Ssm), recruits all the three combinations of nuclear receptors in vitro, but in vivo regulation is observed by trans-retinoic acid-activated RAR/RXR dimer. Indeed, chromatin immunoprecipitation experiment demonstrates binding of RARbeta and RXRalpha in the promoter region of the Ssm. Interestingly, expression of Ssm is almost exclusively observed in spermatocytes in the adult mouse testis, where RA signaling is known to regulate developmental program of male germ cells. The results show that Ssm is a RAR/RXR target gene uniquely using DR1 and exhibits stage-specific expression in the mouse testis with potential function in later stages of spermatogenesis. This finding exemplifies usage of DR1s as retinoic acid response element (RARE) under a specific in vivo context.

Human skin levels of retinoic acid and cytochrome P-450-derived 4-hydroxyretinoic acid after topical application of retinoic acid in vivo compared to concentrations required to stimulate retinoic acid receptor-mediated transcription in vitro.

PubMed Central

Duell, E A; Aström, A; Griffiths, C E; Chambon, P; Voorhees, J J

1992-01-01

Metabolism of retinoic acid to a less active metabolite, 4-hydroxyretinoic acid, occurs via cytochrome P-450 isozyme(s). Effect of a pharmacological dose of retinoic acid on the level of retinoic acid in skin and on cytochrome P-450 activity was investigated. A cream containing 0.1% retinoic acid or cream alone was applied topically to adult human skin for four days under occlusion. Treated areas were removed by a keratome and a microsomal fraction was isolated from each biopsy. In vitro incubation of 3H-retinoic acid with microsomes from in vivo retinoic acid treated sites resulted in a 4.5-fold increase (P = 0.0001, n = 13) in its transformation to 4-hydroxyretinoic acid in comparison to in vitro incubations with microsomes from in vivo cream alone treated sites. This cytochrome P-450 mediated activity was oxygen- and NADPH-dependent and was inhibited 68% by 5 microM ketoconazole (P = 0.0035, n = 8) and 51% by carbon monoxide (P = 0.02, n = 6). Cotransfection of individual retinoic acid receptors (RARs) or retinoid X receptor-alpha (RXR-alpha) and a chloramphenicol acetyl transferase (CAT) reporter plasmid containing a retinoic acid responsive element into CV-1 cells was used to determine the ED50 values for stimulation of CAT activity by retinoic acid and its metabolites. Levels of all trans and 13-cis RA in RA-treated tissues were greater than the ED50 values determined for all three RARs with these compounds. Furthermore, the level of all trans RA was greater than the ED50 for RXR-alpha whereas the 4-OH RA level was greater than the ED50 for RAR-beta and RAR-gamma but less than for RAR-alpha and RXR-alpha. These data suggest that there are sufficient amounts of retinoic acid in treated skin to activate gene transcription over both RARs and RXR-alpha. PMID:1328295

Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations.

PubMed

Lax, Nichola Z; Alston, Charlotte L; Schon, Katherine; Park, Soo-Mi; Krishnakumar, Deepa; He, Langping; Falkous, Gavin; Ogilvy-Stuart, Amanda; Lees, Christoph; King, Rosalind H; Hargreaves, Iain P; Brown, Garry K; McFarland, Robert; Dean, Andrew F; Taylor, Robert W

2015-07-01

Autosomal recessive mutations in the RARS2 gene encoding the mitochondrial arginyl-transfer RNA synthetase cause infantile-onset myoencephalopathy pontocerebellar hypoplasia type 6 (PCH6). We describe 2 sisters with novel compound heterozygous RARS2 mutations who presented perinatally with neurologic features typical of PCH6 but with additional features including cardiomyopathy, hydrops, and pulmonary hypoplasia and who died at 1 day and 14 days of age. Magnetic resonance imaging findings included marked cerebellar hypoplasia, gyral immaturity, punctate lesions in cerebral white matter, and unfused deep cerebral grey matter. Enzyme histochemistry of postmortem tissues revealed a near-global cytochrome c oxidase-deficiency; assessment of respiratory chain enzyme activities confirmed severe deficiencies involving complexes I, III, and IV. Molecular genetic studies revealed 2 RARS2 gene mutations: a c.1A>G, p.? variant predicted to abolish the initiator methionine, and a deep intronic c.613-3927C>T variant causing skipping of exons 6-8 in the mature RARS2 transcript. Neuropathologic investigation included low brain weights, small brainstem and cerebellum, deep cerebral white matter pathology, pontine nucleus neuron loss (in 1 sibling), and peripheral nerve pathology. Mitochondrial respiratory chain immunohistochemistry in brain tissues confirmed an absence of complexes I and IV immunoreactivity with sparing of mitochondrial numbers. These cases expand the clinical spectrum of RARS2 mutations, including antenatal features and widespread mitochondrial respiratory chain deficiencies in postmortem brain tissues.

Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations

PubMed Central

Lax, Nichola Z.; Alston, Charlotte L.; Schon, Katherine; Park, Soo-Mi; Krishnakumar, Deepa; He, Langping; Falkous, Gavin; Ogilvy-Stuart, Amanda; Lees, Christoph; King, Rosalind H.; Hargreaves, Iain P.; Brown, Garry K.; McFarland, Robert; Dean, Andrew F.; Taylor, Robert W.

2015-01-01

Abstract Autosomal recessive mutations in the RARS2 gene encoding the mitochondrial arginyl-transfer RNA synthetase cause infantile-onset myoencephalopathy pontocerebellar hypoplasia type 6 (PCH6). We describe 2 sisters with novel compound heterozygous RARS2 mutations who presented perinatally with neurologic features typical of PCH6 but with additional features including cardiomyopathy, hydrops, and pulmonary hypoplasia and who died at 1 day and 14 days of age. Magnetic resonance imaging findings included marked cerebellar hypoplasia, gyral immaturity, punctate lesions in cerebral white matter, and unfused deep cerebral grey matter. Enzyme histochemistry of postmortem tissues revealed a near-global cytochrome c oxidase-deficiency; assessment of respiratory chain enzyme activities confirmed severe deficiencies involving complexes I, III, and IV. Molecular genetic studies revealed 2 RARS2 gene mutations: a c.1A>G, p.? variant predicted to abolish the initiator methionine, and a deep intronic c.613-3927C>T variant causing skipping of exons 6–8 in the mature RARS2 transcript. Neuropathologic investigation included low brain weights, small brainstem and cerebellum, deep cerebral white matter pathology, pontine nucleus neuron loss (in 1 sibling), and peripheral nerve pathology. Mitochondrial respiratory chain immunohistochemistry in brain tissues confirmed an absence of complexes I and IV immunoreactivity with sparing of mitochondrial numbers. These cases expand the clinical spectrum of RARS2 mutations, including antenatal features and widespread mitochondrial respiratory chain deficiencies in postmortem brain tissues. PMID:26083569

Differential effects of phthalates on the testis and the liver.

PubMed

Bhattacharya, Nandini; Dufour, Jannette M; Vo, My-Nuong; Okita, Janice; Okita, Richard; Kim, Kwan Hee

2005-03-01

Phthalates have been shown to elicit contrasting effects on the testis and the liver, causing testicular degeneration and promoting abnormal hepatocyte proliferation and carcinogenesis. In the present study, we compared the effects of phthalates on testicular and liver cells to better understand the mechanisms by which phthalates cause testicular degeneration. In vivo treatment of rats with di-(2-ethylhexyl) phthalate (DEHP) caused a threefold increase of germ cell apoptosis in the testis, whereas apoptosis was not changed significantly in livers from the same animals. Western blot analyses revealed that peroxisome proliferator-activated receptor (PPAR) alpha is equally abundant in the liver and the testis, whereas PPAR gamma and retinoic acid receptor (RAR) alpha are expressed more in the testis. To determine whether the principal metabolite of DEHP, mono-(2-ethylhexyl) phthalate (MEHP), or a strong peroxisome proliferator, 4-chloro-6(2,3-xylindino)-2-pyrimidinylthioacetic acid (Wy-14,643), have a differential effect in Sertoli and liver cells by altering the function of RAR alpha and PPARs, their nuclear trafficking patterns were compared in Sertoli and liver cells after treatment. Both MEHP and Wy-14,643 increased the nuclear localization of PPAR alpha and PPAR gamma in Sertoli cells, but they decreased the nuclear localization of RAR alpha, as previously shown. Both PPAR alpha and PPAR gamma were in the nucleus and cytoplasm of liver cells, but RAR alpha was predominant in the cytoplasm, regardless of the treatment. At the molecular level, MEHP and Wy-14,643 reduced the amount of phosphorylated mitogen-activated protein kinase (activated MAPK) in Sertoli cells. In comparison, both MEHP and Wy-14,643 increased phosphorylated MAPK in liver cells. These results suggest that phthalates may cause contrasting effects on the testis and the liver by differential activation of the MAPK pathway, RAR alpha, PPAR alpha, and PPAR gamma in these organs.

Both retinoic-acid-receptor- and retinoid-X-receptor-dependent signalling pathways mediate the induction of the brown-adipose-tissue-uncoupling-protein-1 gene by retinoids.

PubMed Central

Alvarez, R; Checa, M; Brun, S; Viñas, O; Mampel, T; Iglesias, R; Giralt, M; Villarroya, F

2000-01-01

The intracellular pathways and receptors mediating the effects of retinoic acid (RA) on the brown-fat-uncoupling-protein-1 gene (ucp-1) have been analysed. RA activates transcription of ucp-1 and the RA receptor (RAR) is known to be involved in this effect. However, co-transfection of an expression vector for retinoid-X receptor (RXR) increases the action of 9-cis RA but not the effects of all-trans RA on the ucp-1 promoter in brown adipocytes. Either RAR-specific ¿p-[(E)-2-(5,6,7,8,-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid¿ or RXR-specific [isopropyl-(E,E)-(R,S)-11-methoxy-3,7, 11-trimethyldodeca-2,4-dienoate, or methoprene] synthetic compounds increase the expression of UCP-1 mRNA and the activity of chloramphenicol acetyltransferase expression vectors driven by the ucp-1 promoter. The RXR-mediated action of 9-cis RA requires the upstream enhancer region at -2469/-2318 in ucp-1. During brown-adipocyte differentiation RXRalpha and RXRgamma mRNA expression is induced in parallel with UCP-1 mRNA, whereas the mRNA for the three RAR subtypes, alpha, beta and gamma, decreases. Co-transfection of murine expression vectors for the different RAR and RXR subtypes indicates that RARalpha and RARbeta as well as RXRalpha are the major retinoid-receptor subtypes capable of mediating the responsiveness of ucp-1 to retinoids. It is concluded that the effects of retinoids on ucp-1 transcription involve both RAR- and RXR-dependent signalling pathways. The responsiveness of brown adipose tissue to retinoids in vivo relies on a complex combination of the capacity of RAR and RXR subtypes to mediate ucp-1 induction and their distinct expression in the differentiated brown adipocyte. PMID:10600643

Heterodimers of Retinoic Acid Receptors and Thyroid Hormone Receptors Display Unique Combinatorial Regulatory Properties

PubMed Central

Lee, Sangho; Privalsky, Martin L.

2009-01-01

Nuclear receptors are ligand-regulated transcription factors that regulate key aspects of metazoan development, differentiation, and homeostasis. Nuclear receptors recognize target genes by binding to specific DNA recognition sequences, denoted hormone response elements (HREs). Many nuclear receptors can recognize HREs as either homodimers or heterodimers. Retinoid X receptors (RXRs), in particular, serve as important heterodimer partners for many other nuclear receptors, including thyroid hormone receptors (TRs), and RXR/TR heterodimers have been proposed to be the primary mediators of target gene regulation by T3 hormone. Here, we report that the retinoic acid receptors (RARs), a distinct class of nuclear receptors, are also efficient heterodimer partners for TRs. These RAR/TR heterodimers form with similar affinities as RXR/TR heterodimers on an assortment of consensus and natural HREs, and preferentially assemble with the RAR partner 5′ of the TR moiety. The corepressor and coactivator recruitment properties of these RAR/TR heterodimers and their transcriptional activities in vivo are distinct from those observed with the corresponding RXR heterodimers. Our studies indicate that RXRs are not unique in their ability to partner with TRs, and that RARs can also serve as robust heterodimer partners and combinatorial regulators of T3-modulated gene expression. PMID:15650024

Activation of the CRABPII/RAR pathway by curcumin induces retinoic acid mediated apoptosis in retinoic acid resistant breast cancer cells

PubMed Central

Thulasiraman, Padmamalini; Garriga, Galen; Danthuluri, Veena; McAndrews, Daniel J.; Mohiuddin, Imran Q.

2017-01-01

Due to the anti-proliferative and anti-apoptotic effects of retinoic acid (RA), this hormone has emerged as a target for several diseases, including cancer. However, development of retinoid resistance is a critical issue and efforts to understand the retinoid signaling pathway may identify useful biomarkers for future clinical trials. Apoptotic responses of RA are exhibited through the cellular RA-binding protein II (CRABPII)/retinoic acid receptor (RAR) signaling cascade. Delivery of RA to RAR by CRABPII enhances the transcriptional activity of genes involved in cell death and cell cycle arrest. The purpose of this study was to investigate the role of curcumin in sensitizing RA-resistant triple-negative breast cancer (TNBC) cells to RA-mediated apoptosis. We provide evidence that curcumin upregulates the expression of CRABPII, RARβ and RARγ in two different TNBC cell lines. Co-treatment of the cells with curcumin and RA results in increased apoptosis as demonstrated by elevated cleavage of poly(ADP-ribose) polymerase and cleaved caspase-9. Additionally, silencing CRABPII reverses curcumin sensitization of TNBC cells to the apoptotic inducing effects of RA. These findings provide mechanistic insights into sensitizing TNBC cells to RA-mediated cell death by curcumin-induced upregulation of the CRABPII/RAR pathway. PMID:28350049

Combinational treatment with retinoic acid derivatives in non-small cell lung carcinoma in vitro.

PubMed

Choi, Eun Jung; Whang, Young Mi; Kim, Seok Jin; Kim, Hyun Jin; Kim, Yeul Hong

2007-09-01

The growth inhibitory effects of four retinoic acid (RA) derivatives, 9-cis RA, 13-cis RA, N-(4-hydroxyphenyl) retinamide (4-HPR), and all-trans retinoic acid (ATRA) were compared. In addition, the effects of various combinations of these four agents were examined on non-small cell lung carcinoma (NSCLC) cell-lines, and on the expressions of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) on these cells. At the clinically achievable concentration of 1 microM, only 4-HPR inhibited the growths of H1299 and H460 cells-lines. However, retinoic acid receptor beta(RAR beta) expression was up-regulated on H460 and H1299 cells treated with 1 microM of ATRA, 13-cis RA, or 9-cis RA. All NSCLC cell lines showed growth inhibition when exposed sequentially to 1 microM ATRA and 0.1 microM 4-HPR. In particular, sequential treatment with 1 microM ATRA or 13-cis RA and 4-HPR markedly inhibited H1703 cell growth; these cells exhibited no basal RAR beta expression and were refractory to 4-HPR. However, in NSCLC cell lines that expressed RAR beta, the expressional levels of RAR beta were up-regulated by ATRA alone and by sequential treatment with ATRA and 4-HPR. 4-HPR was found to be the most active of the four agents in terms of NSCLC growth-inhibition. Moreover, sequential treatments with ATRA or 13-cis RA followed by 4-HPR were found to have synergistic growth-inhibitory effects and to regulate RAR expression.

Retinoic acid receptor signalling directly regulates osteoblast and adipocyte differentiation from mesenchymal progenitor cells

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

Green, A.C.; Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Victoria 3065; Kocovski, P.

Low and high serum retinol levels are associated with increased fracture risk and poor bone health. We recently showed retinoic acid receptors (RARs) are negative regulators of osteoclastogenesis. Here we show RARs are also negative regulators of osteoblast and adipocyte differentiation. The pan-RAR agonist, all-trans retinoic acid (ATRA), directly inhibited differentiation and mineralisation of early osteoprogenitors and impaired the differentiation of more mature osteoblast populations. In contrast, the pan-RAR antagonist, IRX4310, accelerated differentiation of early osteoprogenitors. These effects predominantly occurred via RARγ and were further enhanced by an RARα agonist or antagonist, respectively. RAR agonists similarly impaired adipogenesis in osteogenicmore » cultures. RAR agonist treatment resulted in significant upregulation of the Wnt antagonist, Sfrp4. This accompanied reduced nuclear and cytosolic β-catenin protein and reduced expression of the Wnt target gene Axin2, suggesting impaired Wnt/β-catenin signalling. To determine the effect of RAR inhibition in post-natal mice, IRX4310 was administered to male mice for 10 days and bones were assessed by µCT. No change to trabecular bone volume was observed, however, radial bone growth was impaired. These studies show RARs directly influence osteoblast and adipocyte formation from mesenchymal cells, and inhibition of RAR signalling in vivo impairs radial bone growth in post-natal mice. - Graphical abstract: Schematic shows RAR ligand regulation of osteoblast differentiation in vitro. RARγ antagonists±RARα antagonists promote osteoblast differentiation. RARγ and RARα agonists alone or in combination block osteoblast differentiation, which correlates with upregulation of Sfrp4, and downregulation of nuclear and cytosolic β-catenin and reduced expression of the Wnt target gene Axin2. Red arrows indicate effects of RAR agonists on mediators of Wnt signalling.« less

TaRAR1 and TaSGT1 associate with TaHsp90 to function in bread wheat (Triticum aestivum L.) seedling growth and stripe rust resistance.

PubMed

Wang, Guan-Feng; Fan, Renchun; Wang, Xianping; Wang, Daowen; Zhang, Xiangqi

2015-04-01

RAR1 and SGT1 are important co-chaperones of Hsp90. We previously showed that TaHsp90.1 is required for wheat seedling growth, and that TaHsp90.2 and TaHsp90.3 are essential for resistance (R) gene mediated resistance to stripe rust fungus. Here, we report the characterization of TaRAR1 and TaSGT1 genes in bread wheat. TaRAR1 and TaSGT1 each had three homoeologs, which were located on wheat groups 2 and 3 chromosomes, respectively. Strong inhibition of seedling growth was observed after silencing TaSGT1 but not TaRAR1. In contrast, decreasing the expression of TaRAR1 or TaSGT1 could all compromise R gene mediated resistance to stripe rust fungus infection. Protein-protein interactions were found among TaRAR1, TaSGT1 and TaHsp90. The N-terminus of TaHsp90, the CHORD-I and CHORD-II domains of TaRAR1 and the CS domain of TaSGT1 may be instrumental for the interactions among the three proteins. Based on this work and our previous study on TaHsp90, we speculate that the TaSGT1-TaHsp90.1 interaction is important for maintaining bread wheat seedling growth. The TaRAR1-TaSGT1-TaHsp90.2 and TaRAR1-TaSGT1-TaHsp90.3 interactions are involved in controlling the resistance to stripe rust disease. The new information obtained here should aid further functional investigations of TaRAR1-TaSGT1-TaHsp90 complexes in regulating bread wheat growth and disease resistance.

Plasma renin activity to plasma aldosterone concentration ratio correlates with night-time and pulse pressures in essential hypertensive patients treated with angiotensin-converting enzyme inhibitors/AT1 blockers.

PubMed

Spannella, Francesco; Giulietti, Federico; Balietti, Paolo; Borioni, Elisabetta; Lombardi, Francesca E; Ricci, Maddalena; Cocci, Guido; Landi, Laura; Sarzani, Riccardo

2017-11-01

Angiotensin-converting enzyme inhibitors (ACE-I) and AT1 blockers (ARB) are commonly used antihypertensive drugs, but several factors may affect their effectiveness. We evaluated the associations between ambulatory blood pressure (BP) monitoring (ABPM) parameters and plasma renin activity (PRA)-to-plasma aldosterone concentration (PAC) ratio (RAR) to test renin-angiotensin-aldosterone system inhibition in essential hypertensive patients treated with ACE-I or ARB for at least 12 months. We evaluated 194 consecutive patients referred to our Hypertension Centre. ABPM, PRA and PAC tests were performed without any changes in drug therapy. RAR, PRA and PAC tertiles were considered for the analyses. Mean age: 57.4 ± 12.0 years; male prevalence: 63.9%. No differences between RAR tertiles regarding the use of ACE-I or ARB (P = 0.385), as well as the other antihypertensive drug classes, were found. A reduction of all ABPM values considered (24-h BP, daytime BP and night-time BP and 24-h pulse pressure (PP), daytime PP and night-time PP) and a better BP control were observed at increasing RAR tertiles, with an odds ratio = 0.12 to be not controlled during night-time period for patients in the third tertile compared with patients in the first tertile (P < 0.001). This association remained significant even after adjusting for 24-h BP control. All the associations were also confirmed for PRA tertiles, but not for PAC tertiles. Higher RAR values indicate effective renin-angiotensin-aldosterone system inhibition and lower night-time and pulse pressures in real-life clinical practice. It could be a useful biomarker in the management of essential hypertensive patients treated with ACE-I or ARB.

Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

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

Zheng, Yi; Qin, Ling; Zacarías, Natalia V. Ortiz

CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases2 including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer3. These disease associations have motivated numerous preclinical studies and clinical trials4 (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2–chemokine axis. To aid drug discovery efforts5, heremore » we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]7) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein–protein interactions, receptor–chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.« less

Structure of CC Chemokine Receptor 2 with Orthosteric and Allosteric Antagonists

PubMed Central

Zheng, Yi; Qin, Ling; Ortiz Zacarías, Natalia V.; de Vries, Henk; Han, Gye Won; Gustavsson, Martin; Dabros, Marta; Zhao, Chunxia; Cherney, Robert J.; Carter, Percy; Stamos, Dean; Abagyan, Ruben; Cherezov, Vadim; Stevens, Raymond C.; IJzerman, Adriaan P.; Heitman, Laura H.; Tebben, Andrew; Kufareva, Irina; Handel, Tracy M.

2016-01-01

Summary CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human Class A G protein-coupled receptors (GPCRs). CCR2 is expressed on monocytes, immature dendritic cells and T cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL21. CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases2 including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer3. These disease associations have motivated numerous preclinical studies and clinical trials4 (see ClinicalTrials.gov) in search of therapies that target the CCR2:chemokine axis. To aid drug discovery efforts5, we solved a structure of CCR2 in a ternary complex with an orthosteric (BMS-6816) and allosteric (CCR2-RA-[R]7) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in Class A GPCRs to date; this site spatially overlaps the G protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive GPCR structures solved to date. Like other protein:protein interactions, receptor:chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome drug design obstacles. PMID:27926736

Lung congestion augments the responses of cells in the rapidly adapting receptor pathway to cigarette smoke in rabbit.

PubMed Central

Zhang, Z; Bonham, A C

1995-01-01

1. We examined the effects of cigarette smoke, inhaled alone and during mild pulmonary venous congestion, on the activity of fifty-three neurones in the nucleus tractus solitarii (NTS) that were excited by input from pulmonary rapidly adapting receptors (RAR). Ten neurones excited by slowly adapting stretch receptors (SAR) were also studied. 2. Extracellular recordings of RAR-activated neurones were recorded in alpha-chloralose anaesthetized rabbits. Smoke from low- and high-nicotine cigarettes was delivered through a ventilator. Mild pulmonary venous congestion was produced by inflating a balloon in the left atrium. 3. Inhalation of three breaths of smoke from low-nicotine cigarettes increased the activity of fifty-one out of fifty-three RAR-activated neurones from 5.9 +/- 1.0 to 14.4 +/- 2.1 spikes breath-1 (P < 0.05). 4. The responses of fifteen neurones were compared with smoke inhaled alone or during mild pulmonary venous congestion. Smoke alone increased unit activity from 6.8 +/- 2.3 to 12.6 +/- 3.7 spikes breath-1 (P < 0.05). Small increases in left atrial pressure (2.0 +/- 0.5 mmHg) had no effect on baseline unit activity (7.6 +/- 2.11 vs. 7.7 +/- 2.3 spikes breath-1; P > 0.05), but enhanced the responses to smoke, increasing the activity from 7.6 +/- 2.1 to 17.1 +/- 4.8 spikes breath-1 (P < 0.05). The response was greater than to smoke alone (P < 0.05). 5. Of ten SAR-activated neurones, seven failed to respond to inhaled cigarette smoke, two were excited and one was inhibited. Pulmonary venous congestion had no effect on the unit activity before and after smoke (n = 4 neurones). 6. We conclude that smoke-evoked excitation of RAR lower-order neurones is augmented by pulmonary venous congestion. Images Figure 3 PMID:7602520

Clinical Significance of Retinoic Acid Receptor Beta Promoter Methylation in Prostate Cancer: A Meta-Analysis.

PubMed

Dou, MengMeng; Zhou, XueLiang; Fan, ZhiRui; Ding, XianFei; Li, LiFeng; Wang, ShuLing; Xue, Wenhua; Wang, Hui; Suo, Zhenhe; Deng, XiaoMing

2018-01-01

Retinoic acid receptor beta (RAR beta) is a retinoic acid receptor gene that has been shown to play key roles during multiple cancer processes, including cell proliferation, apoptosis, migration and invasion. Numerous studies have found that methylation of the RAR beta promoter contributed to the occurrence and development of malignant tumors. However, the connection between RAR beta promoter methylation and prostate cancer (PCa) remains unknown. This meta-analysis evaluated the clinical significance of RAR beta promoter methylation in PCa. We searched all published records relevant to RAR beta and PCa in a series of databases, including PubMed, Embase, Cochrane Library, ISI Web of Science and CNKI. The rates of RAR beta promoter methylation in the PCa and control groups (including benign prostatic hyperplasia and normal prostate tissues) were summarized. In addition, we evaluated the source region of available samples and the methods used to detect methylation. To compare the incidence and variation in RAR beta promoter methylation in PCa and non-PCa tissues, the odds ratio (OR) and 95% confidence interval (CI) were calculated accordingly. All the data were analyzed with the statistical software STATA 12.0. Based on the inclusion and exclusion criteria, 15 articles assessing 1,339 samples were further analyzed. These data showed that the RAR beta promoter methylation rates in PCa tissues were significantly higher than the rates in the non-PCa group (OR=21.65, 95% CI: 9.27-50.57). Subgroup analysis according to the source region of samples showed that heterogeneity in Asia was small (I2=0.0%, P=0.430). Additional subgroup analysis based on the method used to detect RAR beta promoter methylation showed that the heterogeneity detected by MSP (methylation-specific PCR) was relatively small (I2=11.3%, P=0.343). Although studies reported different rates for RAR beta promoter methylation in PCa tissues, the total analysis demonstrated that RAR beta promoter methylation may be correlated with PCa carcinogenesis and that the RAR beta gene is particularly susceptible. Additional studies with sufficient data are essential to further evaluate the clinical features and prognostic utility of RAR beta promoter methylation in PCa. © 2018 The Author(s). Published by S. Karger AG, Basel.

Cross-correlation between vagal afferent impulses from pulmonary mechanoreceptors and high-frequency inflation (HFI) and deflation (HFD) in rabbits.

PubMed

Homma, I; Isobe, A; Iwase, M; Onimaru, H; Sibuya, M

1987-04-10

The effects of high-frequency airway inflation (HFI) and high-frequency airway deflation (HFD) generated by a triangular pressure pulse generator on pulmonary mechanoreceptors were examined. The cross-correlograms between vagal afferent impulses from the slowly adapting (SAR) and the rapidly adapting receptors (RAR) and the HFI or the HFD pulses were analysed. HFI stimulated SAR and RAR and HFD stimulated RAR, but inhibited SAR. The time lag of the mode in the correlogram between SAR and HFI was shorter than that of the mode in the correlogram between RAR and HFI. The span of the mode and the trough of SAR was shorter than the span of the mode of RAR. This may indicate that the time to peak of the generator potential of RAR is longer than that of SAR.

Plasmapheresis affects responses of slowly and rapidly adapting airway receptors to pulmonary venous congestion in dogs.

PubMed Central

Kappagoda, C T; Ravi, K

1989-01-01

1. The effects of plasmapheresis on the responses of rapidly adapting receptors (RARs) and slowly adapting receptors (SARs) of the airways to pulmonary venous congestion were examined in dogs anaesthetized with alpha-chloralose. Pulmonary venous congestion was produced in a graded manner by partial obstruction of the mitral valve sufficient to raise the mean left atrial pressure by 5, 10 and 15 mmHg. Plasmapheresis was performed by withdrawing 10% of blood volume twice. 2. Both RARs (n = 11) and SARs (n = 5) responded to pulmonary venous congestion by increasing their activities. The responses of the former were proportionately greater. 3. After plasmapheresis which reduced the concentration of plasma proteins by 12.3 +/- 1.0%, the responses of the RARs to pulmonary venous congestion were enhanced significantly. There was no significant change in the responses of SARs. 4. In another set of six RARs, the effects of graded pulmonary venous congestion were investigated twice with an interval of 45 min between the two observations. No significant differences were noted between the two responses. 5. Collection of lymph from the tracheobronchial lymph duct (n = 6) showed that after plasmapheresis, there was an increase in the control lymph flow. In addition, the lymph flow was enhanced during pulmonary venous congestion (mean left atrial pressure increased by 10 mmHg). 6. It is suggested that a natural stimulus for the excitation of the RAR is a function of the fluid fluxes in the pulmonary extravascular space. PMID:2607464

Rapid Assessment and Response Studies of Injection Drug Use: Knowledge Gain, Capacity Building, and Intervention Development in a Multisite Study

PubMed Central

Stimson, Gerry V.; Fitch, Chris; Jarlais, Don Des; Poznyak, Vladimir; Perlis, Theresa; Oppenheimer, Edna; Rhodes, Tim

2006-01-01

Objectives. We evaluated the World Health Organization’s rapid assessment and response (RAR) method of assessing injection drug use and its associated health problems, focusing on knowledge gain, capacity building, and whether RAR leads to the development of interventions reducing the health effects of injection drug use. Methods. Data were derived from RAR studies conducted in Beijing, China; Bogotá, Colombia; Greater Rosario, Argentina; Hanoi, Vietnam; Kharkiv, Ukraine; Minsk, Belarus; Nairobi, Kenya; Penang, Malaysia; St. Petersburg, Russia; and Tehran, Iran. Results. Substantial gains in knowledge and response capacity were reported at all of the study sites. Before RAR initiation, prevention and intervention programs had been absent or inadequate at most of the sites. The RARs resulted in many new or modified interventions; 7 sites reported 24 health-related interventions that were subsequently developed and influenced by the RARs. Conclusions. RARs, which require relatively little external funding, appear to be effective in linking assessment to development of appropriate interventions. The present results add to the evidence that rapid assessment is an important public health tool. PMID:16380578

Fibroblast TGF-beta Signaling in Breast Development and Cancer

DTIC Science & Technology

2010-09-01

hypermetylation. Among the genes implicated are GSTP1 , APC, RASSF1A, H1N-1 and RAR2 [18,19]. More research is needed to clarify the contribution of any...KG, Wallis BS, Hanson JC, Chuaqui RF, et al. Tumor-associated endothelial cells display GSTP1 and RARbeta2 promoter methylation in human prostate

[Basic and clinical studies of the gene product-targeting therapy based on leukemogenesis--editorial].

PubMed

Chen, Sai-Juan; Chen, Li-Juan; Zhou, Guang-Biao

2005-02-01

In the last twenty years, using all-trans retinoic acid (ATRA) as a differentiation inducer, Shanghai Institute of Hematology has achieved an important breakthrough in the treatment of acute promyelocytic leukemia (APL), which realized the theory of reversing phenotype of cells and provided a successful model of differentiation therapy in cancers. Our group first discovered in the world the variant chromosome translocation t(11;17)(q23;q21) of APL, and cloned the PML-RAR alpha, PLZF-RAR alpha and NPM-RAR alpha fusion genes corresponding to the characterized chromosome translocations t(15;17); t(11;17) and t(5;17) in APL. Moreover, establishment of transgenic mice model of APL proved their effects on leukemogenesis. The ability of ATRA to modify the recruitment of nuclear receptor co-repressor with PML-RAR alpha but not PLZF-RAR alpha caused by the variant chromosome translocation elucidated the therapeutic mechanism of ATRA from the molecular level and provides new insight into transcription-modulating therapy. Since 1994, our group has successfully applied arsenic trioxide (As(2)O(3)) in treating relapsed APL patients, with the complete remission rate of 70% - 80%. The molecular mechanism study revealed that As(2)O(3) exerts a dose-dependent dual effect on APL. Low-dose As(2)O(3) induced partial differentiation of APL cells, while the higher dose induced apoptosis. As(2)O(3) binds ubiquitin like SUMO-1 through the lysine 160 of PML, resulting in the degradation of PML-RAR alpha. Taken together, ATRA and As(2)O(3) target the transcription factor PML-RAR alpha, the former by retinoic acid receptor and the latter by PML sumolization, both induce PML-RAR alpha degradation and APL cells differentiation and apoptosis. Because of the different acting pathways, ATRA and As(2)O(3) have no cross-resistance and can be used as combination therapy. Clinical trial in newly diagnosed APL patients showed that ATRA/As(2)O(3) in combination yields a longer disease-free survival time. With the median survival of 18 months, none of the 20 cases in combination treatment relapsed, whereas 7 relapsed in 37 cases in mono-treatment. This is the best clinical effect achieved in treating adult acute leukemia to this day, possibly making APL the first adult curable leukemia. Based on the great success of the pathogenetic gene target therapy in APL, this strategy may extend to other leukemias. Combination of Gleevec and arsenic agents in treating chronic myeloid leukemia has already make a figure both in clinical and laboratory research, aiming at counteracting the abnormal tyrosine kinase activity of ABL and the degradating BCR-ABL fusion protein. In acute myeloid leukemia M(2b), using new target therapy degradating AML1-ETO fusion protein and reducing the abnormal tyrosine kinase activity of c-kit will also lead to new therapeutic management in acute leukemias.

MiRAR-miRNA Activity Reporter for Living Cells.

PubMed

Turk, Matthew A; Chung, Christina Z; Manni, Emad; Zukowski, Stephanie A; Engineer, Anish; Badakhshi, Yasaman; Bi, Yumin; Heinemann, Ilka U

2018-06-19

microRNA (miRNA) activity and regulation are of increasing interest as new therapeutic targets. Traditional approaches to assess miRNA levels in cells rely on RNA sequencing or quantitative PCR. While useful, these approaches are based on RNA extraction and cannot be applied in real-time to observe miRNA activity with single-cell resolution. We developed a green fluorescence protein (GFP)-based reporter system that allows for a direct, real-time readout of changes in miRNA activity in live cells. The miRNA activity reporter (MiRAR) consists of GFP fused to a 3′ untranslated region containing specific miRNA binding sites, resulting in miRNA activity-dependent GFP expression. Using qPCR, we verified the inverse relationship of GFP fluorescence and miRNA levels. We demonstrated that this novel optogenetic reporter system quantifies cellular levels of the tumor suppressor miRNA let-7 in real-time in single Human embryonic kidney 293 (HEK 293) cells. Our data shows that the MiRAR can be applied to detect changes in miRNA levels upon disruption of miRNA degradation pathways. We further show that the reporter could be adapted to monitor another disease-relevant miRNA, miR-122. With trivial modifications, this approach could be applied across the miRNome for quantification of many specific miRNA in cell cultures, tissues, or transgenic animal models.

Spectrum of mutations in RARS-T patients includes TET2 and ASXL1 mutations.

PubMed

Szpurka, Hadrian; Jankowska, Anna M; Makishima, Hideki; Bodo, Juraj; Bejanyan, Nelli; Hsi, Eric D; Sekeres, Mikkael A; Maciejewski, Jaroslaw P

2010-08-01

While a majority of patients with refractory anemia with ring sideroblasts and thrombocytosis harbor JAK2V617F and rarely MPLW515L, JAK2/MPL-negative cases constitute a diagnostic problem. 23 RARS-T cases were investigated applying immunohistochemical phospho-STAT5, sequencing and SNP-A-based karyotyping. Based on the association of TET2/ASXL1 mutations with MDS/MPN we studied molecular pattern of these genes. Two patients harbored ASXL1 and another 2 TET2 mutations. Phospho-STAT5 activation was present in one mutated TET2 and ASXL1 case. JAK2V617F/MPLW515L mutations were absent in TET2/ASXL1 mutants, indicating that similar clinical phenotype can be produced by various MPN-associated mutations and that additional unifying lesions may be present in RARS-T. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Retinoids, retinoid analogs, and lactoferrin interact and differentially affect cell viability of 2 bovine mammary cell types in vitro.

PubMed

Wang, Y; Baumrucker, C R

2010-07-01

Two bovine mammary cell types (BME-UV1 and MeBo cells) were used to evaluate the effect of natural retinoids, retinoid analogs, and bovine lactoferrin (bLf) on cell viability in vitro. Experiments with Alamar Blue showed a linear relationship between fluorescence and cell viability index. The BME-UV1 cells exhibited twice the metabolic activity but required half the doubling time of the MeBo cells. The BME-UV1 cells were very sensitive to all-trans retinoic acid (atRA) inhibition of cell viability (P<0.05) and exhibited a dose-dependent inhibition with 9-cisRA (9cRA; P<0.05). The MeBo cells exhibited some inhibition with these natural ligands (P<0.05), but they were not as sensitive. The addition of bLf had similar inhibitory effects (P<0.05) on cell viability of the 2 mammary cell types. Applications of RA receptor (RAR) agonist indicated that the stimulation of the RAR in both mammary cell types was highly effective in inhibition of cell viability (P<0.05), whereas the application of an RAR antagonist stimulated MeBo cell viability (P<0.05) and inhibited BME-UV1 cell viability (P<0.05). Finally, the use of the RAR antagonist in conjunction with bLf indicated a rescue of the bLf effect in the MeBo cells, suggesting that bLf is acting through the RAR receptor. Conversely, bLf reverted inhibition of cell viability by 9cRA in the BME-UV1 cell type (P<0.05). We conclude that RAR interaction in bovine mammary cell types regulates cell viability in vitro; we hypothesize that the natural ligands mediate regulation of bovine mammary cell viability in vivo and that bLf can either enhance or reverse the retinoid-induced inhibition of cell viability, depending on the type of bovine mammary cell studied.

Dominant negative retinoic acid receptor initiates tumor formation in mice.

PubMed

Kupumbati, Tara S; Cattoretti, Giorgio; Marzan, Christine; Farias, Eduardo F; Taneja, Reshma; Mira-y-Lopez, Rafael

2006-03-24

Retinoic acid suppresses cell growth and promotes cell differentiation, and pharmacological retinoic acid receptor (RAR) activation is anti-tumorigenic. This begs the question of whether chronic physiological RAR activation by endogenous retinoids is likewise anti-tumorigenic. To address this question, we generated transgenic mice in which expression of a ligand binding defective dominant negative RARalpha (RARalphaG303E) was under the control of the mouse mammary tumor virus (MMTV) promoter. The transgene was expressed in the lymphoid compartment and in the mammary epithelium. Observation of aging mice revealed that transgenic mice, unlike their wild type littermates, developed B cell lymphomas at high penetrance, with a median latency of 40 weeks. MMTV-RARalphaG303E lymphomas were high grade Pax-5+, surface H+L Ig negative, CD69+ and BCL6- and cytologically and phenotypically resembled human adult high grade (Burkitt's or lymphoblastic) lymphomas. We postulated that mammary tumors might arise after a long latency period as seen in other transgenic models of breast cancer. We tested this idea by transplanting transgenic epithelium into the cleared fat pads of wild type hosts, thus bypassing lymphomagenesis. At 17 months post-transplantation, a metastatic mammary adenocarcinoma developed in one of four transplanted glands whereas no tumors developed in sixteen of sixteen endogenous glands with wild type epithelium. These findings suggest that physiological RAR activity may normally suppress B lymphocyte and mammary epithelial cell growth and that global RAR inactivation is sufficient to initiate a stochastic process of tumor development requiring multiple transforming events. Our work makes available to the research community a new animal resource that should prove useful as an experimental model of aggressive sporadic lymphoma in immunologically uncompromised hosts. We anticipate that it may also prove useful as a model of breast cancer.

Design of selective nuclear receptor modulators: RAR and RXR as a case study.

PubMed

de Lera, Angel R; Bourguet, William; Altucci, Lucia; Gronemeyer, Hinrich

2007-10-01

Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are members of the nuclear receptor superfamily whose effects on cell growth and survival can be modulated therapeutically by small-molecule ligands. Although compounds that target these receptors are powerful anticancer drugs, their use is limited by toxicity. An improved understanding of the structural biology of RXRs and RARs and recent advances in the chemical synthesis of modified retinoid and rexinoid ligands should enable the rational design of more selective agents that might overcome such problems. Here, we review structural data for RXRs and RARs, discuss strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general.

The design of Radiation Accident Registry.

PubMed

Chen, Jing; Seely, Bob; Bergman, Lauren; Moir, Deborah

2011-03-01

In order to provide effective monitoring and follow-up on the health effects of individuals accidentally exposed to ionising radiation, a Radiation Accident Registry (RAR) has been designed and constructed as an extension to the existing National Dose Registry (NDR). The RAR has basic functions of recording, monitoring and reporting. This type of registry is able to assist responders in preparing for and managing situations during radiological events and in providing effective follow-up on the long-term health effects of persons exposed to ionising radiation. It is especially important to register radiation-exposed people in vulnerable population groups, such as children and pregnant women, to ensure proper long-term health care and protection. Even though radiation accidents are rare, a registry prepared for such accidents could involve a large population and, in some cases, require lifetime monitoring for individuals. One of the most challenging tasks associated with RAR is the assessment of radiation dose resulting from accidents. In some cases, the assessment of radiation doses to individuals could be a process requiring the involvement of various methods. The development of fast and accurate dose assessment tools will remain a long-term challenge associated with the RAR. To meet this challenge, further research activities in radiation dosimetry for individual monitoring are needed.

GSK3 is a regulator of RAR-mediated differentiation

PubMed Central

Gupta, K; Gulen, F; Sun, L; Aguilera, R; Chakrabarti, A; Kiselar, J; Agarwal, MK; Wald, DN

2015-01-01

Acute myeloid leukemia (AML) is the most common form of leukemia in adults. Unfortunately, the standard therapeutic agents used for this disease have high toxicities and poor efficacy. The one exception to these poor outcomes is the use of the retinoid, all-trans retinoic acid (ATRA), for a rare subtype of AML (APL). The use of the differentiation agent, ATRA, in combination with low-dose chemotherapy leads to the long-term survival and presumed cure of 75–85% of patients. Unfortunately ATRA has not been clinically useful for other subtypes of AML. Though many non-APL leukemic cells respond to ATRA, they require significantly higher concentrations of ATRA for effective differentiation. Here we show that the combination of ATRA with glycogen synthase kinase 3 (GSK3) inhibition significantly enhances ATRA-mediated AML differentiation and growth inhibition. These studies have revealed that ATRA's receptor, the retinoic acid receptor (RAR), is a novel target of GSK3 phosphorylation and that GSK3 can impact the expression and transcriptional activity of the RAR. Overall, our studies suggest the clinical potential of ATRA and GSK3 inhibition for AML and provide a mechanistic framework to explain the promising activity of this combination regimen. PMID:22222598

Differentiated all-trans retinoic acid response of naive CD4+CD25– cells isolated from rats with collagen-induced arthritis and healthy ones under in vitro conditions

PubMed Central

Żyromska, Edyta; Piasecki, Tomasz; Rossowska, Joanna; Kędzierska, Anna; Nowak, Marcin; Żyromski, Marcin; Chełmońska-Soyta, Anna

2017-01-01

Aim o the study To compare the potential of CD4+CD25– cells, isolated from both healthy rats and rats with CIA (Collagen-Induced Arthritis), for differentiation into regulatory T cells in the presence of all-trans retinoic acid in order to learn more about the activation mechanisms and therapeutic potential of regulatory T cells. Material and methods Sorted CD4+CD25– cells were cultured in vitro with/without ATRA, and then the frequency of regulatory T cells and their ability to secrete IL-10 by CD4+ FOXP3+ cells was examined. Gene expression of the foxp3, rarα, rarβ, rxrβ, and ppar β/δ and protein expression of the Rarα, Rarβ, and Rxrβ in cells after stimulation with ATRA were also investigated. Results CD4+CD25– cells isolated from healthy animals or from animals with CIA are characterised by different potential of the differentiation into CD4+CD25+ FOXP3+ cells. Retinoic acid receptor Rxrβ is present in the CD4+CD25– cells isolated from rats with CIA. Conclusions We showed that although ATRA did not increase the frequency of Treg in culture, it significantly increased expression of rarβ and rxrβ only in lymphocytes taken from diseased animals and foxp3 expression only in healthy animals. Moreover, after ATRA stimulation, the frequency of Treg-produced IL-10 tended to be lower in diseased animals than in the healthy group. The results imply that the potential of naïve cell CD4 lymphocytes to differentiate into Tregs and their putative suppressive function is dependent on the donor’s health status. PMID:28680330

Epigenetic alteration of p16 and retinoic acid receptor beta genes in the development of epithelial ovarian carcinoma.

PubMed

Bhagat, Rahul; Kumar, Sandeep Sriram; Vaderhobli, Shilpa; Premalata, Chennagiri S; Pallavi, Venkateshaiah Reddihalli; Ramesh, Gawari; Krishnamoorthy, Lakshmi

2014-09-01

Silencing of tumor suppressor and tumor-related genes by promoter hypermethylation is one of the major events in ovarian carcinogenesis. In this study, we analyzed aberrant promoter methylation of p16 and RAR-β genes in 134 epithelial ovarian carcinomas (EOCs), 23 low malignant potential (LMP) tumors, 26 benign cystadenomas, and 15 normal ovarian tissues. Methylation was investigated by methylation-specific PCR (MSP), and the results were confirmed by bisulfite DNA sequencing. Relative gene expression of p16 and RAR-β was done using quantitative reverse transcriptase PCR (qRT-PCR) on 51 EOC cases, 9 LMP tumors, and 7 benign cystadenomas with 5 normal ovarian tissues. Aberrant methylation for p16 and RAR-β was present in 43 % (58/134) and 31 % (41/134) in carcinoma cases, 22 % (05/23) and 52 % (12/23) in LMP tumors, and 42 % (11/26) and 69 % (18/26) in benign cystadenomas. No methylation was observed in any of the normal ovarian tissues. The mRNA expression level of p16 and RAR-β was significantly downregulated in EOC and LMP tumors than the corresponding normal tissues whereas the expression level was normal in benign cystadenomas for p16 and slightly reduced for RAR-β. A significant correlation of p16 promoter methylation was observed with reduced gene expression in EOC. For RAR-β, no significant correlation was observed between promoter methylation and gene expression. Our results suggest that epigenetic alterations of p16 and RAR-β have an important role in ovarian carcinogenesis and that mechanism along with methylation plays a significant role in downregulation of RAR-β gene in ovarian cancer.

Choguita Rarámuri (Tarahumara) Language Description and Documentation: A Guide to the Deposited Collection and Associated Materials

ERIC Educational Resources Information Center

Caballero, Gabriela

2017-01-01

Choguita Rarámuri (Tarahumara) is a Uto-Aztecan language spoken in Northern Mexico of great typological, theoretical, and historical significance. This paper presents an overview and background of the Choguita Rarámuri language description and documentation project and provides a guide to the documentary collection emerging from this project. This…

A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations via Dysregulation of Retinoic Acid Signaling.

PubMed

Vivante, Asaf; Mann, Nina; Yonath, Hagith; Weiss, Anna-Carina; Getwan, Maike; Kaminski, Michael M; Bohnenpoll, Tobias; Teyssier, Catherine; Chen, Jing; Shril, Shirlee; van der Ven, Amelie T; Ityel, Hadas; Schmidt, Johanna Magdalena; Widmeier, Eugen; Bauer, Stuart B; Sanna-Cherchi, Simone; Gharavi, Ali G; Lu, Weining; Magen, Daniella; Shukrun, Rachel; Lifton, Richard P; Tasic, Velibor; Stanescu, Horia C; Cavaillès, Vincent; Kleta, Robert; Anikster, Yair; Dekel, Benjamin; Kispert, Andreas; Lienkamp, Soeren S; Hildebrandt, Friedhelm

2017-08-01

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of CKD in the first three decades of life. However, for most patients with CAKUT, the causative mutation remains unknown. We identified a kindred with an autosomal dominant form of CAKUT. By whole-exome sequencing, we identified a heterozygous truncating mutation (c.279delG, p.Trp93fs*) of the nuclear receptor interacting protein 1 gene ( NRIP1 ) in all seven affected members. NRIP1 encodes a nuclear receptor transcriptional cofactor that directly interacts with the retinoic acid receptors (RARs) to modulate retinoic acid transcriptional activity. Unlike wild-type NRIP1, the altered NRIP1 protein did not translocate to the nucleus, did not interact with RAR α , and failed to inhibit retinoic acid-dependent transcriptional activity upon expression in HEK293 cells. Notably, we also showed that treatment with retinoic acid enhanced NRIP1 binding to RAR α RNA in situ hybridization confirmed Nrip1 expression in the developing urogenital system of the mouse. In explant cultures of embryonic kidney rudiments, retinoic acid stimulated Nrip1 expression, whereas a pan-RAR antagonist strongly reduced it. Furthermore, mice heterozygous for a null allele of Nrip1 showed a CAKUT-spectrum phenotype. Finally, expression and knockdown experiments in Xenopus laevis confirmed an evolutionarily conserved role for NRIP1 in renal development. These data indicate that dominant NRIP1 mutations can cause CAKUT by interference with retinoic acid transcriptional signaling, shedding light on the well documented association between abnormal vitamin A levels and renal malformations in humans, and suggest a possible gene-environment pathomechanism in this disease. Copyright © 2017 by the American Society of Nephrology.

PREDICTING RETINOID RECEPTOR BINDING AFFINITY: COREPA-M APPLICATION

EPA Science Inventory

Retinoic acid and associated vitamin A derivatives comprise a class of endogenous hormones that activate different retinoic acid receptors RARs). Transcriptional events subsequent to this activation are key to controlling several aspects of vertebrate development. As such, identi...

Enhanced plasma protein carbonylation in patients with myelodysplastic syndromes.

PubMed

Hlaváčková, Alžběta; Štikarová, Jana; Pimková, Kristýna; Chrastinová, Leona; Májek, Pavel; Kotlín, Roman; Čermák, Jaroslav; Suttnar, Jiří; Dyr, Jan Evangelista

2017-07-01

Myelodysplastic syndromes (MDS) represent a heterogeneous group of pre-leukemic disorders, characterized by ineffective hematopoiesis and the abnormal blood cell development of one or more lineages. Oxidative stress, as an important factor in the carcinogenesis of onco-hematological diseases, is also one of the known factors involved in the pathogenesis of MDS. An increase of reactive oxygen species (ROS) may lead to the oxidation of DNA, lipids, and proteins, thereby causing cell damage. Protein carbonylation caused by ROS is defined as an irreversible post-translational oxidative modification of amino acid side chains, and could play an important role in signaling processes. The detection of protein carbonyl groups is a specific useful marker of oxidative stress. In this study, we examined 32 patients divided into three different subtypes of MDS according to the World Health Organization (WHO) classification criteria as refractory anemia with ringed sideroblasts (RARS), refractory cytopenia with multilineage dysplasia (RCMD), refractory anemia with excess blasts-1,2 (RAEB-1,2). We found significant differences in protein carbonylation between the group of all MDS patients and healthy controls (P=0.0078). Furthermore, carbonylated protein levels were significantly elevated in RARS patients compared to healthy donors (P=0.0013) and to RCMD patients (P=0.0277). We also found a significant difference in the total iron binding capacity (TIBC) between individual subgroups of MDS patients (P=0.0263). Moreover, TIBC was decreased in RARS patients compared to RCMD patients (P=0.0203). TIBC moderately negatively correlated with carbonyl levels (r=-0.5978, P=0.0054) in the MDS patients as a whole. Additionally we observed changes in the carbonylated proteins of RARS patients in comparison with healthy controls and their negative controls. Using tandem mass spectrometry (LC-MS/MS) we identified 27 uniquely carbonylated proteins of RARS patients, which were generated by ROS and could influence the pathophysiology of low-risk MDS. These data indicate that increased protein carbonylation is related with RARS as low-risk MDS subgroup. We suggest that this type of post-translational modification in MDS disease is not "only" a consequence of oxidative stress, but also plays an active role in the pathophysiology and iron metabolism within the RARS subgroup of MDS. Measurement of plasma carbonyl levels and the isolation of carbonylated plasma proteins, followed by their identification, could serve as a potential diagnostic and prognostic tool in MDS. Copyright © 2017 Elsevier Inc. All rights reserved.

Lung vagal afferent activity in rats with bleomycin-induced lung fibrosis.

PubMed

Schelegle, E S; Walby, W F; Mansoor, J K; Chen, A T

2001-05-01

Bleomycin treatment in rats results in pulmonary fibrosis that is characterized by a rapid shallow breathing pattern, a decrease in quasi-static lung compliance and a blunting of the Hering-Breuer Inflation Reflex. We examined the impulse activity of pulmonary vagal afferents in anesthetized, mechanically ventilated rats with bleomycin-induced lung fibrosis during the ventilator cycle and static lung inflations/deflations and following the injection of capsaicin into the right atrium. Bleomycin enhanced volume sensitivity of slowly adapting stretch receptors (SARs), while it blunted the sensitivity of these receptors to increasing transpulmonary pressure. Bleomycin treatment increased the inspiratory activity, while it decreased the expiratory activity of rapidly adapting stretch receptors (RARs). Pulmonary C-fiber impulse activity did not appear to be affected by bleomycin treatment. We conclude that the fibrosis-related shift in discharge profile and enhanced volume sensitivity of SARs combined with the increased inspiratory activity of RARs contributes to the observed rapid shallow breathing of bleomycin-induced lung fibrosis.

Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias?

PubMed

Minucci, S; Nervi, C; Lo Coco, F; Pelicci, P G

2001-05-28

Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.

Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells.

PubMed

Benoit, G R; Flexor, M; Besançon, F; Altucci, L; Rossin, A; Hillion, J; Balajthy, Z; Legres, L; Ségal-Bendirdjian, E; Gronemeyer, H; Lanotte, M

2001-07-01

On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective rexinoid program has been described as yet in cellular systems. We report here on the rexinoid signaling capacity that triggers apoptosis of immature promyelocytic NB4 cells as a default pathway in the absence of survival factors. Rexinoid-induced apoptosis displays all features of bona fide programmed cell death and is inhibited by RXR, but not RAR antagonists. Several types of survival signals block rexinoid-induced apoptosis. RARalpha agonists switch the cellular response toward differentiation and induce the expression of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature cell apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is linked to neither the presence nor stability of the promyelocytic leukemia-RARalpha fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids activate in certain leukemia cells a default death pathway onto which several other signaling paradigms converge. This pathway is entirely distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis.

Clinical significance of the summating potential-action potential ratio and the action potential latency difference for condensation and rarefaction clicks in Meniere's disease.

PubMed

Ohashi, Toru; Nishino, Hirohito; Arai, Yoko; Hyodo, Makoto; Takatsu, Mitsuharu

2009-04-01

This study was aimed to elucidate the diagnostic significance of the summating potential (SP)-action potential (AP) ratio and the AP latency difference between condensation and rarefaction clicks (AP con-rar difference) in Meniere's disease. The AP and SP were recorded transtympanically in 67 patients with definite Meniere's disease. The SP/AP ratio and the AP con-rar difference were assessed in terms of 1) their interrelationship, 2) their relationship to hearing level, and 3) the rate of occurrence of abnormal values according to the stages of Meniere's disease. No correlation was found between the SP/AP ratio and the AP con-rar difference. Neither the SP/AP ratio in general nor the AP con-rar difference was correlated with the hearing level. However, enhanced values of the SP/AP ratio (0.35 or higher) were moderately correlated with the hearing level (r = 0.51), and their occurrence rate was 55.2%. An increased AP con-rar difference (0.13 ms or longer) was not correlated with the hearing level, and its occurrence rate was 50.2%; it appeared most frequently at stage 3 (p <0.05). An enhanced SP/AP ratio might not always indicate the presence of endolymphatic hydrops associated with an increase in endolymphatic pressure. An increased AP con-rar difference might reflect the presence of a biased basilar membrane resulting from an increased endolymphatic pressure, and hence it is diagnostically essential to simultaneously evaluate the SP/AP ratio and the AP con-rar difference.

Radiolabeling and initial biological evaluation of [18F]KBM-1 for imaging RAR-α receptors in neuroblastoma.

PubMed

Solingapuram Sai, Kiran Kumar; Das, Bhaskar C; Sattiraju, Anirudh; Almaguel, Frankis G; Craft, Suzanne; Mintz, Akiva

2017-03-15

Retinoic acid receptor alpha (RAR-α) plays a significant role in a number of diseases, including neuroblastoma. Children diagnosed with high-risk neuroblastoma are treated13-cis-retinoic acid, which reduces risk of cancer recurrence. Neuroblastoma cell death is mediated via RAR-α, and expression of RAR-α is upregulated after treatment. A molecular imaging probe that binds RAR-α will help clinicians to diagnose and stratify risk for patients with neuroblastoma, who could benefit from retinoid-based therapy. In this study, we report the radiolabeling, and initial in vivo evaluation of [ 18 F]KBM-1, a novel RAR-α agonist. The radiochemical synthesis of [ 18 F]KBM-1 was carried out through KHF 2 assisted substitution of [ 18 F] - from aryl-substituted pinacolatoesters-based retinoid precursor. In vitro cell uptake assay in human neuroblastoma cell line showed that the uptake of [ 18 F]KBM-1 was significantly inhibited by all three blocking agents (KBM-1, ATRA, BD4) at all the selected incubation times. Standard biodistribution in mice bearing neuroblastoma tumors demonstrated increased tumor uptake from 5min to 60min post radiotracer injection and the uptake ratios for target to non-target (tumor: muscle) increased 2.2-fold to 3.7-fold from 30min to 60min post injection. Tumor uptake in subset of 30min blocking group was 1.7-fold lower than unblocked. These results demonstrate the potential utility of [ 18 F]KBM-1 as a RAR-α imaging agent. Copyright © 2017 Elsevier Ltd. All rights reserved.

Non-induction of radioadaptive response in zebrafish embryos by neutrons

PubMed Central

Ng, Candy Y.P.; Kong, Eva Y.; Kobayashi, Alisa; Suya, Noriyoshi; Uchihori, Yukio; Cheng, Shuk Han; Konishi, Teruaki; Yu, Kwan Ngok

2016-01-01

In vivo neutron-induced radioadaptive response (RAR) was studied using zebrafish (Danio rerio) embryos. The Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility at the National Institute of Radiological Sciences (NIRS), Japan, was employed to provide 2-MeV neutrons. Neutron doses of 0.6, 1, 25, 50 and 100 mGy were chosen as priming doses. An X-ray dose of 2 Gy was chosen as the challenging dose. Zebrafish embryos were dechorionated at 4 h post fertilization (hpf), irradiated with a chosen neutron dose at 5 hpf and the X-ray dose at 10 hpf. The responses of embryos were assessed at 25 hpf through the number of apoptotic signals. None of the neutron doses studied could induce RAR. Non-induction of RAR in embryos having received 0.6- and 1-mGy neutron doses was attributed to neutron-induced hormesis, which maintained the number of damaged cells at below the threshold for RAR induction. On the other hand, non-induction of RAR in embryos having received 25-, 50- and 100-mGy neutron doses was explained by gamma-ray hormesis, which mitigated neutron-induced damages through triggering high-fidelity DNA repair and removal of aberrant cells through apoptosis. Separate experimental results were obtained to verify that high-energy photons could disable RAR. Specifically, 5- or 10-mGy X-rays disabled the RAR induced by a priming dose of 0.88 mGy of alpha particles delivered to 5-hpf zebrafish embryos against a challenging dose of 2 Gy of X-rays delivered to the embryos at 10 hpf. PMID:26850927

Reduced RAR-β gene expression in Benzo(a)Pyrene induced lung cancer mice is upregulated by DOTAP lipo-ATRA treatment.

PubMed

Viswanathan, S; Berlin Grace, V M

2018-08-20

Molecular targeted therapy for specific genes is an emerging research. Retinoic Acid Receptor (RAR-β) is a key tumor suppressor which is found to be lost drastically during much cancer progression. We hence, analyzed the expression level of RAR-β gene during B(a)P induced lung cancer development in mice and studied the lung cancer targeted action of All Trans Retinoic Acid (ATRA) in DOTAP liposomal formulation. The effect of its treatment on lung cancer was determined by histopathological analysis. RAR-β gene expression was assessed by RT-PCR and qPCR. A distinct band for RAR-β gene (density - 0.5123 for lung and 0.5160 for liver) was observed in normal mice, whereas no visible band was observed in cancer induced group, indicating loss of RAR-β gene expression. Both ATRA and lipo-ATRA treated groups showed detectable RAR-β expression with relatively lesser density than the normal group. The expression was more intense in lipo-ATRA treatment (density-0.2973) compared with free ATRA treatment (density-0.1549) in lung tissues. The qPCR results also have highlighted a highly significant (p ≤ 0.01) variation RQ values between lipo-ATRA group (15.46 ± 1.54) and free ATRA group (7.58 ± 1.30) in lung tissue sample on 30th day. The mean RQ value for normal lung on 30th day was 20.86 ± 2.58 against the cancer control. The 120th day mice also showed the similar RAR-β expression pattern with further declined expression levels as there was no treatment given after 30 days. Interestingly, the lipo-ATRA treatment could show a highly significant (p ≤ 0.001) expression (12.00 ± 2.31) when compared with free ATRA treatment (3.31 ± 0.58) which implies that the lipo-ATRA formulation could result in sustained delivery of ATRA in target site. Histopathology of lung and liver on 120th day also revealed an effective therapeutic indication in lipo-ATRA treatment compared to free ATRA treatment due to lipo-ATRA's stealth property and it efficiently inhibited the metastasis to liver. These results revealed that the lipo-ATRA treatment has efficiently delivered ATRA into target site than free ATRA and in-turn it might have induced the expression of RAR-β gene or prevented loss of RAR-β gene in cancer animals. Copyright © 2018 Elsevier B.V. All rights reserved.

Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct

PubMed Central

Nakajima, Tadaaki; Iguchi, Taisen; Sato, Tomomi

2016-01-01

The Müllerian duct develops into the oviduct, uterus, and vagina, all of which are quite distinct in their morphology and function. The epithelial fate of these female reproductive organs in developing mice is determined by factors secreted from the stroma; however, how stromal differentiation occurs in the female reproductive organs derived from the Müllerian duct is still unclear. In the present study, roles of retinoic acid (RA) signaling in developing female reproductive tracts were investigated. Retinol dehydrogenase 10 (RDH10) and aldehyde dehydrogenase family 1 subfamily A2 (ALDH1A2) mRNAs and proteins and transactivation activity of endogenous RA were found in the stroma of proximal Müllerian ducts and gradually decreased from the proximal to caudal regions in fetal mice. In organ-cultured Müllerian ducts, retinaldehyde or RA treatment induced uterine epithelial differentiation, defined as a layer of columnar epithelial cells negative for oviductal and vaginal epithelial markers. In contrast, inhibition of RA receptor (RAR) signaling induced vaginal epithelial differentiation, characterized as vaginal epithelial marker genes–positive stratified epithelium. Grafting experiments of the organ-cultured Müllerian duct revealed irreversible epithelial fate determination. Although RAR did not directly bind to the homeobox A10 (Hoxa10) promoter region, RA–RAR signaling stimulated Hoxa10 expression. Thus, RA–RAR signaling in the Müllerian duct determines the fate of stroma to form the future uterus and vagina. PMID:27911779

Using rapid assessment and response to operationalise physical activity strategic health communication campaigns in Tonga.

PubMed

Turk, Tahir; Latu, Netina; Cocker-Palu, Elizabeth; Liavaa, Villiami; Vivili, Paul; Gloede, Sara; Simons, Allison

2013-04-01

The aim of the present study was to identify stakeholder and program beneficiary needs and wants in relation to a netball communication strategy in Tonga. In addition, the study aimed to more clearly identify audience segments for targeting of communication campaigns and to identify any barriers or benefits to engaging in the physical activity program. A rapid assessment and response (RAR) methodology was used. The elicitation research encompassed qualitative fieldwork approaches, including semistructured interviews with key informants and focus group discussions with program beneficiaries. Desk research of secondary data sources supported in-field findings. A number of potential barriers to behavioural compliance existed, including cultural factors, gender discrimination, socioeconomic factors, stigmatising attitudes, the threat of domestic violence, infrastructure and training issues. Factors contributing to participation in physical activity included the fun and social aspects of the sport, incentives (including career opportunities, highlighting the health benefits of the activity and the provision of religious and cultural sanctions by local leaders towards the increased physical activity of women. The consultative approach of RAR provided a more in-depth understanding of the need for greater levels of physical activity and opportunities for engagement by all stakeholders. The approach facilitated opportunities for the proposed health behaviours to be realised through the communication strategy. Essential insights for the strategy design were identified from key informants, as well as ensuring future engagement of these stakeholders into the strategy. So what? The expanded use of RAR to inform the design of social marketing interventions is a practical approach to data collection for non-communicable diseases and other health issues in developing countries. The approach allows for the rapid mobilisation of scarce resources for the implementation of more strategic, targeted communication campaigns to support behavioural changes.

Non-induction of radioadaptive response in zebrafish embryos by neutrons.

PubMed

Ng, Candy Y P; Kong, Eva Y; Kobayashi, Alisa; Suya, Noriyoshi; Uchihori, Yukio; Cheng, Shuk Han; Konishi, Teruaki; Yu, Kwan Ngok

2016-06-01

In vivo neutron-induced radioadaptive response (RAR) was studied using zebrafish (Danio rerio) embryos. The Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility at the National Institute of Radiological Sciences (NIRS), Japan, was employed to provide 2-MeV neutrons. Neutron doses of 0.6, 1, 25, 50 and 100 mGy were chosen as priming doses. An X-ray dose of 2 Gy was chosen as the challenging dose. Zebrafish embryos were dechorionated at 4 h post fertilization (hpf), irradiated with a chosen neutron dose at 5 hpf and the X-ray dose at 10 hpf. The responses of embryos were assessed at 25 hpf through the number of apoptotic signals. None of the neutron doses studied could induce RAR. Non-induction of RAR in embryos having received 0.6- and 1-mGy neutron doses was attributed to neutron-induced hormesis, which maintained the number of damaged cells at below the threshold for RAR induction. On the other hand, non-induction of RAR in embryos having received 25-, 50- and 100-mGy neutron doses was explained by gamma-ray hormesis, which mitigated neutron-induced damages through triggering high-fidelity DNA repair and removal of aberrant cells through apoptosis. Separate experimental results were obtained to verify that high-energy photons could disable RAR. Specifically, 5- or 10-mGy X-rays disabled the RAR induced by a priming dose of 0.88 mGy of alpha particles delivered to 5-hpf zebrafish embryos against a challenging dose of 2 Gy of X-rays delivered to the embryos at 10 hpf. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Inhibition of the NAD-Dependent Protein Deacetylase SIRT2 Induces Granulocytic Differentiation in Human Leukemia Cells

PubMed Central

Sunami, Yoshitaka; Araki, Marito; Hironaka, Yumi; Morishita, Soji; Kobayashi, Masaki; Liew, Ei Leen; Edahiro, Yoko; Tsutsui, Miyuki; Ohsaka, Akimichi; Komatsu, Norio

2013-01-01

Sirtuins, NAD-dependent protein deacetylases, play important roles in cellular functions such as metabolism and differentiation. Whether sirtuins function in tumorigenesis is still controversial, but sirtuins are aberrantly expressed in tumors, which may keep cancerous cells undifferentiated. Therefore, we investigated whether the inhibition of sirtuin family proteins induces cellular differentiation in leukemic cells. The sirtuin inhibitors tenovin-6 and BML-266 induce granulocytic differentiation in the acute promyelocytic leukemia (APL) cell line NB4. This differentiation is likely caused by an inhibition of SIRT2 deacetylase activity, judging from the accumulation of acetylated α-tubulin, a major SIRT2 substrate. Unlike the clinically used differentiation inducer all-trans retinoic acid, tenovin-6 shows limited effects on promyelocytic leukemia–retinoic acid receptor α (PML-RAR-α) stability and promyelocytic leukemia nuclear body formation in NB4 cells, suggesting that tenovin-6 does not directly target PML-RAR-α activity. In agreement with this, tenovin-6 induces cellular differentiation in the non-APL cell line HL-60, where PML-RAR-α does not exist. Knocking down SIRT2 by shRNA induces granulocytic differentiation in NB4 cells, which demonstrates that the inhibition of SIRT2 activity is sufficient to induce cell differentiation in NB4 cells. The overexpression of SIRT2 in NB4 cells decreases the level of granulocytic differentiation induced by tenovin-6, which indicates that tenovin-6 induces granulocytic differentiation by inhibiting SIRT2 activity. Taken together, our data suggest that targeting SIRT2 is a viable strategy to induce leukemic cell differentiation. PMID:23460888

CTC Sentinel. Volume 10, Issue 2. February 2017

DTIC Science & Technology

2017-02-01

Author research. n Jabhat Ansar al-Din was initially formed as a jihadi coalition in July 2014 constituting four groups : Jaysh al-Muhajireen wa al...security. Aymenn al-Tamimi looks at the implications of the recent realignment of rebel and jihadi groups in Syria, which created two potentially...conflicting power centers revolving around an enlarged Ah- rar al-Sham and Hay’at Tahrir al-Sham, a new al-Qa`ida-aligned umbrella grouping . Robin Simcox finds

Circadian activity rhythms during the last days of Nothobranchius rachovii's life: a descriptive model of circadian system breakdown.

PubMed

Lucas-Sánchez, Alejandro; Martínez-Nicolás, Antonio; Madrid, Juan Antonio; Almaida-Pagán, Pedro Francisco; Mendiola, Pilar; de Costa, Jorge

2015-04-01

Several studies have been performed to identify age-related changes in the circadian system (CS) but the impairment of the CS and its chronodisruption at the end of an organism life have not been studied in depth. Aging commonly affects the input pathways into the biological clock or restraints their processing, therefore simplifying the system output, the overt rhythms. The purpose of this work was to do a complete characterization of changes that occurs in the CS in the last stage of a vertebrate organism life and to develop tools able to detect in which moment of the last days of life is the animal, using an overt rhythm, the rest-activity rhythm (RAR). For that, a fish species proposed as model for aging studies, Nothobranchius rachovii, has been used. A progressive and sequential CS breakdown has been described for the last 22 d of life of N. rachovii (∼7% of total life), suffering a general RAR impairment mainly reflected by changes in phase regularity, complexity, amplitude and the ability to stay synchronized to the LD cycle. Also, an equation of days remaining of life, based on the RAR description, has been calculated and proposed as a tool to identify close-to-death individuals which could be subjected to an adequate restoring treatment to enhance the CS function and improve their well-being.

A simple risk scoring system for prediction of relapse after inpatient alcohol treatment.

PubMed

Pedersen, Mads Uffe; Hesse, Morten

2009-01-01

Predicting relapse after alcoholism treatment can be useful in targeting patients for aftercare services. However, a valid and practical instrument for predicting relapse risk does not exist. Based on a prospective study of alcoholism treatment, we developed the Risk of Alcoholic Relapse Scale (RARS) using items taken from the Addiction Severity Index and some basic demographic information. The RARS was cross-validated using two non-overlapping samples, and tested for its ability to predict relapse across different models of treatment. The RARS predicted relapse to drinking within 6 months after alcoholism treatment in both the original and the validation sample, and in a second validation sample it predicted admission to new treatment 3 years after treatment. The RARS can identify patients at high risk of relapse who need extra aftercare and support after treatment.

[Efficiency of combined methods of hemorroid treatment using hal-rar and laser destruction].

PubMed

Rodoman, G V; Kornev, L V; Shalaeva, T I; Malushenko, R N

2017-01-01

To develop the combined method of treatment of hemorrhoids with arterial ligation under Doppler control and laser destruction of internal and external hemorrhoids. The study included 100 patients with chronic hemorrhoids stage II and III. Combined method of HAL-laser was used in study group, HAL RAR-technique in control group 1 and closed hemorrhoidectomy with linear stapler in control group 2. Сomparative evaluation of results in both groups was performed. Combined method overcomes the drawbacks of traditional surgical treatment and limitations in external components elimination which are inherent for HAL-RAR. Moreover, it has a higher efficiency in treating of hemorrhoids stage II-III compared with HAL-RAR and is equally safe and well tolerable for patients. This method does not increase the risk of recurrence, reduces incidence of complications and time of disability.

Cloning retinoid and peroxisome proliferator-activated nuclear receptors of the Pacific oyster and in silico binding to environmental chemicals

PubMed Central

Vogeler, Susanne; Galloway, Tamara S.; Isupov, Michail

2017-01-01

Disruption of nuclear receptors, a transcription factor superfamily regulating gene expression in animals, is one proposed mechanism through which pollution causes effects in aquatic invertebrates. Environmental pollutants have the ability to interfere with the receptor’s functions through direct binding and inducing incorrect signals. Limited knowledge of invertebrate endocrinology and molecular regulatory mechanisms, however, impede the understanding of endocrine disruptive effects in many aquatic invertebrate species. Here, we isolated three nuclear receptors of the Pacific oyster, Crassostrea gigas: two isoforms of the retinoid X receptor, CgRXR-1 and CgRXR-2, a retinoic acid receptor ortholog CgRAR, and a peroxisome proliferator-activated receptor ortholog CgPPAR. Computer modelling of the receptors based on 3D crystal structures of human proteins was used to predict each receptor’s ability to bind to different ligands in silico. CgRXR showed high potential to bind and be activated by 9-cis retinoic acid and the organotin tributyltin (TBT). Computer modelling of CgRAR revealed six residues in the ligand binding domain, which prevent the successful interaction with natural and synthetic retinoid ligands. This supports an existing theory of loss of retinoid binding in molluscan RARs. Modelling of CgPPAR was less reliable due to high discrepancies in sequence to its human ortholog. Yet, there are suggestions of binding to TBT, but not to rosiglitazone. The effect of potential receptor ligands on early oyster development was assessed after 24h of chemical exposure. TBT oxide (0.2μg/l), all-trans retinoic acid (ATRA) (0.06 mg/L) and perfluorooctanoic acid (20 mg/L) showed high effects on development (>74% abnormal developed D-shelled larvae), while rosiglitazone (40 mg/L) showed no effect. The results are discussed in relation to a putative direct (TBT) disruption effect on nuclear receptors. The inability of direct binding of ATRA to CgRAR suggests either a disruptive effect through a pathway excluding nuclear receptors or an indirect interaction. Our findings provide valuable information on potential mechanisms of molluscan nuclear receptors and the effects of environmental pollution on aquatic invertebrates. PMID:28426724

The Nuclear Transcription Factor RAR Associates with Neuronal RNA Granules and Suppresses Translation

USDA-ARS?s Scientific Manuscript database

All-trans-retinoic acid stimulates dendritic growth in hippocampal neurons within minutes by activating mitogen-activated protein kinase and mTOR and increasing dendritic translation of calcium calmodulin-dependent protein kinase II alpha and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionat...

Molecular characterization and gene expression patterns of retinoid receptors, in normal and regenerating tissues of the sea cucumber, Holothuria glaberrima.

PubMed

Viera-Vera, Jorge; García-Arrarás, José E

2018-05-15

Retinoic acid receptors (RAR) and retinoid X receptors (RXR) are ligand-mediated transcription factors that synchronize intricate signaling networks in metazoans. Dimer formation between these two nuclear receptors mediates the recruitment of co-regulatory complexes coordinating the progression of signaling cascades during developmental and regenerative events. In the present study we identified and characterized the receptors for retinoic acid in the sea cucumber Holothuria glaberrima; a model system capable of regenerative organogenesis during adulthood. Molecular characterizations revealed the presence of three isoforms of RAR and two of RXR as a consequence of alternative splicing events. Various analyses including: primary structure sequencing, phylogenetic analysis, protein domain prediction, and multiple sequence alignment further confirmed their identity. Semiquantitative reverse transcription PCR analysis of each receptor isoform herein identified showed that the retinoid receptors are expressed in all tissues sampled: the mesenteries, respiratory trees, muscles, gonads, and the digestive tract. During regenerative organogenesis two of the receptors (RAR-L and RXR-T) showed differential expression in the posterior segment while RAR-S is differentially expressed in the anterior segment of the intestine. This work presents the first description of the components relaying the signaling for retinoic acid within this model system. Copyright © 2018 Elsevier B.V. All rights reserved.

Promoter methylation of APC and RAR-β genes as prognostic markers in non-small cell lung cancer (NSCLC).

PubMed

Feng, Hongxiang; Zhang, Zhenrong; Qing, Xin; Wang, Xiaowei; Liang, Chaoyang; Liu, Deruo

2016-02-01

Aberrant promoter hypermethylations of tumor suppressor genes are promising markers for lung cancer diagnosis and prognosis. The purpose of this study was to determine methylation status at APC and RAR-β promoters in primary NSCLC, and whether they have any relationship with survival. APC and RAR-β promoter methylation status were determined in 41 NSCLC patients using methylation specific PCR. APC promoter methylation was detectable in 9 (22.0%) tumor samples and 6 (14.6%) corresponding non-tumor samples (P=0.391). RAR-β promoter methylation was detectable in 13 (31.7%) tumor samples and 4 (9.8%) corresponding non-tumor samples (P=0.049) in the NSCLC patients. APC promoter methylation was found to be associated with T stage (P=0.046) and nodal status (P=0.019) in non-tumor samples, and with smoking (P=0.004) in tumor samples. RAR-β promoter methylation was found associated with age (P=0.031) in non-tumor samples and with primary tumor site in tumor samples. Patients with APC promoter methylation in tumor samples showed significantly longer survival than patients without it (Log-rank P=0.014). In a multivariate analysis of prognostic factors, APC methylation in tumor samples was an independent prognostic factor (P=0.012), as were N1 positive lymph node number (P=0.025) and N2 positive lymph node number (P=0.06). Our study shows that RAR-β methylation detected in lung tissue may be used as a predictive marker for NSCLC diagnosis and that APC methylation in tumor sample may be a useful marker for superior survival in NSCLC patients. Copyright © 2015. Published by Elsevier Inc.

Docking simulations suggest that all-trans retinoic acid could bind to retinoid X receptors.

PubMed

Tsuji, Motonori; Shudo, Koichi; Kagechika, Hiroyuki

2015-10-01

Retinoid X receptors (RXRs) are ligand-controlled transcription factors which heterodimerize with other nuclear receptors to regulate gene transcriptions associated with crucial biological events. 9-cis retinoic acid (9cRA), which transactivates RXRs, is believed to be an endogenous RXR ligand. All-trans retinoic acid (ATRA) is a natural ligand for retinoic acid receptors (RARs), which heterodimerize with RXRs. Although the concentration of 9cRA in tissues is very low, ATRA is relatively abundant and some reports show that ATRA activates RXRs. We computationally studied the possibility of ATRA binding to RXRs using two different docking methods with our developed programs to assess the binding affinities of naturally occurring retinoids. The simulations showed good correlations to the reported binding affinities of these molecules for RXRs and RARs.

Towards Building an AOP-based Prenatal Developmental Toxicity Ontology (SOT)

EPA Science Inventory

Retinoid signaling plays an important role in embryo-fetal development and its disruption is broadly teratogenic. The retinoic acid (RA) pathway includes elements in retinoid metabolism and nuclear receptor (RAR, RXR) activation and thus serves as an excellent prototype for adver...

SDSS-IV MaNGA: a distinct mass distribution explored in slow-rotating early-type galaxies

NASA Astrophysics Data System (ADS)

Rong, Yu; Li, Hongyu; Wang, Jie; Gao, Liang; Li, Ran; Ge, Junqiang; Jing, Yingjie; Pan, Jun; Fernández-Trincado, J. G.; Valenzuela, Octavio; Ortíz, Erik Aquino

2018-06-01

We study the radial acceleration relation (RAR) for early-type galaxies (ETGs) in the SDSS MaNGA MPL5 data set. The complete ETG sample show a slightly offset RAR from the relation reported by McGaugh et al. (2016) at the low-acceleration end; we find that the deviation is due to the fact that the slow rotators show a systematically higher acceleration relation than the McGaugh's RAR, while the fast rotators show a consistent acceleration relation to McGaugh's RAR. There is a 1σ significant difference between the acceleration relations of the fast and slow rotators, suggesting that the acceleration relation correlates with the galactic spins, and that the slow rotators may have a different mass distribution compared with fast rotators and late-type galaxies. We suspect that the acceleration relation deviation of slow rotators may be attributed to more galaxy merger events, which would disrupt the original spins and correlated distributions of baryons and dark matter orbits in galaxies.

Interventions for preventing falls in older people living in the community.

PubMed

Gillespie, Lesley D; Robertson, M Clare; Gillespie, William J; Sherrington, Catherine; Gates, Simon; Clemson, Lindy M; Lamb, Sarah E

2012-09-12

Approximately 30% of people over 65 years of age living in the community fall each year. This is an update of a Cochrane review first published in 2009. To assess the effects of interventions designed to reduce the incidence of falls in older people living in the community. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (February 2012), CENTRAL (The Cochrane Library 2012, Issue 3), MEDLINE (1946 to March 2012), EMBASE (1947 to March 2012), CINAHL (1982 to February 2012), and online trial registers. Randomised trials of interventions to reduce falls in community-dwelling older people. Two review authors independently assessed risk of bias and extracted data. We used a rate ratio (RaR) and 95% confidence interval (CI) to compare the rate of falls (e.g. falls per person year) between intervention and control groups. For risk of falling, we used a risk ratio (RR) and 95% CI based on the number of people falling (fallers) in each group. We pooled data where appropriate. We included 159 trials with 79,193 participants. Most trials compared a fall prevention intervention with no intervention or an intervention not expected to reduce falls. The most common interventions tested were exercise as a single intervention (59 trials) and multifactorial programmes (40 trials). Sixty-two per cent (99/159) of trials were at low risk of bias for sequence generation, 60% for attrition bias for falls (66/110), 73% for attrition bias for fallers (96/131), and only 38% (60/159) for allocation concealment.Multiple-component group exercise significantly reduced rate of falls (RaR 0.71, 95% CI 0.63 to 0.82; 16 trials; 3622 participants) and risk of falling (RR 0.85, 95% CI 0.76 to 0.96; 22 trials; 5333 participants), as did multiple-component home-based exercise (RaR 0.68, 95% CI 0.58 to 0.80; seven trials; 951 participants and RR 0.78, 95% CI 0.64 to 0.94; six trials; 714 participants). For Tai Chi, the reduction in rate of falls bordered on statistical significance (RaR 0.72, 95% CI 0.52 to 1.00; five trials; 1563 participants) but Tai Chi did significantly reduce risk of falling (RR 0.71, 95% CI 0.57 to 0.87; six trials; 1625 participants).Multifactorial interventions, which include individual risk assessment, reduced rate of falls (RaR 0.76, 95% CI 0.67 to 0.86; 19 trials; 9503 participants), but not risk of falling (RR 0.93, 95% CI 0.86 to 1.02; 34 trials; 13,617 participants).Overall, vitamin D did not reduce rate of falls (RaR 1.00, 95% CI 0.90 to 1.11; seven trials; 9324 participants) or risk of falling (RR 0.96, 95% CI 0.89 to 1.03; 13 trials; 26,747 participants), but may do so in people with lower vitamin D levels before treatment.Home safety assessment and modification interventions were effective in reducing rate of falls (RR 0.81, 95% CI 0.68 to 0.97; six trials; 4208 participants) and risk of falling (RR 0.88, 95% CI 0.80 to 0.96; seven trials; 4051 participants). These interventions were more effective in people at higher risk of falling, including those with severe visual impairment. Home safety interventions appear to be more effective when delivered by an occupational therapist.An intervention to treat vision problems (616 participants) resulted in a significant increase in the rate of falls (RaR 1.57, 95% CI 1.19 to 2.06) and risk of falling (RR 1.54, 95% CI 1.24 to 1.91). When regular wearers of multifocal glasses (597 participants) were given single lens glasses, all falls and outside falls were significantly reduced in the subgroup that regularly took part in outside activities. Conversely, there was a significant increase in outside falls in intervention group participants who took part in little outside activity.Pacemakers reduced rate of falls in people with carotid sinus hypersensitivity (RaR 0.73, 95% CI 0.57 to 0.93; three trials; 349 participants) but not risk of falling. First eye cataract surgery in women reduced rate of falls (RaR 0.66, 95% CI 0.45 to 0.95; one trial; 306 participants), but second eye cataract surgery did not.Gradual withdrawal of psychotropic medication reduced rate of falls (RaR 0.34, 95% CI 0.16 to 0.73; one trial; 93 participants), but not risk of falling. A prescribing modification programme for primary care physicians significantly reduced risk of falling (RR 0.61, 95% CI 0.41 to 0.91; one trial; 659 participants).An anti-slip shoe device reduced rate of falls in icy conditions (RaR 0.42, 95% CI 0.22 to 0.78; one trial; 109 participants). One trial (305 participants) comparing multifaceted podiatry including foot and ankle exercises with standard podiatry in people with disabling foot pain significantly reduced the rate of falls (RaR 0.64, 95% CI 0.45 to 0.91) but not the risk of falling.There is no evidence of effect for cognitive behavioural interventions on rate of falls (RaR 1.00, 95% CI 0.37 to 2.72; one trial; 120 participants) or risk of falling (RR 1.11, 95% CI 0.80 to 1.54; two trials; 350 participants).Trials testing interventions to increase knowledge/educate about fall prevention alone did not significantly reduce the rate of falls (RaR 0.33, 95% CI 0.09 to 1.20; one trial; 45 participants) or risk of falling (RR 0.88, 95% CI 0.75 to 1.03; four trials; 2555 participants).No conclusions can be drawn from the 47 trials reporting fall-related fractures.Thirteen trials provided a comprehensive economic evaluation. Three of these indicated cost savings for their interventions during the trial period: home-based exercise in over 80-year-olds, home safety assessment and modification in those with a previous fall, and one multifactorial programme targeting eight specific risk factors. Group and home-based exercise programmes, and home safety interventions reduce rate of falls and risk of falling.Multifactorial assessment and intervention programmes reduce rate of falls but not risk of falling; Tai Chi reduces risk of falling.Overall, vitamin D supplementation does not appear to reduce falls but may be effective in people who have lower vitamin D levels before treatment.

CW laser damage testing of RAR nano-textured fused silica and YAG

NASA Astrophysics Data System (ADS)

MacLeod, Bruce D.; Hobbs, Douglas S.; Manni, Anthony D.; Sabatino, Ernest; Bernot, David M.; DeFrances, Sage; Randi, Joseph A.; Thomas, Jeffrey

2017-11-01

A study of the continuous wave (CW) laser induced damage threshold (LiDT) of fused silica and yttrium aluminum garnet (YAG) optics was conducted to further illustrate the enhanced survivability within high power laser systems of an anti-reflection (AR) treatment consisting of randomly distributed surface relief nanostructures (RAR). A series of three CW LiDT tests using the 1070nm wavelength, 16 KW fiber laser test bed at Penn State Electro-Optic Center (PSEOC) were designed and completed, with improvements in the testing protocol, areal coverage, and maximum exposure intensities implemented between test cycles. Initial results for accumulated power, stationary site exposures of RAR nano-textured optics showed no damage and low surface temperatures similar to the control optics with no AR treatment. In contrast, optics with thin-film AR coatings showed high surface temperatures consistent with absorption by the film layers. Surface discriminating absorption measurements made using the Photothermal Common-path Interferometry (PCI) method, showed zero added surface absorption for the RAR nanotextured optics, and absorption levels in the 2-5 part per million range for thin-film AR coated optics. In addition, the surface absorption of thin-film AR coatings was also found to have localized absorption spikes that are likely pre-cursors for damage. Subsequent CW LiDT testing protocol included raster scanning an increased intensity focused beam over the test optic surface where it was found that thin-film AR coated optics damaged at intensities in the 2 to 5 MW/cm2 range with surface temperatures over 250C during the long-duration exposures. Significantly, none of the 10 RAR nano-textured fused silica optics tested could be damaged up to the maximum system intensity of 15.5 MW/cm2, and surface temperatures remained low. YAG optics tested during the final cycle exhibited a similar result with RAR nano-textured surfaces surviving intensities over 3 times higher than thin-film AR coated surfaces. This result was correlated with PCI measurements that also show zero-added surface absorption for the RAR nano-textured YAG optics.

MEK blockade converts AML differentiating response to retinoids into extensive apoptosis.

PubMed

Milella, Michele; Konopleva, Marina; Precupanu, Cristina M; Tabe, Yoko; Ricciardi, Maria Rosaria; Gregorj, Chiara; Collins, Steven J; Carter, Bing Z; D'Angelo, Carmen; Petrucci, Maria Teresa; Foà, Robin; Cognetti, Francesco; Tafuri, Agostino; Andreeff, Michael

2007-03-01

The aberrant function of transcription factors and/or kinase-based signaling pathways that regulate the ability of hematopoietic cells to proliferate, differentiate, and escape apoptosis accounts for the leukemic transformation of myeloid progenitors. Here, we demonstrate that simultaneous retinoid receptor ligation and blockade of the MEK/ERK signaling module, using the small-molecule inhibitor CI-1040, result in a strikingly synergistic induction of apoptosis in both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells with constitutive ERK activation. This proapoptotic synergism requires functional RAR and RXR retinoid receptors, as demonstrated using RAR- and RXR-selective ligands and RAR-defective cells. In the presence of MEK inhibitors, however, retinoid-induced chromatin remodeling, target-gene transcription, and granulocytic differentiation are strikingly inhibited and apoptosis induction becomes independent of death-inducing ligand/receptor pairs; this suggests that apoptosis induction by combined retinoids and MEK inhibitors is entirely distinct from the classical "postmaturation" apoptosis induced by retinoids alone. Finally, we identify disruption of Bcl-2-dependent mitochondrial homeostasis as a possible point of convergence for the proapoptotic synergism observed with retinoids and MEK inhibitors. Taken together, these results indicate that combined retinoid treatment and MEK blockade exert powerful antileukemic effects and could be developed into a novel therapeutic strategy for both AML and APL.

Chlorella vulgaris and Pseudomonas putida interaction modulates phosphate trafficking for reduced arsenic uptake in rice (Oryza sativa L.).

PubMed

Srivastava, Suchi; Srivastava, Sonal; Bist, Vidisha; Awasthi, Surabhi; Chauhan, Reshu; Chaudhry, Vasvi; Singh, Poonam C; Dwivedi, Sanjay; Niranjan, Abhishek; Agrawal, Lalit; Chauhan, Puneet Singh; Tripathi, Rudra Deo; Nautiyal, Chandra Shekhar

2018-06-05

Rice grown in arsenic (As) contaminated areas contributes to high dietary exposure of As inducing multiple adverse effects on human health. The As contamination and application of phosphate fertilizers during seedling stage creates a high P and As stress condition. The flooded paddy fields are also conducive for algal growth and microbial activity. The present study proposes potential role of microalgae, Chlorella vulgaris (CHL) and bacteria, Pseudomonas putida (RAR) on rice plant grown under excess As and phosphate (P) conditions. The results show synchronized interaction of CHL + RAR which, reduces As uptake through enhanced P:As and reduced As:biomass ratio by modulating P trafficking. Gene expression analysis of different phosphate transporters exhibited correlation with reduced As uptake and other essential metals. The balancing of reactive oxygen species (ROS), proline accumulation, hormone modulation, and As sequestration in microbial biomass were elucidated as possible mechanisms of As detoxification. The study concludes that RAR and CHL combination mitigates the As stress during P-enriched conditions in rice by: (i) reducing As availability, (ii) modulating the As uptake, and (iii) improving detoxification mechanism of the plant. The study will be important in assessing the role and applicability of P solubilizing biofertilizers in these conditions. Copyright © 2018 Elsevier B.V. All rights reserved.

The application of the rapid assessment and response methodology for cannabis prevention research among youth in the Netherlands.

PubMed

Dupont, Hans B; Kaplan, Charles D; Braam, Richard V; Verbraeck, Hans T; de Vries, Nanne K

2015-08-01

Drug prevention methods tailored to specific target groups have become increasingly important. There is a growing need to find ways to rapidly assess and situate target groups in their particular contexts. This need is associated with the implementation of evidence-based interventions (EBIs) for these specific target groups. This article describes the application of Rapid Assessment and Response (RAR) as a necessary first step in designing and implementing a prevention intervention plan for problematic cannabis use among "loitering" youth in the South of the Netherlands. Seven RAR studies were conducted using an innovative stepwise model in which the prevention field worker is central. The normative structure for the use of cannabis was found to vary across the neighborhoods of the RAR studies and emerged as the focal point in designing a suitable response. The RAR studies also identified the need in the prevention toolbox for a tailored, low-threshold, effective, individual brief intervention for youth problematic cannabis use. The RAR was found to provide a powerful methodology for detecting target groups and generating contextual and normative data that enable the prevention field worker to select and adapt from the spectrum of existing Evidence based Interventions (EBIs) or develop the most promising model for implementation with the specific target group. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Endoscopic sinus surgery reduces antibiotic utilization in rhinosinusitis

PubMed Central

Bhandarkar, Naveen D.; Mace, Jess C.; Smith, Timothy L.

2011-01-01

Background Antibiotics are a mainstay of treatment for chronic rhinosinusitis (CRS) and recurrent acute rhinosinusitis (RARS). Although quality-of-life outcomes following endoscopic sinus surgery (ESS) have been previously studied, the change in antibiotic utilization following ESS is less well known. Objective We aimed to determine the effect of ESS on antibiotic utilization in CRS and RARS. Methods A multi-institutional, prospective cohort of patients with CRS and RARS was enrolled between January, 2001 and January, 2009. Patients completed the medication subscale of the Chronic Sinusitis Survey, and the Wilcoxon signed-rank test was used to compare differences in the overall reported time of antibiotic between preoperative and postoperative time points. Results 503 patients were followed for an average 17.3 months. Overall, patients reported a 57.2% reduction in time on antibiotics following ESS. The majority of patients (60.4%) reported significantly less antibiotic utilization after ESS (p<0.001) consisting of an 83.7% reduction in the time on antibiotics. Subgroup analysis also revealed a significant reduction in antibiotic utilization for patients with and without nasal polyposis (59.0% and 58.2%; both p<0.001) as well as RARS (61.2%; p=0.001). Conclusion ESS significantly reduces antibiotic utilization for CRS and RARS. This finding demonstrates potential for lower health care expenditures related to antibiotics, as well as reduced risk of both antibiotic related morbidity and development of bacterial resistance. PMID:21666846

Hemorrhoidal artery ligation (HAL) and rectoanal repair (RAR): retrospective analysis of 408 patients in a single center.

PubMed

Scheyer, M; Antonietti, E; Rollinger, G; Lancee, S; Pokorny, H

2015-01-01

Rectoanal repair (RAR), which combines doppler-guided hemorrhoidal artery ligation (HAL) and mucopexy via lifting of the hemorrhoidal prolapse, offers a minimally invasive alternative to conventional hemorrhoidectomy. Patients with grade II hemorrhoids were treated with HAL, and patients with grade III and IV hemorrhoids were treated with the RAR procedure by two surgeons. Postoperative follow-up was performed clinically and by proctoscopy after 8 weeks routinely, and long-term follow-up was performed using a standardized postal questionnaire. The overall complication rate was 29% (n = 118). After short-term follow-up, 26% (n = 106) of patients reported recurrent or persistent prolapsing piles, while 21% (n = 86) of patients had recurrent bleeding. After long-term follow-up, 24% (n = 98) of patients reported prolapsing piles, 3% (n = 12) bleeding, 3% (n = 12) pruritus, and 2% (n = 8) anal pain, while 20% (n = 82) complained of persistent mixed symptoms. HAL and RAR provide prolonged relief for patients with hemorrhoidal disease whose main symptoms are bleeding, pruritus and pain but not for patients with prolapse as an initial indication.

Korean national QPE technique development: Analysis of current QPE results and future plan

NASA Astrophysics Data System (ADS)

Cha, Joo Wan

2013-04-01

Korea Meteorological Administration(KMA) has developed a Real-time ADjusted Radar-AWS (Automatic Weather Station) Rainrate (RAD-RAR) system using eleven radars over the South Korea. The procedure of the RAD-RAR system in real time consists of four steps: 1) the quality control of volumetric reflectivity for each radar, 2) the computation of the every 10-min rain gauge rainfall within each radar, 3) the real time (10 min-updated) rainfall estimation by the Z-R relationship minimizing the difference between the 1.5-km constant altitude plan precipitation indicator and rain gauge rainfall based on Window Probability Matching Method(WPMM) and by the real-time bias correction of RAD-RAR conducted at every 10 minutes for each radar by making the bias, and 4) the composition of the 11-radar estimated rainfall data. In addition, a local gauge correction method applies for RAD-RAR system. Therefore, the correlation coefficient of R2 = 0.81 is obtained between the daily accumulated observed and RAD-RAR estimated rainfall in 2012. We like to develop a new QPE system using the multi-sensor(radar, rain gauge, numerical model output, and lightning) data for newly improving Korean national QPE system. We made the prototype QPE system in 2012 and improve the detail techniques now. In the future, the new high performance QPE system will include a dual polarization radar observation technique for providing more accurate and valuable national QPE data

Refractory Anemia with Ring Sideroblasts (RARS) and RARS with Thrombocytosis (RARS-T) – “2017 Update on Diagnosis, Risk-stratification, and Management”

PubMed Central

Patnaik, Mrinal M.; Tefferi, Ayalew

2017-01-01

Disease Overview Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). Diagnosis MDS-RS is a lower risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥ 450 × 10(9)/L and large atypical megakaryocytes (similar to BCR-ABL1 negative MPN). Mutations and Karyotype Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations; with ASXL1/SETBP1 mutations adversely impacting survival. Cytogenetic abnormalities are uncommon in both diseases. Risk stratification Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-International Prognostic Scoring System (R-IPSS). Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic transformation. Treatment Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs is uncertain. PMID:28188970

The retinoic acid signaling pathway regulates anterior/posterior patterning in the nerve cord and pharynx of amphioxus, a chordate lacking neural crest.

PubMed

Escriva, Hector; Holland, Nicholas D; Gronemeyer, Hinrich; Laudet, Vincent; Holland, Linda Z

2002-06-01

Amphioxus, the closest living invertebrate relative of the vertebrates, has a notochord, segmental axial musculature, pharyngeal gill slits and dorsal hollow nerve cord, but lacks neural crest. In amphioxus, as in vertebrates, exogenous retinoic acid (RA) posteriorizes the embryo. The mouth and gill slits never form, AmphiPax1, which is normally downregulated where gill slits form, remains upregulated and AmphiHox1 expression shifts anteriorly in the nerve cord. To dissect the role of RA signaling in patterning chordate embryos, we have cloned the single retinoic acid receptor (AmphiRAR), retinoid X receptor (AmphiRXR) and an orphan receptor (AmphiTR2/4) from amphioxus. AmphiTR2/4 inhibits AmphiRAR-AmphiRXR-mediated transactivation in the presence of RA by competing for DR5 or IR7 retinoic acid response elements (RAREs). The 5' untranslated region of AmphiTR2/4 contains an IR7 element, suggesting possible auto- and RA-regulation. The patterns of AmphiTR2/4 and AmphiRAR expression during embryogenesis are largely complementary: AmphiTR2/4 is strongly expressed in the cerebral vesicle (homologous to the diencephalon plus anterior midbrain), while AmphiRAR expression is high in the equivalent of the hindbrain and spinal cord. Similarly, while AmphiTR2/4 is expressed most strongly in the anterior and posterior thirds of the endoderm, the highest AmphiRAR expression is in the middle third. Expression of AmphiRAR is upregulated by exogenous RA and completely downregulated by the RA antagonist BMS009. Moreover, BMS009 expands the pharynx posteriorly; the first three gill slit primordia are elongated and shifted posteriorly, but do not penetrate, and additional, non-penetrating gill slit primordia are induced. Thus, in an organism without neural crest, initiation and penetration of gill slits appear to be separate events mediated by distinct levels of RA signaling in the pharyngeal endoderm. Although these compounds have little effect on levels of AmphiTR2/4 expression, RA shifts pharyngeal expression of AmphiTR2/4 anteriorly, while BMS009 extends it posteriorly. Collectively, our results suggest a model for anteroposterior patterning of the amphioxus nerve cord and pharynx, which is probably applicable to vertebrates as well, in which a low anterior level of AmphiRAR (caused, at least in part, by competitive inhibition by AmphiTR2/4) is necessary for patterning the forebrain and formation of gill slits, the posterior extent of both being set by a sharp increase in the level of AmphiRAR. Supplemental data available on-line

The retinoic acid signaling pathway regulates anterior/posterior patterning in the nerve cord and pharynx of amphioxus, a chordate lacking neural crest

NASA Technical Reports Server (NTRS)

Escriva, Hector; Holland, Nicholas D.; Gronemeyer, Hinrich; Laudet, Vincent; Holland, Linda Z.

2002-01-01

Amphioxus, the closest living invertebrate relative of the vertebrates, has a notochord, segmental axial musculature, pharyngeal gill slits and dorsal hollow nerve cord, but lacks neural crest. In amphioxus, as in vertebrates, exogenous retinoic acid (RA) posteriorizes the embryo. The mouth and gill slits never form, AmphiPax1, which is normally downregulated where gill slits form, remains upregulated and AmphiHox1 expression shifts anteriorly in the nerve cord. To dissect the role of RA signaling in patterning chordate embryos, we have cloned the single retinoic acid receptor (AmphiRAR), retinoid X receptor (AmphiRXR) and an orphan receptor (AmphiTR2/4) from amphioxus. AmphiTR2/4 inhibits AmphiRAR-AmphiRXR-mediated transactivation in the presence of RA by competing for DR5 or IR7 retinoic acid response elements (RAREs). The 5' untranslated region of AmphiTR2/4 contains an IR7 element, suggesting possible auto- and RA-regulation. The patterns of AmphiTR2/4 and AmphiRAR expression during embryogenesis are largely complementary: AmphiTR2/4 is strongly expressed in the cerebral vesicle (homologous to the diencephalon plus anterior midbrain), while AmphiRAR expression is high in the equivalent of the hindbrain and spinal cord. Similarly, while AmphiTR2/4 is expressed most strongly in the anterior and posterior thirds of the endoderm, the highest AmphiRAR expression is in the middle third. Expression of AmphiRAR is upregulated by exogenous RA and completely downregulated by the RA antagonist BMS009. Moreover, BMS009 expands the pharynx posteriorly; the first three gill slit primordia are elongated and shifted posteriorly, but do not penetrate, and additional, non-penetrating gill slit primordia are induced. Thus, in an organism without neural crest, initiation and penetration of gill slits appear to be separate events mediated by distinct levels of RA signaling in the pharyngeal endoderm. Although these compounds have little effect on levels of AmphiTR2/4 expression, RA shifts pharyngeal expression of AmphiTR2/4 anteriorly, while BMS009 extends it posteriorly. Collectively, our results suggest a model for anteroposterior patterning of the amphioxus nerve cord and pharynx, which is probably applicable to vertebrates as well, in which a low anterior level of AmphiRAR (caused, at least in part, by competitive inhibition by AmphiTR2/4) is necessary for patterning the forebrain and formation of gill slits, the posterior extent of both being set by a sharp increase in the level of AmphiRAR. Supplemental data available on-line.

Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue

PubMed Central

Landrier, Jean-Francois; Kasiri, Elnaz; Karkeni, Esma; Mihály, Johanna; Béke, Gabriella; Weiss, Kathrin; Lucas, Renata; Aydemir, Gamze; Salles, Jérome; Walrand, Stéphane; de Lera, Angel R.; Rühl, Ralph

2017-01-01

Adiponectin is an adipocyte-derived adipokine with potent antidiabetic, anti-inflammatory, and antiatherogenic activity. Long-term, high-fat diet results in gain of body weight, adiposity, further inflammatory-based cardiovascular diseases, and reduced adiponectin secretion. Vitamin A derivatives/retinoids are involved in several of these processes, which mainly take place in white adipose tissue (WAT). In this study, we examined adiponectin expression as a function of dietary high-fat and high–vitamin A conditions in mice. A decrease of adiponectin expression in addition to an up-regulation of aldehyde dehydrogenase A1 (ALDH1A1), retinoid signaling, and retinoic acid response element signaling was selectively observed in WAT of mice fed a normal–vitamin A, high-fat diet. Reduced adiponectin expression in WAT was also observed in mice fed a high–vitamin A diet. Adipocyte cell culture revealed that endogenous and synthetic retinoic acid receptor (RAR)α- and RARγ-selective agonists, as well as a synthetic retinoid X receptor agonist, efficiently reduced adiponectin expression, whereas ALDH1A1 expression only increased with RAR agonists. We conclude that reduced adiponectin expression under high-fat dietary conditions is dependent on 1) increased ALDH1A1 expression in adipocytes, which does not increase all-trans-retinoic acid levels; 2) further RAR ligand–induced, WAT-selective, increased retinoic acid response element–mediated signaling; and 3) RAR ligand–dependent reduction of adiponectin expression.—Landrier, J.-F., Kasiri, E., Karkeni, E., Mihály, J., Béke, G., Weiss, K., Lucas, R., Aydemir, G., Salles, J., Walrand, S., de Lera, A. R., Rühl, R. Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue. PMID:27729412

Toxcast Chemical and Bioactivity Profiles for In Vitro Targets in the Retinoid Signaling System (SOT)

EPA Science Inventory

A predictive model for prenatal developmental toxicity using ToxCast Phase I showed the RAR assay set to be the strongest weighting factor (Sipes et al. 2011). Retinoid signaling mediates growth and differentiation of the embryo. ToxCast has 6 reporter assays for trans-activation...

Kinetic properties of the human liver cytosolic aldehyde dehydrogenase for retinal isomers.

PubMed

Bhat, P V; Samaha, H

1999-01-15

Retinoic acid exerts pleiotropic effects by acting through two families of nuclear receptors, RAR and RXR. All-trans and 9-cis retinoic acid bind RARs, whereas 9-cis retinoic acid binds and activates only the RXRs. To understand the role of human liver cytosolic aldehyde dehydrogenase (ALDH1) in retinoic acid synthesis, we examined the ability of ALDH 1 to catalyze the oxidation of the naturally occurring retinal isomers. ALDH1 catalyzed the oxidation of all-trans, 9-cis, and 13-cis retinal with equal efficiency. However, the affinity to all-trans retinal (Km = 2.2 microM) was twofold higher than to 9-cis (Km = 5.5 microM) and 13-cis (Km = 4.6 microM) retinal. All-trans retinol was a potent inhibitor of ALDH1 activity, and inhibited all-trans retinal oxidation uncompetitively. Comparison of the kinetic properties of ALDH1 for retinal isomers with those of previously reported rat kidney retinal dehydrogenase showed distinct differences, suggesting that ALDH1 may play a different role in retinal metabolism in liver.

High-Mobility Group Chromatin Proteins 1 and 2 Functionally Interact with Steroid Hormone Receptors To Enhance Their DNA Binding In Vitro and Transcriptional Activity in Mammalian Cells

PubMed Central

Boonyaratanakornkit, Viroj; Melvin, Vida; Prendergast, Paul; Altmann, Magda; Ronfani, Lorenza; Bianchi, Marco E.; Taraseviciene, Laima; Nordeen, Steven K.; Allegretto, Elizabeth A.; Edwards, Dean P.

1998-01-01

We previously reported that the chromatin high-mobility group protein 1 (HMG-1) enhances the sequence-specific DNA binding activity of progesterone receptor (PR) in vitro, thus providing the first evidence that HMG-1 may have a coregulatory role in steroid receptor-mediated gene transcription. Here we show that HMG-1 and the highly related HMG-2 stimulate DNA binding by other steroid receptors, including estrogen, androgen, and glucocorticoid receptors, but have no effect on DNA binding by several nonsteroid nuclear receptors, including retinoid acid receptor (RAR), retinoic X receptor (RXR), and vitamin D receptor (VDR). As highly purified recombinant full-length proteins, all steroid receptors tested exhibited weak binding affinity for their optimal palindromic hormone response elements (HREs), and the addition of purified HMG-1 or -2 substantially increased their affinity for HREs. Purified RAR, RXR, and VDR also exhibited little to no detectable binding to their cognate direct repeat HREs but, in contrast to results with steroid receptors, the addition of HMG-1 or HMG-2 had no stimulatory effect. Instead, the addition of purified RXR enhanced RAR and VDR DNA binding through a heterodimerization mechanism and HMG-1 or HMG-2 had no further effect on DNA binding by RXR-RAR or RXR-VDR heterodimers. HMG-1 and HMG-2 (HMG-1/-2) themselves do not bind to progesterone response elements, but in the presence of PR they were detected as part of an HMG-PR-DNA ternary complex. HMG-1/-2 can also interact transiently in vitro with PR in the absence of DNA; however, no direct protein interaction was detected with VDR. These results, taken together with the fact that PR can bend its target DNA and that HMG-1/-2 are non-sequence-specific DNA binding proteins that recognize DNA structure, suggest that HMG-1/-2 are recruited to the PR-DNA complex by the combined effect of transient protein interaction and DNA bending. In transient-transfection assays, coexpression of HMG-1 or HMG-2 increased PR-mediated transcription in mammalian cells by as much as 7- to 10-fold without altering the basal promoter activity of target reporter genes. This increase in PR-mediated gene activation by coexpression of HMG-1/-2 was observed in different cell types and with different target promoters, suggesting a generality to the functional interaction between HMG-1/-2 and PR in vivo. Cotransfection of HMG-1 also increased reporter gene activation mediated by other steroid receptors, including glucocorticoid and androgen receptors, but it had a minimal influence on VDR-dependent transcription in vivo. These results support the conclusion that HMG-1/-2 are coregulatory proteins that increase the DNA binding and transcriptional activity of the steroid hormone class of receptors but that do not functionally interact with certain nonsteroid classes of nuclear receptors. PMID:9671457

Vitamin A Deficiency Induces Congenital Spinal Deformities in Rats

PubMed Central

Li, Zheng; Shen, Jianxiong; Wu, William Ka Kei; Wang, Xiaojuan; Liang, Jinqian; Qiu, Guixing; Liu, Jiaming

2012-01-01

Most cases of congenital spinal deformities were sporadic and without strong evidence of heritability. The etiology of congenital spinal deformities is still elusive and assumed to be multi-factorial. The current study seeks to elucidate the effect of maternal vitamin A deficiency and the production of congenital spinal deformities in the offsping. Thirty two female rats were randomized into two groups: control group, which was fed a normal diet; vitamin A deficient group, which were given vitamin A-deficient diet from at least 2 weeks before mating till delivery. Three random neonatal rats from each group were killed the next day of parturition. Female rats were fed an AIN-93G diet sufficient in vitamin A to feed the rest of neonates for two weeks until euthanasia. Serum levels of vitamin A were assessed in the adult and filial rats. Anteroposterior (AP) spine radiographs were obtained at week 2 after delivery to evaluate the presence of the skeletal abnormalities especially of spinal deformities. Liver and vertebral body expression of retinaldehyde dehydrogenase (RALDHs) and RARs mRNA was assessed by reverse transcription-real time PCR. VAD neonates displayed many skeletal malformations in the cervical, thoracic, the pelvic and sacral and limbs regions. The incidence of congenital scoliosis was 13.79% (8/58) in the filial rats of vitamin A deficiency group and 0% in the control group. Furthermore, vitamin A deficiency negatively regulate the liver and verterbral body mRNA levels of RALDH1, RALDH2, RALDH3, RAR-α, RAR-β and RAR-γ. Vitamin A deficiency in pregnancy may induce congenital spinal deformities in the postnatal rats. The decreases of RALDHs and RARs mRNA expression induced by vitamin A deprivation suggest that vertebral birth defects may be caused by a defect in RA signaling pathway during somitogenesis. PMID:23071590

Comparative effects of overproducing the AraC-type transcriptional regulators MarA, SoxS, RarA and RamA on antimicrobial drug susceptibility in Klebsiella pneumoniae.

PubMed

Jiménez-Castellanos, Juan-Carlos; Wan Ahmad Kamil, Wan Nur Ismah; Cheung, Ching Hei Phoebe; Tobin, Maryann S; Brown, James; Isaac, Sophie G; Heesom, Kate J; Schneiders, Thamarai; Avison, Matthew B

2016-07-01

In Klebsiella pneumoniae, overproduction of RamA and RarA leads to increased MICs of various antibiotics; MarA and SoxS are predicted to perform a similar function. We have compared the relative effects of overproducing these four AraC-type regulators on envelope permeability (a combination of outer membrane permeability and efflux), efflux pump and porin production, and antibiotic susceptibility in K. pneumoniae. Regulators were overproduced using a pBAD expression vector. Antibiotic susceptibility was measured using disc testing. Envelope permeability was estimated using a fluorescent dye accumulation assay. Porin and efflux pump production was quantified using proteomics and validated using real-time quantitative RT-PCR. Envelope permeability and antibiotic disc inhibition zone diameters both reduced during overproduction of RamA and to a lesser extent RarA or SoxS, but did not change following overproduction of MarA. These effects were associated with overproduction of the efflux pumps AcrAB (for RamA and SoxS) and OqxAB (for RamA and RarA) and the outer membrane protein TolC (for all regulators). Effects on porin production were strain specific. RamA is the most potent regulator of antibiotic permeability in K. pneumoniae, followed by RarA then SoxS, with MarA having very little effect. This observed relative potency correlates well with the frequency at which these regulators are reportedly overproduced in clinical isolates. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Gene Profiling Characteristics of Radioadaptive Response in AG01522 Normal Human Fibroblasts

PubMed Central

Hou, Jue; Wang, Fan; Kong, Peizhong; Yu, Peter K. N.; Wang, Hongzhi; Han, Wei

2015-01-01

Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose. PMID:25886619

A rare single cytogenetic finding of isochromosome 14q in a female with refractory anemia with ring sideroblasts (RARS)

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

Haag, M.M.; Sutcliffe, M.J.; Nelson, R.P.

1994-09-01

Clonal cytogenetic abnormalities occur in 79% of patients with myelodysplastic syndrome (MDS) and can be used to diagnose malignancy. Some of these clonal chromosomal changes have been useful in evaluation of the pathobiological similarity between MDS and acute nonlymphocytic leukemia (ANLL) and can be used to monitor the disease progression. A 44-year-old woman, presenting with normochromic, normocytic anemia was clinically asymptomatic and physical examination revealed no lymphadenopathy or hepatosplenomegaly. Stains for iron demonstrated adequate stores but with numerours ring sideroblasts which constituted approximately 15% of the total erythoblastic population. No increased reticulum or fibrosis was noted. These findings supported amore » diagnosis of MDS, classification refractory anemia with ring sideroblasts (RARS). Bone marrow cytogentic analysis showed an isochromosome 14q as the sole chromosome abnormality and this was confirmed by molecular cytogenetics using a whole chromosome Coatasome probe for No. 14. A population of 46,XX cells (20%) was also observed. Numerous interphase cells had three isolated fluorescent signals for No. 14. Structural and numerical abnormalities of chromosome No. 14 are reported in many hematological disorders, but few structural abnormalities have been reported for RARS and no extra copies, including i(14q), have been reported for MD or RARS. However, examples of extra copies of No. 14, including the isochromosome form, have been reported for ANLL. Since 15% of RARS patients progress to ANLL, there may be prognostic significance to this chromosome abnormality for his patient. The patient is awaiting a suitable donor for bone marrow transplantation. The presence of isochromosome No. 14 in the malignant cells offers an opportunity to monitor disease progression pre-transplantation and minimal residual disease post-transplantation.« less

Prevalence of gastro-oesophageal reflux disease symptoms and reflux-associated respiratory symptoms in asthma.

PubMed

Amarasiri, Lakmali D; Pathmeswaran, Arunasalam; de Silva, H Janaka; Ranasinha, Channa D

2010-09-15

Gastro-oesophageal reflux disease (GORD) symptoms are common in asthma and have been extensively studied, but less so in the Asian continent. Reflux-associated respiratory symptoms (RARS) have, in contrast, been little-studied globally. We report the prevalence of GORD symptoms and RARS in adult asthmatics, and their association with asthma severity and medication use. A cross-sectional analytical study. A validated interviewer-administered GORD scale was used to assess frequency and severity of seven GORD symptoms. Subjects were consecutive asthmatics attending medical clinics. Controls were matched subjects without respiratory symptoms. The mean (SD) composite GORD symptom score of asthmatics was significantly higher than controls (21.8 (17.2) versus 12.0 (7.6); P < 0.001) as was frequency of each symptom and RARS. Prevalence of GORD symptoms in asthmatics was 59.4% (95% CI, 59.1%-59.6%) versus 28.5% in controls (95% CI, 29.0% - 29.4%). 36% of asthmatics experienced respiratory symptoms in association with both typical and atypical GORD symptoms, compared to 10% of controls (P < 0.001). An asthmatic had a 3.5 times higher risk of experiencing a GORD symptom after adjusting for confounders (OR 3.5; 95% CI 2.5-5.3). Severity of asthma had a strong dose-response relationship with GORD symptoms. Asthma medication use did not significantly influence the presence of GORD symptoms. GORD symptoms and RARS were more prevalent in a cohort of Sri Lankan adult asthmatics compared to non-asthmatics. Increased prevalence of RARS is associated with both typical and atypical symptoms of GORD. Asthma disease and its severity, but not asthma medication, appear to influence presence of GORD symptoms.

Prevalence of gastro-oesophageal reflux disease symptoms and reflux-associated respiratory symptoms in asthma

PubMed Central

2010-01-01

Background Gastro-oesophageal reflux disease (GORD) symptoms are common in asthma and have been extensively studied, but less so in the Asian continent. Reflux-associated respiratory symptoms (RARS) have, in contrast, been little-studied globally. We report the prevalence of GORD symptoms and RARS in adult asthmatics, and their association with asthma severity and medication use. Methods A cross-sectional analytical study. A validated interviewer-administered GORD scale was used to assess frequency and severity of seven GORD symptoms. Subjects were consecutive asthmatics attending medical clinics. Controls were matched subjects without respiratory symptoms. Results The mean (SD) composite GORD symptom score of asthmatics was significantly higher than controls (21.8 (17.2) versus 12.0 (7.6); P < 0.001) as was frequency of each symptom and RARS. Prevalence of GORD symptoms in asthmatics was 59.4% (95% CI, 59.1%-59.6%) versus 28.5% in controls (95% CI, 29.0% - 29.4%). 36% of asthmatics experienced respiratory symptoms in association with both typical and atypical GORD symptoms, compared to 10% of controls (P < 0.001). An asthmatic had a 3.5 times higher risk of experiencing a GORD symptom after adjusting for confounders (OR 3.5; 95% CI 2.5-5.3). Severity of asthma had a strong dose-response relationship with GORD symptoms. Asthma medication use did not significantly influence the presence of GORD symptoms. Conclusions GORD symptoms and RARS were more prevalent in a cohort of Sri Lankan adult asthmatics compared to non-asthmatics. Increased prevalence of RARS is associated with both typical and atypical symptoms of GORD. Asthma disease and its severity, but not asthma medication, appear to influence presence of GORD symptoms. PMID:20843346

Selective Cooperation between Fatty Acid Binding Proteins and Peroxisome Proliferator-Activated Receptors in Regulating Transcription

PubMed Central

Tan, Nguan-Soon; Shaw, Natacha S.; Vinckenbosch, Nicolas; Liu, Peng; Yasmin, Rubina; Desvergne, Béatrice; Wahli, Walter; Noy, Noa

2002-01-01

Lipophilic compounds such as retinoic acid and long-chain fatty acids regulate gene transcription by activating nuclear receptors such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptors (PPARs). These compounds also bind in cells to members of the family of intracellular lipid binding proteins, which includes cellular retinoic acid-binding proteins (CRABPs) and fatty acid binding proteins (FABPs). We previously reported that CRABP-II enhances the transcriptional activity of RAR by directly targeting retinoic acid to the receptor. Here, potential functional cooperation between FABPs and PPARs in regulating the transcriptional activities of their common ligands was investigated. We show that adipocyte FABP and keratinocyte FABP (A-FABP and K-FABP, respectively) selectively enhance the activities of PPARγ and PPARβ, respectively, and that these FABPs massively relocate to the nucleus in response to selective ligands for the PPAR isotype which they activate. We show further that A-FABP and K-FABP interact directly with PPARγ and PPARβ and that they do so in a receptor- and ligand-selective manner. Finally, the data demonstrate that the presence of high levels of K-FABP in keratinocytes is essential for PPARβ-mediated induction of differentiation of these cells. Taken together, the data establish that A-FABP and K-FABP govern the transcriptional activities of their ligands by targeting them to cognate PPARs in the nucleus, thereby enabling PPARs to exert their biological functions. PMID:12077340

The efficacy of 9-cis retinoic acid in experimental models of cancer.

PubMed

Gottardis, M M; Lamph, W W; Shalinsky, D R; Wellstein, A; Heyman, R A

1996-01-01

9-cis retinoic acid (9-cis RA) is a retinoid receptor pan-agonist that binds with high affinity to both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Using a variety of in vivo and in vitro cancer models, we present experimental data that 9-cis RA has activity as a potential chemotherapeutic agent. Treatment of the human promyelocytic leukemia cell line HL-60 with 9-cis RA decreases cell proliferation, increases cell differentiation, and increases apoptosis. Induction of apoptosis correlates with an increase in tissue transglutaminase (type II) activity. In vivo, 9-cis RA induces complete tumor regression of an early passage human lip squamous cell carcinoma xenograft. Finally, 9-cis RA inhibits the anchorage-independent growth of the human breast cancer cell lines MCF-7 and LY2 (an antiestrogen-resistant MCF-7 variant). Transient co-transfection assays indicate that 9-cis RA inhibits estrogen receptor transcription of an ERE-tk-LUC reporter through RAR or RXR receptors. These data suggest that retinoid receptors can antagonize estrogen-dependent transcription and provides one possible mechanism for the inhibition of cell growth by 9-cis RA in breast cancer cell lines. In summary, these findings present evidence that 9-cis RA has a wide range of activities in human cancer models.

Effects of physiological versus pharmacological beta-carotene supplementation on cell proliferation and histopathological changes in the lungs of cigarette smoke-exposed ferrets.

PubMed

Liu, C; Wang, X D; Bronson, R T; Smith, D E; Krinsky, N I; Russell, R M

2000-12-01

There remains a remarkable discordance between the results of observational epidemiological studies and intervention trials using beta-carotene as a potential chemopreventive agent. One question that needs to be examined is whether the adverse outcomes of human beta-carotene trials are related to the large doses of beta-carotene that were administered. In the present study, ferrets were given a physiological (low) dose or a pharmacological (high) dose of beta-carotene supplementation (0.43 mg versus 2.4 mg/kg body wt/day, which is equivalent to 6 mg versus 30 mg/day in humans) and exposed to cigarette smoke for 6 months. We investigated the effects of these doses of beta-carotene on retinoid concentrations, expression of retinoic acid receptors (RARs), activator protein 1 (AP-1; c-Jun and c-Fos), cyclin D1, proliferating cellular nuclear antigen (PCNA), and histopathological changes in the lungs of both normal and cigarette smoke-exposed ferrets. Thirty-six male ferrets were treated in six groups-control, smoke-exposed (SM), low-dose beta-carotene (LBC), high-dose beta-carotene (HBC), low-dose beta-carotene plus smoke exposure (LBC+SM) or high-dose beta-carotene plus smoke exposure (HBC+SM)-for 6 months. Retinoic acid concentration and RAR beta gene expression, but not expression of RAR alpha and RAR gamma, was reduced in the lung tissue of HBC+SM, HBC, SM and LBC+SM ferrets, but not in that of LBC ferrets, as compared with the control group. Expression of AP-1 and PCNA was greater in HBC+SM, HBC, SM and LBC+SM ferrets, but not in the LBC ferrets, as compared with the control group. Increased amounts of cyclin D1 and keratinized squamous metaplasia were observed in the lung tissue of HBC+SM, HBC and SM groups but not in that of the LBC+SM, LBC or control groups. These data suggest that, in contrast with a pharmacological dose of beta-carotene, a physiological dose of beta-carotene in smoke-exposed ferrets has no potentially detrimental effects and may afford weak protection against lung damage induced by cigarette smoke.

Nucleophosmin regulates the stability and transcriptional activity of p53.

PubMed

Colombo, Emanuela; Marine, Jean-Christophe; Danovi, Davide; Falini, Brunangelo; Pelicci, Pier Giuseppe

2002-07-01

Nucleophosmin (NPM) is a ubiquitously expressed nucleolar phosphoprotein that continuously shuttles between the nucleus and cytoplasm. It has been proposed to function in ribosomal protein assembly and transport, and also as a molecular chaperone that prevents proteins from aggregating in the crowded environment of the nucleolus. The NPM gene is involved in several tumour-associated chromosome translocations, which have resulted in the formation of fusion proteins that retain the amino terminus of NPM, including NPM ALK, NPM RAR and NPM MLF1 (ref. 6). It is generally thought that the NPM component is not involved in the transforming potential of these fusion proteins, but instead provides a dimerization interface for the oligomerization and the oncogenic conversion of the various NPM partners (ALK, RAR, MLF1). Here we show that NPM interacts directly with the tumour suppressor p53, regulates the increase in stability and transcriptional activation of p53 after different types of stress, and induces p53-dependent premature senescence on overexpression in diploid fibroblasts. These findings indicate that NPM is a crucial regulator of p53 and suggest that alterations of the NPM function by NPM fusion proteins might lead to deregulation of p53 in tumours.

Viral-induced systemic necrosis in plants involves both programmed cell death and the inhibition of viral multiplication, which are regulated by independent pathways.

PubMed

Komatsu, Ken; Hashimoto, Masayoshi; Ozeki, Johji; Yamaji, Yasuyuki; Maejima, Kensaku; Senshu, Hiroko; Himeno, Misako; Okano, Yukari; Kagiwada, Satoshi; Namba, Shigetou

2010-03-01

Resistant plants respond rapidly to invading avirulent plant viruses by triggering a hypersensitive response (HR). An HR is accompanied by a restraint of virus multiplication and programmed cell death (PCD), both of which have been observed in systemic necrosis triggered by a successful viral infection. Here, we analyzed signaling pathways underlying the HR in resistance genotype plants and those leading to systemic necrosis. We show that systemic necrosis in Nicotiana benthamiana, induced by Plantago asiatica mosaic virus (PlAMV) infection, was associated with PCD, biochemical features, and gene expression patterns that are characteristic of HR. The induction of necrosis caused by PlAMV infection was dependent on SGT1, RAR1, and the downstream mitogen-activated protein kinase (MAPK) cascade involving MAPKKKalpha and MEK2. However, although SGT1 and RAR1 silencing led to an increased accumulation of PlAMV, silencing of the MAPKKKalpha-MEK2 cascade did not. This observation indicates that viral multiplication is partly restrained even in systemic necrosis induced by viral infection, and that this restraint requires SGT1 and RAR1 but not the MAPKKKalpha-MEK2 cascade. Similarly, although both SGT1 and MAPKKKalpha were essential for the Rx-mediated HR to Potato virus X (PVX), SGT1 but not MAPKKKalpha was involved in the restraint of PVX multiplication. These results suggest that systemic necrosis and HR consist of PCD and a restraint of virus multiplication, and that the latter is induced through unknown pathways independent from the former.

ISOLATION AND CHARACTERIZATION OF AXOLOTL NPDC-1 AND ITS EFFECTS ON RETINOIC ACID RECEPTOR SIGNALING

PubMed Central

Theodosiou, Maria; Monaghan, James R; Spencer, Michael L; Voss, S Randal; Noonan, Daniel J

2009-01-01

Retinoic acid, a key morphogen in early vertebrate development and tissue regeneration, mediates its effects through the binding of receptors that act as ligand-induced transcription factors. These binding events function to recruit an array of transcription co-regulatory proteins to specific gene promoters. One such co-regulatory protein, neuronal proliferation and differentiation control-1 (NPDC-1), is broadly expressed during mammalian development and functions as an in vitro repressor of retinoic acid receptor (RAR)-mediated transcription. To obtain comparative and developmental insights about NPDC-1 function, we cloned the axolotl (Ambystoma mexicanum) orthologue and measured transcript abundances among tissues sampled during the embryonic and juvenile phases of development, and also during spinal cord regeneration. Structurally, the axolotl orthologue of NPDC-1 retained sequence identity to mammalian sequences in all functional domains. Functionally, we observed that axolotl NPDC-1 mRNA expression peaked late in embryogenesis, with highest levels of expression occurring during the time of limb development, a process regulated by retinoic acid signaling. Also similar to what has been observed in mammals, axolotl NPDC-1 directly interacts with axolotl RAR, modulates axolotl RAR DNA binding, and represses cell proliferation and axolotl RAR-mediated gene transcription. These data justify axolotl as a model to further investigate NPDC-1 and its role in regulating retinoic acid signaling. PMID:17331771

Rectoanal repair versus suture haemorrhoidopexy: a comparative study on suture mucopexy procedures for high-grade haemorrhoids.

PubMed

Theodoropoulos, G E; Michalopoulos, N V; Linardoutsos, D; Stamopoulos, P; Flessas, I; Tsamis, D; Zografos, G C

2012-06-01

The isolated application of Doppler-guided haemorrhoidal artery ligation (DGHAL) may fail due to the increased reprolapse rate for high-grade haemorrhoids. DGHAL has been combined with a proctoscopic-assisted transanal rectal mucopexy of the prolapsing tissue. The technique is called rectoanal repair (RAR) and is an evolution of various mucopexy and suture haemorrhoidopexy (SHP) techniques. A prominent external component may require minimal (muco-) cutaneous excision (MMCE) of protruding anoderm or minor cutaneous excision of skin tags. Fifty-seven patients with symptomatic Goligher grade III and IV haemorrhoids underwent DGHAL followed by either RAR or SHP. In 26 cases, the addition of MMCE was necessary. No significant differences were observed between the two approaches with regards to pain scores measured with visual analogue scale (VAS). On postoperative day 1, mean pain score at rest was 5.81 (±2.23 SD) after SHP versus 5.08 (±2.35 SD) after RAR, while mean pain score at first defecation was 7.31 (±1.6 SD) versus 7.52 (±1.83 SD). There was no difference in the duration of analgesic requirements, postoperative complications and residual prolapse between the 2 procedures. The addition of MMCE did not affect postoperative pain nor analgesic requirements. With the exception of 8 patients who still had with skin tags or minimal protrusion, the remaining of patients (86 %) were asymptomatic and recurrence-free at an average follow-up of 20 months. Overall, 94.8 % of patients stated that they were satisfied with the results, and 91.2 % that they would repeat it if necessary. Performance of either SHP or RAR after DGHAL is a safe and effective surgical tactic for advanced grade haemorrhoids. Our initial results do not confirm any superiority of RAR over traditional SHP.

Retinoid Expression in Onchocercal Skin Disease: Pilot Study

PubMed Central

Mawson, Anthony R; Makunde, Williams H; Penman, Alan D; Hernandez Morales, Veronica de Los Angeles; Kalinga, Akili K; Francis, Filbert; Rubinchik, Semyon; Kibweja, Addow

2017-01-01

Based on the observation that the parasite Onchocerca volvulus selectively absorbs vitamin A from the host, and the known toxicity of vitamin A in higher concentration, it was hypothesized that dying microfilariae (mf) release their stores of vitamin A (retinoids) into the host circulation in toxic concentrations, inducing the signs and symptoms of onchocerciasis. We conducted a pilot study to test the hypothesis in Songea communities in Southern Tanzania, where mass drug administration with ivermectin had not been implemented by the time of the survey. The specific aim was to evaluate the correlation between the diagnosis of onchocerciasis and increased levels of retinoic acid at infection sites. The analysis was performed by determining copy numbers of a genome of O volvulus present in skin snip samples of persons with onchocerciacis, and correlating these numbers with expression levels of retinoic acid receptor-α (RAR-α), which is inducible by retinoic acid. Total DNA and RNA were extracted from each of 25 mf-positive and 25 mf-negative skin samples and evaluated using quantitative polymerase chain reaction with appropriate negative controls. Analysis of the samples, adjusted with glyceraldehyde 3-phosphate dehydrogenase gene levels, revealed that most samples with detectable RAR-α transcripts had higher levels of RAR-α expression than the assay control. However, the quality and number of samples were insufficient for statistical analysis. Fold data on the expression levels of both O volvulus DNA and RAR RNA suggested a possible trend toward higher relative RAR-α expression in samples with higher levels of O volvulus DNA (r2 = 0.25, P = .079). Evidence of a contribution of vitamin A to the pathology of onchocerciasis thus remains elusive. Future studies on the role of retinoids in onchocerciasis will require larger groups of participants as well as careful monitoring of the cold chain and tissue storage procedures in view of the sensitivity of vitamin A to heat and light. PMID:29317828

Retinoid Expression in Onchocercal Skin Disease: Pilot Study.

PubMed

Mawson, Anthony R; Makunde, Williams H; Penman, Alan D; Hernandez Morales, Veronica de Los Angeles; Kalinga, Akili K; Francis, Filbert; Rubinchik, Semyon; Kibweja, Addow

2017-01-01

Based on the observation that the parasite Onchocerca volvulus selectively absorbs vitamin A from the host, and the known toxicity of vitamin A in higher concentration, it was hypothesized that dying microfilariae (mf) release their stores of vitamin A (retinoids) into the host circulation in toxic concentrations, inducing the signs and symptoms of onchocerciasis. We conducted a pilot study to test the hypothesis in Songea communities in Southern Tanzania, where mass drug administration with ivermectin had not been implemented by the time of the survey. The specific aim was to evaluate the correlation between the diagnosis of onchocerciasis and increased levels of retinoic acid at infection sites. The analysis was performed by determining copy numbers of a genome of O volvulus present in skin snip samples of persons with onchocerciacis, and correlating these numbers with expression levels of retinoic acid receptor-α (RAR-α), which is inducible by retinoic acid. Total DNA and RNA were extracted from each of 25 mf-positive and 25 mf-negative skin samples and evaluated using quantitative polymerase chain reaction with appropriate negative controls. Analysis of the samples, adjusted with glyceraldehyde 3-phosphate dehydrogenase gene levels, revealed that most samples with detectable RAR-α transcripts had higher levels of RAR-α expression than the assay control. However, the quality and number of samples were insufficient for statistical analysis. Fold data on the expression levels of both O volvulus DNA and RAR RNA suggested a possible trend toward higher relative RAR-α expression in samples with higher levels of O volvulus DNA ( r 2  = 0.25, P  = .079). Evidence of a contribution of vitamin A to the pathology of onchocerciasis thus remains elusive. Future studies on the role of retinoids in onchocerciasis will require larger groups of participants as well as careful monitoring of the cold chain and tissue storage procedures in view of the sensitivity of vitamin A to heat and light.

Genetic characterization of tigecycline resistance in clinical isolates of Enterobacter cloacae and Enterobacter aerogenes.

PubMed

Veleba, Mark; De Majumdar, Shyamasree; Hornsey, Michael; Woodford, Neil; Schneiders, Thamarai

2013-05-01

The intrinsically encoded ramA gene has been linked to tigecycline resistance through the up-regulation of efflux pump AcrAB in Enterobacter cloacae. The molecular basis for increased ramA expression in E. cloacae and Enterobacter aerogenes, as well as the role of AraC regulator rarA, has not yet been shown. To ascertain the intrinsic molecular mechanism(s) involved in tigecycline resistance in Enterobacter spp., we analysed the expression levels of ramA and rarA and corresponding efflux pump genes acrAB and oqxAB in Enterobacter spp. clinical isolates. The expression levels of ramA, rarA, oqxA and acrA were tested by quantitative real-time RT-PCR. The ramR open reading frames of the ramA-overexpressing strains were sequenced; strains harbouring mutations were transformed with wild-type ramR to study altered ramA expression and tigecycline susceptibility. Tigecycline resistance was mediated primarily by increased ramA expression in E. cloacae and E. aerogenes. Only the ramA-overexpressing E. cloacae isolates showed increased rarA and oqxA expression. Upon complementation with wild-type ramR, all Enterobacter spp. containing ramR mutations exhibited decreased ramA and acrA expression and increased tigecycline susceptibility. Exceptions were one E. cloacae strain and one E. aerogenes strain, where a decrease in ramA levels was not accompanied by lower acrA expression. Increased ramA expression due to ramR deregulation is the primary mediator of tigecycline resistance in clinical isolates of E. cloacae and E. aerogenes. However, some ramA-overexpressing isolates do not show changes in ramR, suggesting alternate pathways of ramA regulation; the rarA regulator and the oqxAB efflux pump may also play a role in tigecycline resistance in E. cloacae.

Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients.

PubMed

Cassandrini, Denise; Cilio, Maria Roberta; Bianchi, Marzia; Doimo, Mara; Balestri, Martina; Tessa, Alessandra; Rizza, Teresa; Sartori, Geppo; Meschini, Maria Chiara; Nesti, Claudia; Tozzi, Giulia; Petruzzella, Vittoria; Piemonte, Fiorella; Bisceglia, Luigi; Bruno, Claudio; Dionisi-Vici, Carlo; D'Amico, Adele; Fattori, Fabiana; Carrozzo, Rosalba; Salviati, Leonardo; Santorelli, Filippo M; Bertini, Enrico

2013-01-01

Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed mutations in RARS2. All patients rapidly developed a neonatal or early-infantile epileptic encephalopathy with intractable seizures. The long-term follow-up revealed a virtual absence of psychomotor development, progressive microcephaly, and feeding difficulties. Mitochondrial respiratory chain enzymes in muscle and fibroblasts were normal in two. Blood and CSF lactate was abnormally elevated in all five patients at early stages while appearing only occasionally abnormal with the progression of the disease. Cerebellar vermis hypoplasia with normal aspect of the cerebral and cerebellar hemispheres appeared within the first months of life at brain MRI. In three patients follow-up neuroimaging revealed a progressive pontocerebellar and cerebral cortical atrophy. Molecular investigations of RARS2 disclosed the c.25A>G/p.I9V and the c.1586+3A>T in family A, the c.734G>A/p.R245Q and the c.1406G>A/p.R469H in family B, and the c.721T>A/p.W241R and c.35A>G/p.Q12R in family C. Functional complementation studies in Saccharomyces cerevisiae showed that mutation MSR1-R531H (equivalent to human p.R469H) abolished respiration whereas the MSR1-R306Q strain (corresponding to p.R245Q) displayed a reduced growth on non-fermentable YPG medium. Although mutations functionally disrupted yeast we found a relatively well preserved arginine aminoacylation of mitochondrial tRNA. Clinical and neuroimaging findings are important clues to raise suspicion and to reach diagnostic accuracy for RARS2 mutations considering that biochemical abnormalities may be absent in muscle biopsy.

Bayesian dose selection design for a binary outcome using restricted response adaptive randomization.

PubMed

Meinzer, Caitlyn; Martin, Renee; Suarez, Jose I

2017-09-08

In phase II trials, the most efficacious dose is usually not known. Moreover, given limited resources, it is difficult to robustly identify a dose while also testing for a signal of efficacy that would support a phase III trial. Recent designs have sought to be more efficient by exploring multiple doses through the use of adaptive strategies. However, the added flexibility may potentially increase the risk of making incorrect assumptions and reduce the total amount of information available across the dose range as a function of imbalanced sample size. To balance these challenges, a novel placebo-controlled design is presented in which a restricted Bayesian response adaptive randomization (RAR) is used to allocate a majority of subjects to the optimal dose of active drug, defined as the dose with the lowest probability of poor outcome. However, the allocation between subjects who receive active drug or placebo is held constant to retain the maximum possible power for a hypothesis test of overall efficacy comparing the optimal dose to placebo. The design properties and optimization of the design are presented in the context of a phase II trial for subarachnoid hemorrhage. For a fixed total sample size, a trade-off exists between the ability to select the optimal dose and the probability of rejecting the null hypothesis. This relationship is modified by the allocation ratio between active and control subjects, the choice of RAR algorithm, and the number of subjects allocated to an initial fixed allocation period. While a responsive RAR algorithm improves the ability to select the correct dose, there is an increased risk of assigning more subjects to a worse arm as a function of ephemeral trends in the data. A subarachnoid treatment trial is used to illustrate how this design can be customized for specific objectives and available data. Bayesian adaptive designs are a flexible approach to addressing multiple questions surrounding the optimal dose for treatment efficacy within the context of limited resources. While the design is general enough to apply to many situations, future work is needed to address interim analyses and the incorporation of models for dose response.

Distinct nuclear body components, PML and SMRT, regulate the trans-acting function of HTLV-1 Tax oncoprotein.

PubMed

Ariumi, Yasuo; Ego, Takeshi; Kaida, Atsushi; Matsumoto, Mikiko; Pandolfi, Pier Paolo; Shimotohno, Kunitada

2003-03-20

Several viruses target cellular promyelocytic leukemia (PML)-nuclear bodies (PML-NBs) to induce their disruption, marked morphological changes in these structures or the relocation to PML-NB components to the cytoplasm of infected cells. PML conversely interferes with viral replication. We demonstrate that PML acts as a coactivator for the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein without direct binding. Tax was identified within interchromatin granule clusters (IGCs)/RNA splicing bodies (SBs), not PML-NBs; Tax expression did not affect PML-NB formation. Moreover, PML and CBP/p300 cooperatively activated Tax-mediated HTLV-1-LTR-dependent gene expression. Interestingly, two PML mutants, PML-RAR and PMLDelta216-331, which fail to form PML-NBs, could also coactivate Tax-mediated trans-acting function but had no effect on retinoic acid receptor (RAR)- or p53-dependent gene expression. In contrast, SMRT (silencing mediator for retinoic acid and thyroid hormone receptors), a nuclear corepressor found within the matrix-associated deacetylase (MAD) nuclear body, relocalized into Tax-associated nuclear bodies upon coexpression with Tax. SMRT coactivated the trans-acting function of Tax through direct binding. Coexpression of SMRT and PML resulted in an additive activation of Tax trans-acting function. Thus, crosstalk between distinct nuclear bodies may control Tax function.

Accretion disks around neutron and strange stars in R+aR2 gravity

NASA Astrophysics Data System (ADS)

Staykov, Kalin V.; Doneva, Daniela D.; Yazadjiev, Stoytcho S.

2016-08-01

We study the electromagnetic spectrum of accretion disks around neutron and strange stars in R+aR2 gravity. Both static and rapidly rotating models are investigated. The results are compared with the General Relativistic results. We found difference between the results in both theories of about 50% for the electromagnetic flux and about 20% in the luminosity for models with equal mass and angular velocity in both theories. The observed differences are much lower for models rotating with Keplerian velocity and with equal masses.

Estimation of Streamflow Characteristics for Charles M. Russell National Wildlife Refuge, Northeastern Montana

USGS Publications Warehouse

Sando, Steven K.; Morgan, Timothy J.; Dutton, DeAnn M.; McCarthy, Peter M.

2009-01-01

Charles M. Russell National Wildlife Refuge (CMR) encompasses about 1.1 million acres (including Fort Peck Reservoir on the Missouri River) in northeastern Montana. To ensure that sufficient streamflow remains in the tributary streams to maintain the riparian corridors, the U.S. Fish and Wildlife Service is negotiating water-rights issues with the Reserved Water Rights Compact Commission of Montana. The U.S. Geological Survey, in cooperation with the U.S. Fish and Wildlife Service, conducted a study to gage, for a short period, selected streams that cross CMR, and analyze data to estimate long-term streamflow characteristics for CMR. The long-term streamflow characteristics of primary interest include the monthly and annual 90-, 80-, 50-, and 20-percent exceedance streamflows and mean streamflows (Q.90, Q.80, Q.50, Q.20, and QM, respectively), and the 1.5-, 2-, and 2.33- year peak flows (PK1.5, PK2, and PK2.33, respectively). The Regional Adjustment Relationship (RAR) was investigated for estimating the monthly and annual Q.90, Q.80, Q.50, Q.20, and QM, and the PK1.5, PK2, and PK2.33 for the short-term CMR gaging stations (hereinafter referred to as CMR stations). The RAR was determined to provide acceptable results for estimating the long-term Q.90, Q.80, Q.50, Q.20, and QM on a monthly basis for the months of March through June, and also on an annual basis. For the months of September through January, the RAR regression equations did not provide acceptable results for any long-term streamflow characteristic. For the month of February, the RAR regression equations provided acceptable results for the long-term Q.50 and QM, but poor results for the long-term Q.90, Q.80, and Q.20. For the months of July and August, the RAR provided acceptable results for the long-term Q.50, Q.20, and QM, but poor results for the long-term Q.90 and Q.80. Estimation coefficients were developed for estimating the long-term streamflow characteristics for which the RAR did not provide acceptable results. The RAR also was determined to provide acceptable results for estimating the PK1.5., PK2, and PK2.33 for the three CMR stations that lacked suitable peak-flow records. Methods for estimating streamflow characteristics at ungaged sites also were derived. Regression analyses that relate individual streamflow characteristics to various basin and climatic characteristics for gaging stations were performed to develop regression equations to estimate streamflow characteristics at ungaged sites. Final equations for the annual Q.50, Q.20, and QM are reported. Acceptable equations also were developed for estimating QM for the months of February, March, April, June, and July, and Q.50, Q.20, and QM on an annual basis. However, equations for QM for the months of February, March, April, June, and July were determined to be less consistent and reliable than the use of estimation coefficients applied to the regression equation results for the annual QM. Acceptable regression equations also were developed for the PK1.5, PK2, and PK2.33.

Effects of rumenic acid rich conjugated linoleic acid supplementation on cognitive function and handgrip performance in older men and women.

PubMed

Jenkins, Nathaniel D M; Housh, Terry J; Miramonti, Amelia A; McKay, Brianna D; Yeo, Noelle M; Smith, Cory M; Hill, Ethan C; Cochrane, Kristen C; Cramer, Joel T

2016-11-01

The purpose of this study was to investigate the effects of 8weeks at 6g per day of RAR CLA versus placebo on cognitive function and handgrip performance in older men and women. Sixty-five (43 women, 22 men) participants (mean±SD; age=72.4±5.9yrs; BMI=26.6±4.2kg·m -2 ) were randomly assigned to a RAR CLA (n=30: 10 men, 20 women) or placebo (PLA; high oleic sunflower oil; n=35: 12 men, 23 women) group in double-blind fashion and consumed 6g·d -1 of their allocated supplement for 8weeks. Before (Visit 1) and after supplementation (Visit 2), subjects completed the Serial Sevens Subtraction Test (S 7 ), Trail Making Test Part A (TM A ) and Part B (TM B ), and Rey's Auditory Verbal Learning Test (RAVLT) to measure cognitive function. The RAVLT included 5, 15-item auditory word recalls (R 1-5 ), an interference word recall (R B ), a 6th word recall (R 6 ), and a 15-item visual word recognition trial (R R ). For handgrip performance, subjects completed maximal voluntary isometric handgrip strength (MVIC) testing before (MVIC PRE ) and after (MVIC POST ) a handgrip fatigue test at 50% MVIC PRE . Hand joint discomfort was measured during MVIC PRE , MVIC POST , and the handgrip fatigue test. There were no treatment differences (p>0.05) for handgrip strength, handgrip fatigue, or cognitive function as measured by the Trail Making Test and Serial Seven's Subtraction Test in men or women. However, RAR CLA supplementation improved cognitive function as indicated by the RAVLT R 5 in men. A qualitative examination of the mean change scores suggested that, compared to PLA, RAR CLA supplementation was associated with a small improvement in joint discomfort in both men and women. Longer-term studies are needed to more fully understand the potential impact of RAR CLA on cognitive function and hand joint discomfort in older adults, particularly in those with lower cognitive function. Copyright © 2016 Elsevier Inc. All rights reserved.

Arsenic as an endocrine disruptor: arsenic disrupts retinoic acid receptor-and thyroid hormone receptor-mediated gene regulation and thyroid hormone-mediated amphibian tail metamorphosis.

PubMed

Davey, Jennifer C; Nomikos, Athena P; Wungjiranirun, Manida; Sherman, Jenna R; Ingram, Liam; Batki, Cavus; Lariviere, Jean P; Hamilton, Joshua W

2008-02-01

Chronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors. The goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation. Human embryonic NT2 or rat pituitary GH3 cells were treated with 0.01-5 microM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element-luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element-luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1- 4.0 microM As. As had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult function and their dysregulation is associated with many disease processes, disruption of these hormone receptor-dependent processes by As is also potentially relevant to human developmental problems and disease risk.

Third Party Involvement in International Terrorist Extortion

DTIC Science & Technology

1976-03-01

wide audience to view the event . Because publicity is considered to be among the primary purposes of terrorism, a scale for measuring publicity was...with Palestineans, rank among the top four groups in total publicity generated. Their activities not only shocked their world-wide audience , but also...907 McKee-Tesca Company Saf rar-Peugeot Pepsi -Cola 902 903 904 908 909 9-*-0 Mercedes Benz Motor Company 911 912 913 914 Northwest Airlines Braniff

Biologic characteristics of 164 patients with myelodysplastic syndromes.

PubMed

Reza, S; Dar, S; Andric, T; Qawi, H; Mundle, S; Shetty, V; Venugopal, P; Ali, I; Lisak, L; Raza, A

1999-04-01

Rates of proliferation, apoptosis and cytokine expression were measured in bone marrow (BM) biopsies of 164 myelodysplastic syndrome (MDS) patients. There were 107 males and 57 females. Median age was 69 years and 101 had refractory anemia (RA), 17 RA with ringed sideroblasts (RARS), 38 with RA and excess blasts (RAEB) and 8 with RAEB in transformation (RAEB-t). Apoptosis measured by in-situ end labeling (ISEL) was directly related to the number of macrophages (p = 0.028, n = 83). Mean tumor necrosis factor alpha (TNF-alpha) and ISEL positivity were higher in RAEB + RAEB-t patients (p = 0.0554 and p = 0.06 respectively) while hemoglobin was higher for RA + RARS group (p = 0.0472). Patients with high apoptosis had lower white blood cell counts (p = 0.0009), lower percentage of blasts (p = 0.0009) and higher number of macrophages (p = 0.0086). We conclude that measurements of apoptosis, proliferation and cytokine expression provide important biological information which helps to distinguish RA + RARS patients from RAEB + RAEB-t patients, and may be of additive prognostic significance.

Suppressive role of OGT-mediated O-GlcNAcylation of BAP1 in retinoic acid signaling.

PubMed

Moon, Seungtae; Lee, Yong-Kyu; Lee, Sang-Wang; Um, Soo-Jong

2017-10-07

BRCA1-associated protein 1 (BAP1) has been implicated in diverse biological functions, including tumor suppression. However, its regulation via glycosylation and its role in embryonic stem (ES) cells are poorly defined. BAP1 was recently reported to interact with O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). Here, we confirmed the physical interaction and investigated its functional significance. The O-GlcNAcylation of BAP1, which requires OGT, was examined in vivo and in vitro, and was proven using alloxan, an OGT inhibitor. OGT promoted the BAP1-induced repression of retinoic acid (RA)-induced RA receptor (RAR) activation. The repressive activity of BAP1 was relieved by alloxan but exacerbated by PUGNAc, an O-GlcNAcase (OGA) inhibitor. Finally, we addressed the role of O-GlcNAcylation in the RA-induced differentiation of murine ES cells. Alkaline phosphatase staining revealed the cooperation of RA and alloxan for impairing the pluripotency of ES cells. This cooperation was also observed by measuring the size of embryonic bodies and the expression of Sox2, a pluripotency marker. Overall, our data suggest that OGT-mediated O-GlcNAcylation of BAP1 prefers the maintenance of pluripotency, whereas its inhibition facilitates RA-induced differentiation in ES cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

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

Huai, Lei; Wang, Cuicui; Zhang, Cuiping

2012-06-08

Highlights: Black-Right-Pointing-Pointer Metformin induces differentiation in NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces activation of the MEK/ERK signaling pathway in APL cells. Black-Right-Pointing-Pointer Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces the relocalization and degradation of the PML-RAR{alpha} fusion protein. Black-Right-Pointing-Pointer The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acutemore » promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RAR{alpha} and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.« less

Age-related change in the retinoid X receptor beta gene expression in peripheral blood mononuclear cells of healthy volunteers: effect of 13-cis retinoic acid supplementation.

PubMed

Brtko, J; Rock, E; Nezbedova, P; Krizanova, O; Dvorcakova, M; Minet-Quinard, R; Farges, M-C; Ribalta, J; Winklhofer-Roob, B M; Vasson, M-P; Macejova, D

2007-01-01

The regulation of cell growth and differentiation and also expression of a number of genes by retinoids are mediated by nuclear retinoid receptors (RARs and/or RXRs). In this study we investigated age-related alteration in both RAR and RXR receptor subtypes gene expression and tissue transglutaminase (tTG) activity before and after supplementation with 13-cis retinoic acid (13cRA) in human peripheral blood mononuclear cells (PBMCs). Healthy men (40) were divided in two groups according to their age (young group: 26.1+/-4.1 years and old group: 65.4+/-3.8 years). Each volunteer received 13cRA (Curacné), 0.5mg/(kgday)) during a period of 4 weeks. We have shown that RXRbeta expression was decreased significantly (p=0.0108) in PBMCs of elderly men when compared to that of young volunteers. Distribution of retinoic acid receptor subtype expression in PBMCs was found in the order: RXRbeta>RARgamma>RXRalpha>RARalpha. The tTG activity in PBMCs reflected a trend to be enhanced after 13-cis retinoic acid supplementation. In conclusion, we demonstrate a significant decrease in the expression of RXRbeta subtype of rexinoid receptors in PBMCs of healthy elderly men. Our data suggest that in healthy elderly men reduction of RXRbeta expression in PBMCs might be a common feature of physiological senescence.

Assessments of direct human exposure: the approach of EU risk assessments compared to scenario-based risk assessment.

PubMed

Wormuth, Matthias; Demou, Evangelia; Scheringer, Martin; Hungerbühler, Konrad

2007-08-01

The awareness of potential risks emerging from the use of chemicals in all parts of daily life has increased the need for risk assessments that are able to cover a high number of exposure situations and thereby ensure the safety of workers and consumers. In the European Union (EU), the practice of risk assessments for chemicals is laid down in a Technical Guidance Document; it is designed to consider environmental and human occupational and residential exposure. Almost 70 EU risk assessment reports (RARs) have been finalized for high-production-volume chemicals during the last decade. In the present study, we analyze the assessment of occupational and consumer exposure to trichloroethylene and phthalates presented in six EU RARs. Exposure scenarios in these six RARs were compared to scenarios used in applications of the scenario-based risk assessment approach to the same set of chemicals. We find that scenarios used in the selected EU RARs to represent typical exposure situations in occupational or private use of chemicals and products do not necessarily represent worst-case conditions. This can be due to the use of outdated information on technical equipment and conditions in workplaces or omission of pathways that can cause consumer exposure. Considering the need for exposure and risk assessments under the new chemicals legislation of the EU, we suggest that a transparent process of collecting data on exposure situations and of generating representative exposure scenarios is implemented to improve the accuracy of risk assessments. Also, the data sets used to assess human exposure should be harmonized, summarized in a transparent fashion, and made accessible for all risk assessors and the public.

Retinoic acid reduces chemotherapy-induced neuropathy in an animal model and patients with lung cancer

PubMed Central

Hernández-Pedro, N.; Fernández-González- Aragón, M.C.; Saavedra-Pérez, D.; Campos-Parra, A.D.; Ríos-Trejo, M.Á.; Cerón-Lizárraga, T.; Martínez-Barrera, L.; Pineda, B.; Ordóñez, G.; Ortiz-Plata, A.; Granados-Soto, V.; Sotelo, J.

2011-01-01

Objective: To evaluate the effect of all-trans retinoic acid (ATRA) as treatment for chemotherapy-induced peripheral neuropathy in an experimental animal model and in a randomized, double-blinded, controlled trial in patients with non-small-cell lung cancer (NSCLC). Methods: Forty male Wistar rats were randomized in 5 groups: group A, control; groups B and C, treated with cisplatin; and groups D and E, treated with paclitaxel. ATRA (20 mg/kg PO) was administered for 15 days in groups C and E. We evaluated neuropathy and nerve regeneration–related morphologic changes in sciatic nerve, the concentration of nerve growth factor (NGF), and retinoic acid receptor (RAR)–α and RAR-β expression. In addition, 95 patients with NSCLC under chemotherapy treatment were randomized to either ATRA (20 mg/m2/d) or placebo. Serum NGF, neurophysiologic tests, and clinical neurotoxicity were assessed. Results: The experimental animals developed neuropathy and axonal degeneration, associated with decreased NGF levels in peripheral nerves. Treatment with ATRA reversed sensorial changes and nerve morphology; this was associated with increased NGF levels and RAR-β expression. Patients treated with chemotherapy had clinical neuropathy and axonal loss assessed by neurophysiology, which was related to decreased NGF levels. ATRA reduced axonal degeneration demonstrated by nerve conduction velocity and clinical manifestations of neuropathy grades ≥2. Conclusions: ATRA reduced chemotherapy-induced experimental neuropathy, increased NGF levels, and induced RAR-β expression in nerve. In patients, reduction of NGF in serum was associated with the severity of neuropathy; ATRA treatment reduced the electrophysiologic alterations. Classification of evidence: This study provides Class II evidence that ATRA improves nerve conduction in patients with chemotherapy-induced peripheral neuropathy. Neurology® 2011;77:987–995 PMID:21865574

Retinoic acid signaling is dispensable for somatic development and function in the mammalian ovary.

PubMed

Minkina, Anna; Lindeman, Robin E; Gearhart, Micah D; Chassot, Anne-Amandine; Chaboissier, Marie-Christine; Ghyselinck, Norbert B; Bardwell, Vivian J; Zarkower, David

2017-04-15

Retinoic acid (RA) is a potent inducer of cell differentiation and plays an essential role in sex-specific germ cell development in the mammalian gonad. RA is essential for male gametogenesis and hence fertility. However, RA can also disrupt sexual cell fate in somatic cells of the testis, promoting transdifferentiation of male Sertoli cells to female granulosa-like cells when the male sexual regulator Dmrt1 is absent. The feminizing ability of RA in the Dmrt1 mutant somatic testis suggests that RA might normally play a role in somatic cell differentiation or cell fate maintenance in the ovary. To test for this possibility we disrupted RA signaling in somatic cells of the early fetal ovary using three genetic strategies and one pharmaceutical approach. We found that deleting all three RA receptors (RARs) in the XX somatic gonad at the time of sex determination did not significantly affect ovarian differentiation, follicle development, or female fertility. Transcriptome analysis of adult triple mutant ovaries revealed remarkably little effect on gene expression in the absence of somatic RAR function. Likewise, deletion of three RA synthesis enzymes (Aldh1a1-3) at the time of sex determination did not masculinize the ovary. A dominant-negative RAR transgene altered granulosa cell proliferation, likely due to interference with a non-RA signaling pathway, but did not prevent granulosa cell specification and oogenesis or abolish fertility. Finally, culture of fetal XX gonads with an RAR antagonist blocked germ cell meiotic initiation but did not disrupt sex-biased gene expression. We conclude that RA signaling, although crucial in the ovary for meiotic initiation, is not required for granulosa cell specification, differentiation, or reproductive function. Copyright © 2017 Elsevier Inc. All rights reserved.

Tissue specific expression of the retinoic acid receptor-beta 2: regulation by short open reading frames in the 5'-noncoding region

PubMed Central

1994-01-01

The 40-S subunit of eukaryotic ribosomes binds to the capped 5'-end of mRNA and scans for the first AUG in a favorable sequence context to initiate translation. Most eukaryotic mRNAs therefore have a short 5'- untranslated region (5'-UTR) and no AUGs upstream of the translational start site; features that seem to assure efficient translation. However, approximately 5-10% of all eukaryotic mRNAs, particularly those encoding for regulatory proteins, have complex leader sequences that seem to compromise translational initiation. The retinoic-acid- receptor-beta 2 (RAR beta 2) mRNA is such a transcript with a long (461 nucleotides) 5'-UTR that contains five, partially overlapping, upstream open reading frames (uORFs) that precede the major ORF. We have begun to investigate the function of this complex 5'-UTR in transgenic mice, by introducing mutations in the start/stop codons of the uORFs in RAR beta 2-lacZ reporter constructs. When we compared the expression patterns of mutant and wild-type constructs we found that these mutations affected expression of the downstream RAR beta 2-ORF, resulting in an altered regulation of RAR beta 2-lacZ expression in heart and brain. Other tissues were unaffected. RNA analysis of adult tissues demonstrated that the uORFs act at the level of translation; adult brains and hearts of transgenic mice carrying a construct with either the wild-type or a mutant UTR, had the same levels of mRNA, but only the mutant produced protein. Our study outlines an unexpected role for uORFs: control of tissue-specific and developmentally regulated gene expression. PMID:7962071

Lack of Correlation between Aberrant p16, RAR-β2, TIMP3, ERCC1, and BRCA1 Protein Expression and Promoter Methylation in Squamous Cell Carcinoma Accompanying Candida albicans-Induced Inflammation

PubMed Central

Terayama, Yui; Matsuura, Tetsuro; Ozaki, Kiyokazu

2016-01-01

Hyperplastic candidiasis is characterized by thickening of the mucosal epithelia with Candida albicans infection with occasional progression to squamous cell carcinoma (SCC). C. albicans is a critical factor in tumor development; however, the oncogenic mechanism is unclear. We have previously produced an animal model for hyperplastic candidiasis in the rat forestomach. In the present study, we investigate whether impaired DNA methylation and associated protein expression of tumor suppressor and DNA repair genes are involved in the SCC carcinogenesis process using this hyperplastic candidiasis model. Promoter methylation and protein expression were analyzed by methylation specific PCR and immunohistochemical staining, respectively, of 5 areas in the forestomachs of alloxan-induced diabetic rats with hyperplastic candidiasis: normal squamous epithelia, squamous hyperplasia, squamous hyperplasia adjacent to SCC, squamous hyperplasia transitioning to SCC, and SCC. We observed nuclear p16 overexpression despite increases in p16 gene promoter methylation during the carcinogenic process. TIMP3 and RAR-β2 promoter methylation progressed until the precancerous stage but disappeared upon malignant transformation. In comparison, TIMP3 protein expression was suppressed during carcinogenesis and RAR-β2 expression was attenuated in the cytoplasm but enhanced in nuclei. ERCC1 and BRCA1 promoters were not methylated at any stage; however, their protein expression disappeared beginning at hyperplasia and nuclear protein re-expression in SCC was observed only for ERCC1. These results suggest that aberrant p16, RAR-β2, TIMP3, ERCC1, and BRCA1 expression might occur that is inconsistent with the respective gene promoter methylation status, and that this overexpression might serve to promote the inflammatory carcinogenesis caused by C. albicans infection. PMID:27410681

Alterations of the tunica vasculosa lentis in the rat model of retinopathy of prematurity.

PubMed

Favazza, Tara L; Tanimoto, Naoyuki; Munro, Robert J; Beck, Susanne C; Garcia Garrido, Marina; Seide, Christina; Sothilingam, Vithiyanjali; Hansen, Ronald M; Fulton, Anne B; Seeliger, Mathias W; Akula, James D

2013-08-01

To study the relationship between retinal and tunica vasculosa lentis (TVL) disease in retinopathy of prematurity (ROP). Although the clinical hallmark of ROP is abnormal retinal blood vessels, the vessels of the anterior segment, including the TVL, are also altered. ROP was induced in Long-Evans pigmented and Sprague Dawley albino rats; room-air-reared (RAR) rats served as controls. Then, fluorescein angiographic images of the TVL and retinal vessels were serially obtained with a scanning laser ophthalmoscope near the height of retinal vascular disease, ~20 days of age, and again at 30 and 64 days of age. Additionally, electroretinograms (ERGs) were obtained prior to the first imaging session. The TVL images were analyzed for percent coverage of the posterior lens. The tortuosity of the retinal arterioles was determined using Retinal Image multiScale Analysis (Gelman et al. in Invest Ophthalmol Vis Sci 46:4734-4738, 2005). In the youngest ROP rats, the TVL was dense, while in RAR rats, it was relatively sparse. By 30 days, the TVL in RAR rats had almost fully regressed, while in ROP rats, it was still pronounced. By the final test age, the TVL had completely regressed in both ROP and RAR rats. In parallel, the tortuous retinal arterioles in ROP rats resolved with increasing age. ERG components indicating postreceptoral dysfunction, the b-wave, and oscillatory potentials were attenuated in ROP rats. These findings underscore the retinal vascular abnormalities and, for the first time, show abnormal anterior segment vasculature in the rat model of ROP. There is delayed regression of the TVL in the rat model of ROP. This demonstrates that ROP is a disease of the whole eye.

Alterations of the Tunica Vasculosa Lentis in the Rat Model of Retinopathy of Prematurity

PubMed Central

Favazza, Tara L; Tanimoto, Naoyuki; Munro, Robert J.; Beck, Susanne C.; Garrido, Marina G.; Seide, Christina; Sothilingam, Vithiyanjali; Hansen, Ronald M.; Fulton, Anne B.; Seeliger, Mathias W.; Akula, James D

2013-01-01

Purpose To study the relation between retinal and tunica vasculosa lentis (TVL) disease in ROP. Although the clinical hallmark of retinopathy of prematurity (ROP) is abnormal retinal blood vessels, the vessels of the anterior segment, including the TVL, are also altered. Methods ROP was induced in Long Evans pigmented and Sprague-Dawley albino rats; room-air-reared (RAR) rats served as controls. Then, fluorescein angiographic images of the TVL and retinal vessels were serially obtained with a scanning laser ophthalmoscope (SLO) near the height of retinal vascular disease, ∼20 days-of-age, and again at 30 and 64 days-of-age. Additionally, electroretinograms (ERGs) were obtained prior to the first imaging session. The TVL images were analyzed for percent coverage of the posterior lens. The tortuosity of the retinal arterioles was determined using Retinal Image multiScale Analysis (RISA; Gelman et al., 2005). Results In the youngest ROP rats, the TVL was dense, while in RAR rats, it was relatively sparse. By 30 days, the TVL in RAR rats had almost fully regressed, while in ROP rats it was still pronounced. By the final test age, the TVL had completely regressed in both ROP and RAR rats. In parallel, the tortuous retinal arterioles in ROP rats resolved with increasing age. ERG components indicating postreceptoral dysfunction, the b-wave and oscillatory potentials (OPs), were attenuated in ROP rats. Conclusions These findings underscore the retinal vascular abnormalities and, for the first time, show abnormal anterior segment vasculature in the rat model of ROP. There is delayed regression of the TVL in the rat model of ROP. This demonstrates that ROP is a disease of the whole eye. PMID:23748796

Genetic characterisation of tigecycline-resistant Enterobacter spp. in blood isolates causing bacteraemia.

PubMed

Cha, Min Kyeong; Kang, Cheol-In; Park, Ga Eun; Kim, So Hyun; Chung, Doo Ryeon; Peck, Kyong Ran; Song, Jae-Hoon

2018-01-05

Tigecycline (TIG) is one of the most important antimicrobial agents used to treat infections by multidrug-resistant bacteria. However, rates of TIG-resistant pathogens have increased recently. This study was conducted to identify the antimicrobial susceptibility profiles and to investigate the role of efflux pumps in high-level TIG-resistant Enterobacter spp. isolates causing bacteraemia. A total of 323 Enterobacter spp. causing bacteraemia were collected from eight hospitals in various regions of South Korea. Minimum inhibitory concentrations (MICs) were determined by the broth microdilution method and Etest. Expression levels of the efflux pump gene acrA and its regulators (ramA and rarA) were examined by quantitative real-time PCR. Isolate relatedness was determined by multilocus sequence typing (MLST). Among the 323 clinical isolates included in this study, 37 (11.5%) were TIG-non-susceptible, of which 8 isolates were highly resistant to TIG with MICs of 8mg/L (4 isolates) or 16mg/L (4 isolates). All high-level TIG-resistant isolates showed increased expression of acrA (0.93-13.3-fold) and ramA (1.4-8.2-fold). Isolates with a tigecycline MIC of 16mg/L also showed overexpression of rarA compared with TIG-susceptible isolates. In this study, overexpression of acrA, ramA and rarA was observed in high-level TIG-resistant Enterobacter spp. isolates. We suggest that rarA might be involved in the regulation of acrA overexpression in high-level TIG-resistant Enterobacter spp. isolates. Efflux pump-mediated resistance should be closely monitored because it could be indirectly attributed to the use of other antibiotics transported by the same efflux pump. Copyright © 2017. Published by Elsevier Ltd.

Administration of recombinant human granulocyte-colony-stimulating factor does not induce long-lasting detectable epigenetic alterations in healthy donors.

PubMed

Leitner, Gerda C; Faschingbauer, Martin; Wenda, Sabine; Weigel, Günter; Fischer, Gottfried

2014-12-01

The short-term safety profile of recombinant human granulocyte-colony-stimulating factor (rHuG-CSF) in the allogeneic stem cell setting seems acceptable; only few data on long-term safety are available. To further study possible epigenetic alterations, we investigated prospectively the influence of rHuG-CSF on DNA methyltransferase (DNMT) activity and on changes in DNA methylation of candidate genes in peripheral blood cells of healthy unrelated stem cell donors within an observation period of 1 year. In this study, 20 stem cell donors (14 male/six female; median age, 40 years; range, 22-54 years) and 20 sex- and age-matched blood component donors (controls) were included. Sampling was performed before rHuG-CSF administration; at the time of donation; and on Days (+1), 7, 30, 100, 180, and 360 in both groups. Analysis of DNMT activity in nuclear extracts was performed using a modified radionuclide assay. We performed methylation-specific polymerase chain reaction to detect the methylation status of promoter CpG islands of the genes of the retinoic acid receptor beta (RAR-B) and the Ras association domain family 1A (RASSF1A). DNMT activity increased significantly on the day of donation and 1 day after (p < 0.05). By Day +7 baseline values were reached. No further significant alterations of DNMT activity in the treated group compared to the controls were observed. We could not detect any differences in the gene methylation of RAR-B and RASSF1A between both groups. In our prospective study no evidence of long-lasting increased DNMT activity or enhanced DNA methylation in a limited panel of target genes after recombinant human G-CSF administration was observed in healthy stem cell donors. © 2014 AABB.

Enhancement of caffeic acid phenethyl ester on all-trans retinoic acid-induced differentiation in human leukemia HL-60 cells

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

Kuo, H.-C.; Kuo, W.-H.; Lee, Y.-J.

2006-10-01

All-trans retinoic acid (ATRA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL); however, the response is sometimes very slow. Furthermore, relapse and resistance to treatment often occur despite continued treatment with ATRA. Thereafter, combination treatment strategies have been suggested to circumvent these problems. The present study demonstrates that caffeic acid phenethyl ester (CAPE), a major component of honeybee propolis, enhanced ATRA-induced granulocytic differentiation in HL-60, a human promyelocytic cell line. The differentiation was assessed by Wright-Giemsa stain, nitroblue tetrazolium reduction, and membrane differentiation marker CD11b. In addition, CAPE enhanced ATRA-induced cell cycle arrest atmore » the G1 phase by decreasing the association of cdk2-cyclin E complex. Finally, it was demonstrated that CAPE promoted the ATRA-mediated nuclear transcription activation of RAR{alpha} assessed by EMSA assay and enhanced the expression of target genes including RAR{alpha}, C/EBP{epsilon}, and p21 protein resulting in the differentiation development of leukemia. It is suggested that CAPE possesses the potential to enhance the efficiency of ATRA in the differentiation therapy of APL.« less

Inverse Kinematics for Upper Limb Compound Movement Estimation in Exoskeleton-Assisted Rehabilitation.

PubMed

Cortés, Camilo; de Los Reyes-Guzmán, Ana; Scorza, Davide; Bertelsen, Álvaro; Carrasco, Eduardo; Gil-Agudo, Ángel; Ruiz-Salguero, Oscar; Flórez, Julián

2016-01-01

Robot-Assisted Rehabilitation (RAR) is relevant for treating patients affected by nervous system injuries (e.g., stroke and spinal cord injury). The accurate estimation of the joint angles of the patient limbs in RAR is critical to assess the patient improvement. The economical prevalent method to estimate the patient posture in Exoskeleton-based RAR is to approximate the limb joint angles with the ones of the Exoskeleton. This approximation is rough since their kinematic structures differ. Motion capture systems (MOCAPs) can improve the estimations, at the expenses of a considerable overload of the therapy setup. Alternatively, the Extended Inverse Kinematics Posture Estimation (EIKPE) computational method models the limb and Exoskeleton as differing parallel kinematic chains. EIKPE has been tested with single DOF movements of the wrist and elbow joints. This paper presents the assessment of EIKPE with elbow-shoulder compound movements (i.e., object prehension). Ground-truth for estimation assessment is obtained from an optical MOCAP (not intended for the treatment stage). The assessment shows EIKPE rendering a good numerical approximation of the actual posture during the compound movement execution, especially for the shoulder joint angles. This work opens the horizon for clinical studies with patient groups, Exoskeleton models, and movements types.

Regeneration of the gut requires retinoic acid in the budding ascidian Polyandrocarpa misakiensis.

PubMed

Kaneko, Nagamoto; Katsuyama, You; Kawamura, Kazuo; Fujiwara, Shigeki

2010-06-01

The protochordate ascidian Polyandrocarpa misakiensis has a striking ability to regenerate. When the posterior half of the adult body is amputated, the anterior half completely loses the esophagus, stomach and intestine. These organs are reconstituted in a week. Histological observation revealed that the regeneration involves transdifferentiation of the atrial epithelium near the cut surface. The morphological features of the gut primordium were similar to those observed in the developing bud of this species. Inhibitors of the synthesis of retinoic acid (RA) suppressed the formation of the gut. 13-cis RA rescued the regenerates from the inhibitor-induced hypoplasia. These results suggest that RA is required for the regeneration of the gut. A gene encoding the RA receptor (Pm-RAR) and its target gene, TRAMP, were expressed in and around the regenerating gut. Pm-RAR-specific and TRAMP-specific double-stranded RNA molecules inhibited the regeneration of the gut, indicating that the RA signal is mediated at least in part by Pm-RAR and TRAMP. These results suggested that RA triggers the transdifferentiation of the atrial epithelium into the gut in regenerating animals, as it does during asexual reproduction.

Effects of retinoic acids on the dendritic morphology of cultured hippocampal neurons.

PubMed

Liu, Ying; Kagechika, Hiroyuki; Ishikawa, Junko; Hirano, Hitoshi; Matsukuma, Satoshi; Tanaka, Kazuko; Nakamura, Shoji

2008-08-01

Vitamin A-derived retinoic acids (RAs) are known to exert a variety of biological actions, including modulatory effects on cell differentiation and apoptosis. A recent study has demonstrated that 13-cis-RA and all-trans-RA suppressed neurogenesis in the dentate gyrus of the hippocampus in adult mice. The present experiments were performed to see whether 13-cis-RA and all-trans-RA could alter the dendritic morphology of cultured hippocampal neurons via RA receptors: retinoic acid receptor (RAR) and retinoid X receptor (RXR). High doses of 13-cis-RA and all-trans-RA exerted a negative effect on the cultured hippocampal neurons, while a low dose of 13-cis-RA but not all-trans-RA caused a positive effect. The negative changes induced by 13-cis-RA and all-trans-RA were antagonized by RXR antagonists and RAR antagonists, respectively. The positive changes induced by a low dose of 13-cis-RA were blocked by both RXR antagonists and RAR antagonists. These results suggest that RAs at high concentrations cause a negative effect on the dendritic morphology of cultured hippocampal neurons through RA receptors, while RAs at low concentrations exert a positive influence on cultured hippocampal neurons.

Optical Enhancement of Exoskeleton-Based Estimation of Glenohumeral Angles

PubMed Central

Cortés, Camilo; Unzueta, Luis; de los Reyes-Guzmán, Ana; Ruiz, Oscar E.; Flórez, Julián

2016-01-01

In Robot-Assisted Rehabilitation (RAR) the accurate estimation of the patient limb joint angles is critical for assessing therapy efficacy. In RAR, the use of classic motion capture systems (MOCAPs) (e.g., optical and electromagnetic) to estimate the Glenohumeral (GH) joint angles is hindered by the exoskeleton body, which causes occlusions and magnetic disturbances. Moreover, the exoskeleton posture does not accurately reflect limb posture, as their kinematic models differ. To address the said limitations in posture estimation, we propose installing the cameras of an optical marker-based MOCAP in the rehabilitation exoskeleton. Then, the GH joint angles are estimated by combining the estimated marker poses and exoskeleton Forward Kinematics. Such hybrid system prevents problems related to marker occlusions, reduced camera detection volume, and imprecise joint angle estimation due to the kinematic mismatch of the patient and exoskeleton models. This paper presents the formulation, simulation, and accuracy quantification of the proposed method with simulated human movements. In addition, a sensitivity analysis of the method accuracy to marker position estimation errors, due to system calibration errors and marker drifts, has been carried out. The results show that, even with significant errors in the marker position estimation, method accuracy is adequate for RAR. PMID:27403044

Arsenic as an Endocrine Disruptor: Arsenic Disrupts Retinoic Acid Receptor–and Thyroid Hormone Receptor–Mediated Gene Regulation and Thyroid Hormone–Mediated Amphibian Tail Metamorphosis

PubMed Central

Davey, Jennifer C.; Nomikos, Athena P.; Wungjiranirun, Manida; Sherman, Jenna R.; Ingram, Liam; Batki, Cavus; Lariviere, Jean P.; Hamilton, Joshua W.

2008-01-01

Background Chronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors. Objectives The goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation. Methods and results Human embryonic NT2 or rat pituitary GH3 cells were treated with 0.01–5 μM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element–luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element–luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1– 4.0 μM As. Conclusions As had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult function and their dysregulation is associated with many disease processes, disruption of these hormone receptor–dependent processes by As is also potentially relevant to human developmental problems and disease risk. PMID:18288313

Gene Regulation by Retinoid Receptors in Human Mammary Epithelial Cells

DTIC Science & Technology

2002-10-01

ceptors for collagen and fibronectin in human fibrosarcoma cells possessing Xia, Y-, S.G. Gil, and W.G. Carter. 1996. Anchorage mediated by integrin...simultaneously block all TdT terminal deoxynucleotidyl transferase pRB retinoblastoma protein wild-type RAR isoforms (-o, -P, and -- ) (Damm et CAT ...P0 pM treated with 0, 0,1, 1.0, or 10 jIM ATRA for 24 hours and cell lysates were assayed for CAT reporter activity. pCMV-GH was used as a transfection

Activated AMPK inhibits PPAR-{alpha} and PPAR-{gamma} transcriptional activity in hepatoma cells.

PubMed

Sozio, Margaret S; Lu, Changyue; Zeng, Yan; Liangpunsakul, Suthat; Crabb, David W

2011-10-01

AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPAR-α) are critical regulators of short-term and long-term fatty acid oxidation, respectively. We examined whether the activities of these molecules were coordinately regulated. H4IIEC3 cells were transfected with PPAR-α and PPAR-γ expression plasmids and a peroxisome-proliferator-response element (PPRE) luciferase reporter plasmid. The cells were treated with PPAR agonists (WY-14,643 and rosiglitazone), AMPK activators 5-aminoimidazole-4-carboxamide riboside (AICAR) and metformin, and the AMPK inhibitor compound C. Both AICAR and metformin decreased basal and WY-14,643-stimulated PPAR-α activity; compound C increased agonist-stimulated reporter activity and partially reversed the effect of the AMPK activators. Similar effects on PPAR-γ were seen, with both AICAR and metformin inhibiting PPRE reporter activity. Compound C increased basal PPAR-γ activity and rosiglitazone-stimulated activity. In contrast, retinoic acid receptor-α (RAR-α), another nuclear receptor that dimerizes with retinoid X receptor (RXR), was largely unaffected by the AMPK activators. Compound C modestly increased AM580 (an RAR agonist)-stimulated activity. The AMPK activators did not affect PPAR-α binding to DNA, and there was no consistent correlation between effects of the AMPK activators and inhibitor on PPAR and the nuclear localization of AMPK-α subunits. Expression of either a constitutively active or dominant negative AMPK-α inhibited basal and WY-14,643-stimulated PPAR-α activity and basal and rosiglitazone-stimulated PPAR-γ activity. We concluded that the AMPK activators AICAR and metformin inhibited transcriptional activities of PPAR-α and PPAR-γ, whereas inhibition of AMPK with compound C activated both PPARs. The effects of AMPK do not appear to be mediated through effects on RXR or on PPAR/RXR binding to DNA. These effects are independent of kinase activity and instead appear to rely on the activated conformation of AMPK. AMPK inhibition of PPAR-α and -γ may allow for short-term processes to increase energy generation before the cells devote resources to increasing their capacity for fatty acid oxidation.

Ethanol impairs activation of retinoic acid receptors in cerebellar granule cells in a rodent model of fetal alcohol spectrum disorders.

PubMed

Kumar, Ambrish; Singh, Chandra K; DiPette, Donald D; Singh, Ugra S

2010-05-01

Ethanol is the main addictive and neurotoxic constituent of alcohol. Ethanol exposure during embryonic development causes dysfunction of the central nervous system (CNS) and leads to fetal alcohol spectrum disorders. The cerebellum is one of the CNS regions that are particularly vulnerable to ethanol toxic effects. Retinoic acid (RA) is a physiologically active metabolite of vitamin A that is locally synthesized in the cerebellum. Studies have shown that RA is required for neuronal development, but it remains unknown if ethanol impairs RA signaling and thus induces neuronal malformations. In this study, we tested the hypothesis that ethanol impairs the expression and activation of RA receptors in cerebellum and in cerebellar granule cells. The cerebellum of ethanol unexposed and exposed pups was used to study the expression of retinoic acid receptors (RARs or RXRs) by immunohistochemistry and by Western blot analysis. We also studied the effect of ethanol on expression of RA receptors in the cerebellar granule cells. Activation of RA receptors (DNA-binding activities) in response to high-dose ethanol was determined by electrophoretic mobility shift and supershift assays. Findings from these studies demonstrated that ethanol exposure reduced the expression of RARalpha/gamma while it increased the expression of RXRalpha/gamma in the cerebellum and in cerebellar granule neurons. Immuno-histological studies further strengthened the expression pattern of RA receptors in response to ethanol. The DNA-binding activity of RARs was reduced, while DNA-binding activity of RXRs was increased in response to ethanol exposure. For the first time, our studies have demonstrated that high-dose ethanol affects the expression and activation of RA receptors, which could impair the signaling events and induce harmful effects on the survival and differentiation of cerebellar granule cells. Taken together, these findings could provide insight into the treatment options for brain defects caused by excessive ethanol exposure, such as in Fetal Alcohol Spectrum Disorders.

Cell-type-specific regulation of the retinoic acid receptor mediated by the orphan nuclear receptor TLX.

PubMed

Kobayashi, M; Yu, R T; Yasuda, K; Umesono, K

2000-12-01

Malformations in the eye can be caused by either an excess or deficiency of retinoids. An early target gene of the retinoid metabolite, retinoic acid (RA), is that encoding one of its own receptors, the retinoic acid receptor beta (RARbeta). To better understand the mechanisms underlying this autologous regulation, we characterized the chick RARbeta2 promoter. The region surrounding the transcription start site of the avian RARbeta2 promoter is over 90% conserved with the corresponding region in mammals and confers strong RA-dependent transactivation in primary cultured embryonic retina cells. This response is selective for RAR but not retinoid X receptor-specific agonists, demonstrating a principal role for RAR(s) in retina cells. Retina cells exhibit a far higher sensitivity to RA than do fibroblasts or osteoblasts, a property we found likely due to expression of the orphan nuclear receptor TLX. Ectopic expression of TLX in fibroblasts resulted in increased sensitivity to RA induction, an effect that is conserved between chick and mammals. We have identified a cis element, the silencing element relieved by TLX (SET), within the RARbeta2 promoter region which confers TLX- and RA-dependent transactivation. These results indicate an important role for TLX in autologous regulation of the RARbeta gene in the eye.

Cell-Type-Specific Regulation of the Retinoic Acid Receptor Mediated by the Orphan Nuclear Receptor TLX†

PubMed Central

Kobayashi, Mime; Yu, Ruth T.; Yasuda, Kunio; Umesono, Kazuhiko

2000-01-01

Malformations in the eye can be caused by either an excess or deficiency of retinoids. An early target gene of the retinoid metabolite, retinoic acid (RA), is that encoding one of its own receptors, the retinoic acid receptor β (RARβ). To better understand the mechanisms underlying this autologous regulation, we characterized the chick RARβ2 promoter. The region surrounding the transcription start site of the avian RARβ2 promoter is over 90% conserved with the corresponding region in mammals and confers strong RA-dependent transactivation in primary cultured embryonic retina cells. This response is selective for RAR but not retinoid X receptor-specific agonists, demonstrating a principal role for RAR(s) in retina cells. Retina cells exhibit a far higher sensitivity to RA than do fibroblasts or osteoblasts, a property we found likely due to expression of the orphan nuclear receptor TLX. Ectopic expression of TLX in fibroblasts resulted in increased sensitivity to RA induction, an effect that is conserved between chick and mammals. We have identified a cis element, the silencing element relieved by TLX (SET), within the RARβ2 promoter region which confers TLX- and RA-dependent transactivation. These results indicate an important role for TLX in autologous regulation of the RARβ gene in the eye. PMID:11073974

Inverse Kinematics for Upper Limb Compound Movement Estimation in Exoskeleton-Assisted Rehabilitation

PubMed Central

Cortés, Camilo; de los Reyes-Guzmán, Ana; Scorza, Davide; Bertelsen, Álvaro; Carrasco, Eduardo; Gil-Agudo, Ángel; Ruiz-Salguero, Oscar; Flórez, Julián

2016-01-01

Robot-Assisted Rehabilitation (RAR) is relevant for treating patients affected by nervous system injuries (e.g., stroke and spinal cord injury). The accurate estimation of the joint angles of the patient limbs in RAR is critical to assess the patient improvement. The economical prevalent method to estimate the patient posture in Exoskeleton-based RAR is to approximate the limb joint angles with the ones of the Exoskeleton. This approximation is rough since their kinematic structures differ. Motion capture systems (MOCAPs) can improve the estimations, at the expenses of a considerable overload of the therapy setup. Alternatively, the Extended Inverse Kinematics Posture Estimation (EIKPE) computational method models the limb and Exoskeleton as differing parallel kinematic chains. EIKPE has been tested with single DOF movements of the wrist and elbow joints. This paper presents the assessment of EIKPE with elbow-shoulder compound movements (i.e., object prehension). Ground-truth for estimation assessment is obtained from an optical MOCAP (not intended for the treatment stage). The assessment shows EIKPE rendering a good numerical approximation of the actual posture during the compound movement execution, especially for the shoulder joint angles. This work opens the horizon for clinical studies with patient groups, Exoskeleton models, and movements types. PMID:27403420

Effects of retinoids and thiazolidinediones on proliferation, insulin release, insulin mRNA, GLUT 2 transporter protein and mRNA of INS-1 cells.

PubMed

Blumentrath, J; Neye, H; Verspohl, E J

2001-09-01

Both 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (ATRA) are active metabolites of vitamin A (retinol). There exists an interaction between retinoid receptors and peroxisome proliferator-activated receptors (PPARgamma). To define their functions in an insulin secreting system the effects of ATRA, 9cRA and the PPARgamma agonist rosiglitazone on cell proliferation, insulin release and glucose transporter (GLUT) 2 of INS-1 cells were tested. Retinoic acid receptor (RAR-alpha and -gamma) and retinoid X receptor (RXR-alpha and -beta) proteins are present (immunoblots). Both 9cRA and ATRA inhibit INS-1 cell proliferation ([3H]-thymidine assay) in a concentration dependent manner. Both 9cRA and ATRA increased insulin release, but only ATRA ralsed the GLUT 2 mRNA in a bell-shaped concentration response curve after 48 h. The insulinotropic effect of one compound is not significantly superimposed by the other indicating that the same binding sites are used by 9cRA and ATRA. The acute and chronic effects of the PPARgamma agonist rosiglitazone on insulin release were additionally determined since glitazones act as transcription factors together with RXR agonists. At high concentrations (100 microM) rosiglitazone inhibited glucose (8.3 mM) stimulated insulin secretion (acute experiment over 60 min). Insulin secretion, however, was increased during a 24 h treatment at a concentration of 10 microM and again inhibited at 100 microM. Changes in preproinsulin mRNA expression were not observed. Rosiglitazone (100 microM) increased GLUT 2 mRNA paralleled by an increase of GLUT 2 protein, but only after 24 h of treatment. This data indicate that RAR and RXR mediate insulin release. The changes in GLUT 2 have no direct impact on insulin release; the inhibition seen at high concentrations of either compound is possibly the result of the observed inhibition of cell proliferation. Effects of rosiglitazone on preproinsulin mRNA and GLUT 2 (mRNA and protein) do not play a role in modulating insulin secretion. With the presence of an RXR receptor agonist the effect of rosiglitazone on insulin release becomes stimulatory. Thus the effects of RAR-, RXR agonists and rosiglitazone depend on their concentrations, the duration of their presence and are due to specific interactions. Copyright 2001 John Wiley & Sons, Ltd.

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

Orfali, Nina; Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.; McKenna, Sharon L.

Retinoids are a family of signaling molecules derived from vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL.more » Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies. - Highlights: • Normal and aberrant retinoid signaling in hematopoiesis and leukemia is reviewed. • We suggest a novel role for RARα in the development of X-RARα gene fusions in APL. • ATRA therapy in APL activates transcription and promotes onco-protein degradation. • Autophagy may be involved in both onco-protein degradation and differentiation. • Pharmacologic autophagy induction may potentiate ATRA's therapeutic effects.« less

HAL-RAR (Doppler guided haemorrhoid artery ligation with recto-anal repair) is a safe and effective procedure for haemorrhoids. Results of a prospective study after two-years follow-up.

PubMed

Hoyuela, Carlos; Carvajal, Fernando; Juvany, Montserrat; Troyano, Daniel; Trias, Miquel; Martrat, Antoni; Ardid, Jordi; Obiols, Joan

2016-04-01

To analyse prospectively results of HAL-RAR technique by evaluating pain, perioperative complications and clinical outcome after two years followup. A prospective study design including 30 consecutive patients with haemorrhoids grade III-IV treated from June 2012. After discharge, patients received a specific questionnaire to record postoperative pain, delayed complications, evolution/disappearance of the symptoms that led to the surgical intervention (bleeding, prolapse, itching, pain and soiling). A visual analog scale (VAS) was used to measure pain. Outpatient follow-up was carried out at 7 days, and 1, 6 and 12 months and annually thereafter. Pre, intra and postoperative data (including physical examination) had been recorded prospectively. The median operating time (range) was 40 (26-60) minutes. Average hospital stay (range) was 11 (3-25) hours. No postoperative complications were observed in 29 cases (96.6%). Median follow-up was 26 (12-36) months. All the patients attended the follow-up. Mean postoperative pain was VAS = 1.7 on the seventh day and it was practically non-existent (VAS = 0.7) 1 month after the procedure. 87.5% of patients confirmed complete relief of symptoms after 30 days and 93% of patients feel free of symptoms 6 months after the procedure. No patient has experienced late complications as dyschezia, urgency, soiling or faecal incontinence. After 24 months follow-up, recurrence of bleeding and prolapse was observed in only 1 patient; 93% of patients have considered results of HAL-RAR as very good or excellent. HAL-RAR is safe and almost painless technique and it has very good results in the control of haemorrhoidal symptoms. This procedure should be considered as an effective first treatment option for haemorrhoids. Copyright © 2016 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

Cross-calibration of Fuji TR image plate and RAR 2492 x-ray film to determine the response of a DITABIS Super Micron image plate scanner

NASA Astrophysics Data System (ADS)

Dunham, G.; Harding, E. C.; Loisel, G. P.; Lake, P. W.; Nielsen-Weber, L. B.

2016-11-01

Fuji TR image plate is frequently used as a replacement detector medium for x-ray imaging and spectroscopy diagnostics at NIF, Omega, and Z facilities. However, the familiar Fuji BAS line of image plate scanners is no longer supported by the industry, and so a replacement scanning system is needed. While the General Electric Typhoon line of scanners could replace the Fuji systems, the shift away from photo stimulated luminescence units to 16-bit grayscale Tag Image File Format (TIFF) leaves a discontinuity when comparing data collected from both systems. For the purposes of quantitative spectroscopy, a known unit of intensity applied to the grayscale values of the TIFF is needed. The DITABIS Super Micron image plate scanning system was tested and shown to potentially rival the resolution and dynamic range of Kodak RAR 2492 x-ray film. However, the absolute sensitivity of the scanner is unknown. In this work, a methodology to cross calibrate Fuji TR image plate and the absolutely calibrated Kodak RAR 2492 x-ray film is presented. Details of the experimental configurations used are included. An energy dependent scale factor to convert Fuji TR IP scanned on a DITABIS Super Micron scanner from 16-bit grayscale TIFF to intensity units (i.e., photons per square micron) is discussed.

Cross-calibration of Fuji TR image plate and RAR 2492 x-ray film to determine the response of a DITABIS Super Micron image plate scanner

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

Dunham, G., E-mail: gsdunha@sandia.gov; Harding, E. C.; Loisel, G. P.

Fuji TR image plate is frequently used as a replacement detector medium for x-ray imaging and spectroscopy diagnostics at NIF, Omega, and Z facilities. However, the familiar Fuji BAS line of image plate scanners is no longer supported by the industry, and so a replacement scanning system is needed. While the General Electric Typhoon line of scanners could replace the Fuji systems, the shift away from photo stimulated luminescence units to 16-bit grayscale Tag Image File Format (TIFF) leaves a discontinuity when comparing data collected from both systems. For the purposes of quantitative spectroscopy, a known unit of intensity appliedmore » to the grayscale values of the TIFF is needed. The DITABIS Super Micron image plate scanning system was tested and shown to potentially rival the resolution and dynamic range of Kodak RAR 2492 x-ray film. However, the absolute sensitivity of the scanner is unknown. In this work, a methodology to cross calibrate Fuji TR image plate and the absolutely calibrated Kodak RAR 2492 x-ray film is presented. Details of the experimental configurations used are included. An energy dependent scale factor to convert Fuji TR IP scanned on a DITABIS Super Micron scanner from 16-bit grayscale TIFF to intensity units (i.e., photons per square micron) is discussed.« less

Carcass and meat quality of Assaf milk fed lambs: Effect of rearing system and sex.

PubMed

Rodríguez, A B; Landa, R; Bodas, R; Prieto, N; Mantecón, A R; Giráldez, F J

2008-10-01

The effect of sex and rearing system on growth and carcass and meat characteristics of milk fed Assaf lambs was studied. Thirty-six lambs, 18 males and 18 females were used. Twelve lambs remained with their mothers throughout the experiment (NR). Within 24-36h of birth, the rest were housed individually and fed twice a day ad libitum (AAR) or at 70% of ad libitum consumption (RAR) with reconstituted cow's milk. Sex did not affect animal performance, yet females showed higher carcass and non-carcass fat deposits. NR lambs showed greater BWG than AAR fed lambs, and AAR, higher than the RAR. Differences between naturally and artificially reared lambs in CCW and killing out percentage were not significant. Empty digestive tract and mesenteric fat weights were greater for RAR than NR lambs, with the AAR lambs demonstrating intermediate values; conversely, omental fat was greater in NR lambs. Carcass ether extract content was greater for NR lambs, possibly due to the greater growth. Use of ad libitum cow's milk substitute in suckling lambs twice a day resulted in less body weight gain but similar killing out percentages compared to naturally raised lambs. A 70% restricted supply increased the days in suckling and reduced carcass fatness and compactness. Except for water loss, which was less in NR than artificially fed lambs, no differences were found in meat characteristics.

Fire regime in a Mexican forest under indigenous resource management.

PubMed

Fulé, Peter Z; Ramos-Gómez, Mauro; Cortés-Montaño, Citlali; Miller, Andrew M

2011-04-01

The Rarámuri (Tarahumara) people live in the mountains and canyons of the Sierra Madre Occidental of Chihuahua, Mexico. They base their subsistence on multiple-use strategies of their natural resources, including agriculture, pastoralism, and harvesting of native plants and wildlife. Pino Gordo is a Rarámuri settlement in a remote location where the forest has not been commercially logged. We reconstructed the forest fire regime from fire-scarred trees, measured the structure of the never-logged forest, and interviewed community members about fire use. Fire occurrence was consistent throughout the 19th and 20th centuries up to our fire scar collection in 2004. This is the least interrupted surface-fire regime reported to date in North America. Studies from other relict sites such as nature reserves in Mexico or the USA have all shown some recent alterations associated with industrialized society. At Pino Gordo, fires recurred frequently at the three study sites, with a composite mean fire interval of 1.9 years (all fires) to 7.6 years (fires scarring 25% or more of samples). Per-sample fire intervals averaged 10-14 years at the three sites. Approximately two-thirds of fires burned in the season of cambial dormancy, probably during the pre-monsoonal drought. Forests were dominated by pines and contained many large living trees and snags, in contrast to two nearby similar forests that have been logged. Community residents reported using fire for many purposes, consistent with previous literature on fire use by indigenous people. Pino Gordo is a valuable example of a continuing frequent-fire regime in a never-harvested forest. The Rarámuri people have actively conserved this forest through their traditional livelihood and management techniques, as opposed to logging the forest, and have also facilitated the fire regime by burning. The data contribute to a better understanding of the interactions of humans who live in pine forests and the fire regimes of these ecosystems, a topic that has been controversial and difficult to assess from historical or paleoecological evidence.

Abscisic-acid-induced cellular apoptosis and differentiation in glioma via the retinoid acid signaling pathway.

PubMed

Zhou, Nan; Yao, Yu; Ye, Hongxing; Zhu, Wei; Chen, Liang; Mao, Ying

2016-04-15

Retinoid acid (RA) plays critical roles in regulating differentiation and apoptosis in a variety of cancer cells. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share structural similarities. Here we proposed that ABA may also play a role in cellular differentiation and apoptosis by sharing a similar signaling pathway with RA that may be involved in glioma pathogenesis. We reported for the first time that the ABA levels were twofold higher in low-grade gliomas compared with high-grade gliomas. In glioma tissues, there was a positive correlation between the ABA levels and the transcription of cellular retinoic acid-binding protein 2 (CRABP2) and a negative correlation between the ABA levels and transcription of fatty acid-binding protein 5 (FABP5). ABA treatment induced a significant increase in the expression of CRABP2 and a decrease in the expression of peroxisome proliferator-activated receptor (PPAR) in glioblastoma cells. Remarkably, both cellular apoptosis and differentiation were increased in the glioblastoma cells after ABA treatment. ABA-induced cellular apoptosis and differentiation were significantly reduced by selectively silencing RAR-α, while RAR-α overexpression exaggerated the ABA-induced effects. These results suggest that ABA may play a role in the pathogenesis of glioma by promoting cellular apoptosis and differentiation through the RA signaling pathway. © 2015 UICC.

Ligand recognition by RAR and RXR receptors: binding and selectivity.

PubMed

Sussman, Fredy; de Lera, Angel R

2005-10-06

Fundamental biological functions, most notably embriogenesis, cell growth, cell differentiation, and cell apoptosis, are in part regulated by a complex genomic network that starts with the binding (and activation) of retinoids to their cognate receptors, members of the superfamily of nuclear receptors. We have studied ligand recognition of retinoic receptors (RXRalpha and RARgamma) using a molecular-mechanics-based docking method. The protocol used in this work is able to rank the affinity of pairs of ligands for a single retinoid receptor, the highest values corresponding to those that adapt better to the shape of the binding site and generate the optimal set of electrostatic and apolar interactions with the receptor. Moreover, our studies shed light onto some of the energetic contributions to retinoid receptor ligand selectivity. In this regard we show that there is a difference in polarity between the binding site regions that anchor the carboxylate in RAR and RXR, which translates itself into large differences in the energy of interaction of both receptors with the same ligand. We observe that the latter energy change is canceled off by the solvation energy penalty upon binding. This energy compensation is borne out as well by experiments that address the effect of site-directed mutagenesis on ligand binding to RARgamma. The hypothesis that the difference in binding site polarity might be exploited to build RXR-selective ligands is tested with some compounds having a thiazolidinedione anchoring group.

Retinoic Acid Is Involved in the Metamorphosis of the Anal Fin into an Intromittent Organ, the Gonopodium, in the Green Swordtail (Xiphophorus hellerii)

PubMed Central

Meyer, Axel; Begemann, Gerrit

2013-01-01

In poeciliid fish the male anal fin has been transformed into a gonopodium, an intromittent organ required for internal fertilization. Elevated testosterone levels induce metamorphosis of a subset of anal fin rays to grow and form the specialized terminal structures of the gonopodium. The molecular mechanisms underlying these processes are largely unknown. Here, we investigated whether retinoic acid (RA) signaling is involved in gonopodium development in the swordtail Xiphophorus hellerii. We showed that aldh1a2, a RA synthesizing enzyme, and the RA receptors, rar-ga and rar-gb, are expressed in anal fins during metamorphosis. aldh1a2 expression is regulated by testosterone in a concentration-dependent manner and is up-regulated in both hormone-induced and naturally developing gonopodia. Androgen receptor (ar), a putative regulator of gonopodial development, is co-expressed with aldh1a2 and the RA receptors in gonopodial rays. Importantly, experimental increase of RA signaling promoted growth of the gonopodium and increased the number of new segments. Based on gene expression analyses and pharmacological manipulation of gonopodium development, we show that the RA signaling pathway is activated in response to androgen signaling and promotes fin ray growth and development during the metamorphosis of the anal fin into the gonopodium. PMID:24204880

Antiageing Mechanisms of a Standardized Supercritical CO2 Preparation of Black Jack (Bidens pilosa L.) in Human Fibroblasts and Skin Fragments

PubMed Central

Dieamant, Gustavo; Pereda, Maria Del Carmen V.; Nogueira, Cecília; Eberlin, Samara; Facchini, Gustavo; Checon, Juliana Tibério; Cesar, Camila Kappke; Mussi, Lilian; Polezel, Márcio Antonio; Martins-Oliveira, Divino; Di Stasi, Luiz Claudio

2015-01-01

The use of topical retinoids to treat skin disorders and ageing can induce local reactions, while oral retinoids are potent teratogens and produce several unwanted effects. This way, efforts to explore complementary care resources should be supported. Based on this, we evaluate the antiageing effects of a supercritical CO2 extract from Bidens pilosa L. (BPE-CO2A) containing a standardized multicomponent mixture of phytol, linolenic, palmitic, linoleic, and oleic acids. BPE-CO2A was assessed for its effects on human dermal fibroblasts (TGF-β1 and FGF levels using ELISA; collagen, elastin, and glycosaminoglycan by colorimetric assays, and mRNA expression of RXR, RAR, and EGFr by qRT-PCR) and human skin fragments (RAR, RXR, collagen, elastin, and glycosaminoglycan by immunohistochemical analysis). Levels of extracellular matrix elements, TGF-β1 and FGF, and EGFr gene expression were significantly increased by BPE-CO2A. The modulation of RXR and RAR was positively demonstrated after the treatment with BPE-CO2A or phytol, a component of BPE-CO2A. The effects produced by BPE-CO2A were similar to or better than those produced by retinol and retinoic acid. The ability to stimulate extracellular matrix elements, increase growth factors, and modulate retinoid and rexinoid receptors provides a basis for the development of preparation containing BPE-CO2A as an antiageing/skin-repair agent. PMID:25883669

The prognostic value of visually assessing enamel microcracks: Do debonding and adhesive removal contribute to their increase?

PubMed

Dumbryte, Irma; Jonavicius, Tomas; Linkeviciene, Laura; Linkevicius, Tomas; Peciuliene, Vytaute; Malinauskas, Mangirdas

2016-05-01

To find a correlation between the severity of enamel microcracks (EMCs) and their increase during debonding and residual adhesive removal (RAR). Following their examination with scanning electron microscopy (SEM), 90 extracted human premolars were divided into three groups of 30: group 1, teeth having pronounced EMCs (visible with the naked eye under normal room illumination); group 2, teeth showing weak EMCs (not apparent under normal room illumination but visible by SEM); and group 3, a control group. EMCs have been classified into weak and pronounced, based on their visibility. Metal brackets (MB) and ceramic brackets (CB), 15 of each type, were bonded to all the teeth from groups 1 and 2. Debonding was performed with pliers, followed by RAR. The location, length, and width of the longest EMCs were measured using SEM before and after debonding. The mean overall width (Woverall) was higher for pronounced EMCs before and after debonding CB (P < .05), and after the removal of MB. Pronounced EMCs showed greater length values using both types of brackets. After debonding, the increase in Woverall of pronounced EMCs was 0.57 µm with MB (P < .05) and 0.30 µm with CB; for weak EMCs, - 0.32 µm with MB and 0.30 µm with CB. Although the teeth having pronounced EMCs showed higher width and length values, this did not predispose to greater EMCs increase after debonding MB and CB followed by RAR.

IRAC Imaging of LSB Galaxies

NASA Astrophysics Data System (ADS)

Schombert, James; McGaugh, Stacy; Lelli, Federico

2017-04-01

We propose a program to observe a large sample of Low Surface Brightness (LSB) galaxies. Large galaxy surveys conducted with Spitzer suffer from the unavoidable selection bias against LSB systems (e.g., the S4G survey). Even those programs thathave specifically targeted LSB galaxies have usually been restricted objects of intermediate surface brightness (between 22 and 23 B mag/ []). Our sample is selected to be of a more extreme LSB nature (with central surface brightness fainter than 23 Bmag/[]). Even warm, Spitzer is the ideal instrument to image these low contrast targets in the near infrared: our sample goes a considerable way towards remedying this hole in the Spitzer legacy archive, also increasing coverage in terms of stellar mass, gas mass, and SFR. The sample will be used to address the newly discovered radial acceleration relation (RAR) in disk galaxies. While issues involving the connection between baryons and dark matter have been known since the development of the global baryonic Tully-Fisher (bTF) relation, it is only in the last six months that the particle physics and theoretical communities have recognized and responded to the local coupling between dark and baryonic matter represented by the RAR. This important new correlation is effectively a new natural law for galaxies. Spitzer photometry has been at the forefront of resolving the stellar mass component in galaxies that make-up the RAR and is the primary reason for the discovery of this new kinematic law.

Bone Marrow Transplant Using a Reduced Intensity Regimen That is Given in Two Steps

ClinicalTrials.gov

2016-11-28

Hematologic Malignancies; Acute Leukemia; Myelodysplastic Syndromes (MDS) Other Than RA or RARS Subtypes; Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma; Myeloma; Chronic Myelogenous (or Myeloid) Leukemia (CML) Resistant to STI Therapy

LE135, a retinoid acid receptor antagonist, produces pain through direct activation of TRP channels

PubMed Central

Yin, Shijin; Luo, Jialie; Qian, Aihua; Yu, Weihua; Hu, Hongzhen

2014-01-01

Background and PurposeRetinoids, through their activation of retinoic acid receptors (RARs) and retinoid X receptors, regulate diverse cellular processes, and pharmacological intervention in their actions has been successful in the treatment of skin disorders and cancers. Despite the many beneficial effects, administration of retinoids causes irritating side effects with unknown mechanisms. Here, we demonstrate that LE135 [4-(7,8,9,10-tetrahydro-5,7,7,10,10-pentamethyl-5H-benzo[e]naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid], a selective antagonist of RARβ, is a potent activator of the capsaicin (TRPV1) and wasabi (TRPA1) receptors, two critical pain-initiating cation channels. Experimental ApproachWe performed to investigate the excitatory effects of LE135 on TRPV1 and TRPA1 channels expressed in HEK293T cells and in dorsal root ganglia neurons with calcium imaging and patch-clamp recordings. We also used site-directed mutagenesis of the channels to determine the structural basis of LE135-induced activation of TRPV1 and TRPA1 channels and behavioural testing to examine if pharmacological inhibition and genetic deletion of the channels affected LE135-evoked pain-related behaviours. Key ResultsLE135 activated both the capsaicin receptor (TRPV1) and the allyl isothiocyanate receptor (TRPA1) heterologously expressed in HEK293T cells and endogenously expressed by sensory nociceptors. Mutations disrupting the capsaicin-binding site attenuated LE135 activation of TRPV1 channels and a single mutation (K170R) eliminated TRPA1 activity evoked by LE135. Intraplantar injection of LE135 evoked pain-related behaviours. Both TRPV1 and TRPA1 channels were involved in LE135-elicited pain-related responses, as shown by pharmacological and genetic ablation studies. Conclusions and ImplicationsThis blocker of retinoid acid signalling also exerted non-genomic effects through activating the pain-initiating TRPV1 and TRPA1 channels. PMID:24308840

Investigation of Combined Action of Food Supplement's and Ionizing Radiation on the Cytogenetic Damage Induction and Ehrlich Ascite Carcinoma Growth on Mice in Vivo

NASA Astrophysics Data System (ADS)

Sorokina, Svetlana; Zaichkina, Svetlana; Dyukina, Alsu; Rozanova, Olga; Balakin, Vladimir; Peleshko, Vladimir; Romanchenko, Sergey; Smirnova, Helena; Aptikaeva, Gella; Shemyakov, Alexander

In recent ten years one of the major problems of modern radiobiology is the study of radiation protective mechanisms with the help of different substances as well as activation of internal resources of the organism. Internal resources mean such phenomena as hormesis and adaptive response which represent cell or body reaction on low doses of inducing factors and predetermine their further high dose effect resistance. At present special interest is attracted by studies of biological effects of low-dose-rate high-LET radiation because of searching for new types of radiation for more effective cancer therapy and searching for new methods of radiation protection. Since natural biologically active substances have low toxicity and are capable of affecting physiological processes taking place in human’s organism and increasing organism’s natural defense system, the interest to protective means of vegetal origin and search of special food supplements intensifies every year. The purpose of this study is to investigate the combined influence of food supplement, low dose rate high-LET radiation simulating high-altitude flight conditions and X-ray radiations on radiosensitivity, induction of radiation adaptive response (RAR) and growth of Ehrlich ascite carcinoma as well. Experiments were performed with males of SHK mice at the age of two months. The animals were being irradiated with low-dose-rate high-LET radiation with the dose of 11,6 cGy (0,5 cGy/day) behind the concrete shield of the 70 GeV protons accelerator (Protvino). The X-ray irradiation was carried out on the RTH device with a voltage of 200 kV (1 Gy/min; Pushchino). The diet composition included products containing big amount of biologically active substances, such as: soybeam meat, buckwheat, lettuce leaves and drug of cod-liver oil. Four groups of mice were fed with selected products mentioned above during the whole irradiation period of 22 days. The control groups received the same food without irradiation. The relation of the amount of the food supplement to the quantity of standard food was selected experimentally. In order to determine the level of radiosensitivity all groups of mice were subjected to X-radiation with the dose of 1,5 Gy and for induction of RAR the animals were irradiated according to the standard scheme (10 cGy+1,5 Gy). The influence of food supplement on the growth of solid tumor was estimated by measuring the size of the tumor at different times after the inoculation of ascitic cells s.c. into the femur. The percent of polychromatic erythrocytes (PCE) with micronucleus (MN) in marrow served as definition criteria of cytogenetic level of damage. The results of the study indicate that: 1) Due to influence of high-LET radiation with the dose of 11,6 Gy, mice who had dietary supplement demonstrated reduction of PCE with MN to the level of natural background radiation comparing with mice who had only standard food; 2) Diet containing soybeam, buckwheat or greens unlike cod-liver oil reduces the sensitivity of mice to X-radiation with the dose of 1,5 Gy and causes significant slowdown in growth of Ehrlich carcinoma; 3) The combined effect of high-LET radiation and the food supplements (except for cod-liver oil) reduces the sensitivity of mice to irradiation with the dose of 1,5 Gy, which demonstrate ability of RAR induction unlike the mice only irradiated with high-LET radiation and causes the slowdown in growth speed of Ehrlich carcinoma in contrast to the mice only irradiated with high-LET with the dose of 11,6 Gy; 4) The combined effect of high-LET radiation and the food supplements (except for cod-liver oil) does not influence the quantity of RAR according to the standard scheme (10 cGy+1,5 Gy).

The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission

DOE PAGES

Chandra, Vikas; Wu, Dalei; Li, Sheng; ...

2017-10-11

Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor beta-retinoic X receptor alpha (RAR beta-RXR alpha) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies. The RAR beta ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within theirmore » quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its hetero-dimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.« less

The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission

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

Chandra, Vikas; Wu, Dalei; Li, Sheng

Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor beta-retinoic X receptor alpha (RAR beta-RXR alpha) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies. The RAR beta ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within theirmore » quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its hetero-dimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.« less

[Studies on the structure-activity relationship of retinoids--Hansch analysis and 3D-OSAR studies on specific ligands of retinoid x receptor].

PubMed

Huang, N; Chu, F; Guo, Z

1998-06-01

Retinoids (Vitamin A, its metabolites and synthetic analogues) play important roles in a variety of biological processes, including cellular differentiation, proliferation and apoptosis. The many diverse actions of retinoids attribute to the ability of regulating transcription of different target genes through activation of multiple retinoid nuclear receptors (RAR of RXR). So, retinoids with selective binding ability to specific receptor may not only have improved therapeutic indices, but may also be invaluable for elucidating the molecular mechanism of retinoidal transcriptional activation. Based on the two dimensional and three dimensional quantitative structure-activity relationships of specific ligands of RXR, we carried out mimesis of environment of ligands interacting with their receptor and, to some extent, mapping the topological and physico-chemical characteristics of receptor. The knowledge of the QSAR study will offer detailed molecular information for design, synthesis and biological evaluation in drug research and development.

Allosteric Regulation of the Hsp90 Dynamics and Stability by Client Recruiter Cochaperones: Protein Structure Network Modeling

PubMed Central

Blacklock, Kristin; Verkhivker, Gennady M.

2014-01-01

The fundamental role of the Hsp90 chaperone in supporting functional activity of diverse protein clients is anchored by specific cochaperones. A family of immune sensing client proteins is delivered to the Hsp90 system with the aid of cochaperones Sgt1 and Rar1 that act cooperatively with Hsp90 to form allosterically regulated dynamic complexes. In this work, functional dynamics and protein structure network modeling are combined to dissect molecular mechanisms of Hsp90 regulation by the client recruiter cochaperones. Dynamic signatures of the Hsp90-cochaperone complexes are manifested in differential modulation of the conformational mobility in the Hsp90 lid motif. Consistent with the experiments, we have determined that targeted reorganization of the lid dynamics is a unifying characteristic of the client recruiter cochaperones. Protein network analysis of the essential conformational space of the Hsp90-cochaperone motions has identified structurally stable interaction communities, interfacial hubs and key mediating residues of allosteric communication pathways that act concertedly with the shifts in conformational equilibrium. The results have shown that client recruiter cochaperones can orchestrate global changes in the dynamics and stability of the interaction networks that could enhance the ATPase activity and assist in the client recruitment. The network analysis has recapitulated a broad range of structural and mutagenesis experiments, particularly clarifying the elusive role of Rar1 as a regulator of the Hsp90 interactions and a stability enhancer of the Hsp90-cochaperone complexes. Small-world organization of the interaction networks in the Hsp90 regulatory complexes gives rise to a strong correspondence between highly connected local interfacial hubs, global mediator residues of allosteric interactions and key functional hot spots of the Hsp90 activity. We have found that cochaperone-induced conformational changes in Hsp90 may be determined by specific interaction networks that can inhibit or promote progression of the ATPase cycle and thus control the recruitment of client proteins. PMID:24466147

Allosteric regulation of the Hsp90 dynamics and stability by client recruiter cochaperones: protein structure network modeling.

PubMed

Blacklock, Kristin; Verkhivker, Gennady M

2014-01-01

The fundamental role of the Hsp90 chaperone in supporting functional activity of diverse protein clients is anchored by specific cochaperones. A family of immune sensing client proteins is delivered to the Hsp90 system with the aid of cochaperones Sgt1 and Rar1 that act cooperatively with Hsp90 to form allosterically regulated dynamic complexes. In this work, functional dynamics and protein structure network modeling are combined to dissect molecular mechanisms of Hsp90 regulation by the client recruiter cochaperones. Dynamic signatures of the Hsp90-cochaperone complexes are manifested in differential modulation of the conformational mobility in the Hsp90 lid motif. Consistent with the experiments, we have determined that targeted reorganization of the lid dynamics is a unifying characteristic of the client recruiter cochaperones. Protein network analysis of the essential conformational space of the Hsp90-cochaperone motions has identified structurally stable interaction communities, interfacial hubs and key mediating residues of allosteric communication pathways that act concertedly with the shifts in conformational equilibrium. The results have shown that client recruiter cochaperones can orchestrate global changes in the dynamics and stability of the interaction networks that could enhance the ATPase activity and assist in the client recruitment. The network analysis has recapitulated a broad range of structural and mutagenesis experiments, particularly clarifying the elusive role of Rar1 as a regulator of the Hsp90 interactions and a stability enhancer of the Hsp90-cochaperone complexes. Small-world organization of the interaction networks in the Hsp90 regulatory complexes gives rise to a strong correspondence between highly connected local interfacial hubs, global mediator residues of allosteric interactions and key functional hot spots of the Hsp90 activity. We have found that cochaperone-induced conformational changes in Hsp90 may be determined by specific interaction networks that can inhibit or promote progression of the ATPase cycle and thus control the recruitment of client proteins.

Rapid Assessment Response (RAR) study: drug use, health and systemic risks--Emthonjeni Correctional Centre, Pretoria, South Africa.

PubMed

Dos Santos, Monika M L; Trautmann, Franz; Wolvaardt, Gustaaf; Palakatsela, Romeo

2014-04-03

Correctional centre populations are one of the populations most at risk of contracting HIV infection for many reasons, such as unprotected sex, violence, rape and tattooing with contaminated equipment. Specific data on drug users in correctional centres is not available for the majority of countries, including South Africa. The study aimed to identify the attitudes and knowledge of key informant (KI) offender and correctional centre staff regarding drug use, health and systemic-related problems so as to facilitate the long-term planning of activities in the field of drug-use prevention and systems strengthening in correctional centres, including suggestions for the development of appropriate intervention and rehabilitation programmes. A Rapid Assessment Response (RAR) methodology was adopted which included observation, mapping of service providers (SP), KI interviews (staff and offenders) and focus groups (FGs). The study was implemented in Emthonjeni Youth Correctional Centre, Pretoria, South Africa. Fifteen KI staff participants were interviewed and 45 KI offenders. Drug use is fairly prevalent in the centre, with tobacco most commonly smoked, followed by cannabis and heroin. The banning of tobacco has also led to black-market features such as transactional sex, violence, gangsterism and smuggling in order to obtain mainly prohibited tobacco products, as well as illicit substances. HIV, health and systemic-related risk reduction within the Correctional Service sector needs to focus on measures such as improvement of staff capacity and security measures, deregulation of tobacco products and the development and implementation of comprehensive health promotion programmes.

In-vitro generation of interleukin-10 secreting B-regulatory cells from donor adipose tissue derived mesenchymal stem cells and recipient peripheral blood mononuclear cells for potential cell therapy.

PubMed

Gupte, Kunal S; Vanikar, Aruna V; Trivedi, Hargovind L; Patel, Chetan N; Patel, Jignesh V

2017-02-01

Interleukin-10 secreting B-cells are a major subset of B-regulatory cells (B-regs), commonly recognized as CD19 + /38 hi /24 hi /IL10 + . They carry out immunomodulation by release of specific cytokines and/or cell-to-cell contact. We have generated B-regs in-vitro from donor adipose tissue derived mesenchymal stem cells (AD-MSC) and renal allograft recipient (RAR) peripheral blood mononuclear cells (PBMC) for potential cell therapy. Mononuclear cells separated by density gradient centrifugation from 50 ml anti-coagulated blood of 15-RAR and respective donors were analysed for baseline B-regs using appropriate antibodies. Equal amount (20 × 10 6  cells/ml) of stimulator (irradiated at 7.45 Gy/min for 10 min) and responder (non-irradiated) cells were co-cultured with in-vitro generated AD-MSC (1 × 10 6  cells/ml) in proliferation medium containing lipopolysaccharide from E. coli K12 strain at 37 °C with 5% CO 2 . Cells were harvested on day-7 and analyzed for viability, sterility, quantity, morphology and phenotyping. In-vitro generated B-reg levels were compared with baseline B-regs. In-vitro generated B-reg count increased to 16.75% from baseline count of 3.35%. B-regs can be successfully generated in-vitro from donor AD-MSC and RAR PBMC for potential cell therapy. Copyright © 2017 Chang Gung University. Published by Elsevier B.V. All rights reserved.

Induction of intermediate mesoderm by retinoic acid receptor signaling from differentiating mouse embryonic stem cells.

PubMed

Oeda, Shiho; Hayashi, Yohei; Chan, Techuan; Takasato, Minoru; Aihara, Yuko; Okabayashi, Koji; Ohnuma, Kiyoshi; Asashima, Makoto

2013-01-01

Renal lineages including kidney are derived from intermediate mesoderm, which are differentiated from a subset of caudal undifferentiated mesoderm. The inductive mechanisms of mammalian intermediate mesoderm and renal lineages are still poorly understood. Mouse embryonic stem cells (mESCs) can be a good in vitro model to reconstitute the developmental pathway of renal lineages and to analyze the mechanisms of the sequential differentiation. We examined the effects of Activin A and retinoic acid (RA) on the induction of intermediate mesoderm from mESCs under defined, serum-free, adherent, monolayer culture conditions. We measured the expression level of intermediate mesodermal marker genes and examined the developmental potential of the differentiated cells into kidney using an ex vivo transplantation assay. Adding Activin A followed by RA to mESC cultures induced the expression of marker genes and proteins for intermediate mesoderm, odd-skipped related 1 (Osr1) and Wilm’s Tumor 1 (Wt1). These differentiated cells integrated into laminin-positive tubular cells and Pax2-positive renal cells in cultured embryonic kidney explants. We demonstrated that intermediate mesodermal marker expression was also induced by RA receptor (RAR) agonist, but not by retinoid X receptor (RXR) agonists. Furthermore, the expression of these markers was decreased by RAR antagonists. We directed the differentiation of mESCs into intermediate mesoderm using Activin A and RA and revealed the role of RAR signaling in this differentiation. These methods and findings will improve our understanding of renal lineage development and could contribute to the regenerative medicine of kidney.

Alpha fetoprotein mediates HBx induced carcinogenesis in the hepatocyte cytoplasm.

PubMed

Zhang, Chao; Chen, Xiangmei; Liu, Hui; Li, Hui; Jiang, Wei; Hou, Wenting; McNutt, Michael A; Lu, Fengmin; Li, Gang

2015-10-15

Although tumor-associated fetal protein AFP has demonstrated utility as a clinical tumor marker, the significance of intracellular AFP is still unclear. The aim of this study was to explore the role of cytoplasmic AFP during HBx induced carcinogenesis, which had not previously been recognized; 614 HCC patients were analyzed for correlation of HBV infection with AFP level, and much higher AFP levels were found in HBsAg positive patients. Tumor tissue specimens from 20 HCC patients were used for analysis of AFP and GADD45α. Analysis of HCC specimens showed that upregulation of cytoplasmic AFP is associated with down-regulation of GADD45α in neoplastic tissue. Transfected HBx promotes transcription of AFP by acting on the elements in the AFP gene regulatory region. HBx itself did not directly impact transcription of GADD45α. However, the obstruction of RAR signaling by HBx induced elevation of AFP, which led to down-regulation of GADD45α. Cytoplasmic AFP was able to interact with RAR, disrupting its entrance into the nucleus and binding to the elements in the regulatory region of the GADD45α gene. Knockdown of AFP in siRNA-transfected AFP positive cell lines was synchronously associated with an incremental increase of RAR binding to DNA, as well as upregulation of GADD45α and it was contrary in AFP gene-transfected AFP negative cell lines. These results indicate cytoplasmic AFP is not only a histochemical tumor biomarker for human hepatoma but is also an intracellular signal molecule and potential participant in HBx induced hepatocarcinogenesis. © 2015 UICC.

The threshold number of protons to induce an adaptive response in zebrafish embryos.

PubMed

Choi, V W Y; Konishi, Teruaki; Oikawa, Masakazu; Cheng, S H; Yu, K N

2013-03-01

In this study, microbeam protons were used to provide the priming dose to induce an in vivo radioadaptive response (RAR) in the embryos of zebrafish, Danio rerio, against subsequent challenging doses provided by x-ray photons. The microbeam irradiation system (Single-Particle Irradiation System to Cell, acronym SPICE) at the National Institute of Radiological Sciences (NIRS), Japan, was employed. The embryos were dechorionated at 4 h post fertilisation (hpf) and irradiated at 5 hpf by microbeam protons. For each embryo, one irradiation point was chosen, to which 5, 10, 20, 30, 40, 50, 100, 200, 300 and 500 protons each with an energy of 3.4 MeV were delivered. The embryos were returned to the incubator until 10 hpf to further receive the challenging exposure, which was achieved using 2 Gy of x-ray irradiation, and then again returned to the incubator until 24 hpf for analyses. The levels of apoptosis in zebrafish embryos at 25 hpf were quantified through terminal dUTP transferase-mediated nick end-labelling (TUNEL) assay. The results revealed that at least 200 protons (with average radiation doses of about 300 and 650 mGy absorbed by an irradiated epithelial and deep cell, respectively) would be required to induce RAR in the zebrafish embryos in vivo. Our previous investigation showed that 5 protons delivered at 10 points on an embryo would already be sufficient to induce RAR in the zebrafish embryos. The difference was explained in terms of the radiation-induced bystander effect as well as the rescue effect.

Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-α and retinoids

PubMed Central

Brodowicz, T; Wiltschke, C; Kandioler-Eckersberger, D; Grunt, T W; Rudas, M; Schneider, S M; Hejna, M; Budinsky, A; Zielinski, C C

1999-01-01

Uncontrolled proliferation and a defect of apoptosis constitute crucial elements in the development and progression of tumours. Among many other biological response modifiers known to influence these mechanisms, the efficacy of retinoids and interferons in the treatment of various malignant entities is currently matter of discussion. In the present study, we have investigated the effects of 9-cis-retinoic acid (9cRA), 13-cis-retinoic acid (13cRA), all-trans-retinoic acid (tRA) and interferon-α on proliferation and apoptosis of human soft tissue sarcoma (STS) cell lines HTB-82 (rhabdomyosarcoma), HTB-91 (fibrosarcoma), HTB-92 (liposarcoma), HTB-93 (synovial sarcoma) and HTB-94 (chondrosarcoma) in relation to p53 genotype as well as p53 expression. HTB-91, HTB-92 and HTB-94 STS cells exhibited mutant p53, whereas wild-type p53 was found in HTB-93 STS cells, and a normal p53 status in HTB-82 STS cells, carrying a silent point mutation only. Interferon-α, irrespective of p53 status, inhibited the proliferation of all five cell lines dose- and time-dependently. Similarly, 9cRA, 13cRA and tRA decreased the proliferation of HTB-82 and HTB-93 STS cells, whereas the proliferation of p53-mutated HTB-91, HTB-92 and HTB-94 STS cells remained unchanged. Furthermore, only 9cRA and tRA were capable of inducing apoptosis in HTB-82 and HTB-93 STS cells, whereas HTB-91, HTB-92 and HTB-94 STS cells did not undergo apoptosis under the influence of 9cRA or tRA. Retinoic acid receptor (RAR)-α and RAR-β mRNA were not detectable by Northern blot analysis in the five STS cell lines, whereas mRNA for the universal retinoic acid receptor, RAR-γ, was expressed in all STS cell lines indicating that retinoid resistance was not associated with a lack of RAR expression. Apoptosis was not induced by interferon-α or 13cRA in any of the five STS cell lines tested. Our results indicate that within the panel of tested STS cell lines, inhibition of proliferation and induction of apoptosis result from different mechanisms which differ in their dependence upon the presence of intact p53. © 1999 Cancer Research Campaign PMID:10424735

Nutrigenomic regulation of adipose tissue development --- role of retinoic acid: A review

PubMed Central

Wang, Bo; Yang, Qiyuan; Harris, Corrine L.; Nelson, Mark L.; Busboom, Jan R.; Zhu, Mei-Jun; Du, Min

2016-01-01

To improve the efficiency of animal production, livestock have been extensively selected or managed to reduce fat accumulation and increase lean growth, which reduces intramuscular or marbling fat content. To enhance marbling, a better understanding of the mechanisms regulating adipogenesis is needed. Vitamin A has recently been shown to have a profound impact on all stages of adipogenesis. Retinoic acid, an active metabolite of vitamin A, activates both retinoic acid receptors (RAR) and retinoid X receptors (RXR), inducing epigenetic changes in key regulatory genes governing adipogenesis. Additionally, Vitamin D and folates interact with the retinoic acid receptors to regulate adipogenesis. In this review, we discuss nutritional regulation of adipogenesis, focusing on retinoic acid and its impact on epigenetic modifications of key adipogenic genes. PMID:27086067

Role of melatonin in the epigenetic regulation of breast cancer.

PubMed

Korkmaz, Ahmet; Sanchez-Barcelo, Emilio J; Tan, Dun-Xian; Reiter, Russel J

2009-05-01

The oncostatic properties of melatonin as they directly or indirectly involve epigenetic mechanisms of cancer are reviewed with a special focus on breast cancer. Five lines of evidence suggest that melatonin works via epigenetic processes: (1) melatonin influences transcriptional activity of nuclear receptors (ERalpha, GR and RAR) involved in the regulation of breast cancer cell growth; (2) melatonin down-regulates the expression of genes responsible for the local synthesis or activation of estrogens including aromatase, an effect which may be mediated by methylation of the CYP19 gene or deacetylation of CYP19 histones; (3) melatonin inhibits telomerase activity and expression induced by either natural estrogens or xenoestrogens; (4) melatonin modulates the cell cycle through the inhibition of cyclin D1 expression; (5) melatonin influences circadian rhythm disturbances dependent on alterations of the light/dark cycle (i.e., light at night) with the subsequent deregulation of PER2 which acts as a tumor suppressor gene.

Performance Measures in Neurosurgical Patient Care: Differing Applications of Patient Safety Indicators.

PubMed

Moghavem, Nuriel; McDonald, Kathryn; Ratliff, John K; Hernandez-Boussard, Tina

2016-04-01

Patient Safety Indicators (PSIs) are administratively coded identifiers of potentially preventable adverse events. These indicators are used for multiple purposes, including benchmarking and quality improvement efforts. Baseline PSI evaluation in high-risk surgeries is fundamental to both purposes. Determine PSI rates and their impact on other outcomes in patients undergoing cranial neurosurgery compared with other surgeries. The Agency for Healthcare Research and Quality (AHRQ) PSI software was used to flag adverse events and determine risk-adjusted rates (RAR). Regression models were built to assess the association between PSIs and important patient outcomes. We identified cranial neurosurgeries based on International Classification of Diseases, Ninth Revision, Clinical Modification codes in California, Florida, New York, Arkansas, and Mississippi State Inpatient Databases, AHRQ, 2010-2011. PSI development, 30-day all-cause readmission, length of stay, hospital costs, and inpatient mortality. A total of 48,424 neurosurgical patients were identified. Procedure indication was strongly associated with PSI development. The neurosurgical population had significantly higher RAR of most PSIs evaluated compared with other surgical patients. Development of a PSI was strongly associated with increased length of stay and hospital cost and, in certain PSIs, increased inpatient mortality and 30-day readmission. In this population-based study, certain accountability measures proposed for use as value-based payment modifiers show higher RAR in neurosurgery patients compared with other surgical patients and were subsequently associated with poor outcomes. Our results indicate that for quality improvement efforts, the current AHRQ risk-adjustment models should be viewed in clinically meaningful stratified subgroups: for profiling and pay-for-performance applications, additional factors should be included in the risk-adjustment models. Further evaluation of PSIs in additional high-risk surgeries is needed to better inform the use of these metrics.

Information Processing in Medical Imaging Meeting (IPMI)

DTIC Science & Technology

1993-09-30

Rousy. France 8:40 Bayesian Identification of a Physiological Model in Dynamic Scintigraphic Data M. Samal . M. Karny. D. Zahalka. Charles Univ.. Prague...5986 200 1st St. SW xcpan@rainbow.uchicago.edu Rochester, MN 55905 USA (Ph) 507-284-4937 (Fax) 507-284-1632 rar@mayo.edu Glynn Robinson Martin Samal

A prospective study of common variants in the RAR-related orphan receptor alpha (RORalpha) gene and risk of neovascular age-related macular degeneration

PubMed Central

Schaumberg, Debra A.; Chasman, Daniel; Morrison, Margaux A.; Adams, Scott M.; Guo, Qun; Hunter, David J.; Hankinson, Susan E.; DeAngelis, Margaret M.

2010-01-01

Objectives The RAR-related orphan receptor alpha (RORalpha) gene is implicated as a candidate for age-related macular degeneration (AMD) through a previous microarray expression study, linkage data, biological plausibility, and two clinic-based cross sectional studies. We aimed to determine if common variants in RORalpha predict future risk of neovascular AMD. Methods We measured genotypes for 18 variants in intron 1 of the RORalpha gene among 164 cases who developed neovascular AMD and 485 age- and sex-matched controls in a prospective nested case-control study within the Nurses’ Health Study and the Health Professionals Follow-up Study. We determined the incidence rate ratios (IRR) and 95% confidence intervals (CI) for neovascular AMD for each variant, and examined interactions with other AMD-associated variants and modifiable risk factors. Results We identified a single SNP (rs12900948) that was significantly associated with increased incidence of neovascular AMD. Participants with one and two copies of the “G” allele were 1.73 (CI= 1.32–2.27) and 2.99 (CI=1.74–5.14) times more likely to develop neovascular AMD. Individuals homozygous for both the “G” allele of rs12900948 and ARMS2 A69S had a 40.8-fold increased risk of neovascular AMD (CI=10.1–164; P for interaction=0.017). Cigarette smokers who carried two copies of the “G” allele had a 9.89-fold risk of neovascular AMD, but the interaction was not significant (P=0.08). We identified a significant AMD-associated haplotype block containing SNPs rs730754, rs8034864, and rs12900948, with P-values for ACA=1.16 × 10−9, ACG=5.85 × 10−12, and GAA=0.0001 when compared to all other haplotypes. Conclusion Common variants and haplotypes within the RORalpha gene appear to act synergistically with the ARMS2 A69S polymorphism to increase risk of neovascular AMD. These data add further evidence of a high level of complexity linking genetic and modifiable risk factors to AMD development and should help efforts at risk prediction. PMID:21060049

Retinoid Pathway and Cancer Therapeutics

PubMed Central

Bushue, Nathan; Wan, Yu-Jui Yvonne

2010-01-01

The retinoids are a class of compounds that are structurally related to vitamin A. Retinoic acid, which is the active metabolite of retinol, regulates a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids exert their effects through a variety of binding proteins including cellular retinol binding protein (CRBP), retinol-binding proteins (RBP), cellular retinoic acid-binding protein (CRABP), and nuclear receptors i.e. retinoic acid receptor (RAR) and retinoid × receptor (RXR). Because of the pleiotropic effects of retinoids, understanding the function of these binding proteins and nuclear receptors assists us in developing compounds that have specific effects. This review summarizes our current understanding of how retinoids are processed and act with the emphasis on the application of retinoids in cancer treatment and prevention. PMID:20654663

GABAA- and glycine-mediated inhibitory modulation of the cough reflex in the caudal nucleus tractus solitarii of the rabbit.

PubMed

Cinelli, Elenia; Iovino, Ludovica; Bongianni, Fulvia; Pantaleo, Tito; Mutolo, Donatella

2016-09-01

Cough-related sensory inputs from rapidly adapting receptors (RARs) and C fibers are processed by second-order neurons mainly located in the caudal nucleus tractus solitarii (NTS). Both GABAA and glycine receptors have been proven to be involved in the inhibitory control of second-order cells receiving RAR projections. We investigated the role of these receptors within the caudal NTS in the modulation of the cough reflex induced by either mechanical or chemical stimulation of the tracheobronchial tree in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections (30-50 nl) of the receptor antagonists bicuculline and strychnine as well as of the receptor agonists muscimol and glycine were performed. Bicuculline (0.1 mM) and strychnine (1 mM) caused decreases in peak abdominal activity and marked increases in respiratory frequency due to decreases in both inspiratory time (Ti) and expiratory time (Te), without concomitant changes in arterial blood pressure. Noticeably, these microinjections induced potentiation of the cough reflex consisting of increases in the cough number associated with decreases either in cough-related Ti after bicuculline or in both cough-related Ti and Te after strychnine. The effects caused by muscimol (0.1 mM) and glycine (10 mM) were in the opposite direction to those produced by the corresponding antagonists. The results show that both GABAA and glycine receptors within the caudal NTS mediate a potent inhibitory modulation of the pattern of breathing and cough reflex responses. They strongly suggest that disinhibition is one important mechanism underlying cough regulation and possibly provide new hints for novel effective antitussive strategies. Copyright © 2016 the American Physiological Society.

Role of the histone deacetylase complex in acute promyelocytic leukaemia.

PubMed

Lin, R J; Nagy, L; Inoue, S; Shao, W; Miller, W H; Evans, R M

1998-02-19

Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex through a class of silencing mediators termed SMRT or N-CoR. Mutant forms of RARalpha, created by chromosomal translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for promyelocytic leukaemia zinc finger) locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML-RARalpha APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF-RARalpha patients respond very poorly, if at all. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.

Testing for Archaic Hominin Admixture on the X Chromosome: Model Likelihoods for the Modern Human RRM2P4 Region From Summaries of Genealogical Topology Under the Structured Coalescent

PubMed Central

Cox, Murray P.; Mendez, Fernando L.; Karafet, Tatiana M.; Pilkington, Maya Metni; Kingan, Sarah B.; Destro-Bisol, Giovanni; Strassmann, Beverly I.; Hammer, Michael F.

2008-01-01

A 2.4-kb stretch within the RRM2P4 region of the X chromosome, previously sequenced in a sample of 41 globally distributed humans, displayed both an ancient time to the most recent common ancestor (e.g., a TMRCA of ∼2 million years) and a basal clade composed entirely of Asian sequences. This pattern was interpreted to reflect a history of introgressive hybridization from archaic hominins (most likely Asian Homo erectus) into the anatomically modern human genome. Here, we address this hypothesis by resequencing the 2.4-kb RRM2P4 region in 131 African and 122 non-African individuals and by extending the length of sequence in a window of 16.5 kb encompassing the RRM2P4 pseudogene in a subset of 90 individuals. We find that both the ancient TMRCA and the skew in non-African representation in one of the basal clades are essentially limited to the central 2.4-kb region. We define a new summary statistic called the minimum clade proportion (pmc), which quantifies the proportion of individuals from a specified geographic region in each of the two basal clades of a binary gene tree, and then employ coalescent simulations to assess the likelihood of the observed central RRM2P4 genealogy under two alternative views of human evolutionary history: recent African replacement (RAR) and archaic admixture (AA). A molecular-clock-based TMRCA estimate of 2.33 million years is a statistical outlier under the RAR model; however, the large variance associated with this estimate makes it difficult to distinguish the predictions of the human origins models tested here. The pmc summary statistic, which has improved power with larger samples of chromosomes, yields values that are significantly unlikely under the RAR model and fit expectations better under a range of archaic admixture scenarios. PMID:18202385

Selected results from LLNL-Hughes RAR for West Coast Scotland Experiment 1992

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

Lehman, S.K.; Johnston, B.; Twogood, R.

1993-01-05

The joint US-UK 1992 West Coast Scotland Experiment (WCSEX) was held in the Sound of Sleat from June 6 to 25. The LLNL-Hughes team fielded a fully polarimetric X-band hill-side real aperture radar to collect internal wave wake data. We present here a sample data set of the best radar runs.

Two Reading Assessments for Youth in Alternative Basic Skills and Livelihood Skills Training Programs

ERIC Educational Resources Information Center

Comings, John P.; Strucker, John; Bell, Brenda

2017-01-01

This article describes two assessment tools that have been used to assess the reading skills of youth participating in alternative basic skills and livelihood skills training programs. The Rapid Assessment of Reading Skills (RARS) was developed to identify potential participants who needed to improve their reading skills before beginning training…

Synergistic activation of Arg1 gene by retinoic acid and IL-4 involves chromatin remodeling for transcription initiation and elongation coupling

PubMed Central

Lee, Bomi; Wu, Cheng-Ying; Lin, Yi-Wei; Park, Sung Wook; Wei, Li-Na

2016-01-01

All-trans Retinoic acid (RA) and its derivatives are potent therapeutics for immunological functions including wound repair. However, the molecular mechanism of RA modulation in innate immunity is poorly understood, especially in macrophages. We found that topical application of RA significantly improves wound healing and that RA and IL-4 synergistically activate Arg1, a critical gene for tissue repair, in M2 polarized macrophages. This involves feed forward regulation of Raldh2, a rate-limiting enzyme for RA biosynthesis, and requires Med25 to coordinate RAR, STAT6 and chromatin remodeler, Brg1 to remodel the +1 nucleosome of Arg1 for transcription initiation. By recruiting elongation factor TFIIS, Med25 also facilitates transcriptional initiation-elongation coupling. This study uncovers synergistic activation of Arg1 by RA and IL-4 in M2 macrophages that involves feed forward regulation of RA synthesis and dual functions of Med25 in nucleosome remodeling and transcription initiation-elongation coupling that underlies robust modulatory activity of RA in innate immunity. PMID:27166374

Isotretinoin revisited: pluripotent effects on human sebaceous gland cells.

PubMed

Zouboulis, Christos C

2006-10-01

Nelson et al. confirmed the previously described antiproliferative effect of isotretinoin on human sebocytes. They attributed a portion of this decrease to cell cycle arrest and detected sebocyte apoptosis, which was not recapitulated by alitretinoin or tretinoin. These events were specific to sebocytes, as isotretinoin failed to induce apoptosis in keratinocytes. Isotretinoin-induced apoptosis was shown to be an RAR-independent mechanism.

Promoter methylation of E-cadherin, p16, and RAR-beta(2) genes in breast tumors and dietary intake of nutrients important in one-carbon metabolism

USDA-ARS?s Scientific Manuscript database

Aberrant DNA methylation plays a critical role in carcinogenesis, and the availability of dietary factors involved in 1-carbon metabolism may contribute to aberrant DNA methylation. We investigated the association of intake of folate, vitamins B(2), B(6), B(12), and methionine with promoter methylat...

Is retinoic acid genetic machinery a chordate innovation?

PubMed

Cañestro, Cristian; Postlethwait, John H; Gonzàlez-Duarte, Roser; Albalat, Ricard

2006-01-01

Development of many chordate features depends on retinoic acid (RA). Because the action of RA during development seems to be restricted to chordates, it had been previously proposed that the "invention" of RA genetic machinery, including RA-binding nuclear hormone receptors (Rars), and the RA-synthesizing and RA-degrading enzymes Aldh1a (Raldh) and Cyp26, respectively, was an important step for the origin of developmental mechanisms leading to the chordate body plan. We tested this hypothesis by conducting an exhaustive survey of the RA machinery in genomic databases for twelve deuterostomes. We reconstructed the evolution of these genes in deuterostomes and showed for the first time that RA genetic machinery--that is Aldh1a, Cyp26, and Rar orthologs--is present in nonchordate deuterostomes. This finding implies that RA genetic machinery was already present during early deuterostome evolution, and therefore, is not a chordate innovation. This new evolutionary viewpoint argues against the hypothesis that the acquisition of gene families underlying RA metabolism and signaling was a key event for the origin of chordates. We propose a new hypothesis in which lineage-specific duplication and loss of RA machinery genes could be related to the morphological radiation of deuterostomes.

Aldose reductase inhibitory compounds from Xanthium strumarium.

PubMed

Yoon, Ha Na; Lee, Min Young; Kim, Jin-Kyu; Suh, Hong-Won; Lim, Soon Sung

2013-09-01

As part of our ongoing search for natural sources of therapeutic and preventive agents for diabetic complications, we evaluated the inhibitory effects of components of the fruit of Xanthium strumarium (X. strumarium) on aldose reductase (AR) and galactitol formation in rat lenses with high levels of glucose. To identify the bioactive components of X. strumarium, 7 caffeoylquinic acids and 3 phenolic compounds were isolated and their chemical structures were elucidated on the basis of spectroscopic evidence and comparison with published data. The abilities of 10 X. strumarium-derived components to counteract diabetic complications were investigated by means of inhibitory assays with rat lens AR (rAR) and recombinant human AR (rhAR). From the 10 isolated compounds, methyl-3,5-di-O-caffeoylquinate showed the most potent inhibition, with IC₅₀ values of 0.30 and 0.67 μM for rAR and rhAR, respectively. In the kinetic analyses using Lineweaver-Burk plots of 1/velocity and 1/substrate, methyl-3,5-di-O-caffeoylquinate showed competitive inhibition of rhAR. Furthermore, methyl-3,5-di-O-caffeoylquinate inhibited galactitol formation in the rat lens and in erythrocytes incubated with a high concentration of glucose, indicating that this compound may be effective in preventing diabetic complications.

Assessment of an apparent relationship between availability of soluble carbohydrates and reduced nitrogen during floral initiation in tobacco

NASA Technical Reports Server (NTRS)

Raper, C. D. Jr; Thomas, J. F.; Tolley-Henry, L.; Rideout, J. W.; Raper CD, J. r. (Principal Investigator)

1988-01-01

Daily relative accumulation rate of soluble carbohydrates (RARS) and reduced nitrogen (RARN) in the shoot, as estimates of source strength, were compared with daily relative growth rates (RGR) of the shoot, as an estimate of sink demand, during floral transformation in apical meristems of tobacco (Nicotiana tabacum 'NC 2326') grown at day/night temperatures of 18/14, 22/18, 26/22, 30/26, and 34/30 C. Source strength was assumed to exceed sink demand for either carbohydrates or nitrogen when the ratio of RARS/RGR or RARN/RGR was greater than unity, and sink demand was assumed to exceed source strength when the ratio was less than unity. Time of floral initiation, which was delayed up to 21 days with increases in temperature over the experimental range, was associated with intervals in which source strength of either carbohydrate or nitrogen exceeded sink demand, while sink demand for the other exceeded source strength. Floral initiation was not observed during intervals in which source strengths of both carbohydrates and nitrogen were greater than or less than sink demand. These results indicate that floral initiation is responsive to an imbalance in the relative availabilities of carbohydrate and nitrogen.

SIGNALLING THROUGH RETINOIC ACID RECEPTORS IN CARDIAC DEVELOPMENT: DOING THE RIGHT THINGS AT THE RIGHT TIMES

PubMed Central

Xavier-Neto, José; Costa, Ângela M. Sousa; Figueira, Ana Carolina M.; Caiaffa, Carlo Donato; do Amaral, Fabio Neves; Peres, Lara Maldanis Cerqueira; da Silva, Bárbara Santos Pires; Santos, Luana Nunes; Moise, Alexander R.; Castillo, Hozana Andrade

2015-01-01

Retinoic acid (RA) is a terpenoid that is synthesized from Vitamin A/retinol (ROL) and binds to the nuclear receptors retinoic acid receptor (RAR)/retinoid X receptor (RXR) to control multiple developmental processes in vertebrates. The available clinic and experimental data provide uncontested evidence for the pleiotropic roles of RA signalling in development of multiple embryonic structures and organs such eyes, central nervous system, gonads, lungs and heart. The development of any of these above-mentioned embryonic organ systems can be effectively utilized to showcase the many strategies utilized by RA signalling. However, it is very likely that the strategies employed to transfer RA signals during cardiac development comprise the majority of the relevant and sophisticated ways through which retinoid signals can be conveyed in a complex biological system. Here, we provide the reader with arguments indicating that RA signalling is exquisitely regulated according to specific phases of cardiac development and that RA signalling itself is one of the major regulators of the timing of cardiac morphogenesis and differentiation. We will focus on the role of signalling by RA receptors (RARs) in early phases of heart development. PMID:25134739

Coordinated gene expression during gilthead sea bream skeletogenesis and its disruption by nutritional hypervitaminosis A.

PubMed

Fernández, Ignacio; Darias, Maria; Andree, Karl B; Mazurais, David; Zambonino-Infante, Jose Luís; Gisbert, Enric

2011-02-09

Vitamin A (VA) has a key role in vertebrate morphogenesis, determining body patterning and growth through the control of cell proliferation and differentiation processes. VA regulates primary molecular pathways of those processes by the binding of its active metabolite (retinoic acid) to two types of specific nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which promote transcription of downstream target genes. This process is well known in most of higher vertebrates; however, scarce information is available regarding fishes. Therefore, in order to gain further knowledge of fish larval development and its disruption by nutritional VA imbalance, the relative expression of some RARs and RXRs, as well as several genes involved in morpho- and skeletogenesis such as peroxisome proliferator-activated receptors (PPARA, PPARB and PPARG); retinol-binding protein (RBP); insulin-like growth factors I and II (IGF1 and IGF2, respectively); bone morphogenetic protein 2 (Bmp2); transforming growth factor β-1 (TGFB1); and genes encoding different extracellular matrix (ECM) proteins such as matrix Gla protein (mgp), osteocalcin (bglap), osteopontin (SPP1), secreted protein acidic and rich in cysteine (SPARC) and type I collagen α1 chain (COL1A1) have been studied in gilthead sea bream. During gilthead sea bream larval development, specific expression profiles for each gene were tightly regulated during fish morphogenesis and correlated with specific morphogenetic events and tissue development. Dietary hypervitaminosis A during early larval development disrupted the normal gene expression profile for genes involved in RA signalling (RARA), VA homeostasis (RBP) and several genes encoding ECM proteins that are linked to skeletogenesis, such as bglap and mgp. Present data reflects the specific gene expression patterns of several genes involved in larval fish RA signalling and skeletogenesis; and how specific gene disruption induced by a nutritional VA imbalance underlie the skeletal deformities. Our results are of basic interest for fish VA signalling and point out some of the potential molecular players involved in fish skeletogenesis. Increased incidences of skeletal deformities in gilthead sea bream fed with hypervitaminosis A were the likely ultimate consequence of specific gene expression disruption at critical development stages.

Coordinated gene expression during gilthead sea bream skeletogenesis and its disruption by nutritional hypervitaminosis A

PubMed Central

2011-01-01

Background Vitamin A (VA) has a key role in vertebrate morphogenesis, determining body patterning and growth through the control of cell proliferation and differentiation processes. VA regulates primary molecular pathways of those processes by the binding of its active metabolite (retinoic acid) to two types of specific nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which promote transcription of downstream target genes. This process is well known in most of higher vertebrates; however, scarce information is available regarding fishes. Therefore, in order to gain further knowledge of fish larval development and its disruption by nutritional VA imbalance, the relative expression of some RARs and RXRs, as well as several genes involved in morpho- and skeletogenesis such as peroxisome proliferator-activated receptors (PPARA, PPARB and PPARG); retinol-binding protein (RBP); insulin-like growth factors I and II (IGF1 and IGF2, respectively); bone morphogenetic protein 2 (Bmp2); transforming growth factor β-1 (TGFB1); and genes encoding different extracellular matrix (ECM) proteins such as matrix Gla protein (mgp), osteocalcin (bglap), osteopontin (SPP1), secreted protein acidic and rich in cysteine (SPARC) and type I collagen α1 chain (COL1A1) have been studied in gilthead sea bream. Results During gilthead sea bream larval development, specific expression profiles for each gene were tightly regulated during fish morphogenesis and correlated with specific morphogenetic events and tissue development. Dietary hypervitaminosis A during early larval development disrupted the normal gene expression profile for genes involved in RA signalling (RARA), VA homeostasis (RBP) and several genes encoding ECM proteins that are linked to skeletogenesis, such as bglap and mgp. Conclusions Present data reflects the specific gene expression patterns of several genes involved in larval fish RA signalling and skeletogenesis; and how specific gene disruption induced by a nutritional VA imbalance underlie the skeletal deformities. Our results are of basic interest for fish VA signalling and point out some of the potential molecular players involved in fish skeletogenesis. Increased incidences of skeletal deformities in gilthead sea bream fed with hypervitaminosis A were the likely ultimate consequence of specific gene expression disruption at critical development stages. PMID:21306609

The role of retinoic acid receptors and their cognate ligands in reproduction in a context of triorganotin based endocrine disrupting chemicals.

PubMed

Macejova, Dana; Toporova, L; Brtko, J

2016-07-01

Retinoic acid (RA), an active form of vitamin A, regulates the embryonic development, male and female reproduction and induces important effects on the cell development, proliferation, and differentiation. These effects are mediated by the retinoid (RAR) and rexinoid nuclear receptors (RXR), which are considered to be a ligand-activated, DNA-binding, trans-acting, and transcription-modulating proteins, involved in a general molecular mechanism responsible for the transcriptional responses in target genes. Organotin compounds are typical environmental contaminants and suspected endocrine disrupting substances. They may affect processes of reproductive system in mammals, predominantly via nuclear receptor signaling pathways. Triorganotins, such as tributyltin chloride (TBTCl) and triphenyltin chloride (TPTCl), are capable to bind to RXR molecules, and thus represent potent agonists of RXR subtypes of nuclear receptors not sharing any structural characteristics with endogenous ligands of nuclear receptors. Th is article summarizes selected effects of biologically active retinoids and rexinoids on both male and female reproduction and also deals with the effects of organotin compounds evoking endocrine disrupting actions in reproduction.

RAR Beta: Actions in Prostate Cancer

DTIC Science & Technology

2005-04-01

spermine Nl-acetyltransferase Although prostate cancer can be clinically managed in its (SSAT) regulates the catabolism and export of intracellu- early...in anticancer strategies for spermidine and spermine pools were minimally de- some time (4). Various antagonists such as the ODC inhibitor creased due...Spm, spermine ; SSAT, spermidine/ spermine N’-acetyl- dressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer transferase; Tag, SV40 large T

Bulk Extractor 1.4 User’s Manual

DTIC Science & Technology

2013-08-01

optimistically decompresses data in ZIP, GZIP, RAR, and Mi- crosoft’s Hibernation files. This has proven useful, for example, in recovering email...command line. Java 7 or above must be installed on the machine for the Bulk Extractor Viewer to run. Instructions on running bulk_extractor from the... Hibernation File Fragments (decompressed and processed, not carved) Subsection 4.6 winprefetch Windows Prefetch files, file fragments (processed

Man-Machine Impact of Technology on Coast Guard Missions and Systems

DTIC Science & Technology

1979-12-01

t Cost of Rar~dom, Acce~ss eoy~mAlr 97 f-Al 1000 MOS RAM-(409 BITS/CHIP) . 100 _ I• z LLJ 10 (I) UI 1.04 I.-I- ’ YEAR ii A .. I. FiueA-.oecs pedo ...of these advances will iTOSt likely be accomplished through focal plane arrays of detectors, charge coupled device readout techniques for the video

A rapid assessment and response approach to review and enhance Advocacy, Communication and Social Mobilisation for Tuberculosis control in Odisha state, India

PubMed Central

2011-01-01

Background Tuberculosis remains a major public health problem in India with the country accounting for 1 in 5 of all TB cases reported globally. An advocacy, communication and social mobilisation project for Tuberculosis control was implemented and evaluated in Odisha state of India. The purpose of the study was to identify the impact of project interventions including the use of 'Interface NGOs' and involvement of community groups such as women's self-help groups, local government bodies, village health sanitation committees, and general health staff in promoting TB control efforts. Methods The study utilized a rapid assessment and response (RAR) methodology. The approach combined both qualitative field work approaches, including semi-structured interviews and focus group discussions with empirical data collection and desk research. Results Results revealed that a combination of factors including the involvement of Interface NGOs, coupled with increased training and engagement of front line health workers and community groups, and dissemination of community based resources, contributed to improved awareness and knowledge about TB in the targeted districts. Project activities also contributed towards improving health worker and community effectiveness to raise the TB agenda, and improved TB literacy and treatment adherence. Engagement of successfully treated patients also assisted in reducing community stigma and discrimination. Conclusion The expanded use of advocacy, communication and social mobilisation activities in TB control has resulted in a number of benefits. These include bridging pre-existing gaps between the health system and the community through support and coordination of general health services stakeholders, NGOs and the community. The strategic use of 'tailored messages' to address specific TB problems in low performing areas also led to more positive behavioural outcomes and improved efficiencies in service delivery. Implications for future studies are that a comprehensive and well planned range of ACSM activities can enhance TB knowledge, attitudes and behaviours while also mobilising specific community groups to build community efficacy to combat TB. The use of rapid assessments combined with other complementary evaluation approaches can be effective when reviewing the impact of TB advocacy, communication and social mobilisation activities. PMID:21663623

A rapid assessment and response approach to review and enhance advocacy, communication and social mobilisation for tuberculosis control in Odisha state, India.

PubMed

Kamineni, Vishnu Vardhan; Turk, Tahir; Wilson, Nevin; Satyanarayana, Srinath; Chauhan, Lakbir Singh

2011-06-10

Tuberculosis remains a major public health problem in India with the country accounting for 1 in 5 of all TB cases reported globally. An advocacy, communication and social mobilisation project for Tuberculosis control was implemented and evaluated in Odisha state of India. The purpose of the study was to identify the impact of project interventions including the use of 'Interface NGOs' and involvement of community groups such as women's self-help groups, local government bodies, village health sanitation committees, and general health staff in promoting TB control efforts. The study utilized a rapid assessment and response (RAR) methodology. The approach combined both qualitative field work approaches, including semi-structured interviews and focus group discussions with empirical data collection and desk research. Results revealed that a combination of factors including the involvement of Interface NGOs, coupled with increased training and engagement of front line health workers and community groups, and dissemination of community based resources, contributed to improved awareness and knowledge about TB in the targeted districts. Project activities also contributed towards improving health worker and community effectiveness to raise the TB agenda, and improved TB literacy and treatment adherence. Engagement of successfully treated patients also assisted in reducing community stigma and discrimination. The expanded use of advocacy, communication and social mobilisation activities in TB control has resulted in a number of benefits. These include bridging pre-existing gaps between the health system and the community through support and coordination of general health services stakeholders, NGOs and the community. The strategic use of 'tailored messages' to address specific TB problems in low performing areas also led to more positive behavioural outcomes and improved efficiencies in service delivery. Implications for future studies are that a comprehensive and well planned range of ACSM activities can enhance TB knowledge, attitudes and behaviours while also mobilising specific community groups to build community efficacy to combat TB. The use of rapid assessments combined with other complementary evaluation approaches can be effective when reviewing the impact of TB advocacy, communication and social mobilisation activities.

Embryonic subcellular distribution of 13-cis- and all-trans-retinoic acid indicates differential cytosolic/nuclear localization.

PubMed

Rühl, R; Plum, C; Elmazar, M M; Nau, H

2001-09-01

Isotretinoin (13-cis-retinoic acid [13CRA], Accutane) is used for the treatment of dermatological diseases. Isotretinoin is, however, teratogenic in animals and humans. The mechanism of action of its teratogenicity is still not clearly identified. It has little or no binding properties to cytosolic retinoid-binding proteins or nuclear retinoid receptors (RAR, RXR). One hypothesis is that the teratogenicity of 2 approximately equipotent teratogenic doses of 13CRA and all-trans-retinoic acids (ATRA) could mainly be correlated to ATRA in the nuclei, where the retinoic acid receptors (RARs) are located. To test this hypothesis, female mice at gestational day 11 were treated with approximately equipotent teratogenic doses of 13-cis-retinoic acid (100 mg/kg orally) or all-trans-retinoic acid (10 mg/kg orally) and sacrificed 1 h and 4 h after administration. Embryos were homogenized and centrifuged into 4 fractions, and the purity of the fractions was tested by quantification of marker constituents for various cell compartments. We analyzed, by RP-HPLC, nuclear, mitochondrial, microsomal, and cytosolic fractions, as well as embryo homogenate and maternal plasma. After treatment with 13-cis-retinoic acid, this substance was mainly located in the nuclear fraction of the embryo (approximately 82%), whereas all-trans-retinoic acid, after ATRA treatment, was mainly located in the cytosolic supernatant (approximately 64%). The binding to cellular retinoid-binding protein (CRABP) may limit the access of ATRA to the nucleus, in contrast to 13CRA, which does not bind to CRABP. The concentration of ATRA in the nuclear fraction was similar after administration of either 13CRA or ATRA. The teratogenic activity of 13-cis-retinoic acid could therefore be explained by its access to the nucleus and its possible conversion to all-trans-retinoic acids, which will interact with the nuclear retinoid receptors.

Vitamin A Is a Negative Regulator of Osteoblast Mineralization

PubMed Central

Hu, Lijuan; Pejler, Gunnar; Andersson, Göran; Jacobson, Annica; Melhus, Håkan

2013-01-01

An excessive intake of vitamin A has been associated with an increased risk of fractures in humans. In animals, a high vitamin A intake leads to a reduction of long bone diameter and spontaneous fractures. Studies in rodents indicate that the bone thinning is due to increased periosteal bone resorption and reduced radial growth. Whether the latter is a consequence of direct effects on bone or indirect effects on appetite and general growth is unknown. In this study we therefore used pair-feeding and dynamic histomorphometry to investigate the direct effect of a high intake of vitamin A on bone formation in rats. Although there were no differences in body weight or femur length compared to controls, there was an approximately halved bone formation and mineral apposition rate at the femur diaphysis of rats fed vitamin A. To try to clarify the mechanism(s) behind this reduction, we treated primary human osteoblasts and a murine preosteoblastic cell line (MC3T3-E1) with the active metabolite of vitamin A; retinoic acid (RA), a retinoic acid receptor (RAR) antagonist (AGN194310), and a Cyp26 inhibitor (R115866) which blocks endogenous RA catabolism. We found that RA, via RARs, suppressed in vitro mineralization. This was independent of a negative effect on osteoblast proliferation. Alkaline phosphatase and bone gamma carboxyglutamate protein (Bglap, Osteocalcin) were drastically reduced in RA treated cells and RA also reduced the protein levels of Runx2 and Osterix, key transcription factors for progression to a mature osteoblast. Normal osteoblast differentiation involved up regulation of Cyp26b1, the major enzyme responsible for RA degradation, suggesting that a drop in RA signaling is required for osteogenesis analogous to what has been found for chondrogenesis. In addition, RA decreased Phex, an osteoblast/osteocyte protein necessary for mineralization. Taken together, our data indicate that vitamin A is a negative regulator of osteoblast mineralization. PMID:24340023

Analysis of Hairless Corepressor Mutants to Characterize Molecular Cooperation with the Vitamin D Receptor in Promoting the Mammalian Hair Cycle

PubMed Central

Hsieh, Jui-Cheng; Slater, Stephanie A.; Whitfield, G. Kerr; Dawson, Jamie L.; Hsieh, Grace; Sheedy, Craig; Haussler, Carol A.; Haussler, Mark R.

2010-01-01

The mammalian hair cycle requires both the vitamin D receptor (VDR) and the hairless (Hr) corepressor, each of which is expressed in the hair follicle. Hr interacts directly with VDR to repress VDR-targeted transcription. Herein, we further map the VDR-interaction domain to regions in the C-terminal half of Hr that contain two LXXLL-like pairs of motifs known to mediate contact of Hr with the RAR-related orphan receptor alpha and with the thyroid hormone receptor, respectively. Site-directed mutagenesis indicates that all four hydrophobic motifs are required for VDR transrepression by Hr. Point mutation of rat Hr at conserved residues corresponding to natural mutants causing alopecia in mice (G985W and a C-terminal deletion ΔAK) and in humans (P95S, C422Y, E611G, R640Q, C642G, N988S, D1030N, A1040T, V1074M and V1154D), as well as alteration of residues in the C-terminal Jumonji C domain implicated in histone demethylation activity (C1025G/E1027G and H1143G) revealed that all Hr mutants retained VDR association, and that transrepressor activity was selectively abrogated in C642G, G985W, N988S, D1030N, V1074M, H1143G and V1154D. Four of these latter Hr mutants (C642G, N988S, D1030N and V1154D) were found to associate normally with histone deacetylase-3. Finally, we identified three regions of human VDR necessary for association with Hr, namely residues 109–111, 134–201, and 202–303. It is concluded that Hr and VDR interact via multiple protein-protein interfaces, with Hr recruiting histone deacetylases and possibly itself catalyzing histone demethylation to effect chromatin remodeling and repress the transcription of VDR target genes that control the hair cycle. PMID:20512927

U.S. EPA, Pesticide Product Label, PINE-CUE 212 DISINFECTING DEODORIZING CLEANER, 01/24/1983

EPA Pesticide Factsheets

2011-04-21

... 1 r.A'~r /r /,,!. 1:1 -"- - ,ClE- l"h.1I1l·(· .. an 1 •• I·t lin.' f. tn",ll,l

XXIV Corps Action Report

DTIC Science & Technology

1945-06-01

looses, Whoa tea ligt of sutiiürinad exeogs eqaipiaeet booane as tab Mr had, eftov -tz.. sare i&estttuteä to obtain it». Eov~ rar, because of ehangeä...shelter, food and medical service wore thvs ?va^l- ^*Tft für an* reason caäualfiiea were of necessity Sid -73 - UNCLASSIFIED BSXCH XX...their duties included posting proclamations, locating civilian food and medical supplies, establishing collec- tion centers, and evacuating

Multiparameter flow cytometry reveals myelodysplasia-related aberrant antigen expression in myelodysplastic/myeloproliferative neoplasms.

PubMed

Kern, Wolfgang; Bacher, Ulrike; Schnittger, Susanne; Alpermann, Tamara; Haferlach, Claudia; Haferlach, Torsten

2013-05-01

Within the myelodysplastic/myeloproliferative neoplasm (MDS/MPN) category of the WHO (2008), only chronic myelomonocytic leukemia was so far evaluated by multiparameter flow cytometry (MFC). To investigate the potential of MFC for MDS/MPNs, unclassifiable (MDS/MPNu), and refractory anemia associated with ring sideroblasts and marked thrombocytosis (RARS-T), we studied 91 patients with these entities (60 males/31 females; 35.3-87.4 years) for MDS-related aberrant immunophenotypes (≥ 2 different cell lineages with ≥ 3 aberrantly expressed antigens). Data were correlated with cytomorphology and cytogenetics. MFC identified MDS-related immunophenotypes in 54/91 (59.3%) of patients. Patients with or without MDS-related immunophenotype did not differ significantly by demographic characteristics, blood values, or median overall survival. MDS-related immunophenotype cases showed a higher number of aberrantly expressed antigens (mean ± SD, 4.9 ± 2.4 vs. 2.0 ± 1.4; P < 0.001). Aberrant karyotypes showed a similar frequency in patients with and without MDS-related immunophenotype (11/54; 20.4% vs. 7/37; 18.9%; P = n.s.). MDS-related immunophenotype are present in more than half of patients with MDS/MPNu and RARS-T. MFC therefore may be helpful to separate cases into more "MDS-like" or "MPN-like" subgroups. Copyright © 2012 International Clinical Cytometry Society.

A proposed experimental diagnosing of specular Andreev reflection using the spin orbit interaction

PubMed Central

Yang, Yanling; Zhao, Bing; Zhang, Ziyu; Bai, Chunxu; Xu, Xiaoguang; Jiang, Yong

2016-01-01

Based on the Dirac-Bogoliubov-de Gennes equation, we theoretically investigate the chirality-resolved transport properties through a superconducting heterojunction in the presence of both the Rashba spin orbit interaction (RSOI) and the Dresselhaus spin orbit interaction (DSOI). Our results show that, if only the RSOI is present, the chirality-resolved Andreev tunneling conductance can be enhanced in the superconducting gap, while it always shows a suppression effect for the case of the DSOI alone. In contrast to the similar dependence of the specular Andreev zero bias tunneling conductance on the SOI, the retro-Andreev zero bias tunneling conductance exhibit the distinct dependence on the RSOI and the DSOI. Moreover, the zero-bias tunneling conductances for the retro-Andreev reflection (RAR) and the specular Andreev reflection (SAR) also show a qualitative difference with respect to the barrier parameters. When the RSOI and the DSOI are finite, three orders of magnitude enhancement of specular Andreev tunneling conductance is revealed. Furthermore, by analyzing the balanced SOI case, we find that the RAR is in favor of a parabolic dispersion, but a linear dispersion is highly desired for the SAR. These results shed light on the diagnosing of the SAR in graphene when subjected to both kinds of SOI. PMID:27388426

Morphology of presumptive rapidly adapting receptors in the rat bronchus.

PubMed Central

Kappagoda, C T; Skepper, J N; McNaughton, L; Siew, E E; Navaratnam, V

1990-01-01

The present investigation was undertaken in rats to determine whether sensory nerves exist in apposition to the bronchial microvessels which may function as rapidly adapting receptors (RAR). The primary and secondary bronchi on both sides were removed and processed for light and electron microscopy. Nerves were frequently found in relation to venules external to the muscle coat of bronchi. They comprised myelinated axons which ended individually as non-myelinated convoluted terminals enclosed within a loose capsule of attenuated cells. Serial sections showed that these terminals were not related to ganglion cells. Cervical vagal section and injection of HRP-WGA into the nodose ganglion provided corroborative evidence of the sensory nature of these terminals. Vagal section caused degenerative changes in the encapsulated nerve terminals in the bronchial walls and horseradish peroxidase labelling was demonstrable in such terminals. Moreover, immunocytochemical studies demonstrated the presence of calcitonin gene regulated peptide and substance P in these structures. It is suggested that they comprise the RAR. Encapsulated nerve terminals were not found in the epithelial layer, in the submucous coat or in the muscularis of bronchi. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 PMID:1691164

Dysregulated endocardial TGFβ signaling and mesenchymal transformation result in heart outflow tract septation failure.

PubMed

Ma, Mancheong; Li, Peng; Shen, Hua; Estrada, Kristine D; Xu, Jian; Kumar, S Ram; Sucov, Henry M

2016-01-01

Heart outflow tract septation in mouse embryos carrying mutations in retinoic acid receptor genes fails with complete penetrance. In this mutant background, ectopic TGFβ signaling in the distal outflow tract is responsible for septation failure, but it was uncertain what tissue was responsive to ectopic TGFβ and why this response interfered with septation. By combining RAR gene mutation with tissue-specific Cre drivers and a conditional type II TGFβ receptor (Tgfbr2) allele, we determined that ectopic activation of TGFβ signaling in the endocardium is responsible for septation defects. Ectopic TGFβ signaling results in ectopic mesenchymal transformation of the endocardium and thereby in improperly constituted distal OFT cushions. Our analysis highlights the interactions between myocardium, endocardium, and neural crest cells in outflow tract morphogenesis, and demonstrates the requirement for proper TGFβ signaling in outflow tract cushion organization and septation. Copyright © 2015. Published by Elsevier Inc.

Selected results from LLNL-Hughes RAR for West Coast Scotland Experiment 1991

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

Lehman, S K; Johnston, B; Twogood, R

1993-01-05

The joint US -- UK 1991 West Coast Scotland Experiment (WCSEX) was held in two locations. From July 5 to 12, 1991, in Upper Loch Linnhe, and from July 18 to July 26, 1991, in the Sound of Sleat. The LLNL-Hughes team fielded a fully polarimetric X-band hill-side real aperture radar to collect internal wave wake data. We present here a sample data set of the best radar runs.

[Analysis of clinical relevance applied to 3methods of reducing weight in overweight or obesity followed-up for one year].

PubMed

Tárraga Marcos, M L; Panisello Royo, J M; Carbayo Herencia, J A; Rosich Domenech, N; Alins Presas, J; Castell Panisello, E; Tárraga López, P J

To analyse the effect of the use/implementation of 3methods to reduce weight in overweight or obese patients during one year of follow up. The design corresponds to a double-blind, randomised, controlled clinical trial with 3arms, and 12 months of follow-up. Patients were randomised into 3intervention groups: obesity motivational intervention, with a nurse previously trained in motivational intervention by expert psychologists (G1; n=60); lower intensity consultation, non-motivational group, with digital platform support (G2; N=61), and a third group that received recommendations for weight loss and follow-up in Primary Care Clinic (G3; n=59). Anthropometric variables (weight, height, and abdominal-waist circumference) were measured, and the percentage of patients who managed to reduce their weight ≥5% was considered as the main measurement of treatment effectiveness. All groups significantly decreased body weight at the end of the study, with a reduction in G1 (-5.6kg) followed by G2 (-4.3kg), and G3 (-1.7kg), with an overall mean: -3.9kg. The indicators of clinical relevance were in G1/G3: relative risk (RR): 4.99 (95% CI: from 2.71 to 9.18); relative risk reduction (RRR): 399.1% (171.3 to 818.0); Absolute risk reduction (RAR): 65.3% (from 51.5 to 79.1) and NNT: 2 (from 2 to 2). In the G2/G3 groups: RR: 3.01 (from 1.57 to 5.76); RRR: 200.5% (from 57.0 to 475.5); RAR: 32.8% (from 16.9 to 48.7) and NNT: 4 (from 3 to 6). In the G1/G2 groups: RR: 1.66 (from 1.25 to 2.20); RRR: 66.1% (from 25.3 to 120.1); RAR: 32.5% (from 16.6 to 48.4) and NNT: 4 (from 3 to 7). All 3groups were able to reduce weight. Although the group with motivational intervention achieved the greatest decrease, as well as the most favourable clinical relevance indicators. Copyright © 2017 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

Toll/Interleukin-1 Receptor Domain Derived from TcpC (TIR-TcpC) Ameliorates Experimental Autoimmune Arthritis by Down-modulating Th17 Cell Response*

PubMed Central

Pasi, Shweta; Kant, Ravi; Surolia, Avadhesha

2016-01-01

Evasion through immunomodulation is one of the several strategies adopted by pathogens to prolong their survival within the host. One such pathogen, Escherichia coli CFT073, utilizes an immunomodulatory protein, TcpC, to combat the host's innate immune defense. TcpC abrogates the function of MyD88 in macrophages, thus perturbing all the signaling processes that involve this adaptor protein. Although central to various signaling pathways initiated by IL-1, IL-18, and toll-like receptors, the precise contribution of MyD88 to the development of autoimmunity, particularly rheumatoid arthritis, still needs extensive exploration. Herein, by using the toll/interleukin-1 receptor (TIR) domain homologous C-terminal motif of TcpC, i.e. TIR-TcpC, we found MyD88 to be critical for the induction and progression of rheumatoid arthritis through its pivotal role in the development of Th17 cells, the subset of CD4+ T-cells widely implicated in various autoimmune disorders. The TIR-TcpC mediated inhibition of signaling through MyD88, and subsequent amelioration of experimental autoimmune arthritis was observed to be an outcome of perturbations in the NFκB-RORγt (RAR-related orphan receptor γt) axis. PMID:27022030

An MPL W515L mutation in refractory anemia with ringed sideroblasts associated with marked thrombocytosis: A case report.

PubMed

Hao, Lin; Sen, Sandeep; Sugumar, Dhivya

2015-02-01

The current study presents the case of a 63-year-old patient exhibiting refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), who was positive for the MPL W515L mutation, but negative for the JAK2 V617F mutation. Following diagnosis, the patient remained asymptomatic for over three years, however, in August 2012, the patient relapsed and was administered with supportive treatment in the form of subcutaneous darbepoetin α at a dose of 300 μg/week, which resulted in an increased hemoglobin concentration, allowing the patient to remain transfusion-independent. The MPL W515L mutation has been reported in two previous cases of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) with ringed sideroblasts, however, to the best of our knowledge, the current report is the first to present a case of RARS-T with an MPL W515L mutation. A clinical trial designed to evaluate the efficacy of a targeted agent against the JAK2 V617F mutation is currently ongoing, with the aim of providing a novel therapeutic strategy for treating MDS/MPN patients. As MPL is located upstream of the JAK-STAT signaling pathway, it is a possible therapeutic target in MDS/MPN patients positive for an MPL W515L mutation, but negative for a JAK2 V617F mutation.

Annotation of the Nuclear Receptors in an Estuarine Fish species, Fundulus heteroclitus

PubMed Central

Baldwin, William S.; Boswell, W. Tyler; Ginjupalli, Gautam; Litoff, Elizabeth J.

2017-01-01

The nuclear receptors (NRs) are ligand-dependent transcription factors that respond to various internal as well as external cues such as nutrients, pheromones, and steroid hormones that play crucial roles in regulation and maintenance of homeostasis and orchestrating the physiological and stress responses of an organism. We annotated the Fundulus heteroclitus (mummichog; Atlantic killifish) nuclear receptors. Mummichog are a non-migratory, estuarine fish with a limited home range often used in environmental research as a field model for studying ecological and evolutionary responses to variable environmental conditions such as salinity, oxygen, temperature, pH, and toxic compounds because of their hardiness. F. heteroclitus have at least 74 NRs spanning all seven gene subfamilies. F. heteroclitus is unique in that no RXRα member was found within the genome. Interestingly, some of the NRs are highly conserved between species, while others show a higher degree of divergence such as PXR, SF1, and ARα. Fundulus like other fish species show expansion of the RAR (NR1B), Rev-erb (NR1D), ROR (NR1F), COUPTF (NR2F), ERR (NR3B), RXR (NR2B), and to a lesser extent the NGF (NR4A), and NR3C steroid receptors (GR/AR). Of particular interest is the co-expansion of opposing NRs, Reverb-ROR, and RAR/RXR-COUPTF. PMID:28804711

13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes.

PubMed

Nelson, Amanda M; Gilliland, Kathryn L; Cong, Zhaoyuan; Thiboutot, Diane M

2006-10-01

Isotretinoin (13-cis retinoic acid (13-cis RA)) is the most potent inhibitor of sebum production, a key component in the pathophysiology of acne, yet its mechanism of action remains largely unknown. The effects of 13-cis RA, 9-cis retinoic acid (9-cis RA), and all-trans retinoic acid (ATRA) on cell proliferation, apoptosis, and cell cycle proteins were examined in SEB-1 sebocytes and keratinocytes. 13-cis RA causes significant dose-dependent and time-dependent decreases in viable SEB-1 sebocytes. A portion of this decrease can be attributed to cell cycle arrest as evidenced by decreased DNA synthesis, increased p21 protein expression, and decreased cyclin D1. Although not previously demonstrated in sebocytes, we report that 13-cis RA induces apoptosis in SEB-1 sebocytes as shown by increased Annexin V-FITC staining, increased TUNEL staining, and increased cleaved caspase 3 protein. Furthermore, the ability of 13-cis RA to induce apoptosis cannot be recapitulated by 9-cis RA or ATRA, and it is not inhibited by the presence of a retinoid acid receptor (RAR) pan-antagonist AGN 193109. Taken together these data indicate that 13-cis RA causes cell cycle arrest and induces apoptosis in SEB-1 sebocytes by a RAR-independent mechanism, which contributes to its sebosuppressive effect and the resolution of acne.

Design of a Film-Cooled Entraining Diffuser.

DTIC Science & Technology

1980-04-01

AD-A783 951 DEFENCE RESEARCH ESTABLISHMENT SUFFIELD RALSTON (ALBERTA) FIG 20/4 NL3 DESIGN OF A FILM-COOLED ENTRAINING DIFFUSER. 1U) APR 80 S B MURRAY...S.B. Murray C PCN 27C01 April 1980 80 4 29 004 DEFENCE RESEARCH ESTABLISHMENT SUFFIELD: RALSTON: ALBERTA WARNING rht ... , i. to - °aton is per lle...ulje(f to -ogoltio • IIl proprieh’~ra~r ind wtent it hh , i j l - UNCLASS I FI ED Li m DEFENCE RESEARCH ESTABLISHMENT SUFFIELD RALSTON ALBERTA

A Historical Review and Analysis of Army Physical Readiness Training and Assessment

DTIC Science & Technology

2013-03-01

with figures that would put to shame the most exaggerated cartoons of the comic papers. The awkward fellows, whose neglected carriage makes them...501.51 Since relatively little was known about the assessment of lean and fat body mass, obesity was defined in terms of body weight. DA Form 2738-R...AR 600-9 (1976) was Chapter 3—“Weight Control.” “Excess body fat is a serious detriment to health, longevity, stamina, and military appearance

State-of-the-Art for Assessing Earthquake Hazards in the United States. Report 17. Interpretation of Strong Ground Motion Records.

DTIC Science & Technology

1981-10-01

earthquake. The analysis works from first "hysical principles and, so rar as possible, uses elementary ray theory and kinematic arguments. Nevertheless...elements of the more sophisticated theory of earthquake mechanisms and seismic wave propagation in the near field were taken into account in the...Broad Principles of Interpretation 163 4.2 Robust Estimation of Parameters 171 4.3 Some Remarks on High-Acceleration Values 180 4.4 The Focussing

Protective Coatings for Aluminum Torpedoes

DTIC Science & Technology

1983-06-01

Circeo it Cmader and Director of CERL, and Dr. L . R. Shaffer is Technical Director. 3 = -. =-e ° 𔄁 -i , i ..... rar DD FORM 1473 2 FOREWORD 3 LIST...Amerccat 9 Thinner 72 A12 Gas Chrouatogrm flughson VIS 3236-26 Wash Primer 73 L FIGURES (Cont’d) Number Page A13 .as Chroasatogram: Hughson TS 3236-23...intercoat adhesion problems providing the old surface is clean. A vinyl coating system manufactured by Ameron, 201 North Berry Street, Bret, CA 92621, was

Induction of HoxB Transcription by Retinoic Acid Requires Actin Polymerization

PubMed Central

Ferrai, Carmelo; Naum-Onganía, Gabriela; Longobardi, Elena; Palazzolo, Martina; Disanza, Andrea; Diaz, Victor M.; Crippa, Massimo P.; Scita, Giorgio

2009-01-01

We have analyzed the role of actin polymerization in retinoic acid (RA)-induced HoxB transcription, which is mediated by the HoxB regulator Prep1. RA induction of the HoxB genes can be prevented by the inhibition of actin polymerization. Importantly, inhibition of actin polymerization specifically affects the transcription of inducible Hox genes, but not that of their transcriptional regulators, the RARs, nor of constitutively expressed, nor of actively transcribed Hox genes. RA treatment induces the recruitment to the HoxB2 gene enhancer of a complex composed of “elongating” RNAPII, Prep1, β-actin, and N-WASP as well as the accessory splicing components p54Nrb and PSF. We show that inhibition of actin polymerization prevents such recruitment. We conclude that inducible Hox genes are selectively sensitive to the inhibition of actin polymerization and that actin polymerization is required for the assembly of a transcription complex on the regulatory region of the Hox genes. PMID:19477923

Induction of HoxB transcription by retinoic acid requires actin polymerization.

PubMed

Ferrai, Carmelo; Naum-Onganía, Gabriela; Longobardi, Elena; Palazzolo, Martina; Disanza, Andrea; Diaz, Victor M; Crippa, Massimo P; Scita, Giorgio; Blasi, Francesco

2009-08-01

We have analyzed the role of actin polymerization in retinoic acid (RA)-induced HoxB transcription, which is mediated by the HoxB regulator Prep1. RA induction of the HoxB genes can be prevented by the inhibition of actin polymerization. Importantly, inhibition of actin polymerization specifically affects the transcription of inducible Hox genes, but not that of their transcriptional regulators, the RARs, nor of constitutively expressed, nor of actively transcribed Hox genes. RA treatment induces the recruitment to the HoxB2 gene enhancer of a complex composed of "elongating" RNAPII, Prep1, beta-actin, and N-WASP as well as the accessory splicing components p54Nrb and PSF. We show that inhibition of actin polymerization prevents such recruitment. We conclude that inducible Hox genes are selectively sensitive to the inhibition of actin polymerization and that actin polymerization is required for the assembly of a transcription complex on the regulatory region of the Hox genes.

High-resolution imaging using a wideband MIMO radar system with two distributed arrays.

PubMed

Wang, Dang-wei; Ma, Xiao-yan; Chen, A-Lei; Su, Yi

2010-05-01

Imaging a fast maneuvering target has been an active research area in past decades. Usually, an array antenna with multiple elements is implemented to avoid the motion compensations involved in the inverse synthetic aperture radar (ISAR) imaging. Nevertheless, there is a price dilemma due to the high level of hardware complexity compared to complex algorithm implemented in the ISAR imaging system with only one antenna. In this paper, a wideband multiple-input multiple-output (MIMO) radar system with two distributed arrays is proposed to reduce the hardware complexity of the system. Furthermore, the system model, the equivalent array production method and the imaging procedure are presented. As compared with the classical real aperture radar (RAR) imaging system, there is a very important contribution in our method that the lower hardware complexity can be involved in the imaging system since many additive virtual array elements can be obtained. Numerical simulations are provided for testing our system and imaging method.

Retinoic acid induces nuclear accumulation of Raf1 during differentiation of HL-60 cells

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

Smith, James; Bunaciu, Rodica P.; Reiterer, Gudrun

All trans-retinoic acid (RA) is a standard therapeutic agent used in differentiation induction therapy treatment of acute promyelocytic leukemia (APL). RA and its metabolites use a diverse set of signal transduction pathways during the differentiation program. In addition to the direct transcriptional targets of the nuclear RAR and RXR receptors, signals derived from membrane receptors and the Raf-MEK-ERK pathway are required. Raf1 phosphorylation and the prolonged activation of Raf1 persisting during the entire differentiation process are required for RA-dependent differentiation of HL-60 cells. Here we identify a nuclear redistribution of Raf1 during the RA-induced differentiation of HL-60 cells. In addition,more » the nuclear accumulation of Raf1 correlates with an increase in Raf1 phosphorylated at serine 621. The serine 621 phosphorylated Raf1 is predominantly localized in the nucleus. The RA-dependent nuclear accumulation of Raf1 suggests a novel nuclear role for Raf1 during the differentiation process.« less

The retinoic acid receptor agonist Am80 increases mucosal inflammation in an IL-6 dependent manner during Trichuris muris infection.

PubMed

Hurst, Rebecca J M; De Caul, Adam; Little, Matthew C; Kagechika, Hiroyuki; Else, Kathryn J

2013-11-01

Vitamin A metabolites, such as all-trans-retinoic acid (RA) that act through the nuclear receptor; retinoic acid receptor (RAR), have been shown to polarise T cells towards Th2, and to be important in resistance to helminth infections. Co-incidentally, people harbouring intestinal parasites are often supplemented with vitamin A, as both vitamin A deficiency and parasite infections often occur in the same regions of the globe. However, the impact of vitamin A supplementation on gut inflammation caused by intestinal parasites is not yet completely understood. Here, we use Trichuris muris, a helminth parasite that buries into the large intestine of mice causing mucosal inflammation, as a model of both human trichuriasis and IBD, treat with an RARα/β agonist (Am80) and quantify the ensuing pathological changes in the gut. Critically, we show, for the first time, that rather than playing an anti-inflammatory role, Am80 actually exacerbates helminth-driven inflammation, demonstrated by an increased colonic crypt length and a significant CD4(+) T cell infiltrate. Further, we established that the Am80-driven crypt hyperplasia and CD4(+) T cell infiltrate were dependent on IL-6, as both were absent in Am80-treated IL-6 knock-out mice. This study presents novel data showing a pro-inflammatory role of RAR ligands in T. muris infection, and implies an undesirable effect for the administration of vitamin A during chronic helminth infection.

Ambulatory Monitoring of Congestive Heart Failure by Multiple Bioelectric Impedance Vectors

PubMed Central

Khoury, Dirar S.; Naware, Mihir; Siou, Jeff; Blomqvist, Andreas; Mathuria, Nilesh S.; Wang, Jianwen; Shih, Hue-Teh; Nagueh, Sherif F.; Panescu, Dorin

2009-01-01

Objectives To investigate properties of multiple bioelectric impedance signals recorded during congestive heart failure (CHF) by utilizing various electrode configurations of an implanted cardiac resynchronization therapy (CRT) system. Background Monitoring of CHF has relied mainly on right-heart sensors. Methods Fifteen normal dogs underwent implantation of CRT systems using standard leads. An additional left atrial (LA) pressure lead-sensor was implanted in 5 dogs. Continuous rapid right ventricular (RV) pacing was applied over several weeks. Left ventricular (LV) catheterization and echocardiography were performed biweekly. Six steady-state impedance signals, utilizing intrathorcaic and intracardiac vectors, were measured via ring (r), coil (c), and device Can electrodes. Results All animals developed CHF after 2–4 weeks of pacing. Impedance diminished gradually during CHF induction, but at varying rates for different vectors. Impedance during CHF decreased significantly in all measured vectors: LVr-Can, −17%; LVr-RVr, −15%; LVr-RAr, −11%; RVr-Can, −12%; RVc-Can, −7%; RAr-Can, −5%. The LVr-Can vector reflected both the fastest and largest change in impedance in comparison to vectors employing only right-heart electrodes, and was highly reflective of changes in LV end-diastolic volume and LA pressure. Conclusions Impedance, acquired via different lead-electrodes, have variable responses to CHF. Impedance vectors employing a LV lead are highly responsive to physiologic changes during CHF. Measuring multiple impedance signals could be useful for optimizing ambulatory monitoring in heart failure patients. PMID:19298923

Assessment of renal artery stenosis: side-by-side comparison of angiography and duplex ultrasound with pressure gradient measurements.

PubMed

Drieghe, Benny; Madaric, Juraj; Sarno, Giovanna; Manoharan, Ganesh; Bartunek, Jozef; Heyndrickx, Guy R; Pijls, Nico H J; De Bruyne, Bernard

2008-02-01

A ratio of distal renal pressure to aortic pressure (P(d)/P(a)) <0.90 can be considered a threshold for defining a significant renal artery stenosis (RAS). The aim of this study was to compare renal angiography (QRA) and colour duplex ultrasound (CDUS) to pressure measurements in assessing RAS. In 56 RAS, percent diameter stenosis (DS(angio)), minimal luminal diameter (MLD), Doppler-derived peak systolic velocity (PSV), end-diastolic velocity (EDV), and renal-to-aortic ratio (RAR) were obtained and compared with the P(d)/P(a) measured with a 0.014" pressure wire. P(d)/P(a) correlated with angiography- and CDUS-derived parameters. The best correlation was observed with EDV (R = -0.61). To identify stenosis associated with a P(d)/P(a) < 0.90, the diagnostic accuracy of DS(angio) > 50%, MLD < 2 mm, PSV > 180 cm/s, EDV > 90 cm/s and RAR > 3.5 were, respectively, 60%, 77%, 45%, 77% and 79%, yet, with a high proportion of false positives (38%, 15%, 55%, 11% and 15%, respectively) indicating an overestimation of the severity of the RAS by both QRA and CDUS. New cut-off values for QRA- and CDUS-derived indices were proposed. Generally accepted QRA and CDUS-derived indices of RAS severity overestimate the actual severity of RAS. This 'overdiagnosis' is likely the main cause of the disappointing results of renal angioplasty for renovascular hypertension.

Retinoid Receptors in Bone and Their Role in Bone Remodeling

PubMed Central

Henning, Petra; Conaway, H. Herschel; Lerner, Ulf H.

2015-01-01

Vitamin A (retinol) is a necessary and important constituent of the body which is provided by food intake of retinyl esters and carotenoids. Vitamin A is known best for being important for vision, but in addition to the eye, vitamin A is necessary in numerous other organs in the body, including the skeleton. Vitamin A is converted to an active compound, all-trans-retinoic acid (ATRA), which is responsible for most of its biological actions. ATRA binds to intracellular nuclear receptors called retinoic acid receptors (RARα, RARβ, RARγ). RARs and closely related retinoid X receptors (RXRα, RXRβ, RXRγ) form heterodimers which bind to DNA and function as ligand-activated transcription factors. It has been known for many years that hypervitaminosis A promotes skeleton fragility by increasing osteoclast formation and decreasing cortical bone mass. Some epidemiological studies have suggested that increased intake of vitamin A and increased serum levels of retinoids may decrease bone mineral density and increase fracture rate, but the literature on this is not conclusive. The current review summarizes how vitamin A is taken up by the intestine, metabolized, stored in the liver, and processed to ATRA. ATRA’s effects on formation and activity of osteoclasts and osteoblasts are outlined, and a summary of clinical data pertaining to vitamin A and bone is presented. PMID:25814978

Aminoacyl-tRNA synthetase deficiencies in search of common themes.

PubMed

Fuchs, Sabine A; Schene, Imre F; Kok, Gautam; Jansen, Jurriaan M; Nikkels, Peter G J; van Gassen, Koen L I; Terheggen-Lagro, Suzanne W J; van der Crabben, Saskia N; Hoeks, Sanne E; Niers, Laetitia E M; Wolf, Nicole I; de Vries, Maaike C; Koolen, David A; Houwen, Roderick H J; Mulder, Margot F; van Hasselt, Peter M

2018-06-06

Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care. Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital. In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy. We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.

A Combination of Soybean and Haematococcus Extract Alleviates Ultraviolet B-Induced Photoaging

PubMed Central

Shin, Jieun; Kim, Jong-Eun; Pak, Kum-Ju; Kang, Jung Il; Kim, Tae-Seok; Lee, Sang-Yoon; Yeo, Ik-Hyun; Park, Jung Han Yoon; Kim, Jong Hun; Kang, Nam Joo; Lee, Ki Won

2017-01-01

Soybean-derived isoflavones have been investigated for their preventative effects against UV-induced symptoms of skin damage including wrinkle formation and inflammation. Haematococcus pluvialis is a freshwater species of Chlorophyta that contains high concentrations of the natural carotenoid pigment astaxanthin. Astaxanthin is known to be involved in retinoic acid receptor (RAR) signaling and previously been associated with the inhibition of activator protein (AP)-1 dependent transcription. Based on previous studies, we hypothesized that a combination of soy extract (SE) and Haematococcus extract (HE) may prevent UVB-induced photoaging through specific signaling pathways, as measured by UVB-induced wrinkling on hairless mice skin and expression changes in human dermal fibroblasts (HDFs). The 1:2 ratio of SE and HE mixture (SHM) showed the optimal benefit in vivo. SHM was found to inhibit wrinkle formation via the downregulation of matrix metalloproteinase (MMP)-1 mRNA and protein expression. SHM also inhibited mitogen-activated protein kinase (MAPK) phosphorylation and the transactivation of AP-1 which plays an important role in regulating MMP expression. These results highlight the potential for SHM to be developed as a therapeutic agent to prevent UVB-induced skin wrinkling. PMID:28327532

A Combination of Soybean and Haematococcus Extract Alleviates Ultraviolet B-Induced Photoaging.

PubMed

Shin, Jieun; Kim, Jong-Eun; Pak, Kum-Ju; Kang, Jung Il; Kim, Tae-Seok; Lee, Sang-Yoon; Yeo, Ik-Hyun; Park, Jung Han Yoon; Kim, Jong Hun; Kang, Nam Joo; Lee, Ki Won

2017-03-22

Soybean-derived isoflavones have been investigated for their preventative effects against UV-induced symptoms of skin damage including wrinkle formation and inflammation. Haematococcus pluvialis is a freshwater species of Chlorophyta that contains high concentrations of the natural carotenoid pigment astaxanthin. Astaxanthin is known to be involved in retinoic acid receptor (RAR) signaling and previously been associated with the inhibition of activator protein (AP)-1 dependent transcription. Based on previous studies, we hypothesized that a combination of soy extract (SE) and Haematococcus extract (HE) may prevent UVB-induced photoaging through specific signaling pathways, as measured by UVB-induced wrinkling on hairless mice skin and expression changes in human dermal fibroblasts (HDFs). The 1:2 ratio of SE and HE mixture (SHM) showed the optimal benefit in vivo. SHM was found to inhibit wrinkle formation via the downregulation of matrix metalloproteinase (MMP)-1 mRNA and protein expression. SHM also inhibited mitogen-activated protein kinase (MAPK) phosphorylation and the transactivation of AP-1 which plays an important role in regulating MMP expression. These results highlight the potential for SHM to be developed as a therapeutic agent to prevent UVB-induced skin wrinkling.

A forward chemical screen in zebrafish identifies a retinoic acid derivative with receptor specificity.

PubMed

Das, Bhaskar C; McCartin, Kellie; Liu, Ting-Chun; Peterson, Randall T; Evans, Todd

2010-04-02

Retinoids regulate key developmental pathways throughout life, and have potential uses for differentiation therapy. It should be possible to identify novel retinoids by coupling new chemical reactions with screens using the zebrafish embryonic model. We synthesized novel retinoid analogues and derivatives by amide coupling, obtaining 80-92% yields. A small library of these compounds was screened for bioactivity in living zebrafish embryos. We found that several structurally related compounds significantly affect development. Distinct phenotypes are generated depending on time of exposure, and we characterize one compound (BT10) that produces specific cardiovascular defects when added 1 day post fertilization. When compared to retinoic acid (ATRA), BT10 shows similar but not identical changes in the expression pattern of embryonic genes that are known targets of the retinoid pathway. Reporter assays determined that BT10 interacts with all three RAR receptor sub-types, but has no activity for RXR receptors, at all concentrations tested. Our screen has identified a novel retinoid with specificity for retinoid receptors. This lead compound may be useful for manipulating components of retinoid signaling networks, and may be further derivatized for enhanced activity.

A Distinct Inhibitory Function for miR-18a in Th17 Cell Differentiation.

PubMed

Montoya, Misty M; Maul, Julia; Singh, Priti B; Pua, Heather H; Dahlström, Frank; Wu, Nanyan; Huang, Xiaozhu; Ansel, K Mark; Baumjohann, Dirk

2017-07-15

Th17 cell responses orchestrate immunity against extracellular pathogens but also underlie autoimmune disease pathogenesis. In this study, we uncovered a distinct and critical role for miR-18a in limiting Th17 cell differentiation. miR-18a was the most dynamically upregulated microRNA of the miR-17-92 cluster in activated T cells. miR-18a deficiency enhanced CCR6 + RAR-related orphan receptor (ROR)γt + Th17 cell differentiation in vitro and increased the number of tissue Th17 cells expressing CCR6, RORγt, and IL-17A in airway inflammation models in vivo. Sequence-specific miR-18 inhibitors increased CCR6 and RORγt expression in mouse and human CD4 + T cells, revealing functional conservation. miR-18a directly targeted Smad4 , Hif1a , and Rora , all key transcription factors in the Th17 cell gene-expression program. These findings indicate that activating signals influence the outcome of Th cell differentiation via differential regulation of mature microRNAs within a common cluster. Copyright © 2017 by The American Association of Immunologists, Inc.

CP-25, a novel compound, protects against autoimmune arthritis by modulating immune mediators of inflammation and bone damage

PubMed Central

Chang, Yan; Jia, Xiaoyi; Wei, Fang; Wang, Chun; Sun, Xiaojing; Xu, Shu; Yang, Xuezhi; Zhao, Yingjie; Chen, Jingyu; Wu, Huaxun; Zhang, Lingling; Wei, Wei

2016-01-01

Paeoniflorin-6′-O-benzene sulfonate (code: CP-25), a novel ester derivative of paeoniflorin (Pae), was evaluated in rats with adjuvant-induced arthritis (AA) to study its potential anti-arthritic activity. AA rats were treated with CP-25 (25, 50, or 100 mg/kg) from days 17 to 29 after immunization. CP-25 effectively reduced clinical and histopathological scores compared with the AA groups. CP-25-treated rats exhibited decreases in pro-inflammatory cytokines (IL-1β, IL-6, IL-17 and TNF-α) coupled with an increase in the anti-inflammatory cytokine TGF-β1 in the serum. CP-25 treatment inhibited M1 macrophage activation and enhanced M2 macrophage activation by influencing cytokine production. Decreases in Th17-IL-17 and the Th17-associated transcription factor RAR-related orphan receptor gamma (ROR-γt) dramatically demonstrated the immunomodulatory effects of CP-25 on abnormal immune dysfunction. In addition, CP-25 suppressed the production of receptor activator of nuclear factor kappa B ligand (RANKL) and matrix metalloproteinase (MMP) 9, which supported its anti-osteoclastic effects. The data presented here demonstrated that CP-25 significantly inhibited the progression of rat AA by reducing inflammation, immunity and bone damage. The protective effects of CP-25 in AA highlight its potential as an ideal new anti-arthritic agent for human RA. PMID:27184722

CP-25, a novel compound, protects against autoimmune arthritis by modulating immune mediators of inflammation and bone damage.

PubMed

Chang, Yan; Jia, Xiaoyi; Wei, Fang; Wang, Chun; Sun, Xiaojing; Xu, Shu; Yang, Xuezhi; Zhao, Yingjie; Chen, Jingyu; Wu, Huaxun; Zhang, Lingling; Wei, Wei

2016-05-17

Paeoniflorin-6'-O-benzene sulfonate (code: CP-25), a novel ester derivative of paeoniflorin (Pae), was evaluated in rats with adjuvant-induced arthritis (AA) to study its potential anti-arthritic activity. AA rats were treated with CP-25 (25, 50, or 100 mg/kg) from days 17 to 29 after immunization. CP-25 effectively reduced clinical and histopathological scores compared with the AA groups. CP-25-treated rats exhibited decreases in pro-inflammatory cytokines (IL-1β, IL-6, IL-17 and TNF-α) coupled with an increase in the anti-inflammatory cytokine TGF-β1 in the serum. CP-25 treatment inhibited M1 macrophage activation and enhanced M2 macrophage activation by influencing cytokine production. Decreases in Th17-IL-17 and the Th17-associated transcription factor RAR-related orphan receptor gamma (ROR-γt) dramatically demonstrated the immunomodulatory effects of CP-25 on abnormal immune dysfunction. In addition, CP-25 suppressed the production of receptor activator of nuclear factor kappa B ligand (RANKL) and matrix metalloproteinase (MMP) 9, which supported its anti-osteoclastic effects. The data presented here demonstrated that CP-25 significantly inhibited the progression of rat AA by reducing inflammation, immunity and bone damage. The protective effects of CP-25 in AA highlight its potential as an ideal new anti-arthritic agent for human RA.

Efficacy validation of synthesized retinol derivatives In vitro: stability, toxicity, and activity.

PubMed

Han, Hye-Sook; Kwon, Youn-Ja; Park, Myoung-Soon; Park, Si-Ho; Cho, So-Mi Kim; Rho, Young-Soy; Kim, Jin-Wou; Sin, Hong-Sig; Um, Soo-Jong

2003-08-15

Retinol (vitamin A) is used as an antiwrinkle agent in the cosmetics industry. However, its photo-instability makes it unsuitable for use in general cosmetic formulations. To improve the photo-stability of retinol, three derivatives (3, 4, and 5) were synthesized and their biological activities were analyzed. 1H NMR and HPLC analysis indicated that derivatives 3 and 5 were much more stable than retinol under our sunlight exposure conditions. When human adult fibroblasts were treated, the IC(50) of derivative 3 was 96 microM, which is similar to that of retinol, as determined by the MTT assay. Derivatives 4 and 5 were 2.5 and 8 times more toxic than retinol, respectively. At 1 microM treatment, like retinol, derivatives 3 and 4 were specifically active for RARalpha out of six retinoid receptors (RAR/RXRalpha, beta, gamma). Dose-dependent analysis confirmed that derivative 4 was as active as retinol and the other two derivatives were less active for RARalpha. The effect of our derivatives on the expression of collagenase, an indicator of wrinkle formation, was measured using the transient co-expression of c-Jun and RT-PCR in HaCaT cells. Collagenase promoter activity, which is increased by c-Jun expression, was reduced 42% by retinol treatment. The other derivatives inhibited collagenase promoter activity similarly. These results were further confirmed by RT-PCR analysis of the collagenase gene. Taken together, our results suggest that retinol derivative 3 is a promising antiwrinkle agent based on its higher photo-stability, lower RARalpha activity (possibly indicating reduced side effects), and similar effect on collagenase expression.

Mla- and Rom1-mediated control of microRNA398 and chloroplast copper/zinc superoxide dismutase regulates cell death in response to the barley powdery mildew fungus.

PubMed

Xu, Weihui; Meng, Yan; Wise, Roger P

2014-03-01

• Barley (Hordeum vulgare L.) Mildew resistance locus a (Mla) confers allele-specific interactions with natural variants of the ascomycete fungus Blumeria graminis f. sp. hordei (Bgh), the causal agent of powdery mildew disease. Significant reprogramming of Mla-mediated gene expression occurs upon infection by this obligate biotrophic pathogen. • We utilized a proteomics-based approach, combined with barley mla, required for Mla12 resistance1 (rar1), and restoration of Mla resistance1 (rom1) mutants, to identify components of Mla-directed signaling. • Loss-of-function mutations in Mla and Rar1 both resulted in the reduced accumulation of chloroplast copper/zinc superoxide dismutase 1 (HvSOD1), whereas loss of function in Rom1 re-established HvSOD1 levels. In addition, both Mla and Rom1 negatively regulated hvu-microRNA398 (hvu-miR398), and up-regulation of miR398 was coupled to reduced HvSOD1 expression. Barley stripe mosaic virus (BSMV)-mediated over-expression of both barley and Arabidopsis miR398 repressed accumulation of HvSOD1, and BSMV-induced gene silencing of HvSod1 impeded Mla-triggered H₂O₂ and hypersensitive reaction (HR) at barley-Bgh interaction sites. • These data indicate that Mla- and Rom1-regulated hvu-miR398 represses HvSOD1 accumulation, influencing effector-induced HR in response to the powdery mildew fungus. No claim to original US Government works. New Phytologist © 2013 New Phytologist Trust.

Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells.

PubMed

Dolatshad, H; Pellagatti, A; Fernandez-Mercado, M; Yip, B H; Malcovati, L; Attwood, M; Przychodzen, B; Sahgal, N; Kanapin, A A; Lockstone, H; Scifo, L; Vandenberghe, P; Papaemmanuil, E; Smith, C W J; Campbell, P J; Ogawa, S; Maciejewski, J P; Cazzola, M; Savage, K I; Boultwood, J

2015-05-01

The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34(+) cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript and/or exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicing/processing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expression/splicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34(+) cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

Monitoring Strategies of Earth Dams by Ground-Based Radar Interferometry: How to Extract Useful Information for Seismic Risk Assessment.

PubMed

Di Pasquale, Andrea; Nico, Giovanni; Pitullo, Alfredo; Prezioso, Giuseppina

2018-01-16

The aim of this paper is to describe how ground-based radar interferometry can provide displacement measurements of earth dam surfaces and of vibration frequencies of its main concrete infrastructures. In many cases, dams were built many decades ago and, at that time, were not equipped with in situ sensors embedded in the structure when they were built. Earth dams have scattering properties similar to landslides for which the Ground-Based Synthetic Aperture Radar (GBSAR) technique has been so far extensively applied to study ground displacements. In this work, SAR and Real Aperture Radar (RAR) configurations are used for the measurement of earth dam surface displacements and vibration frequencies of concrete structures, respectively. A methodology for the acquisition of SAR data and the rendering of results is described. The geometrical correction factor, needed to transform the Line-of-Sight (LoS) displacement measurements of GBSAR into an estimate of the horizontal displacement vector of the dam surface, is derived. Furthermore, a methodology for the acquisition of RAR data and the representation of displacement temporal profiles and vibration frequency spectra of dam concrete structures is presented. For this study a Ku-band ground-based radar, equipped with horn antennas having different radiation patterns, has been used. Four case studies, using different radar acquisition strategies specifically developed for the monitoring of earth dams, are examined. The results of this work show the information that a Ku-band ground-based radar can provide to structural engineers for a non-destructive seismic assessment of earth dams.

Quantifying root-reinforcement of river bank soils by four Australian tree species

NASA Astrophysics Data System (ADS)

Docker, B. B.; Hubble, T. C. T.

2008-08-01

The increased shear resistance of soil due to root-reinforcement by four common Australian riparian trees, Casuarina glauca, Eucalyptus amplifolia, Eucalyptus elata and Acacia floribunda, was determined in-situ with a field shear-box. Root pull-out strengths and root tensile-strengths were also measured and used to evaluate the utility of the root-reinforcement estimation models that assume simultaneous failure of all roots at the shear plane. Field shear-box results indicate that tree roots fail progressively rather than simultaneously. Shear-strengths calculated for root-reinforced soil assuming simultaneous root failure, yielded values between 50% and 215% higher than directly measured shear-strengths. The magnitude of the overestimate varies among species and probably results from differences in both the geometry of the root-system and tensile strengths of the root material. Soil blocks under A. floribunda which presents many, well-spread, highly-branched fine roots with relatively higher tensile strength, conformed most closely with root model estimates; whereas E. amplifolia, which presents a few, large, unbranched vertical roots, concentrated directly beneath the tree stem and of relatively low tensile strength, deviated furthest from model-estimated shear-strengths. These results suggest that considerable caution be exercised when applying estimates of increased shear-strength due to root-reinforcement in riverbank stability modelling. Nevertheless, increased soil shear strength provided by tree roots can be calculated by knowledge of the Root Area Ratio ( RAR) at the shear plane. At equivalent RAR values, A. floribunda demonstrated the greatest earth reinforcement potential of the four species studied.

The Pattern of Soviet Conduct in the Third World, Review and Preview. Part 2

DTIC Science & Technology

1983-03-07

be quoted or copied without approval from OSD/Net Assessment. Aooession For DTIC TAB El Dit I-’I t Y " c•doi ;Avi.- ± end/or L i :itst I pc l 4•al IA...successcors have stooc, y that cecision. (Moscow odes riot recconioze tnis action.) Alth•cuph revolutionary Iran has i nioroved or estaolisned relations...far nesw tne world rar.et ievel and oepat, repotiaiions for a orice increase of roucniv t0w oercenz. ? y marc- I5d. witm the Soviets’ best otfer stiil

Identifying the receptor subtype selectivity of retinoid X and retinoic acid receptors via quantum mechanics.

PubMed

Tsuji, Motonori; Shudo, Koichi; Kagechika, Hiroyuki

2017-03-01

Understanding and identifying the receptor subtype selectivity of a ligand is an important issue in the field of drug discovery. Using a combination of classical molecular mechanics and quantum mechanical calculations, this report assesses the receptor subtype selectivity for the human retinoid X receptor (hRXR) and retinoic acid receptor (hRAR) ligand-binding domains (LBDs) complexed with retinoid ligands. The calculated energies show good correlation with the experimentally reported binding affinities. The technique proposed here is a promising method as it reveals the origin of the receptor subtype selectivity of selective ligands.

A situational picture of HIV/AIDS and injection drug use in Vinnitsya, Ukraine

PubMed Central

Barcal, Katerina; Schumacher, Joseph E; Dumchev, Kostyantyn; Moroz, Larisa Vasiliyevna

2005-01-01

Background New and explosive HIV epidemics are being witnessed in certain countries of Eastern Europe, including Ukraine, as well as a rapid and dramatic increase in the supply, use, and negative public health consequences of illicit drugs. A majority of registered HIV cases in Ukraine occur among injection drug users (IDUs), large numbers of whom report HIV risk behaviors such as needle sharing. The purpose of this study was to apply the World Health Organization's Rapid Assessment and Response on Injection Drug Use (IDU-RAR) guide to create a situational picture in the Vinnitsya Oblast, Ukraine, a region with very scarce information about the HIV/AIDS and injection drug use (IDU) epidemics. Methods The IDU-RAR uses a combination of qualitative data collection techniques commonly employed in social science and evaluation research to quickly depict the extent and nature of the given health problem and propose locally relevant recommendations for improvement. The investigators focused their assessment on the contextual factors, drug use, and intervention and policy components of the IDU-RAR. A combination of network and block sampling techniques was used. Data collection methods included direct observation, review of existing data, structured and unstructured interviews, and focus group discussions. Key informants and locations were visited until no new information was being generated. Results The number of registered HIV cases in Vinnitsya has increased from 3 (1987–1995) to 860 (1999–10/2004), 57 of whom have already died. Ten percent of annual admissions to the area's Regional Narcological Dispensary were for opiate disorders, and the number of registered IDUs rose by 20% from 1999 to 2000. The level of HIV/AIDS awareness is generally poor among the general population but high among high-risk populations. Both HIV/AIDS and injection drug use carry a strong stigma in the community, even among medical professionals. There was very little evidence of primary HIV/AIDS prevention efforts, and IDU prevention efforts focused on promotion of anti-drug messages in the schools. Conclusion Given that Ukraine has sparse resources to be devoted to this problem, action recommendations should be prioritized, realistic, and initially targeted to persons in greatest need. The following action recommendations are prioritized by the following categories: First priority: Voluntary Counseling and Testing; Second Priority: Prevention and Education; and Third Priority: Harm Reduction and Treatment. They are provided in this sequence based on what response can realistically be implemented first with limited additional resources and can make the greatest immediate impact. The persons at greatest risk, HIV positive persons and IDUs, should be attended to first. PMID:16164758

Visualizing Uncertainty for Probabilistic Weather Forecasting based on Reforecast Analogs

NASA Astrophysics Data System (ADS)

Pelorosso, Leandro; Diehl, Alexandra; Matković, Krešimir; Delrieux, Claudio; Ruiz, Juan; Gröeller, M. Eduard; Bruckner, Stefan

2016-04-01

Numerical weather forecasts are prone to uncertainty coming from inaccuracies in the initial and boundary conditions and lack of precision in numerical models. Ensemble of forecasts partially addresses these problems by considering several runs of the numerical model. Each forecast is generated with different initial and boundary conditions and different model configurations [GR05]. The ensembles can be expressed as probabilistic forecasts, which have proven to be very effective in the decision-making processes [DE06]. The ensemble of forecasts represents only some of the possible future atmospheric states, usually underestimating the degree of uncertainty in the predictions [KAL03, PH06]. Hamill and Whitaker [HW06] introduced the "Reforecast Analog Regression" (RAR) technique to overcome the limitations of ensemble forecasting. This technique produces probabilistic predictions based on the analysis of historical forecasts and observations. Visual analytics provides tools for processing, visualizing, and exploring data to get new insights and discover hidden information patterns in an interactive exchange between the user and the application [KMS08]. In this work, we introduce Albero, a visual analytics solution for probabilistic weather forecasting based on the RAR technique. Albero targets at least two different type of users: "forecasters", who are meteorologists working in operational weather forecasting and "researchers", who work in the construction of numerical prediction models. Albero is an efficient tool for analyzing precipitation forecasts, allowing forecasters to make and communicate quick decisions. Our solution facilitates the analysis of a set of probabilistic forecasts, associated statistical data, observations and uncertainty. A dashboard with small-multiples of probabilistic forecasts allows the forecasters to analyze at a glance the distribution of probabilities as a function of time, space, and magnitude. It provides the user with a more accurate measure of forecast uncertainty that could result in better decision-making. It offers different level of abstractions to help with the recalibration of the RAR method. It also has an inspection tool that displays the selected analogs, their observations and statistical data. It gives the users access to inner parts of the method, unveiling hidden information. References [GR05] GNEITING T., RAFTERY A. E.: Weather forecasting with ensemble methods. Science 310, 5746, 248-249, 2005. [KAL03] KALNAY E.: Atmospheric modeling, data assimilation and predictability. Cambridge University Press, 2003. [PH06] PALMER T., HAGEDORN R.: Predictability of weather and climate. Cambridge University Press, 2006. [HW06] HAMILL T. M., WHITAKER J. S.: Probabilistic quantitative precipitation forecasts based on reforecast analogs: Theory and application. Monthly Weather Review 134, 11, 3209-3229, 2006. [DE06] DEITRICK S., EDSALL R.: The influence of uncertainty visualization on decision making: An empirical evaluation. Springer, 2006. [KMS08] KEIM D. A., MANSMANN F., SCHNEIDEWIND J., THOMAS J., ZIEGLER H.: Visual analytics: Scope and challenges. Springer, 2008.

Tripartite Motif 24 (Trim24/Tif1α) Tumor Suppressor Protein Is a Novel Negative Regulator of Interferon (IFN)/Signal Transducers and Activators of Transcription (STAT) Signaling Pathway Acting through Retinoic Acid Receptor α (Rarα) Inhibition*

PubMed Central

Tisserand, Johan; Khetchoumian, Konstantin; Thibault, Christelle; Dembélé, Doulaye; Chambon, Pierre; Losson, Régine

2011-01-01

Recent genetic studies in mice have established that the nuclear receptor coregulator Trim24/Tif1α suppresses hepatocarcinogenesis by inhibiting retinoic acid receptor α (Rara)-dependent transcription and cell proliferation. However, Rara targets regulated by Trim24 remain unknown. We report that the loss of Trim24 resulted in interferon (IFN)/STAT pathway overactivation soon after birth (week 5). Despite a transient attenuation of this pathway by the induction of several IFN/STAT pathway repressors later in the disease, this phenomenon became more pronounced in tumors. Remarkably, Rara haplodeficiency, which suppresses tumorigenesis in Trim24−/− mice, prevented IFN/STAT overactivation. Moreover, together with Rara, Trim24 bound to the retinoic acid-responsive element of the Stat1 promoter and repressed its retinoic acid-induced transcription. Altogether, these results identify Trim24 as a novel negative regulator of the IFN/STAT pathway and suggest that this repression through Rara inhibition may prevent liver cancer. PMID:21768647

A Review About Lycopene-Induced Nuclear Hormone Receptor Signalling in Inflammation and Lipid Metabolism via still Unknown Endogenous Apo-10´-Lycopenoids.

PubMed

Caris-Veyrat, Catherine; Garcia, Ada L; Reynaud, Eric; Lucas, Renata; Aydemir, Gamze; Rühl, Ralph

2017-10-20

Lycopene is the red pigment in tomatoes and tomato products and is an important dietary carotenoid found in the human organism. Lycopene-isomers, oxidative lycopene metabolites and apo-lycopenoids are found in the food matrix. Lycopene intake derived from tomato consumption is associated with alteration of lipid metabolism and a lower incidence of cardiovascular diseases (CVD). Lycopene is mainly described as a potent antioxidant but novel studies are shifting towards its metabolites and their capacity to mediate nuclear receptor signalling. Di-/tetra-hydro-derivatives of apo-10´-lycopenoic acid and apo-15´-lycopenoic acids are potential novel endogenous mammalian lycopene metabolites which may act as ligands for nuclear hormone mediated activation and signalling. In this review, we postulate that complex lycopene metabolism results in various lycopene metabolites which have the ability to mediate transactivation of various nuclear hormone receptors like RARs, RXRs and PPARs. A new mechanistic explanation of how tomato consumption could positively modulate inflammation and lipid metabolism is discussed.

Th17 master transcription factors RORα and RORγ regulate the expression of IL-17C, IL-17D and IL-17F in Cynoglossus semilaevis.

PubMed

Chi, Heng; Bøgwald, Jarl; Dalmo, Roy Ambli; Zhang, Wenjie; Hu, Yong-hua

2016-02-01

The RAR-related orphan receptors (RORs) are members of the nuclear receptor family of intracellular transcription factors. In this study, we examined the regulatory properties of RORα (CsRORα) and RORγ (CsRORγ) in tongue sole (Cynoglossus semilaevis). CsRORα and CsRORγ expression was detected in major lymphoid organs and altered to significant extents after bacterial and viral infection. CsRORα enhanced the activities of CsIL-17C, CsIL-17D, and CsIL-17F promoters, which contain CsRORα and CsRORγ binding sites. CsRORγ also upregulated the promoter activities of CsIL-17D and CsIL-17F but not CsIL-17C. CsRORα and CsRORγ proteins were detected in the nucleus, and overexpression of CsRORα in tongue sole significantly increased the expression of CsIL-17C, CsIL-17D, and CsIL-17F, whereas overexpression of CsRORγ significantly increased the expression of CsIL-17C and CsIL-17F but no CsIL-17D. These results indicate that RORα and RORγ in teleost regulate the expression of IL-17 members in different manners. Copyright © 2015 Elsevier Ltd. All rights reserved.

Treatment of transfusional iron overload in patients with myelodysplastic syndrome or severe anemia: data from multicenter clinical practices.

PubMed

Raptis, Anastasios; Duh, Mei Sheng; Wang, Si-Tien; Dial, Ellison; Fanourgiakis, Ilias; Fortner, Barry; Paley, Carole; Mody-Patel, Nikita; Corral, Mitra; Scott, Jeffrey

2010-01-01

Patients with myelodysplastic syndrome (MDS) or severe anemia requiring repeated red blood cell (RBC) transfusions risk developing transfusional iron overload, which can reduce survival. Iron chelation therapy (ICT) has been shown to improve survival and quality of life in patients; however, ICT utilization in clinical practices is not well understood. Medical records of patients diagnosed with MDS or severe anemia at least 6 months before data extraction, aged at least 21 years at diagnosis, and who received at least one RBC transfusion were reviewed. ICT eligibility was defined as at least 20 units of RBCs transfused or at least two serum ferritin levels exceeding 1000 microg/L. Study endpoint was ICT treatment rate among ICT-eligible patients with lower-risk MDS (International Prognostic Scoring System [low or intermediate-1]; World Health Organization [refractory anemia {RA}, refractory anemia with ringed sideroblasts {RARS}, refractory cytopenia with multilineage dysplasia {RCMD}, refractory cytopenia with multilineage dysplasia and ringed sideroblasts, or 5q]; French-American-British [RA/RARS]). Among 78 ICT-eligible patients with lower-risk MDS, 32 (41%) received ICT. At ICT initiation, treated patients received on average 13.3 transfusions (27.6 units) and mean first post-ICT initiation serum ferritin was twice the MDS Foundation recommendation at 1949 microg/L. Median overall survival for all ICT-eligible patients was significantly longer for those ICT-treated patients than untreated patients (8.7 years vs. 4.7 years, log-rank p = 0.02; multivariate hazard ratio 0.372, p = 0.03). This study finds only 41% of ICT-eligible patients with lower-risk MDS received ICT in clinical practice, and treatment was initiated later than recommended. Receipt of ICT was associated with significantly longer survival.

Universal relations with fermionic dark matter

NASA Astrophysics Data System (ADS)

Krut, A.; Argüelles, C. R.; Rueda, J. A.; Ruffini, R.

2018-01-01

We have recently introduced a new model for the distribution of dark matter (DM) in galaxies, the Ruffini-Argüelles-Rueda (RAR) model, based on a self-gravitating system of massive fermions at finite temperatures. The RAR model, for fermion masses above keV, successfully describes the DM halos in galaxies, and predicts the existence of a denser quantum core towards the center of each configuration. We demonstrate here, for the first time, that the introduction of a cutoff in the fermion phase-space distribution, necessary to account for galaxies finite size and mass, defines a new solution with a compact quantum core which represents an alternative to the central black hole (BH) scenario for SgrA*. For a fermion mass in the range 48keV ≤ mc2 ≤ 345keV, the DM halo distribution fulfills the most recent data of the Milky Way rotation curves while harbors a dense quantum core of 4×106M⊙ within the S2 star pericenter. In particular, for a fermion mass of mc2 ˜ 50keV the model is able to explain the DM halos from typical dwarf spheroidal to normal elliptical galaxies, while harboring dark and massive compact objects from ˜ 103M⊙ tp to 108M⊙ at their respective centers. The model is shown to be in good agreement with different observationally inferred universal relations, such as the ones connecting DM halos with supermassive dark central objects. Finally, the model provides a natural mechanism for the formation of supermassive BHs as heavy as few ˜ 108M⊙. We argue that larger BH masses (few ˜ 109-10M⊙) may be achieved by assuming subsequent accretion processes onto the above heavy seeds, depending on accretion efficiency and environment.

β-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice.

PubMed

Iskandar, Anita R; Liu, Chun; Smith, Donald E; Hu, Kang-Quan; Choi, Sang-Woon; Ausman, Lynne M; Wang, Xiang-Dong

2013-04-01

Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosamino-1-(3-pyridyl)-1-butanone (NNK)-initiated lung cancer in A/J mice. This tumor-promoting effect of nicotine was accompanied by significant reductions in survival probability and lung Sirtuin 1 (SIRT1) expression, which has been proposed as a tumor suppressor. The decreased level of SIRT1 was associated with increased levels of AKT phosphorylation and interleukin (il)-6 mRNA but decreased tumor suppressor p53 and retinoic acid receptor (RAR)-β mRNA levels in the lungs. Using this mouse model, we then determined whether β-cryptoxanthin (BCX), a xanthophyll that is strongly associated with a reduced risk of lung cancer in several cohort studies, can inhibit nicotine-induced emphysema and lung tumorigenesis. We found that BCX supplementation at two different doses was associated with reductions of the nicotine-promoted lung tumor multiplicity and volume, as well as emphysema in mice treated with both NNK and nicotine. Moreover, BCX supplementation restored the nicotine-suppressed expression of lung SIRT1, p53, and RAR-β to that of the control group, increased survival probability, and decreased the levels of lung il-6 mRNA and phosphorylation of AKT. The present study indicates that BCX is a preventive agent against emphysema and lung cancer with SIRT1 as a potential target. In addition, our study establishes a relevant animal lung cancer model for studying tumor growth within emphysematous microenvironments.

Comparative Toxicogenomic Responses to the Flame Retardant mITP in Developing Zebrafish.

PubMed

Haggard, Derik E; Das, Siba R; Tanguay, Robert L

2017-02-20

Monosubstituted isopropylated triaryl phosphate (mITP) is a major component of Firemaster 550, an additive flame retardant mixture commonly used in polyurethane foams. Developmental toxicity studies in zebrafish established mITP as the most toxic component of FM 550, which causes pericardial edema and heart looping failure. Mechanistic studies showed that mITP is an aryl hydrocarbon receptor (AhR) ligand; however, the cardiotoxic effects of mITP were independent of the AhR. We performed comparative whole genome transcriptomics in wild-type and ahr2 hu3335 zebrafish, which lack functional ahr2, to identify transcriptional signatures causally involved in the mechanism of mITP-induced cardiotoxicity. Regardless of ahr2 status, mITP exposure resulted in decreased expression of transcripts related to the synthesis of all-trans-retinoic acid and a host of Hox genes. Clustered gene ontology enrichment analysis showed unique enrichment in biological processes related to xenobiotic metabolism and response to external stimuli in wild-type samples. Transcript enrichments overlapping both genotypes involved the retinoid metabolic process and sensory/visual perception biological processes. Examination of the gene-gene interaction network of the differentially expressed transcripts in both genetic backgrounds demonstrated a strong AhR interaction network specific to wild-type samples, with overlapping genes regulated by retinoic acid receptors (RARs). A transcriptome analysis of control ahr2-null zebrafish identified potential cross-talk among AhR, Nrf2, and Hif1α. Collectively, we confirmed that mITP is an AhR ligand and present evidence in support of our hypothesis that mITP's developmental cardiotoxic effects are mediated by inhibition at the RAR level.

Bexarotene via CBP/p300 induces suppression of NF-κB-dependent cell growth and invasion in thyroid cancer.

PubMed

Cras, Audrey; Politis, Béatrice; Balitrand, Nicole; Darsin-Bettinger, Diane; Boelle, Pierre Yves; Cassinat, Bruno; Toubert, Marie-Elisabeth; Chomienne, Christine

2012-01-15

Retinoic acid (RA) treatment has been used for redifferentiation of metastatic thyroid cancer with loss of radioiodine uptake. The aim of this study was to improve the understanding of RA resistance and investigate the role of bexarotene in thyroid cancer cells. A model of thyroid cancer cell lines with differential response to RA was used to evaluate the biological effects of retinoid and rexinoid and to correlate this with RA receptor levels. Subsequently, thyroid cancer patients were treated with 13-cis RA and bexarotene and response evaluated on radioiodine uptake reinduction on posttherapy scan and conventional imaging. In thyroid cancer patients, 13-cis RA resistance can be bypassed in some tumors by bexarotene. A decreased tumor growth without differentiation was observed confirming our in vitro data. Indeed, we show that ligands of RARs or RXRs exert different effects in thyroid cancer cell lines through either differentiation or inhibition of cell growth and invasion. These effects are associated with restoration of RARβ and RXRγ levels and downregulation of NF-κB targets genes. We show that bexarotene inhibits the transactivation potential of NF-κB in an RXR-dependent manner through decreased promoter permissiveness without interfering with NF-κB nuclear translocation and binding to its responsive elements. Inhibition of transcription results from the release of p300 coactivator from NF-κB target gene promoters and subsequent histone deacetylation. This study highlights dual mechanisms by which retinoids and rexinoids may target cell tumorigenicity, not only via RARs and RXRs, as expected, but also via NF-κB pathway. ©2011 AACR.

Transcriptional regulation of genes involved in retinoic acid metabolism in Senegalese sole larvae.

PubMed

Boglino, Anaïs; Ponce, Marian; Cousin, Xavier; Gisbert, Enric; Manchado, Manuel

2017-01-01

The aim of this study was the characterization of transcriptional regulatory pathways mediated by retinoic acid (RA) in Senegalese sole larvae. For this purpose, pre-metamorphic larvae were treated with a low concentration of DEAB, an inhibitor of RALDH enzyme, until the end of metamorphosis. No differences in growth, eye migration or survival were observed. Nevertheless, gene expression analysis revealed a total of 20 transcripts differentially expressed during larval development and only six related with DEAB treatments directly involved in RA metabolism and actions (rdh10a, aldh1a2, crbp1, igf2r, rarg and cyp26a1) to adapt to a low-RA environment. In a second experiment, post-metamorphic larvae were exposed to the all-trans RA (atRA) observing an opposite regulation for those genes involved in RA synthesis and degradation (rdh10a, aldh1a2, crbp1 and cyp26a1) as well as other related with thyroid- (dio2) and IGF-axes (igfbp1, igf2r and igfbp5) to balance RA levels. In a third experiment, DEAB-pretreated post-metamorphic larvae were exposed to atRA and TTNPB (a specific RAR agonist). Both drugs down-regulated rdh10a and aldh1a2 and up-regulated cyp26a1 expression demonstrating their important role in RA homeostasis. Moreover, five retinoic receptors that mediate RA actions, the thyroid receptor thrb, and five IGF binding proteins changed differentially their expression. Overall, this study demonstrates that exogenous RA modulates the expression of some genes involved in the RA synthesis, degradation and cellular transport through RAR-mediated regulatory pathways establishing a negative feedback regulatory mechanism necessary to balance endogenous RA levels and gradients. Copyright © 2016 Elsevier Inc. All rights reserved.

[Cough induction by high-frequency chest percussion in healthy volunteers and patients with common cold].

PubMed

Lee, P C L; Eccles, R

2004-08-01

In patients with chronic obstructive pulmonary disease, chest percussion is often used to facilitate the drainage of respiratory secretions which may be removed from the airway by coughing. The cough reflex is believed to be mediated by mechanically sensitive rapidly adapting receptors (RARs). Chest percussion stimulation may stimulate RAR cough receptors, but there is no evidence that mechanical airway stimulation in man induces cough. The aim of this study was to determine if cough can be induced by high-frequency chest percussion in healthy subjects and in patients with acute upper respiratory tract infection (URTI). Two groups were studied: 15 healthy subjects and 29 subjects with URTI, mean age 22 years. Percussion stimulation (70 Hz) was applied to the chest. Cough frequency and latency were recorded. All subjects were asked to complete a questionnaire about how they felt after the chest percussion by questionnaires. The results demonstrate that high-frequency chest percussion causes cough in human subjects with a recent history of URTI, but induces relatively little cough in healthy subjects. In URTI subjects there was a significant increase in the number of coughs after three periods of airway vibration, whereas in healthy subjects there was no change in cough. Furthermore, analysis of the questionnaires showed that more of the subjects with URTI felt an urge to cough compared to the healthy subjects in the subjective questionnaires. This study demonstrates that cough can be induced in subjects with URTI by chest percussion. This method of inducing cough in subjects with URTI may be useful for studies on the mechanism of cough and for studies on antitussive medicines.

KLF5/BTEB2, a Krüppel-like zinc-finger type transcription factor, mediates both smooth muscle cell activation and cardiac hypertrophy.

PubMed

Nagai, Ryozo; Shindo, Takayuki; Manabe, Ichiro; Suzuki, Toru; Kurabayashi, Masahiko

2003-01-01

Cardiac and vascular biology need to be approached interactively because they share many common biological features as seen in activation of the local renin-angiotensin system, angiogenesis, and extracellular matrix production. We previously reported KLF5/BTEB2, a Krüppel-like zinc-finger type transcription factor, to activate various gene promoters that are activated in phenotypically modulated smooth muscle cells, such as a nonmuscle type myosin heavy chain gene SMemb, plasminogen activator inhibitor-1 (PAI-1), iNOS, PDGF-A, Egr-1 and VEGF receptors at least in vitro. KLF5/BTEB2 mRNA levels are downregulated with vascular development but upregulated in neointima that is produced in response to vascular injury. Mitogenic stimulation activates KLF5/BTEB2 gene expression through MEK1 and Egr-1. Chromatin immunoprecipitation assay showed KLF5/BTEB2 to be induced and to bind the promoter of the PDGF-A gene in response to angiotensin II stimulation. In order to define the role of KLF5/BTEB2 in cardiovascular remodeling, we targeted the KLF5/BTEB2 gene in mice. Homozygous mice resulted in early embryonic lethality whereas heterozygous mice were apparently normal. However, in response to external stress, arteries of heterozygotes exhibited diminished levels of smooth muscle and adventitial cell activation. Furthermore, cardiac fibrosis and hypertrophy induced by continuous angiotensin II infusion. We also found that RARa binds KLF5/BTEB2, and that Am80, a potent synthetic RAR agonist, inhibits angiotensin II-induced cardiac hypertrophy. These results indicate that KLF5/BTEB2 is an essential transcription factor that causes not only smooth muscle phenotypic modulation but also cardiac hypertrophy and fibrosis.

Causes and Corrections for Propeller-Excited Airborne Noise on a Naval Auxiliary Oiler.

DTIC Science & Technology

1983-11-01

17 1 sas ri-IMFUtei tii llaii tilt- a,, D) = 01519 (at tip)) ~it., eptalil 1iii0i Ik-%(b ,I all 1 .11 Ill Ill MWi gisi I(il/il \\ ifiratioII Isi ’,~t...slipi aind suet Scopue iii, ltinil. ts r li. 1 It,,Aso, -i trl-rar- ratiorr ii. 𔃻 ) = 12 Thui prirs I it( ,fi - i t l-sigt intiirf riat ioin Ifor I i...gir, rimi- tri isi -tatritr pririlrtii 12:1. ililt-atlios:ii, 11 111 iG-, Ir411ir and %tiiii i il lttfr loi- -2 1 , .11"l tin.1 dtriri ot prrii-livr

A retinoic acid receptor β2 agonist reduces hepatic stellate cell activation in nonalcoholic fatty liver disease.

PubMed

Trasino, Steven E; Tang, Xiao-Han; Jessurun, Jose; Gudas, Lorraine J

2016-10-01

Hepatic stellate cells (HSCs) are an important cellular target for the development of novel pharmacological therapies to prevent and treat nonalcoholic fatty liver diseases (NAFLD). Using a high fat diet (HFD) model of NAFLD, we sought to determine if synthetic selective agonists for retinoic acid receptor β2 (RARβ2) and RARγ can mitigate HSC activation and HSC relevant signaling pathways during early stages of NAFLD, before the onset of liver injury. We demonstrate that the highly selective RARβ2 agonist, AC261066, can reduce the activation of HSCs, marked by decreased HSC expression of α-smooth muscle actin (α-SMA), in mice with HFD-induced NAFLD. Livers of HFD-fed mice treated with AC261066 exhibited reduced steatosis, oxidative stress, and expression of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNFα), interleukin 1β (IL-1β), and monocyte chemotactic protein-1 (MCP-1). Kupffer cell (macrophage) expression of transforming growth factor-β1 (TGF-β1), which plays a critical role in early HSC activation, was markedly reduced in AC261066-treated, HFD-fed mice. In contrast, HFD-fed mice treated with an RARγ agonist (CD1530) showed no decreases in steatosis, HSC activation, or Kupffer cell TGF-β1 levels. In conclusion, our data demonstrate that RARβ2 is an attractive target for development of NAFLD therapies. • Hepatic stellate cells (HSCs) are an important pharmacological target for the prevention of nonalcoholic fatty liver diseases (NAFLD). • Retinoids and retinoic acid receptors (RARs) possess favorable metabolic modulating properties. • We show that an agonist for retinoic acid receptor-β2 (RARβ2), but not RARγ, mitigates HSC activation and NAFLD.

Components of the CCR4-NOT complex function as nuclear hormone receptor coactivators via association with the NRC-interacting Factor NIF-1.

PubMed

Garapaty, Shivani; Mahajan, Muktar A; Samuels, Herbert H

2008-03-14

CCR4-NOT is an evolutionarily conserved, multicomponent complex known to be involved in transcription as well as mRNA degradation. Various subunits (e.g. CNOT1 and CNOT7/CAF1) have been reported to be involved in influencing nuclear hormone receptor activities. Here, we show that CCR4/CNOT6 and RCD1/CNOT9, members of the CCR4-NOT complex, potentiate nuclear receptor activity. RCD1 interacts in vivo and in vitro with NIF-1 (NRC-interacting factor), a previously characterized nuclear receptor cotransducer that activates nuclear receptors via its interaction with NRC. As with NIF-1, RCD1 and CCR4 do not directly associate with nuclear receptors; however, they enhance ligand-dependent transcriptional activation by nuclear hormone receptors. CCR4 mediates its effect through the ligand binding domain of nuclear receptors and small interference RNA-mediated silencing of endogenous CCR4 results in a marked decrease in nuclear receptor activation. Furthermore, knockdown of CCR4 results in an attenuated stimulation of RARalpha target genes (e.g. Sox9 and HoxA1) as shown by quantitative PCR assays. The silencing of endogenous NIF-1 also resulted in a comparable decrease in the RAR-mediated induction of both Sox9 and HoxA1. Furthermore, CCR4 associates in vivo with NIF-1. In addition, the CCR4-enhanced transcriptional activation by nuclear receptors is dependent on NIF-1. The small interference RNA-mediated knockdown of NIF-1 blocks the ligand-dependent potentiating effect of CCR4. Our results suggest that CCR4 plays a role in the regulation of certain endogenous RARalpha target genes and that RCD1 and CCR4 might mediate their function through their interaction with NIF-1.

Sodium Octanoate Modulates the Innate Immune Response of Bovine Mammary Epithelial Cells through the TLR2/P38/JNK/ERK1/2 Pathway: Implications during Staphylococcus aureus Internalization.

PubMed

Alva-Murillo, Nayeli; Ochoa-Zarzosa, Alejandra; López-Meza, Joel E

2017-01-01

Bovine mammary epithelial cells (bMECs) contribute to mammary gland defense against invading pathogens, such as Staphylococcus aureus (intracellular facultative), which is recognized by TLR2. In a previous report, we showed that sodium octanoate [NaO, a medium chain fatty acid (C8)] induces (0.25 mM) or inhibits (1 mM) S. aureus internalization into bMECs and differentially regulates the innate immune response (IIR). However, the molecular mechanisms have not been described, which was the aim of this study. The results showed that α5β1 integrin membrane abundance (MA) was increased in 0.25 mM NaO-treated cells, but TLR2 or CD36 MA was not modified. When these receptors were blocked individually, 0.25 mM NaO-increased S. aureus internalization was notably reduced. Interestingly, in this condition, the IIR of the bMECs was impaired because MAPK (p38, JNK, and ERK1/2) phosphorylation and the activation of transcription factors related to these pathways were decreased. In addition, the 1 mM NaO treatment induced TLR2 MA, but neither the integrin nor CD36 MA was modified. The reduction in S. aureus internalization induced by 1 mM NaO was increased further when TLR2 was blocked. In addition, the phosphorylation levels of the MAPKs increased, and 13 transcriptional factors related to the IIR were slightly activated (CBF, CDP, c-Myb, AP-1, Ets-1/Pea-3, FAST-1, GAS/ISRE, AP-2, NFAT-1, OCT-1, RAR/DR-5, RXR/DR-1, and Stat-3). Moreover, the 1 mM NaO treatment up-regulated gene expression of IL-8 and RANTES and secretion of IL-1β. Notably, when 1 mM NaO-treated bMECs were challenged with S. aureus , the gene expression of IL-8 and IL-10 increased, while IL-1β secretion was reduced. In conclusion, our results showed that α5β1 integrin, TLR2 and CD36 are involved in 0.25 mM NaO-increased S. aureus internalization in bMECs. In addition, 1 mM NaO activates bMECs via the TLR2 signaling pathways (p38, JNK, and ERK1/2), which improves IIR before S. aureus invasion. Additionally, NaO (1 mM) might exert anti-inflammatory effects after bacterial internalization.

Two azole fungicides (carcinogenic triadimefon and non-carcinogenic myclobutanil) exhibit different hepatic cytochrome P450 activities in medaka fish.

PubMed

Lin, Chun-Hung; Chou, Pei-Hsin; Chen, Pei-Jen

2014-07-30

Conazoles are a class of imidazole- or triazole-containing drugs commonly used as fungicides in agriculture and medicine. The broad application of azole drugs has led to the contamination of surface aquifers receiving the effluent of municipal or hospital wastewater or agricultural runoff. Several triazoles are rodent carcinogens; azole pollution is a concern to environmental safety and human health. However, the carcinogenic mechanisms associated with cytochrome P450 enzymes (CYPs) of conazoles remain unclear. We exposed adult medaka fish (Oryzias latipes) to continuous aqueous solutions of carcinogenic triadimefon and non-carcinogenic myclobutanil for 7 to 20 days at sub-lethal or environmentally relevant concentrations and assessed hepatic CYP activity and gene expression associated with CYP-mediated toxicity. Both triadimefon and myclobutanil induced hepatic CYP3A activity, but only triadimefon enhanced CYP1A activity. The gene expression of cyp3a38, cyp3a40, pregnane x receptor (pxr), cyp26b, retinoid acid receptor γ1 (rarγ1) and p53 was higher with triadimefon than myclobutanil. As well, yeast-based reporter gene assay revealed that 4 tested conazoles were weak agonists of aryl hydrocarbon receptor (AhR). We reveal differential CYP gene expression with carcinogenic and non-carcinogenic conazoles in a lower vertebrate, medaka fish. Liver CYP-enzyme induction may be a key event in conazole-induced tumorigenesis. This information is essential to evaluate the potential threat of conazoles to human health and fish populations in the aquatic environment. Copyright © 2014 Elsevier B.V. All rights reserved.

Retinoic Acid Protects Cardiomyocytes from High Glucose-Induced Apoptosis via Inhibition of Sustained Activation of NF-κB Signaling

PubMed Central

Nizamutdinova, Irina T.; Guleria, Rakeshwar S.; Singh, Amar B.; Kendall, Jonathan A.; Baker, Kenneth M.; Pan, Jing

2012-01-01

We have previously shown that retinoic acid (RA) has protective effects on high glucose (HG)-induced cardiomyocyte apoptosis. To further elucidate the molecular mechanisms of RA effects, we determined the interaction between nuclear factor (NF)-κB and RA signaling. HG induced a sustained phosphorylation of IKK/IκBα and transcriptional activation of NF-κB in cardiomyocytes. Activated NF-κB signaling has an important role in HG-induced cardiomyocyte apoptosis and gene expression of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1 (MCP-1). All-trans RA (ATRA) and LGD1069, through activation of RAR/RXR-mediated signaling, inhibited the HG-mediated effects in cardiomyocytes. The inhibitory effect of RA on NF-κB activation was mediated through inhibition of IKK/IκBα phosphorylation. ATRA and LGD1069 treatment promoted protein phosphatase 2A (PP2A) activity, which was significantly suppressed by HG stimulation. The RA effects on IKK and IκBα were blocked by okadaic acid or silencing the expression of PP2Ac-subunit, indicating that the inhibitory effect of RA on NF-κB is regulated through activation of PP2A and subsequent dephosphorylation of IKK/IκBα. Moreover, ATRA and LGD1069 reversed the decreased PP2A activity and inhibited the activation of IKK/IκBα and gene expression of MCP-1, IL-6 and TNF-α in the hearts of Zucker diabetic fatty rats. In summary, our findings suggest that the suppressed activation of PP2A contributed to sustained activation of NF-κB in HG-stimulated cardiomyocytes; and that the protective effect of RA on hyperglycemia-induced cardiomyocyte apoptosis and inflammatory responses is partially regulated through activation of PP2A and suppression of NF-κB-mediated signaling and downstream targets. PMID:22718360

Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.

PubMed

Xia, Mingcan; Viera-Hutchins, Loida; Garcia-Lloret, Maria; Noval Rivas, Magali; Wise, Petra; McGhee, Sean A; Chatila, Zena K; Daher, Nancy; Sioutas, Constantinos; Chatila, Talal A

2015-08-01

Traffic-related particulate matter (PM) has been linked to a heightened incidence of asthma and allergic diseases. However, the molecular mechanisms by which PM exposure promotes allergic diseases remain elusive. We sought to determine the expression, function, and regulation of pathways involved in promotion of allergic airway inflammation by PM. We used gene expression transcriptional profiling, in vitro culture assays, and in vivo murine models of allergic airway inflammation. We identified components of the Notch pathway, most notably Jagged 1 (Jag1), as targets of PM induction in human monocytes and murine dendritic cells. PM, especially ultrafine particles, upregulated TH cytokine levels, IgE production, and allergic airway inflammation in mice in a Jag1- and Notch-dependent manner, especially in the context of the proasthmatic IL-4 receptor allele Il4raR576. PM-induced Jag1 expression was mediated by the aryl hydrocarbon receptor (AhR), which bound to and activated AhR response elements in the Jag1 promoter. Pharmacologic antagonism of AhR or its lineage-specific deletion in CD11c(+) cells abrogated the augmentation of airway inflammation by PM. PM activates an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with proasthmatic alleles. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis.

PubMed

Cañete, Ana; Cano, Elena; Muñoz-Chápuli, Ramón; Carmona, Rita

2017-02-20

Vitamin A is an essential micronutrient throughout life. Its physiologically active metabolite retinoic acid (RA), acting through nuclear retinoic acid receptors (RARs), is a potent regulator of patterning during embryonic development, as well as being necessary for adult tissue homeostasis. Vitamin A deficiency during pregnancy increases risk of maternal night blindness and anemia and may be a cause of congenital malformations. Childhood Vitamin A deficiency can cause xerophthalmia, lower resistance to infection and increased risk of mortality. RA signaling appears to be essential for expression of genes involved in developmental hematopoiesis, regulating the endothelial/blood cells balance in the yolk sac, promoting the hemogenic program in the aorta-gonad-mesonephros area and stimulating eryrthropoiesis in fetal liver by activating the expression of erythropoietin. In adults, RA signaling regulates differentiation of granulocytes and enhances erythropoiesis. Vitamin A may facilitate iron absorption and metabolism to prevent anemia and plays a key role in mucosal immune responses, modulating the function of regulatory T cells. Furthermore, defective RA/RARα signaling is involved in the pathogenesis of acute promyelocytic leukemia due to a failure in differentiation of promyelocytes. This review focuses on the different roles played by vitamin A/RA signaling in physiological and pathological mouse hematopoiesis duddurring both, embryonic and adult life, and the consequences of vitamin A deficiency for the blood system.

Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.

PubMed

Cheng, Hao; Xie, Zhiliang; Jones, William P; Wei, Xiaohui Tracey; Liu, Zhongfa; Wang, Dasheng; Kulp, Samuel K; Wang, Jiang; Coss, Christopher C; Chen, Ching-Shih; Marcucci, Guido; Garzon, Ramiro; Covey, Joseph M; Phelps, Mitch A; Chan, Kenneth K

2016-05-01

AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.

Liver X Receptors Balance Lipid Stores in Hepatic Stellate Cells via Rab18, a Retinoid Responsive Lipid Droplet Protein

PubMed Central

O’Mahony, Fiona; Wroblewski, Kevin; O’Byrne, Sheila M.; Jiang, Hongfeng; Clerkin, Kara; Benhammou, Jihane; Blaner, William S.; Beaven, Simon W.

2014-01-01

Liver X receptors (LXRs) are determinants of hepatic stellate cell (HSC) activation and liver fibrosis. Freshly isolated HSCs from Lxrαβ−/− mice have increased lipid droplet (LD) size but the functional consequences of this are unknown. Our aim was to determine whether LXRs link cholesterol to retinoid storage in HSCs and how this impacts activation. Primary HSCs from Lxrαβ−/− and wild-type (WT) mice were profiled by gene array during in vitro activation. Lipid content was quantified by HPLC and mass spectroscopy. Primary HSCs were treated with nuclear receptor ligands, transfected with siRNA and plasmid constructs, and analyzed by immunocytochemistry. Lxrαβ−/− HSCs have increased cholesterol and retinyl esters (CEs & REs). The retinoid increase drives intrinsic retinoic acid receptor (RAR) signaling and activation occurs more rapidly in Lxrαβ−/− HSCs. We identify Rab18 as a novel retinoic acid responsive, lipid droplet associated protein that helps mediate stellate cell activation. Rab18 mRNA, protein, and membrane insertion increase during activation. Both Rab18 GTPase activity and isoprenylation are required for stellate cell lipid droplet loss and induction of activation markers. These phenomena are accelerated in the Lxrαβ−/− HSCs, where there is greater retinoic acid flux. Conversely, Rab18 knockdown retards lipid droplet loss in culture and blocks activation, just like the functional mutants. Rab18 is also induced with acute liver injury in vivo. Conclusion Retinoid and cholesterol metabolism are linked in stellate cells by the LD associated protein, Rab18. Retinoid overload helps explain the pro-fibrotic phenotype of Lxrαβ−/− mice and we establish a pivotal role for Rab18 GTPase activity and membrane insertion in wild-type stellate cell activation. Interference with Rab18 may have significant therapeutic benefit in ameliorating liver fibrosis. PMID:25482505

Group 3 innate lymphoid cells (ILC3s): Origin, differentiation, and plasticity in humans and mice.

PubMed

Montaldo, Elisa; Juelke, Kerstin; Romagnani, Chiara

2015-08-01

Since their discovery, innate lymphoid cells (ILCs) have been the subject of intense research. As their name implies, ILCs are innate cells of lymphoid origin, and can be grouped into subsets based on their cytotoxic activity, cytokine profile, and the transcriptional requirements during ILC differentiation. The main ILC groups are "killer" ILCs, comprising NK cells, and "helper-like" ILCs (including ILC1s, ILC2s, and ILC3s). This review examines the origin, differentiation stages, and plasticity of murine and human ILC3s. ILC3s express the retinoic acid receptor (RAR) related orphan receptor RORγt and the signature cytokines IL-22 and IL-17. Fetal ILC3s or lymphoid tissue inducer cells are required for lymphoid organogenesis, while postnatally developing ILC3s are important for the generation of intestinal cryptopatches and isolated lymphoid follicles as well as for the defence against pathogens and epithelial homeostasis. Here, we discuss the transcription factors and exogenous signals (including cytokines, nutrients and cell-to-cell interaction) that drive ILC3 lineage commitment and acquisition of their distinctive effector program. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Aspergillus fumigatus Preexposure Worsens Pathology and Improves Control of Mycobacterium abscessus Pulmonary Infection in Mice.

PubMed

Monin, Leticia; Mehta, Shail; Elsegeiny, Waleed; Gopal, Radha; McAleer, Jeremy P; Oury, Tim D; Kolls, Jay; Khader, Shabaana A

2018-03-01

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Mutations in this chloride channel lead to mucus accumulation, subsequent recurrent pulmonary infections, and inflammation, which, in turn, cause chronic lung disease and respiratory failure. Recently, rates of nontuberculous mycobacterial (NTM) infections in CF patients have been increasing. Of particular relevance is infection with Mycobacterium abscessus , which causes a serious, life-threatening disease and constitutes one of the most antibiotic-resistant NTM species. Interestingly, an increased prevalence of NTM infections is associated with worsening lung function in CF patients who are also coinfected with Aspergillus fumigatus We established a new mouse model to investigate the relationship between A. fumigatus and M. abscessus pulmonary infections. In this model, animals exposed to A. fumigatus and coinfected with M. abscessus exhibited increased lung inflammation and decreased mycobacterial burden compared with those of mice infected with M. abscessus alone. This increased control of M. abscessus infection in coinfected mice was mucus independent but dependent on both transcription factors T-box 21 (Tbx21) and retinoic acid receptor (RAR)-related orphan receptor gamma t (RORγ-t), master regulators of type 1 and type 17 immune responses, respectively. These results implicate a role for both type 1 and type 17 responses in M. abscessus control in A. fumigatus -coinfected lungs. Our results demonstrate that A. fumigatus , an organism found commonly in CF patients with NTM infection, can worsen pulmonary inflammation and impact M. abscessus control in a mouse model. Copyright © 2018 American Society for Microbiology.

Structure-based design of Trifarotene (CD5789), a potent and selective RARγ agonist for the treatment of acne.

PubMed

Thoreau, Etienne; Arlabosse, Jean-Marie; Bouix-Peter, Claire; Chambon, Sandrine; Chantalat, Laurent; Daver, Sébastien; Dumais, Laurence; Duvert, Gwenaëlle; Feret, Angélique; Ouvry, Gilles; Pascau, Jonathan; Raffin, Catherine; Rodeville, Nicolas; Soulet, Catherine; Tabet, Samuel; Talano, Sandrine; Portal, Thibaud

2018-06-01

Retinoids have a dominant role in topical acne therapy and to date, only RARβ and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known γ-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789. Copyright © 2018 Elsevier Ltd. All rights reserved.

LE135, a retinoid acid receptor antagonist, produces pain through direct activation of TRP channels.

PubMed

Yin, Shijin; Luo, Jialie; Qian, Aihua; Yu, Weihua; Hu, Hongzhen

2014-03-01

Retinoids, through their activation of retinoic acid receptors (RARs) and retinoid X receptors, regulate diverse cellular processes, and pharmacological intervention in their actions has been successful in the treatment of skin disorders and cancers. Despite the many beneficial effects, administration of retinoids causes irritating side effects with unknown mechanisms. Here, we demonstrate that LE135 [4-(7,8,9,10-tetrahydro-5,7,7,10,10-pentamethyl-5H-benzo[e]naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid], a selective antagonist of RARβ , is a potent activator of the capsaicin (TRPV1) and wasabi (TRPA1) receptors, two critical pain-initiating cation channels. We performed to investigate the excitatory effects of LE135 on TRPV1 and TRPA1 channels expressed in HEK293T cells and in dorsal root ganglia neurons with calcium imaging and patch-clamp recordings. We also used site-directed mutagenesis of the channels to determine the structural basis of LE135-induced activation of TRPV1 and TRPA1 channels and behavioural testing to examine if pharmacological inhibition and genetic deletion of the channels affected LE135-evoked pain-related behaviours. LE135 activated both the capsaicin receptor (TRPV1) and the allyl isothiocyanate receptor (TRPA1) heterologously expressed in HEK293T cells and endogenously expressed by sensory nociceptors. Mutations disrupting the capsaicin-binding site attenuated LE135 activation of TRPV1 channels and a single mutation (K170R) eliminated TRPA1 activity evoked by LE135. Intraplantar injection of LE135 evoked pain-related behaviours. Both TRPV1 and TRPA1 channels were involved in LE135-elicited pain-related responses, as shown by pharmacological and genetic ablation studies. This blocker of retinoid acid signalling also exerted non-genomic effects through activating the pain-initiating TRPV1 and TRPA1 channels. © 2013 The British Pharmacological Society.

Rapid assessment response (RAR) study: drug use and health risk - Pretoria, South Africa

PubMed Central

2011-01-01

Background Within a ten year period South Africa has developed a substantial illicit drug market. Data on HIV risk among drug using populations clearly indicate high levels of HIV risk behaviour due to the sharing of injecting equipment and/or drug-related unprotected sex. While there is international evidence on and experience with adequate responses, limited responses addressing drug use and drug-use-related HIV and other health risks are witnessed in South Africa. This study aimed to explore the emerging problem of drug-related HIV transmission and to stimulate the development of adequate health services for the drug users, by linking international expertise and local research. Methods A Rapid Assessment and Response (RAR) methodology was adopted for the study. For individual and focus group interviews a semi-structured questionnaire was utilised that addressed key issues. Interviews were conducted with a total of 84 key informant (KI) participants, 63 drug user KI participants (49 males, 14 females) and 21 KI service providers (8 male, 13 female). Results and Discussion Adverse living conditions and poor education levels were cited as making access to treatment harder, especially for those living in disadvantaged areas. Heroin was found to be the substance most available and used in a problematic way within the Pretoria area. Participants were not fully aware of the concrete health risks involved in drug use, and the vague ideas held appear not to allow for concrete measures to protect themselves. Knowledge with regards to substance related HIV/AIDS transmission is not yet widespread, with some information sources disseminating incorrect or unspecific information. Conclusions The implementation of pragmatic harm-reduction and other evidence-based public health care policies that are designed to reduce the harmful consequences associated with substance use and HIV/AIDS should be considered. HIV testing and treatment services also need to be made available in places accessed by drug users. PMID:21631928

Exercise interventions and prevention of fall-related fractures in older people: a meta-analysis of randomized controlled trials.

PubMed

Zhao, Renqing; Feng, Feifei; Wang, Xinzheng

2017-02-01

This meta-analysis aimed to determine whether exercise interventions were effective in preventing fall-related fractures in older people. The treatment effects on rate of falls, leg strength and balance were also examined. An electronic database search was conducted in PubMed, EMBASE, the Cochrane library and PEDro up to 1 September 2015. Randomized controlled trials (RCTs) that conducted exercise interventions and reported fall-related fracture data in older people were included. The primary outcome was the treatment effects on fall-related fractures determined by relative risk (RR) and 95% confidence interval (CI). The treatment effects on falls, leg strength and balance were also reported using rate ratio (RaR) with 95% CI and standardized mean difference (SMD) with 95% CI, respectively. Random effects models were used for meta-analysis. Fifteen studies including 3136 participants met the inclusion criteria. Exercise had a beneficial effect on reduction of fall-related fractures, with pooled estimates of RR 0.604 (95% CI 0.453 - 0.840, P  = 0.003, I 2  = 0%). The rate of falls (RaR 0.856, 95% CI 0.778 - 0.941, P  = 0.001, I 2  = 45%) and leg strength (SMD 0.613, 95% CI 0.119 - 1.107, P  = 0.015, I 2  = 76.7%) were also potentially affected by exercise interventions. These only had a marginally beneficial effect on balance (SMD 0.468, 95% CI -0.011 - 0.947, P  = 0.055, I 2  = 93.6%). Our findings implied that exercise interventions were effective in preventing fall-related fractures and reducing risk factors of fall-related fractures in older people. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

Establishment of a simple and rapid identification method for Listeria spp. by using high-resolution melting analysis, and its application in food industry.

PubMed

Ohshima, Chihiro; Takahashi, Hajime; Phraephaisarn, Chirapiphat; Vesaratchavest, Mongkol; Keeratipibul, Suwimon; Kuda, Takashi; Kimura, Bon

2014-01-01

Listeria monocytogenes is the causative bacteria of listeriosis, which has a higher mortality rate than that of other causes of food poisoning. Listeria spp., of which L. monocytogenes is a member, have been isolated from food and manufacturing environments. Several methods have been published for identifying Listeria spp.; however, many of the methods cannot identify newly categorized Listeria spp. Additionally, they are often not suitable for the food industry, owing to their complexity, cost, or time consumption. Recently, high-resolution melting analysis (HRMA), which exploits DNA-sequence differences, has received attention as a simple and quick genomic typing method. In the present study, a new method for the simple, rapid, and low-cost identification of Listeria spp. has been presented using the genes rarA and ldh as targets for HRMA. DNA sequences of 9 Listeria species were first compared, and polymorphisms were identified for each species for primer design. Species specificity of each HRM curve pattern was estimated using type strains of all the species. Among the 9 species, 7 were identified by HRMA using rarA gene, including 3 new species. The remaining 2 species were identified by HRMA of ldh gene. The newly developed HRMA method was then used to assess Listeria isolates from the food industry, and the method efficiency was compared to that of identification by 16S rDNA sequence analysis. The 2 methods were in coherence for 92.6% of the samples, demonstrating the high accuracy of HRMA. The time required for identifying Listeria spp. was substantially low, and the process was considerably simplified, providing a useful and precise method for processing multiple samples per day. Our newly developed method for identifying Listeria spp. is highly valuable; its use is not limited to the food industry, and it can be used for the isolates from the natural environment.

Establishment of a Simple and Rapid Identification Method for Listeria spp. by Using High-Resolution Melting Analysis, and Its Application in Food Industry

PubMed Central

Ohshima, Chihiro; Takahashi, Hajime; Phraephaisarn, Chirapiphat; Vesaratchavest, Mongkol; Keeratipibul, Suwimon; Kuda, Takashi; Kimura, Bon

2014-01-01

Listeria monocytogenes is the causative bacteria of listeriosis, which has a higher mortality rate than that of other causes of food poisoning. Listeria spp., of which L. monocytogenes is a member, have been isolated from food and manufacturing environments. Several methods have been published for identifying Listeria spp.; however, many of the methods cannot identify newly categorized Listeria spp. Additionally, they are often not suitable for the food industry, owing to their complexity, cost, or time consumption. Recently, high-resolution melting analysis (HRMA), which exploits DNA-sequence differences, has received attention as a simple and quick genomic typing method. In the present study, a new method for the simple, rapid, and low-cost identification of Listeria spp. has been presented using the genes rarA and ldh as targets for HRMA. DNA sequences of 9 Listeria species were first compared, and polymorphisms were identified for each species for primer design. Species specificity of each HRM curve pattern was estimated using type strains of all the species. Among the 9 species, 7 were identified by HRMA using rarA gene, including 3 new species. The remaining 2 species were identified by HRMA of ldh gene. The newly developed HRMA method was then used to assess Listeria isolates from the food industry, and the method efficiency was compared to that of identification by 16S rDNA sequence analysis. The 2 methods were in coherence for 92.6% of the samples, demonstrating the high accuracy of HRMA. The time required for identifying Listeria spp. was substantially low, and the process was considerably simplified, providing a useful and precise method for processing multiple samples per day. Our newly developed method for identifying Listeria spp. is highly valuable; its use is not limited to the food industry, and it can be used for the isolates from the natural environment. PMID:24918440

Coarse root topology of Norway spruce (Picea abies) and its effects on slope stability

NASA Astrophysics Data System (ADS)

Lith, Aniek; Schmaltz, Elmar; Bogaard, Thom; Keesstra, Saskia

2017-04-01

The structural distribution of coarse roots and its beneficial effects on soil reinforcement has widely been assessed. However, it is still not fully understood how topological features of coarse roots (e.g. branching patterns) are affected by slope inclination and further influence the ability of young trees to reinforce soil. This study aims to analyse empirically the impact of slope gradient on the topological development of coarse roots and thus to assess its effects on soil reinforcement. We performed root system excavations on two young Picea abies: tree A on a gently inclined plane (β ≈ 12°) where slope failures are not expected; tree B on a slope (β ≈ 35°) with failure potential. The diameter (d) of the segments between distinct root nodes (root ends, branching locations, direction changes and attachments to stem) of coarse roots (d > 2mm) were measured in situ. The spatial coordinates (x,y,z) of the nodes and surface were measured on a plane raster grid, from which segment length (ls), direction and inclination towards the surface (βr) were derived. Roots and segments were classified into laterals (βr < 10°), obliques (10° ≤ βr < 70°) and verticals (βr ≥ 70°), with βr,max = 90°. We assigned topological orders to the segments according to developmental (DSC) and functional segment classifications (FSC), to obtain quantitative relations between the topological order and number of segments, total and average ls. The maximal root cohesion (cr) of each segment was assessed using material specific tensile forces (Tr), root area ratio (RAR) and βr, assuming that a potential slip surface would cross the root system parallel to the slope. Laterals depicted the majority of roots (57 %) for tree A orientated rather in upslope direction (76.8 %), whereas tree B showed mostly obliques (54 %) orientated rather in downslope direction (55.4 %). Vertical roots were scarcely observable for both trees. DSC showed a high r2 (> 0.84) for the segments and ls. FSC showed high r2 (> 0.95) for the number of segments and the total length. RAR values of tree B are distributed rather upslope (76.8 % of RARtot), compared to 44.5 % of RARtot for tree A. The average cr (0.15) of each segment of tree B was remarkably higher than of tree A (0.10), leading to the conclusion that the slope has a strong influence on cr itself. This is supported by comparing the distribution of cr for both trees, where tree B tends to produce a higher cr in upslope direction (68.7 % of total cr) than tree A (37.7 %). In contrast to our expectations, tree B shows generally a higher cr compared to tree A, despite lower subsurface biomass. The findings indicate that the distinct branching patterns of coarse roots might determine the distribution of the RAR and thus lead to a higher reinforcement potential of young Picea abies on slopes.

A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensitivity in transcriptional activation of the lactoferrin gene.

PubMed

Lee, M O; Liu, Y; Zhang, X K

1995-08-01

The lactoferrin gene is highly expressed in many different tissues, and its expression is controlled by different regulators. In this report, we have defined a retinoic acid response element (RARE) in the 5'-flanking region of the lactoferrin gene promoter. The lactoferrin-RARE is composed of two AGGTCA-like motifs arranged as a direct repeat with 1-bp spacing (DR-1). A gel retardation assay demonstrated that it bound strongly with retinoid X receptor (RXR) homodimers and RXR-retinoic acid receptor (RAR) heterodimers as well as chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan receptor. In CV-1 cells, the lactoferrin-RARE linked with a heterologous thymidine kinase promoter was strongly activated by RXR homodimers in response to 9-cis-retinoic acid (9-cis-RA) but not to all-trans-RA. When the COUP-TF orphan receptor was cotransfected, the 9-cis-RA-induced RXR homodimer activity was strongly repressed. A unique feature of the lactoferrin-RARE is that it has an AGGTCA-like motif in common with an estrogen-responsive element (ERE). The composite RARE/ERE contributes to the functional interaction between retinoid receptors and the estrogen receptor (ER) and their ligands. In CV-1 cells, cotransfection of the retinoid and estrogen receptors led to mutual inhibition of the other's activity, while an RA-dependent inhibition of ER activity was observed in breast cancer cells. Furthermore, the lactoferrin-RARE/ERE showed differential transactivation activity in different cell types. RAs could activate the lactoferrin-RARE/ERE in human leukemia HL-60 cells and U937 cells but not in human breast cancer cells. By gel retardation analyses, we demonstrated that strong binding of the endogenous COUP-TF in breast cancer cells to the composite element contributed to diminished RA response in these cells. Thus, the lactoferrin-RARE/ERE functions as a signaling switch module that mediates multihormonal responsiveness in the regulation of lactoferrin gene expression.

Assessment of WWMCCS Performance in a Post-Nuclear Attack Environment. Sanitized

DTIC Science & Technology

1975-11-01

34cONTRACT No. 001-75-C-0217 * 1 THIS WORK SPONSOQRED BY THE DEFENSE NUCLEAR AGENC" UNDER RDT&E RMSS CODE X36075669 Q94OAXDDO01O1 H2590D. Pr p r d 1 rTHIS DOCUM...8217 < : " ! , . .I/• I V...... .... . . . . . . 1 "- 7 . . . • .tEPORT DOCJMENTATION PAGE "rAr, . Irt’. ±~ATSSIS9.C.7NF VMC EPPINEI 21 Jan 75-31 Oc- 75 IOST-I.CLLEA...U .. 4II4 .i %Iy•11 .4 @$ . .~ *󈧯.I . 1 . S $P.IL%-V ka"I 1 "- This work sponsored by the Defe.xse Nuclear Agency under %DT&E WISS Code X360075469 Q9

The role of folate metabolism in orofacial development and clefting

PubMed Central

Wahl, Stacey E.; Kennedy, Allyson E.; Wyatt, Brent H.; Moore, Alexander D.; Pridgen, Deborah E.; Cherry, Amanda M.; Mavila, Catherine B.; Dickinson, Amanda J.G.

2015-01-01

Folate deficiency has been associated with numerous diseases and birth defects including orofacial defects. However, whether folate has a role in the face during early orofacial development has been unclear. The present study reveals that pharmacological and antisense oligonucleotide mediated inhibition of DHFR, an integral enzyme in the folate pathway, results in specific changes in the size and shape of the midface and embryonic mouth. Such defects are accompanied by a severe reduction in the muscle and cartilage jaw elements without significant change in neural crest pattern or global levels of methylation. We propose that the orofacial defects associated with DHFR deficient function are the result of decreased cell proliferation and increased cell death via DNA damage. In particular, localized apoptosis may also be depleting the cells of the face that express crucial genes for the differentiation of the jaw structures. Folate supplementation is widely known to reduce human risk for orofacial clefts. In the present study, we show that activating folate metabolism can reduce median oral clefts in the primary palate by increasing cell survival. Moreover, we demonstrate that a minor decrease in DHFR function exacerbates median facial clefts caused by RAR inhibition. This work suggests that folate deficiencies could be a major contributing factor to multifactorial orofacial defects. PMID:26144049

Retinal dehydrogenase gene expression in stomach and small intestine of rats during postnatal development and in vitamin A deficiency.

PubMed

Bhat, P V

1998-04-17

Retinal dehydrogenase (RALDH) catalyzes the oxidation of retinal to all-trans and 9-cis retinoic acid, which function as ligands controlling RAR and RXR nuclear receptor-signaling pathways. We have recently shown the expression of RALDH transcript in the stomach and small intestine by reverse transcription polymerase chain reaction [Bhat, P.V., Labrecque J., Dumas, F., Lacroix, A. and Yoshida, A. (1995) Gene 166, 303-306]. We have examined RALDH expression in the stomach and small intestine before and during postnatal development and in vitamin A deficiency by assaying for mRNA levels and protein as well as for enzyme activity. In -2 day fetuses, RALDH expression was high in the small intestine, whereas RALDH protein was not detectable in the stomach. However, expression of RALDH was seen in the stomach after birth, and gradually increased with age and reached the highest level at postnatal day 42. In the intestine, RALDH expression decreased postnatally. Vitamin A deficiency up-regulated RALDH expression in the stomach and small intestine, and administration of retinoids down-regulated the RALDH expression in these tissues. These results show the differential expression of RALDH in the stomach and small intestine during postnatal development, and that vitamin A status regulates the expression of RALDH gene in these tissues.

Exploring (novel) gene expression during retinoid-induced maturation and cell death of acute promyelocytic leukemia.

PubMed

Benoit, G R; Tong, J H; Balajthy, Z; Lanotte, M

2001-01-01

During recent years, reports have shown that biological responses of acute promyelocytic leukemia (APL) cells to retinoids are more complex than initially envisioned. PML-RARalpha chimeric protein disturbs various biological processes such as cell proliferation, differentiation, and apoptosis. The distinct biological programs that regulate these processes stem from specific transcriptional activation of distinct (but overlapping) sets of genes. These programs are sometimes mutually exclusive and depend on whether the signals are delivered by RAR or RXR agonists. Furthermore, evidence that retinoid nuclear signaling by retinoid, on its own, is not enough to trigger these cellular responses is rapidly accumulating. Indeed, work with NB4 cells show that the fate of APL cells treated by retinoid depends on complex signaling cross-talk. Elucidation of the sequence of events and cascades of transcriptional regulation necessary for APL cell maturation will be an additional tool with which to further improve therapy by retinoids. In this task, the classical techniques used to analyze gene expression have proved time consuming, and their yield has been limited. Global analyses of the APL cell transcriptome are needed. We review the technical approaches currently available (differential display, complementary DNA microarrays), to identify novel genes involved in the determination of cell fate.

Control of Innate and Adaptive Lymphocytes by the RAR-Retinoic Acid Axis.

PubMed

Kim, Chang H

2018-02-01

Lymphocytes, such as T cells, B cells, and innate lymphoid cells (ILCs), play central roles in regulating immune responses. Retinoic acids (RAs) are vitamin A metabolites, produced and metabolized by certain tissue cells and myeloid cells in a tissue-specific manner. It has been established that RAs induce gut-homing receptors on T cells, B cells, and ILCs. A mounting body of evidence indicates that RAs exert far-reaching effects on functional differentiation and fate of these lymphocytes. For example, RAs promote effector T cell maintenance, generation of induced gut-homing regulatory and effector T cell subsets, antibody production by B cells, and functional maturation of ILCs. Key functions of RAs in regulating major groups of innate and adaptive lymphocytes are highlighted in this article.

Refractory anemia with ringed sideroblasts and chronic myelomonocytic leukemia: myelodysplastic/myeloproliferative disease.

PubMed

D'Angelo, Guido

2005-01-01

Here is reported the case of an elderly woman that, after surgical intervention, showed an important anemia, leucocytosis and thrombocytopenia. The leucocytosis was accompanied with clean increase of the monocytes. The morphological appearances, both peripheral blood and bone marrow, showed an evident overlapping of myelodysplastic and myeloproliferative picture, characterized from the presence of refractory anemia with ringed sideroblasts (RARS) and chronic myelomonocytic leukemia (CMML). The case has been reported because it is not frequent, besides, the CMML, until from the beginning of French-American-British (FAB) classification application, has raised problems of classification. Currently, the World Health Organization (WHO) has given an arrangement to the hematological picture with myelodysplastic and myeloproliferative morphological appearances, including this pathology in a new category: myelodysplastic/myeloproliferative diseases (MDS/MPD).

Tolerance to the Intestinal Microbiota Mediated by ROR(γt)(+) Cells.

PubMed

Ohnmacht, Caspar

2016-07-01

Harmless microbes colonizing the gut require the establishment of a well-equilibrated symbiosis between this microbiota and its host. However, the immune system is primed to recognize both conserved microbial patterns and foreign antigens, and therefore developed strong tolerance mechanisms to prevent potential fatal immune reactivity to symbiotic microbes. The transcription factor RAR-related orphan-like γt [ROR(γt); encoded by Rorc] plays a key role in the gut for lymphoid tissue organogenesis, development of innate lymphoid cells type 3 (ILC3s) and proinflammatory type 17 T helper (Th17) cells. Surprisingly, recent research has revealed a contribution of ROR(γt)-expressing cells in a variety of tolerance mechanisms in both the innate and adaptive immune system. Copyright © 2016 Elsevier Ltd. All rights reserved.

Peroxisome proliferator-activated receptor-β/δ inhibits human neuroblastoma cell tumorigenesis by inducing p53- and SOX2-mediated cell differentiation.

PubMed

Yao, Pei-Li; Chen, Liping; Dobrzański, Tomasz P; Zhu, Bokai; Kang, Boo-Hyon; Müller, Rolf; Gonzalez, Frank J; Peters, Jeffrey M

2017-05-01

Neuroblastoma is a common childhood cancer typically treated by inducing differentiation with retinoic acid (RA). Peroxisome proliferator-activated receptor-β/δ, (PPARβ/δ) is known to promote terminal differentiation of many cell types. In the present study, PPARβ/δ was over-expressed in three human neuroblastoma cell lines, NGP, SK-N-BE(2), and IMR-32, that exhibit high, medium, and low sensitivity, respectively, to retinoic acid-induced differentiation to determine if PPARβ/δ and retinoic acid receptors (RARs) could be jointly targeted to increase the efficacy of treatment. All-trans-RA (atRA) decreased expression of SRY (sex determining region Y)-box 2 (SOX2), a stem cell regulator and marker of de-differentiation, in NGP and SK-N-BE(2) cells with inactive or mutant tumor suppressor p53, respectively. However, atRA did not suppress SOX2 expression in IMR-32 cells carrying wild-type p53. Over-expression and/or ligand activation of PPARβ/δ reduced the average volume and weight of ectopic tumor xenografts from NGP, SK-N-BE(2), or IMR-32 cells compared to controls. Compared with that found with atRA, PPARβ/δ suppressed SOX2 expression in NGP and SK-N-BE(2) cells and ectopic xenografts, and was also effective in suppressing SOX2 expression in IMR-32 cells that exhibit higher p53 expression compared to the former cell lines. Combined, these observations demonstrate that activating or over-expressing PPARβ/δ induces cell differentiation through p53- and SOX2-dependent signaling pathways in neuroblastoma cells and tumors. This suggests that combinatorial activation of both RARα and PPARβ/δ may be suitable as an alternative therapeutic approach for RA-resistant neuroblastoma patients. Published [2016]. This article is a U.S. Government work and is in the public domain in the USA.

Retinoids and rexinoids in cancer prevention: from laboratory to clinic.

PubMed

Uray, Iván P; Dmitrovsky, Ethan; Brown, Powel H

2016-02-01

Early in the age of modern medicine the consequences of vitamin A deficiency drew attention to the fundamental link between retinoid-dependent homeostatic regulation and malignant hyperproliferative diseases. The term "retinoid" includes a handful of endogenous and a large group of synthetic derivatives of vitamin A. These multifunctional lipid-soluble compounds directly regulate target genes of specific biological functions and critical signaling pathways to orchestrate complex functions from vision to development, metabolism, and inflammation. Many of the retinoid activities on the cellular level have been well characterized and translated to the regulation of processes like differentiation and cell death, which play critical roles in the outcome of malignant transformation of tissues. In fact, retinoid-based differentiation therapy of acute promyelocytic leukemia was one of the first successful examples of molecularly targeted treatment strategies. The selectivity, high receptor binding affinity and the ability of retinoids to directly modulate gene expression programs present a distinct pharmacological opportunity for cancer treatment and prevention. However, to fully exploit their potential, the adverse effects of retinoids must be averted. In this review we provide an overview of the biology of retinoid (activated by nuclear retinoic acid receptors [RARs]) and rexinoid (engaged by nuclear retinoid X receptors [RXRs]) action concluded from a long line of preclinical studies, in relation to normal and transformed states of cells. We will also discuss the past and current uses of retinoids in the treatment of malignancies, the potential of rexinoids in the cancer prevention setting, both as single agents and in combinations. Copyright © 2016 Elsevier Inc. All rights reserved.

History of retinoic acid receptors.

PubMed

Benbrook, Doris M; Chambon, Pierre; Rochette-Egly, Cécile; Asson-Batres, Mary Ann

2014-01-01

The discovery of retinoic acid receptors arose from research into how vitamins are essential for life. Early studies indicated that Vitamin A was metabolized into an active factor, retinoic acid (RA), which regulates RNA and protein expression in cells. Each step forward in our understanding of retinoic acid in human health was accomplished by the development and application of new technologies. Development cDNA cloning techniques and discovery of nuclear receptors for steroid hormones provided the basis for identification of two classes of retinoic acid receptors, RARs and RXRs, each of which has three isoforms, α, β and ɣ. DNA manipulation and crystallographic studies revealed that the receptors contain discrete functional domains responsible for binding to DNA, ligands and cofactors. Ligand binding was shown to induce conformational changes in the receptors that cause release of corepressors and recruitment of coactivators to create functional complexes that are bound to consensus promoter DNA sequences called retinoic acid response elements (RAREs) and that cause opening of chromatin and transcription of adjacent genes. Homologous recombination technology allowed the development of mice lacking expression of retinoic acid receptors, individually or in various combinations, which demonstrated that the receptors exhibit vital, but redundant, functions in fetal development and in vision, reproduction, and other functions required for maintenance of adult life. More recent advancements in sequencing and proteomic technologies reveal the complexity of retinoic acid receptor involvement in cellular function through regulation of gene expression and kinase activity. Future directions will require systems biology approaches to decipher how these integrated networks affect human stem cells, health, and disease.

MiR-9-5p and miR-106a-5p dysregulated in CD4+ T-cells of multiple sclerosis patients and targeted essential factors of T helper17/regulatory T-cells differentiation

PubMed Central

Majd, Maryam; Hosseini, Aref; Ghaedi, Kamran; Kiani-Esfahani, Abbas; Tanhaei, Somayeh; Shiralian-Esfahani, Hanieh; Rahnamaee, Seyed Yahya; Mowla, Seyed Javad; Nasr-Esfahani, Mohammad Hossein

2018-01-01

Objective(s): Multiple sclerosis (MS) is considered as a chronic type of an inflammatory disease characterized by loss of myelin of CNS. Recent evidence indicates that Interleukin 17 (IL-17)-producing T helper cells (Th17 cells) population are increased and regulatory T cells (Treg cells) are decreased in MS. Despite extensive research in understanding the mechanism of Th17 and Treg differentiation, the role of microRNAs in MS is not completely understood. Thereby, as a step closer, we analyzed the expression profile of miR-9-5p and miR-106a-5p, and protein level of retinoic acid receptor (RAR)-related orphan receptor C (RORC; Th17 master transcription factor) as direct target of miR-106a-5p and forkhead box P3 (FOXP3; Treg master transcription factor) as indirect target of miR-9-5p in CD4+ T cells in two groups of relapsing and remitting in our relapsing-remitting MS (RR-MS) patients. Materials and Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was utilized to assess the expression of miRNAs and mRNAs, in 40 RR-MS patients and 11 healthy individuals. Thus, FOXP3 and RAR-related orphan receptor γt (RORγt) was assessed in CD4+T-cells by flow cytometry. We also investigated the role of these miRNAs in Th17/Treg differentiation pathway through bioinformatics tools. Results: An up-regulation of miR-9-5p and down-regulation of miR-106a-5p in relapsing phase of MS patients were observed compared to healthy controls. RORC and FOXP3 were up-regulated in relapsing and remitting phases of MS, respectively. Conclusion: Expression pattern of miR-9-5p and miR-106a-5p and their targets suggest a possible inducing role of miR-9-5p and suppressing role of miR-106a-5p in differentiation pathway of Th17 cells during MS pathogenesis. PMID:29511494

Fertility in 47,XXX and 45,X patients.

PubMed Central

Dewhurst, J

1978-01-01

Female patients with a sex chromosome abnormality may be fertile. In patients with a 47,XXX cell line there appears to be an increased risk of a cytogenetically abnormal child but the extent of this risk cannot yet be determined; it is probably lower in the non-mosaic 47,XXX patient than the mosaic 46,XX/47,XXX one. Patients with a 45,X cell line rarly become pregnant, and when they do they appear to have a high risk of an abnormal child or repeated unsuccessfuly pregnancies; this risk is certainly exaggerated by the method of reporting; when the poor reproductive perforamcne is first identified leading to the recognition of the maternal cytogenetic fault, the reproductive failure rate is naturally high; when the maternal fault is first identified and the reproductive history then established far better results are evident. PMID:641947

In-silico docking based design and synthesis of [1H,3H] imidazo[4,5-b] pyridines as lumazine synthase inhibitors for their effective antimicrobial activity.

PubMed

Harer, Sunil L; Bhatia, Manish S

2014-10-01

The imidazopyridine moiety is important pharmacophore that has proven to be useful for a number of biologically relevant targets, also reported to display antibacterial, antifungal, antiviral properties. Riboflavin biosynthesis involving catalytic step of Lumazine synthase is absent in animals and human, but present in microorganism, one of marked advantage of this study. Still, this path is not exploited as antiinfective target. Here, we proposed different interactions between [1H,3H] imidazo[4,5-b] pyridine test ligands and target protein Lumazine synthase (protein Data Bank 2C92), one-step synthesis of title compounds and further evaluation of them for in vitro antimicrobial activity. Active pocket of the target protein involved in the interaction with the test ligands molecules was found using Biopredicta tools in VLifeMDS 4.3 Suite. In-silico docking suggests H-bonding, hydrophobic interaction, charge interaction, aromatic interaction, and Vanderwaal forces responsible for stabilizing enzyme-inhibitor complex. Disc diffusion assay method was used for in vitro antimicrobial screening. Investigation of possible interaction between test ligands and target lumazine synthase of Mycobacterium tuberculosis suggested 1i and 2f as best fit candidates showing hydrogen bonding, hydrophobic, aromatic and Vanderwaal's forces. Among all derivatives 1g, 1j, 1k, 1l, 2a, 2c, 2d, 2e, 2h, and 2j exhibited potent activities against bacteria and fungi compared to the standard Ciprofloxacin and Fluconazole, respectively. The superiority of 1H imidazo [4,5-b] pyridine compounds having R' = Cl >No2 > NH2 at the phenyl/aliphatic moiety resident on the imidazopyridine, whereas leading 3H imidazo[4,5-b] pyridine compounds containing R/Ar = Cl > No2 > NH2> OCH3 substituents on the 2(nd) position of imidazole.

In-silico docking based design and synthesis of [1H,3H] imidazo[4,5-b] pyridines as lumazine synthase inhibitors for their effective antimicrobial activity

PubMed Central

Harer, Sunil L.; Bhatia, Manish S.

2014-01-01

Purpose: The imidazopyridine moiety is important pharmacophore that has proven to be useful for a number of biologically relevant targets, also reported to display antibacterial, antifungal, antiviral properties. Riboflavin biosynthesis involving catalytic step of Lumazine synthase is absent in animals and human, but present in microorganism, one of marked advantage of this study. Still, this path is not exploited as antiinfective target. Here, we proposed different interactions between [1H,3H] imidazo[4,5-b] pyridine test ligands and target protein Lumazine synthase (protein Data Bank 2C92), one-step synthesis of title compounds and further evaluation of them for in vitro antimicrobial activity. Materials and Methods: Active pocket of the target protein involved in the interaction with the test ligands molecules was found using Biopredicta tools in VLifeMDS 4.3 Suite. In-silico docking suggests H-bonding, hydrophobic interaction, charge interaction, aromatic interaction, and Vanderwaal forces responsible for stabilizing enzyme-inhibitor complex. Disc diffusion assay method was used for in vitro antimicrobial screening. Results and Discussion: Investigation of possible interaction between test ligands and target lumazine synthase of Mycobacterium tuberculosis suggested 1i and 2f as best fit candidates showing hydrogen bonding, hydrophobic, aromatic and Vanderwaal's forces. Among all derivatives 1g, 1j, 1k, 1l, 2a, 2c, 2d, 2e, 2h, and 2j exhibited potent activities against bacteria and fungi compared to the standard Ciprofloxacin and Fluconazole, respectively. The superiority of 1H imidazo [4,5-b] pyridine compounds having R’ = Cl >No2 > NH2 at the phenyl/aliphatic moiety resident on the imidazopyridine, whereas leading 3H imidazo[4,5-b] pyridine compounds containing R/Ar = Cl > No2 > NH2> OCH3 substituents on the 2nd position of imidazole. PMID:25400412

Similar, but different: structurally related azelaic acid and hexanoic acid trigger differential metabolomic and transcriptomic responses in tobacco cells.

PubMed

Djami-Tchatchou, Arnaud T; Ncube, Efficient N; Steenkamp, Paul A; Dubery, Ian A

2017-11-29

Plants respond to various stress stimuli by activating an enhanced broad-spectrum defensive ability. The development of novel resistance inducers represents an attractive, alternative crop protection strategy. In this regard, hexanoic acid (Hxa, a chemical elicitor) and azelaic acid (Aza, a natural signaling compound) have been proposed as inducers of plant defense, by means of a priming mechanism. Here, we investigated both the mode of action and the complementarity of Aza and Hxa as priming agents in Nicotiana tabacum cells in support of enhanced defense. Metabolomic analyses identified signatory biomarkers involved in the establishment of a pre-conditioned state following Aza and Hxa treatment. Both inducers affected the metabolomes in a similar manner and generated common biomarkers: caffeoylputrescine glycoside, cis-5-caffeoylquinic acid, feruloylglycoside, feruloyl-3-methoxytyramine glycoside and feruloyl-3-methoxytyramine conjugate. Subsequently, quantitative real time-PCR was used to investigate the expression of inducible defense response genes: phenylalanine ammonia lyase, hydroxycinnamoyl CoA quinate transferase and hydroxycinnamoyl transferase to monitor activation of the early phenylpropanoid pathway and chlorogenic acids metabolism, while ethylene response element-binding protein, small sar1 GTPase, heat shock protein 90, RAR1, SGT1, non-expressor of PR genes 1 and thioredoxin were analyzed to report on signal transduction events. Pathogenesis-related protein 1a and defensin were quantified to investigate the activation of defenses regulated by salicylic acid and jasmonic acid respectively. The qPCR results revealed differential expression kinetics and, in general (except for NPR1, Thionin and PR1a), the relative gene expression ratios observed in the Hxa-treated cells were significantly greater than the expression observed in the cells treated with Aza. The results indicate that Aza and Hxa have a similar priming effect through activation of genes involved in the establishment of systemic acquired resistance, associated with enhanced synthesis of hydroxycinnamic acids and related conjugates.

Melatonin Suppresses Neuropathic Pain via MT2-Dependent and -Independent Pathways in Dorsal Root Ganglia Neurons of Mice

PubMed Central

Lin, Jia-Ji; Lin, Ye; Zhao, Tian-Zhi; Zhang, Chun-Kui; Zhang, Ting; Chen, Xiao-Li; Ding, Jia-Qi; Chang, Ting; Zhang, Zhuo; Sun, Chao; Zhao, Dai-Di; Zhu, Jun-Lin; Li, Zhu-Yi; Li, Jin-Lian

2017-01-01

Melatonin (Mel) and its receptors (MT1 and MT2) have a well-documented efficacy in treating different pain conditions. However, the anti-nociceptive effects of Mel and Mel receptors in neuropathic pain (NP) are poorly understood. To elucidate this process, pain behaviors were measured in a dorsal root ganglia (DRG)-friendly sciatic nerve cuffing model. We detected up-regulation of MT2 expression in the DRGs of cuff-implanted mice and its activation by the agonist 8-M-PDOT (8MP). Also, Mel attenuated the mechanical and thermal allodynia induced by cuff implantation. Immunohistochemical analysis demonstrated the expression of MT2 in the DRG neurons, while MT1 was expressed in the satellite cells. In cultured primary neurons, microarray analysis and gene knockdown experiments demonstrated that MT2 activation by 8MP or Mel suppressed calcium signaling pathways via MAPK1, which were blocked by RAR-related orphan receptor alpha (RORα) activation with a high dose of Mel. Furthermore, expression of nitric oxide synthase 1 (NOS1) was down-regulated upon Mel treatment regardless of MT2 or RORα. Application of Mel or 8MP in cuff-implanted models inhibited the activation of peptidergic neurons and neuro-inflammation in the DRGs by down-regulating c-fos, calcitonin gene-related peptide [CGRP], and tumor necrosis factor-1α [TNF-1α] and interleukin-1β [IL-1β]. Addition of the MT2 antagonist luzindole blocked the effects of 8MP but not those of Mel. In conclusion, only MT2 was expressed in the DRG neurons and up-regulated upon cuff implantation. The analgesic effects of Mel in cuff-implanted mice were closely associated with both MT2-dependent (MAPK-calcium channels) and MT2-independent (NOS1) pathways in the DRG. PMID:28656058

Bioactivity of Carotenoids - Chasms of Knowledge.

PubMed

Bohn, Torsten

2017-02-10

Carotenoid dietary intake, especially within fruits/vegetables and their plasma levels have been associated in many epidemiological studies with a reduced risk of several chronic diseases, including type-2 diabetes, cardiovascular diseases, several types of cancer, and agerelated macular degeneration. However, intervention trials with isolated carotenoids (as supplements) have fallen short of fulfi lling the hopes that were placed in these lipophilic pigments, often producing no positive or even adverse effects, such as increased lung cancer rate or total mortality. More recent studies have suggested that certain metabolites, and not necessarily the native compounds may be (the most) biologically active ones, such as certain apocarotenals (originating following enzymatic cleavage) and other more polar compounds, acting as more suitable electrophiles to react with transcription factors such as nuclear factor kappa-B (NF-KB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, it appears that questions of dosing are likewise crucial, as may be interactions of non-provitamin A carotenoids and their derivatives with retinoic acid receptors (RAR) or retinoid X receptors (RXR). Furthermore, our picture on carotenoid metabolism may be incomplete, as our knowledge on e. g. the interaction with the microbiota is virtually nil. In this position article, it is aimed to highlight some of the discrepancies that appear to trouble carotenoid-related research, and point out some of the existing gaps in our knowledge.

Retinoic acid regulates cell-shape and -death of E-FABP (FABP5)-immunoreactive septoclasts in the growth plate cartilage of mice.

PubMed

Bando, Yasuhiko; Yamamoto, Miyuki; Sakiyama, Koji; Sakashita, Hide; Taira, Fuyoko; Miyake, Genki; Iseki, Shoichi; Owada, Yuji; Amano, Osamu

2017-09-01

Septoclasts, which are mononuclear and spindle-shaped cells with many processes, have been considered to resorb the transverse septa of the growth plate (GP) cartilage at the chondro-osseous junction (COJ). We previously reported the expression of epidermal-type fatty acid-binding protein (E-FABP, FABP5) and localization of peroxisome proliferator-activated receptor (PPAR)β/δ, which mediates the cell survival or proliferation, in septoclasts. On the other hand, retinoic acid (RA) can bind to E-FABP and is stored abundantly in the GP cartilage. From these information, it is possible to hypothesize that RA in the GP is incorporated into septoclasts during the cartilage resorption and regulates the growth and/or death of septoclasts. To clarify the mechanism of the cartilage resorption induced by RA, we administered an overdose of RA or its precursor vitamin A (VA)-deficient diet to young mice. In mice of both RA excess and VA deficiency, septoclasts decreased in the number and cell size in association with shorter and lesser processes than those in normal mice, suggesting a substantial suppression of resorption by septoclasts in the GP cartilage. Lack of PPARβ/δ-expression, TUNEL reaction, RA receptor (RAR)β, and cellular retinoic acid-binding protein (CRABP)-II were induced in E-FABP-positive septoclasts under RA excess, suggesting the growth arrest/cell-death of septoclasts, whereas cartilage-derived retinoic acid-sensitive protein (CD-RAP) inducing the cell growth arrest or morphological changes was induced in septoclasts under VA deficiency. These results support and do not conflict with our hypothesis, suggesting that endogenous RA in the GP is possibly incorporated in septoclasts and utilized to regulate the activity of septoclasts resorbing the GP cartilage.

9-Cis-Retinoic Acid Induces Growth Inhibition in Retinoid-Sensitive Breast Cancer and Sea Urchin Embryonic Cells via Retinoid X Receptor α and Replication Factor C3

PubMed Central

Maeng, Sejung; Kim, Gil Jung; Choi, Eun Ju; Yang, Hyun Ok; Lee, Dong-Sup

2012-01-01

There is widespread interest in defining factors and mechanisms that suppress the proliferation of cancer cells. Retinoic acid (RA) is a potent suppressor of mammary cancer and developmental embryonic cell proliferation. However, the molecular mechanisms by which 9-cis-RA signaling induces growth inhibition in RA-sensitive breast cancer and embryonic cells are not apparent. Here, we provide evidence that the inhibitory effect of 9-cis-RA on cell proliferation depends on 9-cis-RA-dependent interaction of retinoid X receptor α (RXRα) with replication factor C3 (RFC3), which is a subunit of the RFC heteropentamer that opens and closes the circular proliferating cell nuclear antigen (PCNA) clamp on DNA. An RFC3 ortholog in a sea urchin cDNA library was isolated by using the ligand-binding domain of RXRα as bait in a yeast two-hybrid screening. The interaction of RFC3 with RXRα depends on 9-cis-RA and bexarotene, but not on all-trans-RA or an RA receptor (RAR)-selective ligand. Truncation and mutagenesis experiments demonstrated that the C-terminal LXXLL motifs in both human and sea urchin RFC3 are critical for the interaction with RXRα. The transient interaction between 9-cis-RA-activated RXRα and RFC3 resulted in reconfiguration of the PCNA-RFC complex. Furthermore, we found that knockdown of RXRα or overexpression of RFC3 impairs the ability of 9-cis-RA to inhibit proliferation of MCF-7 breast cancer cells and sea urchin embryogenesis. Our results indicate that 9-cis-RA-activated RXRα suppresses the growth of RA-sensitive breast cancer and embryonic cells through RFC3. PMID:22949521

Acute promyelocytic leukemia, hypogranular variant, with uncharacteristic staining with chloroacetate esterase.

PubMed

Dunphy, C H; Polski, J M; Johns, G; Evans, H L; Gardner, L J

2001-06-01

A diagnosis of the hypogranular variant of acute promyelocytic leukemia (APLv) may be difficult to establish based on cytomorphology alone. However, the great majority of cases have a classical immunophenotype by flow cytometric immunophenotyping (FCI) (CD13+, CD33+, dim CD64+, HLA-DR-, and CD34-) and a classical enzyme cytochemical (EC) staining pattern. [intensely staining with myeloperoxidase, Sudan Black B, and chloroacetate esterase (CAE) and negative with alpha'-naphthyl acetate and butyrate esterases]. Although the immunophenotype of APLv by FCI has varied in the literature (HLA-DR +/- and CD34 +/-), the EC staining pattern has remained constant. We report a case of APLv with characteristic cytomorphology, compatible FCI data (CD13+, CD33+, dim CD64+, HLA-DR +/-, and CD34-), chromosomal detection of t(15; 17), and molecular detection of the PML/RAR alpha fusion gene; however, staining of the leukemic cells with CAE was quite uncharacteristic. We describe our findings.

Deficiency of retinaldehyde dehydrogenase 1 induces BMP2 and increases bone mass in vivo.

PubMed

Nallamshetty, Shriram; Wang, Hong; Rhee, Eun-Jung; Kiefer, Florian W; Brown, Jonathan D; Lotinun, Sutada; Le, Phuong; Baron, Roland; Rosen, Clifford J; Plutzky, Jorge

2013-01-01

The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak bone density acquisition and skeletal remodeling are complex and compartment specific. Emerging data indicates that retinoids, such as all trans retinoic acid (ATRA) and its precursor all trans retinaldehyde (Rald), exhibit distinct and divergent transcriptional effects in metabolism. Despite these observations, the role of enzymes that control retinoid metabolism in bone remains undefined. In this study, we examined the skeletal phenotype of mice deficient in retinaldehyde dehydrogenase 1 (Aldh1a1), the enzyme responsible for converting Rald to ATRA in adult animals. Bone densitometry and micro-computed tomography (µCT) demonstrated that Aldh1a1-deficient (Aldh1a1(-/-) ) female mice had higher trabecular and cortical bone mass compared to age and sex-matched control C57Bl/6 wild type (WT) mice at multiple time points. Histomorphometry confirmed increased cortical bone thickness and demonstrated significantly higher bone marrow adiposity in Aldh1a1(-/-) mice. In serum assays, Aldh1a1(-/-) mice also had higher serum IGF-1 levels. In vitro, primary Aldh1a1(-/-) mesenchymal stem cells (MSCs) expressed significantly higher levels of bone morphogenetic protein 2 (BMP2) and demonstrated enhanced osteoblastogenesis and adipogenesis versus WT MSCs. BMP2 was also expressed at higher levels in the femurs and tibias of Aldh1a1(-/-) mice with accompanying induction of BMP2-regulated responses, including expression of Runx2 and alkaline phosphatase, and Smad phosphorylation. In vitro, Rald, which accumulates in Aldh1a1(-/-) mice, potently induced BMP2 in WT MSCs in a retinoic acid receptor (RAR)-dependent manner, suggesting that Rald is involved in the BMP2 increases seen in Aldh1a1 deficiency in vivo. Collectively, these data implicate Aldh1a1 as a novel determinant of cortical bone density and marrow adiposity in the skeleton in vivo through modulation of BMP signaling.

Comparative analysis of protein-protein interactions in the defense response of rice and wheat.

PubMed

Cantu, Dario; Yang, Baoju; Ruan, Randy; Li, Kun; Menzo, Virginia; Fu, Daolin; Chern, Mawsheng; Ronald, Pamela C; Dubcovsky, Jorge

2013-03-12

Despite the importance of wheat as a major staple crop and the negative impact of diseases on its production worldwide, the genetic mechanisms and gene interactions involved in the resistance response in wheat are still poorly understood. The complete sequence of the rice genome has provided an extremely useful parallel road map for genetic and genomics studies in wheat. The recent construction of a defense response interactome in rice has the potential to further enhance the translation of advances in rice to wheat and other grasses. The objective of this study was to determine the degree of conservation in the protein-protein interactions in the rice and wheat defense response interactomes. As entry points we selected proteins that serve as key regulators of the rice defense response: the RAR1/SGT1/HSP90 protein complex, NPR1, XA21, and XB12 (XA21 interacting protein 12). Using available wheat sequence databases and phylogenetic analyses we identified and cloned the wheat orthologs of these four rice proteins, including recently duplicated paralogs, and their known direct interactors and tested 86 binary protein interactions using yeast-two-hybrid (Y2H) assays. All interactions between wheat proteins were further tested using in planta bimolecular fluorescence complementation (BiFC). Eighty three percent of the known rice interactions were confirmed when wheat proteins were tested with rice interactors and 76% were confirmed using wheat protein pairs. All interactions in the RAR1/SGT1/ HSP90, NPR1 and XB12 nodes were confirmed for the identified orthologous wheat proteins, whereas only forty four percent of the interactions were confirmed in the interactome node centered on XA21. We hypothesize that this reduction may be associated with a different sub-functionalization history of the multiple duplications that occurred in this gene family after the divergence of the wheat and rice lineages. The observed high conservation of interactions between proteins that serve as key regulators of the rice defense response suggests that the existing rice interactome can be used to predict interactions in wheat. Such predictions are less reliable for nodes that have undergone a different history of duplications and sub-functionalization in the two lineages.

A zebrafish model of PINK1 deficiency reveals key pathway dysfunction including HIF signaling.

PubMed

Priyadarshini, M; Tuimala, J; Chen, Y C; Panula, P

2013-06-01

The PTEN induced putative kinase 1 (PINK1) gene is mutated in patients with hereditary early onset Parkinson's disease (PD). The targets of PINK1 and the mechanisms in PD are still not fully understood. Here, we carried out a high-throughput and unbiased microarray study to identify novel functions and pathways for PINK1. In larval zebrafish, the function of pink1 was inhibited using splice-site morpholino oligonucleotides and the samples were hybridized on a two-color gene expression array. We found 177 significantly altered genes in pink1 morphants compared with the uninjected wildtype controls (log fold change values from -1.6 to +0.9). The five most prominent pathways based on critical biological processes and key toxicological responses were hypoxia-inducible factor (HIF) signaling, TGF-β signaling, mitochondrial dysfunction, RAR activation, and biogenesis of mitochondria. Furthermore, we verified that potentially important genes such as hif1α, catalase, SOD3, and atp1a2a were downregulated in pink1 morphants, whereas genes such as fech, pax2a, and notch1a were upregulated. Some of these genes have been found to play important roles in HIF signaling pathways. The pink1 morphants were found to have heart dysfunction, increased erythropoiesis, increased expression of vascular endothelial growth factors, and increased ROS. Our findings suggest that a lack of pink1 in zebrafish alters many vital and critical pathways in addition to the HIF signaling pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

Identification of heparin-binding EGF-like growth factor as a target in intercellular regulation of epidermal basal cell growth by suprabasal retinoic acid receptors.

PubMed Central

Xiao, J H; Feng, X; Di, W; Peng, Z H; Li, L A; Chambon, P; Voorhees, J J

1999-01-01

The role of retinoic acid receptors (RARs) in intercellular regulation of cell growth was assessed by targeting a dominant-negative RARalpha mutant (dnRARalpha) to differentiated suprabasal cells of mouse epidermis. dnRARalpha lacks transcriptional activation but not DNA-binding and receptor dimerization functions. Analysis of transgenic mice revealed that dnRARalpha dose-dependently impaired induction of basal cell proliferation and epidermal hyperplasia by all-trans RA (tRA). dnRARalpha formed heterodimers with endogenous retinoid X receptor-alpha (RXRalpha) over RA response elements in competition with remaining endogenous RARgamma-RXRalpha heterodimers, and dose-dependently impaired retinoid-dependent gene transcription. To identify genes regulated by retinoid receptors and involved in cell growth control, we analyzed the retinoid effects on expression of the epidermal growth factor (EGF) receptor, EGF, transforming growth factor-alpha, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin genes. In normal epidermis, tRA rapidly and selectively induced expression of HB-EGF but not the others. This induction occurred exclusively in suprabasal cells. In transgenic epidermis, dnRARalpha dose-dependently inhibited tRA induction of suprabasal HB-EGF and subsequent basal cell hyperproliferation. Together, our observations suggest that retinoid receptor heterodimers located in differentiated suprabasal cells mediate retinoid induction of HB-EGF, which in turn stimulates basal cell growth via intercellular signaling. These events may underlie retinoid action in epidermal regeneration during wound healing. PMID:10075925

Activation of RAS/ERK alone is insufficient to inhibit RXRα function and deplete retinoic acid in hepatocytes

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

Wang, Ai-Guo, E-mail: wangaiguotl@hotmail.com; Song, Ya-Nan; Chen, Jun

2014-09-26

Highlights: • The activation of RAS/ERK is insufficient to inhibit RXRα function and deplete RA. • The retinoid metabolism-related genes are down-regulated by ras oncogene. • The atRA has no effect on preventing hepatic tumorigenesis or curing the developed hepatic nodules. - Abstract: Activation of RAS/ERK signaling pathway, depletion of retinoid, and phosphorylation of retinoid X receptor alpha (RXRα) are frequent events found in liver tumors and thought to play important roles in hepatic tumorigenesis. However, the relationships among them still remained to be elucidated. By exploring the transgenic mouse model of hepatic tumorigenesis induced by liver-specific expression of H-ras12Vmore » oncogene, the activation of RAS/ERK, the mRNA expression levels of retinoid metabolism-related genes, the contents of retinoid metabolites, and phosphorylation of RXRα were determined. RAS/ERK signaling pathway was gradually and significantly activated in hepatic tumor adjacent normal liver tissues (P) and hepatic tumor tissues (T) of H-ras12V transgenic mice compared with normal liver tissues (Wt) of wild type mice. On the contrary, the mRNA expression levels of retinoid metabolism-related genes were significantly reduced in P and T compared with Wt. Interestingly, the retinoid metabolites 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (atRA), the well known ligands for nuclear transcription factor RXR and retinoic acid receptor (RAR), were significantly decreased only in T compared with Wt and P, although the oxidized polar metabolite of atRA, 4-keto-all-trans-retinoic-acid (4-keto-RA) was significantly decreased in both P and T compared with Wt. To our surprise, the functions of RXRα were significantly blocked only in T compared with Wt and P. Namely, the total protein levels of RXRα were significantly reduced and the phosphorylation levels of RXRα were significantly increased only in T compared with Wt and P. Treatment of H-ras12V transgenic mice at 5-week-old or 5-month-old with atRA had no effect on the prevention of tumorigenesis or cure of developed nodules in liver. These events imply that the depletion of 9cRA and atRA and the inhibition of RXRα function in hepatic tumors involve more complex mechanisms besides the activation of RAS/ERK pathway.« less

Space industrialization. Volume 3: World and domestic implications

NASA Technical Reports Server (NTRS)

1978-01-01

The status of worldwide space industralization activities is assessed as well as the benefits to be anticipated from enhanced activities. Methods for stimulating space industralization growth are discussed with emphasis on foreign and international activities, national and world impact assessments, industry/government interfaces, legal implications, institutional implications, economics and capitalization, and implementation issues and recommendations.

Alteration of gene expression in the colon of colorectal cancer model rat by dietary sodium gluconate.

PubMed

Kameue, Chiyoko; Tsukahara, Takamitsu; Ushida, Kazunari

2006-03-01

Butyrate induces apoptosis of various cancer cell lines in a p53-independent manner and inhibits the proliferation of cancer cells. In a previous report, we reported a significant reduction in tumor incidence in rat colon as a result of dietary sodium gluconate (GNA). The stimulation of apoptosis through enhanced butyrate production in the large intestine was involved in the antitumorigenic effect of GNA. In the present study, a cDNA microarray analysis was performed to investigate the particular mechanism involved in the antitumorigenic effect of GNA. Some up-regulated genes suggested by microarray analysis were further evaluated using real-time PCR. A microarray revealed that GNA regulates the expression of retinoic acid receptor (RAR) and retinoid X receptor (RXR), and several genes known as the target of retinoids in cancer cells. In other words, the antitumorigenic effect of GNA may involve the regulation of the retinoid signaling pathway by butyrate in a retinoid-independent manner.

Wavelet images and Chou's pseudo amino acid composition for protein classification.

PubMed

Nanni, Loris; Brahnam, Sheryl; Lumini, Alessandra

2012-08-01

The last decade has seen an explosion in the collection of protein data. To actualize the potential offered by this wealth of data, it is important to develop machine systems capable of classifying and extracting features from proteins. Reliable machine systems for protein classification offer many benefits, including the promise of finding novel drugs and vaccines. In developing our system, we analyze and compare several feature extraction methods used in protein classification that are based on the calculation of texture descriptors starting from a wavelet representation of the protein. We then feed these texture-based representations of the protein into an Adaboost ensemble of neural network or a support vector machine classifier. In addition, we perform experiments that combine our feature extraction methods with a standard method that is based on the Chou's pseudo amino acid composition. Using several datasets, we show that our best approach outperforms standard methods. The Matlab code of the proposed protein descriptors is available at http://bias.csr.unibo.it/nanni/wave.rar .

Over-expression of the Pseudomonas syringae harpin-encoding gene hrpZm confers enhanced tolerance to Phytophthora root and stem rot in transgenic soybean.

PubMed

Du, Qian; Yang, Xiangdong; Zhang, Jinhua; Zhong, Xiaofang; Kim, Kyung Seok; Yang, Jing; Xing, Guojie; Li, Xiaoyu; Jiang, Zhaoyuan; Li, Qiyun; Dong, Yingshan; Pan, Hongyu

2018-06-01

Phytophthora root and stem rot (PRR) caused by Phytophthora sojae is one of the most devastating diseases reducing soybean (Glycine max) production all over the world. Harpin proteins in many plant pathogenic bacteria were confirmed to enhance disease and insect resistance in crop plants. Here, a harpin protein-encoding gene hrpZpsta from the P. syringae pv. tabaci strain Psta218 was codon-optimized (renamed hrpZm) and introduced into soybean cultivars Williams 82 and Shennong 9 by Agrobacterium-mediated transformation. Three independent transgenic lines over-expressing hrpZm were obtained and exhibited stable and enhanced tolerance to P. sojae infection in T 2 -T 4 generations compared to the non-transformed (NT) and empty vector (EV)-transformed plants. Quantitative real-time PCR (qRT-PCR) analysis revealed that the expression of salicylic acid-dependent genes PR1, PR12, and PAL, jasmonic acid-dependent gene PPO, and hypersensitive response (HR)-related genes GmNPR1 and RAR was significantly up-regulated after P. sojae inoculation. Moreover, the activities of defense-related enzymes such as phenylalanine ammonia lyase (PAL), polyphenoloxidase (PPO), peroxidase, and superoxide dismutase also increased significantly in the transgenic lines compared to the NT and EV-transformed plants after inoculation. Our results suggest that over-expression of the hrpZm gene significantly enhances PRR tolerance in soybean by eliciting resistance responses mediated by multiple defense signaling pathways, thus providing an alternative approach for development of soybean varieties with improved tolerance against the soil-borne pathogen PRR.

Mucosal-associated invariant T cell-rich congenic mouse strain allows functional evaluation.

PubMed

Cui, Yue; Franciszkiewicz, Katarzyna; Mburu, Yvonne K; Mondot, Stanislas; Le Bourhis, Lionel; Premel, Virginie; Martin, Emmanuel; Kachaner, Alexandra; Duban, Livine; Ingersoll, Molly A; Rabot, Sylvie; Jaubert, Jean; De Villartay, Jean-Pierre; Soudais, Claire; Lantz, Olivier

2015-11-02

Mucosal-associated invariant T cells (MAITs) have potent antimicrobial activity and are abundant in humans (5%-10% in blood). Despite strong evolutionary conservation of the invariant TCR-α chain and restricting molecule MR1, this population is rare in laboratory mouse strains (≈0.1% in lymphoid organs), and lack of an appropriate mouse model has hampered the study of MAIT biology. Herein, we show that MAITs are 20 times more frequent in clean wild-derived inbred CAST/EiJ mice than in C57BL/6J mice. Increased MAIT frequency was linked to one CAST genetic trait that mapped to the TCR-α locus and led to higher usage of the distal Vα segments, including Vα19. We generated a MAIThi congenic strain that was then crossed to a transgenic Rorcgt-GFP reporter strain. Using this tool, we characterized polyclonal mouse MAITs as memory (CD44+) CD4-CD8lo/neg T cells with tissue-homing properties (CCR6+CCR7-). Similar to human MAITs, mouse MAITs expressed the cytokine receptors IL-7R, IL-18Rα, and IL-12Rβ and the transcription factors promyelocytic leukemia zinc finger (PLZF) and RAR-related orphan receptor γ (RORγt). Mouse MAITs produced Th1/2/17 cytokines upon TCR stimulation and recognized a bacterial compound in an MR1-dependent manner. During experimental urinary tract infection, MAITs migrated to the bladder and decreased bacterial load. Our study demonstrates that the MAIThi congenic strain allows phenotypic and functional characterization of naturally occurring mouse MAITs in health and disease.

Isotretinoin and FoxO1

PubMed Central

2011-01-01

Oral isotretinoin (13-cis retinoic acid) is the most effective drug in the treatment of acne and restores all major pathogenetic factors of acne vulgaris. isotretinoin is regarded as a prodrug which after isomerizisation to all-trans-retinoic acid (ATRA) induces apoptosis in cells cultured from human sebaceous glands, meibomian glands, neuroblastoma cells, hypothalamic cells, hippocampus cells, Dalton's lymphoma ascites cells, B16F-10 melanoma cells, and neuronal crest cells and others. By means of translational research this paper provides substantial indirect evidence for isotretinoin's mode of action by upregulation of forkhead box class O (FoxO) transcription factors. FoxOs play a pivotal role in the regulation of androgen receptor transactivation, insulin/insulin like growth factor-1 (IGF-1)-signaling, peroxisome proliferator-activated receptor-γ (PPArγ)- and liver X receptor-α (LXrα)-mediated lipogenesis, β-catenin signaling, cell proliferation, apoptosis, reactive oxygene homeostasis, innate and acquired immunity, stem cell homeostasis, as well as anti-cancer effects. An accumulating body of evidence suggests that the therapeutic, adverse, teratogenic and chemopreventive effecs of isotretinoin are all mediated by upregulation of FoxO-mediated gene transcription. These FoxO-driven transcriptional changes of the second response of retinoic acid receptor (RAR)-mediated signaling counterbalance gene expression of acne due to increased growth factor signaling with downregulated nuclear FoxO proteins. The proposed isotretinoin→ATRA→RAR→FoxO interaction offers intriguing new insights into the mode of isotretinoin action and explains most therapeutic, adverse and teratogenic effects of isotretinoin in the treatment of acne by a common mode of FoxO-mediated transcriptional regulation. PMID:22110774

Transcriptome analysis of vertebral bone in the flounder, Paralichthys olivaceus (Teleostei, Pleuronectiformes), using Illumina sequencing.

PubMed

Ibaraki, Harumi; Wu, Xiaoming; Uji, Susumu; Yokoi, Hayato; Sakai, Yoshifumi; Suzuki, Tohru

2015-12-01

The processes underlying vertebral development in teleosts and tetrapods differ markedly in a variety of ways. At present, the molecular basis of teleost vertebral development and growth is poorly understood. Understanding vertebral development at the molecular level is important for aquaculture to prevent vertebral anomalies that can arise from a variety of factors, including excess vitamin A (all-trans retinol, VA) in the diet. To facilitate studies on teloest vertebral development, we performed transcriptome analysis of four month old flounder, Paralichthys olivaceus, vertebrae using next-generation sequencing. Expression profile obtained demonstrates that some members of the hh, bmp, fgf, wnt gene families, and their receptors, hox, pax, sox, dlx and tbx gene families and ntl, which are known to function in notochord and somite development in embryos, are expressed in the vertebrae. It was also showed that in addition to the retinoic acid receptor (Rar), the vertebrae express alcohol dehydrogenase 1 and retinal dehydrogenase 2 which convert VA to all-trans-retinoic acid (RA). The assembled contigs also included cytochrome p450 family members, which inactivate RA, as well as phosphatidylcholine-retinol O-acetyltransferase, which converts VA to all-trans-retinyl ester, a stock form of VA. These data suggest that in teleost vertebrae, expression of various signals and transcription factors which function in the notochord and somite development is maintained until adult stage, and RA metabolism and signaling are active to regulate transcription of RA-responsible genes, such as hedgehog and hox genes. This is the first transcriptome analysis of teleost fish vertebrae. Copyright © 2015 Elsevier B.V. All rights reserved.

Mucosal-associated invariant T cell–rich congenic mouse strain allows functional evaluation

PubMed Central

Cui, Yue; Franciszkiewicz, Katarzyna; Mburu, Yvonne K.; Mondot, Stanislas; Le Bourhis, Lionel; Premel, Virginie; Martin, Emmanuel; Kachaner, Alexandra; Duban, Livine; Ingersoll, Molly A.; Rabot, Sylvie; Jaubert, Jean; De Villartay, Jean-Pierre; Soudais, Claire; Lantz, Olivier

2015-01-01

Mucosal-associated invariant T cells (MAITs) have potent antimicrobial activity and are abundant in humans (5%–10% in blood). Despite strong evolutionary conservation of the invariant TCR-α chain and restricting molecule MR1, this population is rare in laboratory mouse strains (≈0.1% in lymphoid organs), and lack of an appropriate mouse model has hampered the study of MAIT biology. Herein, we show that MAITs are 20 times more frequent in clean wild-derived inbred CAST/EiJ mice than in C57BL/6J mice. Increased MAIT frequency was linked to one CAST genetic trait that mapped to the TCR-α locus and led to higher usage of the distal Vα segments, including Vα19. We generated a MAIThi congenic strain that was then crossed to a transgenic Rorcgt-GFP reporter strain. Using this tool, we characterized polyclonal mouse MAITs as memory (CD44+) CD4–CD8lo/neg T cells with tissue-homing properties (CCR6+CCR7–). Similar to human MAITs, mouse MAITs expressed the cytokine receptors IL-7R, IL-18Rα, and IL-12Rβ and the transcription factors promyelocytic leukemia zinc finger (PLZF) and RAR-related orphan receptor γ (RORγt). Mouse MAITs produced Th1/2/17 cytokines upon TCR stimulation and recognized a bacterial compound in an MR1-dependent manner. During experimental urinary tract infection, MAITs migrated to the bladder and decreased bacterial load. Our study demonstrates that the MAIThi congenic strain allows phenotypic and functional characterization of naturally occurring mouse MAITs in health and disease. PMID:26524590

Kale BoRACK1 is involved in the plant response to salt stress and Peronospora brassicae Gaumann.

PubMed

Li, Da-Hong; Shen, Fu-Jia; Li, Hong-Yan; Li, Wei

2017-06-01

The receptor for activated C kinase 1 (RACK1) belongs to a protein subfamily containing a tryptophan-aspartic acid-domain (WD) repeat structure. Compelling evidence indicates that RACK1 can interact with many signal molecules and affect different signal transduction pathways. In this study, a kale (Brassica oleracea var. acephala f.tricolor) RACK1 gene (BoRACK1) was cloned by RT-PCR. The amino acid sequence of BoRACK1 had seven WD repeats in which there were typical GH (glycine-histidine) and WD dipeptides. Comparison with AtRACK1 from Arabidopsis revealed 87.1% identity at the amino acid level. Expression pattern analysis by RT-PCR showed that BoRACK1 was expressed in all analyzed tissues of kale and that its transcription in leaves was down-regulated by salt, abscisic acid, and H 2 O 2 at a high concentration. Overexpression of BoRACK1 in kale led to a reduction in symptoms caused by Peronospora brassicae Gaumann on kale leaves. The expression levels of the pathogenesis-related protein genes, PR-1 and PRB-1, increased 2.5-4-fold in transgenic kale, and reactive oxygen species production was more active than in the wild-type. They also exhibited increased tolerance to salt stress in seed germination. H 2 O 2 may also be involved in the regulation of BoRACK1 during seed germination under salt stress. Quantitative real-time PCR analyses showed that the transcript levels of BoRbohs genes were significantly higher in overexpression of BoRACK1 transgenic lines. Yeast two-hybrid assays showed that BoRACK1 could interact with WNK8, eIF6, RAR1, and SGT1. This study and previous work lead us to believe that BoRACK1 may form a complex with regulators of plant salt and disease resistance to coordinate kale reactions to pathogens. Copyright © 2017 Elsevier GmbH. All rights reserved.

Critical analysis of world uranium resources

USGS Publications Warehouse

Hall, Susan; Coleman, Margaret

2013-01-01

The U.S. Department of Energy, Energy Information Administration (EIA) joined with the U.S. Department of the Interior, U.S. Geological Survey (USGS) to analyze the world uranium supply and demand balance. To evaluate short-term primary supply (0–15 years), the analysis focused on Reasonably Assured Resources (RAR), which are resources projected with a high degree of geologic assurance and considered to be economically feasible to mine. Such resources include uranium resources from mines currently in production as well as resources that are in the stages of feasibility or of being permitted. Sources of secondary supply for uranium, such as stockpiles and reprocessed fuel, were also examined. To evaluate long-term primary supply, estimates of uranium from unconventional and from undiscovered resources were analyzed. At 2010 rates of consumption, uranium resources identified in operating or developing mines would fuel the world nuclear fleet for about 30 years. However, projections currently predict an increase in uranium requirements tied to expansion of nuclear energy worldwide. Under a low-demand scenario, requirements through the period ending in 2035 are about 2.1 million tU. In the low demand case, uranium identified in existing and developing mines is adequate to supply requirements. However, whether or not these identified resources will be developed rapidly enough to provide an uninterrupted fuel supply to expanded nuclear facilities could not be determined. On the basis of a scenario of high demand through 2035, 2.6 million tU is required and identified resources in operating or developing mines is inadequate. Beyond 2035, when requirements could exceed resources in these developing properties, other sources will need to be developed from less well-assured resources, deposits not yet at the prefeasibility stage, resources that are currently subeconomic, secondary sources, undiscovered conventional resources, and unconventional uranium supplies. This report’s analysis of 141 mines that are operating or are being actively developed identifies 2.7 million tU of in-situ uranium resources worldwide, approximately 2.1 million tU recoverable after mining and milling losses were deducted. Sixty-four operating mines report a total of 1.4 million tU of in-situ RAR (about 1 million tU recoverable). Seventy-seven developing mines/production centers report 1.3 million tU in-situ Reasonably Assured Resources (RAR) (about 1.1 million tU recoverable), which have a reasonable chance of producing uranium within 5 years. Most of the production is projected to come from conventional underground or open pit mines as opposed to in-situ leach mines. Production capacity in operating mines is about 76,000 tU/yr, and in developing mines is estimated at greater than 52,000 tU/yr. Production capacity in operating mines should be considered a maximum as mines seldom produce up to licensed capacity due to operational difficulties. In 2010, worldwide mines operated at 70 percent of licensed capacity, and production has never exceeded 89 percent of capacity. The capacity in developing mines is not always reported. In this study 35 percent of developing mines did not report a target licensed capacity, so estimates of future capacity may be too low. The Organisation for Economic Co-operation and Development’s Nuclear Energy Agency (NEA) and International Atomic Energy Agency (IAEA) estimate an additional 1.4 million tU economically recoverable resources, beyond that identified in operating or developing mines identified in this report. As well, 0.5 million tU in subeconomic resources, and 2.3 million tU in the geologically less certain inferred category are identified worldwide. These agencies estimate 2.2 million tU in secondary sources such as government and commercial stockpiles and re-enriched uranium tails. They also estimate that unconventional uranium supplies (uraniferous phosphate and black shale deposits) may contain up to 7.6 million tU. Although unconventional resources are currently subeconomic, the improvement of extraction techniques or the production of coproducts may make extraction of uranium from these types of deposits profitable. A large undiscovered resource base is reported by these agencies, however this class of resource should be considered speculative and will require intensive exploration programs to adequately define them as mineable. These resources may all contribute to uranium supply that would fuel the world nuclear fleet well beyond that calculated in this report. Production of resources in both operating and developing uranium mines is subject to uncertainties caused by technical, legal, regulatory, and financial challenges that combined to create long timelines between deposit discovery and mine production. This analysis indicates that mine development is proceeding too slowly to fully meet requirements for an expanded nuclear power reactor fleet in the near future (to 2035), and unless adequate secondary or unconventional resources can be identified, imbalances in supply and demand may occur.

Deficiency of Retinaldehyde Dehydrogenase 1 Induces BMP2 and Increases Bone Mass In Vivo

PubMed Central

Nallamshetty, Shriram; Wang, Hong; Rhee, Eun-Jung; Kiefer, Florian W.; Brown, Jonathan D.; Lotinun, Sutada; Le, Phuong; Baron, Roland; Rosen, Clifford J.; Plutzky, Jorge

2013-01-01

The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak bone density acquisition and skeletal remodeling are complex and compartment specific. Emerging data indicates that retinoids, such as all trans retinoic acid (ATRA) and its precursor all trans retinaldehyde (Rald), exhibit distinct and divergent transcriptional effects in metabolism. Despite these observations, the role of enzymes that control retinoid metabolism in bone remains undefined. In this study, we examined the skeletal phenotype of mice deficient in retinaldehyde dehydrogenase 1 (Aldh1a1), the enzyme responsible for converting Rald to ATRA in adult animals. Bone densitometry and micro-computed tomography (µCT) demonstrated that Aldh1a1-deficient (Aldh1a1−/−) female mice had higher trabecular and cortical bone mass compared to age and sex-matched control C57Bl/6 wild type (WT) mice at multiple time points. Histomorphometry confirmed increased cortical bone thickness and demonstrated significantly higher bone marrow adiposity in Aldh1a1−/− mice. In serum assays, Aldh1a1−/− mice also had higher serum IGF-1 levels. In vitro, primary Aldh1a1−/− mesenchymal stem cells (MSCs) expressed significantly higher levels of bone morphogenetic protein 2 (BMP2) and demonstrated enhanced osteoblastogenesis and adipogenesis versus WT MSCs. BMP2 was also expressed at higher levels in the femurs and tibias of Aldh1a1−/− mice with accompanying induction of BMP2-regulated responses, including expression of Runx2 and alkaline phosphatase, and Smad phosphorylation. In vitro, Rald, which accumulates in Aldh1a1−/− mice, potently induced BMP2 in WT MSCs in a retinoic acid receptor (RAR)-dependent manner, suggesting that Rald is involved in the BMP2 increases seen in Aldh1a1 deficiency in vivo. Collectively, these data implicate Aldh1a1 as a novel determinant of cortical bone density and marrow adiposity in the skeleton in vivo through modulation of BMP signaling. PMID:23951127

The Effect of Weight on Self-Concept, and Psychosocial Correlates of Physical Activity in Youths

ERIC Educational Resources Information Center

Welk, Gregory J.; Joens-Matre, Roxane

2007-01-01

Much more attention has been given to the health implications of overweight and obesity than to the psychosocial implications. In order to combat obesity effectively, it is important to understand the implications of overweight on self-concept, self-esteem, and physical activity levels. Youth obesity has been associated with negative psychosocial…

Biogenic selenium nanoparticles: current status and future prospects.

PubMed

Wadhwani, Sweety A; Shedbalkar, Utkarsha U; Singh, Richa; Chopade, Balu A

2016-03-01

Selenium nanoparticles (SeNPs) are gaining importance in the field of medicine owing to their antibacterial and anticancer properties. SeNPs are biocompatible and non-toxic compared to the counterparts, selenite (SeO3 (-2)) and selenate (SeO4 (-2)). They can be synthesized by physical, chemical, and biological methods and have distinct bright orange-red color. Biogenic SeNPs are stable and do not aggregate owing to natural coating of the biomolecules. Various hypotheses have been proposed to describe the mechanism of microbial synthesis of SeNPs. It is primarily a two-step reduction process from SeO4 (-2) to SeO3 (-2) to insoluble elemental selenium (Se(0)) catalyzed by selenate and selenite reductases. Phenazine-1-carboxylic acid and glutathione are involved in selenite reduction. Se factor A (SefA) and metalloid reductase Rar A present on the surface of SeNPs confer stability to the nanoparticles. SeNPs act as potent chemopreventive and chemotherapeutic agents. Conjugation with antibiotics enhances their anticancer efficacy. These also have applications in nanobiosensors and environmental remediation.

Function of endoplasmic reticulum calcium ATPase in innate immunity-mediated programmed cell death

PubMed Central

Zhu, Xiaohong; Caplan, Jeffrey; Mamillapalli, Padmavathi; Czymmek, Kirk; Dinesh-Kumar, Savithramma P

2010-01-01

Programmed cell death (PCD) initiated at the pathogen-infected sites during the plant innate immune response is thought to prevent the development of disease. Here, we describe the identification and characterization of an ER-localized type IIB Ca2+-ATPase (NbCA1) that function as a regulator of PCD. Silencing of NbCA1 accelerates viral immune receptor N- and fungal-immune receptor Cf9-mediated PCD, as well as non-host pathogen Pseudomonas syringae pv. tomato DC3000 and the general elicitor cryptogein-induced cell death. The accelerated PCD rescues loss-of-resistance phenotype of Rar1, HSP90-silenced plants, but not SGT1-silenced plants. Using a genetically encoded calcium sensor, we show that downregulation of NbCA1 results in the modulation of intracellular calcium signalling in response to cryptogein elicitor. We further show that NbCAM1 and NbrbohB function as downstream calcium decoders in N-immune receptor-mediated PCD. Our results indicate that ER-Ca2+-ATPase is a component of the calcium efflux pathway that controls PCD during an innate immune response. PMID:20075858

A digital interactive human brain atlas based on Chinese visible human datasets for anatomy teaching.

PubMed

Li, Qiyu; Ran, Xu; Zhang, Shaoxiang; Tan, Liwen; Qiu, Mingguo

2014-01-01

As we know, the human brain is one of the most complicated organs in the human body, which is the key and difficult point in neuroanatomy and sectional anatomy teaching. With the rapid development and extensive application of imaging technology in clinical diagnosis, doctors are facing higher and higher requirement on their anatomy knowledge. Thus, to cultivate medical students to meet the needs of medical development today and to improve their ability to read and understand radiographic images have become urgent challenges for the medical teachers. In this context, we developed a digital interactive human brain atlas based on the Chinese visible human datasets for anatomy teaching (available for free download from http://www.chinesevisiblehuman.com/down/DHBA.rar). The atlas simultaneously provides views in all 3 primary planes of section. The main structures of the human brain have been anatomically labeled in all 3 views. It is potentially useful for anatomy browsing, user self-testing, and automatic student assessment. In a word, it is interactive, 3D, user friendly, and free of charge, which can provide a new, intuitive means for anatomy teaching.

[Effects of Gukang on bone-source alkaline phosphatase (BALP) and insulin-like growth factor-1 (IGF-1) in serum of spaying rats].

PubMed

Chen, Yi-fan; Huang, Hong-xing; Li, Ying

2009-02-01

To investigate the effects of Gukang on bone-source alkaline phosphatase (BALP) and insulin-like growth factor 1 (IGF-1) in serum of spaying rats and the mechanism of curative effect of Gukang on osteoporosis. Sixty-eight 6-month-old SD rats were chosen and randomly divided into blank control group (22 rats with sham operation) and operation group (46 rats with spaying operation). Three months after operation, 10 rats were randomly chosen from each group and tested with bone mineral density in order to determine models of osteoporosis made. After modeling, operation group was divided into 3 sub-groups: operation model group, estrogen group and Gukang group, 12 rars in each group. Twelve rats remained in blank control group. Every group were treated through intragastric administration therapy (volume 10 ml/kg). Blank control group and operation model group were irrigated with distilled water,estrogen group with estrogen and Gukang group with Gukang. Three months after treatment, serum of all groups were collected and tested for E2, BALP and IGF-1 with ELISA. The concentration of serum E2, BALP in estrogen group and Gukang group were higher than operation model group, there were significant difference (P < 0.05), but no significant difference in serum E2 between estrogen group and Gukang group (P > 0.05). The concentration of serum IGF-1 in Gukang group was higher than operation model group and blank control group, there were significant difference (P < 0.05). Gukang can increase the level of E2, BALP and IGF-1 in serum of spaying rats. Thus, it can indirectly promote reproduction of osteoblasts, inhibit activity of osteoclasts and promote bone formation.

[Motor behavior of human fetuses during the second trimester of gestation: a longitudinal ultrasound study].

PubMed

Reynoso, C; Crespo-Eguílaz, N; Alcázar, J L; Narbona, J

2015-03-01

The aim of this research is to contribute to knowledge of the normal spontaneous motor behavior of the human fetus during the second trimester of pregnancy. This study focuses on five patterns of spontaneous fetal movement: startle (S), axo-rhizomelic rhythmia (ARR), axial stretching (AS), general movement (GM), and diaphragmatic contraction (DC). A cohort of 13 subjects was followed up using 2D obstetrical ultrasound images at 12, 16, 20, and 24 weeks of gestation. As inclusion criteria, neonatal neurological examination and general movements after eutocic delivery at term were normal in all of the subjects, and their neuromotor and cognitive development until the end of pre-school age were also normal. All these five motor patterns are present at the beginning of the 2(nd) gestational trimester, but their quantitative and qualitative traits are diverse according to gestational ages. The phasic, isolated or rhythmically repeated movements, S and ARR, are prominent at 12 and 16 weeks of gestation, and then their presence gradually diminishes. By contrast, tonic and complex AS and GM movements increase their presence and quality at 20 and 24 weeks. RAR constitute a particular periodic motor pattern not described in previous literature. Moreover, the incidence of DC is progressive throughout the trimester, in clusters of 2-6 arrhythmic and irregular beats. Fetal heart rate increases during fetal motor active periods. All five normal behavioral patterns observed in the ultrasounds reflect the progressive tuning of motor generators in human nervous system during mid-pregnancy. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

Lactobacillus rhamnosus Accelerates Zebrafish Backbone Calcification and Gonadal Differentiation through Effects on the GnRH and IGF Systems

PubMed Central

Avella, Matteo A.; Place, Allen; Du, Shao-Jun; Williams, Ernest; Silvi, Stefania; Zohar, Yonathan; Carnevali, Oliana

2012-01-01

Endogenous microbiota play essential roles in the host’s immune system, physiology, reproduction and nutrient metabolism. We hypothesized that a continuous administration of an exogenous probiotic might also influence the host’s development. Thus, we treated zebrafish from birth to sexual maturation (2-months treatment) with Lactobacillus rhamnosus, a probiotic species intended for human use. We monitored for the presence of L. rhamnosus during the entire treatment. Zebrafish at 6 days post fertilization (dpf) exhibited elevated gene expression levels for Insulin-like growth factors -I and -II, Peroxisome proliferator activated receptors -α and -β, VDR-α and RAR-γ when compared to untreated-10 days old zebrafish. Using a gonadotropin-releasing hormone 3 GFP transgenic zebrafish (GnRH3-GFP), higher GnRH3 expression was found at 6, 8 and 10 dpf upon L. rhamnosus treatment. The same larvae exhibited earlier backbone calcification and gonad maturation. Noteworthy in the gonad development was the presence of first testes differentiation at 3 weeks post fertilization in the treated zebrafish population -which normally occurs at 8 weeks- and a dramatic sex ratio modulation (93% females, 7% males in control vs. 55% females, 45% males in the treated group). We infer that administration of L. rhamnosus stimulated the IGF system, leading to a faster backbone calcification. Moreover we hypothesize a role for administration of L. rhamnosus on GnRH3 modulation during early larval development, which in turn affects gonadal development and sex differentiation. These findings suggest a significant role of the microbiota composition on the host organism development profile and open new perspectives in the study of probiotics usage and application. PMID:23029107

Sertoli cell specific knockdown of RAR-related orphan receptor (ROR) alpha at puberty reduces sperm count in rats.

PubMed

Mandal, Kamal; Sarkar, Rajesh K; Sen Sharma, Souvik; Jain, Ayushi; Majumdar, Subeer S

2018-01-30

Globally, there is an alarming decline in sperm count. Very often hormonal supplementation fails to restore normal sperm count. Sertoli cells (Sc) present within seminiferous tubules provide appropriate niche and factors required for the differentiation of germ cells (Gc) into mature sperm (spermatogenesis). Functionally compromised Sc may be one of the reasons for failure of hormones to facilitate normal spermatogenesis. Although role of secretory proteins and signaling molecules of Sc has been studied well, role of transcription factors regulating sperm count has not been addressed appropriately. Retinoic acid receptor-related orphan receptor (ROR)-alpha is one of such transcription factors reported in testis but its role in testicular function is not yet known. In a separate study, we found abundant ROR-alpha binding sites on promoter regions of several genes upregulated in pubertal rat Sc as compared to infant Sc. Immunostaining studies also revealed presence of ROR alpha in nucleus of pubertal Sc. We generated a transgenic knockdown rat model expressing shRNA targeted to ROR-alpha under Sc specific promoter, which is transcriptionally active only at and after puberty. ROR-alpha knockdown animals were found to have abnormal association of Sc and Gc, including Gc sloughing and restricted release of sperm. The knockdown animals displayed compromised spermatogenesis leading to significant reduction in sperm count. This is the first report describing the Sc specific role of ROR-alpha in maintaining quantitatively normal sperm output. Identification of various such molecules can generate avenues to limit or reverse an alarmingly declining sperm count witnessed globally in men. Copyright © 2017 Elsevier B.V. All rights reserved.

HLA-DR-, CD33+, CD56+, CD16- myeloid/natural killer cell acute leukemia: a previously unrecognized form of acute leukemia potentially misdiagnosed as French-American-British acute myeloid leukemia-M3.

PubMed

Scott, A A; Head, D R; Kopecky, K J; Appelbaum, F R; Theil, K S; Grever, M R; Chen, I M; Whittaker, M H; Griffith, B B; Licht, J D

1994-07-01

We have identified and characterized a previously unrecognized form of acute leukemia that shares features of both myeloid and natural killer (NK) cells. From a consecutive series of 350 cases of adult de novo acute myeloid leukemia (AML), we identified 20 cases (6%) with a unique immunophenotype: CD33+, CD56+, CD11a+, CD13lo, CD15lo, CD34+/-, HLA-DR-, CD16-. Multicolor flow cytometric assays confirmed the coexpression of myeloid (CD33, CD13, CD15) and NK cell-associated (CD56) antigens in each case, whereas reverse transcription polymerase chain reaction (RT-PCR) assays confirmed the identity of CD56 (neural cell adhesion molecule) in leukemic blasts. Although two cases expressed CD4, no case expressed CD2, CD3, or CD8 and no case showed clonal rearrangement of genes encoding the T-cell receptor (TCR beta, gamma, delta). Leukemic blasts in the majority of cases shared unique morphologic features (deeply invaginated nuclear membranes, scant cytoplasm with fine azurophilic granularity, and finely granular Sudan black B and myeloperoxidase cytochemical reactivity) that were remarkably similar to those of acute promyelocytic leukemia (APL); particularly the microgranular variant (FAB AML-M3v). However, all 20 cases lacked the t(15;17) and 17 cases tested lacked the promyelocytic/retinoic acid receptor alpha (RAR alpha) fusion transcript in RT-PCR assays; 12 cases had 46,XX or 46,XY karyotypes, whereas 2 cases had abnormalities of chromosome 17q: 1 with del(17)(q25) and the other with t(11;17)(q23;q21) and the promyelocytic leukemia zinc finger/RAR alpha fusion transcript. All cases tested (6/20), including the case with t(11;17), failed to differentiate in vitro in response to all-trans retinoic acid (ATRA), suggesting that these cases may account for some APLs that have not shown a clinical response to ATRA. Four of 6 cases tested showed functional NK cell-mediated cytotoxicity, suggesting a relationship between these unique CD33+, CD56+, CD16- acute leukemias and normal CD56+, CD16- NK precursor cells. Using a combination of panning and multiparameter flow cytometric sorting, we identified a normal CD56+, CD33+, CD16- counterpart cell at a frequency of 1% to 2% in the peripheral blood of healthy individuals. Our studies suggest that this form of acute leukemia may arise from transformation of a precursor cell common to both the myeloid and NK cell lineages; thus we propose the designation myeloid/NK acute leukemia. Recognition of this new leukemic entity will be important in distinguishing these ATRA-nonresponsive cases from ATRA-responsive true APL.

Differential regulation of membrane-associated mucins in the human ocular surface epithelium.

PubMed

Hori, Yuichi; Spurr-Michaud, Sandra; Russo, Cindy Leigh; Argüeso, Pablo; Gipson, Ilene K

2004-01-01

Membrane-associated mucins present in the apical cells of the ocular surface epithelium (MUC1, -4, and -16) are believed to contribute to the maintenance of a hydrated and wet-surfaced epithelial phenotype. Serum and retinoic acid (RA) have been used to treat drying ocular surface diseases. The goal of this study was to determine whether serum or RA regulates the production of membrane-associated mucins in human conjunctival epithelial cells. A telomerase-immortalized human conjunctival epithelial cell line (HCjE) was used. Cells were cultured in serum-free medium to confluence and then cultured with either 10% calf serum or with 100 nM RA for 0 to 72 hours. Conventional RT-PCR was used to determine the expression of retinoic acid receptors (RARs) and quantitative real-time PCR was used to investigate the mRNA expression of MUC1, -4, and -16. Protein levels were assayed by immunoblot analysis, using the antibodies HMFG-2, 1G8, or OC125, which are specific to MUC1, -4 and -16, respectively. To determine whether RA-associated MUC4 mRNA induction is a direct or indirect effect, HCjE cells were treated with RA and the protein synthesis inhibitor cycloheximide (1.0 microg/mL) for 12 hours. MUC1 and -16, but not -4, mRNAs were detectable in HCjE cells grown in serum-free medium. Real-time PCR revealed that MUC4 mRNA was significantly induced by serum 3 hours after its addition, and that MUC1 and MUC16 mRNA levels were significantly upregulated at 72 hours. Western blot analysis demonstrated that the MUC1, -4, and -16 proteins increased over time after addition of serum. Conventional RT-PCR analysis demonstrated that RAR-alpha and -gamma mRNA were expressed in native human conjunctival tissue as well as in the HCjE cells. Treatment with RA upregulated the expression of both MUC4 and -16 mRNA and protein, but MUC1 was unaffected. Because the protein synthesis inhibitor cycloheximide did not prevent the RA-associated induction of MUC4 mRNA, the action of RA on the MUC4 promoter may be direct. The membrane-associated mucins of the ocular surface epithelia, MUC1, -4, and -16, are differentially regulated by serum and RA in the telomerase-immortalized human conjunctival epithelial cell line. Serum derived from vessels in the conjunctiva may play an important role in mucin regulation in the ocular surface epithelia. These data also support the clinical efficacy of autologous serum and RA application in patients with ocular surface diseases. Furthermore, the data suggest that MUC4 and -16 are particularly important hydrophilic molecules involved in maintenance of a healthy ocular surface.

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

Targeting the vitamin D endocrine system (VDES) for the management of inflammatory and malignant skin diseases: An historical view and outlook.

PubMed

Reichrath, Jörg; Zouboulis, Christos C; Vogt, Thomas; Holick, Michael F

2016-09-01

Vitamin D represents one of the major driving factors for the development of life on earth and for human evolution. While up to 10-20 % of the human organism's requirements in vitamin D can be obtained by the diet (under most living conditions in the USA and Europe), approximately 90 % of all needed vitamin D has to be photosynthesized in the skin through the action of the sun (ultraviolet-B (UV-B)). The skin represents a key organ of the human body's vitamin D endocrine system (VDES), being both the site of vitamin D synthesis and a target tissue for biologically active vitamin D metabolites. It was shown that human keratinocytes possess the enzymatic machinery (CYP27B1) for the synthesis of the biologically most active natural vitamin D metabolite 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), representing an autonomous vitamin D 3 pathway. Cutaneous production of 1,25(OH) 2 D 3 may exert intracrine, autocrine, and paracrine effects on keratinocytes and on neighboring cells. Many skin cells (including keratinocytes, sebocytes, fibroblasts, melanocytes, and skin immune cells) express the vitamin D receptor (VDR), an absolute pre-requisite for the mediation of genomic effects of 1,25(OH) 2 D 3 and analogs. VDR belongs to the superfamily of trans-acting transcriptional regulatory factors, which includes the steroid and thyroid hormone receptors as well as the retinoid X receptors (RXR) and retinoic acid receptors (RAR). Numerous studies, including cDNA microarray analyses of messenger RNAs (mRNAs), indicate that as many as 500-1000 genes may be regulated by VDR ligands that control various cellular functions including growth, differentiation, and apoptosis. The observation that 1,25(OH) 2 D 3 is extremely effective in inducing the terminal differentiation and in inhibiting the proliferation of cultured human keratinocytes has resulted in the use of vitamin D analogs for the treatment of psoriasis. This review gives an historical view and summarizes our present knowledge about the relevance of the VDES for the management of inflammatory and malignant skin diseases.

Demographics of Aging: Implications for the Future.

ERIC Educational Resources Information Center

Betourney, William

Through a series of four successfully field-tested activities, secondary students examine the changing age structure of the U.S. population and consider some of the implications for the future as the proportion of elders increases and the proportion of youth declines. In the first activity "Age/Sex Pyramids," students use population…

Retinoic acid signaling pathways in development and diseases.

PubMed

Das, Bhaskar C; Thapa, Pritam; Karki, Radha; Das, Sasmita; Mahapatra, Sweta; Liu, Ting-Chun; Torregroza, Ingrid; Wallace, Darren P; Kambhampati, Suman; Van Veldhuizen, Peter; Verma, Amit; Ray, Swapan K; Evans, Todd

2014-01-15

Retinoids comprise a group of compounds each composed of three basic parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that functions as a linker unit, and a polar carbon-oxygen functional group. Biochemical conversion of carotenoid or other retinoids to retinoic acid (RA) is essential for normal regulation of a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids regulate various physiological outputs by binding to nuclear receptors called retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which themselves are DNA-binding transcriptional regulators. The functional response of RA and their receptors are modulated by a host of coactivators and corepressors. Retinoids are essential in the development and function of several organ systems; however, deregulated retinoid signaling can contribute to serious diseases. Several natural and synthetic retinoids are in clinical use or undergoing trials for treating specific diseases including cancer. In this review, we provide a broad overview on the importance of retinoids in development and various diseases, highlighting various retinoids in the drug discovery process, ranging all the way from retinoid chemistry to clinical uses and imaging. Copyright © 2013 Elsevier Ltd. All rights reserved.

Seismic noise on Rarotonga: Surface versus downhole

USGS Publications Warehouse

Butler, Rhett; Hutt, C.R.

1992-01-01

Seismic noise data are presented from the new Global Seismographic Network station, RAR, on the Island of Rarotonga in the South Pacific. Data from the first new borehole site in the GSN are compared with a surface vault installation. Initial indications from the data show that borehole siting on a small island significantly reduces long-period (>20 s) horizontal seismic noise levels during the daytime, but little or no improvement is evident at periods shorter than 20 s or on the vertical component.The goal of the Incorporated Research Institutions for Seismology (IRIS) GSN program is broad, uniform coverage of the Earth with a 128-station network. To achieve this goal and provide coverage in oceanic areas, many stations will be sited on islands. A major siting consideration for these new stations is whether to build a surface vault or drill a borehole. Neither option is inexpensive. The costs for drilling a cased hole and a borehole sensor are large, but the benefit of a borehole site is that seismic noise is reduced during certain periods when a surface installation may be subject to wind, weather, and thermal effects. This benefit translates into recording greater numbers of smaller earthquakes and higher signal-to-noise ratio.

Epidemiology of myelodysplastic syndromes in a French general hospital of the Basque country.

PubMed

Bauduer, F; Ducout, L; Dastugue, N; Capdupuy, C; Renoux, M

1998-03-01

Epidemiologic studies concerning myelodysplastic syndromes (MDS) are rare. The estimated incidence varies between 1 and 12.6/100,000/year. The aim of this work was to compare our own experience with these data. Our general hospital represents a structure with 1197 beds which serves a population of 290,000 individuals (French Basques). Most of the inhabitants live in a rural environnement. Twenty percent of the population are aged over 65. During a 4-year period (1993-1996), 90 new cases of MDS were diagnosed on bone marrow studies in our laboratory. Among FAB subtypes refractory anemia (RA) represented 27 cases (31%), RA with ring sideroblasts (RARS): 21 (23%), RA with excess of blasts (RAEB) and in transformation (RAEB-t): 22 (24%), chronic myelomonocytic leukemia (CMML): 10 (11%). Ten cases were unclassifiable (11%). Therapy-related MDS were seen in 8 patients. The sex ratio was 1 and the mean age of the patients was 74.3 (range: 23-96), 37% of them being 80 years or older. The calculated incidence was 7.7/100,000/year for the entire cohort and 31.4/100,000/year for people over 65.

Novel Approaches to Improve Iris Recognition System Performance Based on Local Quality Evaluation and Feature Fusion

PubMed Central

2014-01-01

For building a new iris template, this paper proposes a strategy to fuse different portions of iris based on machine learning method to evaluate local quality of iris. There are three novelties compared to previous work. Firstly, the normalized segmented iris is divided into multitracks and then each track is estimated individually to analyze the recognition accuracy rate (RAR). Secondly, six local quality evaluation parameters are adopted to analyze texture information of each track. Besides, particle swarm optimization (PSO) is employed to get the weights of these evaluation parameters and corresponding weighted coefficients of different tracks. Finally, all tracks' information is fused according to the weights of different tracks. The experimental results based on subsets of three public and one private iris image databases demonstrate three contributions of this paper. (1) Our experimental results prove that partial iris image cannot completely replace the entire iris image for iris recognition system in several ways. (2) The proposed quality evaluation algorithm is a self-adaptive algorithm, and it can automatically optimize the parameters according to iris image samples' own characteristics. (3) Our feature information fusion strategy can effectively improve the performance of iris recognition system. PMID:24693243

Novel approaches to improve iris recognition system performance based on local quality evaluation and feature fusion.

PubMed

Chen, Ying; Liu, Yuanning; Zhu, Xiaodong; Chen, Huiling; He, Fei; Pang, Yutong

2014-01-01

For building a new iris template, this paper proposes a strategy to fuse different portions of iris based on machine learning method to evaluate local quality of iris. There are three novelties compared to previous work. Firstly, the normalized segmented iris is divided into multitracks and then each track is estimated individually to analyze the recognition accuracy rate (RAR). Secondly, six local quality evaluation parameters are adopted to analyze texture information of each track. Besides, particle swarm optimization (PSO) is employed to get the weights of these evaluation parameters and corresponding weighted coefficients of different tracks. Finally, all tracks' information is fused according to the weights of different tracks. The experimental results based on subsets of three public and one private iris image databases demonstrate three contributions of this paper. (1) Our experimental results prove that partial iris image cannot completely replace the entire iris image for iris recognition system in several ways. (2) The proposed quality evaluation algorithm is a self-adaptive algorithm, and it can automatically optimize the parameters according to iris image samples' own characteristics. (3) Our feature information fusion strategy can effectively improve the performance of iris recognition system.

Nuclear retinoid receptors and pregnancy: placental transfer, functions, and pharmacological aspects.

PubMed

Comptour, Aurélie; Rouzaire, Marion; Belville, Corinne; Bouvier, Damien; Gallot, Denis; Blanchon, Loïc; Sapin, Vincent

2016-10-01

Animal models of vitamin A (retinol) deficiency have highlighted its crucial role in reproduction and placentation, whereas an excess of retinoids (structurally or functionally related entities) can cause toxic and teratogenic effects in the embryo and foetus, especially in the first trimester of human pregnancy. Knock-out experimental strategies-targeting retinoid nuclear receptors RARs and RXRs have confirmed that the effects of vitamin A are mediated by retinoic acid (especially all-trans retinoic acid) and that this vitamin is essential for the developmental process. All these data show that the vitamin A pathway and metabolism are as important for the well-being of the foetus, as they are for that of the adult. Accordingly, during this last decade, extensive research on retinoid metabolism has yielded detailed knowledge on all the actors in this pathway, spurring the development of antagonists and agonists for therapeutic and research applications. Natural and synthetic retinoids are currently used in clinical practice, most often on the skin for the treatment of acne, and as anti-oncogenic agents in acute promyelocytic leukaemia. However, because of the toxicity and teratogenicity of retinoids during pregnancy, their pharmacological use needs a sound knowledge of their metabolism, molecular aspects, placental transfer, and action.

Trends in participation rates for wildlife-associated outdoor recreation activities by age and race/ethnicity: implications for cohort-component projection models

Treesearch

John F. Dwyer; Allan Marsinko

1998-01-01

Cohort-component projection models have been used to explore the implications of increased aging and growth of racial/ethnic minority groups on number of participants in outdoor recreation activities in the years ahead. Projections usually assume that participation rates by age and race/ethnicity remain constant over time. This study looks at trends in activity...

Research on Physical Activity in the Elderly: Practical Implications for Program Planning.

ERIC Educational Resources Information Center

Myers, Anita M.; Gonda, Gail

1986-01-01

The authors critically examine the research on physical activity in the elderly to assess the elderly's capacity for exercise and the benefits accruing from exercise. Lower-intensity exercise programs attract a more representative group of senior participants and overcome many barriers. Implications for program planning and efforts are discussed.…

Sources and implications of lead ammunition and fishing tackle on natural resources

USGS Publications Warehouse

Rattner, B.A.; Franson, J. Christian; Sheffield, S.R.; Goddard, C.I.; Leonard, N.J.; Stang, D.; Wingate, P.J.

2008-01-01

A technical review of lead sources that originate from hunting, shooting sports, and fishing activities was undertaken by the American Fisheries Society and The Wildlife Society. The report addresses (1) sources of lead that originate from hunting, shooting sports, and fishing activities, (2) the hazard and risk that lead from these activities pose to natural resources, and (3) the management implications for fish and wildlife professionals and policy makers.

Comparable Molecular Alterations in 4-Nitroquinoline 1-Oxide-induced Oral and Esophageal Cancer in Mice and in Human Esophageal Cancer, Associated with Poor Prognosis of Patients

PubMed Central

YANG, ZHENGDUO; GUAN, BAOXIANG; MEN, TAOYAN; FUJIMOTO, JUNYA; XU, XIAOCHUN

2013-01-01

Background The murine model of 4-nitroquinoline 1-oxide (4-NQO)-induced oral and esophageal cancer is frequently used to assess the effects of different cancer prevention/therapy agents in vivo, but the molecular mechanisms in those 4-NQO-induced carcinogenesis are unknown. This study investigated aberrant expression of cell growth-critical genes in 4-NQO-induced oral and esophageal cancer tissues in mice compared to human disease for association with survival of patients. Materials and Methods C57LB6/129Sv mice were given 4-NQO in their drinking water to induce oral and esophageal cancer. Quantitative-reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry were used to detect gene expression in the cancer tissues from mice and in 4-NQO-treated human esophageal cancer cell lines and esophageal cancer tissues. Methylation-specific PCR and DNA sequencing were performed to assess methylation of Rarb2 promoter in murine tissues. Kaplan-Meier analysis was performed to associate gene expression in esophageal cancer tissues with survival data for patients with esophageal cancer. Results 4-NQO dose-dependently induced pre-malignant and malignant lesions in oral cavity and esophagus in mice that pathologically and morphologically mimicked human oral and esophageal cancer. Molecularly, 4-NQO inhibited Rarβ2 but induced expression of phosphorylated extracellular-signal-regulated kinase 1 and 2 (p-ERK1/2) and Cox2 proteins and Rarβ2 gene promoter methylation in murine tumors. In vitro treatment with 4-NQO altered expression of RARβ2, p-ERK1/2, and COX2 in human esophageal cancer cells. In tissues from 90 patients with esophageal cancer, expression of p-ERK1/2 and COX2 was up-regulated, and p-ERK1/2 expression was associated with advanced clinical tumor stage and consumption of hot beverages, while COX2 expression was associated with tumor de-differentiation in esophageal cancer. Furthermore, expression of p-ERK1/2 was associated with a worse overall survival rate of patients (p=0.014), whereas the association of COX2 expression with worse overall survival rate did not reach statistical significance (p=0.19). Knockdown of COX2 expression using transient transfection of a COX2 antisense expression vector inhibited Ki67 expression, an indicator of cell proliferation, in human esophageal cancer cells. Conclusion 4-NQO-induced cancer in oral cavity and esophagus of mice not only pathologically and morphologically mimicked human oral and esophageal cancer but also shared some molecular alterations (e.g. aberrant expression of Rarb2, p-ERK1/2, and Cox2). This study further demonstrated that targeting of the altered RARβ2-led gene pathway could effectively suppress development of this deadly type of cancer. PMID:23812217

Evidence for social working memory from a parametric functional MRI study.

PubMed

Meyer, Meghan L; Spunt, Robert P; Berkman, Elliot T; Taylor, Shelley E; Lieberman, Matthew D

2012-02-07

Keeping track of various amounts of social cognitive information, including people's mental states, traits, and relationships, is fundamental to navigating social interactions. However, to date, no research has examined which brain regions support variable amounts of social information processing ("social load"). We developed a social working memory paradigm to examine the brain networks sensitive to social load. Two networks showed linear increases in activation as a function of increasing social load: the medial frontoparietal regions implicated in social cognition and the lateral frontoparietal system implicated in nonsocial forms of working memory. Of these networks, only load-dependent medial frontoparietal activity was associated with individual differences in social cognitive ability (trait perspective-taking). Although past studies of nonsocial load have uniformly found medial frontoparietal activity decreases with increasing task demands, the current study demonstrates these regions do support increasing mental effort when such effort engages social cognition. Implications for the etiology of clinical disorders that implicate social functioning and potential interventions are discussed.

Corexit-EC9527A Disrupts Retinol Signaling and Neuronal Differentiation in P19 Embryonal Pluripotent Cells

PubMed Central

Chen, Yanling; Reese, David H.

2016-01-01

Corexit-EC9500A and Corexit-EC9527A are two chemical dispersants that have been used to remediate the impact of the 2010 Deepwater Horizon oil spill. Both dispersants are composed primarily of organic solvents and surfactants and act by emulsifying the crude oil to facilitate biodegradation. The potential adverse effect of the Corexit chemicals on mammalian embryonic development remains largely unknown. Retinol (vitamin A) signaling, mediated by all-trans retinoic acid (RA), is essential for neural tube formation and the development of many organs in the embryo. The physiological levels of RA in cells and tissues are maintained by the retinol signaling pathway (RSP), which controls the biosynthesis of RA from dietary retinol and the catabolism of RA to polar metabolites for removal. RA is a potent activating ligand for the RAR/RXR nuclear receptors. Through RA and the receptors, the RSP modulates the expression of many developmental genes; interference with the RSP is potentially teratogenic. In this study the mouse P19 embryonal pluripotent cell, which contains a functional RSP, was used to evaluate the effects of the Corexit dispersants on retinol signaling and associated neuronal differentiation. The results showed that Corexit-EC9500A was more cytotoxic than Corexit-EC9527A to P19 cells. At non-cytotoxic doses, Corexit-EC9527A inhibited retinol-induced expression of the Hoxa1 gene, which encodes a transcription factor for the regulation of body patterning in the embryo. Such inhibition was seen in the retinol- and retinal- induced, but not RA-induced, Hoxa1 up-regulation, indicating that the Corexit chemicals primarily inhibit RA biosynthesis from retinal. In addition, Corexit-EC9527A suppressed retinol-induced P19 cell differentiation into neuronal cells, indicating potential neurotoxic effect of the chemicals under the tested conditions. The surfactant ingredient, dioctyl sodium sulfosuccinate (DOSS), may be a major contributor to the observed effect of Corexit-EC9527A in the cell. PMID:27684493

Examining Core Elements of International Research Collaboration: Summary of a Workshop

DTIC Science & Technology

2011-06-26

security, and confidentiality; bioethical issues related to human subjects research as well as other activities with bioethical implications, all from...standing academic center of excellence affiliated with a number of universities. The West African Bioethics Center in Nigeria has also established a...confidentiality; bio- ethical issues related to human subjects research as well as other activities with bioethical implications, all from both a domestic

A systematic review on the neural effects of music on emotion regulation: implications for music therapy practice.

PubMed

Moore, Kimberly Sena

2013-01-01

Emotion regulation (ER) is an internal process through which a person maintains a comfortable state of arousal by modulating one or more aspects of emotion. The neural correlates underlying ER suggest an interplay between cognitive control areas and areas involved in emotional reactivity. Although some studies have suggested that music may be a useful tool in ER, few studies have examined the links between music perception/production and the neural mechanisms that underlie ER and resulting implications for clinical music therapy treatment. Objectives of this systematic review were to explore and synthesize what is known about how music and music experiences impact neural structures implicated in ER, and to consider clinical implications of these findings for structuring music stimuli to facilitate ER. A comprehensive electronic database search resulted in 50 studies that met predetermined inclusion and exclusion criteria. Pertinent data related to the objective were extracted and study outcomes were analyzed and compared for trends and common findings. Results indicated there are certain music characteristics and experiences that produce desired and undesired neural activation patterns implicated in ER. Desired activation patterns occurred when listening to preferred and familiar music, when singing, and (in musicians) when improvising; undesired activation patterns arose when introducing complexity, dissonance, and unexpected musical events. Furthermore, the connection between music-influenced changes in attention and its link to ER was explored. Implications for music therapy practice are discussed and preliminary guidelines for how to use music to facilitate ER are shared.

Commercialisation and entrepreneurialism in maternity.

PubMed

Mander, Rosemary

2011-08-01

against an international background, to examine the implications of private sector activity for maternity care in the United Kingdom National Health Service (UK NHS). the private sector and commercial or entrepreneurial activity in maternity services have attracted limited attention in the UK compared with, for e.g., Greece and the Irish Republic. discursive paper. despite rhetoric to the contrary, financial costs have always featured in the UK NHS. Financial payments in maternity have increased gradually. Commercial and entrepreneurial activity in maternity now includes 'entertainment ultrasound', reflecting a greater hegemonic imbalance. The commercialisation of maternity raises organisational, professional, quality-related and systematic issues, which all carry implications for the childbearing woman. the childbearing woman shoulders financial costs, whose origins and implications matter to both midwife and woman. The mixed benefits of medical investigations deserve closer attention. Copyright © 2011 Elsevier Ltd. All rights reserved.

Detection of HPV-DNA, p53 alterations, and methylation in penile squamous cell carcinoma in Japanese men.

PubMed

Yanagawa, Naoki; Osakabe, Mitsumasa; Hayashi, Masahiro; Tamura, Gen; Motoyama, Teiichi

2008-08-01

Penile carcinoma is a rare disease, accordingly there are few studies on molecular changes, and these results also vary greatly. A total of 26 penile squamous cell carcinomas in Japanese men were studied with respect to HPV, p53 alterations, and methylation of gene promoter region. HPV-DNA was detected in three of 26 patients (11.5%). Overexpression of p53 was observed in 13 of 26 patients (50%), and p53 gene mutations were detected in four of 26 patients (15.4%). The frequency of methylation was as follows: DAPK, 26.9% (7/26); FHIT, 88.4% (23/26); MGMT, 19.2% (5/26); p14, 3.8% (1/26); p16, 23.1% (6/26); RAR-beta, 23.1% (6/26); RASSF1A, 11.5% (3/26); and RUNX3, 42.3% (11/26). As for correlation between HPV and p53 alterations, and methylation status, mutations of the p53 gene were detected only in HPV-negative patients, and methylation was more frequently found in HPV-negative than in HPV-positive patients. The present results suggest that the majority of penile squamous cell carcinomas in Japanese men are unrelated to HPV, and gene alterations accumulate more frequently in HPV-unrelated penile carcinomas.

Families of Nuclear Receptors in Vertebrate Models: Characteristic and Comparative Toxicological Perspective

NASA Astrophysics Data System (ADS)

Zhao, Yanbin; Zhang, Kun; Giesy, John P.; Hu, Jianying

2015-02-01

Various synthetic chemicals are ligands for nuclear receptors (NRs) and can cause adverse effects in vertebrates mediated by NRs. While several model vertebrates, such as mouse, chicken, western clawed frog and zebrafish, are widely used in toxicity testing, few NRs have been well described for most of these classes. In this report, NRs in genomes of 12 vertebrates are characterized via bioinformatics approaches. Although numbers of NRs varied among species, with 40-42 genes in birds to 66-74 genes in teleost fishes, all NRs had clear homologs in human and could be categorized into seven subfamilies defined as NR0B-NR6A. Phylogenetic analysis revealed conservative evolutionary relationships for most NRs, which were consistent with traditional morphology-based systematics, except for some exceptions in Dolphin (Tursiops truncatus). Evolution of PXR and CAR exhibited unexpected multiple patterns and the existence of CAR possibly being traced back to ancient lobe-finned fishes and tetrapods (Sarcopterygii). Compared to the more conservative DBD of NRs, sequences of LBD were less conserved: Sequences of THRs, RARs and RXRs were >=90% similar to those of the human, ERs, AR, GR, ERRs and PPARs were more variable with similarities of 60%-100% and PXR, CAR, DAX1 and SHP were least conserved among species.

[Divergence of paralogous growth-hormone-encoding genes and their promoters in Salmonidae].

PubMed

Kamenskaya, D N; Pankova, M V; Atopkin, D M; Brykov, V A

2017-01-01

In many fish species, including salmonids, the growth-hormone is encoded by two duplicated paralogous genes, gh1 and gh2. Both genes were already in place at the time of divergence of species in this group. A comparison of the entire sequence of these genes of salmonids has shown that their conserved regions are associated with exons, while their most variable regions correspond to introns. Introns C and D include putative regulatory elements (sites Pit-1, CRE, and ERE), that are also conserved. In chars, the degree of polymorphism of gh2 gene is 2-3 times as large as that in gh1 gene. However, a comparison across all Salmonidae species would not extent this observation to other species. In both these chars' genes, the promoters are conserved mainly because they correspond to putative regulatory sequences (TATA box, binding sites for the pituitary transcription factor Pit-1 (F1-F4), CRE, GRE and RAR/RXR elements). The promoter of gh2 gene has a greater degree of polymorphism compared with gh1 gene promoter in all investigated species of salmonids. The observed differences in the rates of accumulation of changes in growth hormone encoding paralogs could be explained by differences in the intensity of selection.

Increased dietary intake of vitamin A promotes aortic valve calcification in vivo

PubMed Central

Huk, Danielle J.; Hammond, Harriet L.; Kegechika, Hiroyuki; Lincoln, Joy

2013-01-01

Objective Calcific aortic valve disease (CAVD) is a major public health problem with no effective treatment available other than surgery. We previously showed that mature heart valves calcify in response to retinoic acid (RA) treatment through downregulation of the SRY-transcription factor Sox9. In this study, we investigated the effects of excess vitamin A and its metabolite RA on heart valve structure and function in vivo, and examined the molecular mechanisms of RA signaling during the calcification process in vitro. Methods and Results Using a combination of approaches, we defined CAVD pathogenesis in mice fed 200 IU/g and 20 IU/g of retinyl palmitate for 12 months at molecular, cellular and functional levels. We show that mice fed excess vitamin A develop aortic valve stenosis and leaflet calcification associated with increased expression of osteogenic genes and decreased expression of cartilaginous markers. Using a pharmacological approach, we show that RA-mediated Sox9 repression and calcification is regulated by classical RA signaling and requires both RAR and RXR receptors. Conclusions Our studies demonstrate that excess vitamin A dietary intake promotes heart valve calcification in vivo. Therefore suggesting that hypervitaminosis A could serve as a new risk factor of CAVD in the human population. PMID:23202364

A Computer Program for Practical Semivariogram Modeling and Ordinary Kriging: A Case Study of Porosity Distribution in an Oil Field

NASA Astrophysics Data System (ADS)

Mert, Bayram Ali; Dag, Ahmet

2017-12-01

In this study, firstly, a practical and educational geostatistical program (JeoStat) was developed, and then example analysis of porosity parameter distribution, using oilfield data, was presented. With this program, two or three-dimensional variogram analysis can be performed by using normal, log-normal or indicator transformed data. In these analyses, JeoStat offers seven commonly used theoretical variogram models (Spherical, Gaussian, Exponential, Linear, Generalized Linear, Hole Effect and Paddington Mix) to the users. These theoretical models can be easily and quickly fitted to experimental models using a mouse. JeoStat uses ordinary kriging interpolation technique for computation of point or block estimate, and also uses cross-validation test techniques for validation of the fitted theoretical model. All the results obtained by the analysis as well as all the graphics such as histogram, variogram and kriging estimation maps can be saved to the hard drive, including digitised graphics and maps. As such, the numerical values of any point in the map can be monitored using a mouse and text boxes. This program is available to students, researchers, consultants and corporations of any size free of charge. The JeoStat software package and source codes available at: http://www.jeostat.com/JeoStat_2017.0.rar.

The Implications of Fe2O3 and TiO2 Nanoparticles on the Removal of Trichloroethylene by Activated Carbon in the Presence and Absence of Humic Acid

EPA Science Inventory

The implications of Fe2O3 and TiO2 nanoparticles (NPs) on a granular activated carbon (GAC) adsorber and their impact on the removal of Trichloroethylene (TCE) were investigated in the presence of humic acid (HA). The surface charge of the GAC and NPs was obtained in the presence...

Ubiquitin-Dependent Regulation of the Mammalian Hippo Pathway: Therapeutic Implications for Cancer.

PubMed

Nguyen, Thanh Hung; Kugler, Jan-Michael

2018-04-17

The Hippo pathway serves as a key barrier for oncogenic transformation. It acts by limiting the activity of the proto-oncogenes YAP and TAZ. Reduced Hippo signaling and elevated YAP/TAZ activities are frequently observed in various types of tumors. Emerging evidence suggests that the ubiquitin system plays an important role in regulating Hippo pathway activity. Deregulation of ubiquitin ligases and of deubiquitinating enzymes has been implicated in increased YAP/TAZ activity in cancer. In this article, we review recent insights into the ubiquitin-mediated regulation of the mammalian Hippo pathway, its deregulation in cancer, and possibilities for targeting the Hippo pathway through the ubiquitin system.

Interleukin-22 ameliorates liver fibrogenesis by attenuating hepatic stellate cell activation and downregulating the levels of inflammatory cytokines

PubMed Central

Lu, Dong-Hong; Guo, Xiao-Yun; Qin, Shan-Yu; Luo, Wei; Huang, Xiao-Li; Chen, Mei; Wang, Jia-Xu; Ma, Shi-Jia; Yang, Xian-Wen; Jiang, Hai-Xing

2015-01-01

AIM: To investigate the effect of interleukin (IL)-22 on hepatic fibrosis in mice and the possible mechanism involved. METHODS: Liver fibrosis was induced in male BALB/c mice by CCl4. Recombinant IL-22 (rmIL-22) was administered intraperitoneally in CCl4-treated mice. Fibrosis was assessed by histology and Masson staining. The activation of hepatic stellate cells (HSCs) was investigated by analysis of α-smooth muscle actin expression. The frequencies of T helper (Th) 22 cells, Th17 cells and Th1 cells, the expression of inflammatory cytokines [IL-22, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, IL-1β] and transcription factors [aryl hydrocarbon receptor (AHR), RAR-related orphan receptor (RORγt), T-bet] mRNA in the liver were investigated. In addition, the plasma levels of IL-22, IL-17A, IFN-γ, TNF-α, IL-6 and IL-1β were evaluated. RESULTS: Significant elevations in circulating Th22 cells, Th17 cells, Th1 cells, IL-22, IL-17A, and IFN-γ were observed in the hepatic fibrosis group compared with the control group (P < 0.01). Treatment with rmIL-22 in mice with hepatic fibrosis ameliorated the severity of hepatic fibrosis, which was confirmed by lower hepatic fibrosis pathological scores (P < 0.01). RmIL-22 decreased the frequencies of Th22 cells (6.71% ± 0.97% vs 8.09% ± 0.74%, P < 0.01), Th17 cells (4.34% ± 0.37% vs 5.71% ± 0.24%, P < 0.01), Th1 cells (3.09% ± 0.49% vs 4.91% ± 0.73%, P < 0.01), and the levels of IL-22 (56.23 ± 3.08 vs 70.29 ± 3.01, P < 0.01), IL-17A (30.74 ± 2.77 vs 45.68 ± 2.71, P < 0.01), and IFN-γ (74.78 ± 2.61 vs 124.89 ± 2.82, P < 0.01). Down-regulation of IL-22, IL-17A, IFN-γ, TNF-α, IL-6, IL-1β, AHR RORγt, and T-bet gene expression in the liver was observed in the rmIL-22 group (P < 0.01). CONCLUSION: The frequencies of Th22, Th17 and Th1 cells are elevated in hepatic fibrosis. RmIL-22 can attenuate HSC activation and down-regulate the levels of inflammatory cytokines, thereby ameliorating liver fibrogenesis. PMID:25663772

Sex-related differences in neural activity during emotion regulation.

PubMed

Mak, Amanda K Y; Hu, Zhi-guo; Zhang, John X X; Xiao, Zhuangwei; Lee, Tatia M C

2009-11-01

The sex disparity in the development of depression has long been an important research topic, but the sex-related differences in neural activity during emotion regulation have been less thoroughly studied. It was hypothesized that, during the regulation of emotion, there would be more activation in the prefrontal regions implicated in cognitive processing for males, while there would be more activation in the prefrontal regions implicated in affective processing for females. This fMRI study recruited 12 females and 12 males who were required to view or to regulate the negative and positive emotion induced by some emotion-arousing pictures. During the regulation of negative emotion, both males and females had stronger activation in the left anterior cingulate gyrus, but males showed more activation in the prefrontal regions in general, including the left dorsolateral and lateral orbitofrontal gyrus as well as the right anterior cingulate gyrus, while females only showed stronger activation in the left medial orbitofrontal gyrus. For the regulation of positive emotion, both males and females showed stronger activation in the left dorsomedial prefrontal gyrus, but males were found to also have stronger activity in the left lateral orbitofrontal gyrus. It was concluded that there are common as well as sex-specific sets of brain regions involved in regulating negative and positive emotion, and the findings may have significant implications for females' vulnerability to developing depression.

“Listening” and “talking” to neurons: Implications of immune activation for pain control and increasing the efficacy of opioids

PubMed Central

Watkins, Linda R.; Hutchinson, Mark R.; Milligan, Erin D.; Maier, Steven F.

2008-01-01

It is recently become clear that activated immune cells and immune-like glial cells can dramatically alter neuronal function. By increasing neuronal excitability, these non-neuronal cells are now implicated in the creation and maintenance of pathological pain, such as occurs in response to peripheral nerve injury. Such effects are exerted at multiple sites along the pain pathway, including at peripheral nerves, dorsal root ganglia, and spinal cord. In addition, activated glial cells are now recognized as disrupting the pain suppressive effects of opioid drugs and contributing to opioid tolerance and opioid dependence/withdrawal. While this review focuses on regulation of pain and opioid actions, such immune-neuronal interactions are broad in their implications. Such changes in neuronal function would be expected to occur wherever immune-derived substances come in close contact with neurons. PMID:17706291

T-tube drainage versus primary closure after open common bile duct exploration.

PubMed

Gurusamy, Kurinchi Selvan; Koti, Rahul; Davidson, Brian R

2013-06-21

Between 5% and 11% of people undergoing cholecystectomy have common bile duct stones. Stones may be removed at the time of cholecystectomy by opening and clearing the common bile duct. The optimal technique is unclear. The aim is to assess the benefits and harms of T-tube drainage versus primary closure without biliary stent after open common bile duct exploration for common bile duct stones. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until April 2013. We included all randomised clinical trials comparing T-tube drainage versus primary closure after open common bile duct exploration. Two of four authors independently identified the studies for inclusion and extracted data. We analysed the data with both the fixed-effect and the random-effects model using Review Manager (RevMan) analyses. For each outcome we calculated the risk ratio (RR), rate ratio (RaR), or mean difference (MD) with 95% confidence interval (CI) based on intention-to-treat analysis. We included six trials randomising 359 participants, 178 to T-tube drainage and 181 to primary closure. All trials were at high risk of bias. There was no significant difference in mortality between the two groups (4/178 (weighted percentage 1.2%) in the T-tube group versus 1/181 (0.6%) in the primary closure group; RR 2.25; 95% CI 0.55 to 9.25; six trials). There was no significant difference in the serious morbidity rate between the two groups (24/136 (weighted serious morbidity rate, 145 events per 1000 patients) in the T-tube group versus 9/136 (weighted serious morbidity rate, 66 events per 1000 patients) in the primary closure group; RaR 2.19; 95% CI 0.98 to 4.91; four trials). Quality of life and return to work were not reported in any of the trials. The operating time was significantly longer in the T-tube drainage group compared with the primary closure group (MD 28.90 minutes; 95% CI 17.18 to 40.62 minutes; one trial). The hospital stay was significantly longer in the T-tube drainage group compared with the primary closure group (MD 4.72 days; 95% CI 0.83 days to 8.60 days; five trials). T-tube drainage appeared to result in significantly longer operating time and hospital stay compared with primary closure without any apparent evidence of benefit on clinically important outcomes after open common bile duct exploration. Based on the currently available evidence, there is no justification for the routine use of T-tube drainage after open common bile duct exploration in patients with common bile duct stones. T-tube drainage should not be used outside well designed randomised clinical trials. More randomised trials comparing the effects of T-tube drainage versus primary closure after open common bile duct exploration may be needed. Such trials should be conducted with low risk of bias and assessing the long-term beneficial and harmful effects of T-tube drainage, including long-term complications such as bile stricture and recurrence of common bile duct stones.

Electrical and Optical Activation of Mesoscale Neural Circuits with Implications for Coding.

PubMed

Millard, Daniel C; Whitmire, Clarissa J; Gollnick, Clare A; Rozell, Christopher J; Stanley, Garrett B

2015-11-25

Artificial activation of neural circuitry through electrical microstimulation and optogenetic techniques is important for both scientific discovery of circuit function and for engineered approaches to alleviate various disorders of the nervous system. However, evidence suggests that neural activity generated by artificial stimuli differs dramatically from normal circuit function, in terms of both the local neuronal population activity at the site of activation and the propagation to downstream brain structures. The precise nature of these differences and the implications for information processing remain unknown. Here, we used voltage-sensitive dye imaging of primary somatosensory cortex in the anesthetized rat in response to deflections of the facial vibrissae and electrical or optogenetic stimulation of thalamic neurons that project directly to the somatosensory cortex. Although the different inputs produced responses that were similar in terms of the average cortical activation, the variability of the cortical response was strikingly different for artificial versus sensory inputs. Furthermore, electrical microstimulation resulted in highly unnatural spatial activation of cortex, whereas optical input resulted in spatial cortical activation that was similar to that induced by sensory inputs. A thalamocortical network model suggested that observed differences could be explained by differences in the way in which artificial and natural inputs modulate the magnitude and synchrony of population activity. Finally, the variability structure in the response for each case strongly influenced the optimal inputs for driving the pathway from the perspective of an ideal observer of cortical activation when considered in the context of information transmission. Artificial activation of neural circuitry through electrical microstimulation and optogenetic techniques is important for both scientific discovery and clinical translation. However, neural activity generated by these artificial means differs dramatically from normal circuit function, both locally and in the propagation to downstream brain structures. The precise nature of these differences and the implications for information processing remain unknown. The significance of this work is in quantifying the differences, elucidating likely mechanisms underlying the differences, and determining the implications for information processing. Copyright © 2015 the authors 0270-6474/15/3515702-14$15.00/0.

Ubiquitin-Dependent Regulation of the Mammalian Hippo Pathway: Therapeutic Implications for Cancer

PubMed Central

Nguyen, Thanh Hung

2018-01-01

The Hippo pathway serves as a key barrier for oncogenic transformation. It acts by limiting the activity of the proto-oncogenes YAP and TAZ. Reduced Hippo signaling and elevated YAP/TAZ activities are frequently observed in various types of tumors. Emerging evidence suggests that the ubiquitin system plays an important role in regulating Hippo pathway activity. Deregulation of ubiquitin ligases and of deubiquitinating enzymes has been implicated in increased YAP/TAZ activity in cancer. In this article, we review recent insights into the ubiquitin-mediated regulation of the mammalian Hippo pathway, its deregulation in cancer, and possibilities for targeting the Hippo pathway through the ubiquitin system. PMID:29673168

Attention improves memory by suppressing spiking-neuron activity in the human anterior temporal lobe.

PubMed

Wittig, John H; Jang, Anthony I; Cocjin, John B; Inati, Sara K; Zaghloul, Kareem A

2018-06-01

We identify a memory-specific attention mechanism in the human anterior temporal lobe, an area implicated in semantic processing and episodic memory formation. Spiking neuron activity is suppressed and becomes more reliable in preparation for verbal memory formation. Intracranial electroencephalography signals implicate this region as a source of executive control for attentional selection. Consistent with this interpretation, its surgical removal causes significant memory impairment for attended words relative to unattended words.

Protein Kinase C-θ (PKC-θ) in Natural Killer Cell Function and Anti-Tumor Immunity

PubMed Central

Anel, Alberto; Aguiló, Juan I.; Catalán, Elena; Garaude, Johan; Rathore, Moeez G.; Pardo, Julián; Villalba, Martín

2012-01-01

The protein kinase C-θ (PKCθ), which is essential for T cell function and survival, is also required for efficient anti-tumor immune surveillance. Natural killer (NK) cells, which express PKCθ, play a prominent role in this process, mainly by elimination of tumor cells with reduced or absent major histocompatibility complex class-I (MHC-I) expression. This justifies the increased interest of the use of activated NK cells in anti-tumor immunotherapy in the clinic. The in vivo development of MHC-I-deficient tumors is much favored in PKCθ−/− mice compared with wild-type mice. Recent data offer some clues on the mechanism that could explain the important role of PKCθ in NK cell-mediated anti-tumor immune surveillance: some studies show that PKCθ is implicated in signal transduction and anti-tumoral activity of NK cells elicited by interleukin (IL)-12 or IL-15, while others show that it is implicated in NK cell functional activation mediated by certain killer-activating receptors. Alternatively, the possibility that PKCθ is involved in NK cell degranulation is discussed, since recent data indicate that it is implicated in microtubule-organizing center polarization to the immune synapse in CD4+ T cells. The implication of PKC isoforms in degranulation has been more extensively studied in cytotoxic T lymphocyte, and these studies will be also summarized. PMID:22783260

Acid Rain: Activities for Science Teachers.

ERIC Educational Resources Information Center

Johnson, Eric; And Others

1983-01-01

Seven complete secondary/college level acid rain activities are provided. Activities include overview; background information and societal implications; major concepts; student objectives; vocabulary/material lists; procedures; instructional strategies; and questions/discussion and extension suggestions. Activities consider effects of acid rain on…

The story so far: post-translational regulation of peroxisome proliferator-activated receptors by ubiquitination and SUMOylation

PubMed Central

Wadosky, Kristine M.

2012-01-01

Many studies have implicated the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptor transcription factors in regulating cardiac substrate metabolism and ATP generation. Recently, evidence from a variety of cell culture and organ systems has implicated ubiquitin and small ubiquitin-like modifier (SUMO) conjugation as post-translational modifications that regulate the activity of PPAR transcription factors and their coreceptors/coactivators. Here we introduce the ubiquitin and SUMO conjugation systems and extensively review how they have been shown to regulate all three PPAR isoforms (PPARα, PPARβ/δ, and PPARγ) in addition to the retinoid X receptor and PPARγ coactivator-1α subunits of the larger PPAR transcription factor complex. We then present how the specific ubiquitin (E3) ligases have been implicated and review emerging evidence that post-translational modifications of PPARs with ubiquitin and/or SUMO may play a role in cardiac disease. Because PPAR activity is perturbed in a variety of forms of heart disease and specific proteins regulate this process (E3 ligases), this may be a fruitful area of investigation with respect to finding new therapeutic targets. PMID:22037188

Everyday conversation requires cognitive inference: neural bases of comprehending implicated meanings in conversations.

PubMed

Jang, Gijeong; Yoon, Shin-ae; Lee, Sung-Eun; Park, Haeil; Kim, Joohan; Ko, Jeong Hoon; Park, Hae-Jeong

2013-11-01

In ordinary conversations, literal meanings of an utterance are often quite different from implicated meanings and the inference about implicated meanings is essentially required for successful comprehension of the speaker's utterances. Inference of finding implicated meanings is based on the listener's assumption that the conversational partner says only relevant matters according to the maxim of relevance in Grice's theory of conversational implicature. To investigate the neural correlates of comprehending implicated meanings under the maxim of relevance, a total of 23 participants underwent an fMRI task with a series of conversational pairs, each consisting of a question and an answer. The experimental paradigm was composed of three conditions: explicit answers, moderately implicit answers, and highly implicit answers. Participants were asked to decide whether the answer to the Yes/No question meant 'Yes' or 'No'. Longer reaction time was required for the highly implicit answers than for the moderately implicit answers without affecting the accuracy. The fMRI results show that the left anterior temporal lobe, left angular gyrus, and left posterior middle temporal gyrus had stronger activation in both moderately and highly implicit conditions than in the explicit condition. Comprehension of highly implicit answers had increased activations in additional regions including the left inferior frontal gyrus, left medial prefrontal cortex, left posterior cingulate cortex and right anterior temporal lobe. The activation results indicate involvement of these regions in the inference process to build coherence between literally irrelevant but pragmatically associated utterances under the maxim of relevance. Especially, the left anterior temporal lobe showed high sensitivity to the level of implicitness and showed increased activation for highly versus moderately implicit conditions, which imply its central role in inference such as semantic integration. The right hemisphere activation, uniquely found in the anterior temporal lobe for highly implicit utterances, suggests its competence for integrating distant concepts in implied utterances under the relevance principle. Copyright © 2013 Elsevier Inc. All rights reserved.

Criminal Investigative Activities: World War II and Vietnam Battlefield Implications

DTIC Science & Technology

1988-06-03

WORLD WAR II AND VIET NAM BATTLEFIELD IMPLICATIONS •A thesis presented to the Faculty of the U. S. Army Command and General Staff College in partial...TIME COVERED 114. DATE OF REPORT (Year, Month, Day) 115. PAGE COUNT Master’s Thesis IFROM 8-1&~98 .TO..i-li38I 1988 June 3 I 145 16. SUPPLEMENTARY...CRIMINAL INVESTIGATIVE ACTIVITIES WORLD WAR II AND VIET NAM BATTLEFIELD !MPLICATIONS A thesis presented to the Faculty of the U. S. Army

The First World War and Its Implications for Education in British Museums.

ERIC Educational Resources Information Center

Kavanagh, Gaynor

1988-01-01

Examines how the First World War prompted British museums to change their educational functions. Discusses museums in pre-war Britain, wartime exhibitions and educational activities, the outcome of the war experience, and First World War's implications for education in museums. (GEA)

Childhood Obesity: Implications for Physical Education.

ERIC Educational Resources Information Center

Heston, Melissa L.

1983-01-01

Physical education teachers can help obese children develop effective movement patterns while encouraging an active lifestyle. Teachers should be familiar with: (1) the impact of obesity on children's physical and mental health; (2) the importance of exercise for weight control; and (3) implications for the physical education program. (PP)

Disclosure of Traumas and Immune Function: Health Implications for Psychotherapy.

ERIC Educational Resources Information Center

Pennebaker, James W.; And Others

1988-01-01

Assigned 50 healthy undergraduates the task of writing about either traumatic experiences or superficial topics for four consecutive days. Examination of cellular-immune system function and health center visits suggests that confronting traumatic experiences was physically beneficial. Discusses implications of such active confrontation of…

ARSENIC UPTAKE PROCESSES IN REDUCING ENVIRONMENTS: IMPLICATIONS FOR ACTIVE REMEDIATION AND NATURAL ATTENUATION

EPA Science Inventory

Reductive dissolution of iron oxyhydr(oxides) and release of adsorbed or coprecipitated arsenic is often implicated as a key process that controls the mobility and bioavailability of arsenic in anoxic environments. Yet a complete assessment of arsenic transport and fate requires...

Measuring Physical Activity in the Elderly: Some Implications for Nutrition.

ERIC Educational Resources Information Center

Shephard, Roy J.

1990-01-01

Measurement of physical activity patterns is discussed in terms of data obtained by attitude assessment, activity questionnaires, personal monitoring devices, and fitness assessment. Problems of each technique are described. Application of activity measures to the estimation of total dietary needs is discussed. (SK)

Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy

DTIC Science & Technology

2015-09-01

Award Number: W81XWH-11-1-0384 TITLE: Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells : Implications for...Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells : Implications for Cancer Vaccine Therapy 5b. GRANT NUMBER CA100463 5c...Listeria monocytogenes (Lm) on human dendritic cells (DCs) to optimize Lm-based DC cancer vaccines. The project aims are: 1) Compare the activation and

Punishing Unfairness: Rewarding or the Organization of a Reactively Aggressive Response?

PubMed Central

White, Stuart F.; Brislin, Sarah J.; Sinclair, Stephen; Blair, James R.

2014-01-01

Objectives The neural correlates of human cooperative behavior remain poorly understood. Previous work has suggested that increases in striatal activation while punishing unfair offers represents reward signaling. However, other regions are also implicated when punishing others, for example dorsomedial frontal cortex (dmFC), anterior insula cortex (AIC), and periaqueductal gray (PAG). Moreover, the response of other regions implicated in signaling reward, for example ventromedial prefrontal cortex (vmPFC) or posterior cingulate cortex (PCC), has not been systematically examined. Experimental Design Functional magnetic resonance imaging utilizing parametric modulation was conducted on 21 healthy adults participating in a social exchange paradigm. Principal Observations Participants showed significant positive modulation of activity as a function of delivered punishment in caudate, dmFC, AIC, and PAG; that is, higher punishments by participants of unsatisfactory offers were associated with increasing activity within these regions. However, participants showed significant negative modulation of activity as a function of delivered punishment in vmPFC and PCC; increases in punishment level by participants were associated with decreases in activity within these regions. Conclusions The current data question whether caudate activity when punishing unfair offers should be considered to indicate the reward value of this punishment. Instead, this activity, in conjunction with activity within dmFC, AIC, and PAG, may represent the organization of an untypical, punishing response that represents a reactive aggressive response to provocation. Notably, an inverse, regulatory relationship between vmPFC and PAG activity has been previously implicated in the context of another stimulus for reactive aggression; looming threat (Mobbs et al. [2007]: Science 317:1079–1083). PMID:23868733

The adaptor molecule RIAM integrates signaling events critical for integrin-mediated control of immune function and cancer progression.

PubMed

Patsoukis, Nikolaos; Bardhan, Kankana; Weaver, Jessica D; Sari, Duygu; Torres-Gomez, Alvaro; Li, Lequn; Strauss, Laura; Lafuente, Esther M; Boussiotis, Vassiliki A

2017-08-22

Lymphocyte activation requires adhesion to antigen-presenting cells. This is a critical event linking innate and adaptive immunity. Lymphocyte adhesion is accomplished through LFA-1, which must be activated by a process referred to as inside-out integrin signaling. Among the few signaling molecules that have been implicated in inside-out integrin activation in hematopoietic cells are the small guanosine triphosphatase (GTPase) Rap1 and its downstream effector Rap1-interacting molecule (RIAM), a multidomain protein that defined the Mig10-RIAM-lamellipodin (MRL) class of adaptor molecules. Through its various domains, RIAM is a critical node of signal integration for activation of T cells, recruits monomeric and polymerized actin to drive actin remodeling and cytoskeletal reorganization, and promotes inside-out integrin signaling in T cells. As a regulator of inside-out integrin activation, RIAM affects multiple functions of innate and adaptive immunity. The effects of RIAM on cytoskeletal reorganization and integrin activation have implications in cell migration and trafficking of cancer cells. We provide an overview of the structure and interactions of RIAM, and we discuss the implications of RIAM functions in innate and adaptive immunity and cancer. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Mesodermal retinoic acid signaling regulates endothelial cell coalescence in caudal pharyngeal arch artery vasculogenesis

PubMed Central

Li, Peng; Pashmforoush, Mohammad; Sucov, Henry M.

2011-01-01

Disruption of retinoic acid signaling causes a variety of pharyngeal arch artery and great vessel defects, as well as malformations in many other tissues, including those derived from the pharyngeal endoderm. Previous studies implied that arch artery defects in the context of defective RA signaling occur secondary to pharyngeal pouch segmentation defects, although this model has never been experimentally verified. In this study, we examined arch artery morphogenesis during mouse development, and the role of RA in this process. We show in normal embryos that the arch arteries form by vasculogenic differentiation of pharyngeal mesoderm. Using various genetic backgrounds and tissue-specific mutation approaches, we segregate pharyngeal arch artery and pharyngeal pouch defects in RA receptor mutants, and show that RA signal transduction only in pharyngeal mesoderm is required for arch artery formation. RA does not control pharyngeal mesodermal differentiation to endothelium, but instead promotes the aggregation of endothelial cells into nascent vessels. Expression of VE-cadherin was substantially reduced in RAR mutants, and this deficiency may underlie the arch artery defects. The consequences of disrupted mesodermal and endodermal RA signaling were restricted to the 4th and 6th arch arteries and to the 4th pharyngeal pouch, respectively, suggesting that different regulatory mechanisms control the formation of the more anterior arch arteries and pouches. PMID:22040871

ASAP progress and expenditure report for the month of December 1--31, 1995. Joint UK/US radar program

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

Twogood, R.E.; Brase, J.M.; Chambers, D.H.

1996-01-19

The RAR/SAR is a high-priority radar system for the joint US/UK Program. Based on previous experiment results and coordination with the UK, specifications needed for future radar experiments were identified as follows: dual polarimetric (HH and VV) with medium to high resolution in SAR mode. Secondary airborne installation requirements included; high power (circa 10kw) and SLIER capability to emulate Tupelev-134 type system; initially x-band but easily extendible to other frequencies. In FY96 we intended to enhance the radar system`s capabilities by providing a second polarization (VV), spotlight imaging mode, extended frequency of operation to include S- band, increase power, andmore » interface to an existing infrared sensor. Short term objectives are: continue to evaluate and characterize the radar system; upgrade navigation and real-time processing capability to refine motion compensation; upgrade to dual polarimetry (add VV); and develop a ``spotlight`` mode capability. Accomplishments this reporting period: design specifications for the SAR system polarimetric upgrade are complete. The upgrade is ready to begin the procurement cycle when funds become available. System characterization is one of the highest priority tasks for the SAR. Although the radar is dedicated for our use, Hughes is waiting for contract funding before allowing us access to the hardware« less

Multiple Intelligence Theory for Gifted Education: Criticisms and Implications

ERIC Educational Resources Information Center

Calik, Basak; Birgili, Bengi

2013-01-01

This paper scrutinizes giftedness and gifted learners under the implications of multiple intelligence theory with regard to coaching young scientists. It is one of the pluralistic theories toward intelligence while supporting to view individuals as active participants during teaching and learning processes which correspond with the applications of…

"The Dyslogic Syndrome": Some Improbable Implications to Teacher Education.

ERIC Educational Resources Information Center

Peterson, Daniel L.

The author traces developments in the education of children with learning disabilities and comments on implications for teacher education. He suggests that a critical neglect of the study of cognition exists. The cognitive orientation, which includes emphases on active participation, student responsibility and long-term acquisitions, is discussed,…

The Skills Implications of Electronic Retailing. IES Final Report.

ERIC Educational Resources Information Center

Tackey, Nii Djan; Hillage, Jim; Jagger, Nick; Bates, Peter

The skills and education/training implications of the development of electronic commerce in the United Kingdom's retail industry and its associated supply chain were examined. The major data collection activities were as follows: a literature review; consultation with leading academics and advisers; an e-mail-based call for information from…

BEIR-III report and its implications for radiation protection and public health policy

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

Fabrikant, J.I.

1980-03-01

A general background is given of the implications the BEIR-III Report may have on societal decision-making in the regulation of activities concerned with the health effects of low-level radiation. The scientific basis for establishing appropriate radiation protection guides are discussed. (ACR)

Risk estimation and decision-making: implications of the 1980 BEIR-III report

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

Fabrikant, J.I.

1981-04-01

The report gives a general background of the implications the current Report of the Committee on the Biological Effects of Ionizing Radiation (The BEIR-III Report) may have on societal decision-making in the regulation of activities concerned with the health effects of low-level radiation. (ACR)

SYMPOSIUM #127 – ARE POLYBROMINATED DIPHENYL ETHERS FROM HOUSEHOLD DUST BIOAVAILABLE AND BIOLOGICALLY ACTIVE?

EPA Science Inventory

Recently, household dust has been implicated as a major source of polybrominated diphenyl ether (PBDE) exposure in humans. This finding may have important implications for young children, who are thought to ingest more dust than adults and may be more susceptible to some of the ...

Competitive Sports in the Elementary School: Psychological and Physical Implications.

ERIC Educational Resources Information Center

Jackson, Charles; Shaughnessy, Michael F.

Implications of participation in highly competitive sports by children from 7 through 12 years of age are examined. Evidence supports the conclusion that highly competitive sports are often harmful to both physiological and psychological growth and development. However, through participation in sports and physical activity, children can develop…

Identification of brain nuclei implicated in cocaine-primed reinstatement of conditioned place preference: a behaviour dissociable from sensitization.

PubMed

Brown, Robyn Mary; Short, Jennifer Lynn; Lawrence, Andrew John

2010-12-29

Relapse prevention represents the primary therapeutic challenge in the treatment of drug addiction. As with humans, drug-seeking behaviour can be precipitated in laboratory animals by exposure to a small dose of the drug (prime). The aim of this study was to identify brain nuclei implicated in the cocaine-primed reinstatement of a conditioned place preference (CPP). Thus, a group of mice were conditioned to cocaine, had this place preference extinguished and were then tested for primed reinstatement of the original place preference. There was no correlation between the extent of drug-seeking upon reinstatement and the extent of behavioural sensitization, the extent of original CPP or the extinction profile of mice, suggesting a dissociation of these components of addictive behaviour with a drug-primed reinstatement. Expression of the protein product of the neuronal activity marker c-fos was assessed in a number of brain regions of mice that exhibited reinstatement (R mice) versus those which did not (NR mice). Reinstatement generally conferred greater Fos expression in cortical and limbic structures previously implicated in drug-seeking behaviour, though a number of regions not typically associated with drug-seeking were also activated. In addition, positive correlations were found between neural activation of a number of brain regions and reinstatement behaviour. The most significant result was the activation of the lateral habenula and its positive correlation with reinstatement behaviour. The findings of this study question the relationship between primed reinstatement of a previously extinguished place preference for cocaine and behavioural sensitization. They also implicate activation patterns of discrete brain nuclei as differentiators between reinstating and non-reinstating mice.

Geochemical background/baseline values in top soils of Campania region: assessment of the toxic elements threat to ecosystem and human health

NASA Astrophysics Data System (ADS)

de Vivo, B.; Lima, A.; Albanese, S.; Bove, M.; Cicchella, D.; Civitillo, D.; Cosenza, A.; Grezzi, G.

2009-04-01

In the late years an intense geochemical prospecting activity on the whole territory of Campania region (Southern Italy) has been carried aiming at the definition of the geochemical backgrounds/baselines at both regional and local scale. At the end of 2003 the first edition of an atlas containing 200 maps showing the distribution patterns of 40 chemical elements on the whole regional territory was published (De Vivo et al., 2003, 2006a; Albanese et al., 2007a). The atlas provided a base knowledge of environmental status of the region and allowed to individuate some critical areas to be further investigated by topsoils sampling follow up activity; the topsoils are considered as the best media in order to examine closely the sources and the distribution patterns of harmful elements at a local scale. The topsoils sampling was mainly focused on anthropized areas (at urban and metropolitan scale), industrial settlments, brownfields and intensely cultivated zones, aimed at: • showing the distribution of concentration values and to determine baseline values (or backgrounds, depending on local conditions) of each analyzed element (38) in the top soils; • assessing harmful elements pollution levels and their geographic distribution; • providing reliable analytical data for assessment of toxic element pollution threat to ecosystem and human health; • creating a sound basis for policy makers and legislators who need to address the public concerns regarding environmental pollution. Five atlases (De Vivo et al., 2006b; Albanese et al., 2007b; Lima et al., 2007; Fedele et al., 2007 Cicchella et al., 2009) were produced reporting soil geochemical maps compiled using 1620 samples collected both in the metropolitan and provincial area of Napoli and in the cities of Avellino, Benevento, Caserta and Salerno. Further studies were also carried out taking into account Pb isotopes (Cicchella et al., 2008a), PGE's (Cicchella et al., 2003; 2008b) and bioavailability of harmful elements (Albanese, 2008) distributions to better discriminate the influence of human activities on urban environment. A detailed analysis of harmful elements distribution and some organic compounds (PCB and PAH's) was also completed for the Bagnoli brownfield area, in the western sector of the city of Napoli (Tarzia et al., 2002; De Vivo and Lima, 2008; Albanese et al, in press). Since Bagnoli is located inside an active volcanic field (Campi Flegrei) characterized by a strong geothermal activity that generates hydrothermal fluids, the definition of the anthropic impact on environment for this area was complicated by the presence of two main contamination sources, one natural (originating from the hydrothermal activity) and one anthropogenic (from the industrial activity). At present, a geochemical prospecting based on soil and water sampling is also being completed on two contiguous areas mainly devoted to agriculture in correspondence of the north-western coastal sector of Campania Region territory (Domitio-Flegreo Littoral e Agro Aversano). The latter studies aim at defining the impact of agricultural activities (including the use of fertilizers) on soil and deep waters. All the geochemical data obtained for the whole territory of Campania have been also spatially compared with cancer mortality data distribution (Montella et al., 1996) to individuate, at least, some spatial correspondences between high concentration levels of harmful elements and mortality incidence (Albanese et al., 2008). An interesting overlapping has been found for the Napoli metropolitan area for some elements and cancer types: Zn-Cd-rich areas overlap with areas of high prostate-cancer mortality; bladder and pancreatic cancer are correlated with Pb-Sb-rich areas, whereas, bronchial-tracheal-lung cancer is correlated with As-, Cd- and Pb-rich areas. References ALBANESE, S., DE VIVO, B., LIMA, A. & CICCHELLA, D. 2007a. J. Geoch. Expl., 93, 21-34. ALBANESE, S., LIMA, A., DE VIVO, B. & CICCHELLA, D. 2007b. Geochemical Environmental Atlas of the Soils of Avellino. Aracne Editrice, Roma. ALBANESE, S. 2008. Geochemistry: Expl., Env., Anal., 8, 49-57. ALBANESE S., DE LUCA M. L., DE VIVO B., LIMA A. and GREZZI G., 2008. In: Environmental Geochemistry: Site characterization, Data analysis and Case histories (De Vivo B., Belkin H. E. and Lima A., Eds). Elsevier, Amsterdam, 391-404. ALBANESE, S., CIVITILLO, D., COSENZA, A., DE VIVO, B., & LIMA., A., J. Geoch. Explor.. In press. CICCHELLA, D., DE VIVO, B. & LIMA, A. 2003. Science of the Total Environment, 308 (1-3), 121-131. CICCHELLA, D., DE VIVO, B. & LIMA, A. 2005. Geochemistry: Expl., Env., Anal., 5, 29-40. CICCHELLA, D., DE VIVO, B., LIMA, A., ALBANESE, S., MCGILL, R.A.R. & PARRISH, R.R. 2008a. Geochemistry: Expl.,. Env., Ana.s, 8, 103-112. CICCHELLA, D., FEDELE, L., DE VIVO, B., ALBANESE, S. & LIMA, A. 2008b. Geochemistry: Expl., Env., Anal., 8, 31-40. CICCHELLA, D., ALBANESE, S., DE VIVO, B., LIMA, A., GREZZI, G. & ZUPPETTA, A. 2009. Geochemical Environmental Atlas of the soils of Benevento. Aracne Editrice, Roma. DE VIVO B. and LIMA A., 2008. In: Environmental Geochemistry: Site characterization, Data analysis and Case histories (De Vivo B., Belkin H. E. and Lima A., Eds). Elsevier, Amsterdam, 355-385. DE VIVO, B., LIMA, A., ALBANESE, S. & CICCHELLA, D. 2003. Geochemical Environmental Atlas of Campania Region. De Frede Editore, Napoli. DE VIVO, B., LIMA, A., ALBANESE, S. & CICCHELLA, D. 2006a. Geochemical Environmental Atlas of Campania Region. Aracne Editrice, Roma. DE VIVO, B., CICCHELLA, D., LIMA, A. & ALBANESE, S. 2006b. Geochemical Environmental Atlas of the Urban and Provincial Soils of Napoli. Aracne Editrice, Roma. FEDELE, L., DE VIVO, B., LIMA, A., CICCHELLA, D. & ALBANESE, S. 2007. Geochemical Environmental Atlas of the Soils of Salerno. Aracne Editrice, Roma. LIMA, A., DE VIVO, B., GREZZI, G., ALBANESE, S. & CICCHELLA, D. 2007. Geochemical Environmental Atlas of the Soils of Caserta. Aracne Editrice, Roma. MONTELLA, M., BIDOLI, E., DE MARCO, M. R., REDIVO, A., AND FRANCESCI, S. 1996. Atlante della mortalita` per tumori nella Regione campania, 1998-92. Lega Italiana per la Lotta contro i Tumori, Istituto Nazionale Tumori, Napoli. TARZIA, M., DE VIVO, B., SOMMA, R., AYUSO, R.A., MCGILL, R.A.R. & PARRISH, R.R. 2002. Anthropogenic versus natural pollution: an environmental study of an industrial site under remediation (Naples, Italy). Geochemistry: Expl., Env., Anal., 2, 45-56.

Children's Drawings of Physical Activity: Implications for Needs Assessment and Programming

ERIC Educational Resources Information Center

Sharpe, Patricia A.; Greaney, Mary L.; Royce, Sherer W.; Fields, Regina M.

2004-01-01

This article shows how to explore children's perceptions of physical activity through content analysis of their artwork. Ninety-one children drew pictures of what they perceived to be "physical activity" and created a slogan for promoting physical activity in their community. Drawing content revealed types of popular activities,…

Structure of Work as Purposeful Activity

ERIC Educational Resources Information Center

Quey, Richard L.

1971-01-01

Work is purposeful activity linking the present to the future through manipulation of objects, symbols, and experience and possessing broad implications for education, vocational guidance and human work satisfaction. (Author)

RTG resource book for western states and provinces: Final proceedings

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

NONE

The Western Interstate Energy Board held a workshop and liaison activities among western states, provinces, and utilities on the formation of Regional Transmission Groups (RTGs). Purpose of the activities was to examine the policy implications for western states and provinces in the formation of RTGs in the West, the implications for western ratepayers and utilities of the RTG formation and potential impacts of RTGs on the western electricity system. The workshop contributed to fulfilling the transmission access and competition objectives of Title VII of the Energy Policy Act of 1992.

Second Conference on Early Mars: Geologic Hydrologic, and Climatic Evolution and the Implications for Life

NASA Technical Reports Server (NTRS)

2004-01-01

Some of the topics addressed by the conference paper abstracts included in this document include: martian terrain, terrestrial biological activity and mineral deposits with implications for life on Mars, the martian crust and mantle, weathering and erosion on Mars, evidence for ancient martian environmental and climatic conditions, with implications for the existence of surface and ground water on Mars and the possibility for life, martian valleys, and evidence for water and lava flow on the surface of Mars.

Mode of Action of Lactoperoxidase as Related to Its Antimicrobial Activity: A Review

PubMed Central

Bafort, F.; Parisi, O.; Perraudin, J.-P.; Jijakli, M. H.

2014-01-01

Lactoperoxidase is a member of the family of the mammalian heme peroxidases which have a broad spectrum of activity. Their best known effect is their antimicrobial activity that arouses much interest in in vivo and in vitro applications. In this context, the proper use of lactoperoxidase needs a good understanding of its mode of action, of the factors that favor or limit its activity, and of the features and properties of the active molecules. The first part of this review describes briefly the classification of mammalian peroxidases and their role in the human immune system and in host cell damage. The second part summarizes present knowledge on the mode of action of lactoperoxidase, with special focus on the characteristics to be taken into account for in vitro or in vivo antimicrobial use. The last part looks upon the characteristics of the active molecule produced by lactoperoxidase in the presence of thiocyanate and/or iodide with implication(s) on its antimicrobial activity. PMID:25309750

Integrating research, clinical care, and education in academic health science centers.

PubMed

King, Gillian; Thomson, Nicole; Rothstein, Mitchell; Kingsnorth, Shauna; Parker, Kathryn

2016-10-10

Purpose One of the major issues faced by academic health science centers (AHSCs) is the need for mechanisms to foster the integration of research, clinical, and educational activities to achieve the vision of evidence-informed decision making (EIDM) and optimal client care. The paper aims to discuss this issue. Design/methodology/approach This paper synthesizes literature on organizational learning and collaboration, evidence-informed organizational decision making, and learning-based organizations to derive insights concerning the nature of effective workplace learning in AHSCs. Findings An evidence-informed model of collaborative workplace learning is proposed to aid the alignment of research, clinical, and educational functions in AHSCs. The model articulates relationships among AHSC academic functions and sub-functions, cross-functional activities, and collaborative learning processes, emphasizing the importance of cross-functional activities in enhancing collaborative learning processes and optimizing EIDM and client care. Cross-functional activities involving clinicians, researchers, and educators are hypothesized to be a primary vehicle for integration, supported by a learning-oriented workplace culture. These activities are distinct from interprofessional teams, which are clinical in nature. Four collaborative learning processes are specified that are enhanced in cross-functional activities or teamwork: co-constructing meaning, co-learning, co-producing knowledge, and co-using knowledge. Practical implications The model provides an aspirational vision and insight into the importance of cross-functional activities in enhancing workplace learning. The paper discusses the conceptual and empirical basis to the model, its contributions and limitations, and implications for AHSCs. Originality/value The model's potential utility for health care is discussed, with implications for organizational culture and the promotion of cross-functional activities.

Dynamic changes in brain activity during prism adaptation.

PubMed

Luauté, Jacques; Schwartz, Sophie; Rossetti, Yves; Spiridon, Mona; Rode, Gilles; Boisson, Dominique; Vuilleumier, Patrik

2009-01-07

Prism adaptation does not only induce short-term sensorimotor plasticity, but also longer-term reorganization in the neural representation of space. We used event-related fMRI to study dynamic changes in brain activity during both early and prolonged exposure to visual prisms. Participants performed a pointing task before, during, and after prism exposure. Measures of trial-by-trial pointing errors and corrections allowed parametric analyses of brain activity as a function of performance. We show that during the earliest phase of prism exposure, anterior intraparietal sulcus was primarily implicated in error detection, whereas parieto-occipital sulcus was implicated in error correction. Cerebellum activity showed progressive increases during prism exposure, in accordance with a key role for spatial realignment. This time course further suggests that the cerebellum might promote neural changes in superior temporal cortex, which was selectively activated during the later phase of prism exposure and could mediate the effects of prism adaptation on cognitive spatial representations.

Pre-operative biliary drainage for obstructive jaundice

PubMed Central

Fang, Yuan; Gurusamy, Kurinchi Selvan; Wang, Qin; Davidson, Brian R; Lin, He; Xie, Xiaodong; Wang, Chaohua

2014-01-01

Background Patients with obstructive jaundice have various pathophysiological changes that affect the liver, kidney, heart, and the immune system. There is considerable controversy as to whether temporary relief of biliary obstruction prior to major definitive surgery (pre-operative biliary drainage) is of any benefit to the patient. Objectives To assess the benefits and harms of pre-operative biliary drainage versus no pre-operative biliary drainage (direct surgery) in patients with obstructive jaundice (irrespective of a benign or malignant cause). Search methods We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Clinical Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until February 2012. Selection criteria We included all randomised clinical trials comparing biliary drainage followed by surgery versus direct surgery, performed for obstructive jaundice, irrespective of the sample size, language, and publication status. Data collection and analysis Two authors independently assessed trials for inclusion and extracted data. We calculated the risk ratio (RR), rate ratio (RaR), or mean difference (MD) with 95% confidence intervals (CI) based on the available patient analyses. We assessed the risk of bias (systematic overestimation of benefit or systematic underestimation of harm) with components of the Cochrane risk of bias tool. We assessed the risk of play of chance (random errors) with trial sequential analysis. Main results We included six trials with 520 patients comparing pre-operative biliary drainage (265 patients) versus no pre-operative biliary drainage (255 patients). Four trials used percutaneous transhepatic biliary drainage and two trials used endoscopic sphincterotomy and stenting as the method of pre-operative biliary drainage. The risk of bias was high in all trials. The proportion of patients with malignant obstruction varied between 60% and 100%. There was no significant difference in mortality (40/265, weighted proportion 14.9%) in the pre-operative biliary drainage group versus the direct surgery group (34/255, 13.3%) (RR 1.12; 95% CI 0.73 to 1.71; P = 0.60). The overall serious morbidity was higher in the pre-operative biliary drainage group (60 per 100 patients in the pre-operative biliary drainage group versus 26 per 100 patients in the direct surgery group) (RaR 1.66; 95% CI 1.28 to 2.16; P = 0.0002). The proportion of patients who developed serious morbidity was significantly higher in the pre-operative biliary drainage group (75/102, 73.5%) in the pre-operative biliary drainage group versus the direct surgery group (37/94, 37.4%) (P < 0.001). Quality of life was not reported in any of the trials. There was no significant difference in the length of hospital stay (2 trials, 271 patients; MD 4.87 days; 95% CI −1.28 to 11.02; P = 0.12) between the two groups. Trial sequential analysis showed that for mortality only a small proportion of the required information size had been obtained. There seemed to be no significant differences in the subgroup of trials assessing percutaneous compared to endoscopic drainage. Authors’ conclusions There is currently not sufficient evidence to support or refute routine pre-operative biliary drainage for patients with obstructive jaundice. Pre-operative biliary drainage may increase the rate of serious adverse events. So, the safety of routine pre-operative biliary drainage has not been established. Pre-operative biliary drainage should not be used in patients undergoing surgery for obstructive jaundice outside randomised clinical trials. PMID:22972086

Core Strength: Implications for Fitness and Low Back Pain.

ERIC Educational Resources Information Center

Liemohn, Wendell; Pariser, Gina

2002-01-01

Presents information to promote understanding of the concept of core strength and stability, explain why this concept is important to spine health, and evaluate trunk training activities with respect to their contribution to core strength and stability, noting implications for physical fitness and low back pain. The paper reviews the anatomy and…

Child Abuse and Neglect in Cambodian Refugee Families: Characteristics and Implications for Practice

ERIC Educational Resources Information Center

Chang, Janet; Rhee, Siyon; Berthold, S. Megan

2008-01-01

This study examines the characteristics and patterns of child maltreatment among Cambodian refugee families in Los Angeles and assesses the implications for child welfare practice with Cambodian refugee families. Data were extracted from 243 active Cambodian case files maintained by the Los Angeles County Department of Children and Family Services…

The Implications of A. H. Maslow's "Hierarchy of Needs" Theory for Adult Education.

ERIC Educational Resources Information Center

Warren, Earle Theodore

The Maslow Hierarchy of Needs was reviewed and implications were sought for adult education theory, program planning and operation, promotional activities, and program evaluation. Maslow's work suggested self-actualization as an ultimate goal, meaning that adult education programs should be structured to foster both the acquisition of facts,…

Implications of the International Classification of Functioning, Disability and Health (ICF) for Test Development and Use

ERIC Educational Resources Information Center

Carlson, Janet F.; Benson, Nicholas; Oakland, Thomas

2010-01-01

Implications of the International Classification of Functioning, Disability and Health (ICF) on the development and use of tests in school settings are enumerated. We predict increased demand for behavioural assessments that consider a person's activities, participation and person-environment interactions, including measures that: (a) address…

Some Interrelationships between Constructivist Models of Learning and Current Neurobiological Theory, with Implications for Science Education.

ERIC Educational Resources Information Center

Anderson, O. Roger

1992-01-01

This paper examines how some fundamental mechanisms of nervous system activity can explain human information processing and the acquisition of knowledge and provides additional theoretical support for constructivist applications to science education reform. The implications for scientific epistemology and conceptual change processes in science…

Implications of Mixed Reality and Simulation Technologies on Special Education and Teacher Preparation

ERIC Educational Resources Information Center

Dieker, Lisa; Hynes, Michael; Hughes, Charles; Smith, Eileen

2008-01-01

As technology evolves, so does its impact on people's lives. These changes clearly affect people's daily activities, but how might they also impact education, teachers, and the lives of students with disabilities? This article focuses on technological innovations and their potential implications for students and teachers in schools. This article…

Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor.

PubMed

Laudet, V

1997-12-01

From a database containing the published nuclear hormone receptor (NR) sequences I constructed an alignment of the C, D and E domains of these molecules. Using this alignment, I have performed tree reconstruction using both distance matrix and parsimony analysis. The robustness of each branch was estimated using bootstrap resampling methods. The trees constructed by these two methods gave congruent topologies. From these analyses I defined six NR subfamilies: (i) a large one clustering thyroid hormone receptors (TRs), retinoic acid receptors (RARs), peroxisome proliferator-activated receptors (PPARs), vitamin D receptors (VDRs) and ecdysone receptors (EcRs) as well as numerous orphan receptors such as RORs or Rev-erbs; (ii) one containing retinoid X receptors (RXRs) together with COUP, HNF4, tailless, TR2 and TR4 orphan receptors; (iii) one containing steroid receptors; (iv) one containing the NGFIB orphan receptors; (v) one containing FTZ-F1 orphan receptors; and finally (vi) one containing to date only one gene, the GCNF1 orphan receptor. The relationships between the six subfamilies are not known except for subfamilies I and IV which appear to be related. Interestingly, most of the liganded receptors appear to be derived when compared with orphan receptors. This suggests that the ligand-binding ability of NRs has been gained by orphan receptors during the course of evolution to give rise to the presently known receptors. The distribution into six subfamilies correlates with the known abilities of the various NRs to bind to DNA as homo- or heterodimers. For example, receptors heterodimerizing efficiently with RXR belong to the first or the fourth subfamilies. I suggest that the ability to heterodimerize evolved once, just before the separation of subfamilies I and IV and that the first NR was able to bind to DNA as a homodimer. From the study of NR sequences existing in vertebrates, arthropods and nematodes, I define two major steps of NR diversification: one that took place very early, probably during the multicellularization event leading to all the metazoan phyla, and a second occurring later on, corresponding to the advent of vertebrates. Finally, I show that in vertebrate species the various groups of NRs accumulated mutations at very different rates.

Retinoic acid-independent expression of Meis2 during autopod patterning in the developing bat and mouse limb.

PubMed

Mason, Mandy K; Hockman, Dorit; Curry, Lyle; Cunningham, Thomas J; Duester, Gregg; Logan, Malcolm; Jacobs, David S; Illing, Nicola

2015-01-01

The bat has strikingly divergent forelimbs (long digits supporting wing membranes) and hindlimbs (short, typically free digits) due to the distinct requirements of both aerial and terrestrial locomotion. During embryonic development, the morphology of the bat forelimb deviates dramatically from the mouse and chick, offering an alternative paradigm for identifying genes that play an important role in limb patterning. Using transcriptome analysis of developing Natal long-fingered bat (Miniopterus natalensis) fore- and hindlimbs, we demonstrate that the transcription factor Meis2 has a significantly higher expression in bat forelimb autopods compared to hindlimbs. Validation by reverse transcriptase and quantitative polymerase chain reaction (RT-qPCR) and whole mount in situ hybridisation shows that Meis2, conventionally known as a marker of the early proximal limb bud, is upregulated in the bat forelimb autopod from CS16. Meis2 expression is localised to the expanding interdigital webbing and the membranes linking the wing to the hindlimb and tail. In mice, Meis2 is also expressed in the interdigital region prior to tissue regression. This interdigital Meis2 expression is not activated by retinoic acid (RA) signalling as it is present in the retained interdigital tissue of Rdh10 (trex/trex) mice, which lack RA. Additionally, genes encoding RA-synthesising enzymes, Rdh10 and Aldh1a2, and the RA nuclear receptor Rarβ are robustly expressed in bat fore- and hindlimb interdigital tissues indicating that the mechanism that retains interdigital tissue in bats also occurs independently of RA signalling. Mammalian interdigital Meis2 expression, and upregulation in the interdigital webbing of bat wings, suggests an important role for Meis2 in autopod development. Interdigital Meis2 expression is RA-independent, and retention of interdigital webbing in bat wings is not due to the suppression of RA-induced cell death. Rather, RA signalling may play a role in the thinning (rather than complete loss) of the interdigital tissue in the bat forelimb, while Meis2 may interact with other factors during both bat and mouse autopod development to maintain a pool of interdigital cells that contribute to digit patterning and growth.

Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses.

PubMed

De Grove, Katrien C; Provoost, Sharen; Hendriks, Rudi W; McKenzie, Andrew N J; Seys, Leen J M; Kumar, Smitha; Maes, Tania; Brusselle, Guy G; Joos, Guy F

2017-01-01

Although the prominent role of T H 2 cells in type 2 immune responses is well established, the newly identified type 2 innate lymphoid cells (ILC2s) can also contribute to orchestration of allergic responses. Several experimental and epidemiologic studies have provided evidence that allergen-induced airway responses can be further enhanced on exposure to environmental pollutants, such as diesel exhaust particles (DEPs). However, the components and pathways responsible remain incompletely known. We sought to investigate the relative contribution of ILC2 and adaptive T H 2 cell responses in a murine model of DEP-enhanced allergic airway inflammation. Wild-type, Gata-3 +/nlslacZ (Gata-3-haploinsufficient), RAR-related orphan receptor α (RORα) fl/fl IL7R Cre (ILC2-deficient), and recombination-activating gene (Rag) 2 -/- mice were challenged with saline, DEPs, or house dust mite (HDM) or DEP+HDM. Airway hyperresponsiveness, as well as inflammation, and intracellular cytokine expression in ILC2s and T H 2 cells in the bronchoalveolar lavage fluid and lung tissue were assessed. Concomitant DEP+HDM exposure significantly enhanced allergic airway inflammation, as characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of ILC2s and T H 2 cells, type 2 cytokine production, and airway hyperresponsiveness compared with sole DEPs or HDM. Reduced Gata-3 expression decreased the number of functional ILC2s and T H 2 cells in DEP+HDM-exposed mice, resulting in an impaired DEP-enhanced allergic airway inflammation. Interestingly, although the DEP-enhanced allergic inflammation was marginally reduced in ILC2-deficient mice that received combined DEP+HDM, it was abolished in DEP+HDM-exposed Rag2 -/- mice. These data indicate that dysregulation of ILC2s and T H 2 cells attenuates DEP-enhanced allergic airway inflammation. In addition, a crucial role for the adaptive immune system was shown on concomitant DEP+HDM exposure. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Corexit-EC9527A Disrupts Retinol Signaling and Neuronal Differentiation in P19 Embryonal Pluripotent Cells

DOE PAGES

Chen, Yanling; Reese, David H.; Kelly, Gregory M.

2016-09-29

Corexit-EC9500A and Corexit-EC9527A are two chemical dispersants that have been used to remediate the impact of the 2010 Deepwater Horizon oil spill. Both dispersants are composed primarily of organic solvents and surfactants and act by emulsifying the crude oil to facilitate biodegradation. The potential adverse effect of the Corexit chemicals on mammalian embryonic development remains largely unknown. Retinol (vitamin A) signaling, mediated by all-trans retinoic acid (RA), is essential for neural tube formation and the development of many organs in the embryo. The physiological levels of RA in cells and tissues are maintained by the retinol signaling pathway (RSP), whichmore » controls the biosynthesis of RA from dietary retinol and the catabolism of RA to polar metabolites for removal. RA is a potent activating ligand for the RAR/RXR nuclear receptors. Through RA and the receptors, the RSP modulates the expression of many developmental genes; interference with the RSP is potentially teratogenic. In this study the mouse P19 embryonal pluripotent cell, which contains a functional RSP, was used to evaluate the effects of the Corexit dispersants on retinol signaling and associated neuronal differentiation. The results showed that Corexit-EC9500A was more cytotoxic than Corexit-EC9527A to P19 cells. At non-cytotoxic doses, Corexit-EC9527A inhibited retinol-induced expression of the Hoxa1 gene, which encodes a transcription factor for the regulation of body patterning in the embryo. Such inhibition was seen in the retinol- and retinal- induced, but not RA-induced, Hoxa1 up-regulation, indicating that the Corexit chemicals primarily inhibit RA biosynthesis from retinal. In addition, Corexit-EC9527A suppressed retinol-induced P19 cell differentiation into neuronal cells, indicating potential neurotoxic effect of the chemicals under the tested conditions. In conclusion, the surfactant ingredient, dioctyl sodium sulfosuccinate (DOSS), may be a major contributor to the observed effect of Corexit-EC9527A in the cell.« less

Effects of probiotic administration on zebrafish development and reproduction.

PubMed

Carnevali, O; Avella, M A; Gioacchini, G

2013-07-01

As the consumption of probiotics increases worldwide, scientists focus on identifying bacterial strains able to improve human life quality and evidence the biological pathways affected by probiotic treatment. In this review, some recent observations on the effects of changes of microbiota on zebrafish metabolism were discussed. In addition, the effects of Lactobacillus rhamnosus - a component of the human gut microflora - as a diet supplement on Danio rerio were presented. When administered chronically, L. rhamnosus may affect larval development and the physiology of reproductive system in the zebrafish model. It was hypothesized exogenous L. rhamnosus accelerates larval growth and backbone development by acting on insulin-like growth factors-I (igfI) and -II (igfII), peroxisome proliferator activated receptors-α and -β, (pparα,β) vitamin D receptor-α (vdrα) and retinoic acid receptor-γ (rarγ). Gonadal differentiation was anticipated at 6weeks together with a higher expression of gnrh3 at the larval stage when L. rhamnosus was administered throughout development. Moreover, brood stock alimented with a L. rhamnosus-supplemented diet showed better reproductive performances as per follicles development, ovulated oocytes quantification and embryos quality. A plausible involvement of factors such as leptin, and kiss1 and 2 in the improvements was concluded. The observations made on the physiology of female reproduction were correlated with the gene expression of a gigantic number of factors as the aromatase cytochrome p 19 (cyp19a), the vitellogenin (vtg) and the α isoform of the E2 receptor (erα), luteinizing hormone receptor (lhr), 20-β hydroxysteroid dehydrogenase (20β-hsd), membrane progesterone receptors α and β, cyclin B, activinβA1, smad2, transforming growth factor β1 (tgfβ1), growth differentiation factor9 (gdf9) and bone morphogenetic protein15 (bmp15.) A model in which the exogenous L. rhamnosus in the digestive tract of zebrafish from the first days of life through sexual maturation positively influences the physiological performances of zebrafish was evidenced and a number of pathways that might be influenced by the presence of this human probiotic strain were proposed. Copyright © 2013 Elsevier Inc. All rights reserved.

Corexit-EC9527A Disrupts Retinol Signaling and Neuronal Differentiation in P19 Embryonal Pluripotent Cells

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

Chen, Yanling; Reese, David H.; Kelly, Gregory M.

Corexit-EC9500A and Corexit-EC9527A are two chemical dispersants that have been used to remediate the impact of the 2010 Deepwater Horizon oil spill. Both dispersants are composed primarily of organic solvents and surfactants and act by emulsifying the crude oil to facilitate biodegradation. The potential adverse effect of the Corexit chemicals on mammalian embryonic development remains largely unknown. Retinol (vitamin A) signaling, mediated by all-trans retinoic acid (RA), is essential for neural tube formation and the development of many organs in the embryo. The physiological levels of RA in cells and tissues are maintained by the retinol signaling pathway (RSP), whichmore » controls the biosynthesis of RA from dietary retinol and the catabolism of RA to polar metabolites for removal. RA is a potent activating ligand for the RAR/RXR nuclear receptors. Through RA and the receptors, the RSP modulates the expression of many developmental genes; interference with the RSP is potentially teratogenic. In this study the mouse P19 embryonal pluripotent cell, which contains a functional RSP, was used to evaluate the effects of the Corexit dispersants on retinol signaling and associated neuronal differentiation. The results showed that Corexit-EC9500A was more cytotoxic than Corexit-EC9527A to P19 cells. At non-cytotoxic doses, Corexit-EC9527A inhibited retinol-induced expression of the Hoxa1 gene, which encodes a transcription factor for the regulation of body patterning in the embryo. Such inhibition was seen in the retinol- and retinal- induced, but not RA-induced, Hoxa1 up-regulation, indicating that the Corexit chemicals primarily inhibit RA biosynthesis from retinal. In addition, Corexit-EC9527A suppressed retinol-induced P19 cell differentiation into neuronal cells, indicating potential neurotoxic effect of the chemicals under the tested conditions. In conclusion, the surfactant ingredient, dioctyl sodium sulfosuccinate (DOSS), may be a major contributor to the observed effect of Corexit-EC9527A in the cell.« less

Sitting Behavior and Physical Activity of College Students: Implications for Health Education and Promotion

ERIC Educational Resources Information Center

D'Abundo, Michelle Lee; Sidman, Cara L.; Fiala, Kelly A.

2015-01-01

The purpose of this study was to provide a baseline assessment of sitting behaviors and physical activity among college students in a physical activity and wellness course. The International Physical Activity Questionnaire (IPAQ) was used to measure the physical activity and sitting behaviors of college students. Independent t-tests and ANOVAs…

Drug Testing of Students in Extracurricular Activities: An Update.

ERIC Educational Resources Information Center

Mawdsley, Ralph D.; Russo, Charles J.

2001-01-01

Reviews recent federal appellate court cases dealing with legal issues involving random drug testing of students participating in extracurricular activities. Draws implications for school business officials and other educators. (PKP)

Practical Management of Patients with a History of Immediate Hypersensitivity to Common non-Beta-Lactam Drugs.

PubMed

Macy, Eric

2016-01-01

Immediate hypersensitivity reactions to medications are among the most feared adverse drug reactions, because of their close association with anaphylaxis. This review discusses a practical management approach for patients with a history of an immediate hypersensitivity to a non-beta-lactam medication, where reexposure to the implicated, or similar, medication is clinically necessary. Mechanisms associated with severe immediate hypersensitivity reactions include IgE-mediated mast cell activation, complement-mediated mast cell activation, and direct mast cell activation. Immediate hypersensitivity reactions may also be mediated by vasodilators, other pharmacologic mechanisms, or be secondary to underlying patient-specific biochemical abnormalities such as endocrine tumors or chronic spontaneous urticaria. The key features in the reaction history and the biochemistry of the implicated medication are discussed. Most individuals with a history of immediate hypersensitivity to a medication, who require reuse of that drug, can be safely retreated with a therapeutic course of the implicated drug after a full-dose challenge, graded challenge, or desensitization, with or without premedication and/or any preliminary diagnostic testing, depending on the specific situation.

Reductions in Northeast Refining Activity: Potential Implications for Petroleum Product Markets

EIA Publications

2011-01-01

This report is the Energy Information Administration's (EIA) initial effort to provide information and analysis on the potential impacts on petroleum product markets from reductions in Northeast petroleum refining activity.

Norwegian Aerospace Activities: an Overview

NASA Technical Reports Server (NTRS)

Arnesen, T. (Editor); Rosenberg, G. (Editor)

1986-01-01

Excerpts from a Governmental Investigation concerning Norwegian participation in the European Space Organization (ESA) is presented. The implications and advantages of such a move and a suggestion for the reorganization of Norwegian Aerospace activity is given.

Simulation-Based Mission Rehearsal as a Human Activity System.

DTIC Science & Technology

1996-09-01

explain this demonstrated importance of the people involved in MR, a human activity system model of simulation-based rehearsal was developed. It provides...Implications of this human activity system view are discussed, including: places in the mission preparation process where simulation can benefit operations

Increased Spreading Activation in Depression

ERIC Educational Resources Information Center

Foster, Paul S.; Yung, Raegan C.; Branch, Kaylei K.; Stringer, Kristi; Ferguson, Brad J.; Sullivan, William; Drago, Valeria

2011-01-01

The dopaminergic system is implicated in depressive disorders and research has also shown that dopamine constricts lexical/semantic networks by reducing spreading activation. Hence, depression, which is linked to reductions of dopamine, may be associated with increased spreading activation. However, research has generally found no effects of…

Interventions to Promote Young People's Physical Activity: Issues, Implications and Recommendations for Practice

ERIC Educational Resources Information Center

Cale, Lorraine; Harris, Jo

2006-01-01

There has been increased interest in the development and implementation of physical activity interventions designed to increase young people's physical activity participation in recent years. This is perhaps founded on concerns over youngsters' physical activity levels and the possible health consequences. School-based interventions are the most…

Increasing Physical Activity during the School Day through Physical Activity Classes: Implications for Physical Educators

ERIC Educational Resources Information Center

Adkins, Megan; Bice, Matt; Bartee, Todd; Heelan, Kate

2015-01-01

Across the nation schools are adopting health and wellness policies, specifically physical activity (PA) initiatives that aid healthy long-term lifestyles. Interest has been generated about the inclusion of physical activity classes to complement existing physical education classes. Furthermore, discussion has evolved as to if additional…

Structured Extracurricular Activities among Adolescents: Findings and Implications for School Psychologists

ERIC Educational Resources Information Center

Gilman, Rich; Meyers, Joel; Perez, Laura

2004-01-01

One factor that contributes to adolescent positive mental health is active engagement. Engagement is defined as any activity that is initiated to attain an outcome. In general, two forms of activities exist that correspond with engagement: solitary, non-structured, and non-cooperative pursuits, often without adult supervision (e.g., playing video…

The Effect of Physical Activity on Science Competence and Attitude towards Science Content

ERIC Educational Resources Information Center

Klinkenborg, Ann Maria

2011-01-01

This study examines the effect of physical activity on science instruction. To combat the implications of physical inactivity, schools need to be willing to consider all possible opportunities for students to engage in moderate-to-vigorous physical activity (MVPA). Integrating physical activity with traditional classroom content is one…

Relation of obesity to neural activation in response to food commercials

PubMed Central

Yokum, Sonja; Stice, Eric; Harris, Jennifer L.; Brownell, Kelly D.

2014-01-01

Adolescents view thousands of food commercials annually, but the neural response to food advertising and its association with obesity is largely unknown. This study is the first to examine how neural response to food commercials differs from other stimuli (e.g. non-food commercials and television show) and to explore how this response may differ by weight status. The blood oxygen level-dependent functional magnetic resonance imaging activation was measured in 30 adolescents ranging from lean to obese in response to food and non-food commercials imbedded in a television show. Adolescents exhibited greater activation in regions implicated in visual processing (e.g. occipital gyrus), attention (e.g. parietal lobes), cognition (e.g. temporal gyrus and posterior cerebellar lobe), movement (e.g. anterior cerebellar cortex), somatosensory response (e.g. postcentral gyrus) and reward [e.g. orbitofrontal cortex and anterior cingulate cortex (ACC)] during food commercials. Obese participants exhibited less activation during food relative to non-food commercials in neural regions implicated in visual processing (e.g. cuneus), attention (e.g. posterior cerebellar lobe), reward (e.g. ventromedial prefrontal cortex and ACC) and salience detection (e.g. precuneus). Obese participants did exhibit greater activation in a region implicated in semantic control (e.g. medial temporal gyrus). These findings may inform current policy debates regarding the impact of food advertising to minors. PMID:23576811

Reactive oxygen species-activated nanomaterials as theranostic agents.

PubMed

Kim, Kye S; Lee, Dongwon; Song, Chul Gyu; Kang, Peter M

2015-01-01

Reactive oxygen species (ROS) are generated from the endogenous oxidative metabolism or from exogenous pro-oxidant exposure. Oxidative stress occurs when there is excessive production of ROS, outweighing the antioxidant defense mechanisms which may lead to disease states. Hydrogen peroxide (H2O2) is one of the most abundant and stable forms of ROS, implicated in inflammation, cellular dysfunction and apoptosis, which ultimately lead to tissue and organ damage. This review is an overview of the role of ROS in different diseases. We will also examine ROS-activated nanomaterials with emphasis on hydrogen peroxide, and their potential medical implications. Further development of the biocompatible, stimuli-activated agent responding to disease causing oxidative stress, may lead to a promising clinical use.

Lysine acetyltransferase inhibitors: structure-activity relationships and potential therapeutic implications.

PubMed

Fiorentino, Francesco; Mai, Antonello; Rotili, Dante

2018-05-01

Lysine acetylation is a post-translational modification of both histone and nonhistone proteins that is catalyzed by lysine acetyltransferases and plays a key role in numerous biological contexts. The dysregulation of this enzyme activity is implicated in many human pathologies such as cancer, neurological and inflammatory disorders. Many lysine acetyltransferase inhibitors (KATi) have been developed so far, but there is still the need for new, more potent, metabolically stable and selective KATi as chemical tools for studying KAT biology and/or as potential therapeutic agents. This review will examine the features of KAT enzymes and related diseases, with particular emphasis on KATi (bisubstrate analogs, natural compounds and synthetic derivatives), analyzing their mechanism of action, structure-activity relationships, pharmacokinetic/pharmacodynamic properties and potential future applications.

Academic stress and personality interact to increase the neural response to high-calorie food cues.

PubMed

Neseliler, Selin; Tannenbaum, Beth; Zacchia, Maria; Larcher, Kevin; Coulter, Kirsty; Lamarche, Marie; Marliss, Errol B; Pruessner, Jens; Dagher, Alain

2017-09-01

Psychosocial stress is associated with an increased intake of palatable foods and weight gain in stress-reactive individuals. Personality traits have been shown to predict stress-reactivity. However, it is not known if personality traits influence brain activity in regions implicated in appetite control during psychosocial stress. The current study assessed whether Gray's Behavioural Inhibition System (BIS) scale, a measure of stress-reactivity, was related to the activity of brain regions implicated in appetite control during a stressful period. Twenty-two undergraduate students participated in a functional magnetic resonance imaging (fMRI) experiment once during a non-exam period and once during final exams in a counter-balanced order. In the scanner, they viewed food and scenery pictures. In the exam compared with the non-exam condition, BIS scores related to increased perceived stress and correlated with increased blood-oxygen-level dependent (BOLD) response to high-calorie food images in regions implicated in food reward and subjective value, such as the ventromedial prefrontal cortex, (vmPFC) and the amygdala. BIS scores negatively related to the functional connectivity between the vmPFC and the dorsolateral prefrontal cortex. The results demonstrate that the BIS trait influences stress reactivity. This is observed both as an increased activity in brain regions implicated in computing the value of food cues and decreased connectivity of these regions to prefrontal regions implicated in self-control. This suggests that the effects of real life stress on appetitive brain function and self-control is modulated by a personality trait. This may help to explain why stressful periods can lead to overeating in vulnerable individuals. Copyright © 2017 Elsevier Ltd. All rights reserved.

Space Station Human Factors Research Review. Volume 1: EVA Research and Development

NASA Technical Reports Server (NTRS)

Cohen, Marc M. (Editor); Vykukal, H. C. (Editor)

1988-01-01

An overview is presented of extravehicular activity (EVA) research and development activities at Ames. The majority of the program was devoted to presentations by the three contractors working in parallel on the EVA System Phase A Study, focusing on Implications for Man-Systems Design. Overhead visuals are included for a mission results summary, space station EVA requirements and interface accommodations summary, human productivity study cross-task coordination, and advanced EVAS Phase A study implications for man-systems design. Articles are also included on subsea approach to work systems development and advanced EVA system design requirements.

A Role for Oxytocin-Like Receptor in Social Habituation in a Teleost.

PubMed

Weitekamp, Chelsea A; Solomon-Lane, Tessa K; Del Valle, Pamela; Triki, Zegni; Nugent, Bridget M; Hofmann, Hans A

2017-01-01

Oxytocin (OT) mediates social habituation in rodent model systems, but its role in mediating this effect in other vertebrates is unknown. We used males of the African cichlid fish, Astatotilapia burtoni, to investigate two aspects of isotocin (IT; an OT homolog) signaling in social habituation. First, we examined the expression of IT receptor 2 (ITR2) as well as two immediate early genes in brain regions implicated in social recognition. Next, we examined IT neuron activity using immunohistochemistry. Patterns of gene expression in homologs of the amygdala and hippocampus implicate IT signaling in these regions in social habituation to a territorial neighbor. In the preoptic area, the expression of the ITR2 subtype and IT neuron activity respond to the presence of a male, independent of familiarity. Our results implicate IT in mediating social habituation in a teleost. © 2017 S. Karger AG, Basel.

Europa: Prospects for an ocean and exobiological implications

NASA Technical Reports Server (NTRS)

Oro, John; Squyres, Steven W.; Reynolds, Ray T.; Mills, Thomas M.

1992-01-01

As far as we know, Earth is the only planet in our solar system that supports life. It is natural, therefore, that our understanding of life as a planetary phenomenon is based upon Earth-like planets. There are environments in the solar system where liquid water, commonly believed to be a prerequisite for biological activity, may exist in a distinctly non-Earth-like environment. One such location is Europa, one of the Galilean satellites of Jupiter. The possibility that liquid water exists on Europa presents us with some interesting exobiological implications concerning the potential of the satellite to support life. Topics include the following: an ocean on Europa; thermal evolution of Europa; Europa's three models; exobiological implications; early conditions of Europa; low-temperature abiotic chemistry; possibility of the emergence of life on Europa; prerequisites for the habitability of Europa; energy sources for biosynthesis and metabolic activity; habitability of Europa by anaerobic life; and habitability by aerobic life.

Commentary on "Reading Comprehension Is Not a Single Ability": Implications for Child Language Intervention

ERIC Educational Resources Information Center

Ukrainetz, Teresa A.

2017-01-01

Purpose: This commentary responds to the implications for child language intervention of Catts and Kamhi's (2017) call to move from viewing reading comprehension as a single ability to recognizing it as a complex constellation of reader, text, and activity. Method: Reading comprehension, as Catts and Kamhi explain, is very complicated. In this…

Thai Learners' Linguistic Needs and Language Skills: Implications for Curriculum Development

ERIC Educational Resources Information Center

Ulla, Mark B.; Winitkun, Duangkamon

2017-01-01

Learners' success in language learning always has implications for curriculum and instruction. Thus, it is important to take into account the kinds of learning experiences that these learners will find helpful in learning English as a foreign language; and, highlight them when planning a curriculum and adapting classroom activities. This study,…

Lake States natural resource managers' perspectives on forest land parcelization and its implications for public land management

Treesearch

Michael A. Kilgore; Stephanie A. Snyder

2016-01-01

Field-based public natural resource managers in the Lake States (MI, MN, WI) were surveyed for theirperspectives on various aspects of private forest land parcelization. This includes their perceptions ofrecent changes in parcelization activity, drivers and impacts, mitigation strategies, and ability to influenceparcelization. Their perspectives on the implications...

The Red Light in the Ivory Tower: Contexts and Implications of Entrepreneurial Education. Counterpoints: Studies in the Postmodern Theory of Education. Volume 401

ERIC Educational Resources Information Center

Breault, Donna Adair; Callejo Perez, David M.

2012-01-01

"The Red Light in the Ivory Tower: Contexts and Implications of Entrepreneurial Education" critically analyzes the operational behaviors of prestigious and prestige-seeking universities, particularly within the context of budget shortfalls and increasing competition. The book challenges entrepreneurial activities within universities by exploring…

Mind the Gap! Implications of a Person-Environment Fit Model of Intellectual Disability for Students, Educators, and Schools

ERIC Educational Resources Information Center

Thompson, James R.; Wehmeyer, Michael L.; Hughes, Carolyn

2010-01-01

A person-environment fit conceptualization of intellectual disability (ID) requires educators to focus on the gap between a student's competencies and the demands of activities and settings in schools. In this article the implications of the person-environment fit conceptual model are considered in regard to instructional benefits, special…

Information Privacy in the Marketspace: Implications for the Commercial Uses of Anonymity on the Web.

ERIC Educational Resources Information Center

Hoffman, Donna L.; Novak, Thomas P.; Peralta, Marcos A.

1999-01-01

Suggests that the primary barrier to successful commercial development of the Web is lack of consumer trust in the medium. Examines how customer concerns are affecting growth and development of consumeroriented commercial activity on the Web and investigates the implications of these concerns for potential industry response. Suggests that radical…

Effects of Natural Organic Matter on PCB-Activated Carbon Sorption Kinetics: Implications for Sediment Capping Applications

EPA Science Inventory

In-situ capping of polychlorinated biphenyl (PCB) contaminated sediments with layers of sorbents such as activated carbon has been proposed, but several technical questions remain regarding long-term effectiveness. An activated carbon amended sediment cap was mimicked in laborat...

21 CFR 866.5320 - Properdin factor B immuno-logical test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... involvement of the alternative to the classical pathway of activation of complement (a group of plasma... the skin). Other diseases in which the alternate pathway of complement activation has been implicated...

21 CFR 866.5320 - Properdin factor B immuno-logical test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... involvement of the alternative to the classical pathway of activation of complement (a group of plasma... the skin). Other diseases in which the alternate pathway of complement activation has been implicated...

21 CFR 866.5320 - Properdin factor B immuno-logical test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... involvement of the alternative to the classical pathway of activation of complement (a group of plasma... the skin). Other diseases in which the alternate pathway of complement activation has been implicated...

To Break or to Brake Neuronal Network Accelerated by Ammonium Ions?

PubMed Central

Dynnik, Vladimir V.; Kononov, Alexey V.; Sergeev, Alexander I.; Teplov, Iliya Y.; Tankanag, Arina V.; Zinchenko, Valery P.

2015-01-01

Purpose The aim of present study was to investigate the effects of ammonium ions on in vitro neuronal network activity and to search alternative methods of acute ammonia neurotoxicity prevention. Methods Rat hippocampal neuronal and astrocytes co-cultures in vitro, fluorescent microscopy and perforated patch clamp were used to monitor the changes in intracellular Ca2+- and membrane potential produced by ammonium ions and various modulators in the cells implicated in neural networks. Results Low concentrations of NH4Cl (0.1–4 mM) produce short temporal effects on network activity. Application of 5–8 mM NH4Cl: invariably transforms diverse network firing regimen to identical burst patterns, characterized by substantial neuronal membrane depolarization at plateau phase of potential and high-amplitude Ca2+-oscillations; raises frequency and average for period of oscillations Ca2+-level in all cells implicated in network; results in the appearance of group of «run out» cells with high intracellular Ca2+ and steadily diminished amplitudes of oscillations; increases astrocyte Ca2+-signalling, characterized by the appearance of groups of cells with increased intracellular Ca2+-level and/or chaotic Ca2+-oscillations. Accelerated network activity may be suppressed by the blockade of NMDA or AMPA/kainate-receptors or by overactivation of AMPA/kainite-receptors. Ammonia still activate neuronal firing in the presence of GABA(A) receptors antagonist bicuculline, indicating that «disinhibition phenomenon» is not implicated in the mechanisms of networks acceleration. Network activity may also be slowed down by glycine, agonists of metabotropic inhibitory receptors, betaine, L-carnitine, L-arginine, etc. Conclusions Obtained results demonstrate that ammonium ions accelerate neuronal networks firing, implicating ionotropic glutamate receptors, having preserved the activities of group of inhibitory ionotropic and metabotropic receptors. This may mean, that ammonia neurotoxicity might be prevented by the activation of various inhibitory receptors (i.e. by the reinforcement of negative feedback control), instead of application of various enzyme inhibitors and receptor antagonists (breaking of neural, metabolic and signaling systems). PMID:26217943

Gender and School-Level Differences in Students' Moderate and Vigorous Physical Activity Levels When Taught Basketball through the Tactical Games Model

ERIC Educational Resources Information Center

Harvey, Stephen; Smith, Megan L.; Song, Yang; Robertson, David; Brown, Renee; Smith, Lindsey R.

2016-01-01

The Tactical Games Model (TGM) prefaces the cognitive components of physical education (PE), which has implications for physical activity (PA) accumulation. PA recommendations suggest students reach 50% moderate-vigorous physical activity (MVPA). However, this criterion does not indicate the contribution from vigorous physical activity (VPA).…

THE BACTERICIDAL ACTIVITY OF NORMAL GUINEA PIG SERUM AGAINST LISTERIA MONOCYTOGENES AND ITS INHIBITION BY A LISTERIAL CELL EXTRACT,

DTIC Science & Technology

Normal guinea pig serum contains bactericidins active against Listeria monocytogenes. The listeriocidal activity of the serum did not increase after...factor. Lysozyme was not implicated in the bactericidal system. It was suggested that the bactericidal activity of guinea pig serum might be due either to

Karyotype Analysis Activity: A Constructivist Learning Design

ERIC Educational Resources Information Center

Ahmed, Noveera T.

2015-01-01

This classroom activity is based on a constructivist learning design and engages students in physically constructing a karyotype of three mock patients. Students then diagnose the chromosomal aneuploidy based on the karyotype, list the symptoms associated with the disorder, and discuss the implications of the diagnosis. This activity is targeted…

The Interplay of Scientific Activity, Worldviews and Value Outlooks

ERIC Educational Resources Information Center

Lacey, Hugh

2009-01-01

Scientific activity tends to reflect particular worldviews and their associated value outlooks; and scientific results sometimes have implications for worldviews and the presuppositions of value outlooks. Even so, scientific activity per se neither presupposes nor provides sound rational grounds to accept any worldview or value outlook. Moreover,…

Consumer Online Search and New-Product Marketing

ERIC Educational Resources Information Center

Kim, Ho

2013-01-01

This dissertation contains three essays that study the implications of online search activity for new-product marketing. Using the U.S. motion picture industry as a test case, the first essay examines the dynamic causal relationship between traditional media, consumers' media generation activity, media consumption activity, and market demand…

Differences in Extracurricular Activity Participation Intensity among Middle School Students: Implications for Hispanic Youths

ERIC Educational Resources Information Center

Villarreal, Victor

2017-01-01

Extracurricular activity participation has been associated with a multitude of positive outcomes, including school completion, and research suggests that students at risk for school failure are particularly likely to benefit from participation. However, before extracurricular activity participation can be promoted to address such issues,…

Community-Referenced Math Activities for Moderately and Severely Handicapped Individuals.

ERIC Educational Resources Information Center

Schoen, Sharon F.

Community-referenced activities, which involve combinations of skills used in routine tasks of daily living, are critical for the independent functioning of moderately and severely handicapped persons. The paper examines the characteristics of these activities in order to extract implications for enhancing instruction. The tasks involved in such…

Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease.

PubMed

Wang, Liqun; Xia, Jing; Li, Jonathan; Hagemann, Tracy L; Jones, Jeffrey R; Fraenkel, Ernest; Weitz, David A; Zhang, Su-Chun; Messing, Albee; Feany, Mel B

2018-05-15

Glial cells have increasingly been implicated as active participants in the pathogenesis of neurological diseases, but critical pathways and mechanisms controlling glial function and secondary non-cell autonomous neuronal injury remain incompletely defined. Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. Further, we take cell biological and biophysical approaches to suggest that brain tissue stiffness is increased in Alexander disease. Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis.

A Review of Physiological and Psychological Changes in Aging and Their Implications for Teachers of Adults.

ERIC Educational Resources Information Center

Hand, Samuel E.

This review of literature on the aging process points out primary physiological and psychological changes in maturing adults which have implications for teachers of adults. Visual acuity and hearing decline during adult years and there is a general slowing down process of most bodily activities. Teachers should be aware of the need for good…

The Changing Workplace: Implications of Quality of Work Life Developments for Vocational Education. Research and Development Series No. 249.

ERIC Educational Resources Information Center

Pratzner, Frank C.; Russell, Jill Frymier

Based upon a review of literature and on-site interviews and observations at nine firms that are recognized leaders in the development and implementation of quality of work life (QWL) activities, this report examines implications of QWL developments for future skill requirements and their potential consequences for public vocational education…

Implications of Social Network Sites for Teaching and Learning. Where We Are and Where We Want to Go

ERIC Educational Resources Information Center

Manca, Stefania; Ranieri, Maria

2017-01-01

This conceptual paper deals with some of the implications that the use of social network sites, though not originally developed and conceived for learning purposes, have for schools and academic activities when they are used as tools able to modify and innovate teaching/learning practices and academic culture. Beside the differences that…

Mechanisms implicated in the effects of boron on wound healing.

PubMed

Nzietchueng, Rosine Mayap; Dousset, Brigitte; Franck, Patricia; Benderdour, Mohamed; Nabet, Pierre; Hess, Ketsia

2002-01-01

Recently, we demonstrated that boron modulates the turnover of the extracellular matrix and increases TNFalpha release. In the present study, we used an in vitro test to investigate the direct effect of boron on specific enzymes (elastase, trypsin-like enzymes, collagenase and alkaline phosphatase) implicated in extracellular matrix turnover. Boron decreased the elastase and alkaline phosphatase activity, but had no effect on trypsin and collagenase activities. The effect of boron on the enzyme activities was also tested in fibroblasts considered as an in vivo test. In contrast to the results obtained in vitro, boron enhanced the trypsin-like, collagenase, and cathepsin D activities in fibroblasts. Boron did not modify the generation of free radicals compared to the control and did not seem to act on the intracellular alkaline phosphatase activity, However, as it did enhance phosphorylation, it can be hypothesized that boron may affect living cells via a mediator, which could be TNFalpha whose transduction signal involves a cascade of phosphorylations.

Abnormal salience signaling in schizophrenia: The role of integrative beta oscillations.

PubMed

Liddle, Elizabeth B; Price, Darren; Palaniyappan, Lena; Brookes, Matthew J; Robson, Siân E; Hall, Emma L; Morris, Peter G; Liddle, Peter F

2016-04-01

Aberrant salience attribution and cerebral dysconnectivity both have strong evidential support as core dysfunctions in schizophrenia. Aberrant salience arising from an excess of dopamine activity has been implicated in delusions and hallucinations, exaggerating the significance of everyday occurrences and thus leading to perceptual distortions and delusional causal inferences. Meanwhile, abnormalities in key nodes of a salience brain network have been implicated in other characteristic symptoms, including the disorganization and impoverishment of mental activity. A substantial body of literature reports disruption to brain network connectivity in schizophrenia. Electrical oscillations likely play a key role in the coordination of brain activity at spatially remote sites, and evidence implicates beta band oscillations in long-range integrative processes. We used magnetoencephalography and a task designed to disambiguate responses to relevant from irrelevant stimuli to investigate beta oscillations in nodes of a network implicated in salience detection and previously shown to be structurally and functionally abnormal in schizophrenia. Healthy participants, as expected, produced an enhanced beta synchronization to behaviorally relevant, as compared to irrelevant, stimuli, while patients with schizophrenia showed the reverse pattern: a greater beta synchronization in response to irrelevant than to relevant stimuli. These findings not only support both the aberrant salience and disconnectivity hypotheses, but indicate a common mechanism that allows us to integrate them into a single framework for understanding schizophrenia in terms of disrupted recruitment of contextually appropriate brain networks. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Abnormal salience signaling in schizophrenia: The role of integrative beta oscillations

PubMed Central

Liddle, Elizabeth B.; Price, Darren; Palaniyappan, Lena; Brookes, Matthew J.; Robson, Siân E.; Hall, Emma L.; Morris, Peter G.

2016-01-01

Abstract Aberrant salience attribution and cerebral dysconnectivity both have strong evidential support as core dysfunctions in schizophrenia. Aberrant salience arising from an excess of dopamine activity has been implicated in delusions and hallucinations, exaggerating the significance of everyday occurrences and thus leading to perceptual distortions and delusional causal inferences. Meanwhile, abnormalities in key nodes of a salience brain network have been implicated in other characteristic symptoms, including the disorganization and impoverishment of mental activity. A substantial body of literature reports disruption to brain network connectivity in schizophrenia. Electrical oscillations likely play a key role in the coordination of brain activity at spatially remote sites, and evidence implicates beta band oscillations in long‐range integrative processes. We used magnetoencephalography and a task designed to disambiguate responses to relevant from irrelevant stimuli to investigate beta oscillations in nodes of a network implicated in salience detection and previously shown to be structurally and functionally abnormal in schizophrenia. Healthy participants, as expected, produced an enhanced beta synchronization to behaviorally relevant, as compared to irrelevant, stimuli, while patients with schizophrenia showed the reverse pattern: a greater beta synchronization in response to irrelevant than to relevant stimuli. These findings not only support both the aberrant salience and disconnectivity hypotheses, but indicate a common mechanism that allows us to integrate them into a single framework for understanding schizophrenia in terms of disrupted recruitment of contextually appropriate brain networks. Hum Brain Mapp 37:1361‐1374, 2016. © 2016 Wiley Periodicals, Inc. PMID:26853904

Thyrotropin receptor autoantibodies (TSHRAbs): epitopes, origins and clinical significance.

PubMed

Kohn, Leonard D; Harii, Norikazu

2003-01-01

Epitopes for > 95% stimulating thyrotropin receptor autoantibodies (TSHRAbs) causally implicated in Graves' disease (Basedow's disease or primary hyperthyroidism) have been identified on on the N-terminal portion of the TSHR extracellular domain, residues 8-165. If the stimulating TSHRAb activity is solely dependent on this region, it is termed homogeneous; if its activity is only largely related to this region, it is termed heterogeneous. The presence of a heterogeneous stimulating TSHRAb in a patient is associated with rapid responses to propylthiouracil or methimazole and may be predictive of long term remission with these oral immunosuppressives. Epitopes for two different Graves' autoantibodies that inhibit TSH binding, TSH binding inhibition immunoglobulins or TBIIs, have also been identified on this region of the TSHR. They do not increase cAMP levels, although one may activate the inositol phosphate, Ca++, arachidonate release signal system. The epitope of blocking TSHRAbs with the ability to inhibit TSH binding (TBII activity), TSH activity, and stimulating TSHRAb activity, and that are causally implicated in the primary hypothyroidism of patients with idiopathic myxedema or some patients with Hashimoto's disease have, in contrast, been largely identified largely on the C-terminal portion of the TSHR extracellular domain, residues 270-395. They have been implicated as important in pregnancy where they attenuate the signs and symptoms of Graves' hyperthyroidism. The appearance of these blocking TSHRAbs during pregnancy in Graves' patients might cause overt or occult hypothyroidism, with resultant effects on fetal development and postnatal intelligence levels. The different TSHRAbs can exist in the same patient at any moment in time, potentially making disease expression a sum of their activities. Assays taking advantage of the epitope mapping findings enable us to detect individual TSHRAbs within a single patient and to better understand their clinical significance.

Antifungal activity of Malaysian honey and propolis extracts against pathogens implicated in denture stomatitis

NASA Astrophysics Data System (ADS)

Yusoff, Nik Yusliyana Nik; Mohamad, Suharni; Abdullah, Haswati@Nurhayati; Rahman, Nurhayu Ab

2016-12-01

Malaysian honey and propolis extracts were investigated for their antifungal properties against pathogens implicated in denture stomatitis. Each of the honey and aqueous extracts propolis at net preparation, 1:1 and 1:2 dilutions was evaluated by using agar well diffusion assay and further investigated by minimum inhibitory concentration (MIC) within the range of 500 mg/mL to 62.5 mg/mL against oral fungi. The findings indicated that there was no effect of propolis on Candida spp for both types of propolis based on no inhibition zones was recorded. Meanwhile, for antifungal activity of honey, only honey from Trigona spp has shown activity at net preparation against C. albicans (10.47 ± 0.23 mm), C. tropicalis (12.29 ± 0.23 mm) and C. glabrata (8.69 ± 0.53 mm). For minimum inhibitory concentration, the data indicates that both propolis have shown inhibitory effect at 500 mg/mL. As for honey, Trigona spp was the effective honey that give MIC value at 250 mg/mL against Candida spp. Apis dorsata honey has shown MIC value at 500 mg/mL while Apis mellifera honey had inhibited C.albicans and C.glabrata at 500 mg/mL except for C.tropicalis at 250 mg/mL. It can be concluded that both propolis has shown weaker antifungal activity against oral fungi while only honey produced from Trigona spp had strong antifungal activity compare to other honey against oral fungi implicated in denture stomatitis.

Role determination in nursing--implications for service provision.

PubMed

Chang, A M; Twinn, S

1995-01-01

The current changes in nursing practice which have placed a greater need than ever before for nurses to have clearly defined roles, has resulted from the demand for cost-effective care and for nurses to justify their contribution to that care. This two stage, descriptive study was undertaken as part of a larger study to determine the implications of definition of the role of nursing for service provision in Hong Kong. The initial data collected using group interviews to generate ideas about the activities of the registered nurse (RN) and enrolled nurse (EN), was followed by a questionnaire to a sample of 410 RNs, representing three different grades of nursing staff. The 5-point Likert type questionnaire asked respondents to indicate levels of agreement with 67 activities. Sixty-five of the 67 activities of the RN were agreed to and were statistically significant (P < 0.001) in the difference from the undecided position. The findings also demonstrated a lack of agreement amongst grades of staff in their perception of nursing role. Fifty-six of the same 67 activities were agreed to for the EN and were statistically significant (P < 0.001) in the difference from the undecided position. This similarity between perceptions of EN and RN activities highlights the need to reconsider the contribution of ENs to patient care within the nursing structure in Hong Kong. These findings have implications not only for the management of nursing but also for further research in determining the interpretation of role in nursing to high quality patient care.

Relation of obesity to neural activation in response to food commercials.

PubMed

Gearhardt, Ashley N; Yokum, Sonja; Stice, Eric; Harris, Jennifer L; Brownell, Kelly D

2014-07-01

Adolescents view thousands of food commercials annually, but the neural response to food advertising and its association with obesity is largely unknown. This study is the first to examine how neural response to food commercials differs from other stimuli (e.g. non-food commercials and television show) and to explore how this response may differ by weight status. The blood oxygen level-dependent functional magnetic resonance imaging activation was measured in 30 adolescents ranging from lean to obese in response to food and non-food commercials imbedded in a television show. Adolescents exhibited greater activation in regions implicated in visual processing (e.g. occipital gyrus), attention (e.g. parietal lobes), cognition (e.g. temporal gyrus and posterior cerebellar lobe), movement (e.g. anterior cerebellar cortex), somatosensory response (e.g. postcentral gyrus) and reward [e.g. orbitofrontal cortex and anterior cingulate cortex (ACC)] during food commercials. Obese participants exhibited less activation during food relative to non-food commercials in neural regions implicated in visual processing (e.g. cuneus), attention (e.g. posterior cerebellar lobe), reward (e.g. ventromedial prefrontal cortex and ACC) and salience detection (e.g. precuneus). Obese participants did exhibit greater activation in a region implicated in semantic control (e.g. medial temporal gyrus). These findings may inform current policy debates regarding the impact of food advertising to minors. © The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Asian American Student Engagement in Student Leadership and Activism

ERIC Educational Resources Information Center

Manzano, Lester J.; Poon, OiYan A.; Na, Vanessa S.

2017-01-01

Conceptual models for understanding the ways in which Asian American students engage in leadership and activism are interrogated. The chapter provides a discussion of implications for student affairs professionals working with Asian American student leaders and activists.

Transport Processes in the Ice Shell of Europa — A Review

NASA Astrophysics Data System (ADS)

Rhoden, A. R.

2017-11-01

Recent models and observations of Europa's geologic activity suggest a dynamic ice shell, rich with liquid water, that may change in thickness and activity over time. Implications for Europa's habitability and future exploration will be discussed.

Acquisition of Programming Skills

DTIC Science & Technology

1990-04-01

skills (e.g., arithmetic reasoning, work knowledge, information processing speed); and c) passive versus active learning style. Ability measures...concurrent storage and processing an individual was capable of doing), and an active learning style. Implications of the findings for the development of

Top 10 research questions related to physical activity in preschool children.

PubMed

Pate, Russell R; O'Neill, Jennifer R; Brown, William H; McIver, Kerry L; Howie, Erin K; Dowda, Marsha

2013-12-01

The purpose of this article was to highlight important research needs related to physical activity in 3- to 5-year-old children. We identified research needs in 3 major categories: health effects, patterns of physical activity, and interventions and policies. The top research needs include identifying the health effects of physical activity, the effects of physical activity on the development of healthy weight, the effects of physical activity on learning and behavior, and the health implications of sedentary behavior. Research questions concerning patterns of physical activity include determining the prevalence of 3- to 5-year-olds meeting the current physical activity guidelines; the social and environmental factors that influence physical activity in home, preschool, and community settings; and how physical activity tracks into later childhood, adolescence, and adulthood. Research questions about interventions and policies include identifying the most effective strategies to promote physical activity in home, child care, and community settings and to reach diverse populations of young children, identifying effective intervention implementation and dissemination strategies, and determining the effectiveness of national, state, local, and institutional policies for increasing physical activity. In conclusion, research is needed to establish a full understanding of the health implications of physical activity in 3- to 5-year-old children, to better understand the nature of physical activity behavior in this group, and to learn how to promote physical activity in young children.

Treatment with phosphotidylglycerol-based nanoparticles prevents motor deficits induced by proteasome inhibition: implications for Parkinson's disease.

PubMed

Fitzgerald, Patrick; Mandel, Arkady; Bolton, Anthony E; Sullivan, Aideen M; Nolan, Yvonne

2008-12-22

Failure of the ubiquitin-proteasome system to degrade abnormal proteins may underlie the accumulation of alpha-synuclein and dopaminergic neuronal degeneration that occurs in Parkinson's disease. Consequently, a reduction of functional proteasome activity has been implicated in Parkinson's disease. VP025 (Vasogen Inc.) is a preparation of phospholipid nanoparticles incorporating phosphatidylglycerol that has been shown to have neuroprotective effects. We show that VP025 prevents the deficits in motor coordination and dopamine observed in a proteasome inhibitor rat model of PD. Thus, VP025 may have a therapeutic effect on the impairment of dopaminergic-mediated motor activity induced by proteasome inhibition.

Leadership networks in Catholic parishes: Implications for implementation research in health

PubMed Central

Negrón, Rosalyn; Leyva, Bryan; Allen, Jennifer; Ospino, Hosffman; Tom, Laura; Rustan, Sarah

2014-01-01

Through two case studies of Catholic parishes in Massachusetts, this study explores the implications of leader-centered versus distributed leadership in Catholic parishes for the implementation of evidence-based health interventions. The two parishes involved in the study differ from each other in several ways. In the first, parishioners are less engaged in leadership activities at the decision-making level in the parish. A small group of lay volunteers work with the parish priest and other ordained leaders on parish activities. In the second parish, a large and active lay volunteer leadership have forged an organizational structure that allows more independence from the pastor's direct oversight. In this parish, lay volunteer leaders are the prime drivers of organizational programs and events. In 2012–2013, three types of networks were assessed at each parish: discussion, collaboration, and outside-of-parish ties. The contrasts between each parish include differences in density of collaboration, in frequency of discussion, and network centrality of the respective parish priests. We further identified key actors in the network structures at each parish. We discuss the implications of these findings for understanding organizational capacity in the context of health program implementation. PMID:25441317

Leadership networks in Catholic parishes: implications for implementation research in health.

PubMed

Negrón, Rosalyn; Leyva, Bryan; Allen, Jennifer; Ospino, Hosffman; Tom, Laura; Rustan, Sarah

2014-12-01

Through two case studies of Catholic parishes in Massachusetts, this study explores the implications of leader-centered versus distributed leadership in Catholic parishes for the implementation of evidence-based health interventions. The two parishes involved in the study differ from each other in several ways. In the first, parishioners are less engaged in leadership activities at the decision-making level in the parish. A small group of lay volunteers work with the parish priest and other ordained leaders on parish activities. In the second parish, a large and active lay volunteer leadership have forged an organizational structure that allows more independence from the pastor's direct oversight. In this parish, lay volunteer leaders are the prime drivers of organizational programs and events. In 2012-2013, three types of networks were assessed at each parish: discussion, collaboration, and outside-of-parish ties. The contrasts between each parish include differences in density of collaboration, in frequency of discussion, and network centrality of the respective parish priests. We further identified key actors in the network structures at each parish. We discuss the implications of these findings for understanding organizational capacity in the context of health program implementation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Federalism and social justice: implications for social work.

PubMed

Linhorst, Donald M

2002-07-01

Federalism is a system of government that divides power between two or more levels of government. During the current conservative political climate in the United States, power has shifted increasingly from the federal government to states, a move that has implications for the achievement of social justice. Consequently, it is now necessary for social workers to engage in political activity at the state and local levels, in addition to the federal level, to promote social justice. Implications for social work policy practice, research, and education for advancing social justice within the federal system of government are explored.

Early Hormonal Influences on Childhood Sex-Typed Activity and Playmate Preferences: Implications for the Development of Sexual Orientation.

ERIC Educational Resources Information Center

Berenbaum, Sheri A.; Snyder, Elizabeth

1995-01-01

Examined hormonal influences on activity and playmate preferences in children with congenital adrenal hyperplasia (CAH) age 2.5 to 12 years and their relatives. Found that girls with CAH preferred boys' toys and activities, whereas boys with CAH did not differ significantly from controls. Activity and playmate preferences were not related. (MDM)

Physical Activity and Aging: Implications for Health and Quality of Life in Older Persons.

ERIC Educational Resources Information Center

Chodzko-Zajko, Wojtek J.

1998-01-01

This publication summarizes what is known about the influence of regular physical activity on the health and quality of life of older individuals, addressing both the acute effects of a single bout of physical activity and the more persistent, long-term effects of sustained participation in exercise and physical activity. Section 1 discusses the…

A high-throughput virus-induced gene silencing protocol identifies genes involved in multi-stress tolerance

PubMed Central

2013-01-01

Background Understanding the function of a particular gene under various stresses is important for engineering plants for broad-spectrum stress tolerance. Although virus-induced gene silencing (VIGS) has been used to characterize genes involved in abiotic stress tolerance, currently available gene silencing and stress imposition methodology at the whole plant level is not suitable for high-throughput functional analyses of genes. This demands a robust and reliable methodology for characterizing genes involved in abiotic and multi-stress tolerance. Results Our methodology employs VIGS-based gene silencing in leaf disks combined with simple stress imposition and effect quantification methodologies for easy and faster characterization of genes involved in abiotic and multi-stress tolerance. By subjecting leaf disks from gene-silenced plants to various abiotic stresses and inoculating silenced plants with various pathogens, we show the involvement of several genes for multi-stress tolerance. In addition, we demonstrate that VIGS can be used to characterize genes involved in thermotolerance. Our results also showed the functional relevance of NtEDS1 in abiotic stress, NbRBX1 and NbCTR1 in oxidative stress; NtRAR1 and NtNPR1 in salinity stress; NbSOS1 and NbHSP101 in biotic stress; and NtEDS1, NbETR1, NbWRKY2 and NbMYC2 in thermotolerance. Conclusions In addition to widening the application of VIGS, we developed a robust, easy and high-throughput methodology for functional characterization of genes involved in multi-stress tolerance. PMID:24289810

Microbial reduction of structural iron in interstratified illite-smectite minerals by a sulfate-reducing bacterium

USGS Publications Warehouse

Liu, D.; Dong, H.; Bishop, M.E.; Zhang, Jiahua; Wang, Hongfang; Xie, S.; Wang, Shaoming; Huang, L.; Eberl, D.D.

2012-01-01

Clay minerals are ubiquitous in soils, sediments, and sedimentary rocks and could coexist with sulfate-reducing bacteria (SRB) in anoxic environments, however, the interactions of clay minerals and SRB are not well understood. The objective of this study was to understand the reduction rate and capacity of structural Fe(III) in dioctahedral clay minerals by a mesophilic SRB, Desulfovibrio vulgaris and the potential role in catalyzing smectite illitization. Bioreduction experiments were performed in batch systems, where four different clay minerals (nontronite NAu-2, mixed-layer illite-smectite RAr-1 and ISCz-1, and illite IMt-1) were exposed to D. vulgaris in a non-growth medium with and without anthraquinone-2,6-disulfonate (AQDS) and sulfate. Our results demonstrated that D. vulgaris was able to reduce structural Fe(III) in these clay minerals, and AQDS enhanced the reduction rate and extent. In the presence of AQDS, sulfate had little effect on Fe(III) bioreduction. In the absence of AQDS, sulfate increased the reduction rate and capacity, suggesting that sulfide produced during sulfate reduction reacted with the phyllosilicate Fe(III). The extent of bioreduction of structural Fe(III) in the clay minerals was positively correlated with the percentage of smectite and mineral surface area of these minerals. X-ray diffraction, and scanning and transmission electron microscopy results confirmed formation of illite after bioreduction. These data collectively showed that D. vulgaris could promote smectite illitization through reduction of structural Fe(III) in clay minerals. ?? 2011 Blackwell Publishing Ltd.

Retinoic Acid Receptor β: A Potential Therapeutic Target in Retinoic Acid Treatment of Endometrial Cancer.

PubMed

Tsuji, Keita; Utsunomiya, Hiroki; Miki, Yasuhiro; Hanihara, Mayu; Fue, Misaki; Takagi, Kiyoshi; Nishimoto, Mitsuo; Suzuki, Fumihiko; Yaegashi, Nobuo; Suzuki, Takashi; Ito, Kiyoshi

2017-05-01

Several studies have reported that retinoic acid (RA) might be used to treat malignancies. The effects of RA are mediated by the RA receptor (RAR), and RARα/RARβ especially acts as a tumor suppressor. However, little is known about its role in human endometrial cancer. In this study, we examined the effects of all-trans RA (ATRA) on progression of human endometrial cancer cell line, RL95-2 and Hec1A. We then examined the expression of RARα and RARβ in 50 endometrial cancer tissues by using immunohistochemistry. We found inhibitory effects of ATRA on cell proliferation, apoptosis, and migration in RL95-2 cells, but not in Hec1A cells. RARα or RARβ knockdown individually could not cancel out the inhibition of cell proliferation by ATRA in RL95-2 cells, but simultaneous knockdown of RARα and RARβ could block its effect on proliferation. RARα and RARβ knockdown dose dependently reduced the inhibition of migration by ATRA, but the effect was more pronounced with RARβ knockdown than with RARα knockdown. We confirmed that RARβ gene was directly regulated by ATRA in microarray and real-time reverse transcription polymerase chain reaction. Furthermore, the RARβ agonist (BMS453) significantly suppressed proliferation of RL95-2 cells. In immunohistochemical analysis, RARα expression was positively correlated with tumor grade, and RARβ showed the opposite tendency in endometrial cancer. Retinoic acid might have multiple antitumor effects, and RARβ may be a potent therapeutic target in RA treatment for endometrial cancers.

Validating GPM-based Multi-satellite IMERG Products Over South Korea

NASA Astrophysics Data System (ADS)

Wang, J.; Petersen, W. A.; Wolff, D. B.; Ryu, G. H.

2017-12-01

Accurate precipitation estimates derived from space-borne satellite measurements are critical for a wide variety of applications such as water budget studies, and prevention or mitigation of natural hazards caused by extreme precipitation events. This study validates the near-real-time Early Run, Late Run and the research-quality Final Run Integrated Multi-Satellite Retrievals for GPM (IMERG) using Korean Quantitative Precipitation Estimation (QPE). The Korean QPE data are at a 1-hour temporal resolution and 1-km by 1-km spatial resolution, and were developed by Korea Meteorological Administration (KMA) from a Real-time ADjusted Radar-AWS (Automatic Weather Station) Rainrate (RAD-RAR) system utilizing eleven radars over the Republic of Korea. The validation is conducted by comparing Version-04A IMERG (Early, Late and Final Runs) with Korean QPE over the area (124.5E-130.5E, 32.5N-39N) at various spatial and temporal scales during March 2014 through November 2016. The comparisons demonstrate the reasonably good ability of Version-04A IMERG products in estimating precipitation over South Korea's complex topography that consists mainly of hills and mountains, as well as large coastal plains. Based on this data, the Early Run, Late Run and Final Run IMERG precipitation estimates higher than 0.1mm h-1 are about 20.1%, 7.5% and 6.1% higher than Korean QPE at 0.1o and 1-hour resolutions. Detailed comparison results are available at https://wallops-prf.gsfc.nasa.gov/KoreanQPE.V04/index.html

Aryl Hydrocarbon Receptor Promotes RORγt+ ILCs and Controls Intestinal Immunity and Inflammation

PubMed Central

Qiu, Ju; Zhou, Liang

2013-01-01

Unlike adaptive immune cells that require antigen recognition and functional maturation during infection, innate lymphoid cells (ILCs) usually respond to pathogens promptly and serve as the first line of defense in infectious diseases. RAR-related orphan receptors (RORγt)+ ILCs are one of the innate cell populations that have recently been intensively studied. During the fetal stage of development, RORγt+ ILCs (e.g., lymphoid tissue inducer-LTi cells) are required for lymphoid organogenesis. In adult mice, RORγt+ ILCs are abundantly present in the gut to exert immune defensive functions. Under certain circumstances, however, RORγt+ ILCs can be pathogenic and contribute to intestinal inflammation. Aryl hydrocarbon receptor (Ahr), a ligand-dependent transcriptional factor, is widely expressed by various immune and non-immune cells. In the gut, the ligand for Ahr can be derived/generated from diet, microflora, and/or host cells. Ahr has been shown to regulate different cell populations in the immune system including RORγt+ ILCs, T helper (Th)17/22 cells, γδT cells, regulatory T cells (Tregs), Tr1 cells, and antigen presenting cells (APCs). In this review, we will focus on the development and function of RORγt+ ILCs, and discuss the role of Ahr in intestinal immunity and inflammation in mice and in humans. Better understanding the function of Ahr in the gut is important for developing new therapeutic means to target Ahr in future treatment of infectious and autoimmune diseases. PMID:23975386

Predictors of Olfactory Dysfunction in Rhinosinusitis Using the Brief Smell Identification Test

PubMed Central

Alt, Jeremiah A.; Mace, Jess C.; Buniel, Maria C. F.; Soler, Zachary M.; Smith, Timothy L.

2014-01-01

Objective Associations between olfactory function to quality-of-life (QOL) and disease severity in patients with rhinosinusitis is poorly understood. We sought to evaluate and compare olfactory function between subgroups of patients with rhinosinusitis using the Brief Smell Identification Test (BSIT). Study Design Cross-sectional evaluation of a multi-center cohort. Methods Patients with recurrent acute sinusitis (RARS) and chronic rhinosinusitis (CRS) with and without nasal polyposis were prospectively enrolled from three academic tertiary care sites. Each subject completed the BSIT, in addition to measures of disease-specific QOL. Patient demographics, comorbidities, and clinical measures of disease severity were compared between patients with normal (BSIT; ≥9) and abnormal (BSIT; <9) olfaction scores. Regression modeling was used to identify potential risk factors associated with olfactory impairment. Results Patients with rhinosinusitis (n=445) were found to suffer olfactory dysfunction as measured by the BSIT (28.3%). Subgroups of rhinosinusitis differed in the degree of olfactory dysfunction reported. Worse disease severity, measured by computed tomography and nasal endoscopy, correlated to worse olfaction. Olfactory scores did not consistently correlate with Rhinosinusitis Disability Index or Sinonasal Outcome Test scores. Regression models demonstrated nasal polyposis was the strongest predictor of olfactory dysfunction. Recalcitrant disease and aspirin intolerance were strongly predictive of worse olfactory function. Conclusion Olfactory dysfunction is a complex, multi-factorial process found to be differentially expressed within subgroups of rhinosinusitis. Olfaction was associated with disease severity as measured by imaging and endoscopy, with only weak associations to disease-specific QOL measures. PMID:24402746

Long term curative effects of sequential therapy with all-trans retinoic acid, arsenious oxide and chemotherapy on patients with acute promyelocytic leukemia.

PubMed

Pei, Renzhi; Cao, Junjie; Ma, Junxia; Zhang, Pisheng; Liu, Xuhui; Du, Xiaohong; Chen, Dong; Sha, Keya; Chen, Lieguang; Li, Shuangyue; Wu, Jingyi; Fan, Zhen; Lin, Li; Ye, Peipei; Tang, Shanhao; Zhang, Bibo

2012-11-01

Both all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) have proven to be very effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL). In this study, 73 newly diagnosed APL subjects were treated with an ATRA and As(2)O(3) combination treatment in remission induction and post remission therapy. Tumor burden was examined with PCR of the PML-RAR fusion transcripts, and side effects were evaluated by means of clinical examination. The results showed that ATRA/As(2)O(3) combination therapy yielded a CR rate of 94.5% (69/73) with a shorter time to enter CR (median: 27 days; range: 21-43 days). Four cases failed to enter CR; three of these died of cerebral hemorrhage and disseminated intravascular coagulation (DIC) within 72 hours of starting induction therapy, one older patient died of severe pulmonary infection. The early death rate was 5.5% (4/73). All 69 cases that obtained CR remained in good clinical remission after a follow-up of 35-74 months (median: 52 months).The drug toxicity profile with the use of As(2)O(3) showed mainly hepatotoxicity. Liver dysfunction was slight in most cases. There were no severe side effects in long term follow-up. We conclude that APL patients may benefit from the use of the combination of ATRA and As(2)O(3) in either remission induction or consolidation/maintenance.

INHIBITION OF PHOSPHATASE ACTIVITY MEDIATES EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) SIGNALING IN HUMAN AIRWAY EPITHELIAL CELLS (HAEC) EXPOSED TO ZN2+

EPA Science Inventory

A number of studies have implicated zinc in the toxicity of ambient particulate matter (PM) inhalation. We previously showed that exposure to metal-laden particulate matter inhibits protein tyrosine phosphatase activity in HAEC and leads to Src-dependent activation of EGFR sign...

Cultural-Historical Activity Theory and Domain Analysis: Metatheoretical Implications for Information Science

ERIC Educational Resources Information Center

Wang, Lin

2013-01-01

Background: Cultural-historical activity theory is an important theory in modern psychology. In recent years, it has drawn more attention from related disciplines including information science. Argument: This paper argues that activity theory and domain analysis which uses the theory as one of its bases could bring about some important…

Physical Activity and Executive Control: Implications for Increased Cognitive Health during Older Adulthood

ERIC Educational Resources Information Center

Hillman, Charles H.; Belopolsky, Artem V.; Snook, Erin M.; Kramer, Arthur F.; McAuley, Edward

2004-01-01

Electrocortical and behavioral responses of low, moderate, and high physically active older adults where compared with a younger control group on neutral and incompatible conditions of a flankers task. Compared to younger adults, high and moderate active older adults exhibited increased event-related potentials component P3 amplitude for the…

Toward Active Living: "Comprehensive School Physical Activity Program" Research and Implications

ERIC Educational Resources Information Center

Chen, Senlin; Gu, Xiangli

2018-01-01

Comprehensive school physical activity program (CSPAP) holds much promise as a solution for youth PA promotion, due to its strong theoretical and political support. In this article, we review the current research on CSPAP. Fifty-four published articles that met the inclusion criteria were identified and retrieved using direct library database…

Estrogenic activity, estrogens, and calcium in runoff post-layer litter application from rainfall simulated events

USDA-ARS?s Scientific Manuscript database

Estrogens in runoff from fields fertilized with animal wastes have been implicated as endocrine disruptors of fish in recipient surface waters. The goal of this study was to measure estrogenic activity in runoff post-application of animal waste with the greatest potential for estrogenic activity - ...

Developmental Changes in Dopamine Neurotransmission in Adolescence: Behavioral Implications and Issues in Assessment

ERIC Educational Resources Information Center

Wahlstrom, Dustin; Collins, Paul; White, Tonya; Luciana, Monica

2010-01-01

Adolescence is characterized by increased risk-taking, novelty-seeking, and locomotor activity, all of which suggest a heightened appetitive drive. The neurotransmitter dopamine is typically associated with behavioral activation and heightened forms of appetitive behavior in mammalian species, and this pattern of activation has been described in…

Accelerometer-Measured versus Self-Reported Physical Activity in College Students: Implications for Research and Practice

ERIC Educational Resources Information Center

Downs, Andrew; Van Hoomissen, Jacqueline; Lafrenz, Andrew; Julka, Deana L.

2014-01-01

Objective: To determine the level of moderate-vigorous-intensity physical activity (MVPA) assessed via self-report and accelerometer in the college population, and to examine intrapersonal and contextual variables associated with physical activity (PA). Participants: Participants were 77 college students at a university in the northwest sampled…

Physical Activity and U.S. Public Elementary Schools: Implications for Our Profession

ERIC Educational Resources Information Center

Beaulieu, Lisa; Butterfield, Stephen A.; Mason, Craig A.; Loovis, E. Michael

2012-01-01

Childhood obesity in the U.S. has reached crisis proportion. In response, public elementary schools have embarked on various methods to increase children's physical activity. The purpose of this study was to examine strategies by United States public elementary schools to increase children's physical activity. Of particular concern was how…

Activity Theory and the New Literacy Studies: Modelling the Literacy Learning Activity System.

ERIC Educational Resources Information Center

Kostogriz, Alexander

This paper explores a number of implications arising from the combination of the New Literacy Studies and cultural-historical psychology--in particular, the concept of literacy as social practice and the psychological category of activity. Placing "social" at the center of literacy and psychological studies, these two perspectives are…

True Tension Traverse: What Research Shows about the Antidepressant Effects of Challenge Course Experiences.

ERIC Educational Resources Information Center

Bunting, Camille

2000-01-01

A study of five undergraduate physical education classes explored the influence on positive and negative affect of different types of physical activity. Results indicated that running, skiing, and challenge course activities, especially the 14-foot wall, increased positive affect more than other activities. Implications for physical education…

Technology implications of a cognitive task analysis for locomotive engineers

DOT National Transportation Integrated Search

2009-01-01

This report documents the results of a cognitive task analysis (CTA) that examined the cognitive demands and activities of locomotive engineers in todays environment and the changes in cognitive demands and activities that are likely to arise with...

Implication of global climate change on the distribution and activity of Phytophthora ramorum

Treesearch

Robert C. Venette

2009-01-01

Global climate change is predicted to alter the distribution and activity of several forest pathogens. Boland et al. (2004) suggested that climate change might affect pathogen establishment, rate of disease progress, and the duration of...

Increased Fos expression among midbrain dopaminergic cell groups during birdsong tutoring.

PubMed

Nordeen, E J; Holtzman, D A; Nordeen, K W

2009-08-01

During avian vocal learning, birds memorize conspecific song patterns and then use auditory feedback to match their vocal output to this acquired template. Some models of song learning posit that during tutoring, conspecific visual, social and/or auditory cues activate neuromodulatory systems that encourage acquisition of the tutor's song and attach incentive value to that specific acoustic pattern. This hypothesis predicts that stimuli experienced during social tutoring activate cell populations capable of signaling reward. Using immunocytochemistry for the protein product of the immediate early gene c-Fos, we found that brief exposure of juvenile male zebra finches to a live familiar male tutor increased the density of Fos+ cells within two brain regions implicated in reward processing: the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). This activation of Fos appears to involve both dopaminergic and non-dopaminergic VTA/SNc neurons. Intriguingly, a familiar tutor was more effective than a novel tutor in stimulating Fos expression within these regions. In the periaqueductal gray, a dopamine-enriched cell population that has been implicated in emotional processing, Fos labeling also was increased after tutoring, with a familiar tutor again being more effective than a novel conspecific. As several neural regions implicated in song acquisition receive strong dopaminergic projections from these midbrain nuclei, their activation in conjunction with hearing the tutor's song could help to establish sensory representations that later guide motor sequence learning.

The Electronic Dilemma of TV Advertising: Documentation, The Reactions of Business, Cultural Consequences and Consumer Implications. Working Paper No. 2.

ERIC Educational Resources Information Center

Sepstrup, Preben

This discussion of the influence of advertising on the development of new media covers ways in which advertising uses the media and the implications of new information technologies for consumers and marketing activities. The first of four sections describes how television advertising has been altered by the development of new technologies--cable,…

Iron toxicity in the retina requires Alu RNA and the NLRP3 inflammasome

PubMed Central

Gelfand, Bradley D.; Wright, Charles B.; Kim, Younghee; Yasuma, Tetsuhiro; Yasuma, Reo; Li, Shengjian; Fowler, Benjamin J.; Bastos-Carvalho, Ana; Kerur, Nagaraj; Uittenbogaard, Annette; Han, Youn Seon; Lou, Dingyuan; Kleinman, Mark E.; McDonald, W. Hayes; Núñez, Gabriel; Georgel, Philippe; Dunaief, Joshua L.; Ambati, Jayakrishna

2015-01-01

Excess iron induces tissue damage and is implicated in age-related macular degeneration (AMD). Iron toxicity is widely attributed to hydroxyl radical formation through Fenton's reaction. We report that excess iron, but not other Fenton catalytic metals, induces activation of the NLRP3 inflammasome, a pathway also implicated in AMD. Additionally, iron-induced degeneration of the retinal pigmented epithelium (RPE) is suppressed in mice lacking inflammasome components Caspase-1/11 or Nlrp3 or by inhibition of Caspase-1. Iron overload increases abundance of RNAs transcribed from short interspersed nuclear elements (SINEs): Alu RNAs and the rodent equivalent B1 and B2 RNAs, which are inflammasome agonists. Targeting Alu or B2 RNA prevents iron-induced inflammasome activation and RPE degeneration. Iron-induced SINE RNA accumulation is due to suppression of DICER1 via sequestration of the co-factor poly(C)-binding protein 2 (PCBP2). These findings reveal an unexpected mechanism of iron toxicity, with implications for AMD and neurodegenerative diseases associated with excess iron. PMID:26074074

The Role of Mammalian Sirtuins in the Regulation of Metabolism, Aging, and Longevity

PubMed Central

Satoh, Akiko; Stein, Liana

2013-01-01

Ever since the discovery of sirtuins a decade ago, interest in this family of NAD-dependent deacetylases has exploded, generating multiple lines of evidence implicating sirtuins as evolutionarily conserved regulators of lifespan. In mammals, it has been established that sirtuins regulate physiological responses to metabolism and stress, two key factors that affect the process of aging. Further investigation into the intimate connection among sirtuins, metabolism, and aging has implicated the activation of SIRT1 as both preventative and therapeutic measures against multiple age-associated disorders including type 2 diabetes and Alzheimer’s disease. SIRT1 activation has clear potential to not only prevent age-associated diseases but also to extend healthspan and perhaps lifespan. Sirtuin activating compounds and NAD intermediates are two promising ways to achieve these elusive goals. PMID:21879449

Body-part-specific representations of semantic noun categories.

PubMed

Carota, Francesca; Moseley, Rachel; Pulvermüller, Friedemann

2012-06-01

Word meaning processing in the brain involves ventrolateral temporal cortex, but a semantic contribution of the dorsal stream, especially frontocentral sensorimotor areas, has been controversial. We here examine brain activation during passive reading of object-related nouns from different semantic categories, notably animal, food, and tool words, matched for a range of psycholinguistic features. Results show ventral stream activation in temporal cortex along with category-specific activation patterns in both ventral and dorsal streams, including sensorimotor systems and adjacent pFC. Precentral activation reflected action-related semantic features of the word categories. Cortical regions implicated in mouth and face movements were sparked by food words, and hand area activation was seen for tool words, consistent with the actions implicated by the objects the words are used to speak about. Furthermore, tool words specifically activated the right cerebellum, and food words activated the left orbito-frontal and fusiform areas. We discuss our results in the context of category-specific semantic deficits in the processing of words and concepts, along with previous neuroimaging research, and conclude that specific dorsal and ventral areas in frontocentral and temporal cortex index visual and affective-emotional semantic attributes of object-related nouns and action-related affordances of their referent objects.

Perceptual Characteristics of Female Voices.

ERIC Educational Resources Information Center

Batstone, Susan; Tuomi, Seppo K.

1981-01-01

Male and females listeners rated 21 young female voices on seven scales representing unique vocal features. Voices were described as "passive", or traditionally female, and "active," characterized as "lively,""colorful," and "sexy." Females found active characteristics more salient; males preferred the passive characteristics. Implications for…

Terminology, a Translational Discipline.

ERIC Educational Resources Information Center

Ahrens, Helga

1994-01-01

Discusses the importance of qualified terminology and its implications for terminological activity. Argues that students have to learn how to organize their terminological activity. Suggests that translation is a special kind of intercultural communication and is an indispensable part of translational action. Argues that terminology be examined…

N-Methyl-D-Aspartate Receptor Activation May Contribute to Glufosinate Neurotoxicity

EPA Science Inventory

N-Methyl-D-aspartate Receptor Activation May Contribute to Glufosinate Neurotoxicity Glufosinate (GLF) at high levels in mammals causes convulsions through a mechanism that is not completely understood. The structural similarity of GLF to glutamate (GLU) implicates the glutamate...

The Supreme Court Upholds Drug Testing of Student Participants in Extracurricular Activities.

ERIC Educational Resources Information Center

Mawdsley, Ralph D.; Russo, Charles J.

2003-01-01

Analysis of 2001 United States Supreme Court decision in "Earls v. Board of Education of Tecumseh Public Schools," upholding random drug testing for students participating in extracurricular activities. Discusses implications for school policy and practice. (Contains 15 references.) (PKP)

Child Poverty and Child Rights Meet Active Citizenship: A New Zealand and Sweden Case Study

ERIC Educational Resources Information Center

O'Brien, Michael; Salonen, Tapio

2011-01-01

Children's rights and active citizenship have been significant policy emphases and developments in recent years but the relationship between the two has not been actively explored in relation to the implications for child poverty. Recent policy developments in New Zealand and Sweden are drawn on here to explore this relationship. The article…

School-Based Physical Activity Interventions: Effectiveness, Trends, Issues, Implications and Recommendations for Practice

ERIC Educational Resources Information Center

Cale, Lorraine; Harris, Jo

2006-01-01

The promotion of physical activity within schools and physical education (PE) has attracted growing interest in recent years. Schools have been acknowledged as the primary institution with responsibility for promoting activity in young people and more specifically, school PE has been recognized as having a key role to play. Given this, and based…

Extending the Constructs of Active Learning: Implications for Teachers' Pedagogy and Practice

ERIC Educational Resources Information Center

Drew, Valerie; Mackie, Lorele

2011-01-01

Active learning is a pedagogical construct widely appealed to within the global discourse of lifelong learning. However, an examination of the literature reveals a lack of clarity and consensus as to its meaning. This article provides a critical analysis of a range of dimensions underpinning the concept of active learning including policy…

Costs of Success: Financial Implications of Implementation of Active Learning in Introductory Physics Courses for Students and Administrators

ERIC Educational Resources Information Center

Brewe, Eric; Dou, Remy; Shand, Robert

2018-01-01

Although active learning is supported by strong evidence of efficacy in undergraduate science instruction, institutions of higher education have yet to embrace comprehensive change. Costs of transforming instruction are regularly cited as a key factor in not adopting active-learning instructional practices. Some cite that alternative methods to…

Characteristics of Smokers from a National Sample Who Engaged in Any Physical Activity: Implications for Cardiovascular Health Intervention

ERIC Educational Resources Information Center

Patterson, Freda; Lenhart, Clare M.

2016-01-01

Background: Tobacco is a major cause of cardiovascular disease, and current treatments lack long-term efficacy. Promoting physical activity may be a viable population-level approach to improving cardiovascular health among smokers. Purpose: To characterize smokers engaging in any physical activity based on demographics, quitting behaviors, health…

Development of a Systems Computational Model to Investigate Early Biological Events in Hepatic Activation of Constitutive Androstane Receptor (CAR) by Phenobarbital

EPA Science Inventory

Activation of the nuclear receptor CAR (constitutive active/androstane receptor) is implicated in the control several key biological events such as metabolic pathways. Here, we combined data from literature with information obtained from in vitro assays in the US EPA ToxCast dat...

Association of Orofacial Muscle Activity and Movement during Changes in Speech Rate and Intensity

ERIC Educational Resources Information Center

McClean, Michael D.; Tasko, Stephen M.

2003-01-01

Understanding how orofacial muscle activity and movement covary across changes in speech rate and intensity has implications for the neural control of speech production and the use of clinical procedures that manipulate speech prosody. The present study involved a correlation analysis relating average lower-lip and jaw-muscle activity to lip and…

Implications of Out-of-School Activities for School Engagement in African American Adolescents

ERIC Educational Resources Information Center

Dotterer, Aryn M.; McHale, Susan M.; Crouter, Ann C.

2007-01-01

The connection between out-of-school activities and school engagement was examined in 140, 6th through 9th grade African American adolescents. Youth's out-of-school activities were measured with a series of 7 nightly phone calls and focused on time in structured (homework, academically-oriented, extracurricular/sports) and unstructured (watching…

Systematic Review of Physical Activity Objectives in Extension Strategic Plans: Findings and Implications for Improved Public Health Impact

ERIC Educational Resources Information Center

Harden, Samantha M.; Lindsay, Anne; Everette, Alicia; Gunter, Katherine B.

2016-01-01

Extension programming that incorporates both physical activity and dietary behaviors is necessary for the prevention of certain chronic diseases, including obesity. The purpose of the study presented here was to systematically identify the presence of physical activity objectives in the strategic plan for each Extension system in the United…

Therapy Dogs on Campus: A Counseling Outreach Activity for College Students Preparing for Final Exams

ERIC Educational Resources Information Center

Barker, Sandra B.; Barker, Randolph T.; Schubert, Christine M.

2017-01-01

A university counseling center engaged a therapy dog program for an outreach activity to reduce stress as students prepare for final exams at a large culturally diverse university. This article describes the rationale, planning, and implementation of the activity; presents an evaluation summary; and provides recommendations and implications for…

Activation of Exchange Protein Activated by Cyclic-AMP Enhances Long-Lasting Synaptic Potentiation in the Hippocampus

ERIC Educational Resources Information Center

Gelinas, Jennifer N.; Banko, Jessica L.; Peters, Melinda M.; Klann, Eric; Weeber, Edwin J.; Nguyen, Peter V.

2008-01-01

cAMP is a critical second messenger implicated in synaptic plasticity and memory in the mammalian brain. Substantial evidence links increases in intracellular cAMP to activation of cAMP-dependent protein kinase (PKA) and subsequent phosphorylation of downstream effectors (transcription factors, receptors, protein kinases) necessary for long-term…

Neural correlates of social exclusion across ages: A coordinate-based meta-analysis of functional MRI studies.

PubMed

Vijayakumar, Nandita; Cheng, Theresa W; Pfeifer, Jennifer H

2017-06-01

Given the recent surge in functional neuroimaging studies on social exclusion, the current study employed activation likelihood estimation (ALE) based meta-analyses to identify brain regions that have consistently been implicated across different experimental paradigms used to investigate exclusion. We also examined the neural correlates underlying Cyberball, the most commonly used paradigm to study exclusion, as well as differences in exclusion-related activation between developing (7-18 years of age, from pre-adolescence up to late adolescence) and emerging adult (broadly defined as undergraduates, including late adolescence and young adulthood) samples. Results revealed involvement of the bilateral medial prefrontal and posterior cingulate cortices, right precuneus and left ventrolateral prefrontal cortex across the different paradigms used to examine social exclusion; similar activation patterns were identified when restricting the analysis to Cyberball studies. Investigations into age-related effects revealed that ventrolateral prefrontal activations identified in the full sample were driven by (i.e. present in) developmental samples, while medial prefrontal activations were driven by emerging adult samples. In addition, the right ventral striatum was implicated in exclusion, but only in developmental samples. Subtraction analysis revealed significantly greater activation likelihood in striatal and ventrolateral prefrontal clusters in the developmental samples as compared to emerging adults, though the opposite contrast failed to identify any significant regions. Findings integrate the knowledge accrued from functional neuroimaging studies on social exclusion to date, highlighting involvement of lateral prefrontal regions implicated in regulation and midline structures involved in social cognitive and self-evaluative processes across experimental paradigms and ages, as well as limbic structures in developing samples specifically. Copyright © 2017 Elsevier Inc. All rights reserved.

Timp3 loss accelerates tumour invasion and increases prostate inflammation in a mouse model of prostate cancer.

PubMed

Adissu, Hibret A; McKerlie, Colin; Di Grappa, Marco; Waterhouse, Paul; Xu, Qiang; Fang, Hui; Khokha, Rama; Wood, Geoffrey A

2015-12-01

Altered expression and activity of proteases is implicated in inflammation and cancer progression. An important negative regulator of protease activity is TIMP3 (tissue inhibitor of metalloproteinase 3). TIMP3 expression is lacking in many cancers including advanced prostate cancer, and this may facilitate invasion and metastasis by allowing unrestrained protease activity. To investigate the role of TIMP3 in prostate cancer progression, we crossed TIMP3-deficient mice (Timp3(-/-)) to mice with prostate-specific deletion of the tumor suppressor Pten (Pten(-/-)), a well-established mouse model of prostate cancer. Tumor growth and progression were compared between Pten(-/-), Timp3(-/-) and control (Pten(-/-), Timp3(+/+)) mice at 16 weeks of age by histopathology and markers of proliferation, vascularity, and tumor invasion. Metalloproteinase activity within the tumors was assessed by gelatin zymography. Inflammatory infiltrates were assessed by immunohistochemistry for macrophages and lymphocytes whereas expression of cytokines and other inflammatory mediators was assessed by quantitative real time PCR and multiplex ELISA. Increased tumor growth, proliferation index, increased microvascular density, and invasion was observed in Pten(-/-), Timp3(-/-) prostate tumors compared to Pten(-/-), Timp3(+/+) tumors. Tumor cell invasion in Pten(-/-), Timp3(-/-) mice was associated with increased expression of matrix metalloprotease (MMP)-9 and activation of MMP-2. There was markedly increased inflammatory cell infiltration into the TIMP3-deficient prostate tumors along with increased expression of monocyte chemoattractant protein-1, cyclooxygenase-2, TNF-α, and interleukin-1β; all of which are implicated in inflammation and cancer. This study provides important insights into the role of altered protease activity in promoting prostate cancer invasion and implicates prostate inflammation as an important promoting factor in prostate cancer progression. © 2015 Wiley Periodicals, Inc.

Exploring How Korean Teacher's Attitudes and Self-Efficacy for Using Inquiry and Language Based Teaching Practices Impacts Learning for Culturally and Linguistically Diverse Students: Implications for Science Teacher Education

ERIC Educational Resources Information Center

Park, Jennifer; Chu, Hye-Eun; Martin, Sonya N.

2016-01-01

Demographic trends in Korea indicate that the student population is becoming more diverse with regards to culture, ethnicity and language. These changes have implications for science classrooms where inquiry-based, student-centered activities require culturally and linguistically diverse (CLD) students to connect with their peers and successfully…