Phosphorylation of poly(rC) binding protein 1 (PCBP1) contributes to stabilization of mu opioid receptor (MOR) mRNA via interaction with AU-rich element RNA-binding protein 1 (AUF1) and poly A binding protein (PABP)

PubMed Central

Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee; Wei, Li-Na; Loh, Horace H.

2016-01-01

Gene regulation at the post-transcriptional level is frequently based on cis- and trans-acting factors on target mRNAs. We found a C-rich element (CRE) in mu-opioid receptor (MOR) 3′-untranslated region (UTR) to which poly (rC) binding protein 1 (PCBP1) binds, resulting in MOR mRNA stabilization. RNA immunoprecipitation and RNA EMSA revealed the formation of PCBP1-RNA complexes at the element. Knockdown of PCBP1 decreased MOR mRNA half-life and protein expression. Stimulation by forskolin increased cytoplasmic localization of PCBP1 and PCBP1/MOR 3′-UTR interactions via increased serine phosphorylation that was blocked by protein kinase A (PKA) or (phosphatidyl inositol-3) PI3-kinase inhibitors. The forskolin treatment also enhanced serine- and tyrosine-phosphorylation of AU-rich element binding protein (AUF1), concurrent with its increased binding to the CRE, and led to an increased interaction of poly A binding protein (PABP) with the CRE and poly(A) sites. AUF1 phosphorylation also led to an increased interaction with PCBP1. These findings suggest that a single co-regulator, PCBP1, plays a crucial role in stabilizing MOR mRNA, and is induced by PKA signaling by conforming to AUF1 and PABP. PMID:27836661

A Heroin Addiction Severity-Associated Intronic Single Nucleotide Polymorphism Modulates Alternative Pre-mRNA Splicing of the μ Opioid Receptor Gene OPRM1 via hnRNPH Interactions

PubMed Central

Xu, Jin; Lu, Zhigang; Xu, Mingming; Pan, Ling; Deng, Yi; Xie, Xiaohu; Liu, Huifen; Ding, Shixiong; Hurd, Yasmin L.; Pasternak, Gavril W.; Klein, Robert J.; Cartegni, Luca

2014-01-01

Single nucleotide polymorphisms (SNPs) in the OPRM1 gene have been associated with vulnerability to opioid dependence. The current study identifies an association of an intronic SNP (rs9479757) with the severity of heroin addiction among Han-Chinese male heroin addicts. Individual SNP analysis and haplotype-based analysis with additional SNPs in the OPRM1 locus showed that mild heroin addiction was associated with the AG genotype, whereas severe heroin addiction was associated with the GG genotype. In vitro studies such as electrophoretic mobility shift assay, minigene, siRNA, and antisense morpholino oligonucleotide studies have identified heterogeneous nuclear ribonucleoprotein H (hnRNPH) as the major binding partner for the G-containing SNP site. The G-to-A transition weakens hnRNPH binding and facilitates exon 2 skipping, leading to altered expressions of OPRM1 splice-variant mRNAs and hMOR-1 proteins. Similar changes in splicing and hMOR-1 proteins were observed in human postmortem prefrontal cortex with the AG genotype of this SNP when compared with the GG genotype. Interestingly, the altered splicing led to an increase in hMOR-1 protein levels despite decreased hMOR-1 mRNA levels, which is likely contributed by a concurrent increase in single transmembrane domain variants that have a chaperone-like function on MOR-1 protein stability. Our studies delineate the role of this SNP as a modifier of OPRM1 alternative splicing via hnRNPH interactions, and suggest a functional link between an SNP-containing splicing modifier and the severity of heroin addiction. PMID:25122903

Expression Patterns of Odorant Receptors and Response Properties of Olfactory Sensory Neurons in Aged Mice

PubMed Central

Lee, Anderson C.; Tian, Huikai; Grosmaitre, Xavier

2009-01-01

The sense of smell deteriorates in normal aging, but the underling mechanisms are still elusive. Here we investigated age-related alterations in expression patterns of odorant receptor (OR) genes and functional properties of olfactory sensory neurons (OSNs)—2 critical factors that define the odor detection threshold in the olfactory epithelium. Using in situ hybridization for 9 representative OR genes, we compared the cell densities of each OR in coronal nose sections at different ages (3–27 months). The cell density for different ORs peaked at different time points and a decline was observed for 6 of 9 ORs at advanced ages. Using patch clamp recordings, we then examined the odorant responses of individual OSNs coexpressing a defined OR (MOR23) and green fluorescent protein. The MOR23 neurons recorded from aged animals maintained a similar sensitivity and dynamic range in response to the cognate odorant (lyral) as those from younger mice. The results indicate that although the cell densities of OSNs expressing certain types of ORs decline at advanced ages, individual OSNs can retain their sensitivity. The implications of these findings in age-related olfactory deterioration are discussed. PMID:19759360

Expression patterns of odorant receptors and response properties of olfactory sensory neurons in aged mice.

PubMed

Lee, Anderson C; Tian, Huikai; Grosmaitre, Xavier; Ma, Minghong

2009-10-01

The sense of smell deteriorates in normal aging, but the underling mechanisms are still elusive. Here we investigated age-related alterations in expression patterns of odorant receptor (OR) genes and functional properties of olfactory sensory neurons (OSNs)-2 critical factors that define the odor detection threshold in the olfactory epithelium. Using in situ hybridization for 9 representative OR genes, we compared the cell densities of each OR in coronal nose sections at different ages (3-27 months). The cell density for different ORs peaked at different time points and a decline was observed for 6 of 9 ORs at advanced ages. Using patch clamp recordings, we then examined the odorant responses of individual OSNs coexpressing a defined OR (MOR23) and green fluorescent protein. The MOR23 neurons recorded from aged animals maintained a similar sensitivity and dynamic range in response to the cognate odorant (lyral) as those from younger mice. The results indicate that although the cell densities of OSNs expressing certain types of ORs decline at advanced ages, individual OSNs can retain their sensitivity. The implications of these findings in age-related olfactory deterioration are discussed.

MOR23 promotes muscle regeneration and regulates cell adhesion and migration

PubMed Central

Griffin, Christine A.; Kafadar, Kimberly A.; Pavlath, Grace K.

2009-01-01

Summary Odorant receptors (ORs) in the olfactory epithelium bind to volatile small molecules leading to the perception of smell. ORs are expressed in many tissues but their functions are largely unknown. We show multiple ORs display distinct mRNA expression patterns during myogenesis in vitro and muscle regeneration in vivo. Mouse OR23 (MOR23) expression is induced during muscle regeneration when muscle cells are extensively fusing and plays a key role in regulating migration and adhesion of muscle cells in vitro, two processes common during tissue repair. A soluble ligand for MOR23 is secreted by muscle cells in vitro and muscle tissue in vivo. MOR23 is necessary for proper skeletal muscle regeneration as loss of MOR23 leads to increased myofiber branching, commonly associated with muscular dystrophy. Together these data identify a functional role for an OR outside of the nose and suggest a larger role for ORs during tissue repair. PMID:19922870

Roles of the µ-opioid receptor and its related signaling pathways in the pathogenesis of premenstrual syndrome liver-qi stagnation

PubMed Central

Song, Chunhong; Xue, Ling

2017-01-01

The present study aimed to investigate the roles of the µ-opioid receptor (MOR) and its related signaling pathways in the pathogenesis of premenstrual syndrome (PMS) liver-qi stagnation, along with the therapeutic effects of the Shu-Yu capsule in treating the condition. A PMS liver-qi stagnation rat model was established using a chronic restraint stress method. The protein expression level of MOR within rat hippocampal tissue was detected via western blot analysis and cyclic adenosine monophosphate (cAMP) levels within the supernatant of a rat hippocampal cell culture were determined by ELISA. The western blot analysis indicated that the hippocampal expression level of MOR was significantly elevated in the PMS liver-qi stagnation model group. However, subsequent treatment with a Shu-Yu capsule was found to significantly decrease the level of MOR expression. In addition, in vitro experiments were performed, whereby primary hippocampal neurons were treated with model rat serum. It was observed that the level of MOR expression was significantly elevated, while brain-derived neurotrophic factor (BDNF) and cAMP levels in the culture supernatant were significantly decreased. These effects were reversed by treatment with serum from the Shu-Yu capsule-treated rats. Furthermore, when treated with the MOR activator DAMGO, the following were significantly decreased in the primary neurons: Phosphorylation levels of cAMP response element binding protein and extracellular signal-regulated protein kinases (ERK); BDNF expression; and cAMP content in the culture supernatant. These effects were reversed in primary neurons treated with DAMGO and Shu-Yu-containing rat serum. Collectively, the data suggest that increased MOR expression and activation of the cAMP/ERK signaling pathway in the hippocampus may be involved in the pathogenesis of PMS liver-qi stagnation. Furthermore, the efficacy of the Shu-Yu capsule in treating the condition may be via its regulation of MOR receptor signaling. PMID:28587388

Anti-nociceptive effect of patchouli alcohol: Involving attenuation of cyclooxygenase 2 and modulation of mu-opioid receptor.

PubMed

Yu, Xuan; Wang, Xin-Pei; Yan, Xiao-Jin; Jiang, Jing-Fei; Lei, Fan; Xing, Dong-Ming; Guo, Yue-Ying; Du, Li-Jun

2017-08-09

To explore the anti-nociceptive effect of patchouli alcohol (PA), the essential oil isolated from Pogostemon cablin (Blanco) Bent, and determine the mechanism in molecular levels. The acetic acid-induced writhing test and formalin-induced plantar injection test in mice were employed to confifirm the effect in vivo. Intracellular calcium ion was imaged to verify PA on mu-opioid receptor (MOR). Cyclooxygenase 2 (COX2) and MOR of mouse brain were expressed for determination of PA's target. Cellular experiments were carried out to find out COX2 and MOR expression induced by PA. PA significantly reduced latency period of visceral pain and writhing induced by acetic acid saline solution (P<0.01) and allodynia after intra-plantar formalin (P<0.01) in mice. PA also up-regulated COX2 mRNA and protein (P<0.05) with a down-regulation of MOR (P<0.05) both in in vivo and in vitro experiments, which devote to the analgesic effect of PA. A decrease in the intracellular calcium level (P<0.05) induced by PA may play an important role in its anti-nociceptive effect. PA showed the characters of enhancing the MOR expression and reducing the intracellular calcium ion similar to opioid effect. Both COX2 and MOR are involved in the mechanism of PA's anti-nociceptive effect, and the up-regulation of the receptor expression and the inhibition of intracellular calcium are a new perspective to PA's effect on MOR.

Tyrosinase is the modifier of retinoschisis in mice.

PubMed

Johnson, Britt A; Cole, Brian S; Geisert, Eldon E; Ikeda, Sakae; Ikeda, Akihiro

2010-12-01

X-linked retinoschisis (XLRS) is a form of macular degeneration with a juvenile onset. This disease is caused by mutations in the retinoschisin (RS1) gene. The major clinical pathologies of this disease include splitting of the retina (schisis) and a loss in synaptic transmission. Human XLRS patients display a broad range in phenotypic severity, even among family members with the same mutation. This variation suggests the existence of genetic modifiers that may contribute to disease severity. Previously, we reported the identification of a modifier locus, named Mor1, which affects severity of schisis in a mouse model of XLRS (the Rs1tmgc1 mouse). Homozygosity for the protective AKR allele of Mor1 restores cell adhesion in Rs1tmgc1 mice. Here, we report our study to identify the Mor1 gene. Through collecting recombinant mice followed by progeny testing, we have localized Mor1 to a 4.4-Mb region on chromosome 7. In this genetic region, the AKR strain is known to carry a mutation in the tyrosinase (Tyr) gene. We observed that the schisis phenotype caused by the Rs1 mutation is rescued by a Tyr mutation in the C57BL/6J genetic background, strongly suggesting that Tyr is the Mor1 gene.

Functional Mu Opioid Receptor Polymorphism (OPRM1 A118G) Associated With Heroin Use Outcomes in Caucasian Males: A Pilot Study

PubMed Central

Woodcock, Eric A.; Lundahl, Leslie H.; Burmeister, Margit; Greenwald, Mark K.

2017-01-01

Background Heroin’s analgesic, euphoric and dependence-producing effects are primarily mediated by the mu opioid receptor (MOR). A single gene, OPRM1, encodes the MOR. The functional polymorphism A118G, located in exon 1 of the OPRM1 gene, results in anatomically-specific reductions in MOR expression, which may alter an individual’s response to heroin. In prior studies 118G (rare allele) carriers demonstrated significantly greater opioid tolerance, overdose vulnerability, and pain sensitivity than 118AA homozygotes. Those findings suggest OPRM1 genotype may impact characteristics of heroin use. Methods The present pilot study characterized the impact of OPRM1 genotype (rs1799971, 118G allele carriers vs. 118AA homozygotes) on heroin-use phenotypes associated with heroin dependence severity in a sample of male, Caucasian chronic heroin users (n = 86). Results Results indicate that 118G allele carriers reported significantly more heroin use-related consequences and heroin-quit attempts, and were more likely to have sought treatment for their heroin use than 118AA homozygotes. Conclusions These preliminary findings, consistent with extant data, illustrate a role for OPRM1 allelic variation on heroin use characteristics, and provide support for considering genotype in heroin treatment and relapse prevention. PMID:25911999

Mu-Opioid Receptors in Ganglia, But Not in Muscle, Mediate Peripheral Analgesia in Rat Muscle Pain.

PubMed

Bagues, Ana; Martín, María Isabel; Higuera-Matas, Alejandro; Esteban-Hernández, Jesús; Ambrosio, Emilio; Sánchez-Robles, Eva María

2018-04-01

Previous studies have demonstrated the participation of peripheral μ-opioid receptors (MOR) in the antinociceptive effect of systemically administered morphine and loperamide in an orofacial muscle pain model, induced by hypertonic saline, but not in a spinally innervated one, in rats. In this study, we determine whether this peripheral antinociceptive effect is due to the activation of MOR localized in the muscle, ganglia, or both. To determine the local antinociceptive effect of morphine and loperamide, 2 models of acute muscle pain (trigeminal and spinal) were used. Also, to study the MOR expression, protein quantification was performed in the trigeminal and spinal ganglia, and in the muscles. The behavioral results show that the intramuscular injection of morphine and loperamide did not exert an antinociceptive effect in either muscle (morphine: P = .63, loperamide: P = .9). On the other hand, MOR expression was found in the ganglia but not in the muscles. This expression was on average 44% higher (95% confidence interval, 33.3-53.9) in the trigeminal ganglia than in the spinal one. The peripheral antinociceptive effect of systemically administered opioids may be due to the activation of MOR in ganglia. The greater expression of MOR in trigeminal ganglia could explain the higher antinociceptive effect of opioids in orofacial muscle pain than in spinal muscle pain. Therefore, peripheral opioids could represent a promising approach for the treatment of orofacial pain.

Inhibition of Histone Deacetylases Attenuates Morphine Tolerance and Restores MOR Expression in the DRG of BCP Rats.

PubMed

He, Xiao-Tao; Zhou, Kai-Xiang; Zhao, Wen-Jun; Zhang, Chen; Deng, Jian-Ping; Chen, Fa-Ming; Gu, Ze-Xu; Li, Yun-Qing; Dong, Yu-Lin

2018-01-01

The easily developed morphine tolerance in bone cancer pain (BCP) significantly hindered its clinical use. Increasing evidence suggests that histone deacetylases (HDACs) regulate analgesic tolerance subsequent to continuous opioid exposure. However, whether HDACs contribute to morphine tolerance in the pathogenesis of BCP is still unknown. In the current study, we explored the possible engagement of HDACs in morphine tolerance during the pathogenesis of BCP. After intra-tibia tumor cell inoculation (TCI), we found that the increased expression of HDACs was negatively correlated with the decreased expression of MOR in the DRG following TCI. The paw withdrawal threshold (PWT) and percentage maximum possible effects (MPEs) decreased rapidly in TCI rats when morphine was used alone. In contrast, the concomitant use of SAHA and morphine significantly elevated the PWT and MPEs of TCI rats compared to morphine alone. Additionally, we found that SAHA administration significantly elevated MOR expression in the DRG of TCI rats with or without morphine treatment. Moreover, the TCI-induced increase in the co-expression of MOR and HDAC1 in neurons was significantly decreased after SAHA administration. These results suggest that HDACs are correlated with the downregulation of MOR in the DRG during the pathogenesis of BCP. Inhibition of HDACs using SAHA can be used to attenuate morphine tolerance in BCP.

Low-Dose Cannabinoid Type 2 Receptor Agonist Attenuates Tolerance to Repeated Morphine Administration via Regulating μ-Opioid Receptor Expression in Walker 256 Tumor-Bearing Rats.

PubMed

Zhang, Mingyue; Wang, Kun; Ma, Min; Tian, Songyu; Wei, Na; Wang, Guonian

2016-04-01

Morphine is widely used in patients with moderate and severe cancer pain, whereas the development of drug tolerance remains a major problem associated with opioid use. Previous studies have shown that cannabinoid type 2 (CB2) receptor agonists induce morphine analgesia, attenuate morphine tolerance in normal and neuropathic pain animals, induce transcription of the μ-opioid receptor (MOR) gene in Jurkat T cells, and increase morphine analgesia in cancer pain animals. However, no studies of the effects of CB2 receptor agonists on morphine tolerance in cancer pain have been performed. Therefore, we investigated the effect of repeated intrathecal (IT) injection of the low-dose CB2 receptor agonist AM1241 on the development of morphine tolerance in walker 256 tumor-bearing rats. We also tested the influence of the CB2 receptor agonist AM1241 on MOR protein and messenger ribonucleic acid (mRNA) expression in the rat spinal cord and dorsal root ganglia (DRG). Walker 256 cells were implanted into the plantar region of each rat's right hindpaw. Tumor-bearing rats received IT injection of the CB2 receptor agonist AM1241 or antagonist AM630 with or without morphine subcutaneously twice daily for 8 days. Rats receiving drug vehicle only served as the control group. Mechanical paw withdrawal threshold and thermal paw withdrawal latency were assessed by a von Frey test and hot plate test 30 minutes after drug administration every day. MOR protein and mRNA expression in the spinal cord and DRG were detected after the last day (day 8) of drug administration via Western blot and real-time reverse transcription polymerase chain reaction. The data were analyzed via analysis of variance followed by Student t test with Bonferroni correction for multiple comparisons. Repeated morphine treatments reduced the mechanical withdrawal threshold and thermal latency. Coadministration of a nonanalgetic dose of the CB2 receptor agonist AM1241 with morphine significantly inhibited the development of morphine tolerance and increased the MOR protein expression in the spinal cord and DRG and mRNA expression in the spinal cord in tumor-bearing rats. Our findings indicate that IT injection of a nonanalgetic dose of a CB2 receptor agonist increased the analgesia effect and alleviated tolerance to morphine in tumor-bearing rats, potentially by regulating MOR expression in the spinal cord and DRG. This receptor may be a new target for prevention of the development of opioid tolerance in cancer pain.

Expression of antimicrobial peptide genes in Bombyx mori gut modulated by oral bacterial infection and development.

PubMed

Wu, Shan; Zhang, Xiaofeng; He, Yongqiang; Shuai, Jiangbing; Chen, Xiaomei; Ling, Erjun

2010-11-01

Although Bombyx mori systematic immunity is extensively studied, little is known about the silkworm's intestine-specific responses to bacterial infection. Antimicrobial peptides (AMPs) gene expression analysis of B. mori intestinal tissue to oral infection with the Gram-positive (Staphylococcus aureus) and -negative (Escherichia coli) bacteria revealed that there is specificity in the interaction between host immune responses and parasite types. Neither Att1 nor Leb could be stimulated by S. aureus and E. coli. However, CecA1, Glo1, Glo2, Glo3, Glo4 and Lys, could only be trigged by S. aureus. On the contrary, E. coli stimulation caused the decrease in the expression of CecA1, Glo3 and Glo4 in some time points. Interestingly, there is regional specificity in the silkworm local gut immunity. During the immune response, the increase in Def, Hem and LLP3 was only detected in the foregut and midgut. For CecB1, CecD, LLP2 and Mor, after orally administered with E. coli, the up-regulation was only limited in the midgut and hindgut. CecE was the only AMP that positively responses to the both bacteria in all the testing situations. With development, the expression levels of the AMPs were also changed dramatically. That is, at spinning and prepupa stages, a large increase in the expression of CecA1, CecB1, CecD, CecE, Glo1, Glo2, Glo3, Glo4, Leb, Def, Hem, Mor and Lys was detected in the gut. Unexpectedly, in addition to the IMD pathway genes, the Toll and JAK/STAT pathway genes in the silkworm gut can also be activated by microbial oral infection. But in the developmental course, corresponding to the increase in expression of AMPs at spinning and prepupa stages, only the Toll pathway genes in the gut exhibit the similar increasing trend. Our results imply that the immune responses in the silkworm gut are synergistically regulated by the Toll, JAK/STAT and IMD pathways. However, as the time for approaching pupation, the Toll pathway may play a role in the AMPs expression. Copyright © 2010 Elsevier Ltd. All rights reserved.

Stabilization of the μ-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action.

PubMed

Xu, Jin; Xu, Ming; Brown, Taylor; Rossi, Grace C; Hurd, Yasmin L; Inturrisi, Charles E; Pasternak, Gavril W; Pan, Ying-Xian

2013-07-19

The μ-opioid receptor gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, as illustrated by the identification of an array of splice variants generated by both 5' and 3' alternative splicing. The current study reports the identification of another set of splice variants conserved across species that are generated through exon skipping or insertion that encodes proteins containing only a single transmembrane (TM) domain. Using a Tet-Off system, we demonstrated that the truncated single TM variants can dimerize with the full-length 7-TM μ-opioid receptor (MOR-1) in the endoplasmic reticulum, leading to increased expression of MOR-1 at the protein level by a chaperone-like function that minimizes endoplasmic reticulum-associated degradation. In vivo antisense studies suggested that the single TM variants play an important role in morphine analgesia, presumably through modulation of receptor expression levels. Our studies suggest the functional roles of truncated receptors in other G protein-coupled receptor families.

Effect of Mas-related gene (Mrg) receptors on hyperalgesia in rats with CFA-induced inflammation via direct and indirect mechanisms.

PubMed

Jiang, Jianping; Wang, Dongmei; Zhou, Xiaolong; Huo, Yuping; Chen, Tingjun; Hu, Fenjuan; Quirion, Rémi; Hong, Yanguo

2013-11-01

Mas oncogene-related gene (Mrg) receptors are exclusively distributed in small-sized neurons in trigeminal and dorsal root ganglia (DRG). We investigated the effects of MrgC receptor activation on inflammatory hyperalgesia and its mechanisms. A selective MrgC receptor agonist, bovine adrenal medulla peptide 8-22 (BAM8-22) or melanocyte-stimulating hormone (MSH) or the μ-opioid receptor (MOR) antagonist CTAP was administered intrathecally (i.t.) in rats injected with complete Freund's adjuvant (CFA) in one hindpaw. Thermal and mechanical nociceptive responses were assessed. Neurochemicals were measured by immunocytochemistry, Western blot, ELISA and RT-PCR. CFA injection increased mRNA for MrgC receptors in lumbar DRG. BAM8-22 or MSH, given i.t., generated instant short and delayed long-lasting attenuations of CFA-induced thermal hyperalgesia, but not mechanical allodynia. These effects were associated with decreased up-regulation of neuronal NOS (nNOS), CGRP and c-Fos expression in the spinal dorsal horn and/or DRG. However, i.t. administration of CTAP blocked the induction by BAM8-22 of delayed anti-hyperalgesia and inhibition of nNOS and CGRP expression in DRG. BAM8-22 also increased mRNA for MORs and pro-opiomelanocortin, along with β-endorphin content in the lumbar spinal cord and/or DRG. MrgC receptors and nNOS were co-localized in DRG neurons. Activation of MrgC receptors suppressed up-regulation of pronociceptive mediators and consequently inhibited inflammatory pain, because of the activation of up-regulated MrgC receptors and subsequent endogenous activity at MORs. The uniquely distributed MrgC receptors could be a novel target for relieving inflammatory pain. © 2013 The British Pharmacological Society.

Identification of olfactory receptor genes in the Japanese grenadier anchovy Coilia nasus.

PubMed

Zhu, Guoli; Wang, Liangjiang; Tang, Wenqiao; Wang, Xiaomei; Wang, Cong

2017-01-01

Olfaction is essential for fish to detect odorant elements in the environment and plays a critical role in navigating, locating food and detecting predators. Olfactory function is produced by the olfactory transduction pathway and is activated by olfactory receptors (ORs) through the binding of odorant elements. Recently, four types of olfactory receptors have been identified in vertebrate olfactory epithelium, including main odorant receptors (MORs), vomeronasal type receptors (VRs), trace-amine associated receptors (TAARs) and formyl peptide receptors (FPRs). It has been hypothesized that migratory fish, which have the ability to perform spawning migration, use olfactory cues to return to natal rivers. Therefore, obtaining OR genes from migratory fish will provide a resource for the study of molecular mechanisms that underlie fish spawning migration behaviors. Previous studies of OR genes have mainly focused on genomic data, however little information has been gained at the transcript level. In this study, we identified the OR genes of an economically important commercial fish Coilia nasus through searching for olfactory epithelium transcriptomes. A total of 142 candidate MOR, 52 V2R/OlfC, 32 TAAR and two FPR putative genes were identified. In addition, through genomic analysis we identified several MOR genes containing introns, which is unusual for vertebrate MOR genes. The transcriptome-scale mining strategy proved to be fruitful in identifying large sets of OR genes from species whose genome information is unavailable. Our findings lay the foundation for further research into the possible molecular mechanisms underlying the spawning migration behavior in C. nasus .

Isolation and characterization of alternatively spliced variants of the mouse sigma1 receptor gene, Sigmar1.

PubMed

Pan, Ling; Pasternak, David A; Xu, Jin; Xu, Mingming; Lu, Zhigang; Pasternak, Gavril W; Pan, Ying-Xian

2017-01-01

The sigma1 receptor acts as a chaperone at the endoplasmic reticulum, associates with multiple proteins in various cellular systems, and involves in a number of diseases, such as addiction, pain, cancer and psychiatric disorders. The sigma1 receptor is encoded by the single copy SIGMAR1 gene. The current study identifies five alternatively spliced variants of the mouse sigma1 receptor gene using a polymerase chain reaction cloning approach. All the splice variants are generated by exon skipping or alternative 3' or 5' splicing, producing the truncated sigma1 receptor. Similar alternative splicing has been observed in the human SIGMAR1 gene based on the molecular cloning or genome sequence prediction, suggesting conservation of alternative splicing of SIGMAR1 gene. Using quantitative polymerase chain reactions, we demonstrate differential expression of several splice variants in mouse tissues and brain regions. When expressed in HEK293 cells, all the splice variants fail to bind sigma ligands, implicating that each truncated region in these splice variants is important for ligand binding. However, co-immunoprecipitation (Co-IP) study in HEK293 cells co-transfected with tagged constructs reveals that all the splice variants maintain their ability to physically associate with a mu opioid receptor (mMOR-1), providing useful information to correlate the motifs/sequences necessary for their physical association. Furthermore, a competition Co-IP study showed that all the variants can disrupt in a dose-dependent manner the dimerization of the original sigma1 receptor with mMOR-1, suggesting a potential dominant negative function and providing significant insights into their function.

The proteins interacting with C-terminal of μ receptor are identified by bacterial two-hybrid system from brain cDNA library in morphine-dependent rats.

PubMed

Zhou, Peilan; Jiang, Jiebing; Dong, Zhaoqi; Yan, Hui; You, Zhendong; Su, Ruibin; Gong, Zehui

2015-12-15

Opioid addiction is associated with long-term adaptive changes in the brain that involve protein expression. The carboxyl-terminal of the μ opioid receptor (MOR-C) is important for receptor signal transduction under opioid treatment. However, the proteins that interact with MOR-C after chronic morphine exposure remain unknown. The brain cDNA library of chronic morphine treatment rats was screened using rat MOR-C to investigate the regulator of opioids dependence in the present study. The brain cDNA library from chronic morphine-dependent rats was constructed using the SMART (Switching Mechanism At 5' end of RNA Transcript) technique. Bacterial two-hybrid system was used to screening the rat MOR-C interacting proteins from the cDNA library. RT-qPCR and immunoblotting were used to determine the variation of MOR-C interacting proteins in rat brain after chronic morphine treatment. Column overlay assays, immunocytochemistry and coimmunoprecipitation were used to demonstrate the interaction of MOR-C and p75NTR-associated cell death executor (NADE). 21 positive proteins, including 19 known proteins were screened to interact with rat MOR-C. Expression of several of these proteins was altered in specific rat brain regions after chronic morphine treatment. Among these proteins, NADE was confirmed to interact with rat MOR-C by in vitro protein-protein binding and coimmunoprecipitation in Chinese hamster ovary (CHO) cells and rat brain with or without chronic morphine treatment. Understanding the rat MOR-C interacting proteins and the proteins variation under chronic morphine treatment may be critical for determining the pathophysiological basis of opioid tolerance and addiction. Copyright © 2015. Published by Elsevier Inc.

Heteromerization of the μ- and δ-Opioid Receptors Produces Ligand-Biased Antagonism and Alters μ-Receptor TraffickingS⃞

PubMed Central

Milan-Lobo, Laura

2011-01-01

Heteromerization of opioid receptors has been shown to alter opioid receptor pharmacology. However, how receptor heteromerization affects the processes of endocytosis and postendocytic sorting has not been closely examined. This question is of particular relevance for heteromers of the μ-opioid receptor (MOR) and δ-opioid receptor (DOR), because the MOR is recycled primarily after endocytosis and the DOR is degraded in the lysosome. Here, we examined the endocytic and postendocytic fate of MORs, DORs, and DOR/MOR heteromers in human embryonic kidney 293 cells stably expressing each receptor alone or coexpressing both receptors. We found that the clinically relevant MOR agonist methadone promotes endocytosis of MOR but also the DOR/MOR heteromer. Furthermore, we show that DOR/MOR heteromers that are endocytosed in response to methadone are targeted for degradation, whereas MORs in the same cell are significantly more stable. It is noteworthy that we found that the DOR-selective antagonist naltriben mesylate could block both methadone- and [d-Ala2,NMe-Phe4,Gly-ol5]-enkephalin-induced endocytosis of the DOR/MOR heteromers but did not block signaling from this heteromer. Together, our results suggest that the MOR adopts novel trafficking properties in the context of the DOR/MOR heteromer. In addition, they suggest that the heteromer shows “biased antagonism,” whereby DOR antagonist can inhibit trafficking but not signaling of the DOR/MOR heteromer. PMID:21422164

A qualitative exploration of malaria operational research situation in Nigeria.

PubMed

Ajayi, IkeOluwapo O; Ughasoro, Maduka D; Ogunwale, Akintayo; Odeyinka, Oluwaseun; Babalola, Obafemi; Sharafadeen, Salami; Adamu, Al-Mukhtar Y; Ajumobi, Olufemi; Orimogunje, Taiwo; Nguku, Patrick

2017-01-01

Malaria, remains one of the leading causes of high morbidity and mortality in Nigeria despite implementation of several public health interventions for its control. Operational limitations and methodological gaps have been associated with malaria control interventions and research, and these have necessitated the need for a well-tailored Malaria Operational Research (MOR) agenda. However, there is paucity of evidence-based information on relevant stakeholders' experience, awareness, perceptions and use of MOR and suggestions on setting MOR agenda. As part of a larger study to provide data for national MOR agenda setting, we assessed the MOR research situation from the perspectives of key stakeholders in Nigeria and contribution of MOR to the malaria elimination agenda. We conducted key informant interviews among 40 purposively selected stakeholders from the six geo-political zones in Nigeria. Data was collected using a pre-tested key informant interview guide which comprised issues related to experience, awareness, use of MOR and MOR needs, and suggestions for MOR. We conducted a detailed content analysis. Half of the participants had participated in MOR. Participants perceived MOR as important. Only few were aware of existing framework for MOR in Nigeria while above half expressed that MOR is yet to be used to inform policy in Nigeria. Participants identified several MOR needs such as development of improved diagnostic techniques, and interventions for promoting early diagnosis, prompt treatment and quality programmatic data. Participants opined the need for country-specific prioritised MOR agenda that cut across malaria thematic areas including malaria prevention and case management. Participants suggested the involvement of various stakeholders and multi-disciplinary approach in setting MOR. Although some stakeholders have been involved in MOR, it is still rarely used to inform policy and several needs exist across thematic areas. A broad-based stakeholder involvement, multi-disciplinary approach to agenda setting and its wide dissemination have been suggested.

Olfactory discrimination largely persists in mice with defects in odorant receptor expression and axon guidance.

PubMed

Knott, Thomas K; Madany, Pasil A; Faden, Ashley A; Xu, Mei; Strotmann, Jörg; Henion, Timothy R; Schwarting, Gerald A

2012-07-04

The defining feature of the main olfactory system in mice is that each olfactory sensory neuron expresses only one of more than a thousand different odorant receptor genes. Axons expressing the same odorant receptor converge onto a small number of targets in the olfactory bulb such that each glomerulus is made up of axon terminals expressing just one odorant receptor. It is thought that this precision in axon targeting is required to maintain highly refined odor discrimination. We previously showed that β3GnT2(-/-) mice have severe developmental and axon guidance defects. The phenotype of these mice is similar to adenylyl cyclase 3 (AC3) knockout mice largely due to the significant down-regulation of AC3 activity in β3GnT2(-/-) neurons. Microarray analysis reveals that nearly one quarter of all odorant receptor genes are down regulated in β3GnT2(-/-) mice compared to controls. Analysis of OR expression by quantitative PCR and in situ hybridization demonstrates that the number of neurons expressing some odorant receptors, such as mOR256-17, is increased by nearly 60% whereas for others such as mOR28 the number of neurons is decreased by more than 75% in β3GnT2(-/-) olfactory epithelia. Analysis of axon trajectories confirms that many axons track to inappropriate targets in β3GnT2(-/-) mice, and some glomeruli are populated by axons expressing more than one odorant receptor. Results show that mutant mice perform nearly as well as control mice in an odor discrimination task. In addition, in situ hybridization studies indicate that the expression of several activity dependent genes is unaffected in β3GnT2(-/-) olfactory neurons. Results presented here show that many odorant receptors are under-expressed in β3GnT2(-/-) mice and further demonstrate that additional axon subsets grow into inappropriate targets or minimally innervate glomeruli in the olfactory bulb. Odor evoked gene expression is unchanged and β3GnT2(-/-) mice exhibit a relatively small deficit in their ability to discriminate divergent odors. Results suggest that despite the fact that β3GnT2(-/-) mice have decreased AC3 activity, decreased expression of many ORs, and display many axon growth and guidance errors, odor-evoked activity in cilia of mutant olfactory neurons remains largely intact.

Isolation and characterization of alternatively spliced variants of the mouse sigma1 receptor gene, Sigmar1

PubMed Central

Pan, Ling; Pasternak, David A.; Xu, Jin; Xu, Mingming; Lu, Zhigang; Pasternak, Gavril W.

2017-01-01

The sigma1 receptor acts as a chaperone at the endoplasmic reticulum, associates with multiple proteins in various cellular systems, and involves in a number of diseases, such as addiction, pain, cancer and psychiatric disorders. The sigma1 receptor is encoded by the single copy SIGMAR1 gene. The current study identifies five alternatively spliced variants of the mouse sigma1 receptor gene using a polymerase chain reaction cloning approach. All the splice variants are generated by exon skipping or alternative 3’ or 5’ splicing, producing the truncated sigma1 receptor. Similar alternative splicing has been observed in the human SIGMAR1 gene based on the molecular cloning or genome sequence prediction, suggesting conservation of alternative splicing of SIGMAR1 gene. Using quantitative polymerase chain reactions, we demonstrate differential expression of several splice variants in mouse tissues and brain regions. When expressed in HEK293 cells, all the splice variants fail to bind sigma ligands, implicating that each truncated region in these splice variants is important for ligand binding. However, co-immunoprecipitation (Co-IP) study in HEK293 cells co-transfected with tagged constructs reveals that all the splice variants maintain their ability to physically associate with a mu opioid receptor (mMOR-1), providing useful information to correlate the motifs/sequences necessary for their physical association. Furthermore, a competition Co-IP study showed that all the variants can disrupt in a dose-dependent manner the dimerization of the original sigma1 receptor with mMOR-1, suggesting a potential dominant negative function and providing significant insights into their function. PMID:28350844

Postnatal odorant exposure induces peripheral olfactory plasticity at the cellular level.

PubMed

Cadiou, Hervé; Aoudé, Imad; Tazir, Bassim; Molinas, Adrien; Fenech, Claire; Meunier, Nicolas; Grosmaitre, Xavier

2014-04-02

Mammalian olfactory sensory neurons (OSNs) form the primary elements of the olfactory system. Inserted in the olfactory mucosa lining of the nasal cavity, they are exposed to the environment and their lifespan is brief. Several reports say that OSNs are regularly regenerated during the entire life and that odorant environment affects the olfactory epithelium. However, little is known about the impact of the odorant environment on OSNs at the cellular level and more precisely in the context of early postnatal olfactory exposure. Here we exposed MOR23-green fluorescent protein (GFP) and M71-GFP mice to lyral or acetophenone, ligands for MOR23 or M71, respectively. Daily postnatal exposure to lyral induces plasticity in the population of OSNs expressing MOR23. Their density decreases after odorant exposure, whereas the amount of MOR23 mRNA and protein remain stable in the whole epithelium. Meanwhile, quantitative PCR indicates that each MOR23 neuron has higher levels of olfactory receptor transcripts and also expresses more CNGA2 and phosphodiesterase 1C, fundamental olfactory transduction pathway proteins. Transcript levels return to baseline after 4 weeks recovery. Patch-clamp recordings reveal that exposed MOR23 neurons respond to lyral with higher sensitivity and broader dynamic range while the responses' kinetics were faster. These effects are specific to the odorant-receptor pair lyral-MOR23: there was no effect of acetophenone on MOR23 neurons and no effect of acetophenone and lyral on the M71 population. Together, our results clearly demonstrate that OSNs undergo specific anatomical, molecular, and functional adaptation when chronically exposed to odorants in the early stage of life.

HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in a rat model of bone cancer pain by restoring μ-opioid receptor in spinal cord.

PubMed

Hou, Xinran; Weng, Yingqi; Ouyang, Bihan; Ding, Zhuofeng; Song, Zongbin; Zou, Wangyuan; Huang, Changsheng; Guo, Qulian

2017-08-15

Bone cancer pain (BCP) is a common complication with inadequate management in patients suffering from advanced cancer. Histone deacetylase inhibitors showed significant analgesic effect in multiple inflammatory and neuropathic pain models, but their effect in bone cancer pain has never been explored. In this study, we utilized a BCP rat model with intra-tibial inoculation of Walker 256 mammary gland carcinoma cells, which developed progressive mechanical hypersensitivity but not thermal hypersensitivity. Intrathecal application of trichostatin A (TSA), a classic pan-HDAC inhibitor, ameliorated tactile hypersensitivity and enhanced the analgesic effect of morphine in BCP rats. The analgesic effect of TSA was blocked by co-administration of CTAP, a specific MOR antagonist, confirming the involvement of mu-opioid receptor (MOR). A reduction of MOR expression was observed in the lumbar spinal cord of BCP rats and TSA treatment was able to partially reverse it. In vitro study in PC12 cells also demonstrated the dose-dependent enhancement of MOR expression by TSA treatment. Taking all into consideration, we could draw the conclusion that HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in BCP rats, probably by restoring MOR expression in spinal cord. Copyright © 2017 Elsevier B.V. All rights reserved.

Morphine drives internal ribosome entry site-mediated hnRNP K translation in neurons through opioid receptor-dependent signaling

PubMed Central

Lee, Pin-Tse; Chao, Po-Kuan; Ou, Li-Chin; Chuang, Jian-Ying; Lin, Yen-Chang; Chen, Shu-Chun; Chang, Hsiao-Fu; Law, Ping-Yee; Loh, Horace H.; Chao, Yu-Sheng; Su, Tsung-Ping; Yeh, Shiu-Hwa

2014-01-01

Heterogeneous nuclear ribonucleoprotein K (hnRNP K) binds to the promoter region of mu-opioid receptor (MOR) to regulate its transcriptional activity. How hnRNP K contributes to the analgesic effects of morphine, however, is largely unknown. We provide evidence that morphine increases hnRNP K protein expression via MOR activation in rat primary cortical neurons and HEK-293 cells expressing MORs, without increasing mRNA levels. Using the bicistronic reporter assay, we examined whether morphine-mediated accumulation of hnRNP K resulted from translational control. We identified potential internal ribosome entry site elements located in the 5′ untranslated regions of hnRNP K transcripts that were regulated by morphine. This finding suggests that internal translation contributes to the morphine-induced accumulation of hnRNP K protein in regions of the central nervous system correlated with nociceptive and antinociceptive modulatory systems in mice. Finally, we found that down-regulation of hnRNP K mediated by siRNA attenuated morphine-induced hyperpolarization of membrane potential in AtT20 cells. Silencing hnRNP K expression in the spinal cord increased nociceptive sensitivity in wild-type mice, but not in MOR-knockout mice. Thus, our findings identify the role of translational control of hnRNP K in morphine-induced analgesia through activation of MOR. PMID:25361975

Effect of acute and continuous morphine treatment on transcription factor expression in subregions of the rat caudate putamen. Marked modulation by D4 receptor activation.

PubMed

Gago, Belén; Suárez-Boomgaard, Diana; Fuxe, Kjell; Brené, Stefan; Reina-Sánchez, María Dolores; Rodríguez-Pérez, Luis M; Agnati, Luigi F; de la Calle, Adelaida; Rivera, Alicia

2011-08-17

Acute administration of the dopamine D(4) receptor (D(4)R) agonist PD168,077 induces a down-regulation of the μ opioid receptor (MOR) in the striosomal compartment of the rat caudate putamen (CPu), suggesting a striosomal D(4)R/MOR receptor interaction in line with their high co-distribution in this brain subregion. The present work was designed to explore if a D(4)R/MOR receptor interaction also occurs in the modulation of the expression pattern of several transcription factors in striatal subregions that play a central role in drug addiction. Thus, c-Fos, FosB/ΔFosB and P-CREB immunoreactive profiles were quantified in the rat CPu after either acute or continuous (6-day) administration of morphine and/or PD168,077. Acute and continuous administration of morphine induced different patterns of expression of these transcription factors, effects that were time-course and region dependent and fully blocked by PD168,077 co-administration. Moreover, this effect of the D(4)R agonist was counteracted by the D(4)R antagonist L745,870. Interestingly, at some time-points, combined treatment with morphine and PD168,077 substantially increased c-Fos, FosB/ΔFosB and P-CREB expression. The results of this study give indications for a general antagonistic D(4)R/MOR receptor interaction at the level of transcription factors. The change in the transcription factor expression by D(4)R/MOR interactions in turn suggests a modulation of neuronal activity in the CPu that could be of relevance for drug addiction. Copyright © 2011 Elsevier B.V. All rights reserved.

Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation

PubMed Central

Antonio, Tamara; Childers, Steven R.; Rothman, Richard B.; Dersch, Christina M.; King, Christine; Kuehne, Martin; Bornmann, William G.; Eshleman, Amy J.; Janowsky, Aaron; Simon, Eric R.; Reith, Maarten E. A.; Alper, Kenneth

2013-01-01

Objective The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of μ-opioid receptor (MOR)-related G proteins by iboga alkaloids. Methods Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([35S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices. Results And Significance In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [35S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [35S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [35S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids. PMID:24204784

Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation.

PubMed

Antonio, Tamara; Childers, Steven R; Rothman, Richard B; Dersch, Christina M; King, Christine; Kuehne, Martin; Bornmann, William G; Eshleman, Amy J; Janowsky, Aaron; Simon, Eric R; Reith, Maarten E A; Alper, Kenneth

2013-01-01

The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of μ-opioid receptor (MOR)-related G proteins by iboga alkaloids. Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([(35)S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices. In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [(35)S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [(35)S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [(35)S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.

Morphine administration during low ovarian hormone stage results in transient over expression of fear memories in females.

PubMed

Perez-Torres, Emily M; Ramos-Ortolaza, Dinah L; Morales, Roberto; Santini, Edwin; Rios-Ruiz, Efrain J; Torres-Reveron, Annelyn

2015-01-01

Acute exposure to morphine after a traumatic event reduces trauma related symptoms in humans and conditioned fear expression in male rats. We aimed to determine whether acute administration of morphine alters consolidation of fear learning and extinction. Male and female rats in proestrus and metaestrus (high and low ovarian hormones respectively) underwent fear conditioning and received saline or morphine (2.5 mg/kg s.c.). The next day they underwent extinction. Results showed increased freezing during extinction only in the morphine metaestrus group while morphine did not affect males or proestrus females. Recall of extinction was similar on all groups. On a second experiment, a subset of rats conditioned during metaestrus was administered morphine prior to extinction producing no effects. We then measured mu opioid receptor (MOR) expression in the amygdala and periaqueductal gray (PAG) at the end of extinction (day 2). In males and proestrus females, morphine caused an increase in MOR in the amygdala but no in the PAG. In metaestrus females, morphine did not change MOR expression in either structure. These data suggests that ovarian hormones may interact with MORs in the amygdala to transiently alter memory consolidation. Morphine given after trauma to females with low ovarian hormones might increase the recall of fear responses, making recovery harder.

Spatiotemporal control of opioid signaling and behavior

PubMed Central

Siuda, Edward R.; Copits, Bryan A.; Schmidt, Martin J.; Baird, Madison A.; Al-Hasani, Ream; Planer, William J.; Funderburk, Samuel C.; McCall, Jordan G.; Gereau, Robert W.; Bruchas, Michael R.

2015-01-01

Summary Optogenetics is now a widely accepted tool for spatiotemporal manipulation of neuronal activity. However, a majority of optogenetic approaches use binary on/off control schemes. Here we extend the optogenetic toolset by developing a neuromodulatory approach using a rationale-based design to generate a Gi-coupled, optically-sensitive, mu-opioid-like receptor, we term opto-MOR. We demonstrate that opto-MOR engages canonical mu-opioid signaling through inhibition of adenylyl cyclase, activation of MAPK and G protein-gated inward rectifying potassium (GIRK) channels, and internalizes with similar kinetics as the mu-opioid receptor. To assess in vivo utility we expressed a Cre-dependent viral opto-MOR in RMTg/VTA GABAergic neurons, which led to a real-time place preference. In contrast, expression of opto-MOR in GABAergic neurons of the ventral pallidum hedonic cold spot, led to real-time place aversion. This tool has generalizable application for spatiotemporal control of opioid signaling and, furthermore, can be used broadly for mimicking endogenous neuronal inhibition pathways. PMID:25937173

Olfactory discrimination largely persists in mice with defects in odorant receptor expression and axon guidance

PubMed Central

2012-01-01

Background The defining feature of the main olfactory system in mice is that each olfactory sensory neuron expresses only one of more than a thousand different odorant receptor genes. Axons expressing the same odorant receptor converge onto a small number of targets in the olfactory bulb such that each glomerulus is made up of axon terminals expressing just one odorant receptor. It is thought that this precision in axon targeting is required to maintain highly refined odor discrimination. We previously showed that β3GnT2−/− mice have severe developmental and axon guidance defects. The phenotype of these mice is similar to adenylyl cyclase 3 (AC3) knockout mice largely due to the significant down-regulation of AC3 activity in β3GnT2−/− neurons. Results Microarray analysis reveals that nearly one quarter of all odorant receptor genes are down regulated in β3GnT2−/− mice compared to controls. Analysis of OR expression by quantitative PCR and in situ hybridization demonstrates that the number of neurons expressing some odorant receptors, such as mOR256-17, is increased by nearly 60% whereas for others such as mOR28 the number of neurons is decreased by more than 75% in β3GnT2−/− olfactory epithelia. Analysis of axon trajectories confirms that many axons track to inappropriate targets in β3GnT2−/− mice, and some glomeruli are populated by axons expressing more than one odorant receptor. Results show that mutant mice perform nearly as well as control mice in an odor discrimination task. In addition, in situ hybridization studies indicate that the expression of several activity dependent genes is unaffected in β3GnT2−/− olfactory neurons. Conclusions Results presented here show that many odorant receptors are under-expressed in β3GnT2−/− mice and further demonstrate that additional axon subsets grow into inappropriate targets or minimally innervate glomeruli in the olfactory bulb. Odor evoked gene expression is unchanged and β3GnT2−/− mice exhibit a relatively small deficit in their ability to discriminate divergent odors. Results suggest that despite the fact that β3GnT2−/− mice have decreased AC3 activity, decreased expression of many ORs, and display many axon growth and guidance errors, odor-evoked activity in cilia of mutant olfactory neurons remains largely intact. PMID:22559903

mu-Opioid receptor-independent fashion of the suppression of sodium currents by mu-opioid analgesics in thalamic neurons.

PubMed

Hashimoto, Keisuke; Amano, Taku; Kasakura, Akiko; Uhl, George R; Sora, Ichiro; Sakai, Norio; Kuzumaki, Naoko; Suzuki, Tsutomu; Narita, Minoru

2009-03-27

Most reports in the literature have shown that the effects of opioid analgesics are primarily mediated by mu-opioid receptor (MOR), whereas other potential targets of opioid analgesics have not been thoroughly characterized. In this study, we found that extracellular application of morphine, fentanyl or oxycodone, which are all considered to be MOR agonists, at relatively high concentrations, but not endogenous mu-opioid peptides, produced a concentration-dependent suppression of sodium currents in cultured thalamic neurons. These effects of opioids were not affected by either a MOR antagonist naloxone or a deletion of MOR gene. Among these opioids, fentanyl strongly suppressed sodium currents to the same degree as lidocaine, and both morphine and oxycodone slightly but significantly reduced sodium currents when they were present extracellularly. In contrast, the intracellular application of morphine, but not oxycodone, fentanyl or lidocaine, reduced sodium currents. These results suggest that morphine, fentanyl and oxycodone each produce the MOR-independent suppression of sodium currents by distinct mechanisms in thalamic neurons.

Molecular signatures of mu opioid receptor and somatostatin receptor 2 in pancreatic cancer

PubMed Central

Jorand, Raphael; Biswas, Sunetra; Wakefield, Devin L.; Tobin, Steven J.; Golfetto, Ottavia; Hilton, Kelsey; Ko, Michelle; Ramos, Joe W.; Small, Alexander R.; Chu, Peiguo; Singh, Gagandeep; Jovanovic-Talisman, Tijana

2016-01-01

Pancreatic ductal adenocarcinoma (PDAC), a particularly aggressive malignancy, has been linked to atypical levels, certain mutations, and aberrant signaling of G-protein–coupled receptors (GPCRs). GPCRs have been challenging to target in cancer because they organize into complex networks in tumor cells. To dissect such networks with nanometer-scale precision, here we combine traditional biochemical approaches with superresolution microscopy methods. A novel interaction specific to PDAC is identified between mu opioid receptor (MOR) and somatostatin receptor 2 (SSTR2). Although MOR and SSTR2 did not colocalize in healthy pancreatic cells or matching healthy patient tissues, the pair did significantly colocalize in pancreatic cancer cells, multicellular tumor spheroids, and cancerous patient tissues. Moreover, this association in pancreatic cancer cells correlated with functional cross-talk and increased metastatic potential of cells. Coactivation of MOR and SSTR2 in PDAC cells led to increased expression of mesenchymal markers and decreased expression of an epithelial marker. Together these results suggest that the MOR-SSTR2 heteromer may constitute a novel therapeutic target for PDAC. PMID:27682590

Spatiotemporal control of opioid signaling and behavior.

PubMed

Siuda, Edward R; Copits, Bryan A; Schmidt, Martin J; Baird, Madison A; Al-Hasani, Ream; Planer, William J; Funderburk, Samuel C; McCall, Jordan G; Gereau, Robert W; Bruchas, Michael R

2015-05-20

Optogenetics is now a widely accepted tool for spatiotemporal manipulation of neuronal activity. However, a majority of optogenetic approaches use binary on/off control schemes. Here, we extend the optogenetic toolset by developing a neuromodulatory approach using a rationale-based design to generate a Gi-coupled, optically sensitive, mu-opioid-like receptor, which we term opto-MOR. We demonstrate that opto-MOR engages canonical mu-opioid signaling through inhibition of adenylyl cyclase, activation of MAPK and G protein-gated inward rectifying potassium (GIRK) channels and internalizes with kinetics similar to that of the mu-opioid receptor. To assess in vivo utility, we expressed a Cre-dependent viral opto-MOR in RMTg/VTA GABAergic neurons, which led to a real-time place preference. In contrast, expression of opto-MOR in GABAergic neurons of the ventral pallidum hedonic cold spot led to real-time place aversion. This tool has generalizable application for spatiotemporal control of opioid signaling and, furthermore, can be used broadly for mimicking endogenous neuronal inhibition pathways. Copyright © 2015 Elsevier Inc. All rights reserved.

Renilla luciferase reporter assay to study 3'UTR-driven posttranscriptional regulations of OPRM1.

PubMed

Vincelli, Gabriele; Bedini, Andrea

2015-01-01

The regulation of MOR expression at the level of mRNA is relevant for its role in pain transmission and in other functions involving opioid receptors. Recently, the role of the 3'UTR in the posttranscriptional regulation of MOR expression has been highlighted. Here we describe a Renilla luciferase reporter assay for the study of the effect of any selective treatment on the 3'UTR-dependent regulation of OPRM1 in a model of glial cells.

Identification of a Putative Mexican Strain of Serratia entomophila Pathogenic against Root-Damaging Larvae of Scarabaeidae (Coleoptera)▿ †

PubMed Central

Nuñez-Valdez, M. Eugenia; Calderón, Marco A.; Aranda, Eduardo; Hernández, Luciano; Ramírez-Gama, Rosa M.; Lina, Laura; Rodríguez-Segura, Zitlhally; Gutiérrez, María del C.; Villalobos, Francisco J.

2008-01-01

The larvae of scarab beetles, known as “white grubs” and belonging to the genera Phyllophaga and Anomala (Coleoptera: Scarabaeidae), are regarded as soil-dwelling pests in Mexico. During a survey conducted to find pathogenic bacteria with the potential to control scarab larvae, a native Serratia sp. (strain Mor4.1) was isolated from a dead third-instar Phyllophaga blanchardi larva collected from a cornfield in Tres Marías, Morelos, Mexico. Oral bioassays using healthy P. blanchardi larvae fed with the Mor4.1 isolate showed that this strain was able to cause an antifeeding effect and a significant loss of weight. Mortality was observed for P. blanchardi, P. trichodes, and P. obsoleta in a multidose experiment. The Mor4.1 isolate also caused 100% mortality 24 h after intracoelomic inoculation of the larvae of P. blanchardi, P. ravida, Anomala donovani and the lepidopteran insect Manduca sexta. Oral and injection bioassays were performed with concentrated culture broths of the Mor4.1 isolate to search for disease symptoms and mortality caused by extracellular proteins. The results have shown that Mor4.1 broths produce significant antifeeding effects and mortality. Mor4.1 broths treated with proteinase K lost the ability to cause disease symptoms and mortality, in both the oral and the injection bioassays, suggesting the involvement of toxic proteins in the disease. The Mor4.1 isolate was identified as a putative Serratia entomophila Mor4.1 strain based on numerical taxonomy and phylogenetic analyses done with the 16S rRNA gene sequence. The potential of S. entomophila Mor4.1 and its toxins to be used in an integrated pest management program is discussed. PMID:18083879

Role of MicroRNA-143 in Nerve Injury-Induced Upregulation of Dnmt3a Expression in Primary Sensory Neurons

PubMed Central

Xu, Bo; Cao, Jing; Zhang, Jun; Jia, Shushan; Wu, Shaogen; Mo, Kai; Wei, Guihua; Liang, Lingli; Miao, Xuerong; Bekker, Alex; Tao, Yuan-Xiang

2017-01-01

Peripheral nerve injury increased the expression of the DNA methyltransferase 3A (Dnmt3a) mRNA and its encoding Dnmt3a protein in injured dorsal root ganglia (DRG). This increase is considered as an endogenous instigator in neuropathic pain genesis through epigenetic silencing of pain-associated genes (such as Oprm1) in injured DRG. However, how DRG DNMT3a is increased following peripheral nerve injury is still elusive. We reported here that peripheral nerve injury caused by the fifth spinal nerve ligation (SNL) downregulated microRNA (miR)-143 expression in injured DRG. This downregulation was required for SNL-induced DRG Dnmt3a increase as rescuing miR-143 downregulation through microinjection of miR-143 mimics into injured DRG blocked the SNL-induced increase in Dnmt3a and restored the SNL-induced decreases in Oprm1 mRNA and its encoding mu opioid receptor (MOR) in injured DRG, impaired spinal cord central sensitization and neuropathic pain, and improved morphine analgesic effects following SNL. Mimicking SNL-induced DRG miR-143 downregulation through DRG microinjection of miR143 inhibitors in naive rats increased the expression of Dnmt3a and reduced the expression of Oprm1 mRNA and MOR in injected DRG and produced neuropathic pain-like symptoms. These findings suggest that miR-143 is a negative regulator in Dnmt3a expression in the DRG under neuropathic pain conditions and may be a potential target for therapeutic management of neuropathic pain. PMID:29170626

Cloning and functional identification of moricins from the diamondback moth, Plutella xylostella (L.).

PubMed

Xia, X-F; Li, Y; Yu, X-Q; Lin, J-H; Li, S-Y; Li, Q; You, M-S

2017-10-01

Antimicrobial peptides (AMPs) are small-molecule peptides that play crucial roles in insect innate immune responses. To better understand the function of AMPs in Plutella xylostella, one of the main pests of cruciferous vegetables, three full-length cDNAs encoding moricins were cloned from Pl. xylostella. Two variants of the moricin named PxMor2 and PxMor3 were heterologously expressed and purified. A secondary structure analysis using circular dichroism demonstrated that the two peptides adopted an α-helical structure in the membrane-like environment, but in aqueous solution, they were present in random coiled conformation. Antimicrobial activity assays demonstrated that PxMor2 exhibited high activity against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli; however, PxMor3 only demonstrated high activity against E. coli. Scanning electron microscopy and confocal laser-scanning microscopy analyses suggest that PxMors can lead to the disruption of bacterial membrane, which might be the mechanism by which PxMors inhibit bacterial growth. This study contributes to the understanding of Pl. xylostella AMPs and immune responses, and also enriches the knowledge of insect moricin. © 2017 The Royal Entomological Society.

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

Ray, R.; Logan, J.; Ray, R.

Evidence points to the endogenous opioid system, and the mu-opioid receptor (MOR) in particular, in mediating the rewarding effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the human MOR gene (OPRM1 A118G) has been shown to alter receptor protein level in preclinical models and smoking behavior in humans. To clarify the underlying mechanisms for these associations, we conducted an in vivo investigation of the effects of OPRM1 A118G genotype on MOR binding potential (BP{sub ND} or receptor availability). Twenty-two smokers prescreened for genotype (12 A/A, 10 */G) completed two [{sup 11}C] carfentanil positron emission tomographymore » (PET) imaging sessions following overnight abstinence and exposure to a nicotine-containing cigarette and a denicotinized cigarette. Independent of session, smokers homozygous for the wild-type OPRM1 A allele exhibited significantly higher levels of MOR BP{sub ND} than smokers carrying the G allele in bilateral amygdala, left thalamus, and left anterior cingulate cortex. Among G allele carriers, the extent of subjective reward difference (denicotinized versus nicotine cigarette) was associated significantly with MOR BP{sub ND} difference in right amygdala, caudate, anterior cingulate cortex, and thalamus. Future translational investigations can elucidate the role of MORs in nicotine addiction, which may lead to development of novel therapeutics.« less

Low μ-Opioid Receptor Status in Alcohol Dependence Identified by Combined Positron Emission Tomography and Post-Mortem Brain Analysis

PubMed Central

Hermann, Derik; Hirth, Natalie; Reimold, Matthias; Batra, Anil; Smolka, Michael N; Hoffmann, Sabine; Kiefer, Falk; Noori, Hamid R; Sommer, Wolfgang H; Reischl, Gerald; la Fougère, Christian; Mann, Karl; Spanagel, Rainer; Hansson, Anita C

2017-01-01

Blockade of the μ-opioid receptor (MOR) by naltrexone reduces relapse risk in a subpopulation of alcohol-dependent patients. Previous positron-emission-tomography (PET) studies using the MOR ligand [11C]carfentanil have found increased MOR availability in abstinent alcoholics, which may reflect either increased MOR expression or lower endogenous ligand concentration. To differentiate between both effects, we investigated two cohorts of alcoholic subjects using either post-mortem or clinical PET analysis. Post-mortem brain tissue of alcohol-dependent subjects and controls (N=43/group) was quantitatively analyzed for MOR ([3H]DAMGO)-binding sites and OPRM1 mRNA in striatal regions. [11C]carfentanil PET was performed in detoxified, medication free alcohol-dependent patients (N=38), followed by a randomized controlled study of naltrexone versus placebo and follow-up for 1 year (clinical trial number: NCT00317031). Because the functional OPRM1 variant rs1799971:A>G affects the ligand binding, allele carrier status was considered in the analyses. MOR-binding sites were reduced by 23–51% in post-mortem striatal tissue of alcoholics. In the PET study, a significant interaction of OPRM1 genotype, binding potential (BPND) for [11C]carfentanil in the ventral striatum, and relapse risk was found. Particularly in G-allele carriers, lower striatal BPND was associated with a higher relapse risk. Interestingly, this effect was more pronounced in the naltrexone treatment group. Reduced MOR is interpreted as a neuroadaptation to an alcohol-induced release of endogenous ligands in patients with severe alcoholism. Low MOR availability may explain the ineffectiveness of naltrexone treatment in this subpopulation. Finally, low MOR-binding sites are proposed as a molecular marker for a negative disease course. PMID:27510425

The benzomorphan-based LP1 ligand is a suitable MOR/DOR agonist for chronic pain treatment.

PubMed

Pasquinucci, Lorella; Parenti, Carmela; Turnaturi, Rita; Aricò, Giuseppina; Marrazzo, Agostino; Prezzavento, Orazio; Ronsisvalle, Simone; Georgoussi, Zafiroula; Fourla, Danai-Dionysia; Scoto, Giovanna M; Ronsisvalle, Giuseppe

2012-01-02

Powerful analgesics relieve pain primarily through activating mu opioid receptor (MOR), but the long-term use of MOR agonists, such as morphine, is limited by the rapid development of tolerance. Recently, it has been observed that simultaneous stimulation of the delta opioid receptor (DOR) and MOR limits the incidence of tolerance induced by MOR agonists. 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide (LP1) is a centrally acting agent with antinociceptive activity comparable to morphine and is able to bind and activate MOR and DOR. The aim of this work was to evaluate and compare the induction of tolerance to antinociceptive effects from treatment with LP1 and morphine. Here, we evaluated the pharmacological effects of LP1 administered at a dose of 4 mg/kg subcutaneously (s.c.) twice per day for 9 days to male Sprague-Dawley rats. In addition, the LP1 mechanism of action was assessed by measurement of LP1-induced [(35)S]GTPγS binding to the MOR and DOR. Data obtained from the radiant heat tail flick test showed that LP1 maintained its antinociceptive profile until the ninth day, while tolerance to morphine (10mg/kg s.c. twice per day) was observed on day 3. Moreover, LP1 significantly enhanced [(35)S]GTPγS binding in the membranes of HEK293 cells expressing either the MOR or the DOR. LP1 is a novel analgesic agent for chronic pain treatment, and its low tolerance-inducing capability may be correlated with its ability to bind both the MOR and DOR. Copyright © 2011 Elsevier Inc. All rights reserved.

Micro-opioid receptor agonist diminishes POMC gene expression and anorexia by central insulin in neonatal chicks.

PubMed

Shiraishi, Jun-Ichi; Yanagita, Kouchi; Fujita, Masanori; Bungo, Takashi

2008-07-18

Pro-opiomelanocortin (POMC) neurons in the hypothalamus are direct targets of peripheral satiety signals, such as leptin and insulin in mammals. The stimulation of these signals activates hypothalamic POMC neurons and elevates POMC-derived melanocortin peptides that inhibit food intake in mammals. On the other hand, it has been recognized that beta-endorphin, a post-translational processing of POMC, acts in an autoreceptor manner to the micro-opioid receptor (MOR) on POMC neurons, diminishing POMC neuronal activity in mammals. Recently, we found that central insulin functions as an anorexic peptide in chicks. Thus, the present study was done to elucidate whether beta-endorphin affects the activation of POMC neurons by insulin in neonatal chicks. Consequently, quantitative real-time PCR analysis shows that intracerebroventricular (ICV) injection of insulin with beta-endorphin significantly decreases brain POMC mRNA expression when compared with insulin alone. In addition, co-injection of MOR agonist (beta-endorphin or [d-Ala2, N-MePhe4, Gly5-ol]-enkephalin (DAMGO)) significantly attenuates insulin-induced hypophagia in chicks. These data suggest that beta-endorphin regulates the activity of the central melanocortin system, and its activation may provide an inhibitory feedback mechanism in the brain of neonatal chicks.

Rapid, transient, and dose-dependent expression of Hsp70 messenger RNA in the rat brain after morphine treatment

PubMed Central

Ammon-Treiber, Susanne; Grecksch, Gisela; Stumm, Ralf; Riechert, Uta; Tischmeyer, Helga; Reichenauer, Anke; Höllt, Volker

2004-01-01

Induction of Hsp70 in the brain has been reported after intake of drugs of abuse like amphetamine and lysergic acid diethylamide. In this investigation, gene expression of Hsp70 and other heat shock genes in the rat brain was studied in response to morphine. Twenty milligrams per kilogram morphine intraperitoneally resulted in a marked induction of Hsp70 messenger RNA (mRNA) expression in the frontal cortex with a maximum increase of 13.2-fold after 2 hours. A moderate increase of Hsp27 mRNA expression (6.7-fold) could be observed after 4 hours, whereas mRNA expression of Hsp90 and of the constitutive Hsc70 did not exceed a mean factor of 1.8-fold during the 24 hours interval. The increase in Hsp70 mRNA was dose dependent, showing a significant elevation after doses ranging from 10 to 50 mg/kg morphine. In situ hybridization revealed enhanced Hsp70 mRNA expression mainly in cortical areas, in the hippocampus, in the paraventricular and supraoptic nuclei of the hypothalamus, in the locus coeruleus, as well in the pineal body. The double in situ hybridization technique revealed increased Hsp70 mRNA expression mainly in VGLUT1-positive neurons and to a lesser extent in olig1-positive oligodendroglia. Immunohistochemistry revealed a marked increase of Hsp70 protein in neuronal cells and blood vessels after 12 hours. In contrast to animal experiments, morphine did not increase Hsp70 mRNA expression in vitro in μ-opioid receptor (MOR1)–expressing human embryonic kidney 293 cells, suggesting no direct MOR1-mediated cellular effect. To exclude a body temperature–related morphine effect on Hsp70 mRNA expression, the temperature was recorded. Five to 20 mg/kg resulted in hyperthermia (maximum 40.6°), whereas a high dose (50 mg/kg) that produced the highest mRNA induction, showed a clear hypothermia (minimum 37.2°C). These findings argue against the possibility that Hsp70 induction by morphine is caused by its effect on body temperature. It may be speculated that increased expression of Hsp70 after morphine application protects brain structures against potentially hazardous effects of opiates. PMID:15497504

Opiate antagonist prevents μ- and δ-opiate receptor dimerization to facilitate ability of agonist to control ethanol-altered natural killer cell functions and mammary tumor growth.

PubMed

Sarkar, Dipak K; Sengupta, Amitabha; Zhang, Changqing; Boyadjieva, Nadka; Murugan, Sengottuvelan

2012-05-11

In the natural killer (NK) cells, δ-opiate receptor (DOR) and μ-opioid receptor (MOR) interact in a feedback manner to regulate cytolytic function with an unknown mechanism. Using RNK16 cells, a rat NK cell line, we show that MOR and DOR monomer and dimer proteins existed in these cells and that chronic treatment with a receptor antagonist reduced protein levels of the targeted receptor but increased levels of opposing receptor monomer and homodimer. The opposing receptor-enhancing effects of MOR and DOR antagonists were abolished following receptor gene knockdown by siRNA. Ethanol treatment increased MOR and DOR heterodimers while it decreased the cellular levels of MOR and DOR monomers and homodimers. The opioid receptor homodimerization was associated with an increased receptor binding, and heterodimerization was associated with a decreased receptor binding and the production of cytotoxic factors. Similarly, in vivo, opioid receptor dimerization, ligand binding of receptors, and cell function in immune cells were promoted by chronic treatment with an opiate antagonist but suppressed by chronic ethanol feeding. Additionally, a combined treatment of an MOR antagonist and a DOR agonist was able to reverse the immune suppressive effect of ethanol and reduce the growth and progression of mammary tumors in rats. These data identify a role of receptor dimerization in the mechanism of DOR and MOR feedback interaction in NK cells, and they further elucidate the potential for the use of a combined opioid antagonist and agonist therapy for the treatment of immune incompetence and cancer and alcohol-related diseases.

Endometriosis Is Associated With a Shift in MU Opioid and NMDA Receptor Expression in the Brain Periaqueductal Gray

PubMed Central

Torres-Reverón, Annelyn; Palermo, Karylane; Hernández-López, Anixa; Hernández, Siomara; Cruz, Myrella L.; Thompson, Kenira J.; Flores, Idhaliz; Appleyard, Caroline B.

2016-01-01

Studies have examined how endometriosis interacts with the nervous system, but little attention has been paid to opioidergic systems, which are relevant to pain signaling. We used the autotransplantation rat model of endometriosis and allowed to progress for 60 days. The brain was collected and examined for changes in endogenous opioid peptides, mu opioid receptors (MORs), and the N-methyl-d-aspartate subunit receptor (NR1) in the periaqueductal gray (PAG), since both of these receptors can regulate PAG activity. No changes in endogenous opioid peptides in met- and leu-enkephalin or β-endorphin levels were observed within the PAG. However, MOR immunoreactivity was significantly decreased in the ventral PAG in the endometriosis group. Endometriosis reduced by 20% the number of neuronal profiles expressing MOR and reduced by 40% the NR1 profiles. Our results suggest that endometriosis is associated with subtle variations in opioidergic and glutamatergic activity within the PAG, which may have implications for pain processing. PMID:27089914

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

PubMed Central

Largent-Milnes, Tally M.; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H.; Vanderah, Todd W.

2017-01-01

Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)–G protein coupling from Gi/o to Gs that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L5/L6 spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to Gs in the damaged (ipsilateral) spinal dorsal horn. This MOR-Gs coupling occurred without changing Gi/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-Gs coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-Gs coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this Gs coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-Gs coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. PMID:18468954

Effects of bingeing on fat during adolescence on the reinforcing effects of cocaine in adult male mice.

PubMed

Blanco-Gandía, M Carmen; Cantacorps, Lídia; Aracil-Fernández, Auxiliadora; Montagud-Romero, Sandra; Aguilar, María A; Manzanares, Jorge; Valverde, Olga; Miñarro, José; Rodríguez-Arias, Marta

2017-02-01

Binge eating is a specific form of overeating characterized by intermittent excessive eating. In addition to altering the neurobiological reward system, several studies have highlighted that consumption of palatable food increases vulnerability to drug use. The aim of the present study was to evaluate the effects of a high-fat diet consumed in a binge pattern during adolescence on the reinforcing effects of cocaine. After 40 days of binge-eating for 2 h, three days a week (PND 29-69), the reinforcing effects of cocaine on conditioning place preference and intravenous self-administration paradigm were evaluated in adolescent male mice. Circulating leptin and ghrelin levels and the effects of bingeing on fat on CB1 mu opioid receptor (MOr) and ghrelin receptor (GHSR) gene expression in the Nucleus Accumbens (NAcc) and Ventral Tegmental Area (VTA) were also assessed. Our results showed a significant escalation in the consumption of a high-fat diet between the first and last week. High-fat binge (HFB) animals were more sensitive to the reinforcing effects of a subthreshold dose of cocaine in the paradigms assayed, and animals under fat withdrawal were more vulnerable to the reinstatement of conditioned place preference. HFB mice also showed enhanced cocaine self-administration. After fat withdrawal, exposure to a new fat binge reinstated cocaine seeking. Although HFB did not modify leptin levels, a decrease in plasmatic ghrelin was observed. Moreover, this pattern of fatty diet resulted in a reduction of MOr and CB1 gene expression in the NAcc and an increase in GHSR expression in the VTA. We propose that bingeing on fat during adolescence induces long-lasting changes in the brain through the sensitization of brain reward circuits, which predisposes individuals to seek cocaine during adulthood. Copyright © 2016 Elsevier Ltd. All rights reserved.

Peptidases prevent mu-opioid receptor internalization in dorsal horn neurons by endogenously released opioids.

PubMed

Song, Bingbing; Marvizón, Juan Carlos G

2003-03-01

To evaluate the effect of peptidases on mu-opioid receptor (MOR) activation by endogenous opioids, we measured MOR-1 internalization in rat spinal cord slices. A mixture of inhibitors of aminopeptidases (amastatin), dipeptidyl carboxypeptidase (captopril), and neutral endopeptidase (phosphoramidon) dramatically increased the potencies of Leu-enkephalin and dynorphin A to produce MOR-1 internalization, and also enhanced the effects of Met-enkephalin and alpha-neoendorphin, but not endomorphins or beta-endorphin. The omission of any one inhibitor abolished Leu-enkephalin-induced internalization, indicating that all three peptidases degraded enkephalins. Amastatin preserved dynorphin A-induced internalization, and phosphoramidon, but not captopril, increased this effect, indicating that the effect of dynorphin A was prevented by aminopeptidases and neutral endopeptidase. Veratridine (30 microm) or 50 mm KCl produced MOR-1 internalization in the presence of peptidase inhibitors, but little or no internalization in their absence. These effects were attributed to opioid release, because they were abolished by the selective MOR antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)) and were Ca(2+) dependent. The effect of veratridine was protected by phosphoramidon plus amastatin or captopril, but not by amastatin plus captopril or by phosphoramidon alone, indicating that released opioids are primarily cleaved by neutral endopeptidase, with a lesser involvement of aminopeptidases and dipeptidyl carboxypeptidase. Therefore, because the potencies of endomorphin-1 and endomorphin-2 to elicit internalization were unaffected by peptidase inhibitors, the opioids released by veratridine were not endomorphins. Confocal microscopy revealed that MOR-1-expressing neurons were in close proximity to terminals containing opioids with enkephalin-like sequences. These findings indicate that peptidases prevent the activation of extrasynaptic MOR-1 in dorsal horn neurons.

Peptidases prevent μ-opioid receptor internalization in dorsal horn neurons by endogenously released opioids

PubMed Central

Song, Bingbing; Marvizón, Juan Carlos G.

2008-01-01

To evaluate the effect of peptidases on μ-opioid receptor (MOR) activation by endogenous opioids, we measured MOR-1 internalization in rat spinal cord slices. A mixture of inhibitors of aminopeptidases (amastatin), dipeptidyl carboxypeptidase (captopril), and neutral endopeptidase (phosphoramidon) dramatically increased the potencies of Leu-enkephalin and dynorphin A to produce MOR-1 internalization, and also enhanced the effects of Met-enkephalin and α-neoendorphin, but not endomorphins or β-endorphin. Omission of any one inhibitor abolished Leu-enkephalin-induced internalization, indicating that all three peptidases degraded enkephalins. Amastatin preserved dynorphin A-induced internalization, and phosphoramidon, but not captopril, increased this effect, indicating that the effect of dynorphin A was prevented by aminopeptidases and neutral endopeptidase. Veratridine (30 μM) or 50 mM KCl produced MOR-1 internalization in the presence of peptidase inhibitors, but little or no internalization in their absence. These effects were attributed to opioid release, because they were abolished by the selective MOR antagonist CTAP and were Ca2+-dependent. The effect of veratridine was protected by phosphoramidon plus amastatin or captopril, but not by amastatin plus captopril or by phosphoramidon alone, indicating that released opioids are mainly cleaved by neutral endopeptidase, with a lesser involvement of aminopeptidases and dipeptidyl carboxypeptidase. Therefore, since the potencies of endomorphin-1 and -2 to elicit internalization were unaffected by peptidase inhibitors, the opioids released by veratridine were not endomorphins. Confocal microscopy revealed that MOR-1-expressing neurons were in close proximity to terminals containing opioids with enkephalin-like sequences. These findings indicate that peptidases prevent the activation of extrasynaptic MOR-1 in dorsal horn neurons. PMID:12629189

14-Alkoxy- and 14-acyloxypyridomorphinans: μ agonist/δ antagonist opioid analgesics with diminished tolerance and dependence side effects.

PubMed

Ananthan, Subramaniam; Saini, Surendra K; Dersch, Christina M; Xu, Heng; McGlinchey, Nicholas; Giuvelis, Denise; Bilsky, Edward J; Rothman, Richard B

2012-10-11

In the search for opioid ligands with mixed functional activity, a series of 5'-(4-chlorophenyl)-4,5α-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h, its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence, and related side effects.

14-Alkoxy- and 14-Acyloxypyridomorphinans: Mu Agonist/Delta Antagonist Opioid Analgesics with Diminished Tolerance and Dependence Side Effects

PubMed Central

Ananthan, Subramaniam; Saini, Surendra K.; Dersch, Christina M.; Xu, Heng; McGlinchey, Nicholas; Giuvelis, Denise; Bilsky, Edward J.; Rothman, Richard B.

2012-01-01

In the search for opioid ligands with mixed functional activity, a series of 5′-(4-chlorophenyl)-4,5α-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects on prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine on repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence and related side effects. PMID:23016952

Black cohosh (Actaea racemosa, Cimicifuga racemosa) behaves as a mixed competitive ligand and partial agonist at the human mu opiate receptor

PubMed Central

Rhyu, Mee-Ra; Lu, Jian; Webster, Donna E.; Fabricant, Daniel S.; Farnsworth, Norman R.; Wang, Z. Jim

2008-01-01

Black cohosh is a commonly used botanical dietary supplement for the treatment of climacteric complaints. Since the opiate system in the brain is intimately associated with mood, temperature and sex hormonal levels, we investigated the activity of black cohosh extracts at the human μ opiate receptor (hMOR) expressed in Chinese hamster ovary cells. The 100% methanol-, 75% ethanol- and 40% 2-propanol- extracts of black cohosh effectively displaced the specific binding of [3H]DAMGO to hMOR. Further studies of the clinically used ethanol extract indicated that black cohosh acted as a mixed competitive ligand, displacing 77 ± 4% [3H]DAMGO to hMOR (Ki = 62.9 μg/ml). Using the [35S]GTPγS assay, the action of black cohosh was found to be consistent with an agonist, with an EC50 of 68.8 ± 7.7 μg/ml. These results demonstrate for the first time that black cohosh contains active principle(s) that activate hMOR, supporting its beneficial role in alleviating menopausal symptoms. PMID:17177511

Black cohosh (Actaea racemosa, Cimicifuga racemosa) behaves as a mixed competitive ligand and partial agonist at the human mu opiate receptor.

PubMed

Rhyu, Mee-Ra; Lu, Jian; Webster, Donna E; Fabricant, Daniel S; Farnsworth, Norman R; Wang, Z Jim

2006-12-27

Black cohosh is a commonly used botanical dietary supplement for the treatment of climacteric complaints. Because the opiate system in the brain is intimately associated with mood, temperature, and sex hormonal levels, the activity of black cohosh extracts at the human mu opiate receptor (hMOR) expressed in Chinese hamster ovary cells was investigated. The 100% methanol, 75% ethanol, and 40% 2-propanol extracts of black cohosh effectively displaced the specific binding of [3H]DAMGO to hMOR. Further studies of the clinically used ethanol extract indicated that black cohosh acted as a mixed competitive ligand, displacing 77 +/- 4% [3H]DAMGO to hMOR (Ki = 62.9 microg/mL). Using the [35S]GTPgammaS assay, the action of black cohosh was found to be consistent with an agonist, with an EC50 of 68.8 +/- 7.7 microg/mL. These results demonstrate for the first time that black cohosh contains active principle(s) that activate hMOR, supporting its beneficial role in alleviating menopausal symptoms.

Mu opioid receptors in GABAergic forebrain neurons moderate motivation for heroin and palatable food

PubMed Central

Charbogne, Pauline; Gardon, Olivier; Martín-García, Elena; Keyworth, Helen L.; Matsui, Aya; Mechling, Anna E.; Bienert, Thomas; Nasseef, Taufiq; Robé, Anne; Moquin, Luc; Darcq, Emmanuel; Ben Hamida, Sami; Robledo, Patricia; Matifas, Audrey; Befort, Katia; Gavériaux-Ruff, Claire; Harsan, Laura-Adela; Von Everfeldt, Dominik; Hennig, Jurgen; Gratton, Alain; Kitchen, Ian; Bailey, Alexis; Alvarez, Veronica A.; Maldonado, Rafael; Kieffer, Brigitte L.

2016-01-01

BACKGROUND Mu opioid receptors (MORs) are central to pain control, drug reward and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in GABAergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. METHODS We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in GABAergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology and microdialysis, probed neuronal activation by c-Fos immunohistochemistry and resting state-functional magnetic resonance imaging, and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. RESULTS Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area (VTA), local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. CONCLUSIONS Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus beyond a well-established role in reward processing, operating at the level of local VTA neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors. PMID:28185645

Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord.

PubMed

Dai, Wen-Ling; Xiong, Feng; Yan, Bing; Cao, Zheng-Yu; Liu, Wen-Tao; Liu, Ji-Hua; Yu, Bo-Yang

2016-12-22

Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Blockade of D2DR with its antagonist (sulpiride and L-741,626, i.t.) attenuated morphine antinociceptive tolerance without affecting basal pain perception. Sulpiride (i.t.) also down-regulated the expression of phosphorylation of NR1, PKC, MAPKs and suppressed the activation of astrocytes and microglia induced by chronic morphine administration. Particularly, D2DR was found to interact with μ opioid receptor (MOR) in neurons, and chronic morphine treatment enhanced the MOR/D2DR interactions. Sulpiride (i.t.) could disrupt the MOR/D2DR interactions and attenuate morphine tolerance, indicating that neuronal D2DR in the spinal cord may be involved in morphine tolerance possibly by interacting with MOR. These results may present new opportunities for the treatment and management of morphine-induced antinociceptive tolerance which often observed in clinic.

Endogenous opioid system: a promising target for future smoking cessation medications.

PubMed

Norman, Haval; D'Souza, Manoranjan S

2017-05-01

Nicotine addiction continues to be a health challenge across the world. Despite several approved medications, smokers continue to relapse. Several human and animal studies have evaluated the role of the endogenous opioid system as a potential target for smoking cessation medications. In this review, studies that have elucidated the role of the mu (MORs), delta (DORs), and kappa (KORs) opioid receptors in nicotine reward, nicotine withdrawal, and reinstatement of nicotine seeking will be discussed. Additionally, the review will discuss discrepancies in the literature and therapeutic potential of the endogenous opioid system, and suggest studies to address gaps in knowledge with respect to the role of the opioid receptors in nicotine dependence. Data available till date suggest that blockade of the MORs and DORs decreased the rewarding effects of nicotine, while activation of the MORs and DORs decreased nicotine withdrawal-induced aversive effects. In contrast, activation of the KORs decreased the rewarding effects of nicotine, while blockade of the KORs decreased nicotine withdrawal-induced aversive effects. Interestingly, blockade of the MORs and KORs attenuated reinstatement of nicotine seeking. In humans, MOR antagonists have shown benefits in select subpopulations of smokers and further investigation is required to realize their full therapeutic potential. Future work must assess the influence of polymorphisms in opioid receptor-linked genes in nicotine dependence, which will help in both identifying individuals vulnerable to nicotine addiction and the development of opioid-based smoking cessation medications. Overall, the endogenous opioid system continues to be a promising target for future smoking cessation medications.

Association of time-dependent changes in mu opioid receptor mRNA, but not BDNF, TrkB, or MeCP2 mRNA and protein expression in the rat nucleus accumbens with incubation of heroin craving.

PubMed

Theberge, Florence R M; Pickens, Charles L; Goldart, Evan; Fanous, Sanya; Hope, Bruce T; Liu, Qing-Rong; Shaham, Yavin

2012-12-01

Responding to heroin cues progressively increases after cessation of heroin self-administration (incubation of heroin craving). We investigated whether this incubation is associated with time-dependent changes in brain-derived neurotrophic factor (BDNF) and methyl-CpG binding protein 2 (MeCP2) signaling and mu opioid receptor (MOR) expression in nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC). We also investigated the effect of the preferential MOR antagonist naloxone on cue-induced heroin seeking during abstinence. We trained rats to self-administer heroin or saline for 9-10 days and then dissected the NAc, DS, and mPFC at different abstinence days and measured mRNA and protein levels of BDNF, TrkB, and MeCP2, as well as MOR mRNA (Oprm1). In other groups, we assessed cue-induced heroin seeking in extinction tests after 1, 11, and 30 abstinence days, and naloxone's (0-1.0 mg/kg) effect on extinction responding after 1 and 15 days. Cue-induced heroin seeking progressively increased or incubated during abstinence. This incubation was not associated with changes in BDNF, TrkB, or MeCP2 mRNA or protein levels in NAc, DS, or mPFC; additionally, no molecular changes were observed after extinction tests on day 11. In NAc, but not DS or mPFC, MOR mRNA decreased on abstinence day 1 and returned to basal levels over time. Naloxone significantly decreased cue-induced heroin seeking after 15 abstinence days but not 1 day. Results suggest a role of MOR in incubation of heroin craving. As previous studies implicated NAc BDNF in incubation of cocaine craving, our data suggest that different mechanisms contribute to incubation of heroin versus cocaine craving.

Association of time-dependent changes in mu opioid receptor mRNA, but not BDNF, TrkB, or MeCP2 mRNA and protein expression in the rat nucleus accumbens with incubation of heroin craving

PubMed Central

Theberge, Florence R. M.; Pickens, Charles L.; Goldart, Evan; Fanous, Sanya; Hope, Bruce T.; Liu, Qing-Rong

2013-01-01

Rationale and objectives Responding to heroin cues progressively increases after cessation of heroin self-administration (incubation of heroin craving). We investigated whether this incubation is associated with time-dependent changes in brain-derived neurotrophic factor (BDNF) and methyl-CpG binding protein 2 (MeCP2) signaling and mu opioid receptor (MOR) expression in nucleus accumbens (NAc), dorsal striatum (DS), and medial pre-frontal cortex (mPFC). We also investigated the effect of the preferential MOR antagonist naloxone on cue-induced heroin seeking during abstinence. Methods We trained rats to self-administer heroin or saline for 9–10 days and then dissected the NAc, DS, and mPFC at different abstinence days and measured mRNA and protein levels of BDNF, TrkB, and MeCP2, as well as MOR mRNA (Oprm1). In other groups, we assessed cue-induced heroin seeking in extinction tests after 1, 11, and 30 abstinence days, and naloxone’s (0–1.0 mg/kg) effect on extinction responding after 1 and 15 days. Results Cue-induced heroin seeking progressively increased or incubated during abstinence. This incubation was not associated with changes in BDNF, TrkB, or MeCP2 mRNA or protein levels in NAc, DS, or mPFC; additionally, no molecular changes were observed after extinction tests on day 11. In NAc, but not DS or mPFC, MOR mRNA decreased on abstinence day 1 and returned to basal levels over time. Naloxone significantly decreased cue-induced heroin seeking after 15 abstinence days but not 1 day. Conclusions Results suggest a role of MOR in incubation of heroin craving. As previous studies implicated NAc BDNF in incubation of cocaine craving, our data suggest that different mechanisms contribute to incubation of heroin versus cocaine craving. PMID:22790874

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

PubMed

Charbogne, Pauline; Gardon, Olivier; Martín-García, Elena; Keyworth, Helen L; Matsui, Aya; Mechling, Anna E; Bienert, Thomas; Nasseef, Taufiq; Robé, Anne; Moquin, Luc; Darcq, Emmanuel; Ben Hamida, Sami; Robledo, Patricia; Matifas, Audrey; Befort, Katia; Gavériaux-Ruff, Claire; Harsan, Laura-Adela; von Elverfeldt, Dominik; Hennig, Jurgen; Gratton, Alain; Kitchen, Ian; Bailey, Alexis; Alvarez, Veronica A; Maldonado, Rafael; Kieffer, Brigitte L

2017-05-01

Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Molecular receptive range variation among mouse odorant receptors for aliphatic carboxylic acids

PubMed Central

Repicky, Sarah E.; Luetje, Charles W.

2009-01-01

The ability of mammals to identify and distinguish among many thousands of different odorants suggests a combinatorial use of odorant receptors, with each receptor detecting multiple odorants and each odorant interacting with multiple receptors. Numerous receptors may be devoted to the sampling of particularly important regions of odor space. Here we explore the similarities and differences in the molecular receptive ranges of four mouse odorant receptors (MOR23-1, MOR31-4, MOR32-11 and MOR40-4), which have previously been identified as receptors for aliphatic carboxylic acids. Each receptor was expressed in Xenopus oocytes, along with Gαolf and the cystic fibrosis transmembrane regulator to allow electrophysiological assay of receptor responses. We find that even though these receptors are relatively unrelated, there is extensive overlap among their receptive ranges. That is, these receptors sample a similar region of odor space. However, the receptive range of each receptor is unique. Thus, these receptors contribute to the depth of coverage of this small region of odor space. Such a group of receptors with overlapping, but distinct receptive ranges, may participate in making fine distinctions among complex mixtures of closely related odorant compounds. PMID:19166503

MorTAL Kombat: the story of defense against TAL effectors through loss-of-susceptibility

PubMed Central

Hutin, Mathilde; Pérez-Quintero, Alvaro L.; Lopez, Camilo; Szurek, Boris

2015-01-01

Many plant-pathogenic xanthomonads rely on Transcription Activator-Like (TAL) effectors to colonize their host. This particular family of type III effectors functions as specific plant transcription factors via a programmable DNA-binding domain. Upon binding to the promoters of plant disease susceptibility genes in a sequence-specific manner, the expression of these host genes is induced. However, plants have evolved specific strategies to counter the action of TAL effectors and confer resistance. One mechanism is to avoid the binding of TAL effectors by mutations of their DNA binding sites, resulting in resistance by loss-of-susceptibility. This article reviews our current knowledge of the susceptibility hubs targeted by Xanthomonas TAL effectors, possible evolutionary scenarios for plants to combat the pathogen with loss-of-function alleles, and how this knowledge can be used overall to develop new pathogen-informed breeding strategies and improve crop resistance. PMID:26236326

Fructose:Glucose Ratios—A Study of Sugar Self-Administration and Associated Neural and Physiological Responses in the Rat

PubMed Central

Levy, AnneMarie; Marshall, Paul; Zhou, Yan; Kreek, Mary Jeanne; Kent, Katrina; Daniels, Stephen; Shore, Ari; Downs, Tiana; Fernandes, Maria Fernanda; Mutch, David M.; Leri, Francesco

2015-01-01

This study explored whether different ratios of fructose (F) and glucose (G) in sugar can engender significant differences in self-administration and associated neurobiological and physiological responses in male Sprague-Dawley rats. In Experiment 1, animals self-administered pellets containing 55% F + 45% G or 30% F + 70% G, and Fos immunoreactivity was assessed in hypothalamic regions regulating food intake and reward. In Experiment 2, rats self-administered solutions of 55% F + 42% G (high fructose corn syrup (HFCS)), 50% F + 50% G (sucrose) or saccharin, and mRNA of the dopamine 2 (D2R) and mu-opioid (MOR) receptor genes were assessed in striatal regions involved in addictive behaviors. Finally, in Experiment 3, rats self-administered HFCS and sucrose in their home cages, and hepatic fatty acids were quantified. It was found that higher fructose ratios engendered lower self-administration, lower Fos expression in the lateral hypothalamus/arcuate nucleus, reduced D2R and increased MOR mRNA in the dorsal striatum and nucleus accumbens core, respectively, as well as elevated omega-6 polyunsaturated fatty acids in the liver. These data indicate that a higher ratio of fructose may enhance the reinforcing effects of sugar and possibly lead to neurobiological and physiological alterations associated with addictive and metabolic disorders. PMID:26007337

Fructose:glucose ratios--a study of sugar self-administration and associated neural and physiological responses in the rat.

PubMed

Levy, AnneMarie; Marshall, Paul; Zhou, Yan; Kreek, Mary Jeanne; Kent, Katrina; Daniels, Stephen; Shore, Ari; Downs, Tiana; Fernandes, Maria Fernanda; Mutch, David M; Leri, Francesco

2015-05-22

This study explored whether different ratios of fructose (F) and glucose (G) in sugar can engender significant differences in self-administration and associated neurobiological and physiological responses in male Sprague-Dawley rats. In Experiment 1, animals self-administered pellets containing 55% F + 45% G or 30% F + 70% G, and Fos immunoreactivity was assessed in hypothalamic regions regulating food intake and reward. In Experiment 2, rats self-administered solutions of 55% F + 42% G (high fructose corn syrup (HFCS)), 50% F + 50% G (sucrose) or saccharin, and mRNA of the dopamine 2 (D2R) and mu-opioid (MOR) receptor genes were assessed in striatal regions involved in addictive behaviors. Finally, in Experiment 3, rats self-administered HFCS and sucrose in their home cages, and hepatic fatty acids were quantified. It was found that higher fructose ratios engendered lower self-administration, lower Fos expression in the lateral hypothalamus/arcuate nucleus, reduced D2R and increased MOR mRNA in the dorsal striatum and nucleus accumbens core, respectively, as well as elevated omega-6 polyunsaturated fatty acids in the liver. These data indicate that a higher ratio of fructose may enhance the reinforcing effects of sugar and possibly lead to neurobiological and physiological alterations associated with addictive and metabolic disorders.

Berberine Improves Intestinal Motility and Visceral Pain in the Mouse Models Mimicking Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D) Symptoms in an Opioid-Receptor Dependent Manner

PubMed Central

Pan, Qiuhui; Fichna, Jakub; Zheng, Lijun; Wang, Kesheng; Yu, Zhen; Li, Yongyu; Li, Kun; Song, Aihong; Liu, Zhongchen; Song, Zhenshun; Kreis, Martin

2015-01-01

Background and Aims Berberine and its derivatives display potent analgesic, anti-inflammatory and anticancer activity. Here we aimed at characterizing the mechanism of action of berberine in the gastrointestinal (GI) tract and cortical neurons using animal models and in vitro tests. Methods The effect of berberine was characterized in murine models mimicking diarrhea-predominant irritable bowel syndrome (IBS-D) symptoms. Then the opioidantagonists were used to identify the receptors involved. Furthermore, the effect of berberineon opioid receptors expression was established in the mouse intestine and rat fetal cortical neurons. Results In mouse models, berberine prolonged GI transit and time to diarrhea in a dose-dependent manner, and significantly reduced visceral pain. In physiological conditions the effects of berberine were mediated by mu- (MOR) and delta- (DOR) opioidreceptors; hypermotility, excessive secretion and nociception were reversed by berberine through MOR and DOR-dependent action. We also found that berberine increased the expression of MOR and DOR in the mouse bowel and rat fetal cortical neurons. Conclusion Berberine significantly improved IBS-D symptoms in animal models, possibly through mu- and delta- opioid receptors. Berberine may become a new drug candidate for the successful treatment of IBS-D in clinical conditions. PMID:26700862

Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling.

PubMed

Largent-Milnes, Tally M; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H; Vanderah, Todd W

2008-08-01

Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in mu-opioid receptor (MOR)-G protein coupling from G(i/o) to G(s) that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L(5)/L(6) spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G(s) in the damaged (ipsilateral) spinal dorsal horn. This MOR-G(s) coupling occurred without changing G(i/o) coupling levels and without changing the expression of MOR or Galpha proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G(s) coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G(s) coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G(s) coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G(s) coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. The current study investigates whether Oxytrex (oxycodone with an ultra-low dose of naltrexone) alleviates mechanical and thermal hypersensitivities in an animal model of neuropathic pain over a period of 7 days, given locally or systemically. In this report, we first describe an injury-induced shift in mu-opioid receptor coupling from G(i/o) to G(s), suggesting why a mu-opioid agonist may have reduced efficacy in the nerve-injured state. These data present a novel approach to neuropathic pain therapy.

Analysis of radar images of the active volcanic zone at Krafla, Iceland: The effects of look azimuth biasing

NASA Technical Reports Server (NTRS)

Garvin, J. B.; Williams, R. S., Jr.

1989-01-01

The geomorphic expression of Mid-Ocean-Ridge (MOR) volcanism in a subaerial setting occurs uniquely on Earth in Iceland, and the most recent MOR eruptive activity has been concentrated in the Northeastern Volcanic Zone in an area known as Krafla. Within the Krafla region are many of the key morphologic elements of MOR-related basaltic volcanism, as well as volcanic explosion craters, subglacial lava shields, tectonic fissure swarms known as gjar, and basaltic-andesite flows with well developed ogives (pressure-ridges). The objective was to quantify the degree to which the basic volcanic and structural features can be mapped from directional SAR imagery as a function of the look azimuth. To accomplish this, the current expression of volcanic and tectonic constructs was independently mapped within the Krafla region on the E, W, and N-looking SAR images, as well as from SPOT Panchromatic imagery acquired in 1987. The initial observations of the E, W, and N images indicates that fresh a'a lava surfaces are extremely radar bright (rough at 3 cm to meter scales) independent of look direction; this suggests that these flows do not have strong flow direction related structures at meter and cm scales, which is consistent with typical Icelandic a'a lava surfaces in general. The basic impression from a preliminary analysis of the effects of look azimuth biasing on interpretation of the geology of an active MOR volcanic zone is that up to 30 percent of the diagnostic features can be missed at any given look direction, but that having two orthogonal look direction images is probably sufficient to prevent gross misinterpretation.

Temporal Control of Transforming Growth Factor (TGF) - Betal Expression on Mammary Cell Multistep Transformation

DTIC Science & Technology

1999-10-01

deregulated cell mors and may eventually regress through growth (18). The importance of APC and 0- cat - apoptosis (25). enin in the development of colorectal...progression. In support of this idea, Torre Amione et al. [74] demonstrated that, unlike parental tumor cells, fibrosarcoma cells transfected to express 10

Satiety and the role of μ-opioid receptors in the portal vein.

PubMed

De Vadder, Filipe; Gautier-Stein, Amandine; Mithieux, Gilles

2013-12-01

Mu-opioid receptors (MORs) are known to influence food intake at the brain level, through their involvement in the food reward system. MOR agonists stimulate food intake. On the other hand, MOR antagonists suppress food intake. MORs are also active in peripheral organs, especially in the small intestine where they control the gut motility. Recently, an indirect role in the control of food intake was ascribed to MORs in the extrinsic gastrointestinal neural system. MORs present in the neurons of the portal vein walls sense blood peptides released from the digestion of dietary protein. These peptides behave as MOR antagonists. Their MOR antagonist action initiates a gut-brain circuitry resulting in the induction of intestinal gluconeogenesis, a function controlling food intake. Thus, periportal MORs are a key mechanistic link in the satiety effect of protein-enriched diets. Copyright © 2013 Elsevier Ltd. All rights reserved.

Exposure to opiates in female adolescents alters mu opiate receptor expression and increases the rewarding effects of morphine in future offspring.

PubMed

Vassoler, Fair M; Wright, Siobhan J; Byrnes, Elizabeth M

2016-04-01

Prescription opiate use and abuse has increased dramatically over the past two decades, including increased use in adolescent populations. Recently, it has been proposed that use during this critical period may affect future offspring even when use is discontinued prior to conception. Here, we utilize a rodent model to examine the effects of adolescent morphine exposure on the reward functioning of the offspring. Female Sprague Dawley rats were administered morphine for 10 days during early adolescence (post-natal day 30-39) using an escalating dosing regimen. Animals then remained drug free until adulthood at which point they were mated with naïve males. Adult offspring (F1 animals) were tested for their response to morphine-induced (0, 1, 2.5, 5, and 10 mg/kg, s.c.) conditioned place preference (CPP) and context-independent morphine-induced sensitization. Naïve littermates were used to examine mu opiate receptor expression in the nucleus accumbens and ventral tegmental area. Results indicate that F1 females whose mothers were exposed to morphine during adolescence (Mor-F1) demonstrate significantly enhanced CPP to the lowest doses of morphine compared with Sal-F1 females. There were no differences in context-independent sensitization between maternal treatment groups. Protein expression analysis showed significantly increased levels of accumbal mu opiate receptor in Mor-F1 offspring and decreased levels in the VTA. Taken together, these findings demonstrate a shift in the dose response curve with regard to the rewarding effects of morphine in Mor-F1 females which may in part be due to altered mu opiate receptor expression in the nucleus accumbens and VTA. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exposure to Opiates in Female Adolescents Alters Mu Opiate Receptor Expression and Increases the Rewarding Effects of Morphine in Future Offspring

PubMed Central

Vassoler, Fair M.; Wright, Siobhan J.; Byrnes, Elizabeth M.

2016-01-01

Prescription opiate use and abuse has increased dramatically over the past two decades, including increased use in adolescent populations. Recently, it has been proposed that use during this critical period may affect future offspring even when use is discontinued prior to conception. Here, we utilize a rodent model to examine the effects of adolescent morphine exposure on the reward functioning of the offspring. Female Sprague Dawley rats were administered morphine for 10 days during early adolescence (post-natal day 30–39) using an escalating dosing regimen. Animals then remained drug free until adulthood at which point they were mated with naïve males. Adult offspring (F1 animals) were tested for their response to morphine-induced (0, 1, 2.5, 5, and 10 mg/kg, s.c.) conditioned place preference (CPP) and context-independent morphine-induced sensitization. Naïve littermates were used to examine mu opiate receptor expression in the nucleus accumbens and ventral tegmental area. Results indicate that F1 females whose mothers were exposed to morphine during adolescence (Mor-F1) demonstrate significantly enhanced CPP to the lowest doses of morphine compared with Sal-F1 females. There were no differences in context-independent sensitization between maternal treatment groups. Protein expression analysis showed significantly increased levels of accumbal mu opiate receptor in Mor-F1 offspring and decreased levels in the VTA. Taken together, these findings demonstrate a shift in the dose response curve with regard to the rewarding effects of morphine in Mor-F1 females which may in part be due to altered mu opiate receptor expression in the nucleus accumbens and VTA. PMID:26700246

Concentrating Solar Power Projects - Morón | Concentrating Solar Power |

Science.gov Websites

, 2018 Project Overview Project Name: Morón Country: Spain Location: Morón de la Frontera (Seville ? Background Technology: Parabolic trough Status: Operational Country: Spain City: Morón de la Frontera Region NREL Morón This page provides information on Morón, a concentrating solar power (CSP) project

Temporal Control of Transforming Growth Factor (TGF) - Betal Expression on Mammary Cell Multistep Transformation

DTIC Science & Technology

2001-10-01

tu- vation of transcription and deregulated cell mors and may eventually regress through growth (18). The importance of APC and [- cat - apoptosis (25...receptors, fibrosarcoma cells transfected to express 10ng/ml TPRII [621, ALK-1 [63], and endoglin [64], and one of its TGF-131 in vitro are unable to

Differential activation of G-proteins by mu-opioid receptor agonists.

PubMed

Saidak, Zuzana; Blake-Palmer, Katherine; Hay, Debbie L; Northup, John K; Glass, Michelle

2006-03-01

We investigated the ability of the activated mu-opioid receptor (MOR) to differentiate between myristoylated G(alphai1) and G(alphaoA) type G(alpha) proteins, and the maximal activity of a range of synthetic and endogenous agonists to activate each G(alpha) protein. Membranes from HEK293 cells stably expressing transfected MOR were chaotrope extracted to denature endogenous G-proteins and reconstituted with specific purified G-proteins. The G(alpha) subunits were generated in bacteria and were demonstrated to be recognised equivalently to bovine brain purified G(alpha) protein by CB(1) cannabinoid receptors. The ability of agonists to catalyse the MOR-dependent GDP/[(35)S]GTP(gamma)S exchange was then compared for G(alphai1) and G(alphaoA). Activation of MOR by DAMGO produced a high-affinity saturable interaction for G(alphaoA) (K(m)=20+/-1 nM) but a low-affinity interaction with G(alphai1) (K(m)=116+/-12 nM). DAMGO, met-enkephalin and leucine-enkephalin displayed maximal G(alpha) activation among the agonists evaluated. Endomorphins 1 and 2, methadone and beta-endorphin activated both G(alpha) to more than 75% of the maximal response, whereas fentanyl partially activated both G-proteins. Buprenorphine and morphine demonstrated a statistically significant difference between the maximal activities between G(alphai1) and G(alphaoA). Interestingly, DAMGO, morphine, endomorphins 1 and 2, displayed significant differences in the potencies for the activation of the two G(alpha). Differences in maximal activity and potency, for G(alphai1) versus G(alphaoA), are both indicative of agonist selective activation of G-proteins in response to MOR activation. These findings may provide a starting point for the design of drugs that demonstrate greater selectivity between these two G-proteins and therefore produce a more limited range of effects.

Differential activation of G-proteins by μ-opioid receptor agonists

PubMed Central

Saidak, Zuzana; Blake-Palmer, Katherine; Hay, Debbie L; Northup, John K; Glass, Michelle

2006-01-01

We investigated the ability of the activated μ-opioid receptor (MOR) to differentiate between myristoylated Gαi1 and GαoA type Gα proteins, and the maximal activity of a range of synthetic and endogenous agonists to activate each Gα protein. Membranes from HEK293 cells stably expressing transfected MOR were chaotrope extracted to denature endogenous G-proteins and reconstituted with specific purified G-proteins. The Gα subunits were generated in bacteria and were demonstrated to be recognised equivalently to bovine brain purified Gα protein by CB1 cannabinoid receptors. The ability of agonists to catalyse the MOR-dependent GDP/[35S]GTPγS exchange was then compared for Gαi1 and GαoA. Activation of MOR by DAMGO produced a high-affinity saturable interaction for GαoA (Km=20±1 nM) but a low-affinity interaction with Gαi1 (Km=116±12 nM). DAMGO, met-enkephalin and leucine-enkephalin displayed maximal Gα activation among the agonists evaluated. Endomorphins 1 and 2, methadone and β-endorphin activated both Gα to more than 75% of the maximal response, whereas fentanyl partially activated both G-proteins. Buprenorphine and morphine demonstrated a statistically significant difference between the maximal activities between Gαi1 and GαoA. Interestingly, DAMGO, morphine, endomorphins 1 and 2, displayed significant differences in the potencies for the activation of the two Gα. Differences in maximal activity and potency, for Gαi1 versus GαoA, are both indicative of agonist selective activation of G-proteins in response to MOR activation. These findings may provide a starting point for the design of drugs that demonstrate greater selectivity between these two G-proteins and therefore produce a more limited range of effects. PMID:16415903

Functional interactions between endogenous cannabinoid and opioid systems: focus on alcohol, genetics and drug-addicted behaviors.

PubMed

López-Moreno, J A; López-Jiménez, A; Gorriti, M A; de Fonseca, F Rodríguez

2010-04-01

Although the first studies regarding the endogenous opioid system and addiction were published during the 1940s, addiction and cannabinoids were not addressed until the 1970s. Currently, the number of opioid addiction studies indexed in PubMed-Medline is 16 times greater than the number of cannabinoid addiction reports. More recently, functional interactions have been demonstrated between the endogenous cannabinoid and opioid systems. For example, the cannabinoid brain receptor type 1 (CB1) and mu opioid receptor type 1 (MOR1) co-localize in the same presynaptic nerve terminals and signal through a common receptor-mediated G-protein pathway. Here, we review a great variety of behavioral models of drug addiction and alcohol-related behaviors. We also include data providing clear evidence that activation of the cannabinoid and opioid endogenous systems via WIN 55,512-2 (0.4-10 mg/kg) and morphine (1.0-10 mg/kg), respectively, produces similar levels of relapse to alcohol in operant alcohol self-administration tasks. Finally, we discuss genetic studies that reveal significant associations between polymorphisms in MOR1 and CB1 receptors and drug addiction. For example, the SNP A118G, which changes the amino acid aspartate to asparagine in the MOR1 gene, is highly associated with altered opioid system function. The presence of a microsatellite polymorphism of an (AAT)n triplet near the CB1 gene is associated with drug addiction phenotypes. But, studies exploring haplotypes with regard to both systems, however, are lacking.

Region specific up-regulation of oxytocin receptors in the opioid oprm1 (-/-) mouse model of autism.

PubMed

Gigliucci, Valentina; Leonzino, Marianna; Busnelli, Marta; Luchetti, Alessandra; Palladino, Viola Stella; D'Amato, Francesca R; Chini, Bice

2014-01-01

Autism spectrum disorders (ASDs) are characterized by impaired communication, social impairments, and restricted and repetitive behaviors and interests. Recently, altered motivation and reward processes have been suggested to participate in the physiopathology of ASDs, and μ-opioid receptors (MORs) have been investigated in relation to social reward due to their involvement in the neural circuitry of reward. Mice lacking a functional MOR gene (Oprm1 (-/-) mice) display abnormal social behavior and major autistic-like core symptoms, making them an animal model of autism. The oxytocin (OXT) system is a key regulator of social behavior and co-operates with the opioidergic system in the modulation of social behavior. To better understand the opioid-OXT interplay in the central nervous system, we first determined the expression of the oxytocin receptor (OXTR) in the brain of WT C57BL6/J mice by quantitative autoradiography; we then evaluated OXTR regional alterations in Oprm1 (-/-) mice. Moreover, we tested these mice in a paradigm of social behavior, the male-female social interaction test, and analyzed the effects of acute intranasal OXT treatment on their performance. In autoradiography, Oprm1 (-/-) mice selectively displayed increased OXTR expression in the Medial Anterior Olfactory Nucleus, the Central and Medial Amygdaloid nuclei, and the Nucleus Accumbens. Our behavioral results confirmed that Oprm1 (-/-) male mice displayed social impairments, as indicated by reduced ultrasonic calls, and that these were rescued by a single intranasal administration of OXT. Taken together, our results provide evidence of an interaction between OXT and opioids in socially relevant brain areas and in the modulation of social behavior. Moreover, they suggest that the oxytocinergic system may act as a compensative mechanism to bypass and/or restore alterations in circuits linked to impaired social behavior.

Comparing analgesia and μ-opioid receptor internalization produced by intrathecal enkephalin

PubMed Central

Chen, Wenling; Song, Bingbing; Lao, Lijun; Pérez, Orlando A.; Kim, Woojae; Marvizón, Juan Carlos G.

2007-01-01

Summary Opioid receptors in the spinal cord produce strong analgesia, but the mechanisms controlling their activation by endogenous opioids remain unclear. We have previously shown in spinal cord slices that peptidases preclude μ-opioid receptor (MOR) internalization by opioids. Our present goals were to investigate whether enkephalin-induced analgesia is also precluded by peptidases, and whether it is mediated by MORs or δ-opioid receptors (DORs). Tail-flick analgesia and MOR internalization were measured in rats injected intrathecally with Leu-enkephalin and peptidase inhibitors. Without peptidase inhibitors, Leu-enkephalin produced neither analgesia nor MOR internalization at doses up to 100 nmol, whereas with peptidase inhibitors it produced analgesia at 0.3 nmol and MOR internalization at 1 nmol. Leu-enkephalin was ten times more potent to produce analgesia than to produce MOR internalization, suggesting that DORs were involved. Selective MOR or DOR antagonists completely blocked the analgesia elicited by 0.3 nmol Leu-enkephalin (a dose that produced little MOR internalization), indicating that it involved these two receptors, possibly by an additive or synergistic interaction. The selective MOR agonist endomorphin-2 produced analgesia even in the presence of a DOR antagonist, but at doses substantially higher than Leu-enkephalin. Unlike Leu-enkephalin, endomorphin-2 had the same potencies to induce analgesia and MOR internalization. We concluded that low doses of enkephalins produce analgesia by activating both MORs and DORs. Analgesia can also be produced exclusively by MORs at higher agonist doses. Since peptidases prevent the activation of spinal opioid receptors by enkephalins, the coincident release of opioids and endogenous peptidase inhibitors may be required for analgesia. PMID:17845806

Response of the μ-opioid system to social rejection and acceptance.

PubMed

Hsu, D T; Sanford, B J; Meyers, K K; Love, T M; Hazlett, K E; Wang, H; Ni, L; Walker, S J; Mickey, B J; Korycinski, S T; Koeppe, R A; Crocker, J K; Langenecker, S A; Zubieta, J-K

2013-11-01

The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n=18), we used an μ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids have a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well being in the social environment.

The effects of endomorphins on striatal [3H]GABA release induced by electrical stimulation: an in vitro superfusion study in rats.

PubMed

Bagosi, Zsolt; Jászberényi, Miklós; Telegdy, Gyula

2009-05-01

The endomorphins (EM1 and EM2) are selective endogenous ligands for mu-opioid receptors (MOR1 and MOR2) with neurotransmitter and neuromodulator roles in mammals. In the present study we investigated the potential actions of EMs on striatal GABA release and the implication of different MORs in these processes. Rat striatal slices were preincubated with tritium-labelled GABA ([(3)H]GABA), pretreated with selective MOR1 and MOR2 antagonist beta-funaltrexamine and selective MOR1 antagonist naloxonazine and then superfused with the selective MOR agonists, EM1 and EM2. EM1 significantly decreased the striatal [(3)H]GABA release induced by electrical stimulation. Beta-funaltrexamine antagonized the inhibitory action of EM1, but naloxonazine did not affect it considerably. EM2 was ineffective, even in case of specific enzyme inhibitor diprotin A pretreatment. The results demonstrate that EM1 decreases GABA release in the basal ganglia through MOR2, while EM2 does not influence it.

Acute myeloid leukemia risk by industry and occupation.

PubMed

Tsai, Rebecca J; Luckhaupt, Sara E; Schumacher, Pam; Cress, Rosemary D; Deapen, Dennis M; Calvert, Geoffrey M

2014-11-01

Acute myeloid leukemia (AML) is the most common type of leukemia found in adults. Identifying jobs that pose a risk for AML may be useful for identifying new risk factors. A matched case-control analysis was conducted using California Cancer Registry data from 1988 to 2007. This study included 8999 cases of AML and 24 822 controls. Industries with a statistically significant increased AML risk were construction (matched odds ratio [mOR] = 1.13); crop production (mOR = 1.41); support activities for agriculture and forestry (mOR = 2.05); and animal slaughtering and processing (mOR = 2.09). Among occupations with a statistically significant increased AML risk were miscellaneous agricultural workers (mOR = 1.76); fishers and related fishing workers (mOR = 2.02); nursing, psychiatric and home health aides (mOR = 1.65); and janitors and building cleaners (mOR = 1.54). Further investigation is needed to confirm study findings and to identify specific exposures responsible for the increased risks.

Acute myeloid leukemia risk by industry and occupation

PubMed Central

Tsai, Rebecca J.; Luckhaupt, Sara E.; Schumacher, Pam; Cress, Rosemary D.; Deapen, Dennis M.; Calvert, Geoffrey M.

2015-01-01

Acute myeloid leukemia (AML) is the most common type of leukemia found in adults. Identifying jobs that pose a risk for AML may be useful for identifying new risk factors. A matched case–control analysis was conducted using California Cancer Registry data from 1988 to 2007. This study included 8999 cases of AML and 24 822 controls. Industries with a statistically significant increased AML risk were construction (matched odds ratio [mOR] = 1.13); crop production (mOR = 1.41); support activities for agriculture and forestry (mOR = 2.05); and animal slaughtering and processing (mOR = 2.09). Among occupations with a statistically significant increased AML risk were miscellaneous agricultural workers (mOR = 1.76); fishers and related fishing workers (mOR = 2.02); nursing, psychiatric and home health aides (mOR = 1.65); and janitors and building cleaners (mOR = 1.54). Further investigation is needed to confirm study findings and to identify specific exposures responsible for the increased risks. PMID:24547710

Morphine induces endocytosis of neuronal μ-opioid receptors through the sustained transfer of Gα subunits to RGSZ2 proteins

PubMed Central

Rodríguez-Muñoz, María; de la Torre-Madrid, Elena; Sánchez-Blázquez, Pilar; Garzón, Javier

2007-01-01

Background In general, opioids that induce the recycling of μ-opioid receptors (MORs) promote little desensitization, although morphine is one exception to this rule. While morphine fails to provoke significant internalization of MORs in cultured cells, it does stimulate profound desensitization. In contrast, morphine does promote some internalization of MORs in neurons although this does not prevent this opioid from inducing strong antinociceptive tolerance. Results In neurons, morphine stimulates the long-lasting transfer of MOR-activated Gα subunits to proteins of the RGS-R7 and RGS-Rz subfamilies. We investigated the influence of this regulatory process on the capacity of morphine to promote desensitization and its association with MOR recycling in the mature nervous system. In parallel, we also studied the effects of [D-Ala2, N-MePhe4, Gly-ol5] encephalin (DAMGO), a potent inducer of MOR internalization that promotes little tolerance. We observed that the initial exposure to icv morphine caused no significant internalization of MORs but rather, a fraction of the Gα subunits was stably transferred to RGS proteins in a time-dependent manner. As a result, the antinociception produced by a second dose of morphine administered 6 h after the first was weaker. However, this opioid now stimulated the phosphorylation, internalization and recycling of MORs, and further exposure to morphine promoted little tolerance to this moderate antinociception. In contrast, the initial dose of DAMGO stimulated intense phosphorylation and internalization of the MORs associated with a transient transfer of Gα subunits to the RGS proteins, recovering MOR control shortly after the effects of the opioid had ceased. Accordingly, the recycled MORs re-established their association with G proteins and the neurons were rapidly resensitized to DAMGO. Conclusion In the nervous system, morphine induces a strong desensitization before promoting the phosphorylation and recycling of MORs. The long-term sequestering of morphine-activated Gα subunits by certain RGS proteins reduces the responses to this opioid in neurons. This phenomenon probably increases free Gβγ dimers in the receptor environment and leads to GRK phosphorylation and internalization of the MORs. Although, the internalization of the MORs permits the transfer of opioid-activated Gα subunits to the RGSZ2 proteins, it interferes with the stabilization of this regulatory process and recycled MORs recover the control on these Gα subunits and opioid tolerance develops slowly. PMID:17634133

Opiorphin causes a panicolytic-like effect in rat panic models mediated by μ-opioid receptors in the dorsal periaqueductal gray.

PubMed

Maraschin, Jhonatan Christian; Rangel, Marcel Pereira; Bonfim, Antonio Joaquim; Kitayama, Mariana; Graeff, Frederico Guilherme; Zangrossi, Hélio; Audi, Elisabeth Aparecida

2016-02-01

Reported evidence indicates that endogenous opioid peptides regulate the expression of escape behavior in rats, a panic-related defensive response, through μ-opioid receptors (MORs) in the dorsal periaqueductal gray (dPAG). These peptides are rapidly catabolized by degrading enzymes, including neutral endopeptidase (NEP) and aminopeptidase N (APN). Opiorphin is a peptide inhibitor of both NEP and APN and potentiates the action of endogenous enkephalins. This study evaluated the effects of intravenous and intra-dPAG administration of opiorphin on escape responses in the elevated T-maze and in a dPAG electrical stimulation test in rats. We also evaluated the involvement of MORs in the effects of opiorphin using the selective MOR antagonist CTOP. A dose of 2.0 mg/kg, i.v., of opiorphin impaired escape performance in both tests. Similar effects were observed with intra-dPAG administration of 5.0 nmol of opiorphin. Local pretreatment with 1.0 nmol CTOP antagonized the anti-escape effects of intra-dPAG opiorphin in both tests, as well as the effect of systemically administered opiorphin (2.0 mg/kg, i.v.) in the electrical stimulation test. These results indicate that opiorphin has an antipanic-like effect that is mediated by MORs in the dPAG. They may open new perspectives for the development of opiorphin analogues with greater bioavailability and physicochemical characteristics in the pursuit of new medications for the treatment of panic disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mu-opioid receptor redistribution in the locus coeruleus upon precipitation of withdrawal in opiate-dependent rats.

PubMed

Scavone, Jillian L; Van Bockstaele, Elisabeth J

2009-03-01

Administration of mu-opioid receptor (MOR) agonists is known to produce adaptive changes within noradrenergic neurons of the rat locus coeruleus (LC). Alterations in the subcellular distribution of MOR have been shown to occur in the LC in response to full agonists and endogenous peptides; however, there is considerable debate in the literature whether trafficking of MOR occurs after chronic exposure to the partial-agonist morphine. In the present study, we examined adaptations in MOR after chronic opioid exposure using immunofluorescence and electron microscopy (EM), using receptor internalization as a functional endpoint. MOR trafficking in LC neurons was characterized in morphine-dependent rats that were given naltrexone at a dose known to precipitate withdrawal. After chronic morphine exposure, a subtle redistribution of MOR immunoreactivity from the membrane to the cytosol was detected within dendrites of LC neurons. Interestingly, an acute injection of naltrexone in rats exposed to chronic morphine produced a robust internalization of MOR, whereas administration of naltrexone failed to do so in naïve animals. These findings provide anatomical evidence for modified regulation of MOR trafficking after chronic morphine treatment in brain noradrenergic neurons. Adaptations in the MOR signaling pathways that regulate internalization may occur as a consequence of chronic treatment and precipitation of withdrawal. Mechanisms underlying this effect might include differential MOR regulation in the LC, or downstream effects of withdrawal-induced enkephalin (ENK) release from afferents to the LC. (c) 2009 Wiley-Liss, Inc.

Trivalent ions modification for high-silica mordenite: A first principles study

NASA Astrophysics Data System (ADS)

Chen, Fayun; Zhang, Laijun; Feng, Gang; Wang, Xuewen; Zhang, Rongbin; Liu, Jianwen

2018-03-01

Using periodic DFT-D3-U methods, the present work give a mechanistic insight into the high silica B-, Al-, Ga- and Fe-MOR with H, Li, Na, and K as charge balance ions. The acid properties of the zeolite were probed via NH3 and pyridine adsorption. It is found that the charge balance ions influence the location of the trivalent ions, the cell volumes, as well as the synthesis difficulty of the zeolites. The energy differences for B, Al, Ga and Fe in different T sites are small for the H-form zeolites, while large for the Na- and K-form zeolites. For H-form MOR, the proton of the sbnd OH group prefers to bond to O(7) and O(3) and pointing to the 12MR for trivalent ions in T1 sites. The proton bonds to O(3), O(2), O(2) and O(5), respectively, for B, Al, Ga and Fe in T2 site of MOR, with the sbnd OH group pointing to intersection of 12MR and the side-pocket, except for the B-MOR that sbnd OH group pointing to the 12MR. For trivalent ions located in T3 and T4 sites, the protons prefers to bond to O(1) and O(2), respectively, with the sbnd OH group pointing to the intersection of 8MR and side-pocket as well as the intersection of 12MR and side-pocket. All incorporated B, Al, Ga, and Fe framework ions are tetra-coordinated, except the B atoms are tri-coordinated. The NH4-form MOR has smaller cell volume than the other form MOR. Na and K are energetically more favored charge balance ions than Li and NH3 for MOR zeolites synthesis, and the H-form zeolite is the most difficult to be synthesized directly. The strength of the Brønsted acidity follows the order: HBMOR < HFeMOR ≈ HGaMOR < HAlMOR, vs. the Lewis acidity order: HBMOR < HAlMOR < HFeMOR ≈ HGaMOR. NH3 could be adsorbed inside all kinds of channels, and especially favors in the small 8MR vs. pyridine could only be adsorbed in the main channel of MOR due to the steric effect. It indicates that the acid sites in the side pocket and the small 8-membered ring and the side pocket could not be effectively determined just by the pyridine adsorption experiments. In comparison, the NH3 adsorption experiments could detect all kinds of Brønsted sites of the MOR zeolites.

Cocaine Dysregulates Opioid Gating of GABA Neurotransmission in the Ventral Pallidum

PubMed Central

Scofield, Michael D.; Rice, Kenner C.; Cheng, Kejun; Roques, Bernard P.

2014-01-01

The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these projections coexpress GABA and the neuropeptide enkephalin, a δ and μ opioid receptor (MOR) ligand. Of these two, the MOR in the VP is known to be involved in reward-related behaviors, such as hedonic responses to palatable food, alcohol intake, and reinstatement of cocaine seeking. Stimulating MORs in the VP decreases extracellular GABA, indicating that the effects of MORs in the VP on cocaine seeking are via modulating GABA neurotransmission. Here, we use whole-cell patch-clamp on a rat model of withdrawal from cocaine self-administration to test the hypothesis that MORs presynaptically regulate GABA transmission in the VP and that cocaine withdrawal changes the interaction between MORs and GABA. We found that in cocaine-extinguished rats pharmacological activation of MORs no longer presynaptically inhibited GABA release, whereas blocking the MORs disinhibited GABA release. Moreover, MOR-dependent long-term depression of GABA neurotransmission in the VP was lost in cocaine-extinguished rats. Last, GABA neurotransmission was found to be tonically suppressed in cocaine-extinguished rats. These substantial synaptic changes indicated that cocaine was increasing tone on MOR receptors. Accordingly, increasing endogenous tone by blocking the enzymatic degradation of enkephalin inhibited GABA neurotransmission in yoked saline rats but not in cocaine-extinguished rats. In conclusion, our results indicate that following withdrawal from cocaine self-administration enkephalin levels in the VP are elevated and the opioid modulation of GABA neurotransmission is impaired. This may contribute to the difficulties withdrawn addicts experience when trying to resist relapse. PMID:24431463

Phosphorylation state of mu-opioid receptor determines the alternative recycling of receptor via Rab4 or Rab11 pathway.

PubMed

Wang, Feifei; Chen, Xiaoqing; Zhang, Xiaoqing; Ma, Lan

2008-08-01

Agonist-induced phosphorylation, internalization, and intracellular trafficking of G protein-coupled receptors are critical in regulating both cellular responsiveness and signal transduction. The current study investigated the role of receptor phosphorylation state in regulation of agonist-induced internalization and intracellular trafficking of mu-opioid receptor (MOR). Our results showed that after agonist stimulation, the recycle of a mutant MOR that lacks the C-terminal residues after Asn(362) (MOR362T) was greatly decreased, whereas a C-terminal phosphorylation sites-mutated MOR (MOR3A), which is deficient in agonist-induced phosphorylation recycled back to the membrane at a level comparable to that of the wild-type receptor, however, interestingly at a slower rate. Inhibition of functions of either Rab4 or Rab11 by dominant-negative mutants and small interfering RNA both significantly impaired the recycling of the wild-type MOR, whereas the recycling of the phosphorylation-deficient mutant was only inhibited by the dominant-negative mutant and small interfering RNA of Rab11, suggesting that the recycling of nonphosphorylated MOR is exclusively via Rab11-mediated pathway. Furthermore, phosphorylated MOR was observed accumulated in Rab5- and Rab4-, but not Rab11-positive vesicles. Our data indicate that both phosphorylated and nonphosphorylated MOR internalize via Rab5-dependent pathway after agonist stimulation, and the phosphorylated and nonphosphorylated MORs recycle through distinct vesicular trafficking pathways mediated by Rab4 and Rab11, respectively, which may ultimately lead to differential cellular responsiveness or downstream signaling.

The µ-opioid system promotes visual attention to faces and eyes.

PubMed

Chelnokova, Olga; Laeng, Bruno; Løseth, Guro; Eikemo, Marie; Willoch, Frode; Leknes, Siri

2016-12-01

Paying attention to others' faces and eyes is a cornerstone of human social behavior. The µ-opioid receptor (MOR) system, central to social reward-processing in rodents and primates, has been proposed to mediate the capacity for affiliative reward in humans. We assessed the role of the human MOR system in visual exploration of faces and eyes of conspecifics. Thirty healthy males received a novel, bidirectional battery of psychopharmacological treatment (an MOR agonist, a non-selective opioid antagonist, or placebo, on three separate days). Eye-movements were recorded while participants viewed facial photographs. We predicted that the MOR system would promote visual exploration of faces, and hypothesized that MOR agonism would increase, whereas antagonism decrease overt attention to the information-rich eye region. The expected linear effect of MOR manipulation on visual attention to the stimuli was observed, such that MOR agonism increased while antagonism decreased visual exploration of faces and overt attention to the eyes. The observed effects suggest that the human MOR system promotes overt visual attention to socially significant cues, in line with theories linking reward value to gaze control and target selection. Enhanced attention to others' faces and eyes represents a putative behavioral mechanism through which the human MOR system promotes social interest. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Functional μ-Opioid-Galanin Receptor Heteromers in the Ventral Tegmental Area.

PubMed

Moreno, Estefanía; Quiroz, César; Rea, William; Cai, Ning-Sheng; Mallol, Josefa; Cortés, Antoni; Lluís, Carme; Canela, Enric I; Casadó, Vicent; Ferré, Sergi

2017-02-01

The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of μ-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders. The μ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder. Copyright © 2017 the authors 0270-6474/17/371176-11$15.00/0.

Functional μ-Opioid-Galanin Receptor Heteromers in the Ventral Tegmental Area

PubMed Central

Moreno, Estefanía; Quiroz, César; Rea, William; Cai, Ning-Sheng; Cortés, Antoni

2017-01-01

The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of μ-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin–opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR–Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders. SIGNIFICANCE STATEMENT The μ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin–opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder. PMID:28007761

The effects of endomorphins and diprotin A on striatal dopamine release induced by electrical stimulation-an in vitro superfusion study in rats.

PubMed

Bagosi, Zsolt; Jászberényi, Miklós; Bujdosó, Erika; Szabó, Gyula; Telegdy, Gyula

2006-12-01

The endomorphins (EM1: Tyr-Pro-Trp-Phe-NH2, and EM2: Tyr-Pro-Phe-Phe-NH2) are recently discovered endogenous ligands for mu-opioid receptors (MORs) with role of neurotransmitters or neuromodulators in mammals. Cessation of their physiological action may be effected through rapid enzymatic degradation by the dipeptidyl-peptidase IV (DPPIV) found in the brain synaptic membranes. An in vitro superfusion system was utilized to investigate the actions of EM1, EM2 and specific DPPIV inhibitor diprotin A on the striatal release of dopamine (DA) induced by electrical stimulation in rats. The involvement of the different MORs (MOR1 and MOR2) in this process was studied by pretreatment with MOR antagonists beta-funaltrexamine (a MOR1 and MOR2 antagonist) and naloxonazine (a MOR1 antagonist). EM1 significantly increased the tritium-labelled dopamine DA release induced by electrical stimulation. EM2 was effective only when the slices were pretreated with diprotin A. beta-Funaltrexamine antagonized the stimulatory effects of both EM1 and EM2. The administration of naloxonazine did not appreciably influence the action of EM1, but blocked the action of EM2, at least when the slices were pretreated with diprotin A. These data suggest that both EM1 and EM2 increase DA release from the striatum and, though diprotin A does not affect the action of EM1, it inhibits the enzymatic degradation of EM2. The DA-stimulating action induced by EM1 seems to be mediated by MOR2, while that evoked by EM2 appears to be transmitted by MOR1.

Improvement of Morphine-Mediated Analgesia by Inhibition of β-Arrestin 2 Expression in Mice Periaqueductal Gray Matter

PubMed Central

Li, Yuting; Liu, Xing; Liu, Chang; Kang, Jiuhong; Yang, Jingyu; Pei, Gang; Wu, Chunfu

2009-01-01

Morphine is a well-known μ-opioid receptor (MOR) agonist and an efficient analgesic, but its long-term use inevitably leads to drug addiction and tolerance. Here, we show that specific inhibition of β-arrestin2 with its siRNA lentivirus microinjected in mice periaqueductal gray matter (PAG) significantly improved both acute and chronic morphine analgesia and delayed the tolerance in the hotplate test. The specific effect of β-arrestin2 was proven by overexpression or knockdown of its homology β-arrestin1 in PAG, which showed no significant effects on morphine analgesia. These findings suggest that specific siRNA targeting β-arrestin2 may constitute a new approach to morphine therapy and other MOR agonist-mediated analgesia and tolerance. PMID:19399231

Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism

PubMed Central

Milan-Lobo, Laura; Enquist, Johan; van Rijn, Richard M.; Whistler, Jennifer L.

2013-01-01

Delta (DOR) and mu opioid receptors (MOR) can complex as heteromers, conferring functional properties in agonist binding, signaling and trafficking that can differ markedly from their homomeric counterparts. Because of these differences, DOR/MOR heteromers may be a novel therapeutic target in the treatment of pain. However, there are currently no ligands selective for DOR/MOR heteromers, and, consequently, their role in nociception remains unknown. In this study, we used a pharmacological opioid cocktail that selectively activates and stabilizes the DOR/MOR heteromer at the cell surface by blocking its endocytosis to assess its role in antinociception. We found that mice treated chronically with this drug cocktail showed a significant right shift in the ED50 for opioid-mediated analgesia, while mice treated with a drug that promotes degradation of the heteromer did not. Furthermore, promoting degradation of the DOR/MOR heteromer after the right shift in the ED50 had occurred, or blocking signal transduction from the stabilized DOR/MOR heteromer, shifted the ED50 for analgesia back to the left. Taken together, these data suggest an anti-analgesic role for the DOR/MOR heteromer in pain. In conclusion, antagonists selective for DOR/MOR heteromer could provide an avenue for alleviating reduced analgesic response during chronic pain treatment. PMID:23554887

A survey of single nucleotide polymorphisms identified from whole-genome sequencing and their functional effect in the porcine genome

USDA-ARS?s Scientific Manuscript database

Genetic variants detected from sequence have been used to successfully identify causal variants and map complex traits in several organisms. High and moderate impact variants, those expected to alter or disrupt the protein coded by a gene and those that regulate protein production, likely have a mor...

Identifying novel members of the Wntless interactome through genetic and candidate gene approaches.

PubMed

Petko, Jessica; Tranchina, Trevor; Patel, Goral; Levenson, Robert; Justice-Bitner, Stephanie

2018-04-01

Wnt signaling is an important pathway that regulates several aspects of embryogenesis, stem cell maintenance, and neural connectivity. We have recently determined that opioids decrease Wnt secretion, presumably by inhibiting the recycling of the Wnt trafficking protein Wntless (Wls). This effect appears to be mediated by protein-protein interaction between Wls and the mu-opioid receptor (MOR), the primary cellular target of opioid drugs. The goal of this study was to identify novel protein interactors of Wls that are expressed in the brain and may also play a role in reward or addiction. Using genetic and candidate gene approaches, we show that among a variety of protein, Wls interacts with the dopamine transporter (target of cocaine), cannabinoid receptors (target of THC), Adenosine A2A receptor (target of caffeine), and SGIP1 (endocytic regulator of cannabinoid receptors). Our study shows that aside from opioid receptors, Wntless interacts with additional proteins involved in reward and/or addiction. Future studies will determine whether Wntless and WNT signaling play a more universal role in these processes. Copyright © 2017 Elsevier Inc. All rights reserved.

The ataxic mouse as a model for studying downbeat nystagmus.

PubMed

Stahl, John S; Thumser, Zachary C; Oommen, Brian S

2012-01-01

Downbeat nystagmus (DBN) is a common eye movement complication of cerebellar disease. Use of mice to study pathophysiology of vestibulocerebellar disease is increasing, but it is unclear if mice can be used to study DBN; it has not been reported in this species. We determined whether DBN occurs in the ataxic mutant tottering, which carries a mutation in the Cacna1a gene for P/Q calcium channels. Spontaneous DBN occurred only rarely, and its magnitude did not exhibit the relationship to head tilt seen in human patients. DBN during yaw rotation was more common and shares some properties with the tilt-independent, gaze-independent component of human DBN, but differs in its dependence on vision. Hyperactivity of otolith circuits responding to pitch tilts is hypothesized to contribute to the gaze-independent component of human DBN. Mutants exhibited hyperactivity of the tilt maculo-ocular reflex (tiltMOR) in pitch. The hyperactivity may serve as a surrogate for DBN in mouse studies. TiltMOR hyperactivity correlates with hyperdeviation of the eyes and upward deviation of the head during ambulation; these may be alternative surrogates. Muscimol inactivation of the cerebellar flocculus suggests a floccular role in the tiltMOR hyperactivity and provides insight into the rarity of frank DBN in ataxic mice.

The ataxic mouse as a model for studying downbeat nystagmus

PubMed Central

Stahl, John S.; Thumser, Zachary C.; Oommen, Brian S.

2016-01-01

Downbeat nystagmus (DBN) is a common eye movement complication of cerebellar disease. Use of mice to study pathophysiology of vestibulocerebellar disease is increasing, but it is unclear if mice can be used to study DBN; it has not been reported in this species. We determined whether DBN occurs in the ataxic mutant tottering, which carries a mutation in the Cacna1a gene for P/Q calcium channels. Spontaneous DBN occurred only rarely, and its magnitude did not exhibit the relationship to head tilt seen in human patients. DBN during yaw rotation was more common and shares some properties with the tilt-independent, gaze-independent component of human DBN, but differs in its dependence on vision. Hyperactivity of otolith circuits responding to pitch tilts is hypothesized to contribute to the gaze-independent component of human DBN. Mutants exhibited hyperactivity of the tilt maculo-ocular reflex (tiltMOR) in pitch. The hyperactivity may serve as a surrogate for DBN in mouse studies. TiltMOR hyperactivity correlates with hyperdeviation of the eyes and upward deviation of the head during ambulation; these may be alternative surrogates. Muscimol inactivation of the cerebellar flocculus suggests a floccular role in the tiltMOR hyperactivity and provides insight into the rarity of frank DBN in ataxic mice. PMID:23302704

Treatment of pruritus with topically applied opiate receptor antagonist.

PubMed

Bigliardi, Paul L; Stammer, Holger; Jost, Gerhard; Rufli, Theo; Büchner, Stanislaw; Bigliardi-Qi, Mei

2007-06-01

Pruritus is the most common and distressing skin symptom, and treatment of itch is a problem for thousands of people. The currently available therapies are not very effective. Therefore there is an urgent need to find new effective topical drugs against itching. We conducted two separate studies to evaluate the efficacy of topically applied naltrexone, an opioid receptor antagonist, in the treatment of severe pruritus. The objective of the first open study was to correlate the clinical efficacy of topically applied naltrexone in different pruritic skin disorders to a change of epidermal mu-opiate receptor (MOR) expression. The second study was a double-blind, placebo-controlled, crossover study on pruritus in atopic dermatitis. Initially we performed an open pilot study on 18 patients with different chronic pruritic disorders using a topical formulation of 1% naltrexone for 2 weeks. A punch biopsy was performed in 11 patients before and after the application of the naltrexone cream and the staining of epidermal MOR was measured. Subsequently, a randomized, placebo-controlled, crossover trial was performed with the same formulation. We included in this trial 40 patients with localized and generalized atopic dermatitis with severe pruritus. In the open study more than 70% of the patients using the 1% naltrexone cream experienced a significant reduction of pruritus. More interestingly, the topical treatment with naltrexone caused an increase of epidermal MOR staining. The regulation of the epidermal opioid receptor correlated with the clinical assessment. The placebo-controlled, crossover trial demonstrated clearly that the cream containing naltrexone had an overall 29.4% better effect compared with placebo. The formulation containing naltrexone required a median of 46 minutes to reduce the itch symptoms to 50%; the placebo, 74 minutes. We could only take biopsy specimens in 11 patients, which means that a satisfactory statistical analysis of the changes of epidermal MOR staining was not possible. In addition, there was an insufficient number of patients with nephrogenic pruritus and pruritic psoriasis to draw definitive conclusions. The placebo-controlled study showed a significant advantage of topically applied naltrexone over the placebo formulation. This finding is supported by the biopsy results from the open studies, showing a regulation of MOR expression in epidermis after treatment with topical naltrexone, especially in atopic dermatitis. These results clearly show potential for topically applied opioid receptor antagonist in the treatment of pruritus. The placebo formulation also had some antipruritic effects. This underlines the importance of rehydration therapy for dry skin in the treatment of pruritus.

Small Sample Properties of Asymptotically Efficient Estimators of the Parameters of a Bivariate Gaussian–Weibull Distribution

Treesearch

Steve P. Verrill; James W. Evans; David E. Kretschmann; Cherilyn A. Hatfield

2012-01-01

Two important wood properties are stiffness (modulus of elasticity or MOE) and bending strength (modulus of rupture or MOR). In the past, MOE has often been modeled as a Gaussian and MOR as a lognormal or a two or three parameter Weibull. It is well known that MOE and MOR are positively correlated. To model the simultaneous behavior of MOE and MOR for the purposes of...

Maximum likelihood estimation of the parameters of a bivariate Gaussian-Weibull distribution from machine stress-rated data

Treesearch

Steve P. Verrill; David E. Kretschmann; James W. Evans

2016-01-01

Two important wood properties are stiffness (modulus of elasticity, MOE) and bending strength (modulus of rupture, MOR). In the past, MOE has often been modeled as a Gaussian and MOR as a lognormal or a two- or threeparameter Weibull. It is well known that MOE and MOR are positively correlated. To model the simultaneous behavior of MOE and MOR for the purposes of wood...

Platinum-mordenite catalysts for n-Hexane isomerization: Characterization by X-ray absorption spectroscopy and chemical probes

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

Otten, M.M.; Clayton, M.J.; Lamb, H.H.

Platinum-mordenite (Pt-MOR) catalysts were prepared from NH{sub 4}-MOR by ion exchange with (Pt{sup II}(NH{sub 3}){sub 4})(OH){sub 2}, calcination in O{sub 2} at 350{degrees}C, and reduction in H{sub 2} at 350{degrees}C. The resultant Pt-H-MOR was active for n-hexane isomerization and hydrocracking via bifunctional catalysis at 240-300{degrees}C and 1 atm. The observed activation energies for C{sub 6} branched-isomer formation are unusually low, suggesting that the isomerization rates were controlled by pore diffusion. A Pt-KH-MOR catalyst was prepared by ion exchange with aqueous KNO{sub 3} and re-reduction at 350{degrees}C; elemental analysis evidenced 90% exchange of protons for K{sup +} ions. The product distributionmore » and observed activation energies for C{sub 6} branched-isomer formation over Pt-KH-MOR are consistent with n-hexane isomerization via bifunctional catalysis. Hydrocracking was strongly suppressed, and light hydrocarbons were formed primarily by Pt-catalyzed hydrogenolysis. From in-situ extended X-ray absorption fine structure spectroscopy and H{sub 2} temperature-programmed desorption, we conclude that the Pt-MOR catalysts consist of small Pt clusters hosted within the mordenite crystals. The PtL{sub III}X-ray absorption near-edge structure (XANES) spectra of Pt-H-MOR and Pt-KH-MOR are closely similar, suggesting that the electronic structure of the Pt clusters is unaffected by mordenite acid-base chemistry. The infrared spectrum of CO adsorbed on Pt-H-MOR contains an intense band at 2084 cm{sup -1}, which is assigned to linear CO moieties on Pt clusters. The infrared spectrum of CO adsorbed on Pt-KH-MOR evidences a red shift of the linear CO band, which the authors suggest is due to electrostatic interactions between carbonyl O atoms and nearby K{sup +} ions. 45 refs., 9 figs., 6 tabs.« less

Brain mu-opioid receptor binding predicts treatment outcome in cocaine-abusing outpatients

PubMed Central

Ghitza, Udi E.; Preston, Kenzie L.; Epstein, David H.; Kuwabara, Hiroto; Endres, Christopher J.; Bencherif, Badreddine; Boyd, Susan J.; Copersino, Marc L.; Frost, J. James; Gorelick, David A.

2010-01-01

Background Cocaine users not seeking treatment have increased regional brain mu-opioid receptor (mOR) binding that correlates with cocaine craving and tendency to relapse. In cocaine-abusing outpatients in treatment, the relationship of mOR binding and treatment outcome is unknown. Methods We determined whether regional brain mOR binding before treatment correlates with outcome and compared it to standard clinical predictors of outcome. Twenty-five individuals seeking outpatient treatment for cocaine abuse or dependence (DSM-IV) received up to 12 weeks of cognitive-behavioral therapy and cocaine-abstinence reinforcement whereby each cocaine-free urine was reinforced with vouchers redeemable for goods. Regional brain mOR binding was measured before treatment using positron emission tomography (PET) with [11C] carfentanil (a selective mOR agonist). Main outcome measures were: 1) overall percentage of urines positive for cocaine during first month of treatment, 2) longest duration (weeks) of abstinence from cocaine during treatment, all verified by urine toxicology. Results Elevated mOR binding in the medial frontal and middle frontal gyri before treatment correlated with greater cocaine use during treatment. Elevated mOR binding in the anterior cingulate, medial frontal, middle frontal, middle temporal, and sub-lobar insular gyri correlated with shorter duration of cocaine abstinence during treatment. Regional mOR binding contributed significant predictive power for treatment outcome beyond that of standard clinical variables such as baseline drug and alcohol use. Conclusions Elevated mOR binding in brain regions associated with reward sensitivity is a significant independent predictor of treatment outcome in cocaine-abusing outpatients, suggesting a key role for the brain endogenous opioid system in cocaine addiction. PMID:20579973

It still hurts: altered opioid activity in the brain during social rejection and acceptance in major depressive disorder

PubMed Central

Hsu, David T; Sanford, Benjamin J; Meyers, Kortni K; Love, Tiffany M; Hazlett, Kathleen E; Walker, Sara J; Mickey, Brian J; Koeppe, Robert A; Langenecker, Scott A; Zubieta, Jon-Kar

2015-01-01

The μ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen “social pain.” We used positron emission tomography scanning with the selective MOR radioligand [11C]carfentanil to test the hypothesis that MOR system activation in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n = 17) compared to healthy controls (HCs, n = 18). During rejection, MDD patients showed reduced MOR activation (e.g., reduced endogenous opioid release) in brain regions regulating stress, mood, and motivation, and slower emotional recovery compared to HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with MOR activation in the nucleus accumbens, a reward structure. Abnormal MOR function in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse, and contribute to poor treatment outcomes. PMID:25600108

Regulation of µ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

PubMed Central

Williams, John T.; Ingram, Susan L.; Henderson, Graeme; Chavkin, Charles; von Zastrow, Mark; Schulz, Stefan; Koch, Thomas; Evans, Christopher J.

2013-01-01

Morphine and related µ-opioid receptor (MOR) agonists remain among the most effective drugs known for acute relief of severe pain. A major problem in treating painful conditions is that tolerance limits the long-term utility of opioid agonists. Considerable effort has been expended on developing an understanding of the molecular and cellular processes that underlie acute MOR signaling, short-term receptor regulation, and the progression of events that lead to tolerance for different MOR agonists. Although great progress has been made in the past decade, many points of contention and controversy cloud the realization of this progress. This review attempts to clarify some confusion by clearly defining terms, such as desensitization and tolerance, and addressing optimal pharmacological analyses for discerning relative importance of these cellular mechanisms. Cellular and molecular mechanisms regulating MOR function by phosphorylation relative to receptor desensitization and endocytosis are comprehensively reviewed, with an emphasis on agonist-biased regulation and areas where knowledge is lacking or controversial. The implications of these mechanisms for understanding the substantial contribution of MOR signaling to opioid tolerance are then considered in detail. While some functional MOR regulatory mechanisms contributing to tolerance are clearly understood, there are large gaps in understanding the molecular processes responsible for loss of MOR function after chronic exposure to opioids. Further elucidation of the cellular mechanisms that are regulated by opioids will be necessary for the successful development of MOR-based approaches to new pain therapeutics that limit the development of tolerance. PMID:23321159

Peripheral μ-opioid receptor mediated inhibition of calcium signaling and action potential-evoked calcium fluorescent transients in primary afferent CGRP nociceptive terminals.

PubMed

Baillie, Landon D; Schmidhammer, Helmut; Mulligan, Sean J

2015-06-01

While μ-opioid receptor (MOR) agonists remain the most powerful analgesics for the treatment of severe pain, serious adverse side effects that are secondary to their central nervous system actions pose substantial barriers to therapeutic use. Preclinical and clinical evidence suggest that peripheral MORs play an important role in opioid analgesia, particularly under inflammatory conditions. However, the mechanisms of peripheral MOR signaling in primary afferent pain fibres remain to be established. We have recently introduced a novel ex vivo optical imaging approach that, for the first time, allows the study of physiological functioning within individual peripheral nociceptive fibre free nerve endings in mice. In the present study, we found that MOR activation in selectively identified, primary afferent CGRP nociceptive terminals caused inhibition of N-type Ca(2+) channel signaling and suppression of action potential-evoked Ca(2+) fluorescent transients mediated by 'big conductance' Ca(2+)-activated K(+) channels (BKCa). In the live animal, we showed that the peripherally acting MOR agonist HS-731 produced analgesia and that BKCa channels were the major effectors of the peripheral MOR signaling. We have identified two key molecular transducers of MOR activation that mediate significant inhibition of nociceptive signaling in primary afferent terminals. Understanding the mechanisms of peripheral MOR signaling may promote the development of pathway selective μ-opioid drugs that offer improved therapeutic profiles for achieving potent analgesia while avoiding serious adverse central side effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Fast Modulation of μ-Opioid Receptor (MOR) Recycling Is Mediated by Receptor Agonists*

PubMed Central

Roman-Vendrell, Cristina; Yu, Y. Joy; Yudowski, Guillermo Ariel

2012-01-01

The μ-opioid receptor (MOR) is a member of the G protein-coupled receptor family and the main target of endogenous opioid neuropeptides and morphine. Upon activation by ligands, MORs are rapidly internalized via clathrin-coated pits in heterologous cells and dissociated striatal neurons. After initial endocytosis, resensitized receptors recycle back to the cell surface by vesicular delivery for subsequent cycles of activation. MOR trafficking has been linked to opioid tolerance after acute exposure to agonist, but it is also involved in the resensitization process. Several studies describe the regulation and mechanism of MOR endocytosis, but little is known about the recycling of resensitized receptors to the cell surface. To study this process, we induced internalization of MOR with [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) and morphine and imaged in real time single vesicles recycling receptors to the cell surface. We determined single vesicle recycling kinetics and the number of receptors contained in them. Then we demonstrated that rapid vesicular delivery of recycling MORs to the cell surface was mediated by the actin-microtubule cytoskeleton. Recycling was also dependent on Rab4, Rab11, and the Ca2+-sensitive motor protein myosin Vb. Finally, we showed that recycling is acutely modulated by the presence of agonists and the levels of cAMP. Our work identifies a novel trafficking mechanism that increases the number of cell surface MORs during acute agonist exposure, effectively reducing the development of opioid tolerance. PMID:22378794

Multimodal Imaging of Pathophysiological Changes and Their Role in Development of Breast Cancer Brain Metastasis

DTIC Science & Technology

2010-09-01

vascular and tissue oxygenation. Moreover, by introducing hypoxia reporter gene ( HRE -luciferase) into breast tumor lines, we will be able to use...luciferase re porter gene under the re gulation of an artificial HIF-1-dependent promoter, 5 HRE (14, 1 5). Integrati on of MRI and BLI will provide...mor hypoxi a. 5 x 10 4 MDA-MB231- HRE -ODD-luc cells were directly inje cted into caudal nucle ar area of right side mouse brain. BLI was applied to

Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands.

PubMed

Bender, Aaron M; Clark, Mary J; Agius, Michael P; Traynor, John R; Mosberg, Henry I

2014-01-15

In this letter, we describe a series of 4-substituted piperidine and piperazine compounds based on tetrahydroquinoline 1, a compound that shows balanced, low nanomolar binding affinity for the mu opioid receptor (MOR) and the delta opioid receptor (DOR). We have shown that by changing the length and flexibility profile of the side chain in this position, binding affinity is improved at both receptors by a significant degree. Furthermore, several of the compounds described herein display good efficacy at MOR, while simultaneously displaying DOR antagonism. The MOR agonist/DOR antagonist has shown promise in the reduction of negative side effects displayed by selective MOR agonists, namely the development of dependence and tolerance. Copyright © 2013 Elsevier Ltd. All rights reserved.

Endomorphin-2 is Released from Newborn Rat Primary Sensory Neurons in a Frequency- and Calcium- Dependent Manner

PubMed Central

Scanlin, Heather L.; Carroll, Elizabeth A.; Jenkins, Victoria K.; Balkowiec, Agnieszka

2008-01-01

Recent evidence indicates that endomorphins, endogenous mu-opioid receptor (MOR) agonists, modulate synaptic transmission in both somatic and visceral sensory pathways. Here we show that endomorphin-2 (END-2) is expressed in newborn rat dorsal root ganglion (DRG) and nodose-petrosal ganglion complex (NPG) neurons, and rarely co-localizes with brain-derived neurotrophic factor (BDNF). In order to examine activity-dependent release of END-2 from neurons, we established a model using dispersed cultures of DRG and NPG cells activated by patterned electrical field stimulation. To detect release of END-2, we developed a novel rapid capture ELISA, in which END-2 capture antibody was added to neuronal cultures shortly before their electrical stimulation. The conventional assay was effective at reliably detecting END-2 only when the cells were stimulated in the presence of CTAP, a MOR-selective antagonist. This suggests that the strength of the novel assay is related primarily to rapid capture of released END-2 before it binds to endogenous MORs. Using the rapid capture ELISA, we found that stimulation protocols known to induce plastic changes at sensory synapses were highly effective at releasing END-2. Removal of extracellular calcium or blocking voltage-activated calcium channels significantly reduced the release. Together, our data provide the first evidence that END-2 is expressed by newborn DRG neurons of all sizes found in this age group, and can be released from these, as well as from NPG neurons, in an activity-dependent manner. These results point to END-2 as a likely mediator of activity-dependent plasticity in sensory pathways. PMID:18513316

Treatment with Sulforaphane Produces Antinociception and Improves Morphine Effects during Inflammatory Pain in Mice.

PubMed

Redondo, Alejandro; Chamorro, Pablo Aníbal Ferreira; Riego, Gabriela; Leánez, Sergi; Pol, Olga

2017-12-01

The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts potent antioxidative and anti-inflammatory effects; however, its participation in the modulation of chronic inflammatory pain and on the antinociceptive effects of μ -opioid receptor (MOR) agonists has not been evaluated. We investigated whether the induction of Nrf2 could alleviate chronic inflammatory pain and augment the analgesic effects of morphine and mechanisms implicated. In male C57BL/6 mice with inflammatory pain induced by complete Freund's adjuvant (CFA) subplantarly administered, we assessed: 1) antinociceptive actions of the administration of 5 and 10 mg/kg of a Nrf2 activator, sulforaphane (SFN); and 2) effects of SFN on the antinociceptive actions of morphine and on protein levels of Nrf2, heme oxygenase 1 (HO-1), and NAD(P)H: quinone oxidoreductase 1 (NQO1) enzymes, microglial activation and inducible nitric oxide synthase (NOS2) overexpression, as well as on mitogen-activated protein kinase (MAPK) and MOR expression in the spinal cord and paw of animals with inflammatory pain. Results showed that treatment with SFN inhibited allodynia and hyperalgesia induced by CFA and increased the local antinociceptive actions of morphine. This treatment also augmented the expression of Nrf2, HO-1, NQO1, and MOR, and inhibited NOS2 and CD11b/c overexpression and MAPK phosphorylation induced by inflammation. Thus, this study shows that the induction of Nrf2 might inhibit inflammatory pain and enhance the analgesic effects of morphine by inhibiting oxidative stress and inflammatory responses induced by peripheral inflammation. This study suggests the administration of SFN alone and in combination with morphine are potential new ways of treating chronic inflammatory pain. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Involvement of delta and mu opioid receptors in the acute and sensitized locomotor action of cocaine in mice.

PubMed

Kotlinska, J H; Gibula-Bruzda, E; Witkowska, E; Izdebski, J

2013-10-01

Analogs of deltorphins, such as cyclo(Nδ, Nδ-carbonyl-d-Orn2, Orn4)deltorphin (DEL-6) and deltorphin II N-(ureidoethyl)amide (DK-4) are functional agonists predominantly for the delta opioid receptors (DOR) in the guinea-pig ileum and mouse vas deferens bioassays. The purpose of this study was to examine an influence of these peptides (5, 10 or 20 nmol, i.c.v.) on the acute cocaine-induced (10mg/kg, i.p.) locomotor activity and the expression of sensitization to cocaine locomotor effect. Sensitization to locomotor effect of cocaine was developed by five injections of cocaine at the dose of 10mg/kg, i.p. every 3 days. Our results indicated that DK-4 and DEL-6 differently affected the acute and sensitized cocaine locomotion. Co-administration of DEL-6 with cocaine enhanced acute cocaine locomotion only at the dose of 10 nmol, with minimal effects at the doses 5 and 20 nmol, whereas co-administration of DK-4 with cocaine enhanced acute cocaine-induced locomotion in a dose-dependent manner. Similarly to the acute effects, DEL-6 only at the dose of 10 nmol but DK-4 dose-dependently enhanced the expression of cocaine sensitization. Pre-treatment with DOR antagonist - naltrindole (5 nmol, i.c.v.) and mu opioid receptor (MOR) antagonist, β-funaltrexamine abolished the ability of both peptides to potentiate the effects of cocaine. Our study suggests that MOR and DOR are involved in the interactions between cocaine and both deltorphins analogs. A distinct dose-response effects of these peptides on cocaine locomotion probably arise from differential functional activation (targeting) of the DOR and MOR by both deltorphins analogs. Copyright © 2013 Elsevier Inc. All rights reserved.

Low expression of D2R and Wntless correlates with high motivation for heroin.

PubMed

Tacelosky, Diana M; Alexander, Danielle N; Morse, Megan; Hajnal, Andras; Berg, Arthur; Levenson, Robert; Grigson, Patricia S

2015-12-01

Drug overdose now exceeds car accidents as the leading cause of accidental death in the United States. Of those drug overdoses, a large percentage of the deaths are due to heroin and/or pharmaceutical overdose, specifically misuse of prescription opioid analgesics. It is imperative, then, that we understand the mechanisms that lead to opioid abuse and addiction. The rewarding actions of opioids are mediated largely by the mu-opioid receptor (MOR), and signaling by this receptor is modulated by various interacting proteins. The neurotransmitter dopamine also contributes to opioid reward, and opioid addiction has been linked to reduced expression of dopamine D2 receptors (D2R) in the brain. That said, it is not known if alterations in the expression of these proteins relate to drug exposure and/or to the "addiction-like" behavior exhibited for the drug. Here, we held total drug self-administration constant across acquisition and showed that reduced expression of the D2R and the MOR interacting protein, Wntless, in the medial prefrontal cortex was associated with greater addiction-like behavior for heroin in general and with a greater willingness to work for the drug in particular. In contrast, reduced expression of the D2R in the nucleus accumbens and hippocampus was correlated with greater seeking during signaled nonavailability of the drug. Taken together, these data link reduced expression of both the D2R and Wntless to the explicit motivation for the drug rather than to differences in total drug intake per se. (c) 2015 APA, all rights reserved).

Dacite petrogenesis on mid-ocean ridges: Evidence for oceanic crustal melting and assimilation

USGS Publications Warehouse

Wanless, V.D.; Perfit, M.R.; Ridley, W.I.; Klein, E.

2010-01-01

Whereas the majority of eruptions at oceanic spreading centers produce lavas with relatively homogeneous mid-ocean ridge basalt (MORB) compositions, the formation of tholeiitic andesites and dacites at mid-ocean ridges (MORs) is a petrological enigma. Eruptions of MOR high-silica lavas are typically associated with ridge discontinuities and have produced regionally significant volumes of lava. Andesites and dacites have been observed and sampled at several locations along the global MOR system; these include propagating ridge tips at ridge-transform intersections on the Juan de Fuca Ridge and eastern Gal??pagos spreading center, and at the 9??N overlapping spreading center on the East Pacific Rise. Despite the formation of these lavas at various ridges, MOR dacites show remarkably similar major element trends and incompatible trace element enrichments, suggesting that similar processes are controlling their chemistry. Although most geochemical variability in MOR basalts is consistent with low-pressure fractional crystallization of various mantle-derived parental melts, our geochemical data for MOR dacitic glasses suggest that contamination from a seawater-altered component is important in their petrogenesis. MOR dacites are characterized by elevated U, Th, Zr, and Hf, low Nb and Ta concentrations relative to rare earth elements (REE), and Al2O3, K2O, and Cl concentrations that are higher than expected from low-pressure fractional crystallization alone. Petrological modeling of MOR dacites suggests that partial melting and assimilation are both integral to their petrogenesis. Extensive fractional crystallization of a MORB parent combined with partial melting and assimilation of amphibole-bearing altered crust produces a magma with a geochemical signature similar to a MOR dacite. This supports the hypothesis that crustal assimilation is an important process in the formation of highly evolved MOR lavas and may be significant in the generation of evolved MORB in general. Additionally, these processes are likely to be more common in regions of episodic magma supply and enhanced magma-crust interaction such as at the ends of ridge segments. ?? The Author 2010. Published by Oxford University Press. All rights reserved.

μ-Opioid Receptors Selectively Regulate Basal Inhibitory Transmission in the Central Amygdala: Lack of Ethanol Interactions

PubMed Central

Kang-Park, Maeng-Hee; Kieffer, Brigitte L.; Roberts, Amanda J.; Roberto, Marisa; Madamba, Samuel G.; Siggins, George Robert; Moore, Scott D.

2009-01-01

Endogenous opioid systems are implicated in the actions of ethanol. For example, μ-opioid receptor (MOR) knockout (KO) mice self-administer less alcohol than the genetically intact counterpart wild-type (WT) mice (Roberts et al., 2000). MOR KO mice also exhibit less anxiety-like behavior than WT mice (Filliol et al., 2000). To investigate the neurobiological mechanisms underlying these behaviors, we examined the effect of ethanol in brain slices from MOR KO and WT mice using sharp-electrode and whole-cell patch recording techniques. We focused our study in the central nucleus of the amygdala (CeA) because it is implicated in alcohol drinking behavior and stress behavior. We found that the amplitudes of evoked inhibitory postsynaptic currents (IPSCs) or inhibitory postsynaptic potentials (IPSPs) were significantly greater in MOR KO mice than WT mice. In addition, the baseline frequencies of spontaneous and miniature GABAA receptor-mediated inhibitory postsynaptic currents were significantly greater in CeA neurons from MOR KO than WT mice. However, ethanol enhancements of evoked IPSP and IPSC amplitudes and the frequency of miniature IPSCs were comparable between WT and MOR KO mice. Baseline spontaneous and miniature excitatory postsynaptic currents (EPSCs) and ethanol effects on EPSCs were not significantly different between MOR KO and WT mice. Based on knowledge of CeA circuitry and projections, we hypothesize that the role of MOR- and GABA receptor-mediated mechanisms in CeA underlying reinforcing effects of ethanol operate independently, possibly through pathway-specific responses within CeA. PMID:18854491

μ-Opioid receptor availability in the amygdala is associated with smoking for negative affect relief.

PubMed

Falcone, Mary; Gold, Allison B; Wileyto, E Paul; Ray, Riju; Ruparel, Kosha; Newberg, Andrew; Dubroff, Jacob; Logan, Jean; Zubieta, Jon-Kar; Blendy, Julie A; Lerman, Caryn

2012-08-01

The perception that smoking relieves negative affect contributes to smoking persistence. Endogenous opioid neurotransmission, and the μ-opioid receptor (MOR) in particular, plays a role in affective regulation and is modulated by nicotine. We examined the relationship of MOR binding availability in the amygdala to the motivation to smoke for negative affect relief and to the acute effects of smoking on affective responses. Twenty-two smokers were scanned on two separate occasions after overnight abstinence using [¹¹C]carfentanil positron emission tomography imaging: after smoking a nicotine-containing cigarette and after smoking a denicotinized cigarette. Self-reports of smoking motives were collected at baseline, and measures of positive and negative affect were collected pre- and post- cigarette smoking. Higher MOR availability in the amygdala was associated with motivation to smoke to relieve negative affect. However, MOR availability was unrelated to changes in affect after smoking either cigarette. Increased MOR availability in amygdala may underlie the motivation to smoke for negative affective relief. These results are consistent with previous data highlighting the role of MOR neurotransmission in smoking behavior.

Endogenous Opioid Mechanisms Are Implicated in Obesity and Weight Loss in Humans.

PubMed

Burghardt, Paul R; Rothberg, Amy E; Dykhuis, Kate E; Burant, Charles F; Zubieta, Jon-Kar

2015-08-01

Successful long-term weight loss is challenging. Brain endogenous opioid systems regulate associated processes; however, their role in the maintenance of weight loss has not been adequately explored in humans. In a preliminary study, the objective was to assess central μ-opioid receptor (MOR) system involvement in eating behaviors and their relationship to long-term maintenance of weight loss. This was a case-control study with follow-up of the treatment group at 1 year after intervention. The study was conducted at a tertiary care university medical center. Lean healthy (n = 7) and chronically obese (n = 7) men matched for age and ethnicity participated in the study. MOR availability measures were acquired with positron emission tomography and [(11)C]carfentanil. Lean healthy men were scanned twice under both fasted and fed conditions. Obese men were placed on a very low-calorie diet to achieve 15% weight loss from baseline weight and underwent two positron emission tomography scans before and two after weight loss, incorporating both fasted and fed states. Brain MOR availability and activation were measured by reductions in MOR availability (nondisplaceable binding potential) from the fed compared with the fasted-state scans. Baseline MOR nondisplaceable binding potential was reduced in obese compared with the lean and partially recovered obese after weight loss in regions that regulate homeostatic, hedonic, and emotional responses to feeding. Reductions in negative affect and feeding-induced MOR system activation in the right temporal pole were highly correlated in leans but not in obese men. A trend for an association between MOR activation in the right temporal pole before weight loss and weight regain 1 year was found. Although these preliminary studies have a small sample size, these results suggest that obesity and diet-induced weight loss impact central MOR binding and endogenous opioid system function. MOR system activation in response to an acute meal may be related to the risk of weight regain.

MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial

PubMed Central

Behrens, Frank; Tak, Paul P; Østergaard, Mikkel; Stoilov, Rumen; Wiland, Piotr; Huizinga, Thomas W; Berenfus, Vadym Y; Vladeva, Stoyanka; Rech, Juergen; Rubbert-Roth, Andrea; Korkosz, Mariusz; Rekalov, Dmitriy; Zupanets, Igor A; Ejbjerg, Bo J; Geiseler, Jens; Fresenius, Julia; Korolkiewicz, Roman P; Schottelius, Arndt J; Burkhardt, Harald

2015-01-01

Objectives To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). Methods Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. Results Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. Conclusions MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. Trial registration number NCT01023256 PMID:24534756

Dopamine D4 Receptor Counteracts Morphine-Induced Changes in μ Opioid Receptor Signaling in the Striosomes of the Rat Caudate Putamen

PubMed Central

Suárez-Boomgaard, Diana; Gago, Belén; Valderrama-Carvajal, Alejandra; Roales-Buján, Ruth; Van Craenenbroeck, Kathleen; Duchou, Jolien; Borroto-Escuela, Dasiel O.; Medina-Luque, José; de la Calle, Adelaida; Fuxe, Kjell; Rivera, Alicia

2014-01-01

The mu opioid receptor (MOR) is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine induces changes in MOR protein levels, its pharmacological profile, and MOR-mediated G-protein activation in the striosomal compartment of the rat CPu, by using immunohistochemistry and receptor and DAMGO-stimulated [35S]GTPγS autoradiography. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment in the absence of changes in enkephalin and dynorphin mRNA levels. In addition, co-treatment of morphine with the dopamine D4 receptor (D4R) agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [3H]DAMGO Bmax values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to Gi/0 protein, the present results give support for the existence of antagonistic functional D4R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine. PMID:24451133

Long-term outcome following medial open reduction in developmental dysplasia of the hip: a retrospective cohort study.

PubMed

Gardner, Richard O E; Bradley, Catharine S; Sharma, Om P; Feng, Lin; Shin, Michelle EyunJung; Kelley, Simon P; Wedge, J H

2016-06-01

Avascular necrosis (AVN) is a serious complication of treatment for developmental dysplasia of the hip. There is ongoing controversy regarding AVN and its influence on hip development following medial open reduction (MOR). The aim of our study was to (1) determine the long-term prevalence of AVN following MOR, (2) evaluate hip development after MOR, and (3) identify predictors of AVN and radiographic outcome at skeletal maturity after MOR. A retrospective cohort analysis of 60 patients (70 hips) who underwent MOR with a mean follow-up of 10.83 years (5.23-16.74) was conducted. AVN was recorded according to Bucholz and Ogden classification and radiographic outcome based on Severin grading. AVN and hip morphology related to length of follow-up were evaluated. Chi-squared and t-tests were used to identify relationships between AVN and other variables. Logistic regression was used to assess predictors of AVN and Severin outcome. The rate of clinically significant AVN (types 2-4) following MOR was 32.9 % with type 2 accounting for 82.6 % of these cases. While early acetabular development was satisfactory, long-term outcome was unsatisfactory in 26 % of cases with AVN (vs 8.7 % of cases without AVN). A higher rate of AVN was identified when hips were immobilized in ≥60° of abduction postoperatively. A higher rate of poor Severin outcome was identified in hips with AVN. Our findings suggest that there is a high rate of AVN and unsatisfactory long-term outcome following MOR. AVN remains a significant concern following MOR surgery for developmental dysplasia of the hip that may not be apparent until long-term evaluation.

17β-estradiol rapidly facilitates lordosis through G protein-coupled estrogen receptor 1 (GPER) via deactivation of medial preoptic nucleus μ-opioid receptors in estradiol primed female rats.

PubMed

Long, Nathan; Serey, Chhorvann; Sinchak, Kevin

2014-09-01

In female rats sexual receptivity (lordosis) can be induced with either a single large dose of estradiol benzoate (EB), or a priming dose of EB that does not induce sexual receptivity followed by 17β-estradiol (E2). Estradiol priming initially inhibits lordosis through a multi-synaptic circuit originating in the arcuate nucleus of the hypothalamus (ARH) that activates and internalizes μ-opioid receptors (MOR) in medial preoptic nucleus (MPN) neurons. Lordosis is facilitated when MPN MOR are deactivated after the initial estradiol-induced activation. We tested the hypothesis that E2 given 47.5 h post EB acts rapidly through G protein-coupled estrogen receptor 1 (GPER) in the ARH to deactivate MPN MOR and facilitate lordosis. Ovariectomized Long Evans rats implanted with a third ventricle cannula were primed with 2 μg EB. DMSO control, E2, or G1 (GPER selective agonist) was infused 47.5 h later, and rats were tested for sexual receptivity. E2 and G1 infusions significantly increased levels of sexual receptivity compared to DMSO controls and pretreatment with G15 (GPER antagonist) blocked the facilitation of sexual receptivity. Brains were processed for MPN MOR immunohistochemistry to measure MPN MOR activation levels. E2 and G1 both significantly reduced MPN MOR activation compared to DMSO controls, while pretreatment with G15 blocked MPN MOR deactivation. In another group of EB treated ovariectomized rats, GPER immunofluorescence positive staining was observed throughout the ARH. Together these data indicate that in the 2 μg EB primed rat, E2 rapidly signals through GPER in the ARH to deactivate MPN MOR and facilitate lordosis. Published by Elsevier Inc.

Platinum Nickel Nanowires as Methanol Oxidation Electrocatalysts

DOE PAGES

Alia, Shaun M.; Pylypenko, Svitlana; Neyerlin, Kenneth C.; ...

2015-08-27

We investigated platinum(Pt) nickel (Ni) nanowires (PtNiNWs) as methanol oxidation reaction (MOR) catalysts in rotating disk electrode (RDE) half-cells under acidic conditions. Pt-ruthenium (Ru) nanoparticles have long been the state of the art MOR catalyst for direct methanol fuel cells (DMFCs) where Ru provides oxophilic sites, lowering the potential for carbon monoxide oxidation and the MOR onset. Ru, however, is a precious metal that has long term durability concerns. Ni/Ni oxide species offer a potential to replace Ru in MOR electrocatalysis. PtNiNWs were investigated for MOR and oxygen annealing was investigated as a route to improve catalyst performance (mass activitymore » 65% greater) and stability to potential cycling. Our results presented show that PtNiNWs offer significant promise in the area, but also result in Ni ion leaching that is a concern requiring further evaluation in fuel cells.« less

Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability.

PubMed

Crowley, Rachel Saylor; Riley, Andrew P; Sherwood, Alexander M; Groer, Chad E; Shivaperumal, Nirajmohan; Biscaia, Miguel; Paton, Kelly; Schneider, Sebastian; Provasi, Davide; Kivell, Bronwyn M; Filizola, Marta; Prisinzano, Thomas E

2016-12-22

Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective μ-opioid receptor (MOR) agonist (EC 50 = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects.

Production of G protein-coupled receptors in an insect-based cell-free system.

PubMed

Sonnabend, Andrei; Spahn, Viola; Stech, Marlitt; Zemella, Anne; Stein, Christoph; Kubick, Stefan

2017-10-01

The biochemical analysis of human cell membrane proteins remains a challenging task due to the difficulties in producing sufficient quantities of functional protein. G protein-coupled receptors (GPCRs) represent a main class of membrane proteins and drug targets, which are responsible for a huge number of signaling processes regulating various physiological functions in living cells. To circumvent the current bottlenecks in GPCR studies, we propose the synthesis of GPCRs in eukaryotic cell-free systems based on extracts generated from insect (Sf21) cells. Insect cell lysates harbor the fully active translational and translocational machinery allowing posttranslational modifications, such as glycosylation and phosphorylation of de novo synthesized proteins. Here, we demonstrate the production of several GPCRs in a eukaryotic cell-free system, performed within a short time and in a cost-effective manner. We were able to synthesize a variety of GPCRs ranging from 40 to 133 kDa in an insect-based cell-free system. Moreover, we have chosen the μ opioid receptor (MOR) as a model protein to analyze the ligand binding affinities of cell-free synthesized MOR in comparison to MOR expressed in a human cell line by "one-point" radioligand binding experiments. Biotechnol. Bioeng. 2017;114: 2328-2338. © 2017 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc. © 2017 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.

Mu opioid receptor stimulation activates c-Jun N-terminal kinase 2 by distinct arrestin-dependent and independent mechanisms.

PubMed

Kuhar, Jamie Rose; Bedini, Andrea; Melief, Erica J; Chiu, Yen-Chen; Striegel, Heather N; Chavkin, Charles

2015-09-01

G protein-coupled receptor desensitization is typically mediated by receptor phosphorylation by G protein-coupled receptor kinase (GRK) and subsequent arrestin binding; morphine, however, was previously found to activate a c-Jun N-terminal kinase (JNK)-dependent, GRK/arrestin-independent pathway to produce mu opioid receptor (MOR) inactivation in spinally-mediated, acute anti-nociceptive responses [Melief et al.] [1]. In the current study, we determined that JNK2 was also required for centrally-mediated analgesic tolerance to morphine using the hotplate assay. We compared JNK activation by morphine and fentanyl in JNK1(-/-), JNK2(-/-), JNK3(-/-), and GRK3(-/-) mice and found that both compounds specifically activate JNK2 in vivo; however, fentanyl activation of JNK2 was GRK3-dependent, whereas morphine activation of JNK2 was GRK3-independent. In MOR-GFP expressing HEK293 cells, treatment with either arrestin siRNA, the Src family kinase inhibitor PP2, or the protein kinase C (PKC) inhibitor Gö6976 indicated that morphine activated JNK2 through an arrestin-independent Src- and PKC-dependent mechanism, whereas fentanyl activated JNK2 through a Src-GRK3/arrestin-2-dependent and PKC-independent mechanism. This study resolves distinct ligand-directed mechanisms of JNK activation by mu opioid agonists and understanding ligand-directed signaling at MOR may improve opioid therapeutics. Copyright © 2015 Elsevier Inc. All rights reserved.

Opioid Modulation of Value-Based Decision-Making in Healthy Humans.

PubMed

Eikemo, Marie; Biele, Guido; Willoch, Frode; Thomsen, Lotte; Leknes, Siri

2017-08-01

Modifying behavior to maximize reward is integral to adaptive decision-making. In rodents, the μ-opioid receptor (MOR) system encodes motivation and preference for high-value rewards. Yet it remains unclear whether and how human MORs contribute to value-based decision-making. We reasoned that if the human MOR system modulates value-based choice, this would be reflected by opposite effects of agonist and antagonist drugs. In a double-blind pharmacological cross-over study, 30 healthy men received morphine (10 mg), placebo, and the opioid antagonist naltrexone (50 mg). They completed a two-alternative decision-making task known to induce a considerable bias towards the most frequently rewarded response option. To quantify MOR involvement in this bias, we fitted accuracy and reaction time data with the drift-diffusion model (DDM) of decision-making. The DDM analysis revealed the expected bidirectional drug effects for two decision subprocesses. MOR stimulation with morphine increased the preference for the stimulus with high-reward probability (shift in starting point). Compared to placebo, morphine also increased, and naltrexone reduced, the efficiency of evidence accumulation. Since neither drug affected motor-coordination, speed-accuracy trade-off, or subjective state (indeed participants were still blinded after the third session), we interpret the MOR effects on evidence accumulation efficiency as a consequence of changes in effort exerted in the task. Together, these findings support a role for the human MOR system in value-based choice by tuning decision-making towards high-value rewards across stimulus domains.

MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial.

PubMed

Behrens, Frank; Tak, Paul P; Østergaard, Mikkel; Stoilov, Rumen; Wiland, Piotr; Huizinga, Thomas W; Berenfus, Vadym Y; Vladeva, Stoyanka; Rech, Juergen; Rubbert-Roth, Andrea; Korkosz, Mariusz; Rekalov, Dmitriy; Zupanets, Igor A; Ejbjerg, Bo J; Geiseler, Jens; Fresenius, Julia; Korolkiewicz, Roman P; Schottelius, Arndt J; Burkhardt, Harald

2015-06-01

To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. NCT01023256. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Cell-autonomous regulation of Mu-opioid receptor recycling by substance P.

PubMed

Bowman, Shanna L; Soohoo, Amanda L; Shiwarski, Daniel J; Schulz, Stefan; Pradhan, Amynah A; Puthenveedu, Manojkumar A

2015-03-24

How neurons coordinate and reprogram multiple neurotransmitter signals is an area of broad interest. Here, we show that substance P (SP), a neuropeptide associated with inflammatory pain, reprograms opioid receptor recycling and signaling. SP, through activation of the neurokinin 1 (NK1R) receptor, increases the post-endocytic recycling of the mu-opioid receptor (MOR) in trigeminal ganglion (TG) neurons in an agonist-selective manner. SP-mediated protein kinase C (PKC) activation is both required and sufficient for increasing recycling of exogenous and endogenous MOR in TG neurons. The target of this cross-regulation is MOR itself, given that mutation of either of two PKC phosphorylation sites on MOR abolishes the SP-induced increase in recycling and resensitization. Furthermore, SP enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Our results define a physiological pathway that cross-regulates opioid receptor recycling via direct modification of MOR and suggest a mode of homeostatic interaction between the pain and analgesic systems.

Cell-Autonomous Regulation of Mu-Opioid Receptor Recycling by Substance P

PubMed Central

Bowman, Shanna L.; Soohoo, Amanda L.; Shiwarski, Daniel J.; Schulz, Stefan; Pradhan, Amynah A.; Puthenveedu, Manojkumar A.

2015-01-01

SUMMARY How neurons coordinate and reprogram multiple neurotransmitter signals is an area of broad interest. Here, we show that substance P (SP), a neuropep-tide associated with inflammatory pain, reprograms opioid receptor recycling and signaling. SP, through activation of the neurokinin 1 (NK1R) receptor, increases the post-endocytic recycling of the muopioid receptor (MOR) in trigeminal ganglion (TG) neurons in an agonist-selective manner. SP-mediated protein kinase C (PKC) activation is both required and sufficient for increasing recycling of exogenous and endogenous MOR in TG neurons. The target of this cross-regulation is MOR itself, given that mutation of either of two PKC phosphorylation sites on MOR abolishes the SP-induced increase in recycling and resensitization. Furthermore, SP enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Our results define a physiological pathway that cross-regulates opioid receptor recycling via direct modification of MOR and suggest a mode of homeo-static interaction between the pain and analgesic systems. PMID:25801029

Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities.

PubMed

Harland, Aubrie A; Yeomans, Larisa; Griggs, Nicholas W; Anand, Jessica P; Pogozheva, Irina D; Jutkiewicz, Emily M; Traynor, John R; Mosberg, Henry I

2015-11-25

In a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.

Decreased consumption of sweet fluids in mu opioid receptor knockout mice: a microstructural analysis of licking behavior

PubMed Central

Ostlund, Sean B.; Kosheleff, Alisa; Maidment, Nigel T.; Murphy, Niall P.

2013-01-01

Summary Rationale Evidence suggests that the palatability of food (i.e., the hedonic impact produced by its sensory features) can promote feeding and may underlie compulsive eating, leading to obesity. Pharmacological studies implicate opioid transmission in the hedonic control of feeding, though these studies often rely on agents lacking specificity for particular opioid receptors. Objectives Here, we investigated the role of mu opioid receptors (MORs) specifically in determining hedonic responses to palatable sweet stimuli. Methods In Experiment 1, licking microstructure when consuming sucrose solution (2 to 20 %) was compared in MOR knockout and wildtype mice as a function of sucrose concentration and level of food deprivation. In Experiment 2, a similar examination was conducted using the palatable but calorie-free stimulus sucralose (0.001 to 1%), allowing study of licking behavior independent of homeostatic variables. Results In Experiment 1, MOR knockout mice exhibited several alterations in sucrose licking. Although wildtype mice exhibited a two-fold increase in the burst length when food deprived, relative to the nondeprived test, this aspect of sucrose licking was generally insensitive to manipulations of food deprivation for MOR knockout mice. Furthermore, during concentration testing, their rate of sucrose licking was less than half that of wildtype mice. During sucralose testing (Experiment 2), MOR knockout mice licked at approximately half the wildtype rate, providing more direct evidence that MOR knockout mice were impaired in processing stimulus palatability. Conclusions These results suggest that transmission through MORs mediates hedonic responses to palatable stimuli, and therefore likely contributes to normal and pathological eating. PMID:23568577

Morphine decreases social interaction of adult male rats, while THC does not affect it.

PubMed

Šlamberová, R; Mikulecká, A; Macúchová, E; Hrebíčková, I; Ševčíková, M; Nohejlová, K; Pometlová, M

2016-12-22

The aim of the present study was to compare effect of three low doses of morphine (MOR) and delta9-tetrahydrocannabinol (THC) on social behavior tested in Social interaction test (SIT). 45 min prior to testing adult male rats received one of the drugs or solvents: MOR (1; 2.5; 5 mg/kg); saline as a solvent for MOR; THC (0.5; 1; 2 mg/kg); ethanol as a solvent for THC. Occurrence and time spent in specific patterns of social interactions (SI) and non-social activities (locomotion and rearing) was video-recorded for 5 min and then analyzed. MOR in doses of 1 and 2.5 mg/kg displayed decreased SI in total. Detailed analysis of specific patterns of SI revealed decrease in mutual sniffing and allo-grooming after all doses of MOR. The highest dose (5 mg/kg) of MOR decreased following and increased genital investigation. Rearing activity was increased by lower doses of MOR (1 and 2.5 mg/kg). THC, in each of the tested doses, did not induce any specific changes when compared to matching control group (ethanol). However, an additional statistical analysis showed differences between all THC groups and their ethanol control group when compared to saline controls. There was lower SI in total, lower mutual sniffing and allo-grooming, but higher rearing in THC and ethanol groups than in saline control group. Thus, changes seen in THC and ethanol groups are seemed to be attributed mainly to the effect of the ethanol. Based on the present results we can assume that opioids affect SI more than cannabinoid.

Comparative study on the sedative effects of morphine, methadone, butorphanol or tramadol, in combination with acepromazine, in dogs.

PubMed

Monteiro, Eduardo Raposo; Junior, Adolfo Rodrigues; Assis, Hemir Martins Quirilos; Campagnol, Daniela; Quitzan, Juliany Gomes

2009-01-01

To compare the effects of morphine (MOR), methadone (MET), butorphanol (BUT) and tramadol (TRA), in combination with acepromazine, on sedation, cardiorespiratory variables, body temperature and incidence of emesis in dogs. Prospective randomized, blinded, experimental trial. Six adult mixed-breed male dogs weighing 12.0 +/- 4.3 kg. Dogs received intravenous administration (IV) of acepromazine (0.05 mg kg(-1)) and 15 minutes later, one of four opioids was randomly administered IV in a cross-over design, with at least 1-week intervals. Dogs then received MOR 0.5 mg kg(-1); MET 0.5 mg kg(-1); BUT 0.15 mg kg(-1); or TRA 2.0 mg kg(-1). Indirect systolic arterial pressure (SAP), heart rate (HR), respiratory rate (f(R)), rectal temperature, pedal withdrawal reflex and sedation were evaluated at regular intervals for 90 minutes. Acepromazine administration decreased SAP, HR and temperature and produced mild sedation. All opioids further decreased temperature and MOR, BUT and TRA were associated with further decreases in HR. Tramadol decreased SAP whereas BUT decreased f(R) compared with values before opioid administration. Retching was observed in five of six dogs and vomiting occurred in one dog in MOR, but not in any dog in the remaining treatments. Sedation scores were greater in MET followed by MOR and BUT. Tramadol was associated with minor changes in sedation produced by acepromazine alone. When used with acepromazine, MET appears to provide better sedation than MOR, BUT and TRA. If vomiting is to be avoided, MET, BUT and TRA may be better options than MOR.

Impact of Lipid Composition and Receptor Conformation on the Spatio-temporal Organization of μ-Opioid Receptors in a Multi-component Plasma Membrane Model

PubMed Central

Marino, Kristen A.; Prada-Gracia, Diego; Provasi, Davide; Filizola, Marta

2016-01-01

The lipid composition of cell membranes has increasingly been recognized as playing an important role in the function of various membrane proteins, including G Protein-Coupled Receptors (GPCRs). For instance, experimental and computational evidence has pointed to lipids influencing receptor oligomerization directly, by physically interacting with the receptor, and/or indirectly, by altering the bulk properties of the membrane. While the exact role of oligomerization in the function of class A GPCRs such as the μ-opioid receptor (MOR) is still unclear, insight as to how these receptors oligomerize and the relevance of the lipid environment to this phenomenon is crucial to our understanding of receptor function. To examine the effect of lipids and different MOR conformations on receptor oligomerization we carried out extensive coarse-grained molecular dynamics simulations of crystal structures of inactive and/or activated MOR embedded in an idealized mammalian plasma membrane composed of 63 lipid types asymmetrically distributed across the two leaflets. The results of these simulations point, for the first time, to specific direct and indirect effects of the lipids, as well as the receptor conformation, on the spatio-temporal organization of MOR in the plasma membrane. While sphingomyelin-rich, high-order lipid regions near certain transmembrane (TM) helices of MOR induce an effective long-range attractive force on individual protomers, both long-range lipid order and interface formation are found to be conformation dependent, with a larger number of different interfaces formed by inactive MOR compared to active MOR. PMID:27959924

Methane oxidation and attenuation of sulphur compounds in landfill top cover systems: Lab-scale tests.

PubMed

Raga, Roberto; Pivato, Alberto; Lavagnolo, Maria Cristina; Megido, Laura; Cossu, Raffaello

2018-03-01

In this study, a top cover system is investigated as a control for emissions during the aftercare of new landfills and for old landfills where biogas energy production might not be profitable. Different materials were studied as landfill cover system in lab-scale columns: mechanical-biological pretreated municipal solid waste (MBP); mechanical-biological pretreated biowaste (PB); fine (PBS f ) and coarse (PBS c ) mechanical-biological pretreated mixtures of biowaste and sewage sludge, and natural soil (NS). The effectiveness of these materials in removing methane and sulphur compounds from a gas stream was tested, even coupled with activated carbon membranes. Concentrations of CO 2 , CH 4 , O 2 , N 2 , H 2 S and mercaptans were analysed at different depths along the columns. Methane degradation was assessed using mass balance and the results were expressed in terms of methane oxidation rate (MOR). The highest maximum and mean MOR were observed for MBP (17.2gCH 4 /m 2 /hr and 10.3gCH 4 /m 2 /hr, respectively). Similar values were obtained with PB and PBS c . The lowest values of MOR were obtained for NS (6.7gCH 4 /m 2 /hr) and PBS f (3.6gCH 4 /m 2 /hr), which may be due to their low organic content and void index, respectively. Activated membranes with high load capacity did not seem to have an influence on the methane oxidation process: MBP coupled with 220g/m 2 and 360g/m 2 membranes gave maximum MOR of 16.5gCH 4 /m 2 /hr and 17.4gCH 4 /m 2 /hr, respectively. Activated carbon membranes proved to be very effective on H 2 S adsorption. Furthermore, carbonyl sulphide, ethyl mercaptan and isopropyl mercaptan seemed to be easily absorbed by the filling materials. Copyright © 2017. Published by Elsevier B.V.

Phalanx. Volume 48, Number 1. March 2015

DTIC Science & Technology

2015-03-01

There are many reasons that people present their work at conferences in the year 2015, such as justifying their travel, advertising their work...Dr. Patrick Allen Lt Col Andrew Armacost Donald Bates Col (s) Suzanne Beers , FS Dr. Ted Bennett Jr. Joseph Bonnet Mary T. Bonnet Dr. W...received the MOR Journal Award. MORS Presidents 40th MORS President: Suzanne Beers , 2005–2006 Suzanne Beers served as Secretary in 2001–2002, Vice

Reliability Implications in Wood Systems of a Bivariate Gaussian-Weibull Distribution and the Associated Univariate Pseudo-truncated Weibull

Treesearch

Steve P. Verrill; James W. Evans; David E. Kretschmann; Cherilyn A. Hatfield

2014-01-01

Two important wood properties are the modulus of elasticity (MOE) and the modulus of rupture (MOR). In the past, the statistical distribution of the MOE has often been modeled as Gaussian, and that of the MOR as lognormal or as a two- or three-parameter Weibull distribution. It is well known that MOE and MOR are positively correlated. To model the simultaneous behavior...

Gene Expression in Aminergic and Peptidergic Cells During Aggression and Defeat: Relevance to Violence, Depression and Drug Abuse

PubMed Central

Nikulina, Ella M.; Takahashi, Aki; Covington, Herbert E.; Yap, Jasmine J.; Boyson, Christopher O.; Shimamoto, Akiko; de Almeida, Rosa M. M.

2013-01-01

In this review, we examine how experiences in social confrontations alter gene expression in mesocorticolimbic cells. The focus is on the target of attack and threat due to the prominent role of social defeat stress in the study of coping mechanisms and victimization. The initial operational definition of the socially defeated mouse by Ginsburg and Allee (1942) enabled the characterization of key endocrine, cardiovascular, and metabolic events during the initial response to an aggressive opponent and during the ensuing adaptations. Brief episodes of social defeat stress induce an augmented response to stimulant challenge as reflected by increased locomotion and increased extracellular dopamine (DA) in the nucleus accumbens (NAC). Cells in the ventral tegmental area (VTA) that project to the NAC were more active as indicated by increased expression of c-fos and Fos-immunoreactivity and BDNF. Intermittent episodes of social defeat stress result in increased mRNA for MOR in brainstem and limbic structures. These behavioral and neurobiological indices of sensitization persist for several months after the stress experience. The episodically defeated rats also self-administered intravenous cocaine during continuous access for 24 h (“binge”). By contrast, continuous social stress, particularly in the form of social subordination stress, leads to reduced appetite, compromised endocrine activities, and cardiovascular and metabolic abnormalities, and prefer sweets less as index of anhedonia. Cocaine challenges in subordinate rats result in a blunted psychomotor stimulant response and a reduced DA release in NAC. Subordinate rats self-administer cocaine less during continuous access conditions. These contrasting patterns of social stress result from continuous vs. intermittent exposure to social stress, suggesting divergent neuroadaptations for increased vulnerability to cocaine self-administration vs. deteriorated reward mechanisms characteristic of depressive-like profiles. PMID:21416141

Enhancing mud supply from the Lower Missouri River to the Mississippi River Delta USA: Dam bypassing and coastal restoration

NASA Astrophysics Data System (ADS)

Kemp, G. Paul; Day, John W.; Rogers, J. David; Giosan, Liviu; Peyronnin, Natalie

2016-12-01

Sand transport to the Mississippi River Delta (MRD) remains sufficient to build wetlands in shallow, sheltered coastal bays fed by engineered diversions on the Mississippi River (MR) and its Atchafalaya River (AR) distributary. But suspended mud (silt & clay) flux to the coast has dropped from a mean of 390 Mt y-1 in the early 1950s, to 100 Mt y-1 since 1970. This fine-grained sediment travels deeper into receiving estuarine basins and plays a critical role in sustaining existing marshes. Virtually all of the 300 Mt y-1 of missing mud once flowed from the Missouri River (MOR) Basin before nearly 100 dams were built as part of the Pick-Sloan water development project. About 100 Mt y-1 is now intercepted by main-stem Upper MOR dams closed in 1953. But the remaining 200 Mt y-1 is trapped by impoundments built on tributaries to the Lower MOR in the 1950s and 1960s. Sediment flux during the post-dam high MOR discharge years of 1973, 1993 and 2011 approached pre-dam levels when tributaries to the Lower MOR, including the Platte and Kansas Rivers, contributed to flood flows. West bank tributaries drain a vast, arid part of the Great Plains, while those entering from the east bank traverse the lowlands of the MOR floodplain. Both provinces are dominated by highly erodible loess soils. Staunching the continued decline in MR fine-grained sediment flux has assumed greater importance now that engineered diversions are being built to reconnect the Lowermost MR to the MRD. Tributary dam bypassing in the Lower MOR basin could increase mud supply to the MRD by 100-200 Mt y-1 within 1-2 decades. Such emergency measures to save the MRD are compatible with objectives of the Missouri River Restoration and Platte River Recovery Programs to restore MOR riparian habitat for endangered species. Rapid mobilization to shunt fine-grained sediments past as many as 50 Lower MOR tributary dams in several U.S. states will undoubtedly require as much regional coordination and funding in the 21st century as the monumental effort it took to build the dams in the last century.

HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines.

PubMed

El-Hage, Nazira; Wu, Guanghan; Wang, Juan; Ambati, Jayakrishna; Knapp, Pamela E; Reed, Janelle L; Bruce-Keller, Annadora J; Hauser, Kurt F

2006-01-15

Opiates exacerbate human immunodeficiency virus type 1 (HIV-1) Tat(1-72)-induced release of key proinflammatory cytokines by astrocytes, which may accelerate HIV neuropathogenesis in opiate abusers. The release of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), in particular, is potentiated by opiate-HIV Tat interactions in vitro. Although MCP-1 draws monocytes/macrophages to sites of CNS infection, and activated monocytes/microglia release factors that can damage bystander neurons, the role of MCP-1 in neuro-acquired immunodeficiency syndrome (neuroAIDS) progression in opiate abusers, or nonabusers, is uncertain. Using a chemotaxis assay, N9 microglial cell migration was found to be significantly greater in conditioned medium from mouse striatal astrocytes exposed to morphine and/or Tat(1-72) than in vehicle-, mu-opioid receptor (MOR) antagonist-, or inactive, mutant Tat(delta31-61)-treated controls. Conditioned medium from astrocytes treated with morphine and Tat caused the greatest increase in motility. The response was attenuated using conditioned medium immunoneutralized with MCP-1 antibodies, or medium from MCP-1(-/-) astrocytes. In the presence of morphine (time-release, subcutaneous implant), intrastriatal Tat increased the proportion of neural cells that were astroglia and F4/80+ macrophages at 7 days post-injection. This was not seen after treatment with Tat alone, or with morphine plus inactive Tat(delta31-61) or naltrexone. Glia displayed increased MOR and MCP-1 immunoreactivity after morphine and/or Tat exposure. The findings indicate that MCP-1 underlies most of the response of microglia, suggesting that one way in which opiates exacerbate neuroAIDS is by increasing astroglial-derived proinflammatory chemokines at focal sites of CNS infection and promoting macrophage entry and local microglial activation. Importantly, increased glial expression of MOR can trigger an opiate-driven amplification/positive feedback of MCP-1 production and inflammation. 2005 Wiley-Liss, Inc.

HIV Tat1-72 and Opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines

PubMed Central

El-Hage, Nazira; Wu, Guanghan; Wang, Juan; Ambati, Jayakrishna; Knapp, Pamela E.; Reed, Janelle L.; Bruce-Keller, Annadora J.; Hauser, Kurt F.

2011-01-01

Opiates exacerbate HIV-1 Tat1-72–induced release of key proinflammatory cytokines by astrocytes, which may accelerate HIV neuropathogenesis in opiate abusers. The release of monocyte chemoattractant protein-1 (MCP-1 or CCL2), in particular, is potentiated by opiate-HIV Tat interactions in vitro. Although MCP-1 draws monocytes/macrophages to sites of CNS infection, and activated monocytes/microglia release factors that can damage bystander neurons, its role in neuroAIDS progression in opiate abusers, or non-abusers, is uncertain. Using a chemotaxis assay, N9 microglial cell migration was significantly greater in conditioned medium from mouse striatal astrocytes exposed to morphine and/or Tat1-72 than in vehicle-, μ opioid receptor (MOR) antagonist-, or inactive, mutant TatΔ31-61-treated controls. Conditioned medium from astrocytes treated with morphine and Tat caused the greatest increase in motility. The response was attenuated using conditioned medium immunoneutralized with MCP-1 antibodies, or medium from MCP-1−/− astrocytes. In the presence of morphine (time-release, subcutaneous implant), intrastriatal Tat increased the proportion of neural cells that were astroglia and F4/80+ macrophages at 7 days post-injection. This was not seen following treatment with Tat alone, or with morphine plus inactive TatΔ31-61 or naltrexone. Glia displayed increased MOR and MCP-1 immunoreactivity following morphine and/or Tat exposure. The findings indicate that MCP-1 underlies most of the response of microglia, suggesting that one way in which opiates exacerbate neuroAIDS is by increasing astroglial-derived proinflammatory chemokines at focal sites of CNS infection and promoting macrophage entry and local microglial activation. Importantly, increased glial expression of MOR can trigger an opiate-driven amplification/positive feedback of MCP-1 production and inflammation. PMID:16206161

Acute inflammation induces segmental, bilateral, supraspinally mediated opioid release in the rat spinal cord, as measured by μ-opioid receptor internalization

PubMed Central

Chen, Wenling; Marvizón, Juan Carlos G.

2009-01-01

The objective of this study was to measure opioid release in the spinal cord during acute and long-term inflammation using μ-opioid receptor (MOR) internalization. In particular, we determined whether opioid release occurs in the segments receiving the noxious signals or in the entire spinal cord, and whether it involves supraspinal signals. Internalization of neurokinin 1 receptors (NK1Rs) was measured to track the intensity of the noxious stimulus. Rats received peptidase inhibitors intrathecally to protect opioids from degradation. Acute inflammation of the hindpaw with formalin induced moderate MOR internalization in the L5 segment bilaterally, whereas NK1R internalization occurred only ipsilaterally. MOR internalization was restricted to the lumbar spinal cord, regardless of whether the peptidase inhibitors were injected in a lumbar or thoracic site. Formalin-induced MOR internalization was substantially reduced by isoflurane anesthesia. It was also markedly reduced by a lidocaine block of the cervical-thoracic spinal cord (which did not affect the evoked NK1R internalization) indicating that spinal opioid release is mediated supraspinally. In the absence of peptidase inhibitors, formalin and hindpaw clamp induced a small amount of MOR internalization, which was significantly higher than in controls. To study spinal opioid release during chronic inflammation, we injected Complete Freund's Adjuvant (CFA) in the hindpaw and peptidase inhibitors intrathecally. Two days later, no MOR or NK1R internalization was detected. Furthermore, CFA inflammation decreased MOR internalization induced by clamping the inflamed hindpaw. These results show that acute inflammation, but not chronic inflammation, induce segmental opioid release in the spinal cord that involves supraspinal signals. PMID:19298846

Suppressed Fat Appetite after Roux-en-Y Gastric Bypass Surgery Associates with Reduced Brain μ-opioid Receptor Availability in Diet-Induced Obese Male Rats.

PubMed

Hankir, Mohammed K; Patt, Marianne; Patt, Jörg T W; Becker, Georg A; Rullmann, Michael; Kranz, Mathias; Deuther-Conrad, Winnie; Schischke, Kristin; Seyfried, Florian; Brust, Peter; Hesse, Swen; Sabri, Osama; Krügel, Ute; Fenske, Wiebke K

2016-01-01

Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [ 11 C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [ 11 C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.

Suppressed Fat Appetite after Roux-en-Y Gastric Bypass Surgery Associates with Reduced Brain μ-opioid Receptor Availability in Diet-Induced Obese Male Rats

PubMed Central

Hankir, Mohammed K.; Patt, Marianne; Patt, Jörg T. W.; Becker, Georg A.; Rullmann, Michael; Kranz, Mathias; Deuther-Conrad, Winnie; Schischke, Kristin; Seyfried, Florian; Brust, Peter; Hesse, Swen; Sabri, Osama; Krügel, Ute; Fenske, Wiebke K.

2017-01-01

Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [11C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [11C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting. PMID:28133443

Nicotine-specific and non-specific effects of cigarette smoking on endogenous opioid mechanisms.

PubMed

Nuechterlein, Emily B; Ni, Lisong; Domino, Edward F; Zubieta, Jon-Kar

2016-08-01

This study investigates differences in μ-opioid receptor mediated neurotransmission in healthy controls and overnight-abstinent smokers, and potential effects of the OPRM1 A118G genotype. It also examines the effects of smoking denicotinized (DN) and average nicotine (N) cigarettes on the μ-opioid system. Positron emission tomography with (11)C-carfentanil was used to determine regional brain μ-opioid receptor (MOR) availability (non-displaceable binding potential, BPND) in a sample of 19 male smokers and 22 nonsmoking control subjects. Nonsmokers showed greater MOR BPND than overnight abstinent smokers in the basal ganglia and thalamus. BPND in the basal ganglia was negatively correlated with baseline craving levels and Fagerström scores. Interactions between group and genotype were seen in the nucleus accumbens bilaterally and the amygdala, with G-allele carriers demonstrating lower BPND in these regions, but only among smokers. After smoking the DN cigarette, smokers showed evidence of MOR activation in the thalamus and nucleus accumbens. No additional activation was observed after the N cigarette, with a mean effect of increases in MOR BPND (i.e., deactivation) with respect to the DN cigarette effects in the thalamus and left amygdala. Changes in MOR BPND were related to both Fagerström scores and changes in craving. This study showed that overnight-abstinent smokers have lower concentrations of available MORs than controls, an effect that was related to both craving and the severity of addiction. It also suggests that nicotine non-specific elements of the smoking experience have an important role in regulating MOR-mediated neurotransmission, and in turn modulating withdrawal-induced craving ratings. Copyright © 2016 Elsevier Inc. All rights reserved.

Acute inflammation induces segmental, bilateral, supraspinally mediated opioid release in the rat spinal cord, as measured by mu-opioid receptor internalization.

PubMed

Chen, W; Marvizón, J C G

2009-06-16

The objective of this study was to measure opioid release in the spinal cord during acute and long-term inflammation using mu-opioid receptor (MOR) internalization. In particular, we determined whether opioid release occurs in the segments receiving the noxious signals or in the entire spinal cord, and whether it involves supraspinal signals. Internalization of neurokinin 1 receptors (NK1Rs) was measured to track the intensity of the noxious stimulus. Rats received peptidase inhibitors intrathecally to protect opioids from degradation. Acute inflammation of the hind paw with formalin induced moderate MOR internalization in the L5 segment bilaterally, whereas NK1R internalization occurred only ipsilaterally. MOR internalization was restricted to the lumbar spinal cord, regardless of whether the peptidase inhibitors were injected in a lumbar or thoracic site. Formalin-induced MOR internalization was substantially reduced by isoflurane anesthesia. It was also markedly reduced by a lidocaine block of the cervical-thoracic spinal cord (which did not affect the evoked NK1R internalization) indicating that spinal opioid release is mediated supraspinally. In the absence of peptidase inhibitors, formalin and hind paw clamp induced a small amount of MOR internalization, which was significantly higher than in controls. To study spinal opioid release during chronic inflammation, we injected complete Freund's adjuvant (CFA) in the hind paw and peptidase inhibitors intrathecally. Two days later, no MOR or NK1R internalization was detected. Furthermore, CFA inflammation decreased MOR internalization induced by clamping the inflamed hind paw. These results show that acute inflammation, but not chronic inflammation, induces segmental opioid release in the spinal cord that involves supraspinal signals.

THE ROLE OF AMYGDALAR MU OPIOID RECEPTORS IN ANXIETY-RELATED RESPONSES IN TWO RAT MODELS

PubMed Central

Wilson, Marlene A.; Junor, Lorain

2009-01-01

Amygdala opioids such as enkephalin appear to play some role in the control of anxiety and the anxiolytic effects of benzodiazepines, although the opioid receptor subtypes mediating such effects are unclear. This study compared the influences of mu opioid receptor (MOR) activation in the central nucleus of the amygdala (CEA) on unconditioned fear or anxiety-like responses in two models, the elevated plus maze and the defensive burying test. The role of MOR in the anxiolytic actions of the benzodiazepine agonist diazepam was also examined using both models. Either the MOR agonist [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO) or the MOR antagonists Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) or β-funaltrexamine (FNA) were bilaterally infused into the CEA of rats prior to testing. The results show that microinjection of DAMGO in the CEA decreased open arm time in the plus maze, while CTAP increased open arm behaviors. In contrast, DAMGO injections in the CEA reduced burying behaviors and increased rearing following exposure to a predator odor, suggesting a shift in the behavioral response in this context. Amygdala injections of the MOR agonist DAMGO or the MOR antagonist CTAP failed to change the anxiolytic effects of diazepam in either test. Our results demonstrate that MOR activation in the central amygdala exerts distinctive effects in two different models of unconditioned fear or anxiety-like responses, and suggest that opioids may exert context-specific regulation of amygdala output circuits and behavioral responses during exposure to potential threats (open arms of the maze) versus discrete threats (predator odor). PMID:18216773

A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic

PubMed Central

Foran, Stacy E.; Carr, Daniel B.; Lipkowski, Andrzej W.; Maszczynska, Iwona; Marchand, James E.; Misicka, Aleksandra; Beinborn, Martin; Kopin, Alan S.; Kream, Richard M.

2000-01-01

To elucidate mechanisms of acute and chronic pain, it is important to understand how spinal excitatory systems influence opioid analgesia. The tachykinin substance P (SP) represents the prototypic spinal excitatory peptide neurotransmitter/neuromodulator, acting in concert with endogenous opioid systems to regulate analgesic responses to nociceptive stimuli. We have synthesized and pharmacologically characterized a chimeric peptide containing overlapping NH2- and COOH-terminal functional domains of the endogenous opioid endomorphin-2 (EM-2) and the tachykinin SP, respectively. Repeated administration of the chimeric molecule YPFFGLM-NH2, designated ESP7, into the rat spinal cord produces opioid-dependent analgesia without loss of potency over 5 days. In contrast, repeated administration of ESP7 with concurrent SP receptor (SPR) blockade results in a progressive loss of analgesic potency, consistent with the development of tolerance. Furthermore, tolerant animals completely regain opioid sensitivity after post hoc administration of ESP7 alone, suggesting that coactivation of SPRs is essential to maintaining opioid responsiveness. Radioligand binding and signaling assays, using recombinant receptors, confirm that ESP7 can coactivate μ-opioid receptors (MOR) and SPRs in vitro. We hypothesize that coincidental activation of the MOR- and SPR-expressing systems in the spinal cord mimics an ongoing state of reciprocal excitation and inhibition, which is normally encountered in nociceptive processing. Due to the ability of ESP7 to interact with both MOR and SPRs, it represents a unique prototypic, anti-tolerance-forming analgesic with future therapeutic potential. PMID:10852965

Understanding adherence to therapeutic guidelines: a multilevel analysis of statin prescription in the Skaraborg Primary Care Database.

PubMed

Hjerpe, Per; Ohlsson, Henrik; Lindblad, Ulf; Boström, Kristina Bengtsson; Merlo, Juan

2011-04-01

In Skaraborg, Sweden, the economic responsibility for tax-financed prescription drug costs was transferred from the regional administrative level to the local level (health care centre; HCC) in 2003. The aim of this study was to investigate the impact of this decentralization of economic responsibility on adherence to guidelines for prescribing lipid-lowering drugs. Data from all 24 public HCCs in Skaraborg on prescriptions for lipid-lowering drugs during 2003 and 2005 were extracted from the Skaraborg Primary Care Database (SPCD). Multilevel regression analysis (MLRA) was used to disentangle the variances at different levels of data (patient, physician, HCC). The outcome variable on the patient level was the prescription of the recommended statin (yes/no). Sex and age of the patients and sex, age and occupational status of the physician were included as fixed effects. The variance was expressed as the median odds ratio (MOR). The prevalence of adherence to guidelines for the prescription of statins increased from 77% in 2003 to 84% in 2005. The MLRA showed that in 2003 the variance was equally distributed between the HCC and physician levels (MOR(HCC2003)=1.89 vs. MOR(PHYSICIAN2003)=1.88). The variance between physicians and between HCCs decreased considerably between 2003 and 2005. The inclusion of individual and physician characteristics did not explain any of the remaining variance. The decentralized budget appears to have increased adherence to guidelines and reduced inefficient variation in prescribing.

Stemming Colorectal Cancer Growth and Metastasis: HOXA5 Forces Cancer Stem Cells to Differentiate.

PubMed

Tan, Si Hui; Barker, Nick

2015-12-14

Wnt signaling drives colorectal cancer stem cells, but effective therapeutics targeting these cells and their signaling pathways are lacking. In this issue of Cancer Cell, Ordóñez-Morán and colleagues describe a promising therapeutic intervention for colorectal cancers that selectively induces cancer stem cell differentiation through HOXA5 expression and Wnt signaling inhibition. Copyright © 2015 Elsevier Inc. All rights reserved.

Multiple Oral Re-reading treatment for alexia: The parts may be greater than the whole.

PubMed

Lacey, Elizabeth H; Lott, S N; Snider, S F; Sperling, A; Friedman, R B

2010-08-01

This study examines the reasons for the success of Multiple Oral Re-reading (MOR; Moyer, 1979), a non-invasive, easily administered alexia treatment that has been reported in the literature and is currently in clinical use. The treatment consists of reading text passages aloud multiple times a day. Findings that MOR improves reading speed on practised as well as novel text have been inconsistent, making MOR's role in the rehabilitation of alexia unclear. We hypothesised that MOR's treatment mechanism works through repetition of high frequency words (i.e., bottom-up processing). We designed and controlled our text passages to test the hypothesis that participants would not improve on all novel text but would improve on text that includes a critical mass of the words contained in the passages they were re-reading. We further hypothesised that the improvement would be at the level of their specific alexic deficit. We tested four participants with phonological alexia and two with pure alexia during 8 weeks of MOR treatment. Contrary to the conclusions of previous studies, our results indicate that improvements in top-down processing cannot explain generalisation in MOR and that much of the improvement in reading is through repetition of the practised words. However, most patients also showed improvement when specific phrases were re-used in novel passages, indicating that practice of difficult words in context may be crucial to reading improvement.

Pharmacological evidence for the mediation of the panicolytic effect of fluoxetine by dorsal periaqueductal gray matter μ-opioid receptors.

PubMed

Roncon, Camila Marroni; Almada, Rafael Carvalho; Maraschin, Jhonatan Christian; Audi, Elisabeth Aparecida; Zangrossi, Hélio; Graeff, Frederico Guilherme; Coimbra, Norberto Cysne

2015-12-01

Previously reported results have shown that the inhibitory effect of fluoxetine on escape behavior, interpreted as a panicolytic-like effect, is blocked by pretreatment with either the opioid receptor antagonist naloxone or the 5-HT1A receptor (5-HT1A-R) antagonist WAY100635 via injection into the dorsal periaqueductal gray matter (dPAG). Additionally, reported evidence indicates that the μ-opioid receptor (MOR) interacts with the 5-HT1A-R in the dPAG. In the present work, pretreatment of the dPAG with the selective MOR blocker CTOP antagonized the anti-escape effect of chronic fluoxetine (10 mg/kg, i.p., daily, for 21 days), as measured in the elevated T-maze (ETM) test, indicating mediation of this effect by the MOR. In addition, the combined administration of sub-effective doses of the selective MOR agonist DAMGO (intra-dPAG) and sub-effective doses of chronic as well as subchronic (7 days) fluoxetine increased avoidance and escape latencies, suggesting that the activation of MORs may facilitate and accelerate the effects of fluoxetine. The current observation that MORs located in the dPAG mediate the anti-escape effect of fluoxetine may open new perspectives for the development of more efficient and fast-acting panic-alleviating drugs. Copyright © 2015 Elsevier Ltd. All rights reserved.

Nucleus accumbens mu opioid receptors regulate context-specific social preferences in the juvenile rat.

PubMed

Smith, Caroline J W; Wilkins, Kevin B; Li, Sara; Tulimieri, Maxwell T; Veenema, Alexa H

2018-03-01

The μ opioid receptor (MOR) in the nucleus accumbens (NAc) is involved in assigning pleasurable, or hedonic value to rewarding stimuli. Importantly, the hedonic value of a given rewarding stimulus likely depends on an individual's current motivational state. Here, we examined the involvement of MORs in the motivation to interact with a novel or a familiar (cage mate) conspecific in juvenile rats. First, we demonstrated that the selective MOR antagonist CTAP administered into the NAc reduces social novelty preference of juvenile males, by decreasing the interaction time with the novel conspecific and increasing the interaction time with the cage mate. Next, we found that a 3-h separation period from the cage mate reduces social novelty preference in both juvenile males and females, which was primarily driven by an increase in interaction time with the cage mate. Last, we showed that MOR agonism (intracerebroventricularly or in the NAc) restored social novelty preference in juvenile males that did not show social novelty preference following social isolation. Taken together, these data support a model in which endogenous MOR activation in the NAc facilitates the relative hedonic value of novel over familiar social stimuli. Our results may implicate the MOR in neuropsychiatric disorders characterized by altered social motivation, such as major depression and autism spectrum disorder. Copyright © 2017 Elsevier Ltd. All rights reserved.

An Outbreak of Vibrio cholerae O1 infections on Ebeye Island, Republic of the Marshall Islands, associated with use of an adequately chlorinated water source.

PubMed

Beatty, Mark E; Jack, Tom; Sivapalasingam, Sumathi; Yao, Sandra S; Paul, Irene; Bibb, Bill; Greene, Kathy D; Kubota, Kristy; Mintz, Eric D; Brooks, John T

2004-01-01

In December 2000, physicians in the Republic of the Marshall Islands reported the first known outbreak of Vibrio cholerae O1 infection (biotype El Tor, serotype Ogawa) from this country. In a matched case-control study on Ebeye Island, patients with cholera (n=53) had greater odds than persons without cholera (n=104) to have drunk adequately chlorinated water collected from a US military installation on neighboring Kwajalein Island and transported back to Ebeye (matched odds ratio [MOR], 8.0; P=.01). Transporting or storing drinking water in a water cooler with a spout and a tight-fitting lid was associated with reduced odds of illness (MOR, 0.24; P<.01), as was drinking bottled water (MOR, 0.08; P<.01), boiled water (MOR, 0.47; P=.02), or water flavored with powdered drink mixes (MOR, 0.18; P<.01). No cases of cholera were reported among Kwajalein residents. This outbreak highlights the critical importance of handling and storing drinking water safely, especially during outbreaks of gastrointestinal illness.

The transcription factor C/EBPβ in the dorsal root ganglion contributes to peripheral nerve trauma–induced nociceptive hypersensitivity

PubMed Central

Li, Zhisong; Mao, Yuanyuan; Liang, Lingli; Wu, Shaogen; Yuan, Jingjing; Mo, Kai; Cai, Weihua; Mao, Qingxiang; Cao, Jing; Bekker, Alex; Zhang, Wei; Tao, Yuan-Xiang

2017-01-01

Changes in gene transcription in the dorsal root ganglion (DRG) after nerve trauma contribute to the genesis of neuropathic pain. We report that peripheral nerve trauma caused by chronic constriction injury (CCI) increased the abundance of the transcription factor C/EBPβ (CCAAT/enhancer binding protein β) in the DRG. Blocking this increase mitigated the development and maintenance of CCI-induced mechanical, thermal, and cold pain hypersensitivities without affecting basal responses to acute pain and locomotor activity. Conversely, mimicking this increase produced hypersensitivity to mechanical, thermal, or cold pain. In the ipsilateral DRG, C/EBPβ promoted a decrease in the abundance of the voltage-gated potassium channel subunit Kv1.2 and µ opioid receptor (MOR) at the mRNA and protein levels, which would be predicted to increase excitability in the ipsilateral DRG neurons and reduce the efficacy of morphine analgesia. These effects required C/EPBβ-mediated transcriptional activation of Ehmt2 (euchromatic histonelysine N-methyltransferase 2), which encodes G9a, an epigenetic silencer of the genes encoding Kv1.2 and MOR. Blocking the increase in C/EBPβ in the DRG improved morphine analgesia after CCI. These results suggest that C/EBPβ is an endogenous initiator of neuropathic pain and could be a potential target for the prevention and treatment of this disorder. PMID:28698219

Synthesis and Structure-Activity Relationships of (-)-cis-N-Normetazocine-Based LP1 Derivatives.

PubMed

Pasquinucci, Lorella; Parenti, Carmela; Amata, Emanuele; Georgoussi, Zafiroula; Pallaki, Paschalina; Camarda, Valeria; Calò, Girolamo; Arena, Emanuela; Montenegro, Lucia; Turnaturi, Rita

2018-05-05

(−)- cis - N -Normetazocine represents a rigid scaffold able to mimic the tyramine moiety of endogenous opioid peptides, and the introduction of different N -substituents influences affinity and efficacy of respective ligands at MOR (mu opioid receptor), DOR (delta opioid receptor), and KOR (kappa opioid receptor). We have previously identified LP1, a MOR/DOR multitarget opioid ligand, with an N -phenylpropanamido substituent linked to (−)- cis - N -Normetazocine scaffold. Herein, we report the synthesis, competition binding and calcium mobilization assays of new compounds 10 ⁻ 16 that differ from LP1 by the nature of the N -substituent. In radioligand binding experiments, the compounds 10 ⁻ 13 , featured by an electron-withdrawing or electron-donating group in the para position of phenyl ring, displayed improved affinity for KOR (K i = 0.85⁻4.80 μM) in comparison to LP1 (7.5 μM). On the contrary, their MOR and DOR affinities were worse (K i = 0.18⁻0.28 μM and K i = 0.38⁻1.10 μM, respectively) with respect to LP1 values (K i = 0.049 and 0.033 μM). Analogous trends was recorded for the compounds 14 ⁻ 16 , featured by indoline, tetrahydroquinoline, and diphenylamine functionalities in the N -substituent. In calcium mobilization assays, the compound 10 with a p -fluorophenyl in the N -substituent shared the functional profile of LP1 (pEC 50 MOR = 7.01), although it was less active. Moreover, the p -methyl- ( 11 ) and p -cyano- ( 12 ) substituted compounds resulted in MOR partial agonists and DOR/KOR antagonists. By contrast, the derivatives 13 ⁻ 15 resulted as MOR antagonists, and the derivative 16 as a MOR/KOR antagonist (pK B MOR = 6.12 and pK B KOR = 6.11). Collectively, these data corroborated the critical role of the N -substituent in (−)- cis - N -Normetazocine scaffold. Thus, the new synthesized compounds could represent a template to achieve a specific agonist, antagonist, or mixed agonist/antagonist functional profile.

(-)-Norpseudoephedrine, a metabolite of cathinone with amphetamine-like stimulus properties, enhances the analgesic and rate decreasing effects of morphine, but inhibits its discriminative properties.

PubMed

Nencini, P; Fraioli, S; Pascucci, T; Nucerito, C V

1998-04-01

Like psychomotor stimulants, a weak amphetamine-like agent, such as phenylpropanolamine, enhances the analgesic effects of morphine (MOR). Thus, it is possible that full psychomotor stimulant potency is not required to increase the analgesic action of opiates. The validity of this assumption is here tested by studying the ability of (-)-norpseudoephedrine (NPE), an enantiomer of phenylpropanolamine and a metabolite of cathinone, to influence both the analgesic effects of MOR and its discriminative stimulus properties. In mice NPE (5.6-10.0-17.0 mg/kg i.p.) did not prolong the latency to lick or to remove paws from a plate warmed at 54 degrees C. However, it significantly potentiated the analgesic effect of 3.2 mg/kg of MOR. These results were replicated in rats by use of the formalin test, which measures the numbers of hind paw flinches produced by injecting 50 microl of formalin into the dorsal surface of the paw. The higher dose of NPE (17 mg/kg) increased the effect of sub-analgesic doses of MOR (0.56 and 1.0 mg/kg). In rats trained to discriminate between 0.5 mg/kg of amphetamine and solvent in a two-lever operant behavior reinforced by water access. NPE induced a dose-dependent increment of drug lever responding from 0% at 1.0 mg/kg to 100% at 32.0 mg/kg. In contrast, NPE did not generalize for the MOR cue up to the dose of 56.0 mg/kg, which produced a substantial reduction of the response rate. However, when given in combination, NPE attenuated the discriminative effects of MOR and potentiated its inhibitory action on the response rate. These results exclude a direct action of NPE on the mu opiate system. In conclusion, NPE preserves amphetamine-like properties and these properties are probably responsible for the interaction of the drug with the analgesic and discriminative effects of MOR. Therefore, this study contradicts the assumption that the analgesic effects of MOR can be enhanced by a sympathomimetic drug that lacks significant psychostimulant actions.

Mor-Bell Logger: Skidding Case Study

Treesearch

Bryce J. Stokes; Jerry L. Koger; Frank J. Pickle

1983-01-01

A production equation was developed for the Mor-Bell logger for skidding while thinning a loblolly pine plantation. Production and costs for skidding and iron gate delimbing were determined for a range of operating conditions.

Mixed Kappa/Mu Opioid Receptor Agonists: The 6β-Naltrexamines

PubMed Central

Cami-Kobeci, Gerta; Neal, Adrian P.; Bradbury, Faye A.; Purington, Lauren C.; Aceto, Mario D.; Harris, Louis S.; Lewis, John W.; Traynor, John R.; Husbands, Stephen M.

2011-01-01

Ligands from the naltrexamine series have consistently demonstrated agonist activity at kappa opioid receptors (KOR), with varying activity at the mu opioid receptor (MOR). Various 6β-cinnamoylamino derivatives were made with the aim of generating ligands with a KOR agonist/MOR partial agonist profile, as ligands with this activity may be of interest as treatment agents for cocaine abuse. The ligands all displayed the desired high affinity, non-selective binding in vitro and in the functional assays were high efficacy KOR agonists with some partial agonist activity at MOR. Two of the new ligands (12a, 12b) have been evaluated in vivo, with 12a acting as a KOR agonist, and therefore somewhat similar to the previously evaluated analogues 3–6, while 12b displayed predominant MOR agonist activity. PMID:19253970

17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(4'-pyridylcarboxamido)morphinan (NAP) Modulating the Mu Opioid Receptor in a Biased Fashion.

PubMed

Zhang, Yan; Williams, Dwight A; Zaidi, Saheem A; Yuan, Yunyun; Braithwaite, Amanda; Bilsky, Edward J; Dewey, William L; Akbarali, Hamid I; Streicher, John M; Selley, Dana E

2016-03-16

Mounting evidence has suggested that G protein-coupled receptors can be stabilized in multiple conformations in response to distinct ligands, which exert discrete functions through selective activation of various downstream signaling events. In accordance with this concept, we report biased signaling of one C6-heterocyclic substituted naltrexamine derivative, namely, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(4'-pyridylcarboxamido)morphinan (NAP) at the mu opioid receptor (MOR). NAP acted as a low efficacy MOR partial agonist in the G protein-mediated [(35)S]GTPγS binding assay, whereas it did not significantly induce calcium flux or β-arrestin2 recruitment. In contrast, it potently blocked MOR full agonist-induced β-arrestin2 recruitment and translocation. Additionally, NAP dose-dependently antagonized MOR full agonist-induced intracellular calcium flux and β-arrestin2 recruitment. Further results in an isolated organ bath preparation confirmed that NAP reversed the morphine-induced reduction in colon motility. Ligand docking and dynamics simulation studies of NAP at the MOR provided more supporting evidence for biased signaling of NAP at an atomic level. Due to the fact that NAP is MOR selective and preferentially distributed peripherally upon systemic administration while β-arrestin2 is reportedly required for impairment of intestinal motility by morphine, biased antagonism of β-arrestin2 recruitment by NAP further supports its utility as a treatment for opioid-induced constipation.

Risk Factors for Measles Virus Infection Among Adults During a Large Outbreak in Postelimination Era in Mongolia, 2015.

PubMed

Hagan, José E; Takashima, Yoshihiro; Sarankhuu, Amarzaya; Dashpagma, Otgonbayar; Jantsansengee, Baigalmaa; Pastore, Roberta; Nyamaa, Gunregjav; Yadamsuren, Buyanjargal; Mulders, Mick N; Wannemuehler, Kathleen A; Anderson, Raydel; Bankamp, Bettina; Rota, Paul; Goodson, James L

2017-12-05

In 2015, a large nationwide measles outbreak occurred in Mongolia, with very high incidence in the capital city of Ulaanbaatar and among young adults. We conducted an outbreak investigation including a matched case-control study of risk factors for laboratory-confirmed measles among young adults living in Ulaanbaatar. Young adults with laboratory-confirmed measles, living in the capital city of Ulaanbaatar, were matched with 2-3 neighborhood controls. Conditional logistic regression was used to estimate adjusted matched odds ratios (aMORs) for risk factors, with 95% confidence intervals. During March 1-September 30, 2015, 20 077 suspected measles cases were reported; 14 010 cases were confirmed. Independent risk factors for measles included being unvaccinated (adjusted matched odds ratio [aMOR] 2.0, P < .01), being a high school graduate without college education (aMOR 2.6, P < .01), remaining in Ulaanbaatar during the outbreak (aMOR 2.5, P < .01), exposure to an inpatient healthcare facility (aMOR 4.5 P < .01), and being born outside of Ulaanbaatar (aMOR 1.8, P = .02). This large, nationwide outbreak shortly after verification of elimination had high incidence among young adults, particularly those born outside the national capital. In addition, findings indicated that nosocomial transmission within health facilities helped amplify the outbreak. Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia.

PubMed

Psifogeorgou, Kassi; Psigfogeorgou, Kassi; Terzi, Dimitra; Papachatzaki, Maria Martha; Varidaki, Artemis; Ferguson, Deveroux; Gold, Stephen J; Zachariou, Venetia

2011-04-13

The signaling molecule RGS9-2 is a potent modulator of G-protein-coupled receptor function in striatum. Our earlier work revealed a critical role for RGS9-2 in the actions of the μ-opioid receptor (MOR) agonist morphine. In this study, we demonstrate that RGS9-2 may act as a positive or negative modulator of MOR-mediated behavioral responses in mice depending on the agonist administered. Paralleling these findings we use coimmunoprecipitation assays to show that the signaling complexes formed between RGS9-2 and Gα subunits in striatum are determined by the MOR agonist, and we identify RGS9-2 containing complexes associated with analgesic tolerance. In striatum, MOR activation promotes the formation of complexes between RGS9-2 and several Gα subunits, but morphine uniquely promotes an association between RGS9-2 and Gαi3. In contrast, RGS9-2/Gαq complexes assemble after acute application of several MOR agonists but not after morphine application. Repeated morphine administration leads to the formation of distinct complexes, which contain RGS9-2, Gβ5, and Gαq. Finally, we use simple pharmacological manipulations to disrupt RGS9-2 complexes formed during repeated MOR activation to delay the development of analgesic tolerance to morphine. Our data provide a better understanding of the brain-region-specific signaling events associated with opiate analgesia and tolerance and point to pharmacological approaches that can be readily tested for improving chronic analgesic responsiveness.

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

Chibani, Siwar, E-mail: siwar.chibani@univ-lorraine.fr; Chebbi, Mouheb; Badawi, Michael, E-mail: michael.badawi@univ-lorraine.fr

The potential use of some cation-exchanged mordenite (H{sup +}, Na{sup +}, Cu{sup +}, and Ag{sup +}) as a selective adsorbent for volatile iodine species (ICH{sub 3} and I{sub 2}), which can be released during a nuclear accident together with a steam carrier gas, is investigated using density functional theory. It is found that in the case of Cu-MOR and Ag-MOR, the absolute values of interaction energies of ICH{sub 3} and I{sub 2} are higher than that of water which indicates that these forms of zeolite could be suitable for selective adsorption of iodine species. In contrast, the H-MOR and Na-MORmore » are found to be unsuitable for this purpose. A systematic investigation of all adsorption sites allowed us to analyze the structural effects affecting the adsorption behavior. For the Ag-MOR and Cu-MOR zeolites, the iodine compounds are adsorbed preferentially in the large channel of mordenite (main channel) while water prefers the small channel or the side pocket where it forms stronger hydrogen bonds. The factors governing the interaction energies between the cationic sites and the different molecules are analyzed and the important role of van der Waals interactions in these systems is highlighted.« less

The rewarding effects of ethanol are modulated by binge eating of a high-fat diet during adolescence.

PubMed

Blanco-Gandía, M Carmen; Ledesma, Juan Carlos; Aracil-Fernández, Auxiliadora; Navarrete, Francisco; Montagud-Romero, Sandra; Aguilar, Maria A; Manzanares, Jorge; Miñarro, José; Rodríguez-Arias, Marta

2017-07-15

Binge-eating is considered a specific form of overeating characterized by intermittent and high caloric food intake in a short period of time. Epidemiologic studies support a positive relation between the ingestion of fat and ethanol (EtOH), specifically among adolescent subjects. The aim of this work was to clarify the role of the compulsive, limited and intermittent intake of a high-fat food during adolescence on the rewarding effects of EtOH. After binge-eating for 2 h, three days a week from postnatal day (PND) 29, the reinforcing effects of EtOH were tested with EtOH self-administration (SA), conditioned place preference (CPP) and ethanol locomotor sensitization procedures in young adult mice. Animals in the high fat binge (HFB) group that underwent the EtOH SA procedure presented greater EtOH consumption and a higher motivation to obtain the drug. HFB mice also developed preference for the paired compartment in the CPP with a subthreshold dose of EtOH. Independently of the diet, mice developed EtOH-induced locomotor sensitization. After the SA procedure, HFB mice exhibited reduced levels of the mu opioid receptor (MOr) and increased cannabinoid 1 receptor (CB1r) gene expression in the nucleus accumbens (N Acc), and decreased of tyrosine hydroxylase (TH) gene expression in the ventral tegmental area (VTA). Taken together the results suggest that bingeing on fat may represent a vulnerability factor to an escalation of EtOH consumption. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of N-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Ligands.

PubMed

Harland, Aubrie A; Bender, Aaron M; Griggs, Nicholas W; Gao, Chao; Anand, Jessica P; Pogozheva, Irina D; Traynor, John R; Jutkiewicz, Emily M; Mosberg, Henry I

2016-05-26

N-Acetylation of the tetrahydroquinoline (THQ) core of a series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands increases DOR affinity, resulting in ligands with balanced MOR and DOR affinities. We report a series of N-substituted THQ analogues that incorporate various carbonyl-containing moieties to maintain DOR affinity and define the steric and electronic requirements of the binding pocket across the opioid receptors. 4h produced in vivo antinociception (ip) for 1 h at 10 mg/kg.

The neural mobilization technique modulates the expression of endogenous opioids in the periaqueductal gray and improves muscle strength and mobility in rats with neuropathic pain

PubMed Central

2014-01-01

Background The neural mobilization (NM) technique is a noninvasive method that has been proven to be clinically effective in reducing pain; however, the molecular mechanisms involved remain poorly understood. The aim of this study was to analyze whether NM alters the expression of the mu-opioid receptor (MOR), the delta-opioid receptor (DOR) and the Kappa-opioid receptor (KOR) in the periaqueductal gray (PAG) and improves locomotion and muscle force after chronic constriction injury (CCI) in rats. Methods The CCI was imposed on adult male rats followed by 10 sessions of NM every other day, starting 14 days after the CCI injury. At the end of the sessions, the PAG was analyzed using Western blot assays for opioid receptors. Locomotion was analyzed by the Sciatic functional index (SFI), and muscle force was analyzed by the BIOPAC system. Results An improvement in locomotion was observed in animals treated with NM compared with injured animals. Animals treated with NM showed an increase in maximal tetanic force of the tibialis anterior muscle of 172% (p < 0.001) compared with the CCI group. We also observed a decrease of 53% (p < 0.001) and 23% (p < 0.05) in DOR and KOR levels, respectively, after CCI injury compared to those from naive animals and an increase of 17% (p < 0.05) in KOR expression only after NM treatment compared to naive animals. There were no significant changes in MOR expression in the PAG. Conclusion These data provide evidence that a non-pharmacological NM technique facilitates pain relief by endogenous analgesic modulation. PMID:24884961

Validation of the mothers object relations scales in 2–4 year old children and comparison with the child–parent relationship scale

PubMed Central

2013-01-01

Background The quality of the parent–child relationship has an important effect on a wide range of child outcomes. The evaluation of interventions to promote healthy parenting and family relationships is dependent on outcome measures which can quantify the quality of parent–child relationships. Between the Mothers’ Object Relations – Short Form (MORS-SF) scale for babies and the Child–parent Relationship Scale (C-PRS) there is an age gap where no validated scales are available. We report the development and testing of an adaptation of the MORS-SF; the MORS (Child) scale and its use in children from the age of 2 years to 4 years. This scale aims to capture the nature of the parent–child relationship in a form which is short enough to be used in population surveys and intervention evaluations. Methods Construct and criterion validity, item salience and internal consistency were assessed in a sample of 166 parents of children aged 2–4 years old and compared with that of the C-PRS. The performance of the MORS (Child) as part of a composite measure with the HOME inventory was compared with that of the C-PRS using data collected in a randomised controlled trial and the national evaluation of Sure Start. Results MORS (Child) performed well in children aged 2–4 with high construct and criterion validity, item salience and internal consistency. One item in the C-PRS failed to load on either subscale and parents found this scale slightly more difficult to complete than the MORS (Child). The two measures performed very similarly in a factor analysis with the HOME inventory producing almost identical loadings. Conclusions Adapting the MORS-SF for children aged 2–4 years old produces a scale to assess parent–child relationships that is easy to use and outperforms the more commonly used C-PRS in several respects. PMID:23518176

Opiate-induced dopamine release is modulated by severity of alcohol dependence: an [(18)F]fallypride positron emission tomography study.

PubMed

Spreckelmeyer, Katja N; Paulzen, Michael; Raptis, Mardjan; Baltus, Thomas; Schaffrath, Sabrina; Van Waesberghe, Julia; Zalewski, Magdalena M; Rösch, Frank; Vernaleken, Ingo; Schäfer, Wolfgang M; Gründer, Gerhard

2011-10-15

Preclinical data implicate the reinforcing effects of alcohol to be mediated by interaction between the opioid and dopamine systems of the brain. Specifically, alcohol-induced release of β-endorphins stimulates μ-opioid receptors (MORs), which is believed to cause dopamine release in the brain reward system. Individual differences in opioid or dopamine neurotransmission have been suggested to be responsible for enhanced liability to abuse alcohol. In the present study, a single dose of the MOR agonist remifentanil was administered in detoxified alcohol-dependent patients and healthy control subjects to mimic the β-endorphin-releasing properties of ethanol and to assess the effects of direct MOR stimulation on dopamine release in the mesolimbic reward system. Availability of D(2/3) receptors was assessed before and after single-dose administration of the MOR agonist remifentanil in 11 detoxified alcohol-dependent patients and 11 healthy control subjects with positron emission tomography with the radiotracer [(18)F]fallypride. Severity of dependence as assessed with the Alcohol Use Disorders Identification Test was compared with remifentanil-induced percentage change in [(18)F]fallypride binding (Δ%BP(ND)). The [(18)F]fallypride binding potentials (BP(ND)s) were significantly reduced in the ventral striatum, dorsal putamen, and amygdala after remifentanil application in both patients and control subjects. In the patient group, ventral striatum Δ%BP(ND) was correlated with the Alcohol Use Disorders Identification Test score. The data provide evidence for a MOR-mediated interaction between the opioid and the dopamine system, supporting the assumption that one way by which alcohol unfolds its rewarding effects is via a MOR-(γ-aminobutyric acid)-dopamine pathway. No difference in dopamine release was found between patients and control subjects, but evidence for a patient-specific association between sensitivity to MOR stimulation and severity of alcohol dependence was found. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Optimum concentration gradient of the electrocatalyst, Nafion® and poly(tetrafluoroethylene) in a membrane-electrode-assembly for enhanced performance of direct methanol fuel cells.

PubMed

Liu, Jing Hua; Jeon, Min Ku; Lee, Ki Rak; Woo, Seong Ihl

2010-12-14

A combinatorial library of membrane-electrode-assemblies (MEAs) which consisted of 27 different compositions was fabricated to optimize the multilayer structure of direct methanol fuel cells. Each spot consisted of three layers of ink and a gradient was generated by employing different concentrations of the three components (Pt catalyst, Nafion® and polytetrafluoroethylene (PTFE)) of each layer. For quick evaluation of the library, a high-throughput optical screening technique was employed for methanol electro-oxidation reaction (MOR) activity. The screening results revealed that gradient layers could lead to higher MOR activity than uniform layers. It was found that the MOR activity was higher when the concentrations of Pt catalyst and Nafion ionomer decreased downward from the top layer to the bottom layer. On the other hand, higher MOR activity was observed when PTFE concentration increased downward from the top to the bottom layer.

Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations.

PubMed

Meral, Derya; Provasi, Davide; Prada-Gracia, Diego; Möller, Jan; Marino, Kristen; Lohse, Martin J; Filizola, Marta

2018-05-16

Various experimental and computational techniques have been employed over the past decade to provide structural and thermodynamic insights into G Protein-Coupled Receptor (GPCR) dimerization. Here, we use multiple microsecond-long, coarse-grained, biased and unbiased molecular dynamics simulations (a total of ~4 milliseconds) combined with multi-ensemble Markov state models to elucidate the kinetics of homodimerization of a prototypic GPCR, the µ-opioid receptor (MOR), embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/cholesterol lipid bilayer. Analysis of these computations identifies kinetically distinct macrostates comprising several different short-lived dimeric configurations of either inactive or activated MOR. Calculated kinetic rates and fractions of dimers at different MOR concentrations suggest a negligible population of MOR homodimers at physiological concentrations, which is supported by acceptor photobleaching fluorescence resonance energy transfer (FRET) experiments. This study provides a rigorous, quantitative explanation for some conflicting experimental data on GPCR oligomerization.

Aberrant mesolimbic dopamine-opiate interaction in obesity.

PubMed

Tuominen, Lauri; Tuulari, Jetro; Karlsson, Henry; Hirvonen, Jussi; Helin, Semi; Salminen, Paulina; Parkkola, Riitta; Hietala, Jarmo; Nuutila, Pirjo; Nummenmaa, Lauri

2015-11-15

Dopamine and opioid neurotransmitter systems share many functions such as regulation of reward and pleasure. μ-Opioid receptors (MOR) modulate the mesolimbic dopamine system in ventral tegmental area and striatum, key areas implicated in reward. We hypothesized that dopamine and opioid receptor availabilities correlate in vivo and that this correlation is altered in obesity, a disease with altered reward processing. Twenty lean females (mean BMI 22) and 25 non-binge eating morbidly obese females (mean BMI 41) underwent two positron emission tomography scans with [(11)C]carfentanil and [(11)C]raclopride to measure the MOR and dopamine D2 receptor (DRD2) availability, respectively. In lean subjects, the MOR and DRD2 availabilities were positively associated in the ventral striatum (r=0.62, p=0.003) and dorsal caudate nucleus (r=0.62, p=0.004). Moreover, DRD2 availability in the ventral striatum was associated with MOR availability in other regions of the reward circuitry, particularly in the ventral tegmental area. In morbidly obese subjects, this receptor interaction was significantly weaker in ventral striatum but unaltered in the caudate nucleus. Finally, the association between DRD2 availability in the ventral striatum and MOR availability in the ventral tegmental area was abolished in the morbidly obese. The study demonstrates a link between DRD2 and MOR availabilities in living human brain. This interaction is selectively disrupted in mesolimbic dopamine system in morbid obesity. We propose that interaction between the dopamine and opioid systems is a prerequisite for normal reward processing and that disrupted cross-talk may underlie altered reward processing in obesity. Copyright © 2015 Elsevier Inc. All rights reserved.

Volatile abundances and oxygen isotopes in basaltic to dacitic lavas on mid-ocean ridges: The role of assimilation at spreading centers

USGS Publications Warehouse

Wanless, V.D.; Perfit, M.R.; Ridley, W.I.; Wallace, P.J.; Grimes, Craig B.; Klein, E.M.

2011-01-01

Most geochemical variability in MOR basalts is consistent with low- to moderate-pressure fractional crystallization of various mantle-derived parental melts. However, our geochemical data from MOR high-silica glasses, including new volatile and oxygen isotope data, suggest that assimilation of altered crustal material plays a significant role in the petrogenesis of dacites and may be important in the formation of basaltic lavas at MOR in general. MOR high-silica andesites and dacites from diverse areas show remarkably similar major element trends, incompatible trace element enrichments, and isotopic signatures suggesting similar processes control their chemistry. In particular, very high Cl and elevated H2O concentrations and relatively light oxygen isotope ratios (~ 5.8‰ vs. expected values of ~ 6.8‰) in fresh dacite glasses can be explained by contamination of magmas from a component of ocean crust altered by hydrothermal fluids. Crystallization of silicate phases and Fe-oxides causes an increase in δ18O in residual magma, but assimilation of material initially altered at high temperatures results in lower δ18O values. The observed geochemical signatures can be explained by extreme fractional crystallization of a MOR basalt parent combined with partial melting and assimilation (AFC) of amphibole-bearing altered oceanic crust. The MOR dacitic lavas do not appear to be simply the extrusive equivalent of oceanic plagiogranites. The combination of partial melting and assimilation produces a distinct geochemical signature that includes higher incompatible trace element abundances and distinct trace element ratios relative to those observed in plagiogranites.

8-OH-DPAT abolishes the pulmonary C-fiber-mediated apneic response to fentanyl largely via acting on 5HT1A receptors in the nucleus tractus solitarius

PubMed Central

Zhuang, Jianguo; Zhang, Zhenxiong; Zhang, Cancan

2012-01-01

Intravenous bolus injection of morphine causes a vagal-mediated brief apnea (∼3 s), while continuous injection, via action upon central μ-opioid receptor (MOR), arrests ventilation (>20 s) that is eliminated by stimulating central 5-hydroxytryptamine 1A receptors (5HT1ARs). Bronchopulmonary C-fibers (PCFs) are essential for triggering a brief apnea, and their afferents terminate at the caudomedial region of the nucleus tractus solitarius (mNTS) that densely expresses 5HT1ARs. Thus we asked whether the vagal-mediated apneic response to MOR agonists was PCF dependent, and if so, whether this apnea was abolished by systemic administration of 8-hydroxy-2-(di-n-propylamino)tetral (8-OH-DPAT) largely through action upon mNTS 5HT1ARs. Right atrial bolus injection of fentanyl (5.0 μg/kg, a MOR agonist) was performed in the anesthetized and spontaneously breathing rats before and after: 1) selective blockade of PCFs' conduction and subsequent bivagotomy; 2) intravenous administration of 5HT1AR agonist 8-OH-DPAT; 3) intra-mNTS injection of 8-OH-DPAT; and 4) intra-mNTS injection of 5HT1AR antagonist WAY-100635 followed by 8-OH-DPAT (iv). We found the following: First, fentanyl evoked an immediate apnea (2.5 ± 0.4 s, ∼6-fold longer than the baseline expiratory duration, TE), which was abolished by either blocking PCFs' conduction or bivagotomy. Second, this apnea was prevented by systemic 8-OH-DPAT challenge. Third, intra-mNTS injection of 8-OH-DPAT greatly attenuated the apnea by 64%. Finally, intra-mNTS microinjection of WAY-100635 significantly attenuated (58%) the apneic blockade by 8-OH-DPAT (iv). We conclude that the vagal-mediated apneic response to MOR activation depends on PCFs, which is fully antagonized by systemic 8-OH-DPAT challenge largely via acting on mNTS 5HT1ARs. PMID:22696579

Impact of Psychological Stress on Pain Perception in an Animal Model of Endometriosis.

PubMed

Hernandez, Siomara; Cruz, Myrella L; Seguinot, Inevy I; Torres-Reveron, Annelyn; Appleyard, Caroline B

2017-10-01

Pain in patients with endometriosis is considered a significant source of stress but does not always correlate with severity of the condition. We have demonstrated that stress can worsen endometriosis in an animal model. Here, we tested the impact of a psychological stress protocol on pain thresholds and pain receptors. Endometriosis was induced in female rats by suturing uterine horn tissue next to the intestinal mesentery. Sham rats had sutures only. Rats were exposed to water avoidance stress for 7 consecutive days or handled for 5 minutes (no stress). Fecal pellets and serum corticosterone (CORT) levels were measured as an index of anxiety. Pain perception was assessed using hot plate and Von Frey tests. Substance P, enkephalin, endomorphin-2, Mu opioid receptor (MOR), and neurokinin-1 receptor expression in the spinal cord were measured by immunohistochemistry. Fecal pellets and CORT were significantly higher in the endo-stress (ES) group than endo-no stress (ENS; P < .01) and sham-no stress groups (SNS; P < .01). The ES rats had more colonic damage ( P < .001 vs SNS; P < .05 vs ENS), vesicle mast cell infiltration ( P < .01 vs ENS), and more severe vesicles than ENS. The ES developed significant hyperalgesia ( P < .05) but stress reversed the allodynic effect caused by endo ( P < .001). The MOR expression was significantly reduced in ENS versus SNS ( P < .05) and more enkephalin expression was found in endo groups. Animals subjected to stress develop more severe symptoms but interestingly stress seems to have beneficial effects on abdominal allodynia, which could be a consequence of the stress-induced analgesia phenomenon.

Increased serum IL-6 level time-dependently regulates hyperalgesia and spinal mu opioid receptor expression during CFA-induced arthritis

PubMed Central

Tekieh, E.; Zaringhalam, Jalal; Manaheji, H.; Maghsoudi, N.; Alani, B.; Zardooz, H.

2011-01-01

Interleukin (IL)-6 is known to cause pro- and anti-inflammatory effects during different stages of inflammation. Recent therapeutic investigations have focused on treatment of various inflammatory disorders with anti-cytokine substances. As a result, the aim of this study was to further elucidate the influence of IL-6 in hyperalgesia and edema during different stages of Complete Freund's Adjuvant (CFA)-induced arthritis (AA) in male Wistar rats. AA was induced by a single subcutaneous injection of CFA into the rats' hindpaw. Anti-IL-6 was administered either daily or weekly during the 21 days of study. Spinal mu opioid receptor (mOR) expression was detected by Western blotting. Daily and weekly treatment with an anti-IL-6 antibody significantly decreased paw edema in the AA group compared to the AA control group. Additionally, daily and weekly anti-IL-6 administration significantly reduced hyperalgesia on day 7 in the AA group compared to the AA control group; however, there were significant increases in hyperalgesia in the antibody-treated group on days 14 and 21 compared to the AA control group. IL-6 antibody-induced increases in hyperalgesia on the 14th and 21st days after CFA injection correlated with a time-dependent, significant reduction in spinal mOR expression during anti-IL-6 treatment. Our study confirmed the important time-dependent relationship between serum IL-6 levels and hyperalgesia during AA. These results suggest that the stages of inflammation in AA must be considered for anti-hyperalgesic and anti-inflammatory interventions via anti-IL-6 antibody treatment. PMID:27857662

Increased serum IL-6 level time-dependently regulates hyperalgesia and spinal mu opioid receptor expression during CFA-induced arthritis.

PubMed

Tekieh, E; Zaringhalam, Jalal; Manaheji, H; Maghsoudi, N; Alani, B; Zardooz, H

2011-01-01

Interleukin (IL)-6 is known to cause pro- and anti-inflammatory effects during different stages of inflammation. Recent therapeutic investigations have focused on treatment of various inflammatory disorders with anti-cytokine substances. As a result, the aim of this study was to further elucidate the influence of IL-6 in hyperalgesia and edema during different stages of Complete Freund's Adjuvant (CFA)-induced arthritis (AA) in male Wistar rats. AA was induced by a single subcutaneous injection of CFA into the rats' hindpaw. Anti-IL-6 was administered either daily or weekly during the 21 days of study. Spinal mu opioid receptor (mOR) expression was detected by Western blotting. Daily and weekly treatment with an anti-IL-6 antibody significantly decreased paw edema in the AA group compared to the AA control group. Additionally, daily and weekly anti-IL-6 administration significantly reduced hyperalgesia on day 7 in the AA group compared to the AA control group; however, there were significant increases in hyperalgesia in the antibody-treated group on days 14 and 21 compared to the AA control group. IL-6 antibody-induced increases in hyperalgesia on the 14 th and 21 st days after CFA injection correlated with a time-dependent, significant reduction in spinal mOR expression during anti-IL-6 treatment. Our study confirmed the important time-dependent relationship between serum IL-6 levels and hyperalgesia during AA. These results suggest that the stages of inflammation in AA must be considered for anti-hyperalgesic and anti-inflammatory interventions via anti-IL-6 antibody treatment.

Framework of calculating the measures of resilience (MOR) for intermodal transportation systems.

DOT National Transportation Integrated Search

2010-07-01

Recent catastrophic events, such as Hurricane Katrina, have accentuated the value of measures of resilience (MOR) for the response and : restoration of transportation systems following a disaster and have therefore become a topic of great concern for...

Human factors analysis of workstation design: Earth Radiation Budget Satellite Mission Operations Room

NASA Technical Reports Server (NTRS)

Stewart, L. J.; Murphy, E. D.; Mitchell, C. M.

1982-01-01

A human factors analysis addressed three related yet distinct issues within the area of workstation design for the Earth Radiation Budget Satellite (ERBS) mission operation room (MOR). The first issue, physical layout of the MOR, received the most intensive effort. It involved the positioning of clusters of equipment within the physical dimensions of the ERBS MOR. The second issue for analysis was comprised of several environmental concerns, such as lighting, furniture, and heating and ventilation systems. The third issue was component arrangement, involving the physical arrangement of individual components within clusters of consoles, e.g., a communications panel.

Opioidergic mechanisms underlying the actions of Vitex agnus-castus L

PubMed Central

Webster, Donna E.; He, Ying; Chen, Shao.-Nong; Pauli, Guido F.; Farnsworth, Norman R.; Wang, Zaijie Jim

2010-01-01

Vitex agnus-castus (VAC) has been used since ancient Greek times and has been shown clinically to be effective for the treatment of pre-menstrual syndrome. However, its mechanism of action has only been partially determined. Compounds, fractions, and extracts isolated from VAC were used in this study to thoroughly investigate possible opioidergic activity. First, an extract of VAC was found to bind and activate μ- and δ-, but not κ- opioid receptor subtypes (MOR, DOR, and KOR respectively). The extract was then resuspended in 10% methanol and partitioned sequentially with petroleum ether, CHCl3, and EtOAc to form four fractions including a water fraction. The highest affinity for MOR was concentrated in the CHCl3 fraction, whereas the highest affinity for DOR was found in the CHCl3 and EtOAc fractions. However, the petroleum ether fraction had the highest agonist activity at MOR and DOR. Several flavonoids from VAC were found to bind to both MOR and DOR in a dose-dependent manner; however only casticin, a marker compound for genus Vitex, was found to have agonist activity selective for DOR at high concentrations. These results suggest VAC may exert its therapeutic effects through the activation of MOR, DOR, but not KOR. PMID:20854795

Opioidergic mechanisms underlying the actions of Vitex agnus-castus L.

PubMed

Webster, Donna E; He, Ying; Chen, Shao-Nong; Pauli, Guido F; Farnsworth, Norman R; Wang, Zaijie Jim

2011-01-01

Vitex agnus-castus (VAC) has been used since ancient Greek times and has been shown clinically to be effective for the treatment of pre-menstrual syndrome. However, its mechanism of action has only been partially determined. Compounds, fractions, and extracts isolated from VAC were used in this study to thoroughly investigate possible opioidergic activity. First, an extract of VAC was found to bind and activate μ- and δ-, but not κ-opioid receptor subtypes (MOR, DOR, and KOR respectively). The extract was then resuspended in 10% methanol and partitioned sequentially with petroleum ether, CHCl(3), and EtOAc to form four fractions including a water fraction. The highest affinity for MOR was concentrated in the CHCl(3) fraction, whereas the highest affinity for DOR was found in the CHCl(3) and EtOAc fractions. The petroleum ether fraction had the highest agonist activity at MOR and DOR. Several flavonoids from VAC were found to bind to both MOR and DOR in a dose-dependent manner; however only casticin, a marker compound for genus Vitex, was found to have agonist activity selective for DOR at high concentrations. These results suggest VAC may exert its therapeutic effects through the activation of MOR, DOR, but not KOR. Copyright © 2010 Elsevier Inc. All rights reserved.

DNA-binding proteins from marine bacteria expand the known sequence diversity of TALE-like repeats

PubMed Central

de Lange, Orlando; Wolf, Christina; Thiel, Philipp; Krüger, Jens; Kleusch, Christian; Kohlbacher, Oliver; Lahaye, Thomas

2015-01-01

Transcription Activator-Like Effectors (TALEs) of Xanthomonas bacteria are programmable DNA binding proteins with unprecedented target specificity. Comparative studies into TALE repeat structure and function are hindered by the limited sequence variation among TALE repeats. More sequence-diverse TALE-like proteins are known from Ralstonia solanacearum (RipTALs) and Burkholderia rhizoxinica (Bats), but RipTAL and Bat repeats are conserved with those of TALEs around the DNA-binding residue. We study two novel marine-organism TALE-like proteins (MOrTL1 and MOrTL2), the first to date of non-terrestrial origin. We have assessed their DNA-binding properties and modelled repeat structures. We found that repeats from these proteins mediate sequence specific DNA binding conforming to the TALE code, despite low sequence similarity to TALE repeats, and with novel residues around the BSR. However, MOrTL1 repeats show greater sequence discriminating power than MOrTL2 repeats. Sequence alignments show that there are only three residues conserved between repeats of all TALE-like proteins including the two new additions. This conserved motif could prove useful as an identifier for future TALE-likes. Additionally, comparing MOrTL repeats with those of other TALE-likes suggests a common evolutionary origin for the TALEs, RipTALs and Bats. PMID:26481363

A Cyclic Tetrapeptide (“Cyclodal”) and Its Mirror-Image Isomer Are Both High-Affinity μ Opioid Receptor Antagonists

PubMed Central

Weltrowska, Grazyna; Nguyen, Thi M.-D.; Chung, Nga N.; Wood, JodiAnne; Ma, Xiaoyu; Guo, Jason; Wilkes, Brian C.; Ge, Yang; Laferrière, André; Coderre, Terence J.; Schiller, Peter W.

2016-01-01

Head-to-tail cyclization of the μ opioid receptor (MOR) agonist [Dmt1]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2 (9; Dmt = 2′,6′-dimethyltyrosine) resulted in a highly active, selective MOR antagonist, c[-d-Arg-Phe-Lys-Dmt-] (1) (“cyclodal”), with subnanomolar binding affinity. A docking study of cyclodal using the crystal structure of MOR in the inactive form showed a unique binding mode with the two basic residues of the ligand forming salt bridges with the Asp127 and Glu229 receptor residues. Cyclodal showed high plasma stability and was able to cross the blood–brain barrier to reverse morphine-induced, centrally mediated analgesia when given intravenously. Surprisingly, the mirror-image isomer (optical antipode) of cyclodal, c[-Arg-d-Phe-d-Lys-d-Dmt-] (2), also turned out to be a selective MOR antagonist with 1 nM binding affinity, and thus, these two compounds represent the first example of mirror image opioid receptor ligands with both optical antipodes having high binding affinity. Reduction of the Lys-Dmt peptide bond in cyclodal resulted in an analogue, c[-d-Arg-Phe-LysΨ[CH2NH]Dmt-] (8), with MOR agonist activity. PMID:27676089

Supraspinal inhibitory effects of chimeric peptide MCRT on gastrointestinal motility in mice.

PubMed

He, Chunbo; Li, Hailan; Zhang, Jing; Kang, Yanping; Jia, Fang; Dong, Shouliang; Zhou, Lanxia

2017-09-01

Chimeric peptide MCRT, based on morphiceptin and PFRTic-NH 2 , was a bifunctional ligand of μ- and δ-opioid receptors (MOR-DOR) and produced potent analgesia in tail-withdrawal test. The study focused on the supraspinal effects of morphiceptin, PFRTic-NH 2 and MCRT on gastrointestinal motility. Moreover, opioid receptor antagonists, naloxone (non-selective), cyprodime (MOR selective) and naltrindole (DOR selective) were utilized to explore the mechanisms. Intracerebroventricular administration was achieved via the implanted cannula. Gastric emptying and intestinal transit were measured to evaluate gastrointestinal motility. (1) At supraspinal level, morphiceptin, PFRTic-NH 2 and MCRT significantly decreased gastric emptying and intestinal transit; (2) MCRT at 1 nmol/mouse, far higher than its analgesic dose (ED 50  = 29.8 pmol/mouse), failed to regulate the gastrointestinal motility; (3) MCRT-induced gastrointestinal dysfunction could be completely blocked by naloxone and naltrindole, but not affected by cyprodime. (1) Morphiceptin and PFRTic-NH 2 played important roles in the regulation of gastrointestinal motility; (2) MCRT possessed higher bioactivity of pain relief than gastrointestinal regulation, suggesting its promising analgesic property; (3) MCRT-induced motility disorders were sensitive to DOR but not to MOR blockade, indicating the pain-relieving specificity of speculated MOR subtype or splice variant or MOR-DOR heterodimer. © 2017 Royal Pharmaceutical Society.

The framework for calculating the measure of resilience for intermodal transportation systems.

DOT National Transportation Integrated Search

2009-08-14

A literature review indicates no conforming approval on the measure of resilience (MOR) for intermodal : transportation systems (1, 2, 3). The objective of this report is to develop a framework for calculating the : measure of resilience (MOR) to dis...

μ Opioid receptor: novel antagonists and structural modeling

NASA Astrophysics Data System (ADS)

Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

2016-02-01

The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.

Opioid Peptidomimetics: Leads for the Design of Bioavailable Mixed Efficacy Mu Opioid Receptor (MOR) Agonist/Delta Opioid Receptor (DOR) Antagonist Ligands

PubMed Central

Mosberg, Henry I.; Yeomans, Larisa; Harland, Aubrie A.; Bender, Aaron M.; Sobczyk-Kojiro, Katarzyna; Anand, Jessica P.; Clark, Mary J.; Jutkiewicz, Emily M.; Traynor, John R.

2013-01-01

We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a mu opioid receptor (MOR) agonist, delta opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance. PMID:23419026

Prevention of the Angiogenic Switch in Human Breast Cancer

DTIC Science & Technology

2009-03-01

av er ag e 1 - 2 c m 3 . B lo od , 1 04 : 2 39 a, A bs tra ct # 83 9, 2 00 4. 17 The FASEB Journal • FJ Express Summary Prolonged dormancy of...contralateral ank of the mouse. Thus, the observed differences in vascular permeability between angiogenic and nonangiogenic tumors appeared to be lo ...Kovalski K, Ossowski L. Tu- mor dormancy induced by downregulation of uro - kinase receptor in human carcinoma involves inte- grin and MAPK signaling. J

Joint Diagonalization Applied to the Detection and Discrimination of Unexploded Ordnance

DTIC Science & Technology

2012-08-01

center (Das et al., 1990; Barrow and Nelson, 2001; Bell et al., 2001; Pasion and Oldenburg , 2001; Zhang et al., 2003; Smith and Mor- rison, 2004; Tarokh et...matrix for the complete transmitter/receiver ar- ray by tiling all the Nr × Nt available samples of expression 5: S ¼ GscUlΛ̇lUTl ðGprÞT...L. R., and D. W. Oldenburg , 2001, A discrimination algorithm for UXO using time-domain electromagnetics: Journal of Environmental and Engineering

Functional Differentiation of SWI/SNF Remodelers in Transcription and Cell Cycle Control▿ †

PubMed Central

Moshkin, Yuri M.; Mohrmann, Lisette; van Ijcken, Wilfred F. J.; Verrijzer, C. Peter

2007-01-01

Drosophila BAP and PBAP represent two evolutionarily conserved subclasses of SWI/SNF chromatin remodelers. The two complexes share the same core subunits, including the BRM ATPase, but differ in a few signature subunits: OSA defines BAP, whereas Polybromo (PB) and BAP170 specify PBAP. Here, we present a comprehensive structure-function analysis of BAP and PBAP. An RNA interference knockdown survey revealed that the core subunits BRM and MOR are critical for the structural integrity of both complexes. Whole-genome expression profiling suggested that the SWI/SNF core complex is largely dysfunctional in cells. Regulation of the majority of target genes required the signature subunit OSA, PB, or BAP170, suggesting that SWI/SNF remodelers function mostly as holoenzymes. BAP and PBAP execute similar, independent, or antagonistic functions in transcription control and appear to direct mostly distinct biological processes. BAP, but not PBAP, is required for cell cycle progression through mitosis. Because in yeast the PBAP-homologous complex, RSC, controls cell cycle progression, our finding reveals a functional switch during evolution. BAP mediates G2/M transition through direct regulation of string/cdc25. Its signature subunit, OSA, is required for directing BAP to the string/cdc25 promoter. Our results suggest that the core subunits play architectural and enzymatic roles but that the signature subunits determine most of the functional specificity of SWI/SNF holoenzymes in general gene control. PMID:17101803

Aerobic exercise modulates anticipatory reward processing via the μ-opioid receptor system.

PubMed

Saanijoki, Tiina; Nummenmaa, Lauri; Tuulari, Jetro J; Tuominen, Lauri; Arponen, Eveliina; Kalliokoski, Kari K; Hirvonen, Jussi

2018-06-08

Physical exercise modulates food reward and helps control body weight. The endogenous µ-opioid receptor (MOR) system is involved in rewarding aspects of both food and physical exercise, yet interaction between endogenous opioid release following exercise and anticipatory food reward remains unresolved. Here we tested whether exercise-induced opioid release correlates with increased anticipatory reward processing in humans. We scanned 24 healthy lean men after rest and after a 1 h session of aerobic exercise with positron emission tomography (PET) using MOR-selective radioligand [ 11 C]carfentanil. After both PET scans, the subjects underwent a functional magnetic resonance imaging (fMRI) experiment where they viewed pictures of palatable versus nonpalatable foods to trigger anticipatory food reward responses. Exercise-induced changes in MOR binding in key regions of reward circuit (amygdala, thalamus, ventral and dorsal striatum, and orbitofrontal and cingulate cortices) were used to predict the changes in anticipatory reward responses in fMRI. Exercise-induced changes in MOR binding correlated negatively with the exercise-induced changes in neural anticipatory food reward responses in orbitofrontal and cingulate cortices, insula, ventral striatum, amygdala, and thalamus: higher exercise-induced opioid release predicted higher brain responses to palatable versus nonpalatable foods. We conclude that MOR activation following exercise may contribute to the considerable interindividual variation in food craving and consumption after exercise, which might promote compensatory eating and compromise weight control. © 2018 Wiley Periodicals, Inc.

DNA-binding proteins from marine bacteria expand the known sequence diversity of TALE-like repeats.

PubMed

de Lange, Orlando; Wolf, Christina; Thiel, Philipp; Krüger, Jens; Kleusch, Christian; Kohlbacher, Oliver; Lahaye, Thomas

2015-11-16

Transcription Activator-Like Effectors (TALEs) of Xanthomonas bacteria are programmable DNA binding proteins with unprecedented target specificity. Comparative studies into TALE repeat structure and function are hindered by the limited sequence variation among TALE repeats. More sequence-diverse TALE-like proteins are known from Ralstonia solanacearum (RipTALs) and Burkholderia rhizoxinica (Bats), but RipTAL and Bat repeats are conserved with those of TALEs around the DNA-binding residue. We study two novel marine-organism TALE-like proteins (MOrTL1 and MOrTL2), the first to date of non-terrestrial origin. We have assessed their DNA-binding properties and modelled repeat structures. We found that repeats from these proteins mediate sequence specific DNA binding conforming to the TALE code, despite low sequence similarity to TALE repeats, and with novel residues around the BSR. However, MOrTL1 repeats show greater sequence discriminating power than MOrTL2 repeats. Sequence alignments show that there are only three residues conserved between repeats of all TALE-like proteins including the two new additions. This conserved motif could prove useful as an identifier for future TALE-likes. Additionally, comparing MOrTL repeats with those of other TALE-likes suggests a common evolutionary origin for the TALEs, RipTALs and Bats. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

The median hazard ratio: a useful measure of variance and general contextual effects in multilevel survival analysis.

PubMed

Austin, Peter C; Wagner, Philippe; Merlo, Juan

2017-03-15

Multilevel data occurs frequently in many research areas like health services research and epidemiology. A suitable way to analyze such data is through the use of multilevel regression models (MLRM). MLRM incorporate cluster-specific random effects which allow one to partition the total individual variance into between-cluster variation and between-individual variation. Statistically, MLRM account for the dependency of the data within clusters and provide correct estimates of uncertainty around regression coefficients. Substantively, the magnitude of the effect of clustering provides a measure of the General Contextual Effect (GCE). When outcomes are binary, the GCE can also be quantified by measures of heterogeneity like the Median Odds Ratio (MOR) calculated from a multilevel logistic regression model. Time-to-event outcomes within a multilevel structure occur commonly in epidemiological and medical research. However, the Median Hazard Ratio (MHR) that corresponds to the MOR in multilevel (i.e., 'frailty') Cox proportional hazards regression is rarely used. Analogously to the MOR, the MHR is the median relative change in the hazard of the occurrence of the outcome when comparing identical subjects from two randomly selected different clusters that are ordered by risk. We illustrate the application and interpretation of the MHR in a case study analyzing the hazard of mortality in patients hospitalized for acute myocardial infarction at hospitals in Ontario, Canada. We provide R code for computing the MHR. The MHR is a useful and intuitive measure for expressing cluster heterogeneity in the outcome and, thereby, estimating general contextual effects in multilevel survival analysis. © 2016 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.

The median hazard ratio: a useful measure of variance and general contextual effects in multilevel survival analysis

PubMed Central

Wagner, Philippe; Merlo, Juan

2016-01-01

Multilevel data occurs frequently in many research areas like health services research and epidemiology. A suitable way to analyze such data is through the use of multilevel regression models (MLRM). MLRM incorporate cluster‐specific random effects which allow one to partition the total individual variance into between‐cluster variation and between‐individual variation. Statistically, MLRM account for the dependency of the data within clusters and provide correct estimates of uncertainty around regression coefficients. Substantively, the magnitude of the effect of clustering provides a measure of the General Contextual Effect (GCE). When outcomes are binary, the GCE can also be quantified by measures of heterogeneity like the Median Odds Ratio (MOR) calculated from a multilevel logistic regression model. Time‐to‐event outcomes within a multilevel structure occur commonly in epidemiological and medical research. However, the Median Hazard Ratio (MHR) that corresponds to the MOR in multilevel (i.e., ‘frailty’) Cox proportional hazards regression is rarely used. Analogously to the MOR, the MHR is the median relative change in the hazard of the occurrence of the outcome when comparing identical subjects from two randomly selected different clusters that are ordered by risk. We illustrate the application and interpretation of the MHR in a case study analyzing the hazard of mortality in patients hospitalized for acute myocardial infarction at hospitals in Ontario, Canada. We provide R code for computing the MHR. The MHR is a useful and intuitive measure for expressing cluster heterogeneity in the outcome and, thereby, estimating general contextual effects in multilevel survival analysis. © 2016 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd. PMID:27885709

Endomorphin-2 Inhibition of Substance P Signaling within Lamina I of the Spinal Cord Is Impaired in Diabetic Neuropathic Pain Rats

PubMed Central

Wan, Fa-Ping; Bai, Yang; Kou, Zhen-Zhen; Zhang, Ting; Li, Hui; Wang, Ya-Yun; Li, Yun-Qing

2017-01-01

Opiate analgesia in the spinal cord is impaired in diabetic neuropathic pain (DNP), but until now the reason is unknown. We hypothesized that it resulted from a decreased inhibition of substance P (SP) signaling within the dorsal horn of the spinal cord. To investigate this possibility, we evaluated the effects of endomorphin-2 (EM2), an endogenous ligand of the μ-opioid receptor (MOR), on SP release within lamina I of the spinal dorsal horn (SDH) in rats with DNP. We established the DNP rat model and compared the analgesic efficacy of EM2 between inflammation pain and DNP rat models. Behavioral results suggested that the analgesic efficacy of EM2 was compromised in the condition of painful diabetic neuropathy. Then, we measured presynaptic SP release induced by different stimulating modalities via neurokinin-1 receptor (NK1R) internalization. Although there was no significant change in basal and evoked SP release between control and DNP rats, EM2 failed to inhibit SP release by noxious mechanical and thermal stimuli in DNP but not in control and inflammation pain model. We also observed that EM2 decreased the number of FOS-positive neurons within lamina I of the SDH but did not change the amount of FOS/NK1R double-labeled neurons. Finally, we identified a remarkable decrease in MORs within the primary afferent fibers and dorsal root ganglion (DRG) neurons by Western blot (WB) and immunohistochemistry (IHC). Taken together, these data suggest that reduced presynaptic MOR expression might account for the loss of the inhibitory effect of EM2 on SP signaling, which might be one of the neurobiological foundations for decreased opioid efficacy in the treatment of DNP. PMID:28119567

Opioid receptor and β-arrestin2 densities and distribution change after sexual experience in the ventral tegmental area of male rats.

PubMed

Garduño-Gutiérrez, René; León-Olea, Martha; Rodríguez-Manzo, Gabriela

2018-05-15

Sexual experience modifies brain functioning and copulatory efficiency. Sexual activity, ejaculation in particular, is a rewarding behavior associated with the release of endogenous opioids, which modulate the activity of the mesolimbic dopaminergic system (MLS). In sexually exhausted rats, repeated ejaculation produces μ (MOR) and δ opioid receptor (DOR) internalization in ventral tegmental area (VTA) neurons, as well as long-lasting behavioral changes suggestive of brain plasticity processes. We hypothesized that in sexually naïve rats the endogenous opioids released during sexual experience acquisition, might contribute to brain plasticity processes involved in the generation of the behavioral changes induced by sexual experience. To this aim, using double immunohistochemistry and confocal microscopy, we compared in vivo MOR, DOR and β-arrestin2 densities and activation in the VTA of sexually naïve males, sexually experienced rats not executing sexual activity prior to sacrifice and sexually experienced animals that ejaculated once before sacrifice. Results showed that sexual experience acquisition improved male's copulatory ability and induced persistent changes in the density, cellular distribution and activation of MOR and β-arrestin2 in VTA neurons. DOR density was not modified, but its cellular location changed after sexual experience, revealing that these two opioid receptors were differentially activated during sexual experience acquisition. It is concluded that the endogenous opioids released during sexual activity produce adjustments in VTA neurons of sexually naïve male rats that might contribute to the behavioral plasticity expressed as an improvement in male copulatory parameters, promoted by the acquisition of sexual experience. Copyright © 2018 Elsevier Inc. All rights reserved.

Electrical stimulation of the insular cortex as a novel target for the relief of refractory pain: An experimental approach in rodents.

PubMed

Dimov, Luiz Fabio; Toniolo, Elaine Flamia; Alonso-Matielo, Heloísa; de Andrade, Daniel Ciampi; Garcia-Larrea, Luis; Ballester, Gerson; Teixeira, Manoel Jacobsen; Dale, Camila Squarzoni

2018-07-02

Cortical electrical stimulation (CES) has shown to be an effective therapeutic alternative for neuropathic pain refractory to pharmacological treatment. The primary motor cortex(M1) was the main cortical target used in the vast majority of both invasive and non-invasive studies. Despite positive results M1-based approaches still fail to relieve pain in a significant proportion of individuals. It has been advocated that the direct stimulation of cortical areas directly implicated in the central integration of pain could increase the efficacy of analgesic brain stimulation. Here, we evaluated the behavioral effects of electrical stimulation of the insular cortex (ESI) on pain sensitivity in an experimental rat model of peripheral neuropathy, and have described the pathways involved. Animals underwent chronic constriction of the sciatic nerve in the right hind limb and had concentric electrodes implanted in the posterior dysranular insular cortex. Mechanical nociception responses were evaluated before and at the end of a 15-min session of ESI (60Hz, 210μs, 1V). ESI reversed mechanical hypersensitivity in the paw contralateral to the brain hemisphere stimulated, without inducing motor impairment in the open-field test. Pharmacological blockade of μ-opioid (MOR) or type 1-cannabinoid receptors (CB1R) abolished ESI-induced antinociceptive effects. Evaluation of CB1R and MOR spatial expression demonstrated differential modulation of CB1R and MOR in the periaqueductal gray matter (PAG) of ESI-treated rats in sub-areas involved in pain processing/modulation. These results indicate that ESI induces antinociception by functionally modulating opioid and cannabinoid systems in the PAG pain circuitry in rats with experimentally induced neuropathic pain. Copyright © 2017 Elsevier B.V. All rights reserved.

Bupropion and naltrexone combination alters high fructose corn syrup self-administration and gene expression in rats.

PubMed

Levy, AnneMarie; Daniels, Stephen; Hudson, Roger; Horman, Thomas; Flynn, Amanda; Zhou, Yan; Leri, Francesco

2018-06-01

Contrave ® is an adjunct pharmacotherapy for obesity that contains bupropion (BUP) and naltrexone (NTX). To further explore the psychopharmacology of this drug combination, male Sprague-Dawley rats were implanted with subcutaneous osmotic mini-pumps releasing: 40 mg/kg/day BUP, 4 mg/kg/day NTX, or 40 + 4 mg/kg/day BUP and NTX (BN). During 12 days of exposure, the animals were tested on operant intraoral self-administration (IOSA) of high fructose corn syrup (HFCS) on continuous (FR1) and progressive ratio (PR) schedules, on home cage drinking of HFCS, and on HFCS taste reactivity. Locomotion activity was also assessed. At the conclusion of the study, mRNA expression of genes involved in reward processing, appetite and mood were quantified. It was found that BN produced effects that could largely be ascribed to either BUP or NTX independently. More specifically, BN-induced reductions of HFCS IOSA on a FR1 schedule and home cage drinking, as well as alterations of MOR and POMC mRNA in the nucleus accumbens core and hypothalamus respectively, were attributable to NTX; while alterations of hippocampal BDNF mRNA was attributable to BUP. But, there was also some evidence of drug synergy: only BN caused persistent reductions of HFCS IOSA and drinking; BN produced the least gain of body weight; and only BN-treated rats displayed altered D2R mRNA in the caudate-putamen. Taken together, these observations support the use of BUP + NTX as a mean to alter consumption of sugars and reducing their impact on brain systems involved in reward, appetite and mood. Copyright © 2018 Elsevier Ltd. All rights reserved.

Binding Sequences for RdgB, a DNA Damage-Responsive Transcriptional Activator, and Temperature-Dependent Expression of Bacteriocin and Pectin Lyase Genes in Pectobacterium carotovorum subsp. carotovorum▿ †

PubMed Central

Yamada, Kazuteru; Kaneko, Jun; Kamio, Yoshiyuki; Itoh, Yoshifumi

2008-01-01

Pectobacterium carotovorum subsp. carotovorum strain Er simultaneously produces the phage tail-like bacteriocin carotovoricin (Ctv) and pectin lyase (Pnl) in response to DNA-damaging agents. The regulatory protein RdgB of the Mor/C family of proteins activates transcription of pnl through binding to the promoter. However, the optimal temperature for the synthesis of Ctv (23°C) differs from that for synthesis of Pnl (30°C), raising the question of whether RdgB directly activates ctv transcription. Here we report that RdgB directly regulates Ctv synthesis. Gel mobility shift assays demonstrated RdgB binding to the P0, P1, and P2 promoters of the ctv operons, and DNase I footprinting determined RdgB-binding sequences (RdgB boxes) on these and on the pnl promoters. The RdgB box of the pnl promoter included a perfect 7-bp inverted repeat with high binding affinity to the regulator (Kd [dissociation constant] = 150 nM). In contrast, RdgB boxes of the ctv promoters contained an imperfect inverted repeat with two or three mismatches that consequently reduced binding affinity (Kd = 250 to 350 nM). Transcription of the rdgB and ctv genes was about doubled at 23°C compared with that at 30°C. In contrast, the amount of pnl transcription tripled at 30°C. Thus, the inverse synthesis of Ctv and Pnl as a function of temperature is apparently controlled at the transcriptional level, and reduced rdgB expression at 30°C obviously affected transcription from the ctv promoters with low-affinity RdgB boxes. Pathogenicity toward potato tubers was reduced in an rdgB knockout mutant, suggesting that the RdgAB system contributes to the pathogenicity of this bacterium, probably by activating pnl expression. PMID:18689515

ARC-2010-ACD10-0066-004

NASA Image and Video Library

2010-04-09

Netherlands Memorandum of Record (MOR) agreement signing the NASA Ames Research Center, Mofffett Field, California. Signing the MOR are on left Dr. Louis B.J.Vertegaal, Director of Physical Sciences, Chemistry, and Advanced Chemical Technologies for Sustainability, of the Netherlands Organisation for Scientific Research (NWO) and on right Dr. S. Pete Worden, Director NASA Ames Research Center

Solar photocatalytic degradation of isoproturon over TiO2/H-MOR composite systems.

PubMed

Sharma, Mangalampalli V Phanikrishna; Durgakumari, Valluri; Subrahmanyam, Machiraju

2008-12-30

The photocatalytic degradation and mineralization of isoproturon herbicide was investigated in aqueous solution containing TiO2 over H-mordenite (H-MOR) photocatalysts under solar light. The catalysts are characterized by X-ray diffraction (XRD), UV-Vis diffused reflectance spectra (UV-Vis DRS), Fourier transform-infra red spectra (FT-IR) and scanning electron microscopy (SEM) techniques. The effect of TiO2, H-MOR support and different wt% of TiO2 over the support on the photocatalytic degradation and influence of parameters such as TiO2 loading, catalyst amount, pH and initial concentration of isoproturon on degradation are evaluated. 15wt% TiO2/H-MOR composite is found to be optimum. The degradation reaction follows pseudo-first order kinetics and is discussed in terms of Langmuir-Hinshelwood (L-H) kinetic model. The extent of isoproturon mineralization studied with chemical oxygen demand (COD) and total organic carbon (TOC) measurements and approximately 80% mineralization occurred in 5h. A plausible mechanism is proposed based on the intermediates identified by liquid chromatography-mass spectroscopy (LC-MS).

Origin of geochemical mantle components: Role of spreading ridges and thermal evolution of mantle

NASA Astrophysics Data System (ADS)

Kimura, Jun-Ichi; Gill, James B.; van Keken, Peter E.; Kawabata, Hiroshi; Skora, Susanne

2017-02-01

We explore the element redistribution at mid-ocean ridges (MOR) using a numerical model to evaluate the role of decompression melting of the mantle in Earth's geochemical cycle, with focus on the formation of the depleted mantle component. Our model uses a trace element mass balance based on an internally consistent thermodynamic-petrologic computation to explain the composition of MOR basalt (MORB) and residual peridotite. Model results for MORB-like basalts from 3.5 to 0 Ga indicate a high mantle potential temperature (Tp) of 1650-1500°C during 3.5-1.5 Ga before decreasing gradually to ˜1300°C today. The source mantle composition changed from primitive (PM) to depleted as Tp decreased, but this source mantle is variable with an early depleted reservoir (EDR) mantle periodically present. We examine a two-stage Sr-Nd-Hf-Pb isotopic evolution of mantle residues from melting of PM or EDR at MORs. At high-Tp (3.5-1.5 Ga), the MOR process formed extremely depleted DMM. This coincided with formation of the majority of the continental crust, the subcontinental lithospheric mantle, and the enriched mantle components formed at subduction zones and now found in OIB. During cooler mantle conditions (1.5-0 Ga), the MOR process formed most of the modern ocean basin DMM. Changes in the mode of mantle convection from vigorous deep mantle recharge before ˜1.5 Ga to less vigorous afterward is suggested to explain the thermochemical mantle evolution.

Different amounts of ejaculatory activity, a natural rewarding behavior, induce differential mu and delta opioid receptor internalization in the rat's ventral tegmental area.

PubMed

Garduño-Gutiérrez, René; León-Olea, Martha; Rodríguez-Manzo, Gabriela

2013-12-06

Opioid receptors internalize upon specific agonist stimulation. The in vivo significance of receptor internalization is not well established, partly due to the limited in vivo models used to study this phenomenon. Ejaculation promotes endogenous opioid release which activates opioid receptors at the brain, including the mesolimbic system and medial preoptic area. The objective of the present work was to analyze if there was a correlation between the degree of in vivo mu (MOR) and delta opioid receptor (DOR) internalization in the ventral tegmental area and the execution of different amounts of ejaculatory behavior of male rats. To this aim, we analyzed the brains of rats that ejaculated once or six successive times and of sexually exhausted rats with an established sexual inhibition, using immunofluorescence and confocal microscopy. Results showed that MOR and DOR internalization increased as a consequence of ejaculation. There was a relationship between the amount of sexual activity executed and the degree of internalization for MOR, but not for DOR. MOR internalization was larger in rats that ejaculated repeatedly than in animals ejaculating only once. Significant DOR internalization was found only in animals ejaculating once. Changes in MOR, DOR and beta arrestin2 detection, associated to sexual activity, were also found. It is suggested that copulation to satiety might be useful as a model system to study the biological significance of receptor internalization. © 2013 Published by Elsevier B.V.

Soft-x-ray magneto-optical Kerr effect and element-specific hysteresis measurement

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

Kortright, J.B.; Rice, M.

1997-04-01

Interest in the utilization of x-ray magneto-optical properties to provide element-specific magnetic information, combined with recent development of tunable linear polarizers for spectroscopic polarization measurement, have led the authors to the study of magneto-optical rotation (MOR) near core levels of magnetic atoms in magnetic multilayer and alloy films. Their initial observation of Faraday rotation (in transmission) demonstrated that for Fe MOR is easily measured and is larger at its L{sub 3} resonance than in the near-visible spectral regions. This work also demonstrated that the spectroscopic behavior of the MOR signal in transmission, resulting from the differential reaction of left- andmore » right-circular components of a linearly polarized beam, is related to the magnetic circular dichroism (MCD), or differential absorption, as expected by a Kramers-Kronig transformation. Thus MCD measurements using circular polarization and MOR measurements using linear polarization can provide complementary, and in some cases equivalent, information. On beamline 6.3.2 the authors have begun to investigate soft x-ray MOR in the reflection geometry, the x-ray magneto-optic Kerr effect (XMOKE). Early measurements have demonstrated the ability to measure element-specific hysteresis loops and large rotations compared to analogous near-visible measurements. The authors are investigating the spectral dependence of the XMOKE signal, and have initiated systematic materials studies of sputter-deposited films of Fe, Fe{sub x}Cr{sub 1{minus}x} alloys, and Fe/Cr multilayers.« less

Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol-dependent individuals.

PubMed

Turton, Samuel; Myers, James Fm; Mick, Inge; Colasanti, Alessandro; Venkataraman, Ashwin; Durant, Claire; Waldman, Adam; Brailsford, Alan; Parkin, Mark C; Dawe, Gemma; Rabiner, Eugenii A; Gunn, Roger N; Lightman, Stafford L; Nutt, David J; Lingford-Hughes, Anne

2018-06-25

Addiction has been proposed as a 'reward deficient' state, which is compensated for with substance use. There is growing evidence of dysregulation in the opioid system, which plays a key role in reward, underpinning addiction. Low levels of endogenous opioids are implicated in vulnerability for developing alcohol dependence (AD) and high mu-opioid receptor (MOR) availability in early abstinence is associated with greater craving. This high MOR availability is proposed to be the target of opioid antagonist medication to prevent relapse. However, changes in endogenous opioid tone in AD are poorly characterised and are important to understand as opioid antagonists do not help everyone with AD. We used [ 11 C]carfentanil, a selective MOR agonist positron emission tomography (PET) radioligand, to investigate endogenous opioid tone in AD for the first time. We recruited 13 abstinent male AD and 15 control participants who underwent two [ 11 C]carfentanil PET scans, one before and one 3 h following a 0.5 mg/kg oral dose of dexamphetamine to measure baseline MOR availability and endogenous opioid release. We found significantly blunted dexamphetamine-induced opioid release in 5 out of 10 regions-of-interest including insula, frontal lobe and putamen in AD compared with controls, but no significantly higher MOR availability AD participants compared with HC in any region. This study is comparable to our previous results of blunted dexamphetamine-induced opioid release in gambling disorder, suggesting that this dysregulation in opioid tone is common to both behavioural and substance addictions.

Convergent, not serial, striatal and pallidal circuits regulate opioid-induced food intake

PubMed Central

Taha, Sharif A.; Katsuura, Yoshihiro; Noorvash, David; Seroussi, Ariel; Fields, Howard L.

2009-01-01

Mu opioid receptor (MOR) signaling in the nucleus accumbens (NAcc) elicits marked increases in the consumption of palatable tastants. However, the mechanism and circuitry underlying this effect are not fully understood. Multiple downstream target regions have been implicated in mediating this effect but the role of the ventral pallidum (VP), a primary target of NAcc efferents, has not been well defined. To probe the mechanisms underlying increased consumption, we identified behavioral changes in licking patterns following NAcc MOR stimulation. Because the temporal structure of licking reflects the physiological substrates modulating consumption, these measures provide a useful tool in dissecting the cause of increased consumption following NAcc MOR stimulation. Next, we used a combination of pharmacological inactivation and lesions to define the role of the VP in hyperphagia following infusion of the MOR-specific agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) into the NAcc. In agreement with previous studies, results from lick microstructure analysis suggest that NAcc MOR stimulation augments intake through a palatability-driven mechanism. Our results also demonstrate an important role for the VP in normal feeding behavior: pharmacological inactivation of the VP suppresses baseline and NAcc DAMGO-induced consumption. However, this interaction does not occur through a serial circuit requiring direct projections from the NAcc to the VP. Rather, our results indicate that NAcc and VP circuits converge on a common downstream target that regulates food intake. PMID:19336249

Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study.

PubMed

Schrepf, Andrew; Harper, Daniel E; Harte, Steven E; Wang, Heng; Ichesco, Eric; Hampson, Johnson P; Zubieta, Jon-Kar; Clauw, Daniel J; Harris, Richard E

2016-10-01

Endogenous opioid system dysfunction potentially contributes to chronic pain in fibromyalgia (FM), but it is unknown if this dysfunction is related to established neurobiological markers of hyperalgesia. We previously reported that µ-opioid receptor (MOR) availability was reduced in patients with FM as compared with healthy controls in several pain-processing brain regions. In the present study, we compared pain-evoked functional magnetic resonance imaging with endogenous MOR binding and clinical pain ratings in female opioid-naive patients with FM (n = 18) using whole-brain analyses and regions of interest from our previous research. Within antinociceptive brain regions, including the dorsolateral prefrontal cortex (r = 0.81, P < 0.001) and multiple regions of the anterior cingulate cortex (all r > 0.67; all P < 0.02), reduced MOR availability was associated with decreased pain-evoked neural activity. Additionally, reduced MOR availability was associated with lower brain activation in the nucleus accumbens (r = 0.47, P = 0.050). In many of these regions, pain-evoked activity and MOR binding potential were also associated with lower clinical affective pain ratings. These findings are the first to link endogenous opioid system tone to regional pain-evoked brain activity in a clinical pain population. Our data suggest that dysregulation of the endogenous opioid system in FM could lead to less excitation in antinociceptive brain regions by incoming noxious stimulation, resulting in the hyperalgesia and allodynia commonly observed in this population. We propose a conceptual model of affective pain dysregulation in FM.

Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors

PubMed Central

Hipólito, Lucia; Wilson-Poe, Adrianne; Campos-Jurado, Yolanda; Zhong, Elaine; Gonzalez-Romero, Jose; Virag, Laszlo; Whittington, Robert; Comer, Sandra D.; Carlton, Susan M.; Walker, Brendan M.; Bruchas, Michael R.

2015-01-01

Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes. SIGNIFICANCE STATEMENT This study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between inflammatory pain and opioid abuse liability, and should help to facilitate the development of novel and safer opioid-based strategies for treating chronic pain. PMID:26338332

Prevalence of antibiotic prescription in pediatric outpatients in Italy: the role of local health districts and primary care physicians in determining variation. A multilevel design for healthcare decision support.

PubMed

Di Martino, Mirko; Lallo, Adele; Kirchmayer, Ursula; Davoli, Marina; Fusco, Danilo

2017-11-17

According to scientific literature, antibacterials are prescribed for common pediatric conditions that do not benefit from antibiotic therapy. The link between antibiotic use and bacterial resistance is well known. Antibiotic overprescribing generates high social costs and severe consequences for children. Our objectives were to analyze antibiotic prescription patterns in pediatric outpatients residing in the Lazio region (Italy), to identify physicians' characteristics associated with increased propensity for prescription, to identify the priority axes for action to improve the rational use of antibiotics. We enrolled all children aged 13 years or less in 2014. Antibiotic prescription patterns were analyzed during a one-year follow-up period. The main outcome measures were the antibiotic prescription prevalence, and the geographic variation in antibiotic prescribing. Multilevel models were performed to analyze variation. Variation was expressed as Median Odds Ratios (MORs). If the MOR is 1.00, there is no variation between clusters. If there is considerable between-cluster variation, the MOR will be large. We enrolled 636,911 children. Most of them were aged 6-13 years (57.3%). In 2015, the antibiotic prescription prevalence was 46% in the 0-13, 58% in the 0-5, and 37% in the 6-13 age group. Overall, penicillins were the most prescribed antibiotics, their consumption increased from 43% to 52% during the 2007-2015 period. In 2015, the antibiotic prescription prevalence ranged from 30% to 62% across local health districts (LHDs) of the region. Moreover, a significant (p < 0.001) variation was observed between physicians working in the same LHD: MORs were equal to 1.52 (1.48-1.56) and 1.46 (1.44-1.48) in the 0-5 and 6-13 age groups, respectively. The probability of prescribing antibiotics was significantly (p < 0.001) lower for more-experienced physicians. Pediatric antibiotic use in the Lazio region is much higher than in other European countries. The intra-regional drug prescribing variability underlines the lack of therapeutic protocols shared at regional level and raises equity issues in access to optimal care. Both LHD managers and individual physicians should be involved in training interventions to improve the targeted use of antibiotics and mitigate the effect of contextual variables, such as the spatial-related socioeconomic status of the patient/parent binomial.

Direct nuclear magnetic resonance observation of odorant binding to mouse odorant receptor MOR244-3.

PubMed

Burger, Jessica L; Jeerage, Kavita M; Bruno, Thomas J

2016-06-01

Mammals are able to perceive and differentiate a great number of structurally diverse odorants through the odorant's interaction with odorant receptors (ORs), proteins found within the cell membrane of olfactory sensory neurons. The natural gas industry has used human olfactory sensitivity to sulfur compounds (thiols, sulfides, etc.) to increase the safety of fuel gas transport, storage, and use through the odorization of this product. In the United States, mixtures of sulfur compounds are used, but the major constituent of odorant packages is 2-methylpropane-2-thiol, also known as tert-butyl mercaptan. It has been fundamentally challenging to understand olfaction and odorization due to the low affinity of odorous ligands to the ORs and the difficulty in expressing a sufficient number of OR proteins. Here, we directly observed the binding of tert-butyl mercaptan and another odiferous compound, cis-cyclooctene, to mouse OR MOR244-3 on living cells by saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy. This effort lays the groundwork for resolving molecular mechanisms responsible for ligand binding and resulting signaling, which in turn will lead to a clearer understanding of odorant recognition and competition. Published by Elsevier Inc.

Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment.

PubMed

Hendriksz, Christian; Santra, Saikat; Jones, Simon A; Geberhiwot, Tarekegn; Jesaitis, Lynne; Long, Brian; Qi, Yulan; Hawley, Sara M; Decker, Celeste

2018-04-01

Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced ≥1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

On the global distribution of hydrothermal vent fields: One decade later

NASA Astrophysics Data System (ADS)

Beaulieu, S. E.; Baker, E. T.; German, C. R.

2012-12-01

Since the last global compilation one decade ago, the known number of active submarine hydrothermal vent fields has almost doubled. At the end of 2009, a total of 518 active vent fields was catalogued, with about half (245) visually confirmed and others (273) inferred active at the seafloor. About half (52%) of these vent fields are at mid-ocean ridges (MORs), 25% at volcanic arcs, 21% at back-arc spreading centers (BASCs), and 2% at intra-plate volcanoes and other settings. One third are in high seas, and the nations with the most known active vent fields within EEZs are Tonga, USA, Japan, and New Zealand. The increase in known vent fields reflects a number of factors, including increased national and commercial interests in seafloor hydrothermal deposits as mineral resources. Here, we have comprehensively documented the percentage of strike length at MORs and BASCs that has been systematically explored for hydrothermal activity. As of the end of 2009, almost 30% of the ~60,000 km of MORs had been surveyed at least with spaced vertical profiles to detect hydrothermal plumes. A majority of the vents discovered at MORs in the past decade occurred at segments with < 60 mm/yr full spreading rate. Discoveries at ultra-slow MORs in the past decade included the deepest known vent (Beebe at Mid-Cayman Rise) and high-temperature black smoker vents (e.g., Dragon at SWIR and Loki's Castle at Mohns Ridge), and the highest temperature vent was measured at the slow-spreading S MAR (Turtle Pits). Using a previously published equation for the linear relationship between the number of active vent fields per 100 km strike length (F_s) vs. weighted-average full spreading rate (u_s), we predicted 676 vent fields remaining to be discovered at MORs. Even accounting for the lower F_s at slower spreading rates, almost half of the vents that are predicted remaining to be discovered at MORs are at ultra-slow to slow spreading rates (< 40 mm/yr) and about 1/3 at intermediate rates (40-80 mm/yr). MOR regions that are little explored tend to be at high latitudes, such as the ultra-slow to slow spreading Arctic MORs (e.g., Kolbeinsey and Mohns Ridges), the ultra-slow American-Antarctic Ridge, and the intermediate spreading Pacific-Antarctic Ridge. Although a greater percentage of the ~11,000 km of BASCs has been surveyed for hydrothermal activity, the discoveries at BASCs in the past decade were mainly at segments with intermediate to fast spreading rates. Using the same equation for F_s vs. u_s, we predicted 71 vent fields remaining to be discovered at BASCs, and most are likely to be found at ultra-slow and slow spreading segments (e.g., Andaman Basin, and central to northern Mariana Trough). With 2/3 of our overall predicted total vent fields at spreading ridges remaining to be discovered, we expect that the next decade of exploration will continue to yield new discoveries, leading to new insights into biogeography of vent fauna and the global impacts of fluxes of heat and materials from vents into our oceans.

Local analgesic effect of tramadol is mediated by opioid receptors in late postoperative pain after plantar incision in rats.

PubMed

de Oliveira Junior, José Oswaldo; de Freitas, Milena Fernandes; Bullara de Andrade, Carolina; Chacur, Marucia; Ashmawi, Hazem Adel

2016-01-01

Tramadol is a drug used to treat moderate to severe pain. It is known to present a peripheral effect, but the local mechanisms underlying its actions remain unclear. The role of peripheral opioid receptors in postoperative pain is not well understood. In the present study, we examined the peripheral opioid receptors to determine the local effect of tramadol in a plantar incision pain model. Rats were subjected to plantar incision and divided into four groups on postoperative day (POD) 1: SF_SF, 0.9% NaCl injected into the right hindpaw; SF_TraI, 0.9% NaCl and tramadol injected into the right hindpaw; SF_TraC, 0.9% NaCl and tramadol injected into the contralateral hindpaw; and Nal_Tra, naloxone and tramadol injected into the ipsilateral hindpaw. To determine the animals' nociceptive threshold, mechanical hyperalgesia was measured before incision, on POD1 before treatment and at 15, 30, 45, and 60 minutes after the incision. The same procedure was repeated on the POD2. The expression levels of μ-opioid receptor (MOR) and δ-opioid receptor (DOR) were obtained through immunoblotting assays in the lumbar dorsal root ganglia (L3-L6) in naïve rats and 1, 2, 3, and 7 days after the incision. Our results showed that the plantar incision was able to cause an increase in mechanical hyperalgesia and that tramadol reversed this hyperalgesia on POD1 and POD2. Tramadol injections in the contralateral paw did not affect the animals' nociceptive threshold. Naloxone was able to antagonize the tramadol effect partially on POD1 and completely on POD2. The DOR expression increased on POD2, POD3, and POD7, whereas the MOR expression did not change. Together, our results show that tramadol promoted a local analgesic effect in the postoperative pain model that was antagonized by naloxone in POD2, alongside the increase of DOR expression.

Adiponectin Enhances the Responsiveness of the Olfactory System

PubMed Central

Loch, Diana; Heidel, Christian; Breer, Heinz; Strotmann, Jörg

2013-01-01

The peptide hormone adiponectin is secreted by adipose tissue and the circulating concentration is reversely correlated with body fat mass; it is considered as starvation signal. The observation that mature sensory neurons of the main olfactory epithelium express the adiponectin receptor 1 has led to the concept that adiponectin may affect the responsiveness of the olfactory system. In fact, electroolfactogram recordings from olfactory epithelium incubated with exogenous adiponectin resulted in large amplitudes upon odor stimulation. To determine whether the responsiveness of the olfactory sensory neurons was enhanced, we have monitored the odorant-induced expression of the immediate early gene Egr1. It was found that in an olfactory epithelium incubated with nasally applied adiponectin the number of Egr1 positive cells was significantly higher compared to controls, suggesting that adiponectin rendered the olfactory neurons more responsive to an odorant stimulus. To analyze whether the augmented responsiveness of sensory neurons was strong enough to elicit a higher neuronal activity in the olfactory bulb, the number of activated periglomerular cells of a distinct glomerulus was determined by monitoring the stimulus-induced expression of c-fos. The studies were performed using the transgenic mOR256-17-IRES-tauGFP mice which allowed to visualize the corresponding glomerulus and to stimulate with a known ligand. The data indicate that upon exposure to 2,3-hexanedione in adiponectin-treated mice the number of activated periglomerular neurons was significantly increased compared to controls. The results of this study indicate that adiponectin increases the responsiveness of the olfactory system, probably due to a higher responsiveness of olfactory sensory neurons. PMID:24130737

Demonstrate Scale-up Procedure for Glass Composite Material (GCM) for Incorporation of Iodine Loaded AgZ.

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

Nenoff, Tina M.; Garino, Terry J.; Croes, Kenneth James

2015-07-01

Two large size Glass Composite Material (GCM) waste forms containing AgI-MOR were fabricated. One contained methyl iodide-loaded AgI-MOR that was received from Idaho National Laboratory (INL, Test 5, Beds 1 – 3) and the other contained iodine vapor loaded AgIMOR that was received from Oak Ridge National Laboratory (ORNL, SHB 2/9/15 ). The composition for each GCM was 20 wt% AgI-MOR and 80 wt% Ferro EG2922 low sintering temperature glass along with enough added silver flake to prevent any I2 loss during the firing process. The silver flake amounts were 1.2 wt% for the GCM with the INL AgI-MOR andmore » 3 wt% for the GCM contained the ORNL AgI-MOR. The GCMs, nominally 100 g, were first uniaxially pressed to 6.35 cm (2.5 inch) diameter disks then cold isostatically pressed, before firing in air to 550°C for 1hr. They were cooled slowly (1°C/min) from the firing temperature to avoid any cracking due to temperature gradients. The final GCMs were ~5 cm in diameter (~2 inches) and non-porous with densities of ~4.2 g/cm³. X-ray diffraction indicated that they consisted of the amorphous glass phase with small amounts of mordenite and AgI. Furthermore, the presence of the AgI was confirmed by X-ray fluorescence. Methodology for the scaled up production of GCMs to 6 inch diameter or larger is also presented.« less

Molecular interactions of alcohols with zeolite BEA and MOR frameworks.

PubMed

Stückenschneider, Kai; Merz, Juliane; Schembecker, Gerhard

2013-12-01

Zeolites can adsorb small organic molecules such as alcohols from a fermentation broth. Also in the zeolite-catalyzed conversion of alcohols to biofuels, biochemicals, or gasoline, adsorption is the first step. Several studies have investigated the adsorption of alcohols in different zeolites experimentally, but computational investigations in this field have mostly been restricted to zeolite MFI. In this study, the adsorption of C1-C4 alcohols in BEA and MOR was investigated using density functional theory (DFT). Calculated adsorption geometries and the corresponding energies of the designed cluster models were comparable to periodic calculations, and the adsorption energies were in the same range as the corresponding computational and experimental values reported in the literature for zeolite MFI. Thus, BEA and MOR may be good adsorption materials for alcohols in the field of downstream processing and catalysis. Aside from the DFT calculations, adsorption isotherms were determined experimentally in this study from aqueous solutions. For BEA, the adsorption of significant amounts of alcohol from aqueous solution was observed experimentally. In contrast, MOR was loaded with only a very small amount of alcohol. Although differences were found between the affinities obtained from gas-phase DFT calculations and those observed experimentally in aqueous solution, the computational data presented here represent molecular level information on the geometries and energies of C1-C4 alcohols adsorbed in zeolites BEA and MOR. This knowledge should prove very useful in the design of zeolite materials intended for use in adsorption and catalytic processes, as it allows adsorption behavior to be predicted via judiciously designed computational models.

Interacting Cannabinoid and Opioid Receptors in the Nucleus Accumbens Core Control Adolescent Social Play

PubMed Central

Manduca, Antonia; Lassalle, Olivier; Sepers, Marja; Campolongo, Patrizia; Cuomo, Vincenzo; Marsicano, Giovanni; Kieffer, Brigitte; Vanderschuren, Louk J. M. J; Trezza, Viviana; Manzoni, Olivier J. J.

2016-01-01

Social play behavior is a highly rewarding, developmentally important form of social interaction in young mammals. However, its neurobiological underpinnings remain incompletely understood. Previous work has suggested that opioid and endocannabinoid neurotransmission interact in the modulation of social play. Therefore, we combined behavioral, pharmacological, electrophysiological, and genetic approaches to elucidate the role of the endocannabinoid 2-arachidonoylglycerol (2-AG) in social play, and how cannabinoid and opioid neurotransmission interact to control social behavior in adolescent rodents. Systemic administration of the 2-AG hydrolysis inhibitor JZL184 or the opioid receptor agonist morphine increased social play behavior in adolescent rats. These effects were blocked by systemic pretreatment with either CB1 cannabinoid receptor (CB1R) or mu-opioid receptor (MOR) antagonists. The social play-enhancing effects of systemic morphine or JZL184 treatment were also prevented by direct infusion of the CB1R antagonist SR141716 and the MOR antagonist naloxone into the nucleus accumbens core (NAcC). Searching for synaptic correlates of these effects in adolescent NAcC excitatory synapses, we observed that CB1R antagonism blocked the effect of the MOR agonist DAMGO and, conversely, that naloxone reduced the effect of a cannabinoid agonist. These results were recapitulated in mice, and completely abolished in CB1R and MOR knockout mice, suggesting that the functional interaction between CB1R and MOR in the NAcC in the modulation of social behavior is widespread in rodents. The data shed new light on the mechanism by which endocannabinoid lipids and opioid peptides interact to orchestrate rodent socioemotional behaviors. PMID:27899885

Relationships of density, microfibril angle, and sound velocity with stiffness and strength in mature wood of Douglas-fir

Treesearch

B. Lachenbruch; G.R. Johnson; G.M. Downes; R. Evans

2010-01-01

The relative importance of density, acoustic velocity, and microfibril angle (MFA) for the prediction of stiffness (MOE) and strength (MOR) has not been well established for Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco). MOE and MOR of small clear specimens of mature wood were better predicted by density and velocity than by either variable...

Graphene decorated with mu-opioid receptor: the ionic screening effect and detection of enkephalin

NASA Astrophysics Data System (ADS)

Ping, Jinglei; Johnson, A. T. Charlie; Liu, Renyu; A. T. Charlie Johnson Team; Renyu Liu Collaboration

2015-03-01

We investigated the properties of graphene field effect transistors (GFETs) decorated with a computaionally redesigned, water-soluble variant of the human mu-opioid receptor (wsMOR) in physiological buffer solution. The shift of the Fermi level in the GFETs is quantitatively described by chemical-gating effect of charges on the wsMOR that are screened by the ionic solution. Our results suggest that sensitivity to the molecular target is lost when the Debye screening length of the solution is shorter than the distance from the graphene to the wsMOR; thus de-salting may be necessary when wsMOR decorated GFETs are used as biosensors in solution. We used this insight to detect DAMGO, a synthetic analog to the endogenous opioid peptide encephalin, at a concentration of 10 pM (5.1 pg/mL) in artificial cerebrospinal fluid (aCSF) diluted to 5% of its normal salt concentration. When the sensors were measured in a dry state, the limit of detection for DAGMO was 1 pM (0.5 pg/mL), one-third of the baseline in human body.Funding for this work was provided by DARPA.

Numerical Analysis of the Bending Properties of Cathay Poplar Glulam

PubMed Central

Gao, Ying; Wu, Yuxuan; Zhu, Xudong; Zhu, Lei; Yu, Zhiming; Wu, Yong

2015-01-01

This paper presents the formulae and finite element analysis models for predicting the Modulus of Elastic (MOE) and Modulus of Rupture (MOR) of Cathay poplar finger-jointed glulam. The formula of the MOE predicts the MOE of Cathay poplar glulam glued with one-component polyurethane precisely. Three formulae are used to predict the MOR, and Equation (12) predicts the MOR of Cathay poplar glulam precisely. The finite element analysis simulation results of both the MOE and MOR are similar to the experimental results. The predicted results of the finite element analysis are shown to be more accurate than those of the formulae, because the finite element analysis considers the glue layers, but the formulae do not. Three types of typical failure modes due to bending were summarized. The bending properties of Cathay poplar glulam were compared to those of Douglas fir glulam. The results show that Cathay poplar glulam has a lower stiffness, but a marginally higher strength. One-component polyurethane adhesive is shown to be more effective than resorcinol formaldehyde resin adhesive for Cathay poplar glulam. This study shows that Cathay poplar has the potential to be a glulam material in China. PMID:28793619

Platinum-ruthenium nanotubes and platinum-ruthenium coated copper nanowires as efficient catalysts for electro-oxidation of methanol

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

Zheng, Jie; Cullen, David A.; Forest, Robert V.

2015-01-15

The sluggish kinetics of methanol oxidation reaction (MOR) is a major barrier to the commercialization of direct methanol fuel cells (DMFCs). In this study, we report a facile synthesis of platinum–ruthenium nanotubes (PtRuNTs) and platinum–ruthenium-coated copper nanowires (PtRu/CuNWs) by galvanic displacement reaction using copper nanowires as a template. The PtRu compositional effect on MOR is investigated; the optimum Pt/Ru bulk atomic ratio is about 4 and surface atomic ratio about 1 for both PtRuNTs and PtRu/CuNWs. Enhanced specific MOR activities are observed on both PtRuNTs and PtRu/CuNWs compared with the benchmark commercial carbon-supported PtRu catalyst (PtRu/C, Hispec 12100). Finally, x-raymore » photoelectron spectroscopy (XPS) reveals a larger extent of electron transfer from Ru to Pt on PtRu/CuNWs, which may lead to a modification of the d-band center of Pt and consequently a weaker bonding of CO (the poisoning intermediate) on Pt and a higher MOR activity on PtRu/CuNWs.« less

Occupational risks for idiopathic pulmonary fibrosis mortality in the United States.

PubMed

Pinheiro, Germania A; Antao, Vinicius C; Wood, John M; Wassell, James T

2008-01-01

Metal and wood dust exposures have been identified as possible occupational risk factors for idiopathic pulmonary fibrosis (IPF). We analyzed mortality data using ICD-10 code J84.1--"Other interstitial pulmonary diseases with fibrosis," derived age-adjusted mortality rates for 1999-2003, and assessed occupational risks for 1999, by calculating proportionate mortality ratios (PMRs) and mortality odds ratios (MORs) using a matched case-control approach. We identified 84,010 IPF deaths, with an age-adjusted mortality rate of 75.7 deaths/million. Mortality rates were highest among males, whites, and those aged 85 and older. Three industry categories with potential occupational exposures recognized as risk factors for IPF were identified: "Wood buildings and mobile homes" (PMR = 4.5, 95% confidence interval (CI) 1.2-11.6 and MOR = 5.3, 95% CI 1.2-23.8), "Metal mining" (PMR = 2.4, 95% CI 1.3-4.0 and MOR = 2.2, 95% CI 1.1-4.4), and "Fabricated structural metal products" (PMR = 1.9, 95% CI 1.1-3.1 and MOR = 1.7, 95% CI 1.0-3.1). Workers in these industry categories may benefit from toxicological studies and improved surveillance for this disease.

14-Amino-4,5-Epoxymorphinan Derivatives and Their Pharmacological Actions

NASA Astrophysics Data System (ADS)

Lewis, John W.; Husbands, Stephen M.

14-Hydroxy-7,8-dihydromorphinone (oxymorphone) and its derivatives (oxycodone, naloxone, naltrexone) have become among the most important clinical agents to have been produced from opium. 14-Aminocodeinone and its 7,8-dihydro and morphinone derivatives are of more recent origin thanks to the work of Professor Gordon Kirby and his collaborators. The 14-amino parent compounds have proved of limited interest but their 14-acylamino- and 14-alkylamino derivatives have been extensively studied. The 4'-substituted cinnamoylamino-17-cyclopropylmethyl-7,8-dihydronormorphinones, C-CAM and M-CAM are the best available selective MOR irreversible antagonists and the related dihydrocodeinone MC-CAM, 4'-chlorocinnamoylamino-17-cyclopropylmethyl-7,8-dihydronorcodeinone, is a long-acting MOR partial agonist with extended MOR-pseudoirreversible antagonist activity that could be a candidate for pharmacotherapy of opiate abuse/dependence.

Comparison of nondestructive testing methods for evaluating No. 2 Southern Pine lumber: Part B, modulus of rupture

Treesearch

B.Z. Yang; R.D. Seale; R. Shmulsky; J. Dahlen; X. Wang

2017-01-01

The identification of strength-reducing characteristics that impact modulus of rupture (MOR) is a key differentiation between lumber grades. Because global design values for MOR are at the fifth percentile level and in-grade lumber can be highly variable, it is important that nondestructive evaluation technology be used to better discern the potential wood strength. In...

Maritime Mass Rescue Interventions: Availability and Associated Technology

DTIC Science & Technology

2010-12-01

MOR Liferaft Description: The Zodiac MOR (Means of Rescue) was specially developed to meet the latest requirements introduced for Roll On/Roll Off...Mass Rescue Interventions; Availability and Associated Technology NOTICE This document is disseminated under the sponsorship of the Department of...Homeland Security in the interest of information exchange. The United States Government assumes no liability for its contents or use thereof. The

Statistical models for the distribution of modulus of elasticity and modulus of rupture in lumber with implications for reliability calculations

Treesearch

Steve P. Verrill; Frank C. Owens; David E. Kretschmann; Rubin Shmulsky

2017-01-01

It is common practice to assume that a two-parameter Weibull probability distribution is suitable for modeling lumber properties. Verrill and co-workers demonstrated theoretically and empirically that the modulus of rupture (MOR) distribution of visually graded or machine stress rated (MSR) lumber is not distributed as a Weibull. Instead, the tails of the MOR...

Follow-Up Care for Older Women With Breast Cancer

DTIC Science & Technology

1999-08-01

range of patient outcomes, including primary tumor therapy and mortality, self -reported upper body function, and overall physical function. Methods...mor therapy, all cause mortality, self -reported function and overall physical function than upper body function, and overall physical was the interview...Major Analytic Variables mor therapy and all cause mortality, as well as self -reported upper body and overall physical Dependent Variables. Our first

Draft Genome Sequence of Arthrobacter chlorophenolicus Strain Mor30.16, Isolated from the Bean Rhizosphere.

PubMed

Miranda-Ríos, José Antonio; Ramírez-Trujillo, José Augusto; Nova-Franco, Bárbara; Lozano-Aguirre Beltrán, Luis Fernando; Iturriaga, Gabriel; Suárez-Rodríguez, Ramón

2015-05-07

Bacteria of the genus Arthrobacter are commonly found in the soil and plant rhizosphere. In this study we report the draft genome of Arthrobacter chlorophenolicus strain Mor30.16 that was isolated from rhizosphere of beans grown in Cuernavaca Morelos, Mexico. This strain promotes growth and ameliorates drought stress in bean plants. Copyright © 2015 Miranda-Ríos et al.

Welding occupations and mortality from Parkinson's disease and other neurodegenerative diseases among United States men, 1985-1999.

PubMed

Stampfer, Meir J

2009-05-01

Metal welding produces gaseous fumes that contain manganese, resulting in potential occupational exposure to welders. It has been hypothesized that occupational exposure among welders could increase risk of Parkinson's disease and other neurodegenerative diseases. The present study examines welding occupation and mortality from neurodegenerative diseases among men in the United States using the National Cause of Death databases 1985 to 1999. Information was abstracted from death certificates for states that collected data on occupation. Of 4,252,490 men who died during the study period, 107,773 had welding-related occupations. Multivariable logistic regression models were used to calculate mortality odds ratios (MOR) and 95% confidence intervals (CI) for odds of dying from Parkinson's disease or other neurodegenerative diseases among men who were welders as compared with men of other occupations, adjusting for attained age, race, region of residence, and year of death. During the study period, 49,174 deaths were attributed to Parkinson's disease, 54,892 to Alzheimer's disease, and 19,018 to presenile dementia. There was no evidence of an increased odds of Parkinson's disease mortality among welders as compared with men with other occupations (MOR = 0.83, 95% CI 0.78-0.88). Furthermore, welding occupation was unrelated to the odds of mortality from Alzheimer's disease (MOR = 0.94, 95% CI 0.89-1.00) or presenile dementia (MOR = 0.96, 95% CI 0.87-1.06). Earlier research suggested that welding exposures could predispose individuals to earlier onset Parkinson's disease. However, there was no evidence in this data of an increased mortality odds ratio associated with welding occupations among men younger than 65 (MOR = 1.03, 95% CI 0.74-1.44); while there was a suggestion of a lower odds Parkinson's disease death among men age 65 years and older (MOR = 0.82, 95% CI 0.77-0.88). Data from this large study do not support an association between welding occupations and death from Parkinson's disease or other neurodegenerative diseases, nor that welders are at increased odds of dying from Parkinson's disease at a younger age.

Sub-4 nm PtZn Intermetallic Nanoparticles for Enhanced Mass and Specific Activities in Catalytic Electrooxidation Reaction

DOE PAGES

Qi, Zhiyuan; Xiao, Chaoxian; Liu, Cong; ...

2017-03-08

Atomically ordered intermetallic nanoparticles (iNPs) have sparked considerable interest in fuel cell applications by virtue of their exceptional electronic and structural properties. However, the synthesis of small iNPs in a controllable manner remains a formidable challenge because of the high temperature generally required in the formation of intermetallic phases. Here in this paper we report a general method for the synthesis of PtZn iNPs (3.2 ± 0.4 nm) on multiwalled carbon nanotubes (MWNT) via a facile and capping agent free strategy using a sacrificial mesoporous silica (mSiO 2) shell. The as-prepared PtZn iNPs exhibited ca. 10 times higher mass activitymore » in both acidic and basic solution toward the methanol oxidation reaction (MOR) compared to larger PtZn iNPs synthesized on MWNT without the mSiO 2 shell. Density functional theory (DFT) calculations predict that PtZn systems go through a “non-CO” pathway for MOR because of the stabilization of the OH* intermediate by Zn atoms, while a pure Pt system forms highly stable COH* and CO* intermediates, leading to catalyst deactivation. Experimental studies on the origin of the backward oxidation peak of MOR coincide well with DFT predictions. Moreover, the calculations demonstrate that MOR on smaller PtZn iNPs is energetically more favorable than larger iNPs, due to their high density of corner sites and lower-lying energetic pathway. Therefore, smaller PtZn iNPs not only increase the number but also enhance the activity of the active sites in MOR compared with larger ones. This work opens a new avenue for the synthesis of small iNPs with more undercoordinated and enhanced active sites for fuel cell applications.« less

Differential cardiorespiratory effects of endomorphin 1, endomorphin 2, DAMGO, and morphine.

PubMed

Czapla, M A; Gozal, D; Alea, O A; Beckerman, R C; Zadina, J E

2000-09-01

The novel endogenous mu-opioid receptor (MOR) agonists endomorphin 1 (EM1) and 2 (EM2) were tested for their cardiorespiratory effects in conscious, freely behaving rats. After systemic (intravenous) administration of EM1, EM2, or the selective MOR agonist DAMGO, analgesia, minute ventilation (V E), heart rate (HR) and mean arterial blood pressure (BP) were measured. The threshold dose for analgesia was similar for all 3 peptides ( approximately 900 nmol/kg). All 3 compounds elicited biphasic V E responses, with marked, short-lived V E depressions (4-6 s) followed by more sustained V E increases (10-12 min). However, compared with responses elicited by EM2 or DAMGO, EM1 decreased V E only at higher doses, and produced greater V E stimulation. Morphine produced a V E decrease, but no subsequent V E increase. EM2 and DAMGO decreased HR and BP, while EM1 decreased HR, but did not decrease BP in conscious rats at doses up to 9,600 nmol/kg. In anesthetized rats, all 3 peptides decreased HR and BP. The decreases in V E, HR, and BP were blocked by the MOR antagonist, naloxone HCI (NIx). Only the HR and BP responses, however, were blocked by naloxone-methiodide (MeNIx), indicating central mediation of V E responses and peripheral mediation of cardiovascular responses. We conclude that MOR-selective compounds vary in their cardiorespiratory response characteristics which could be linked to differential cellular actions. The results support the concept that the analgesic, respiratory, and cardiovascular effects of MOR agonists can be dissociated and that EM1-like compounds could provide the basis for novel, safer analgesics.

A tracer experiment to study flow paths of water in a forest soil

NASA Astrophysics Data System (ADS)

Feyen, H.; Wunderli, H.; Wydler, H.; Papritz, A.

1999-12-01

This contribution discusses a tracer experiment, which was performed to study the flow paths of water in a macroporous forest soil. The experiment was performed in the framework of a study on the cycling of nitrogen in forested Prealpine catchments, in which losses of nitrate from virtually pristine areas were observed. Two soil plots with distinct micro-topography and top-soil were investigated: a well drained mor humus on a mound and a wet muck humus in a small depression. To reveal the effect of the soil horizons on the flow regime, tracers were applied both onto the soil surface and injected into the sub-soil. Tracers injected directly into the gleyic sub-soil reached the outlet (at a distance of 3.3 m) about 1000 times faster than could be expected from the saturated hydraulic conductivity of the soil matrix. Peak concentrations were observed after 18 (muck humus, tracer recovery 31%) to 70 min (mor humus, tracer recovery 40%). The peak concentration was 10 times smaller on the drier mor humus plot as compared to the muck humus. The mobile water content of the sub-soil varied between 0.5 (muck humus) and 1.3% (mor humus) of the total available soil water. The discrepancy in residence time, peak concentration and volume of mobile water between both sub-soils can be attributed to the differently structured sub-soil (longer travel distance and mixing volume in the drier mor humus). Tracers applied onto the soil surface resulted in a much slower breakthrough (tracer peaks after 400-700 min). Thus, in contrast to the sub-soil, flow through the matrix was the predominating transport process in the upper humus layers of both plots.

μ-Opioid Receptor-Mediated Inhibition of Intercalated Neurons and Effect on Synaptic Transmission to the Central Amygdala.

PubMed

Blaesse, Peter; Goedecke, Lena; Bazelot, Michaël; Capogna, Marco; Pape, Hans-Christian; Jüngling, Kay

2015-05-13

The amygdala is a key region for the processing of information underlying fear, anxiety, and fear extinction. Within the local neuronal networks of the amygdala, a population of inhibitory, intercalated neurons (ITCs) modulates the flow of information among various nuclei of amygdala, including the basal nucleus (BA) and the centromedial nucleus (CeM) of the amygdala. These ITCs have been shown to be important during fear extinction and are target of a variety of neurotransmitters and neuropeptides. Here we provide evidence that the activation of μ-opioid receptors (MORs) by the specific agonist DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin) hyperpolarizes medially located ITCs (mITCs) in acute brain slices of mice. Moreover, we use whole-cell patch-clamp recordings in combination with local electrical stimulation or glutamate uncaging to analyze the effect of MOR activation on local microcircuits. We show that the GABAergic transmission between mITCs and CeM neurons is attenuated by DAMGO, whereas the glutamatergic transmission on CeM neurons and mITCs is unaffected. Furthermore, MOR activation induced by theta burst stimulation in BA suppresses plastic changes of feedforward inhibitory transmission onto CeM neurons as revealed by the MOR antagonist CTAP d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2. In summary, the mITCs constitute a target for the opioid system, and therefore, the activation of MOR in ITCs might play a central role in the modulation of the information processing between the basolateral complex of the amygdala and central nuclei of the amygdala. Copyright © 2015 Blaesse, Goedecke et al.

Risk factors for typhoid in Darjeeling, West Bengal, India: evidence for practical action.

PubMed

Sharma, Puran K; Ramakrishnan, R; Hutin, Y; Manickam, P; Gupte, M D

2009-06-01

To identify risk factors for typhoid and propose prevention measures. Case-control study; we compared hospital-based typhoid cases defined as fever>38 degrees C for >or=3 days with four-fold rise in 'O' antibodies on paired sera (Widal) with community, age and neighbourhood matched controls. We obtained information on drinking water, fruits, vegetables, milk products and sanitation; and calculated matched odds ratios (MOR) and attributable fractions in the population (AFP) for the risk factors or failure to use prevention measures. The 123 typhoid cases (median age: 25 years, 47% female) and 123 controls did not differ with respect to baseline characteristics. Cases were less likely to store drinking water in narrow-mouthed containers (MOR: 0.4, 95% CI: 0.2-0.7, AFP 29%), tip containers to draw water (MOR: 0.4, 95% CI: 0.2-0.7, AFP 33%) and have home latrines (MOR: 0.5, 95% CI: 0.3-0.8, AFP 23%). Cases were more likely to consume butter (OR: 2.3, 95% CI: 1.3-4.1, AFP 28%), yoghurt (OR: 2.3, 95% CI: 1.4-3.7, AFP 34%) and raw fruits and vegetables, including onions (MOR: 2.1, 95% CI: 1.2-3.9, AFP 34%), cabbages (OR: 2.8, 95% CI: 1.7-4.8, AFP 44%) and unwashed guavas (OR: 1.9, 95% CI: 1.2-3, AFP 25%). Typhoid was associated with unsafe water and sanitation practices as well as with consumption of milk products, fruits and vegetables. We propose to chlorinate drinking water at the point of use, wash/cook raw fruits and vegetables and ensure safer preparation/storage of local milk products.

Opiate agonist-induced re-distribution of Wntless, a mu-opioid receptor interacting protein, in rat striatal neurons.

PubMed

Reyes, B A S; Vakharia, K; Ferraro, T N; Levenson, R; Berrettini, W H; Van Bockstaele, E J

2012-01-01

Wntless (WLS), a mu-opioid receptor (MOR) interacting protein, mediates Wnt protein secretion that is critical for neuronal development. We investigated whether MOR agonists induce re-distribution of WLS within rat striatal neurons. Adult male rats received either saline, morphine or [d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) directly into the lateral ventricles. Following thirty minutes, brains were extracted and tissue sections were processed for immunogold silver detection of WLS. In saline-treated rats, WLS was distributed along the plasma membrane and within the cytoplasmic compartment of striatal dendrites as previously described. The ratio of cytoplasmic to total dendritic WLS labeling was 0.70±0.03 in saline-treated striatal tissue. Morphine treatment decreased this ratio to 0.48±0.03 indicating a shift of WLS from the intracellular compartment to the plasma membrane. However, following DAMGO treatment, the ratio was 0.85±0.05 indicating a greater distribution of WLS intracellularly. The difference in the re-distribution of the WLS following different agonist exposure may be related to DAMGO's well known ability to induce internalization of MOR in contrast to morphine, which is less effective in producing receptor internalization. Furthermore, these data are consistent with our hypothesis that MOR agonists promote dimerization of WLS and MOR, thereby preventing WLS from mediating Wnt secretion. In summary, our findings indicate differential agonist-induced trafficking of WLS in striatal neurons following distinct agonist exposure. Adaptations in WLS trafficking may represent a novel pharmacological target in the treatment of opiate addiction and/or pain. Copyright © 2011 Elsevier Inc. All rights reserved.

Endogenous Opioid Antagonism in Physiological Experimental Pain Models: A Systematic Review

PubMed Central

Werner, Mads U.; Pereira, Manuel P.; Andersen, Lars Peter H.; Dahl, Jørgen B.

2015-01-01

Opioid antagonists are pharmacological tools applied as an indirect measure to detect activation of the endogenous opioid system (EOS) in experimental pain models. The objective of this systematic review was to examine the effect of mu-opioid-receptor (MOR) antagonists in placebo-controlled, double-blind studies using ʻinhibitoryʼ or ʻsensitizingʼ, physiological test paradigms in healthy human subjects. The databases PubMed and Embase were searched according to predefined criteria. Out of a total of 2,142 records, 63 studies (1,477 subjects [male/female ratio = 1.5]) were considered relevant. Twenty-five studies utilized ʻinhibitoryʼ test paradigms (ITP) and 38 studies utilized ʻsensitizingʼ test paradigms (STP). The ITP-studies were characterized as conditioning modulation models (22 studies) and repetitive transcranial magnetic stimulation models (rTMS; 3 studies), and, the STP-studies as secondary hyperalgesia models (6 studies), ʻpainʼ models (25 studies), summation models (2 studies), nociceptive reflex models (3 studies) and miscellaneous models (2 studies). A consistent reversal of analgesia by a MOR-antagonist was demonstrated in 10 of the 25 ITP-studies, including stress-induced analgesia and rTMS. In the remaining 14 conditioning modulation studies either absence of effects or ambiguous effects by MOR-antagonists, were observed. In the STP-studies, no effect of the opioid-blockade could be demonstrated in 5 out of 6 secondary hyperalgesia studies. The direction of MOR-antagonist dependent effects upon pain ratings, threshold assessments and somatosensory evoked potentials (SSEP), did not appear consistent in 28 out of 32 ʻpainʼ model studies. In conclusion, only in 2 experimental human pain models, i.e., stress-induced analgesia and rTMS, administration of MOR-antagonist demonstrated a consistent effect, presumably mediated by an EOS-dependent mechanisms of analgesia and hyperalgesia. PMID:26029906

Sub-4 nm PtZn Intermetallic Nanoparticles for Enhanced Mass and Specific Activities in Catalytic Electrooxidation Reaction

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

Qi, Zhiyuan; Xiao, Chaoxian; Liu, Cong

2017-03-22

Atomically ordered intermetallic nanoparticles (iNPs) have sparked considerable interest in fuel cell applications by virtue of their exceptional electronic and structural properties. However, the synthesis of small iNPs in a controllable manner remains a formidable challenge because of the high temperature generally required in the formation of intermetallic phases. Here we report a general method for the synthesis of PtZn. iNPs (3.2 +/- 0.4 nm) on multiwalled carbon nanotubes (MWNT) via a facile and capping agent free strategy using a sacrificial mesoporous silica (mSiO(2)) shell. The as-prepared PtZn iNPs exhibited ca. 10 times higher mass activity in both acidic andmore » basic solution toward the methanol oxidation reaction (MOR) compared to larger PtZn iNPs synthesized on MWNT without the mSiO2 shell. Density functional theory (DFT) calculations predict that PtZn systems go through a "non-CO" pathway for MOR because of the stabilization of the OH* intermediate by Zn atoms, while a pure Pt system forms highly stable COH* and CO* intermediates, leading to catalyst deactivation. Experimental studies on the origin of the backward oxidation peak of MOR coincide well with DFT predictions. Moreover, the calculations demonstrate that MOR on smaller PtZn iNPs is energetically more favorable than larger iNPs, due to their high density of corner sites and lower-lying energetic pathway. Therefore, smaller PtZn iNPs not only increase the number but also enhance the activity of the active sites in MOR compared with larger ones. This work opens a new avenue for the synthesis of small iNPs with more undercoordinated and enhanced active sites for fuel cell applications.« less

Sulphur geodynamic cycle

PubMed Central

Kagoshima, Takanori; Sano, Yuji; Takahata, Naoto; Maruoka, Teruyuki; Fischer, Tobias P.; Hattori, Keiko

2015-01-01

Evaluation of volcanic and hydrothermal fluxes to the surface environments is important to elucidate the geochemical cycle of sulphur and the evolution of ocean chemistry. This paper presents S/3He ratios of vesicles in mid-ocean ridge (MOR) basalt glass together with the ratios of high-temperature hydrothermal fluids to calculate the sulphur flux of 100 Gmol/y at MOR. The S/3He ratios of high-temperature volcanic gases show sulphur flux of 720 Gmol/y at arc volcanoes (ARC) with a contribution from the mantle of 2.9%, which is calculated as 21 Gmol/y. The C/S flux ratio of 12 from the mantle at MOR and ARC is comparable to the C/S ratio in the surface inventory, which suggests that these elements in the surface environments originated from the upper mantle. PMID:25660256

Caged Naloxone Reveals Opioid Signaling Deactivation Kinetics

PubMed Central

Banghart, Matthew R.; Shah, Ruchir C.; Lavis, Luke D.

2013-01-01

The spatiotemporal dynamics of opioid signaling in the brain remain poorly defined. Photoactivatable opioid ligands provide a means to quantitatively measure these dynamics and their underlying mechanisms in brain tissue. Although activation kinetics can be assessed using caged agonists, deactivation kinetics are obscured by slow clearance of agonist in tissue. To reveal deactivation kinetics of opioid signaling we developed a caged competitive antagonist that can be quickly photoreleased in sufficient concentrations to render agonist dissociation effectively irreversible. Carboxynitroveratryl-naloxone (CNV-NLX), a caged analog of the competitive opioid antagonist NLX, was readily synthesized from commercially available NLX in good yield and found to be devoid of antagonist activity at heterologously expressed opioid receptors. Photolysis in slices of rat locus coeruleus produced a rapid inhibition of the ionic currents evoked by multiple agonists of the μ-opioid receptor (MOR), but not of α-adrenergic receptors, which activate the same pool of ion channels. Using the high-affinity peptide agonist dermorphin, we established conditions under which light-driven deactivation rates are independent of agonist concentration and thus intrinsic to the agonist-receptor complex. Under these conditions, some MOR agonists yielded deactivation rates that are limited by G protein signaling, whereas others appeared limited by agonist dissociation. Therefore, the choice of agonist determines which feature of receptor signaling is unmasked by CNV-NLX photolysis. PMID:23960100

Follow-Up Care for Older Women With Breast Cancer

DTIC Science & Technology

2000-05-01

better predictor of upper body mor therapy, all cause mortality, self -reported function and overall physical function than upper body function, and...outcomes, including primary tu- Major Analytic Variables mor therapy and all cause mortality, as well as self -reported upper body and overall physical ...comorbidity and their relation to a range of patient outcomes, including primary tumor therapy and mortality, self -reported upper body function, and overall

The Genomic Evolution of Prostate Cancer

DTIC Science & Technology

2017-06-01

This study is supported by the AACI Fellowship for Trans- lational Cancer Research and DOD Prostate Cancer Research Program PRTA (DVW) and the...degraded during post -mor- tem time before fixation, which is supported by the low quality of RNA from matched frozen tissue. A limitation of this study ...is that a portion of the study used autopsy specimens, which have already undergone some degree of post -mor- tem degradation prior to PAXgene and

The `One-Two Punch' of Alcoholism: Role of Central Amygdala Dynorphins / Kappa-Opioid Receptors

PubMed Central

Kissler, Jessica L.; Sirohi, Sunil; Reis, Daniel J.; Jansen, Heiko T.; Quock, Raymond M.; Smith, Daniel G.; Walker, Brendan M.

2013-01-01

Background The dynorphin (DYN)/κ-opioid receptor (KOR) system undergoes neuroadaptations following chronic alcohol exposure that promote excessive operant self-administration and negative affective-like states; however, the exact mechanisms are unknown. The present studies tested the hypothesis that an upregulated DYN/KOR system mediates excessive alcohol self-administration that occurs during withdrawal in alcohol-dependent rats by assessing DYN A peptide expression and KOR function, in combination with site-specific pharmacological manipulations. Methods Male Wistar rats were trained to self-administer alcohol using operant behavioral strategies and subjected to intermittent alcohol vapor- or air-exposure. Changes in self-administration were assessed by pharmacological challenges during acute withdrawal. In addition, 22-kHz ultrasonic vocalizations were utilized to measure negative affective-like states. Immunohistochemical techniques assessed DYN A peptide expression and [35S]GTPγS coupling assays were performed to assess KOR function. Results Alcohol-dependent rats displayed increased alcohol self-administration, negative affective-like behavior, DYN A-like immunoreactivity and KOR signaling in the amygdala compared to non-dependent controls. Site-specific infusions of a KOR antagonist selectively attenuated self-administration in dependent rats whereas, a MOR/DOR antagonist cocktail selectively reduced self-administration in non-dependent rats. A MOR antagonist/partial KOR agonist attenuated self-administration in both cohorts. Conclusion Increased DYN A and increased KOR signaling could set the stage for a `one-two punch' during withdrawal that drives excessive alcohol consumption in alcohol-dependence. Importantly, intra-CeA pharmacological challenges functionally confirmed a DYN/KOR system involvement in the escalated alcohol self-administration. Together, the DYN/KOR system is heavily dysregulated in alcohol dependence and contributes to the excessive alcohol consumption during withdrawal. PMID:23611261

Efficacy of Massachusetts and 793B Vaccines Against Infectious Bronchitis Moroccan-Italy 02 Virus in Specific-Pathogen-Free Chickens and Commercial Broilers.

PubMed

Belkasmi, Sakhia F Z; Fellahi, Siham; Umar, Sajid; Delpont, Mattias; Delverdier, Maxence; Lucas, Marie-Noëlle; Bleuart, Céline; Kichou, Faouzi; Nassik, Saâdia; Guerin, Jean-Luc; Fihri, Ouafaa Fassi; Ducatez, Mariette F; El Houadfi, Mohammed

2017-12-01

The ability of commercial vaccines H120 and 4/91 to protect against Moroccan-Italy 02 infectious bronchitis virus (Mor-It02) was investigated in specific-pathogen-free (SPF) chickens and commercial broiler chickens. Commercial broiler chicks (Experiment 1) were vaccinated at the hatchery with H120 vaccine at Day 1, and challenged at Day 21 with 10 4 50% egg-infective dose (EID 50 ) of Mor-It02. All chicks were observed daily for clinical signs attributable to Mor-It02 infection during the 10 days postchallenge (pc). At 5 and 10 days pc, chicks were humanely sacrificed for necropsy examination, and tissues were collected for histopathology evaluation. To better understand the findings on commercial broilers, day-old SPF chicks were divided into five groups in a second experiment: Group Mass/4-91, vaccinated with H120 and 4/91 respectively at Days 1 and 15 of age; Group Mass/Mass, vaccinated by H120 at Days 1 and 15; Group Mass, vaccinated with H120 at Day 1; Group NV, kept unvaccinated; and Group NC, kept as a negative control (unchallenged). At Day 24 of age, Groups Mass/4-91, Mass/Mass, Mass, and NV were challenged with 10 4 EID 50 of Mor-It02. In both experiments, blood samples were collected at different periods for serologic analyses. Oropharyngeal swabs were collected for virus detection by reverse-transcription PCR. In Experiments 1 and 2, respiratory signs started as early as 24 hr pc and maximum severity was observed on Days 3 and 4 pc. The viral shedding rate was significantly lower in Group Mass/4-91 compared to other challenged groups. Serologic analysis in both experiments showed that the sera of challenged group exhibited significantly higher antibody titers than sera collected before challenge. Histopathologic investigations in SPF birds showed deciliation and hyperplasia in Group NV and less-pronounced lesions in Groups Mass/Mass and Mass. In commercial broilers vaccinated with H120 alone, hyperplasia and deciliation were observed in 90% of the tracheas. These experiments illustrated that Mor-It02 is pathogenic for chickens and a combination of live H120 and 4/91 vaccines given respectively at Day 1 and Day 15 of age confer a good protection against Mor-It02.

Regional variation in wood modulus of elasticity (stiffness) and modulus of rupture (strength) of planted loblolly pine in the United States

Treesearch

Antony Finto; Lewis Jordan; Laurence R. Schimleck; Alexander Clark; Ray A. Souter; Richard F. Daniels

2011-01-01

Modulus of elasticity (MOE), modulus of rupture (MOR), and specific gravity (SG) are important properties for determining the end-use and value of a piece of lumber. This study addressed the variation in MOE, MOR, and SG with physiographic region, tree height, and wood type. Properties were measured from two static bending samples (dimensions 25.4 mm × 25.4 mm × 406.4...

Silver-mordenite for radiologic gas capture from complex streams. Dual catalytic CH 3I decomposition and I confinement

DOE PAGES

Nenoff, Tina M.; Rodriguez, Mark A.; Soelberg, Nick R.; ...

2014-05-09

The selective capture of radiological iodine ( 129I) is a persistent concern for safe nuclear energy. In these nuclear fuel reprocessing scenarios, the gas streams to be treated are extremely complex, containing several distinct iodine-containing molecules amongst a large variety of other species. Silver-containing mordenite (MOR) is a longstanding benchmark for radioiodine capture, reacting with molecular iodine (I 2) to form AgI. However the mechanisms for organoiodine capture is not well understood. Here we investigate the capture of methyl iodide from complex mixed gas streams by combining chemical analysis of the effluent gas stream with in depth characterization of themore » recovered sorbent. Tools applied include infrared spectroscopy, thermogravimetric analysis with mass spectrometry, micro X-ray fluorescence, powder X-ray diffraction analysis, and pair distribution function analysis. Moreover, the MOR zeolite catalyzes decomposition of the methyl iodide through formation of surface methoxy species (SMS), which subsequently reacts with water in the mixed gas stream to form methanol, and with methanol to form dimethyl ether, which are both detected downstream in the effluent. The liberated iodine reacts with Ag in the MOR pore to the form subnanometer AgI clusters, smaller than the MOR pores, suggesting that the iodine is both physically and chemically confined within the zeolite.« less

Rice straw-wood particle composite for sound absorbing wooden construction materials.

PubMed

Yang, Han-Seung; Kim, Dae-Jun; Kim, Hyun-Joong

2003-01-01

In this study, rice straw-wood particle composite boards were manufactured as insulation boards using the method used in the wood-based panel industry. The raw material, rice straw, was chosen because of its availability. The manufacturing parameters were: a specific gravity of 0.4, 0.6, and 0.8, and a rice straw content (10/90, 20/80, and 30/70 weight of rice straw/wood particle) of 10, 20, and 30 wt.%. A commercial urea-formaldehyde adhesive was used as the composite binder, to achieve 140-290 psi of bending modulus of rupture (MOR) with 0.4 specific gravity, 700-900 psi of bending MOR with 0.6 specific gravity, and 1400-2900 psi of bending MOR with a 0.8 specific gravity. All of the composite boards were superior to insulation board in strength. Width and length of the rice straw particle did not affect the bending MOR. The composite boards made from a random cutting of rice straw and wood particles were the best and recommended for manufacturing processes. Sound absorption coefficients of the 0.4 and 0.6 specific gravity boards were higher than the other wood-based materials. The recommended properties of the rice straw-wood particle composite boards are described, to absorb noises, preserve the temperature of indoor living spaces, and to be able to partially or completely substitute for wood particleboard and insulation board in wooden constructions.

Moringa oleifera Lam.: Protease activity against blood coagulation cascade

PubMed Central

Satish, A; Sairam, Sudha; Ahmed, Faiyaz; Urooj, Asna

2012-01-01

Background: The present study evaluated the protease activity of aqueous extracts of Moringa oleifera (Moringaceae) leaf (MOL) and root (MOR). Materials and Methods: Protease activity was assayed using casein, human plasma clot and human fibrinogen as substrates. Results: Caseinolytic activity of MOL was significantly higher (P ≤ 0.05) than that of MOR. Similar observations were found in case of human plasma clot hydrolyzing activity, wherein MOL caused significantly higher (P ≤ 0.05) plasma clot hydrolysis than MOR. Zymographic techniques were used to detect proteolytic enzymes following electrophoretic separation in gels. Further, both the extracts exhibited significant procoagulant activity as reflected by a significant decrease (P ≤ 0.05) in recalcification time, accompanied by fibrinogenolytic and fibrinolytic activities; clotting time was decreased from 180 ± 10 sec to 119 ± 8 sec and 143 ± 10 sec by MOL and MOR, respectively, at a concentration of 2.5 mg/mL. Fibrinogenolytic (human fibrinogen) and fibrinolytic activity (human plasma clot) was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), plate method and colorimetric method. Zymographic profile indicated that both the extracts exerted their procoagulant activity by selectively hydrolyzing Aα and Bβ subunits of fibrinogen to form fibrin clot, thereby exhibiting fibrinogenolytic activity. However, prolonged incubation resulted in degradation of the formed fibrin clot, suggesting fibrinolytic like activity. Conclusions: These findings support the traditional usage of M. oleifera extracts for wound healing. PMID:22224061

Moringa oleifera Lam.: Protease activity against blood coagulation cascade.

PubMed

Satish, A; Sairam, Sudha; Ahmed, Faiyaz; Urooj, Asna

2012-01-01

The present study evaluated the protease activity of aqueous extracts of Moringa oleifera (Moringaceae) leaf (MOL) and root (MOR). Protease activity was assayed using casein, human plasma clot and human fibrinogen as substrates. Caseinolytic activity of MOL was significantly higher (P ≤ 0.05) than that of MOR. Similar observations were found in case of human plasma clot hydrolyzing activity, wherein MOL caused significantly higher (P ≤ 0.05) plasma clot hydrolysis than MOR. Zymographic techniques were used to detect proteolytic enzymes following electrophoretic separation in gels. Further, both the extracts exhibited significant procoagulant activity as reflected by a significant decrease (P ≤ 0.05) in recalcification time, accompanied by fibrinogenolytic and fibrinolytic activities; clotting time was decreased from 180 ± 10 sec to 119 ± 8 sec and 143 ± 10 sec by MOL and MOR, respectively, at a concentration of 2.5 mg/mL. Fibrinogenolytic (human fibrinogen) and fibrinolytic activity (human plasma clot) was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), plate method and colorimetric method. Zymographic profile indicated that both the extracts exerted their procoagulant activity by selectively hydrolyzing Aα and Bβ subunits of fibrinogen to form fibrin clot, thereby exhibiting fibrinogenolytic activity. However, prolonged incubation resulted in degradation of the formed fibrin clot, suggesting fibrinolytic like activity. These findings support the traditional usage of M. oleifera extracts for wound healing.

How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways.

PubMed

Schneider, Sebastian; Provasi, Davide; Filizola, Marta

2016-11-22

Substantial attention has recently been devoted to G protein-biased agonism of the μ-opioid receptor (MOR) as an ideal new mechanism for the design of analgesics devoid of serious side effects. However, designing opioids with appropriate efficacy and bias is challenging because it requires an understanding of the ligand binding process and of the allosteric modulation of the receptor. Here, we investigated these phenomena for TRV-130, a G protein-biased MOR small-molecule agonist that has been shown to exert analgesia with less respiratory depression and constipation than morphine and that is currently being evaluated in human clinical trials for acute pain management. Specifically, we carried out multimicrosecond, all-atom molecular dynamics (MD) simulations of the binding of this ligand to the activated MOR crystal structure. Analysis of >50 μs of these MD simulations provides insights into the energetically preferred binding pathway of TRV-130 and its stable pose at the orthosteric binding site of MOR. Information transfer from the TRV-130 binding pocket to the intracellular region of the receptor was also analyzed, and was compared to a similar analysis carried out on the receptor bound to the classical unbiased agonist morphine. Taken together, these studies lead to a series of testable hypotheses of ligand-receptor interactions that are expected to inform the structure-based design of improved opioid analgesics.

Development of 5-Substituted N-Methylmorphinan-6-ones as Potent Opioid Analgesics with Improved Side-Effect Profile.

PubMed

Schmidhammer, Helmut; Spetea, Mariana

2012-01-01

One of the most important functions of the opioid system is the control of pain. Among the three main opioid receptor classes (μ, δ, κ), the μ (MOR) is the main type targeted for pharmacotherapy of pain. Opioid analgesics such as morphine, oxycodone and fentanyl are agonists at the MOR and are the mainstay for the treatment of moderate-to-severe pain. However, adverse effects related to opioid use are severe and often lead to early discontinuation and inadequate analgesia. The development of more effective and safer medications for the management of pain still remains a major direction in pharmaceutical research. Chemical approaches towards the identification of novel MOR analgesics with reduced side effects include structural modifications of 14-alkoxy-N-methylmorphinan-6-ones in key positions that are important for binding, selectivity, potency, and efficacy at opioid receptors. This paper describes a representative strategy to improve the therapeutic usefulness of opioid analgesics from the morphinan class of drugs by targeting position 5. The focus is on chemical and biological studies and structure-activity relationships of this series of ligands. We report on 14-alkoxymorphinan-6-ones having a methyl and benzyl group at position 5 as strong opioid antinociceptive agents with reduced propensity to cause undesired effects compared to morphine although interacting selectively with MORs.

Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine

PubMed Central

Garzón, Javier; de la Torre-Madrid, Elena; Rodríguez-Muñoz, María; Vicente-Sánchez, Ana; Sánchez-Blázquez, Pilar

2009-01-01

Background Although the systemic administration of cannabinoids produces antinociception, their chronic use leads to analgesic tolerance as well as cross-tolerance to morphine. These effects are mediated by cannabinoids binding to peripheral, spinal and supraspinal CB1 and CB2 receptors, making it difficult to determine the relevance of each receptor type to these phenomena. However, in the brain, the CB1 receptors (CB1Rs) are expressed at high levels in neurons, whereas the expression of CB2Rs is marginal. Thus, CB1Rs mediate the effects of smoked cannabis and are also implicated in emotional behaviors. We have analyzed the production of supraspinal analgesia and the development of tolerance at CB1Rs by the direct injection of a series of cannabinoids into the brain. The influence of the activation of CB1Rs on supraspinal analgesia evoked by morphine was also evaluated. Results Intracerebroventricular (icv) administration of cannabinoid receptor agonists, WIN55,212-2, ACEA or methanandamide, generated a dose-dependent analgesia. Notably, a single administration of these compounds brought about profound analgesic tolerance that lasted for more than 14 days. This decrease in the effect of cannabinoid receptor agonists was not mediated by depletion of CB1Rs or the loss of regulated G proteins, but, nevertheless, it was accompanied by reduced morphine analgesia. On the other hand, acute morphine administration produced tolerance that lasted only 3 days and did not affect the CB1R. We found that both neural mu-opioid receptors (MORs) and CB1Rs interact with the HINT1-RGSZ module, thereby regulating pertussis toxin-insensitive Gz proteins. In mice with reduced levels of these Gz proteins, the CB1R agonists produced no such desensitization or morphine cross-tolerance. On the other hand, experimental enhancement of Gz signaling enabled an acute icv administration of morphine to produce a long-lasting tolerance at MORs that persisted for more than 2 weeks, and it also impaired the analgesic effects of cannabinoids. Conclusion In the brain, cannabinoids can produce analgesic tolerance that is not associated with the loss of surface CB1Rs or their uncoupling from regulated transduction. Neural specific Gz proteins are essential mediators of the analgesic effects of supraspinal CB1R agonists and morphine. These Gz proteins are also responsible for the long-term analgesic tolerance produced by single doses of these agonists, as well as for the cross-tolerance between CB1Rs and MORs. PMID:19284549

High Tech High School Interns Develop a Mid-Ocean Ridge Database for Research and Education

NASA Astrophysics Data System (ADS)

Staudigel, D.; Delaney, R.; Staudigel, H.; Koppers, A. A.; Miller, S. P.

2004-12-01

Mid-ocean ridges (MOR) represent one of the most important geographical and geological features on planet Earth. MORs are the locations where plates spread apart, they are the locations of the majority of the Earths' volcanoes that harbor some of the most extreme life forms. These concepts attract much research, but mid-ocean ridges are still effectively underrepresented in the Earth science class rooms. As two High Tech High School students, we began an internship at Scripps to develop a database for mid-ocean ridges as a resource for science and education. This Ridge Catalog will be accessible via http://earthref.org/databases/RC/ and applies a similar structure, design and data archival principle as the Seamount Catalog under EarthRef.org. Major research goals of this project include the development of (1) an archival structure for multibeam and sidescan data, standard bathymetric maps (including ODP-DSDP drill site and dredge locations) or any other arbitrary digital objects relating to MORs, and (2) to compile a global data set for some of the most defining characteristics of every ridge segment including ridge segment length, depth and azimuth and half spreading rates. One of the challenges included the need of making MOR data useful to the scientist as well as the teacher in the class room. Since the basic structure follows the design of the Seamount Catalog closely, we could move our attention to the basic data population of the database. We have pulled together multibeam data for the MOR segments from various public archives (SIOExplorer, SIO-GDC, NGDC, Lamont), and pre-processed it for public use. In particular, we have created individual bathymetric maps for each ridge segment, while merging the multibeam data with global satellite bathymetry data from Smith & Sandwell (1997). The global scale of this database will give it the ability to be used for any number of applications, from cruise planning to data

Temperatures and cooling rates recorded in REE in coexisting pyroxenes in ophiolitic and abyssal peridotites

NASA Astrophysics Data System (ADS)

Dygert, Nick; Liang, Yan

2015-06-01

Mantle peridotites from ophiolites are commonly interpreted as having mid-ocean ridge (MOR) or supra-subduction zone (SSZ) affinity. Recently, an REE-in-two-pyroxene thermometer was developed (Liang et al., 2013) that has higher closure temperatures (designated as TREE) than major element based two-pyroxene thermometers for mafic and ultramafic rocks that experienced cooling. The REE-in-two-pyroxene thermometer has the potential to extract meaningful cooling rates from ophiolitic peridotites and thus shed new light on the thermal history of the different tectonic regimes. We calculated TREE for available literature data from abyssal peridotites, subcontinental (SC) peridotites, and ophiolites around the world (Alps, Coast Range, Corsica, New Caledonia, Oman, Othris, Puerto Rico, Russia, and Turkey), and augmented the data with new measurements for peridotites from the Trinity and Josephine ophiolites and the Mariana trench. TREE are compared to major element based thermometers, including the two-pyroxene thermometer of Brey and Köhler (1990) (TBKN). Samples with SC affinity have TREE and TBKN in good agreement. Samples with MOR and SSZ affinity have near-solidus TREE but TBKN hundreds of degrees lower. Closure temperatures for REE and Fe-Mg in pyroxenes were calculated to compare cooling rates among abyssal peridotites, MOR ophiolites, and SSZ ophiolites. Abyssal peridotites appear to cool more rapidly than peridotites from most ophiolites. On average, SSZ ophiolites have lower closure temperatures than abyssal peridotites and many ophiolites with MOR affinity. We propose that these lower temperatures can be attributed to the residence time in the cooling oceanic lithosphere prior to obduction. MOR ophiolites define a continuum spanning cooling rates from SSZ ophiolites to abyssal peridotites. Consistent high closure temperatures for abyssal peridotites and the Oman and Corsica ophiolites suggests hydrothermal circulation and/or rapid cooling events (e.g., normal faulting, unroofing) control the late thermal histories of peridotites from transform faults and slow and fast spreading centers with or without a crustal section.

High-silica Rocks from Oceans, Arcs and Ophiolites: What Can They Tell Us About Ophiolite Origins?

NASA Astrophysics Data System (ADS)

Perfit, M. R.; Lundstrom, C.; Wanless, V. D.

2015-12-01

Although the volumes of high-silica rocks in submarine oceanic and supra-subduction zone environments are not well constrained, their common occurrence, field relations and compositions have led to various hypotheses suggesting that silicic intrusions (plagiogranites) in ophiolites formed by similar processes to high-silica volcanic rocks at mid-ocean ridge (MOR) or island arc environments. Geochemical attributes of andesite-rhyolite suites from MOR (East Pacific Rise, Juan de Fuca Ridge, Galapagos Spreading Center, Pacific-Antarctic Rise) and back-arc basins (Manus Basin, Lau Basin, East Scotia Ridge) show both similarities and differences to plagiogranitic suites (qtz. diorite-tonalite-trondhjemite) from ophiolites (Troodos and Semail). Both suites are commonly attributed to: extreme (>90%) fractional crystallization of basaltic melts; fractional crystallization coupled with assimilation of hydrated oceanic crust (AFC); or partial melting of preexisting crust. Normalized incompatible trace element patterns show either highly elevated, relatively flat patterns with negative Eu and Sr anomalies similar to high silica volcanics or have complimentary patterns with low abundance, more depleted patterns with positive Eu and Sr anomalies. None of the mechanisms, however, provide a consistent explanation for the compositional and isotopic variations that are observed among plagiogranites. In fact, ophiolitic plagiogranites can have at least two petrogenetic signatures - one indicative of a MORB parent and another that has been related to later, off-axis formation associated with supra-subduction zone magmatism. Based on thermal gradient experiments, the systematic changes in Fe and Si stable isotope ratios with differentiation observed in ophiolite and MOR high-silica suites may result from melt-mineral reactions within a temperature gradient near the boundaries of MOR magma lenses. Comparative major element, trace element and isotopic data will be presented from MOR, BAB and ophiolites to address questions of their origins. Although the mechanism(s) by which plagiogranite bodies form and their relationship to andesitic to rhyolitic lavas still remains enigmatic geochemical comparisons between them provide important clues toward understanding their petrotectonic origins.

Increased risk of advanced neoplasms among asymptomatic siblings of patients with colorectal cancer.

PubMed

Ng, Siew C; Lau, James Y W; Chan, Francis K L; Suen, Bing Yee; Leung, Wai-Keung; Tse, Yee Kit; Ng, Simon S M; Lee, Janet F Y; To, Ka-Fai; Wu, Justin C Y; Sung, Joseph J Y

2013-03-01

Colorectal cancer (CRC) is the second-most common cancer in Hong Kong. Relatives of patients with CRC have an increased risk of colorectal neoplasm. We assessed the prevalence of advanced neoplasms among asymptomatic siblings of patients with CRC. Patients with CRC were identified from the Prince of Wales Hospital CRC Surgery Registry from 2001 to 2011. Colonoscopies were performed for 374 siblings of patients (age, 52.6 ± 7.4 y) and 374 age- and sex-matched siblings of healthy subjects who had normal colonoscopies and did not have a family history of CRC (controls, 52.7 ± 7.4 y). We identified individuals with advanced neoplasms (defined as cancers or adenomas of at least 10 mm in diameter, high-grade dysplasia, with villous or tubulovillous characteristics). The prevalence of advanced neoplasms was 7.5% among siblings of patients and 2.9% among controls (matched odds ratio [mOR], 3.07; 95% confidence interval [CI], 1.5-6.3; P = .002). The prevalence of adenomas larger than 10 mm was higher among siblings of patients than in controls (5.9% vs 2.1%; mOR, 3.34; 95% CI, 1.45-7.66; P = .004), as was the presence of colorectal adenomas (31.0% vs 18.2%; mOR, 2.19; 95% CI, 1.52-3.17; P < .001). Six cancers were detected among siblings of patients; no cancers were detected in controls. The prevalence of advanced neoplasms among siblings of patients was higher when their index case was female (mOR, 4.95; 95% CI, 1.81-13.55) and had distally located CRC (mOR, 3.10; 95% CI, 1.34-7.14). In Hong Kong, siblings of patients with CRC have a higher prevalence of advanced neoplasms, including CRC, than siblings of healthy individuals. Screening is indicated in this high-risk population. ClinicalTrials.gov number: NCT00164944. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Investigation of the interaction between the atypical agonist c[YpwFG] and MOR.

PubMed

Gentilucci, Luca; Squassabia, Federico; De Marco, Rossella; Artali, Roberto; Cardillo, Giuliana; Tolomelli, Alessandra; Spampinato, Santi; Bedini, Andrea

2008-05-01

Endogenous and exogenous opiates are currently considered the drugs of choice for treating different kinds of pain. However, their prolonged use produces several adverse symptoms, and in addition, many forms of pain are resistant to any kind of therapy. Therefore, the discovery of compounds active towards mu-opioid receptors (MORs) by alternative pharmacological mechanisms could be of value for developing novel classes of analgesics. There is evidence that some unusual molecules can bind opioid receptors, albeit lacking some of the typical opioid pharmacophoric features. In particular, the recent discovery of a few compounds that showed agonist behavior even in the absence of the primary pharmacophore, namely a protonable amine, led to a rediscussion of the importance of ionic interactions in stabilizing the ligand-receptor complex and in activating signal transduction. Very recently, we synthesized a library of cyclic analogs of the endogenous, MOR-selective agonist endomorphin-1 (YPWF-NH(2)), containing a Gly5 bridge between Tyr1 and Phe4. The cyclopeptide c[YpwFG] showed good affinity and agonist behavior. This atypical MOR agonist does not have the protonable Tyr amine. In order to gain more information about plausible mechanisms of interaction between c[YpwFG] and the opioid receptor, we synthesized a selected set of derivatives containing different bridges between Tyr1 and Phe4, and tested their affinities towards mu-opioid receptors. We performed conformational analysis of the cyclopeptides by NMR spectroscopy and molecular dynamics, and investigated plausible, unprecedented modes of interaction with the MOR by molecular docking. The successive quantum mechanics/molecular mechanics investigation of the complexes obtained by the molecular docking procedure furnished a more detailed description of the binding mode and the electronic properties of the ligands. The comparison with the binding mode of the potent agonist JOM-6 seems to indicate that the cyclic endomorphin-1 analogs interact with the receptor by way of an alternative mechanism, still maintaining the ability to activate the receptor.

Proceedings of Military Operations Research Symposia (Index) Volume 3. 31st through 40th inclusive

DTIC Science & Technology

1980-11-01

Rist Prize, 35th MORS) 35-75 Couch Jr. and William H Newhart Jr), Designing to system performance/cost/effectiveness, 32-9 Benedict Frank C. Tactical...George L (with Creighton W Cook), Design -to- of threat-oriented ordnance for combat. (Rist Prize. cest: fact or fantasy. 32-125 35th MORS) 35-75...1 Cook Creighton IV (with George L Arnold). Design -to- performance in military vehicles. 35-92 cost: fact or fantasy. 32-125 Dixon Thomas E (with Rif

Epidemic leptospirosis associated with pulmonary hemorrhage-Nicaragua, 1995.

PubMed

Trevejo, R T; Rigau-Pérez, J G; Ashford, D A; McClure, E M; Jarquín-González, C; Amador, J J; de los Reyes, J O; Gonzalez, A; Zaki, S R; Shieh, W J; McLean, R G; Nasci, R S; Weyant, R S; Bolin, C A; Bragg, S L; Perkins, B A; Spiegel, R A

1998-11-01

In October 1995, epidemic "hemorrhagic fever," without jaundice or renal manifestations, was reported in rural Nicaragua following heavy flooding; 2259 residents were evaluated for nonmalarial febrile illnesses (cumulative incidence, 6.1%) and 15 (0.7%) died with pulmonary hemorrhage. A case-control study found that case-patients were more likely than controls to have ever walked in creeks (matched odds ratio [MOR], 15.0; 95% confidence interval [CI], 1.7-132.3), have household rodents (MOR, 10.4; 95% CI, 1.1-97.1), or own dogs with titers >/=400 to Leptospira species (MOR, 23.4; 95% CI, 3.6-infinity). Twenty-six of 51 case-patients had serologic or postmortem evidence of acute leptospirosis. Leptospira species were isolated from case-patients and potential animal reservoirs. This leptospirosis epidemic likely resulted from exposure to flood waters contaminated by urine from infected animals, particularly dogs. Leptospirosis should be included in the differential diagnosis for nonmalarial febrile illness, particularly during periods of flooding or when pulmonary hemorrhage occurs.

It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder.

PubMed

Hsu, D T; Sanford, B J; Meyers, K K; Love, T M; Hazlett, K E; Walker, S J; Mickey, B J; Koeppe, R A; Langenecker, S A; Zubieta, J-K

2015-02-01

The μ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen 'social pain.' We used positron emission tomography scanning with the selective MOR radioligand [(11)C]carfentanil to test the hypothesis that MOR system activation (reflecting endogenous opioid release) in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n=17) compared with healthy controls (HCs, n=18). During rejection, MDD patients showed reduced endogenous opioid release in brain regions regulating stress, mood and motivation, and slower emotional recovery compared with HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with endogenous opioid release in the nucleus accumbens, a reward structure. Altered endogenous opioid activity in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse and contribute to poor treatment outcomes.

Controlled Synthesis of Pt Nanowires with Ordered Large Mesopores for Methanol Oxidation Reaction

NASA Astrophysics Data System (ADS)

Zhang, Chengwei; Xu, Lianbin; Yan, Yushan; Chen, Jianfeng

2016-08-01

Catalysts for methanol oxidation reaction (MOR) are at the heart of key green-energy fuel cell technology. Nanostructured Pt materials are the most popular and effective catalysts for MOR. Controlling the morphology and structure of Pt nanomaterials can provide opportunities to greatly increase their activity and stability. Ordered nanoporous Pt nanowires with controlled large mesopores (15, 30 and 45 nm) are facilely fabricated by chemical reduction deposition from dual templates using porous anodic aluminum oxide (AAO) membranes with silica nanospheres self-assembled in the channels. The prepared mesoporous Pt nanowires are highly active and stable electrocatalysts for MOR. The mesoporous Pt nanowires with 15 nm mesopores exhibit a large electrochemically active surface area (ECSA, 40.5 m2 g-1), a high mass activity (398 mA mg-1) and specific activity (0.98 mA cm-2), and a good If/Ib ratio (1.15), better than the other mesoporous Pt nanowires and the commercial Pt black catalyst.

Cholera Epidemic Associated with Consumption of Unsafe Drinking Water and Street-Vended Water—Eastern Freetown, Sierra Leone, 2012

PubMed Central

Nguyen, Von D.; Sreenivasan, Nandini; Lam, Eugene; Ayers, Tracy; Kargbo, David; Dafae, Foday; Jambai, Amara; Alemu, Wondimagegnehu; Kamara, Abdul; Islam, M. Sirajul; Stroika, Steven; Bopp, Cheryl; Quick, Robert; Mintz, Eric D.; Brunkard, Joan M.

2014-01-01

During 2012, Sierra Leone experienced a cholera epidemic with 22,815 reported cases and 296 deaths. We conducted a matched case-control study to assess risk factors, enrolling 49 cases and 98 controls. Stool specimens were analyzed by culture, polymerase chain reaction (PCR), and pulsed-field gel electrophoresis (PFGE). Conditional logistic regression found that consuming unsafe water (matched odds ratio [mOR]: 3.4; 95% confidence interval [CI]: 1.1, 11.0), street-vended water (mOR: 9.4; 95% CI: 2.0, 43.7), and crab (mOR: 3.3; 95% CI: 1.03, 10.6) were significant risk factors for cholera infection. Of 30 stool specimens, 13 (43%) showed PCR evidence of toxigenic Vibrio cholerae O1. Six specimens yielded isolates of V. cholerae O1, El Tor; PFGE identified a pattern previously observed in seven countries. We recommended ensuring the quality of improved water sources, promoting household chlorination, and educating street vendors on water handling practices. PMID:24470563

Cholera epidemic associated with consumption of unsafe drinking water and street-vended water--Eastern Freetown, Sierra Leone, 2012.

PubMed

Nguyen, Von D; Sreenivasan, Nandini; Lam, Eugene; Ayers, Tracy; Kargbo, David; Dafae, Foday; Jambai, Amara; Alemu, Wondimagegnehu; Kamara, Abdul; Islam, M Sirajul; Stroika, Steven; Bopp, Cheryl; Quick, Robert; Mintz, Eric D; Brunkard, Joan M

2014-03-01

During 2012, Sierra Leone experienced a cholera epidemic with 22,815 reported cases and 296 deaths. We conducted a matched case-control study to assess risk factors, enrolling 49 cases and 98 controls. Stool specimens were analyzed by culture, polymerase chain reaction (PCR), and pulsed-field gel electrophoresis (PFGE). Conditional logistic regression found that consuming unsafe water (matched odds ratio [mOR]: 3.4; 95% confidence interval [CI]: 1.1, 11.0), street-vended water (mOR: 9.4; 95% CI: 2.0, 43.7), and crab (mOR: 3.3; 95% CI: 1.03, 10.6) were significant risk factors for cholera infection. Of 30 stool specimens, 13 (43%) showed PCR evidence of toxigenic Vibrio cholerae O1. Six specimens yielded isolates of V. cholerae O1, El Tor; PFGE identified a pattern previously observed in seven countries. We recommended ensuring the quality of improved water sources, promoting household chlorination, and educating street vendors on water handling practices.

Graphene-cobaltite-Pd hybrid materials for use as efficient bifunctional electrocatalysts in alkaline direct methanol fuel cells.

PubMed

Sharma, Chandra Shekhar; Awasthi, Rahul; Singh, Ravindra Nath; Sinha, Akhoury Sudhir Kumar

2013-12-14

Hybrid materials comprising of Pd, MCo2O4 (where M = Mn, Co or Ni) and graphene have been prepared for use as efficient bifunctional electrocatalysts in alkaline direct methanol fuel cells. Structural and electrochemical characterizations were carried out using X-ray diffraction, transmission electron microscopy, X-ray photoelectron spectroscopy, chronoamperometry and cyclic, CO stripping, and linear sweep voltammetries. The study revealed that all the three hybrid materials are active for both methanol oxidation (MOR) and oxygen reduction (ORR) reactions in 1 M KOH. However, the Pd-MnCo2O4/GNS hybrid electrode exhibited the greatest MOR and ORR activities. This active hybrid electrode has also outstanding stability under both MOR and ORR conditions, while Pt- and other Pd-based catalysts undergo degradation under similar experimental conditions. The Pd-MnCo2O4/GNS hybrid catalyst exhibited superior ORR activity and stability compared to even Pt in alkaline solutions.

Mars observer radio science (MORS) observations in polar regions

NASA Technical Reports Server (NTRS)

Simpson, Richard A.

1992-01-01

MORS observations will focus on two major areas of study: (1) the gravity field of Mars and its interpretation in terms of internal structure and history and (2) the structure of the atmosphere, with emphasis on both temperature-pressure profiles of the background atmosphere and small scale inhomogeneities resulting from turbulence. Scattering of cm wavelength radio signals from Mars' surface at highly oblique angles will also be studied during the primary mission; nongrazing scattering experiments may be possible during an extended mission. During the MORS primary mission, measurements of the spacecraft distance and velocity with respect to Earth based tracking stations will be used to develop models of the global gravity field. The improvement in knowledge of the gravity field will be especially evident in polar regions. The spatial and temporal coverage of atmospheric radio occultation measurements are determined by the geometry of the spacecraft orbit and the direction to the Earth. Profiles of atmospheric temperature and pressure will extend from the surface to altitudes of 50 to 70 km.

The noradrenergic component in tapentadol action counteracts μ-opioid receptor-mediated adverse effects on adult neurogenesis.

PubMed

Meneghini, Vasco; Cuccurazzu, Bruna; Bortolotto, Valeria; Ramazzotti, Vera; Ubezio, Federica; Tzschentke, Thomas M; Canonico, Pier Luigi; Grilli, Mariagrazia

2014-05-01

Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippocampus. Literature data also suggest that norepinephrine is a positive modulator of hippocampal neurogenesis in vitro and in vivo. On the basis of these observations, we investigated whether tapentadol, a novel central analgesic combining μ-opioid receptor (MOR) agonism with norepinephrine reuptake inhibition (NRI), may produce less inhibition of hippocampal neurogenesis compared with morphine. When tested in vitro, morphine inhibited neuronal differentiation, neurite outgrowth, and survival of adult mouse hippocampal neural progenitors and their progeny, via MOR interaction. By contrast, tapentadol was devoid of these adverse effects on cell survival and reduced neurite outgrowth and the number of newly generated neurons only at nanomolar concentrations where the MOR component is predominant. On the contrary, at higher (micromolar) concentrations, tapentadol elicited proneurogenic and antiapoptotic effects via activation of β2 and α2 adrenergic receptors, respectively. Altogether, these data suggest that the noradrenergic component in tapentadol has the potential to counteract the adverse MOR-mediated effects on hippocampal neurogenesis. As a proof of concept, we showed that reboxetine, an NRI antidepressant, counteracted both antineurogenic and apoptotic effects of morphine in vitro. In line with these observations, chronic tapentadol treatment did not negatively affect hippocampal neurogenesis in vivo. In light of the increasing long-term use of opiates in chronic pain, in principle, the tapentadol combined mechanism of action may result in less or no reduction in adult neurogenesis compared with classic opiates.

μ-Opioid modulation in the rostral solitary nucleus and reticular formation alters taste reactivity: evidence for a suppressive effect on consummatory behavior.

PubMed

Kinzeler, Nicole R; Travers, Susan P

2011-09-01

The neural control of feeding involves many neuromodulators, including the endogenous opioids that bind μ-opioid receptors (MORs). Injections of the MOR agonist, Damgo, into limbic and hypothalamic forebrain sites increase intake, particularly of palatable foods. Indeed, forebrain Damgo injections increase sucrose-elicited licking but reduce aversive responding (gaping) to quinine, suggesting that MOR activation may enhance taste palatability. A μ-opioid influence on taste reactivity has not been assessed in the brain stem. However, MORs are present in the first-order taste relay, the rostral nucleus of the solitary tract (rNST), and in the immediately subjacent reticular formation (RF), a region known to be essential for consummatory responses. Thus, to evaluate the consequences of rNST/dorsal RF Damgo in this region, we implanted rats with intraoral cannulas, electromyographic electrodes, and brain cannulas aimed at the ventral border of the rNST. Licking and gaping elicited with sucrose, water, and quinine were assessed before and after intramedullary Damgo and saline infusions. Damgo slowed the rate, increased the amplitude, and decreased the size of fluid-induced lick and gape bouts. In addition, the neutral stimulus water, which typically elicits licks, began to evoke gapes. Thus, the current results demonstrate that μ-opioid activation in the rNST/dorsal RF exerts complex effects on oromotor responding that contrast with forebrain effects and are more indicative of a suppressive, rather than a facilitatory effect on ingestion.

Enterprise Cloud Architecture for Chinese Ministry of Railway

NASA Astrophysics Data System (ADS)

Shan, Xumei; Liu, Hefeng

Enterprise like PRC Ministry of Railways (MOR), is facing various challenges ranging from highly distributed computing environment and low legacy system utilization, Cloud Computing is increasingly regarded as one workable solution to address this. This article describes full scale cloud solution with Intel Tashi as virtual machine infrastructure layer, Hadoop HDFS as computing platform, and self developed SaaS interface, gluing virtual machine and HDFS with Xen hypervisor. As a result, on demand computing task application and deployment have been tackled per MOR real working scenarios at the end of article.

Multiphase whole-body CT angiography before multiorgan retrieval in clinically brain dead patients: Role and influence on clinical practice.

PubMed

Tache, A; Badet, N; Azizi, A; Behr, J; Verdy, S; Delabrousse, E

2016-06-01

To evaluate the contribution of multiphase whole-body CT angiography (CTA) for identifying the contra-indications to multiorgan retrieval (MOR) and improving the preoperative organ harvesting strategy. One hundred and eleven consecutive patients who were clinically brain dead underwent multiphase whole-body CTA to confirm the diagnosis of brain death and for assessment of MOR. The CTA protocol included volumetric acquisitions of the brain and abdominopelvic cavity without IV administration of iodinated contrast material, then images of the thorax-abdomen-pelvis 25s after IV contrast administration, of the brain at 60s and finally an abdominopelvic CT acquisition at 90s. The diagnosis of brain death was based on well-established criteria. The assessment of thorax, abdomen and pelvis was based on a systematic checklist. Post-processing imaging techniques were used in all patients. No organs were retrieved from 21 patients due to patient refusal (19%). Twenty-two potential MOR were denied because of general contra-indications including 12/22 (54%) based on CTA criteria alone. Finally, 68 patients were eligible for MOR and 160 organs were harvested. The exclusion of specific organs was based on CTA alone for 2/16 livers, 4/70 kidneys and 5/55 lungs. Fifty hearts and 58 pancreases were not harvested, none based on CTA results alone. Hepatic abnormalities and vascular anatomical variants were identified in 10% of patients. At least one renal artery variant was found in 28% of patients, 13% presented with a double renal vein and 8% with a hepato-mesenteric artery. Multiphase whole-body CTA for MOR is based on the simultaneous association of cerebral CTA to determine brain death with CTA of the thorax, abdomen and pelvis. This rapid, standardized and easily accessible procedure has no harmful effects on harvested kidneys. It makes it possible to select the donors and the organs to be harvested and allows the retrieving surgeon to identify and anticipate technical difficulties. Copyright © 2015 Editions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

Animal-related factors associated with moderate-to-severe diarrhea in children younger than five years in western Kenya: A matched case-control study.

PubMed

Conan, Anne; O'Reilly, Ciara E; Ogola, Eric; Ochieng, J Benjamin; Blackstock, Anna J; Omore, Richard; Ochieng, Linus; Moke, Fenny; Parsons, Michele B; Xiao, Lihua; Roellig, Dawn; Farag, Tamer H; Nataro, James P; Kotloff, Karen L; Levine, Myron M; Mintz, Eric D; Breiman, Robert F; Cleaveland, Sarah; Knobel, Darryn L

2017-08-01

Diarrheal disease remains among the leading causes of global mortality in children younger than 5 years. Exposure to domestic animals may be a risk factor for diarrheal disease. The objectives of this study were to identify animal-related exposures associated with cases of moderate-to-severe diarrhea (MSD) in children in rural western Kenya, and to identify the major zoonotic enteric pathogens present in domestic animals residing in the homesteads of case and control children. We characterized animal-related exposures in a subset of case and control children (n = 73 pairs matched on age, sex and location) with reported animal presence at home enrolled in the Global Enteric Multicenter Study in western Kenya, and analysed these for an association with MSD. We identified potentially zoonotic enteric pathogens in pooled fecal specimens collected from domestic animals resident at children's homesteads. Variables that were associated with decreased risk of MSD were washing hands after animal contact (matched odds ratio [MOR] = 0.2; 95% CI 0.08-0.7), and presence of adult sheep that were not confined in a pen overnight (MOR = 0.1; 0.02-0.5). Variables that were associated with increased risk of MSD were increasing number of sheep owned (MOR = 1.2; 1.0-1.5), frequent observation of fresh rodent excreta (feces/urine) outside the house (MOR = 7.5; 1.5-37.2), and participation of the child in providing water to chickens (MOR = 3.8; 1.2-12.2). Of 691 pooled specimens collected from 2,174 domestic animals, 159 pools (23%) tested positive for one or more potentially zoonotic enteric pathogens (Campylobacter jejuni, C. coli, non-typhoidal Salmonella, diarrheagenic E. coli, Giardia, Cryptosporidium, or rotavirus). We did not find any association between the presence of particular pathogens in household animals, and MSD in children. Public health agencies should continue to promote frequent hand washing, including after animal contact, to reduce the risk of MSD. Future studies should address specific causal relations of MSD with sheep and chicken husbandry practices, and with the presence of rodents.

Ca isotope fractionation and Sr/Ca partitioning associated with anhydrite formation at mid-ocean ridge hydrothermal systems: An experimental approach

NASA Astrophysics Data System (ADS)

Syverson, D. D.; Scheuermann, P.; Pester, N. J.; Higgins, J. A.; Seyfried, W. E., Jr.

2016-12-01

The elemental and isotopic mass balance of Ca and Sr between seawater and basalt at mid-ocean ridge (MOR) hydrothermal systems is an integrated reflection of the various physiochemical processes, which induce chemical exchange, in the subseafloor. Specifically, the processes of anhydrite precipitation and recrystallization are recognized to be important controls on governing the Ca and Sr elemental and isotope compositions of high temperature vent fluids, however, few experimental data exist to constrain these geochemical effects. Thus, to better understand the associated Sr/Ca partitioning and Ca isotope fractionation and rate of exchange between anhydrite and dissolved constituents, anhydrite precipitation and recrystallization experiments were performed at 175, 250, and 350°C and 500 bar at chemical conditions indicative of active MOR hydrothermal systems. The experimental data suggest that upon entrainment of seawater into MOR hydrothermal systems, anhydrite will precipitate rapidly and discriminate against the heavy isotopes of Ca (Δ44/40Ca(Anh-Fluid) = -0.68 - -0.25 ‰), whereas Sr/Ca partitioning depends on the saturation state of the evolving hydrothermal fluid with respect to anhydrite at each PTX (KD(Anh-Fluid) = 1.24 - 0.55). Coupling experimental constraints with the temperature gradient inferred for high temperature MOR hydrothermal systems in the oceanic crust, data suggest that the Ca isotope and Sr elemental composition of anhydrite formed near the seafloor will be influenced by disequilibrium effects, while, at higher temperatures further into the oceanic crust, anhydrite will be representative of equilibrium Sr/Ca partitioning and Ca isotope fractionation conditions. These experimental observations are consistent with analyzed Sr/Ca and Ca isotope compositions of anhydrites and vent fluids sampled from modern MOR hydrothermal systems1,2 and can be used to further constrain the geochemical effects of hydrothermal circulation in the oceanic crust throughout Earth's history. 1 Tivey, M. K. Generation of Seafloor Hydrothermal Deposits. Oceanography 20, 50-66 (2007).2 Amini, M. et al. Calcium isotope (δ44/40Ca) fractionation along hydrothermal pathways, Logatchev field (Mid-Atlantic Ridge, 14°45'N). Geochimica et Cosmochimica Acta 72, 4107-4122 (2008).

Automatic Black-Box Model Order Reduction using Radial Basis Functions

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

Stephanson, M B; Lee, J F; White, D A

Finite elements methods have long made use of model order reduction (MOR), particularly in the context of fast freqeucny sweeps. In this paper, we discuss a black-box MOR technique, applicable to a many solution methods and not restricted only to spectral responses. We also discuss automated methods for generating a reduced order model that meets a given error tolerance. Numerical examples demonstrate the effectiveness and wide applicability of the method. With the advent of improved computing hardware and numerous fast solution techniques, the field of computational electromagnetics are progressed rapidly in terms of the size and complexity of problems thatmore » can be solved. Numerous applications, however, require the solution of a problem for many different configurations, including optimization, parameter exploration, and uncertainly quantification, where the parameters that may be changed include frequency, material properties, geometric dimensions, etc. In such cases, thousands of solutions may be needed, so solve times of even a few minutes can be burdensome. Model order reduction (MOR) may alleviate this difficulty by creating a small model that can be evaluated quickly. Many MOR techniques have been applied to electromagnetic problems over the past few decades, particularly in the context of fast frequency sweeps. Recent works have extended these methods to allow more than one parameter and to allow the parameters to represent material and geometric properties. There are still limitations with these methods, however. First, they almost always assume that the finite element method is used to solve the problem, so that the system matrix is a known function of the parameters. Second, although some authors have presented adaptive methods (e.g., [2]), the order of the model is often determined before the MOR process begins, with little insight about what order is actually needed to reach the desired accuracy. Finally, it not clear how to efficiently extend most methods to the multiparameter case. This paper address the above shortcomings be developing a method that uses a block-box approach to the solution method, is adaptive, and is easily extensible to many parameters.« less

The Impact of Radiation Oncologists on the Early Adoption of Hypofractionated Radiation Therapy for Early-Stage Breast Cancer.

PubMed

Boero, Isabel J; Gillespie, Erin F; Hou, Jiayi; Paravati, Anthony J; Kim, Ellen; Einck, John P; Yashar, Catheryn; Mell, Loren K; Murphy, James D

2017-03-01

Despite multiple randomized trials showing the efficacy of hypofractionated radiation therapy in early-stage breast cancer, the United States has been slow to adopt this treatment. The goal of this study was to evaluate the impact of individual radiation oncologists on the early adoption of hypofractionated radiation therapy for early-stage breast cancer. We identified 22,233 Medicare beneficiaries with localized breast cancer that was diagnosed from 2004 to 2011 who underwent breast-conserving surgery with adjuvant radiation. Multilevel, multivariable logistic models clustered by radiation oncologist and geographic practice area were used to determine the impact of the provider and geographic region on the likelihood of receiving hypofractionated compared with standard fractionated radiation therapy while controlling for a patient's clinical and demographic covariates. Odds ratios (OR) describe the impact of demographic or clinical covariates, and the median OR (MOR) describes the relative impact of the individual radiation oncologist and geographic region on the likelihood of undergoing hypofractionated radiation therapy. Among the entire cohort, 2333 women (10.4%) were treated with hypofractionated radiation therapy, with unadjusted rates ranging from 0.0% in the bottom quintile of radiation oncologists to 30.4% in the top quintile. Multivariable analysis found that the individual radiation oncologist (MOR 3.08) had a greater impact on the use of hypofractionation than did geographic region (MOR 2.10) or clinical and demographic variables. The impact of the provider increased from the year 2004 to 2005 (MOR 2.82) to the year 2010 to 2011 (MOR 3.16) despite the publication of long-term randomized trial results in early 2010. Male physician and radiation oncologists treating the highest volume of breast cancer patients were less likely to perform hypofractionation (P<.05). The individual radiation oncologist strongly influenced the likelihood of a patient's receiving hypofractionated radiation therapy, and this trend increased despite the publication of long-term data showing equivalence to standard fractionation. Future research should focus on physician-related factors that influence this decision. Copyright © 2016 Elsevier Inc. All rights reserved.

Recent advances in the development of 14-alkoxy substituted morphinans as potent and safer opioid analgesics.

PubMed

Spetea, M; Schmidhammer, H

2012-01-01

Morphine and other opioid morphinans produce analgesia primarily through μ opioid receptors (MORs), which mediate beneficial but also non-beneficial actions. There is a continued search for efficacious opioid analgesics with reduced complications. The cornerstone in the development of 14-alkoxymorphinans as novel analgesic drugs was the synthesis of the highly potent MOR agonist 14-O-methyloxymorphone. This opioid showed high antinociceptive potency but also the adverse effects associated with morphine type compounds. Further developments represent the introduction of a methyl and benzyl group at position 5 of 14-O-methyloxymorphone leading to the strong opioid analgesics 14-methoxymetopon and its 5-benzyl analogue, which exhibited less pronounced side effects than morphine although interacting selectively with MORs. Introduction of arylalkyl substituents such as phenylpropoxy in position 14 led to a series of extremely potent antinociceptive agents with enhanced affinities at all three opioid receptor types. During the past years, medicinal chemistry and opioid research focused increasingly on exploring the therapeutic potential of peripheral opioid receptors by peripheralization of opioids in order to minimize the occurrence of centrally-mediated side effects. Strategies to reduce penetration to the central nervous system (CNS) include chemical modifications that increase hydrophilicity. Zwitterionic 6-amino acid conjugates of 14-Oalkyloxymorphones were developed in an effort to obtain opioid agonists that have limited access to the CNS. These compounds show high antinociceptive potency by interacting with peripheral MORs. Opioid drugs with peripheral site of action represent an important target for the treatment of severe and chronic pain without the adverse actions of centrally acting opioids.

Magma Plumbing System at a Young Back-Arc Spreading Center: The Marsili Volcano, Southern Tyrrhenian Sea

NASA Astrophysics Data System (ADS)

Trua, T.; Marani, M. P.; Gamberi, F.

2018-01-01

Although spreading rate is commonly taken as a proxy for decompression mantle melting at mid-ocean ridges (MORs), magmatism at back-arc spreading centers (BASCs) is further influenced by the subduction-related flux melting of the mantle. These regions consequently show a diversity of crustal structures, lava compositions, and morphologies not typically found in MORs. Here we investigate the crustal plumbing system of the small-scale, Marsili back-arc spreading center of the Southern Tyrrhenian Sea using plagioclase data from a wide spectrum of lavas (basalts to andesites) dredged from its summit and flanks. We employ petrological modeling to identify the plagioclase populations carried in the individual lavas, allocate them to plausible magmatic components present within the plumbing system, and trace the processes occurring during magma ascent to the surface. The properties of the system, such as mush porosity and abundance of the melt bodies, vary from one magma extraction zone to another along the BASC, evidencing the local variability of melt supply conditions. The plagioclase crystals document a range of relationships with the host lavas, indicating magma extraction from a composite, vertically extensive mush and melt-lens system resembling that of MORs. At the same time, however, in small BASCs, such as in the case of the Marsili Basin, crustal accretion and resulting morphology are significantly influenced by the three-dimensional setting of the basin margins. This is an important deviation from the conventional model based on the linear continuity and essentially two-dimensional framework of MORs.

Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers

PubMed Central

Mick, Inge; Myers, Jim; Ramos, Anna C; Stokes, Paul R A; Erritzoe, David; Colasanti, Alessandro; Gunn, Roger N; Rabiner, Eugenii A; Searle, Graham E; Waldman, Adam D; Parkin, Mark C; Brailsford, Alan D; Galduróz, José C F; Bowden-Jones, Henrietta; Clark, Luke; Nutt, David J; Lingford-Hughes, Anne R

2016-01-01

Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [11C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [11C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [11C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [11C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions. PMID:26552847

A robust computational technique for model order reduction of two-time-scale discrete systems via genetic algorithms.

PubMed

Alsmadi, Othman M K; Abo-Hammour, Zaer S

2015-01-01

A robust computational technique for model order reduction (MOR) of multi-time-scale discrete systems (single input single output (SISO) and multi-input multioutput (MIMO)) is presented in this paper. This work is motivated by the singular perturbation of multi-time-scale systems where some specific dynamics may not have significant influence on the overall system behavior. The new approach is proposed using genetic algorithms (GA) with the advantage of obtaining a reduced order model, maintaining the exact dominant dynamics in the reduced order, and minimizing the steady state error. The reduction process is performed by obtaining an upper triangular transformed matrix of the system state matrix defined in state space representation along with the elements of B, C, and D matrices. The GA computational procedure is based on maximizing the fitness function corresponding to the response deviation between the full and reduced order models. The proposed computational intelligence MOR method is compared to recently published work on MOR techniques where simulation results show the potential and advantages of the new approach.

Mesoporous graphene-like nanobowls as Pt electrocatalyst support for highly active and stable methanol oxidation

NASA Astrophysics Data System (ADS)

Yan, Zaoxue; He, Guoqiang; Jiang, Zhifeng; Wei, Wei; Gao, Lina; Xie, Jimin

2015-06-01

Mesoporous graphene-like nanobowls (GLBs) with high surface area of 1091 m2 g-1, high pore volume of 2.7 cm3 g-1 and average pore diameter of 9.8 nm are synthesized through template method. The GLBs with inherent excellent electrical conductivity and chemical inertia show the properties of well mass transfer, poison resistance and stable loading of smaller Pt particles. Therefore, the Pt/GLB catalyst shows much higher activity and stability than that of commercial Pt/C (TKK) for methanol oxidation reaction (MOR). Therein, the peak current density on Pt/GLB (2075 mA mgPt-1) for MOR is 2.87 times that of commercial Pt/C (723 mA mgPt-1); and the onset potential for the MOR on the former is negatively shifted about 160 mV compared with that on the latter. The catalytic performances of the Pt/GLB are also better than those of the Pt loading on mesoporous amorphous carbon nanobowls (Pt/BLC), indicating promotion effect of graphite on Pt catalytic performance.

Mordenite/Nafion and analcime/Nafion composite membranes prepared by spray method for improved direct methanol fuel cell performance

NASA Astrophysics Data System (ADS)

Prapainainar, Paweena; Du, Zehui; Kongkachuichay, Paisan; Holmes, Stuart M.; Prapainainar, Chaiwat

2017-11-01

The aim of this work was to improve proton exchange membranes (PEMs) used in direct methanol fuel cells (DMFCs). A membrane with a high proton conductivity and low methanol permeability was required. Zeolite filler in Nafion (NF matrix) composite membranes were prepared using two types of zeolite, mordenite (MOR) and analcime (ANA). Spray method was used to prepare the composite membranes, and properties of the membranes were investigated: mechanical properties, solubility, water and methanol uptake, ion-exchange capacity (IEC), proton conductivity, methanol permeability, and DMFC performance. It was found that MOR filler showed higher performance than ANA. The MOR/Nafion composite membrane gave better properties than ANA/Nafion composite membrane, including a higher proton conductivity and a methanol permeability that was 2-3 times lower. The highest DMFC performance (10.75 mW cm-2) was obtained at 70 °C and with 2 M methanol, with a value 1.5 times higher than that of ANA/Nafion composite membrane and two times higher than that of commercial Nafion 117 (NF 117).

Asymmetric synthesis and in vitro and in vivo activity of tetrahydroquinolines featuring a diverse set of polar substitutions at the 6 position as mixed-efficacy μ opioid receptor/δ opioid receptor ligands.

PubMed

Bender, Aaron M; Griggs, Nicholas W; Anand, Jessica P; Traynor, John R; Jutkiewicz, Emily M; Mosberg, Henry I

2015-08-19

We previously reported a small series of mixed-efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist peptidomimetics featuring a tetrahydroquinoline scaffold and showed the promise of this series as effective analgesics after intraperitoneal administration in mice. We report here an expanded structure-activity relationship study of the pendant region of these compounds and focus in particular on the incorporation of heteroatoms into this side chain. These analogues provide new insight into the binding requirements for this scaffold at MOR, DOR, and the κ opioid receptor (KOR), and several of them (10j, 10k, 10m, and 10n) significantly improve upon the overall MOR agonist/DOR antagonist profile of our previous compounds. In vivo data for 10j, 10k, 10m, and 10n are also reported and show the antinociceptive potency and duration of action of compounds 10j and 10m to be comparable to those of morphine.

Pulmonary Tuberculosis Is Associated With Biomass Fuel Use Among Rural Women in Pakistan: An Age- and Residence-Matched Case-Control Study.

PubMed

Rabbani, Unaib; Sahito, Ambreen; Nafees, Asaad Ahmed; Kazi, Ambreen; Fatmi, Zafar

2017-04-01

Facility-based, age- and residential area-matched case-control study was conducted in Sindh, Pakistan to determine association between biomass fuel use for cooking and pulmonary tuberculosis (TB). Cases were women with pulmonary TB, and controls were those suffering from other diseases. Current users of biomass fuel were at higher risk of pulmonary TB (adjusted matched odds ratio [mOR] = 3.0; 95% CI = 1.1-4.9) compared with nonusers. In comparison with former biomass users (women not using biomass for >10 years), recent biomass users (women who switched from biomass to nonbiomass ≤10 years ago), and current (lifetime) users were at a higher risk in a dose-response manner (adjusted mOR = 2.8, 95% CI = 0.9-8.2 and adjusted mOR = 3.9, 95% CI = 1.4-10.7, respectively). Population attributable fraction for TB related to biomass fuel use was 40.6% (95% CI = 35.5%-45.7%). This study strengthens the evidence that biomass fuel use for cooking is associated with pulmonary TB and risk increases with duration of exposure.

Morin Flavonoid Adsorbed on Mesoporous Silica, a Novel Antioxidant Nanomaterial

PubMed Central

Arriagada, Francisco; Correa, Olosmira; Günther, Germán; Nonell, Santi; Mura, Francisco; Olea-Azar, Claudio

2016-01-01

Morin (2´,3, 4´,5,7-pentahydroxyflavone) is a flavonoid with several beneficial health effects. However, its poor water solubility and it sensitivity to several environmental factors avoid its use in applications like pharmaceutical and cosmetic. In this work, we synthetized morin-modified mesoporous silica nanoparticles (AMSNPs-MOR) as useful material to be used as potential nanoantioxidant. To achieve this, we characterized its adsorption kinetics, isotherm and the antioxidant capacity as hydroxyl radical (HO•) scavenger and singlet oxygen (1O2) quencher. The experimental data could be well fitted with Langmuir, Freundlich and Temkin isotherm models, besides the pseudo-second order kinetics model. The total quenching rate constant obtained for singlet oxygen deactivation by AMSNPs-MOR was one order of magnitude lower than the morin rate constant reported previously in neat solvents and lipid membranes. The AMSNPs-MOR have good antioxidant properties by itself and exhibit a synergic effect with morin on the antioxidant property against hydroxyl radical. This effect, in the range of concentrations studied, was increased when the amount of morin adsorbed increased. PMID:27812111

Discovery and Distribution of Black Smokers on the Western Galapagos Spreading Center: Implications for Spatial and Temporal Controls on High Temperature Venting at Ridge/Hotspot Intersections

NASA Astrophysics Data System (ADS)

Haymon, R. M.; Anderson, P. G.; Baker, E. T.; Resing, J. A.; White, S. M.; MacDonald, K. C.

2006-12-01

Though nearly one-fifth of the mid-ocean ridge (MOR) lies on or near hotspots, it has been debated whether hotspots increase or decrease MOR hydrothermal flux, or affect vent biota. Despite hotspot enhancement of melt supply, high-temperature vent plumes are enigmatically sparse along two previously-surveyed ridge- hotspot intersections [Reykjanes Ridge (RR), Southeast Indian Ridge (SEIR)]. This has been attributed to crustal thickening by excess volcanism. During the 2005-06 GalAPAGoS expedition, we conducted nested sonar, plume, and camera surveys along a 540 km-long portion of the Galapagos Spreading Center (GSC) where the ridge intersects the Galapagos hotspot at lon. 94.5 -89.5 deg. W. Although MOR hydrothermal springs were first found along the eastern GSC crest in 1977 near lon. 86 deg. W, the GalAPAGoS smokers are the first active high-temperature vents to be found anywhere along the Cocos-Nazca plate boundary. Active and/or recently-inactive smokers were located beneath plumes at 5 sites on the seafloor between lon. 91 deg. W and 94.5 deg. W (see Anderson et al., this session) during near-bottom, real-time fiber-optic Medea camera surveys. Smokers occur along eruptive seafloor fissures atop axial volcanic ridges near the middles of ridge segments, mainly in areas underlain by relatively shallow, continuous axial magma chamber (AMC) seismic reflectors. These findings (1) support magmatic, rather than tectonic, control of GSC smoker distribution; (2) demonstrate that thick crust at MOR-hotspot intersections does not prevent high-temperature hydrothermal vents from forming; and, (3) appear to be inconsistent with models suggesting that enhanced hydrothermal cooling causes abrupt deepening of the AMC and transition from non-rifted to rifted GSC morphology near lon. 92.7 deg. W. The widely-spaced smoker sites located on different GSC segments exhibit remarkably similar characteristics and seafloor settings. Most sites are mature or extinct, and are on lava flows of visually-similar ages (estimated to be tens-to-hundreds of years old). Possibly a volcanic pulse may have activated the hotspot- affected western GSC, and powered contemporaneous hydrothermal vents that now are waning. It may be that hotspots produce episodes of near-synchronous, extensive ridge volcanism and hydrothermal activity, followed by periods of quiescence. This idea is consistent with: the episodic eruption histories of Hawaii and Iceland; variably anomalous hydrothermal plume incidence (low on RR, SEIR, GSC; high on Mid-Atlantic Ridge near Azores hotspot); models of episodic melt extraction from mantle plumes; and evidence for magma propagation along hotspot-influenced ridges. Our hypothesis potentially can be tested by studies of gene flow between animal communities located on either side of the Galapagos hotspot, and by dating of GSC hydrothermal chimneys and the lava flows on which they are constructed.

Persistence of evolutionary memory: primordial six-transmembrane helical domain mu opiate receptors selectively linked to endogenous morphine signaling.

PubMed

Kream, Richard M; Sheehan, Melinda; Cadet, Patrick; Mantione, Kirk J; Zhu, Wei; Casares, Federico; Stefano, George B

2007-12-01

Biochemical, molecular and pharmacological evidence for two unique six-transmembrane helical (TMH) domain opiate receptors expressed from the micro opioid receptor (MOR) gene have been shown. Designated micro3 and micro4 receptors, both protein species are Class A rhodopsin-like members of the superfamily of G-protein coupled receptors but are selectively tailored to mediate the cellular regulatory effects of endogenous morphine and related morphinan alkaloids via stimulation of nitric oxide (NO) production and release. Both micro3 and micro4 receptors lack an amino acid sequence of approximately 90 amino acids that constitute the extracellular N-terminal and TMH1 domains and part of the first intracellular loop of the micro1 receptor, but retain the empirically defined ligand binding pocket distributed across conserved TMH2, TMH3, and TMH7 domains of the micro1 sequence. Additionally, the receptor proteins are terminated by unique intracellular C-terminal amino acid sequences that serve as putative coupling or docking domains required for constitutive NO synthase activation. Because the recognition profile of micro3 and micro4 receptors is restricted to rigid benzylisoquinoline alkaloids typified by morphine and its extended family of chemical congeners, it is hypothesized that conformational stabilization provided by interaction of extended extracellular N-terminal protein domains and the extracellular loops is required for binding of endogenous opioid peptides as well as synthetic flexible opiate alkaloids.

Development and accuracy of a multipoint method for measuring visibility.

PubMed

Tai, Hongda; Zhuang, Zibo; Sun, Dongsong

2017-10-01

Accurate measurements of visibility are of great importance in many fields. This paper reports a multipoint visibility measurement (MVM) method to measure and calculate the atmospheric transmittance, extinction coefficient, and meteorological optical range (MOR). The relative errors of atmospheric transmittance and MOR measured by the MVM method and traditional transmissometer method are analyzed and compared. Experiments were conducted indoors, and the data were simultaneously processed. The results revealed that the MVM can effectively improve the accuracy under different visibility conditions. The greatest improvement of accuracy was 27%. The MVM can be used to calibrate and evaluate visibility meters.

Special issue on Military Operations Research Society (MORS) Symposium (80th): Expanding the Boundaries of National Security Analysis (Phalanx: The Bulletin of Military Operations Research. Volume 45, Number 2, June 2012)

DTIC Science & Technology

2012-06-01

brianmccue@alum.mit.edu Letters to the Editor, John Willis, Augustine Consulting, Inc., jwillis@aciedge.com Modeling and Simulation , James N. Bexfield, FS, OSD...concepts that are now being applied to modern analytical thinking. The tuto- rials are free to MORS members and $75 for the day for nonmembers. The...Overview of Agent- based Modeling and Simulation and Complex Adaptive Systems •  Visual Data Analysis •  Analyzing Combat Identification •  Guidelines for

CLEAR: Communications Link Expert Assistance Resource

NASA Technical Reports Server (NTRS)

Hull, Larry G.; Hughes, Peter M.

1987-01-01

Communications Link Expert Assistance Resource (CLEAR) is a real time, fault diagnosis expert system for the Cosmic Background Explorer (COBE) Mission Operations Room (MOR). The CLEAR expert system is an operational prototype which assists the MOR operator/analyst by isolating and diagnosing faults in the spacecraft communication link with the Tracking and Data Relay Satellite (TDRS) during periods of realtime data acquisition. The mission domain, user requirements, hardware configuration, expert system concept, tool selection, development approach, and system design were discussed. Development approach and system implementation are emphasized. Also discussed are system architecture, tool selection, operation, and future plans.

Long-term Immunogenicity of Elosulfase Alfa in the Treatment of Morquio A Syndrome: Results From MOR-005, a Phase III Extension Study.

PubMed

Long, Brian; Tompkins, Troy; Decker, Celeste; Jesaitis, Lynne; Khan, Shahid; Slasor, Peter; Harmatz, Paul; O'Neill, Charles A; Schweighardt, Becky

2017-01-01

Elosulfase alfa is an enzyme replacement therapy for the treatment of Morquio A syndrome (mucopolysaccharidosis IVA), a lysosomal storage disorder caused by a deficiency of the enzyme N-acetylgalactose-amine-6-sulfatase. We previously reported immunogenicity data from our 24-week placebo-controlled Phase III study, MOR-004. Here, we report the long-term immunogenicity profile of elosulfase alfa from MOR-005, the Phase III extension trial to assess potential correlations between antidrug antibodies and efficacy and safety profile outcomes throughout 120 weeks of treatment. The long-term immunogenicity of elosulfase alfa was evaluated in patients with Morquio A syndrome in an open-label extension study for a total of 120 weeks. All patients received 2.0 mg/kg elosulfase alfa either weekly or every other week before establishment of 2.0 mg/kg/wk as the recommended dose, at which time all patients received weekly treatment. Efficacy measures were compared with those from the MOR-004 baseline, enabling analysis of changes over 120 weeks. The primary efficacy measure was the change from baseline in 6-minute walk test. Secondary measures included changes from baseline in 3-minute stair climb test and normalized urine keratan sulfate, a pharmacodynamic metric. All patients treated with elosulfase alfa developed antidrug total antibodies (TAb) by week 24 of MOR-004. In the extension study, all patients, including those who had previously received placebo, were TAb positive by study week 36 (MOR-005 week 12). All patients remained TAb positive throughout the study, and TAb titers were similar across treatment groups at week 120. Nearly all patients tested positive for neutralizing antibodies (NAb) at least once, with incidence of NAb positivity peaking at 85.9% at study week 36, then steadily declining to 66.0% at study week 120. In all treatment groups, mean urine keratan sulfate remained below treatment-naive baseline despite the presence of antidrug antibodies. No relationship was observed between TAb titers or NAb positivity and changes in urine keratan sulfate, 6-minute walk test, or 3-minute stair climb test from baseline to week 120. No consistent associations were detected between antidrug antibodies and the occurrence of hypersensitivity adverse events or anaphylaxis over the course of the study. Immunogenicity results from this long-term study are consistent with previously reported 24-week results. Despite the sustained presence of antidrug antibodies, elosulfase alfa was well tolerated, and patients continued to benefit from treatment through week 120. No associations were detected between higher TAb titers or NAb positivity and reduced treatment effect or worsened safety profile measures. ClinicalTrials.gov identifier: NCT01415427. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Impact of morphine on the expression of insulin receptor and protein levels of insulin/IGFs in rat neural stem cells.

PubMed

Salarinasab, Sadegh; Nourazarian, AliReza; Nikanfar, Masoud; Abdyazdani, Nima; Kazemi, Masoumeh; Feizy, Navid; Rahbarghazi, Reza

2017-11-01

Alzheimer's disease is correlated with neuronal degeneration and loss of neuronal precursors in different parts of the brain. It has been found disturbance in the homeostasis neural stem cells (NSCs) can cause neurodegeneration. Morphine, an analgesic agent, can disrupt the dynamic and normal state of NSCs. However, more investigations are required to clearly address underlying mechanisms. The current experiment aimed to investigate the effects of morphine on the cell distribution of insulin factor and receptor and insulin-like growth factors (IGF1, IGF2) in NSCs. NSCs were isolated from rats and stemness feature confirmed by antibodies against nestin and Sox2. The cells were exposed to 100μM morphine, 50μM naloxone and combination of these two drugs for 72h. The neural cell growth, changes in levels of insulin and insulin-like growth factors secreted by NSCs as well as the insulin-receptor-gene expression were assessed by flow cytometry, ELlSA, and real-time PCR, respectively. Cell cycle assay revealed the exposure of cells to morphine for 72h increased cell apoptosis and decreased neural stem cell growth. The biosynthesis of insulin, insulin-like growth factors, and insulin receptor were reduced (p<0.05) after NSCs exposure to morphine at the concentration of 100μM for 24, 48 and 72h. Naloxone is a competitive antagonist which binds MOR where morphine (and endogenous opioids) bind, and reversed the detrimental effects of morphine. It can be concluded that morphine initiated irregularity in NSCs kinetics and activity by reducing the secretion of insulin and insulin-like growth factors and down-regulation of insulin receptor. Copyright © 2017 Elsevier B.V. All rights reserved.

Panicolytic-like action of bradykinin in the dorsal periaqueductal gray through μ-opioid and B2-kinin receptors.

PubMed

Sestile, Caio César; Maraschin, Jhonatan Christian; Gama, Vanessa Scalco; Zangrossi, Hélio; Graeff, Frederico Guilherme; Audi, Elisabeth Aparecida

2017-09-01

A wealth of evidence has shown that opioid and kinin systems may control proximal defense in the dorsal periaqueductal gray matter (dPAG), a critical panic-associated area. Studies with drugs that interfere with serotonin-mediated neurotransmission suggest that the μ-opioid receptor (MOR) synergistically interacts with the 5-HT 1A receptor in the dPAG to inhibit escape, a panic-related behavior. A similar inhibitory effect has also been reported after local administration of bradykinin (BK), which is blocked by the non-selective opioid receptor antagonist naloxone. The latter evidence, points to an interaction between BK and opioids in the dPAG. We further explored the existence of this interaction through the dPAG electrical stimulation model of panic. We also investigated whether intra-dPAG injection of captopril, an inhibitor of the angiotensin-converting enzyme (ACE) that also degrades BK, causes a panicolytic-like effect. Our results showed that intra-dPAG injection of BK inhibited escape performance in a dose-dependent way, and this panicolytic-like effect was blocked by the BK type 2 receptor (B2R) antagonist HOE-140, and by the selective MOR antagonist CTOP. Conversely, the panicolytic-like effect caused by local administration of the selective MOR agonist DAMGO was antagonized by pre-treatment with either CTOP or HOE-140, indicating cross-antagonism between MOR and B2R. Finally, intra-dPAG injection of captopril also impaired escape in a dose-dependent way, and this panicolytic-like effect was blocked by pretreatment with HOE-140, suggesting mediation by endogenous BK. The panicolytic-like effect of captopril indicates that the use of ACE inhibitors in the clinical management of panic disorder may be worth exploring. Copyright © 2017 Elsevier Ltd. All rights reserved.

Single-Dose Adductor Canal Block With Local Infiltrative Analgesia Compared With Local Infiltrate Analgesia After Total Knee Arthroplasty: A Randomized, Double-Blind, Placebo-Controlled Trial.

PubMed

Nader, Antoun; Kendall, Mark C; Manning, David W; Beal, Matthew; Rahangdale, Rohit; Dekker, Robert; De Oliveira, Gildasio S; Kamenetsky, Eric; McCarthy, Robert J

A single-dose adductor canal block can provide postoperative analgesia for patients undergoing total knee arthroplasty (TKA). The purpose of this study was to assess postoperative opioid consumption after ultrasound-guided single-injection bupivacaine compared with saline adductor canal block for patients undergoing TKA. After institutional review board approval, written informed consent was obtained from patients (>18 years old) undergoing elective TKA. Subjects were randomized into 2 groups as follows: adductor canal blockade with 10 mL of bupivacaine 0.25% with epinephrine 1:300,000 or 10 mL of normal saline. All patients received a periarticular infiltration mixture intraoperatively with scheduled and patient requested oral and IV analgesics postoperatively for breakthrough pain. Personnel blinded to group allocation recorded pain scores and opioid consumption every 6 hours. Pain burden, area under the numeric rating score for pain, was calculated for 36 hours. The primary outcome was postoperative IV/IM morphine (mg morEq) consumption at 36 hours after surgery. Forty (28 women/12 men) subjects were studied. Postoperative opioid consumption was reduced in the bupivacaine 48 (39 to 61) mg morEq compared with saline 60 (49 to 85) mg morEq, difference -12 (-33 to -2) mg morEq (P = 0.03). Pain burden at rest was decreased in the bupivacaine 71 (37 to 120) score · hours compared with saline 131 (92 to 161) score · hours, difference -60 (-93 to -14) score · hours (P = 0.009). Adductor canal blockade with bupivacaine 0.25% with epinephrine 1:300,000 effectively reduces pain and opioid requirement in the postoperative period after TKA. Adductor canal blockade is an effective pain management adjunct for patients undergoing TKA.

μ-Opioid Receptor Trafficking on Inhibitory Synapses in the Rat Brainstem

PubMed Central

Browning, Kirsteen N.; Kalyuzhny, Alexander E.; Travagli, R. Alberto

2011-01-01

Whole-cell recordings were made from identified gastric-projecting rat dorsal motor nucleus of the vagus (DMV) neurons. The amplitude of evoked IPSCs (eIPSCs) was unaffected by perfusion with met-enkephalin (ME) or by μ-, δ-, or κ-opioid receptor selective agonists, namely d-Ala2-N-Me-Phe4-Glycol5-enkephalin (DAMGO), cyclic [d-Pen2-d-Pen5]-enkephalin, or trans-3,4-dichloro-N-methyl-N-[2-(1-pyrolytinil)-cyclohexyl]-benzeneacetamide methane sulfonate (U50,488), respectively. Brief incubation with the adenylate cyclase activator forskolin or the nonhydrolysable cAMP analog 8-bromo-cAMP, thyrotropin releasing hormone, or cholecystokinin revealed the ability of ME and DAMGO to inhibit IPSC amplitude; this inhibition was prevented by pretreatment with the μ-opioid receptor (MOR1) selective antagonist d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2. Conversely, incubation with the adenylate cyclase inhibitor dideoxyadenosine, with the protein kinase A (PKA) inhibitor N-[2-(p-Bromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H89), or with the Golgi-disturbing agent brefeldin A, blocked the ability of forskolin to facilitate the inhibitory actions of ME. Immunocytochemical experiments revealed that under control conditions, MOR1 immunoreactivity (MOR1-IR) was colocalized with glutamic acid decarboxylase (GAD)-IR in profiles apposing DMV neurons only after stimulation of the cAMP–PKA pathway. Pretreatment with H89 or brefeldin A or incubation at 4°C prevented the forskolin-mediated insertion of MOR1 on GAD-IR-positive profiles. These results suggest that the cAMP–PKA pathway regulates trafficking of μ-opioid receptors into the cell surface of GABAergic nerve terminals. By consequence, the inhibitory actions of opioid peptides in the dorsal vagal complex may depend on the state of activation of brainstem vagal circuits. PMID:15317860

Improved silicon carbide for advanced heat engines

NASA Technical Reports Server (NTRS)

Whalen, T. J.; Winterbottom, W. L.

1986-01-01

Work performed to develop silicon carbide materials of high strength and to form components of complex shape and high reliability is described. A beta-SiC powder and binder system was adapted to the injection molding process and procedures and process parameters developed capable of providing a sintered silicon carbide material with improved properties. The initial effort has been to characterize the baseline precursor materials (beta silicon carbide powder and boron and carbon sintering aids), develop mixing and injection molding procedures for fabricating test bars, and characterize the properties of the sintered materials. Parallel studies of various mixing, dewaxing, and sintering procedures have been carried out in order to distinguish process routes for improving material properties. A total of 276 MOR bars of the baseline material have been molded, and 122 bars have been fully processed to a sinter density of approximately 95 percent. The material has a mean MOR room temperature strength of 43.31 ksi (299 MPa), a Weibull characteristic strength of 45.8 ksi (315 MPa), and a Weibull modulus of 8.0. Mean values of the MOR strengths at 1000, 1200, and 14000 C are 41.4, 43.2, and 47.2 ksi, respectively. Strength controlling flaws in this material were found to consist of regions of high porosity and were attributed to agglomerates originating in the initial mixing procedures. The mean stress rupture lift at 1400 C of five samples tested at 172 MPa (25 ksi) stress was 62 hours and at 207 MPa (30 ksi) stress was 14 hours. New fluid mixing techniques have been developed which significantly reduce flaw size and improve the strength of the material. Initial MOR tests indicate the strength of the fluid-mixed material exceeds the baseline property by more than 33 percent.

An urban, water-borne outbreak of diarrhoea and shigellosis in a district town in eastern India.

PubMed

Saha, T; Murhekar, M; Hutin, Y J; Ramamurthy, T

2009-01-01

In September 2007, the Gayeshpur municipality reported a cluster of cases with diarrhoea. We aimed to identify the causative agent and the source of the disease. We defined a case as the occurrence of diarrhoea (> 3 loose stools/day) with fever or bloody stools in a resident of Gayeshpur in September-October 2007. We asked healthcare facilities to report cases, collected stool specimens from patients, constructed an epidemic curve, drew a map and calculated the incidence by age and sex. We also conducted a matched case-control study (58 in each group), calculated matched odds ratio (MOR) and population attributable fraction (PAF), as well as assessed the environment. We identified 461 cases (attack rate: 46/1000 population) and isolated Shigella flexneri (serotype 2a and 3a) from 3 of 4 stool specimens. The attack rate was higher among females (52/1000) and those in the age group of 45-59 years (71/1000). The outbreak started on 22 September, peaked multiple times and subsided on 12 October 2007. Cases were clustered distal to a leaking pipeline that crossed an open drain to intermittently supply non-chlorinated water to taps. The 58 cases and 58 controls were matched for age and sex. Drinking tap water (MOR: 10; 95% CI: 3-32; PAF: 89%), washing utensils in tap water (MOR: 3.7; 95% CI: 1.2-11.3) and bathing in tap water (MOR: 3.5; 95% CI: 1.1-11) were associated with the illness. This outbreak of diarrhoea and Shigella flexneri dysentery was caused by contamination of tap water and subsided following repair of the pipeline. We recommended regular chlorination of the water and maintenance of pipelines.

Increased morbidity odds ratio of primary liver cancer and cirrhosis of the liver among vinyl chloride monomer workers

PubMed Central

Du C., L.; Wang, J. D.

1998-01-01

OBJECTIVES: To determine if there is an increased risk of admission to hospital for various diseases among vinyl chloride monomer (VCM) workers. METHODS: 2224 workers with occupational exposure to VCM were identified for occurrence of disease based on a search of hospital computer files on labour insurance. These data were compared with those of workers manufacturing optical equipment and motorcycles from 1 January 1985 to 31 March 1994. Cardiovascular and cerebrovascular diseases were used as reference diseases, and the age adjusted morbidity odds ratio (MOR) was calculated. RESULTS: A significantly increased risk of admission to hospital among VCM workers due to primary liver cancer (MOR 4.5-6.5), cirrhosis of the liver (MOR 1.7- 2.1), and other chronic diseases (MOR 1.5-2.0) was found. There were eight cases of primary liver cancer, all with heavy previous exposure to VCM. Another four cases of hepatoma in polyvinyl chloride (PVC) workers were found in the death registry. Ten out of 11 cases of hepatoma, with detailed medical information, were carriers of hepatitis B virus. The average latent period (20 years) was not different from other studies. Alternative agents of primary liver cancer were largely ruled out, suggesting that the combination of hepatitis B and VCM may lead to primary liver cancer. CONCLUSION: There is an increased risk of primary liver cancer in workers exposed to VCM, although the incomplete coverage of the Labor Insurance Bureau data warrants cautious interpretation of the results. Further study exploring the synergistic effects of VCM and hepatitis B is also indicated.   PMID:9849539

Spinal Endomorphin 2 Antinociception and the Mechanisms That Produce It Are Both Sex- and Stage of Estrus Cycle–Dependent in Rats

PubMed Central

Liu, Nai-Jiang; Gintzler, Alan R.

2014-01-01

Endomorphin 2 (EM2) is the predominant endogenous mu-opioid receptor (MOR) ligand in the spinal cord. Given its endogenous presence, antinociceptive responsiveness to the intrathecal application of EM2 most likely reflects its ability to modulate nociception when released in situ. In order to explore the physiological pliability of sex-dependent differences in spinal MOR-mediated antinociception, we investigated the antinociception produced by intrathecal EM2 in male, proestrus female, and diestrus female rats. Antinociception was reflected by changes in tail flick latency to radiant heat. In females, the spinal EM2 antinociceptive system oscillated between analgesically active and inactive states. During diestrus, when circulating estrogens are low, spinal EM2 antinociceptive responsiveness was minimal. In contrast, during proestrus, when circulating estrogens are high, spinal EM2 antinociception was robust and comparable in magnitude to that manifest by males. Furthermore, in proestrus females, spinal EM2 antinociception required spinal dynorphin and kappaopioid receptor activation, concomitant with MOR activation. This is required for neither spinal EM2 antinociception in males nor the antinociception elicited in proestrus females by spinal sufentanil or [d-Ala2,N-methyl-Phe4,Gly-ol5]-enkephalin, which are prototypic MOR-selective nonpeptide and peptide agonists, respectively. These results reveal that spinal EM2 antinociception and the signaling mechanisms used to produce it fundamentally differ in males and females. Perspective The inability to mount spinal EM2 antinociception during defined stages of the estrus (and presumably menstrual) cycle and impaired transition from spinal EM2 analgesically nonresponsive to responsive physiological states could be causally associated with the well-documented greater severity and frequency of chronic intractable pain syndromes in women vs men. PMID:24084000

Association Between Occupational Exposures and Sarcoidosis: An Analysis From Death Certificates in the United States, 1988-1999.

PubMed

Liu, Hongbo; Patel, Divya; Welch, Alison M; Wilson, Carla; Mroz, Margaret M; Li, Li; Rose, Cecile S; Van Dyke, Michael; Swigris, Jeffrey J; Hamzeh, Nabeel; Maier, Lisa A

2016-08-01

Sarcoidosis is a disease that is associated with occupational and environmental antigens, in the setting of a susceptible host. The aim of this study was to examine the association between sarcoidosis mortality and previously reported occupational exposures based on sex and race. The decedents enrolled in this study were derived from United States death certificates from 1988-1999. Cause of death was coded according to ICD-9 and ICD-10. The usual occupation was coded with Bureau of the Census Occupation Codes. Mortality odds ratio (MOR) were determined and multiple Poisson regression were performed to evaluate the independent exposure effects after adjustment for age, sex, race and other occupational exposures. Of the 7,118,535 decedents in our study, 3,393 were identified as sarcoidosis-related, including 1,579 identified as sarcoidosis being the underlying cause of death. The sarcoidosis-related MOR of any occupational exposure was 1.52 (95% CI, 1.35-1.71). Women with any exposure demonstrated an increased MOR compared to women without (MOR 1.65, 95% CI, 1.45-1.89). The mortality risk was significantly elevated in those with employment involving metal working, health care, teaching, sales, banking, and administration. Higher sarcoidosis-related mortality risks associated with specific exposures were noted in women vs men and blacks vs whites. Findings of prior occupations and risk of sarcoidosis were verified using sarcoidosis mortality rates. There were significant differences in risk for sarcoidosis mortality by occupational exposures based on sex and race. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

On the G-Protein-Coupled Receptor Heteromers and Their Allosteric Receptor-Receptor Interactions in the Central Nervous System: Focus on Their Role in Pain Modulation

PubMed Central

Borroto-Escuela, Dasiel O.; Romero-Fernandez, Wilber; Rivera, Alicia; Van Craenenbroeck, Kathleen; Tarakanov, Alexander O.; Agnati, Luigi F.; Fuxe, Kjell

2013-01-01

The modulatory role of allosteric receptor-receptor interactions in the pain pathways of the Central Nervous System and the peripheral nociceptors has become of increasing interest. As integrators of nociceptive and antinociceptive wiring and volume transmission signals, with a major role for the opioid receptor heteromers, they likely have an important role in the pain circuits and may be involved in acupuncture. The delta opioid receptor (DOR) exerts an antagonistic allosteric influence on the mu opioid receptor (MOR) function in a MOR-DOR heteromer. This heteromer contributes to morphine-induced tolerance and dependence, since it becomes abundant and develops a reduced G-protein-coupling with reduced signaling mainly operating via β-arrestin2 upon chronic morphine treatment. A DOR antagonist causes a return of the Gi/o binding and coupling to the heteromer and the biological actions of morphine. The gender- and ovarian steroid-dependent recruitment of spinal cord MOR/kappa opioid receptor (KOR) heterodimers enhances antinociceptive functions and if impaired could contribute to chronic pain states in women. MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, mediating morphine induced itch. Other mechanism for the antinociceptive actions of acupuncture along meridians may be that it enhances the cross-desensitization of the TRPA1 (chemical nociceptor)-TRPV1 (capsaicin receptor) heteromeric channel complexes within the nociceptor terminals located along these meridians. Selective ionotropic cannabinoids may also produce cross-desensitization of the TRPA1-TRPV1 heteromeric nociceptor channels by being negative allosteric modulators of these channels leading to antinociception and antihyperalgesia. PMID:23956775

Distinct Mu, Delta, and Kappa Opioid Receptor Mechanisms Underlie Low Sociability and Depressive-Like Behaviors During Heroin Abstinence

PubMed Central

Lutz, Pierre-Eric; Ayranci, Gulebru; Chu-Sin-Chung, Paul; Matifas, Audrey; Koebel, Pascale; Filliol, Dominique; Befort, Katia; Ouagazzal, Abdel-Mouttalib; Kieffer, Brigitte L

2014-01-01

Addiction is a chronic disorder involving recurring intoxication, withdrawal, and craving episodes. Escaping this vicious cycle requires maintenance of abstinence for extended periods of time and is a true challenge for addicted individuals. The emergence of depressive symptoms, including social withdrawal, is considered a main cause for relapse, but underlying mechanisms are poorly understood. Here we establish a mouse model of protracted abstinence to heroin, a major abused opiate, where both emotional and working memory deficits unfold. We show that delta and kappa opioid receptor (DOR and KOR, respectively) knockout mice develop either stronger or reduced emotional disruption during heroin abstinence, establishing DOR and KOR activities as protective and vulnerability factors, respectively, that regulate the severity of abstinence. Further, we found that chronic treatment with the antidepressant drug fluoxetine prevents emergence of low sociability, with no impact on the working memory deficit, implicating serotonergic mechanisms predominantly in emotional aspects of abstinence symptoms. Finally, targeting the main serotonergic brain structure, we show that gene knockout of mu opioid receptors (MORs) in the dorsal raphe nucleus (DRN) before heroin exposure abolishes the development of social withdrawal. This is the first result demonstrating that intermittent chronic MOR activation at the level of DRN represents an essential mechanism contributing to low sociability during protracted heroin abstinence. Altogether, our findings reveal crucial and distinct roles for all three opioid receptors in the development of emotional alterations that follow a history of heroin exposure and open the way towards understanding opioid system-mediated serotonin homeostasis in heroin abuse. PMID:24874714

Biomaterials Approaches for Utilizing the Regenerative Potential of the Peripheral Nerve Injury Microenvironment

NASA Astrophysics Data System (ADS)

Wrobel, Melissa Renee

Clinically available treatments are insufficient to achieve full functional recovery in large (> 3cm) peripheral nerve injuries (PNI). The objectives in this thesis were 1) to study often overlooked elements of intrinsic PNI repair including release of inhibitory CSPGs and post-injury responses of inflammatory macrophages and dedifferentiated Schwann cells; 2) to create biomaterial scaf-folds featuring topographical and adhesive cues to enhance neurite outgrowth; and 3) to test the ability of those cues to direct macrophages and Schwann cells towards a pro-regenerative phe-notype. It is hypothesized that recapitulating the positive and negative cues of the PNI microenvi-ronment can better improve regeneration. The effect of a characteristic CSPG, Chondroitin Sul-fate A (CSA), was tested on neurite dynamics of dissociated chick embryo dorsal root ganglion (DRG) neurons using time lapse video microscopy. DRG growth was recorded on different ad-hesive substrates, including a novel, porcine-derived spinal cord matrix (SCM). The SCM signifi-cantly increased neurite extension, reduced neurite stalling, and mitigated CSA inhibition. Flow cytometry was used to measure changes in cell-substrate binding receptor expression in the neurons. Results showed a significant increase in Syndecan-3 receptor expression in neurons treated with CSA, suggesting a possible priming of the cells for regrowth. The CSA was success-fully immobilized within electrospun hyaluronic acid (HA) nanofibers using a methacrylation re-action. Blended electrospinning was used to create scaffolds featuring the CSA and SCM cues. Results showed significantly increased neurite outgrowth on scaffolds with the SCM and low levels of CSA. Higher incorporation of CSA maintained its inhibitory properties. Next the CSA, SCM, and HA fiber cues were tested for their effects on macrophage and Schwann cell pheno-type. It was hypothesized that one or more of the cues would accelerate the macrophages return to rest following classical activation (M1/pro-inflammatory) with lipopolysaccharide (LPS; 1microg/mL) and would accelerate the transformation of Schwann cells from an immature state fol-lowing injury to a mature/pro-myelinating one. Cell phenotypes were functionally assessed using quantified reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence, and sandwich-ELISA based antibody arrays to measure changes in mRNA expression, mor-phology, and cytokine release, respectively. Macrophages cultured with the SCM and HA fibers had significantly reduced M1 gene expression, released lower levels of M1 cytokines (IL-1a, RANTES and TFN-a) and assumed an elongated morphology indicative of M2. These cues also induced changes in the Schwann cells including significantly reduced area, increased elongation, decreased expression of immature genes (GFAP) and increased expression of mature genes (Krox20 and Oct6). These results suggest that the SCM and HA nanofibers could trigger non-neuronal cells towards regenerative programs more quickly than traditional PNI interventions. Changes induced by biomaterials have distinct benefits over the use of immunomodulatory cy-tokines and would be a novel approach to direct repair. Our collective studies offer improved in-sight into the endogenous potential of the injured peripheral nerve and offer ways to incorporate intrinsic repair cues into a biomaterial system for treating large gaps.

Biomolecular characterization and protein sequences of the Campanian hadrosaur B. canadensis.

PubMed

Schweitzer, Mary H; Zheng, Wenxia; Organ, Chris L; Avci, Recep; Suo, Zhiyong; Freimark, Lisa M; Lebleu, Valerie S; Duncan, Michael B; Vander Heiden, Matthew G; Neveu, John M; Lane, William S; Cottrell, John S; Horner, John R; Cantley, Lewis C; Kalluri, Raghu; Asara, John M

2009-05-01

Molecular preservation in non-avian dinosaurs is controversial. We present multiple lines of evidence that endogenous proteinaceous material is preserved in bone fragments and soft tissues from an 80-million-year-old Campanian hadrosaur, Brachylophosaurus canadensis [Museum of the Rockies (MOR) 2598]. Microstructural and immunological data are consistent with preservation of multiple bone matrix and vessel proteins, and phylogenetic analyses of Brachylophosaurus collagen sequenced by mass spectrometry robustly support the bird-dinosaur clade, consistent with an endogenous source for these collagen peptides. These data complement earlier results from Tyrannosaurus rex (MOR 1125) and confirm that molecular preservation in Cretaceous dinosaurs is not a unique event.

Synthesis of new opioid derivatives with a propellane skeleton and their pharmacologies: Part 5, novel pentacyclic propellane derivatives with a 6-amide side chain.

PubMed

Nakajima, Ryo; Yamamoto, Naoshi; Hirayama, Shigeto; Iwai, Takashi; Saitoh, Akiyoshi; Nagumo, Yasuyuki; Fujii, Hideaki; Nagase, Hiroshi

2015-10-01

We designed and synthesized pentacyclic propellane derivatives with a 6-amide side chain to afford compounds with higher MOR/KOR ratio and lower sedative effects than nalfurafine. The obtained etheno-bridged derivative with a β-amide side chain, YNT-854, showed a higher MOR/KOR ratio than nalfurafine. YNT-854 also exhibited a higher dose ratio between the sedative effect and the analgesic effect than observed with nalfurafine, which may guide the future design of useful analgesics with a weaker sedative effect than nalfurafine. Copyright © 2015 Elsevier Ltd. All rights reserved.

Influence of model order reduction methods on dynamical-optical simulations

NASA Astrophysics Data System (ADS)

Störkle, Johannes; Eberhard, Peter

2017-04-01

In this work, the influence of model order reduction (MOR) methods on optical aberrations is analyzed within a dynamical-optical simulation of a high precision optomechanical system. Therefore, an integrated modeling process and new methods have to be introduced for the computation and investigation of the overall dynamical-optical behavior. For instance, this optical system can be a telescope optic or a lithographic objective. In order to derive a simplified mechanical model for transient time simulations with low computational cost, the method of elastic multibody systems in combination with MOR methods can be used. For this, software tools and interfaces are defined and created. Furthermore, mechanical and optical simulation models are derived and implemented. With these, on the one hand, the mechanical sensitivity can be investigated for arbitrary external excitations and on the other hand, the related optical behavior can be predicted. In order to clarify these methods, academic examples are chosen and the influences of the MOR methods and simulation strategies are analyzed. Finally, the systems are investigated with respect to the mechanical-optical frequency responses, and in conclusion, some recommendations for the application of reduction methods are given.

Endogenous central amygdala mu-opioid receptor signaling promotes sodium appetite in mice.

PubMed

Smith, Craig M; Walker, Lesley L; Leeboonngam, Tanawan; McKinley, Michael J; Denton, Derek A; Lawrence, Andrew J

2016-11-29

Due to the importance of dietary sodium and its paucity within many inland environments, terrestrial animals have evolved an instinctive sodium appetite that is commensurate with sodium deficiency. Despite a well-established role for central opioid signaling in sodium appetite, the endogenous influence of specific opioid receptor subtypes within distinct brain regions remains to be elucidated. Using selective pharmacological antagonists of opioid receptor subtypes, we reveal that endogenous mu-opioid receptor (MOR) signaling strongly drives sodium appetite in sodium-depleted mice, whereas a role for kappa (KOR) and delta (DOR) opioid receptor signaling was not detected, at least in sodium-depleted mice. Fos immunohistochemistry revealed discrete regions of the mouse brain displaying an increased number of activated neurons during sodium gratification: the rostral portion of the nucleus of the solitary tract (rNTS), the lateral parabrachial nucleus (LPB), and the central amygdala (CeA). The CeA was subsequently targeted with bilateral infusions of the MOR antagonist naloxonazine, which significantly reduced sodium appetite in mice. The CeA is therefore identified as a key node in the circuit that contributes to sodium appetite. Moreover, endogenous opioids, acting via MOR, within the CeA promote this form of appetitive behavior.

Complementary roles for amygdala and periaqueductal gray in temporal-difference fear learning.

PubMed

Cole, Sindy; McNally, Gavan P

2009-01-01

Pavlovian fear conditioning is not a unitary process. At the neurobiological level multiple brain regions and neurotransmitters contribute to fear learning. At the behavioral level many variables contribute to fear learning including the physical salience of the events being learned about, the direction and magnitude of predictive error, and the rate at which these are learned about. These experiments used a serial compound conditioning design to determine the roles of basolateral amygdala (BLA) NMDA receptors and ventrolateral midbrain periaqueductal gray (vlPAG) mu-opioid receptors (MOR) in predictive fear learning. Rats received a three-stage design, which arranged for both positive and negative prediction errors producing bidirectional changes in fear learning within the same subjects during the test stage. Intra-BLA infusion of the NR2B receptor antagonist Ifenprodil prevented all learning. In contrast, intra-vlPAG infusion of the MOR antagonist CTAP enhanced learning in response to positive predictive error but impaired learning in response to negative predictive error--a pattern similar to Hebbian learning and an indication that fear learning had been divorced from predictive error. These findings identify complementary but dissociable roles for amygdala NMDA receptors and vlPAG MOR in temporal-difference predictive fear learning.

Model Order Reduction of Aeroservoelastic Model of Flexible Aircraft

NASA Technical Reports Server (NTRS)

Wang, Yi; Song, Hongjun; Pant, Kapil; Brenner, Martin J.; Suh, Peter

2016-01-01

This paper presents a holistic model order reduction (MOR) methodology and framework that integrates key technological elements of sequential model reduction, consistent model representation, and model interpolation for constructing high-quality linear parameter-varying (LPV) aeroservoelastic (ASE) reduced order models (ROMs) of flexible aircraft. The sequential MOR encapsulates a suite of reduction techniques, such as truncation and residualization, modal reduction, and balanced realization and truncation to achieve optimal ROMs at grid points across the flight envelope. The consistence in state representation among local ROMs is obtained by the novel method of common subspace reprojection. Model interpolation is then exploited to stitch ROMs at grid points to build a global LPV ASE ROM feasible to arbitrary flight condition. The MOR method is applied to the X-56A MUTT vehicle with flexible wing being tested at NASA/AFRC for flutter suppression and gust load alleviation. Our studies demonstrated that relative to the fullorder model, our X-56A ROM can accurately and reliably capture vehicles dynamics at various flight conditions in the target frequency regime while the number of states in ROM can be reduced by 10X (from 180 to 19), and hence, holds great promise for robust ASE controller synthesis and novel vehicle design.

Proposal for Laser Cooling of Alkaline Earth Monoalkoxide Free Radicals

NASA Astrophysics Data System (ADS)

Baum, Louis; Kozyryev, Ivan; Matsuda, Kyle; Doyle, John M.

2016-05-01

Cold samples of polyatomic molecules will open new avenues in physics, chemistry, and quantum science. Non-diagonal Franck-Condon factors, technically challenging wavelengths, and the lack of strong electronic transitions inhibit direct laser cooling of nonlinear molecules. We identify a scheme for optical cycling in certain molecules with six or more atoms. Replacing hydrogen in alcohols with an alkaline earth metal (M) leads to alkaline earth monoalkoxide free radicals (MOR), which have favorable properties for laser cooling. M-O bond is very ionic, so the metal orbitals are slightly affected by the nature of R on the ligand. Diagonal Franck-Condon factors, laser accessible transitions, and a small hyperfine structure make MOR molecules suitable for laser cooling. We explore a scheme for optical cycling on the A - X transition of SrOCH3 . Molecules lost to dark vibrational states will be repumped on the B - X transition. Extension to larger species is possible through expansion of the R group since transitions involve the promotion of the metal-centered nonbonding valence electron. We will detail our estimations of the Franck-Condon factors, simulations of the cooling process and describe progress towards the Doppler cooling of MOR polyatomics.

Three dimensional graphene foam supported platinum-ruthenium bimetallic nanocatalysts for direct methanol and direct ethanol fuel cell applications

NASA Astrophysics Data System (ADS)

Kung, Chih-Chien; Lin, Po-Yuan; Xue, Yuhua; Akolkar, Rohan; Dai, Liming; Yu, Xiong; Liu, Chung-Chiun

2014-06-01

A novel composite material of hierarchically structured platinum-ruthenium (PtRu) nanoparticles grown on large surface area three dimensional graphene foam (3D GF) is reported. 3D GF was incorporated with PtRu bimetallic nanoparticles as an electrochemical nanocatalyst for methanol and ethanol oxidation. PtRu/3D GF nanocatalyst showed a higher tolerance to poisoning by CO and exhibited improved catalytic activity for both methanol oxidation reaction (MOR) and ethanol oxidation reaction (EOR). Cyclic voltammetry (CV) results and long-term cycling stability tests demonstrated that GF provided a promising platform for the development of electrochemical nanocatalysts. Specifically, PtRu/3D GF nanocatalyst showed excellent catalytic activity toward MOR and EOR compared with PtRu/Graphene (Commercial graphene), PtRu/C (Vulcan XC-72R carbon), and PtRu alone. The crystal size of PtRu on 3D GF was reduced to 3.5 nm and its active surface area was enhanced to 186.2 m2 g-1. Consequently, the MOR and EOR rates were nearly doubled on PtRu/3D GF compared to those on PtRu/Graphene.

β-Arrestins: Regulatory Role and Therapeutic Potential in Opioid and Cannabinoid Receptor-Mediated Analgesia

PubMed Central

Bohn, Laura M.

2016-01-01

Pain is a complex disorder with neurochemical and psychological components contributing to the severity, the persistence, and the difficulty in adequately treating the condition. Opioid and cannabinoids are two classes of analgesics that have been used to treat pain for centuries and are arguably the oldest of “pharmacological” interventions used by man. Unfortunately, they also produce several adverse side effects that can complicate pain management. Opioids and cannabinoids act at G protein-coupled receptors (GPCRs), and much of their effects are mediated by the mu-opioid receptor (MOR) and cannabinoid CB1 receptor (CB1R), respectively. These receptors couple to intracellular second messengers and regulatory proteins to impart their biological effects. In this chapter, we review the role of the intracellular regulatory proteins, β-arrestins, in modulating MOR and CB1R and how they influence the analgesic and side-effect profiles of opioid and cannabinoid drugs in vivo. This review of the literature suggests that the development of opioid and cannabinoid agonists that bias MOR and CB1R toward G protein signaling cascades and away from β-arrestin interactions may provide a novel mechanism by which to produce analgesia with less severe adverse effects. PMID:24292843

Endogenous central amygdala mu-opioid receptor signaling promotes sodium appetite in mice

PubMed Central

Smith, Craig M.; Walker, Lesley L.; Leeboonngam, Tanawan; McKinley, Michael J.; Denton, Derek A.; Lawrence, Andrew J.

2016-01-01

Due to the importance of dietary sodium and its paucity within many inland environments, terrestrial animals have evolved an instinctive sodium appetite that is commensurate with sodium deficiency. Despite a well-established role for central opioid signaling in sodium appetite, the endogenous influence of specific opioid receptor subtypes within distinct brain regions remains to be elucidated. Using selective pharmacological antagonists of opioid receptor subtypes, we reveal that endogenous mu-opioid receptor (MOR) signaling strongly drives sodium appetite in sodium-depleted mice, whereas a role for kappa (KOR) and delta (DOR) opioid receptor signaling was not detected, at least in sodium-depleted mice. Fos immunohistochemistry revealed discrete regions of the mouse brain displaying an increased number of activated neurons during sodium gratification: the rostral portion of the nucleus of the solitary tract (rNTS), the lateral parabrachial nucleus (LPB), and the central amygdala (CeA). The CeA was subsequently targeted with bilateral infusions of the MOR antagonist naloxonazine, which significantly reduced sodium appetite in mice. The CeA is therefore identified as a key node in the circuit that contributes to sodium appetite. Moreover, endogenous opioids, acting via MOR, within the CeA promote this form of appetitive behavior. PMID:27849613

PtRu nanoparticles embedded in nitrogen doped carbon with highly stable CO tolerance and durability

NASA Astrophysics Data System (ADS)

Ling, Ying; Yang, Zehui; Yang, Jun; Zhang, Yunfeng; Zhang, Quan; Yu, Xinxin; Cai, Weiwei

2018-02-01

As is well known, the lower durability and sluggish methanol oxidation reaction (MOR) of PtRu alloy electrocatalyst blocks the commercialization of direct methanol fuel cells (DMFCs). Here, we design a new PtRu electrocatalyst, with highly stable CO tolerance and durability, in which the PtRu nanoparticles are embedded in nitrogen doped carbon layers derived from carbonization of poly(vinyl pyrrolidone). The newly fabricated electrocatalyst exhibits no loss in electrochemical surface area (ECSA) and MOR activity after potential cycling from 0.6-1.0 V versus reversible hydrogen electrode, while commercial CB/PtRu retains only 50% of its initial ECSA. Meanwhile, due to the same protective layers, the Ru dissolution is decelerated, resulting in stable CO tolerance. Methanol oxidation reaction (MOR) testing indicates that the activity of newly fabricated electrocatalyst is two times higher than that of commercial CB/PtRu, and the fuel cell performance of the embedded PtRu electrocatalyst was comparable to that of commercial CB/PtRu. The embedded PtRu electrocatalyst is applicable in real DMFC operation. This study offers important and useful information for the design and fabrication of durable and CO tolerant electrocatalysts.

Mu-opioid receptors modulate the stability of dendritic spines

PubMed Central

Liao, Dezhi; Lin, Hang; Law, Ping Yee; Loh, Horace H.

2005-01-01

Opioids classically regulate the excitability of neurons by suppressing synaptic GABA release from inhibitory neurons. Here, we report a role for opioids in modulating excitatory synaptic transmission. By activating ubiquitously clustered μ-opioid receptor (MOR) in excitatory synapses, morphine caused collapse of preexisting dendritic spines and decreased synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Meanwhile, the opioid antagonist naloxone increased the density of spines. Chronic treatment with morphine decreased the density of dendritic spines even in the presence of Tetrodotoxin, a sodium channel blocker, indicating that the morphine's effect was not caused by altered activity in neural network through suppression of GABA release. The effect of morphine on dendritic spines was absent in transgenic mice lacking MORs and was blocked by CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2), a μ-receptor antagonist. These data together with others suggest that endogenous opioids and/or constitutive activity of MORs participate in maintaining normal morphology and function of spines, challenging the classical model of opioids. Abnormal alteration of spines may occur in drug addiction when opioid receptors are overactivated by exogenous opiates. PMID:15659552

Prevalence of heroin markers in urine for pain management patients.

PubMed

Knight, Julie; Puet, Brandi L; DePriest, Anne; Heltsley, Rebecca; Hild, Cheryl; Black, David L; Robert, Timothy; Caplan, Yale H; Cone, Edward J

2014-10-01

Surveys of current trends indicate heroin abuse is associated with nonmedical use of pain relievers. Consequently, there is an interest in evaluating the presence of heroin-specific markers in chronic pain patients who are prescribed controlled substances. A total of 926,084 urine specimens from chronic pain patients were tested for heroin/diacetylmorphine (DAM), 6-acetylmorphine (6AM), 6-acetylcodeine (6AC), codeine (COD), and morphine (MOR). Heroin and markers were analyzed using liquid chromatography tandem mass spectrometry (LC-MS-MS). Opiates were analyzed following hydrolysis using LC-MS-MS. The prevalence of heroin use was 0.31%, as 2871 were positive for one or more heroin-specific markers including DAM, 6AM, or 6AC (a known contaminant of illicit heroin). Of these, 1884 were additionally tested for the following markers of illicit drug use: 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), methamphetamine (MAMP), 11-nor-9-carboxy-Δ(9)-tetracannabinol (THCCOOH), and benzoylecgonine (BZE); 654 (34.7%) had positive findings for one or more of these analytes. The overall prevalence of heroin markers were as follows: DAM 1203 (41.9%), 6AM 2570 (89.5%), 6AC 1082 (37.7%). MOR was present in 2194 (76.4%) and absent (

Animal-related factors associated with moderate-to-severe diarrhea in children younger than five years in western Kenya: A matched case-control study

PubMed Central

Conan, Anne; O’Reilly, Ciara E.; Ogola, Eric; Ochieng, J. Benjamin; Blackstock, Anna J.; Omore, Richard; Ochieng, Linus; Moke, Fenny; Parsons, Michele B.; Xiao, Lihua; Roellig, Dawn; Farag, Tamer H.; Nataro, James P.; Kotloff, Karen L.; Levine, Myron M.; Mintz, Eric D.; Breiman, Robert F.; Cleaveland, Sarah

2017-01-01

Background Diarrheal disease remains among the leading causes of global mortality in children younger than 5 years. Exposure to domestic animals may be a risk factor for diarrheal disease. The objectives of this study were to identify animal-related exposures associated with cases of moderate-to-severe diarrhea (MSD) in children in rural western Kenya, and to identify the major zoonotic enteric pathogens present in domestic animals residing in the homesteads of case and control children. Methodology/Principal findings We characterized animal-related exposures in a subset of case and control children (n = 73 pairs matched on age, sex and location) with reported animal presence at home enrolled in the Global Enteric Multicenter Study in western Kenya, and analysed these for an association with MSD. We identified potentially zoonotic enteric pathogens in pooled fecal specimens collected from domestic animals resident at children’s homesteads. Variables that were associated with decreased risk of MSD were washing hands after animal contact (matched odds ratio [MOR] = 0.2; 95% CI 0.08–0.7), and presence of adult sheep that were not confined in a pen overnight (MOR = 0.1; 0.02–0.5). Variables that were associated with increased risk of MSD were increasing number of sheep owned (MOR = 1.2; 1.0–1.5), frequent observation of fresh rodent excreta (feces/urine) outside the house (MOR = 7.5; 1.5–37.2), and participation of the child in providing water to chickens (MOR = 3.8; 1.2–12.2). Of 691 pooled specimens collected from 2,174 domestic animals, 159 pools (23%) tested positive for one or more potentially zoonotic enteric pathogens (Campylobacter jejuni, C. coli, non-typhoidal Salmonella, diarrheagenic E. coli, Giardia, Cryptosporidium, or rotavirus). We did not find any association between the presence of particular pathogens in household animals, and MSD in children. Conclusions and significance Public health agencies should continue to promote frequent hand washing, including after animal contact, to reduce the risk of MSD. Future studies should address specific causal relations of MSD with sheep and chicken husbandry practices, and with the presence of rodents. PMID:28783751

Effects of sea-level changes on mid-ocean ridge magmatism and implications for emission rates of carbon.

NASA Astrophysics Data System (ADS)

Cerpa, N.; Katz, R. F.; Keller, T.

2017-12-01

Glacial cycles move water between ice sheets and the ocean, and hence cause regional pressure changes in the solid Earth. The rate of sea-level (SL) change during this cycle is comparable to the rate of mantle upwelling beneath mid-ocean ridges (MORs), and hence we expect the induced pressure variations to modify the rate and depth of silicate melting. SL variations may therefore induce changes in the supply and composition of magma at MORs, which could affect the flux of carbon into the climate system. Likewise, the trace-element geochemistry of magmas tapped by ridge volcanism may vary during these cycles due to variations in melt flux. Such variations may have been recorded by sediment-hosted volcanic glass fragments [Ferguson et al., 2017]. We investigate these questions using computational models of melt production and transport in which volatiles participate in the thermodynamics of melting. Published models of the effect of SL on MORs predict up to 10% variation in carbon emission rates for absolute changes in SL of 50-100 m with possible lag times of several tens of kyrs [Burley et al., 2015; Hasenclever et al., 2017]. A major assumption of those models is that water and carbon are passive, incompatible elements. But small concentrations of those volatiles affect the solidus of mantle peridotite and increase the volume of upper mantle undergoing partial melting. Hence the current predictions of variation in MOR carbon emission might be an underestimate. Moreover, published models neglect the effects of volatiles on melt transport. Recents studies have demonstrated that volatiles can induce channelized transport [Keller and Katz 2016], potentially affecting the rate at which carbon is extracted from the mantle. In this study, we investigate the interplay between SL variations, melting, and segregation of volatile-rich melts. We use two-phase magma/mantle dynamics coupled to melting models that treat water and carbon dioxide as thermodynamic components. We compare models of equilibrium and disequilibrium melting to assess the influence of reaction kinetics on magma productivity at MORs during SL variations. Our calculations provide new estimates of the lag and amplitude of carbon emissions during glacial cycles. We address the impact of SL variations on the trace-element composition of magmas.

Implausibility of the vibrational theory of olfaction

DOE PAGES

Block, Eric; Ertem, Mehmed Z.; Jang, Seogjoo; ...

2015-04-21

The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies, ultimately leading to olfactory perception. A previous study reported that human subjects differentiated hydrogen/deuterium isotopomers (isomers with isotopic atoms) of the musk compound cyclopentadecanone as evidence supporting the theory. Here, we find no evidence for such differentiation at the molecular level. In fact, we find that the human musk-recognizing receptor, OR5AN1, identified using a heterologous OR expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of thesemore » compounds in vitro. Furthermore, the mouse (methylthio)methanethiol (MTMT)-recognizing receptor, MOR244-3, and other selected human and mouse ORs, responded similarly to normal, deuterated, and ¹³C isotopomers of their respective ligands, paralleling our results with the musk receptor OR5AN1. These findings suggest that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other ORs examined. Also, contrary to the vibration theory predictions, muscone-d₃₀ lacks the 1,380-1,550 cm⁻¹ IR bands claimed to be essential for musk odor. Furthermore, our theoretical analysis shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of non-odorant molecular vibrational modes. As a result, these and other concerns about electron transfer at ORs, together with our extensive experimental data, argue against the plausibility of the vibration theory.« less

Implausibility of the vibrational theory of olfaction

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

Block, Eric; Ertem, Mehmed Z.; Jang, Seogjoo

The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies, ultimately leading to olfactory perception. A previous study reported that human subjects differentiated hydrogen/deuterium isotopomers (isomers with isotopic atoms) of the musk compound cyclopentadecanone as evidence supporting the theory. Here, we find no evidence for such differentiation at the molecular level. In fact, we find that the human musk-recognizing receptor, OR5AN1, identified using a heterologous OR expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of thesemore » compounds in vitro. Furthermore, the mouse (methylthio)methanethiol (MTMT)-recognizing receptor, MOR244-3, and other selected human and mouse ORs, responded similarly to normal, deuterated, and ¹³C isotopomers of their respective ligands, paralleling our results with the musk receptor OR5AN1. These findings suggest that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other ORs examined. Also, contrary to the vibration theory predictions, muscone-d₃₀ lacks the 1,380-1,550 cm⁻¹ IR bands claimed to be essential for musk odor. Furthermore, our theoretical analysis shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of non-odorant molecular vibrational modes. As a result, these and other concerns about electron transfer at ORs, together with our extensive experimental data, argue against the plausibility of the vibration theory.« less

Engineering endomorphin drugs: state of the art

PubMed Central

Lazarus, Lawrence H; Okada, Yoshio

2011-01-01

Importance of the field Although EM-1 (H-Tyr-Pro-Phe-Trp-NH2) and EM-2 (H-Tyr-Pro-Phe-Phe-NH2) are primarily considered agonists for the μ-opioid receptor (MOR), systematic alterations to specific residues provided antagonists and ligands with mixed μ/δ-opioid properties suitable for application to health related topics. Areas covered in this review This review attempts to succinctly provide insight on the development and bioactivity of endomorphin analogues during the past decade. Rational design approaches will focus on the engineering of endomorphin agonists, antagonists and mixed ligands for their application as a multi-target ligand. What the reader will gain While the application of endomorphins as antinociceptive agents and numerous biological endpoints were experimental delineated in laboratory animals and in vitro, clinical use is currently absent. However, structural alterations provide enhanced stability, formation of MOR antagonists or mixed and dual μ/δ-acting ligands could find considerable therapeutic potential. Take home message Aside from alleviating pain, EM analogues open new horizons in the treatment of medical syndromes involving neural reward mechanisms and extraneural regulation effects on homeostasis. Highly selective MOR antagonists may be promising to reduce inflammation, attenuate addiction to drugs and excess consumption of high caloric food, ameliorate alcoholism, affect the immune system and combat opioid bowel dysfunction. PMID:22214283

New Geochemical Analyses Reveal Crustal Accretionary Processes at The Overlapping Spreading Center Near 3 N East Pacific Rise

NASA Astrophysics Data System (ADS)

Smithka, I. N.; Perfit, M. R.

2013-12-01

Mid-ocean ridges (MORs) are the sites of oceanic lithosphere creation and construction. Ridge discontinuities are a global phenomenom but are not as well understood as ridge axes. Geochemical analyses provide insights into upper mantle processes since elements fractionate with melting and freezing as well as reside in material to retain source signature. Lavas collected from ridge discontinuities consist of greater chemical diversity and represent variations in source, melting parameters, and local crustal processes. The small overlapping spreading center (OSC) near the third parallel north on the East Pacific Rise has been superficially analyzed previously, but here we present new isotope analyses and expand our understanding of MOR processes and processes near OSCs. Initial analyses of lavas collected in 2000 on AHA-NEMO2 revealed normal MOR basalt trends in rare earth element enrichments as well as in major element concentrations. Crystal fractionation varies along the tips of both axes, with MgO and TiO2 concentrations increasing towards the OSC basin. Newly analyzed Sr, Nd, and Pb isotope ratios will further constrain the nature of geochemical diversity along axis. As the northern tip seems to be propagating and the southern tip dying, lavas collected from each may reflect two different underlying mantle melting and magma storage processes.

Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain.

PubMed

Miranda, Hugo F; Noriega, Viviana; Zanetta, Pilar; Prieto, Juan Carlos; Prieto-Rayo, Juan Carlos; Aranda, Nicolás; Sierralta, Fernando

2014-07-15

Opioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated. The potency of opioids in the writhing test compared to the hot plate assay was from 2.5 (fentanyl) to 15.5 (morphine) times, respectively. The ED50 was used in a fixed ratio for each of the six pairs of opioid combinations, which, resulted in a synergistic antinociception except for methadone/tramadol and fentanyl/tramadol which were additive, in the hot plate. The opioid antagonists naltrexone, naltrindole and nor-binaltorphimine, suggests that the synergism of morphine combinations are due to the activation of MOR subtypes with partially contribution of DOR and KOR, however fentanyl and methadone combinations are partially due to the activation of MOR and DOR subtypes and KOR lack of participation. The antinociceptive effects of tramadol combinations, are partially due to the activation of MOR, DOR and KOR opioid subtypes. These results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity.

Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain

PubMed Central

2014-01-01

Background Opioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated. Results The potency of opioids in the writhing test compared to the hot plate assay was from 2.5 (fentanyl) to 15.5 (morphine) times, respectively. The ED50 was used in a fixed ratio for each of the six pairs of opioid combinations, which, resulted in a synergistic antinociception except for methadone/tramadol and fentanyl/tramadol which were additive, in the hot plate. The opioid antagonists naltrexone, naltrindole and nor-binaltorphimine, suggests that the synergism of morphine combinations are due to the activation of MOR subtypes with partially contribution of DOR and KOR, however fentanyl and methadone combinations are partially due to the activation of MOR and DOR subtypes and KOR lack of participation. The antinociceptive effects of tramadol combinations, are partially due to the activation of MOR, DOR and KOR opioid subtypes. Conclusion These results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity. PMID:25017386

Electrocatalytic performance of Pt nanoparticles sputter-deposited on indium tin oxide toward methanol oxidation reaction: The particle size effect

NASA Astrophysics Data System (ADS)

Ting, Chao-Cheng; Chao, Chih-Hsuan; Tsai, Cheng Yu; Cheng, I.-Kai; Pan, Fu-Ming

2017-09-01

We sputter-deposited Pt nanoparticles with an average size ranging from 2.0 nm to 8.5 nm on the indium-tin oxide (ITO) glass substrate, and studied the effect of the size of Pt nanoparticles on electrocatalytic activity of the Pt/ITO electrode toward methanol oxidation reaction (MOR) in acidic solution. X-ray photoelectron spectroscopy (XPS) reveals an interfacial oxidized Pt layer present between Pt nanoparticles and the ITO substrate, which may modify the surface electronic structure of Pt nanoparticles and thus influences the electrocatalytic properties of the Pt catalyst toward MOR. According to electrochemical analyses, smaller Pt nanoparticles exhibit slower kinetics for CO electrooxidation and MOR. However, a smaller particle size enables better CO tolerance because the bifunctional mechanism is more effective on smaller Pt nanoparticles. The electrocatalytic activity decays rapidly for Pt nanoparticles with a size smaller than 3 nm and larger than 8 nm. The rapid activity decay is attributed to Pt dissolution for smaller nanoparticles and to CO poisoning for larger ones. Pt nanoparticles of 5-6 nm in size loaded on ITO demonstrate a greatly improved electrocatalytic activity and stability compared with those deposited on different substrates in our previous studies.

Challenges and Experiences of Building Multidisciplinary Datasets across Cultures

NASA Astrophysics Data System (ADS)

Jamiyansharav, K.; Laituri, M.; Fernandez-Gimenez, M.; Fassnacht, S. R.; Venable, N. B. H.; Allegretti, A. M.; Reid, R.; Baival, B.; Jamsranjav, C.; Ulambayar, T.; Linn, S.; Angerer, J.

2017-12-01

Efficient data sharing and management are key challenges to multidisciplinary scientific research. These challenges are further complicated by adding a multicultural component. We address the construction of a complex database for social-ecological analysis in Mongolia. Funded by the National Science Foundation (NSF) Dynamics of Coupled Natural and Human (CNH) Systems, the Mongolian Rangelands and Resilience (MOR2) project focuses on the vulnerability of Mongolian pastoral systems to climate change and adaptive capacity. The MOR2 study spans over three years of fieldwork in 36 paired districts (Soum) from 18 provinces (Aimag) of Mongolia that covers steppe, mountain forest steppe, desert steppe and eastern steppe ecological zones. Our project team is composed of hydrologists, social scientists, geographers, and ecologists. The MOR2 database includes multiple ecological, social, meteorological, geospatial and hydrological datasets, as well as archives of original data and survey in multiple formats. Managing this complex database requires significant organizational skills, attention to detail and ability to communicate within collective team members from diverse disciplines and across multiple institutions in the US and Mongolia. We describe the database's rich content, organization, structure and complexity. We discuss lessons learned, best practices and recommendations for complex database management, sharing, and archiving in creating a cross-cultural and multi-disciplinary database.

Distortion in the spacer region of Pm during activation of middle transcription of phage Mu.

PubMed Central

Artsimovitch, I; Kahmeyer-Gabbe, M; Howe, M M

1996-01-01

Transcription from the middle promoter, Pm, of phage Mu is initiated by Escherichia coli RNA polymerase holoenzyme (E sigma 70; RNAP) and the phage-encoded activator, Mor. Point mutations in the spacer region between the -10 hexamer and the Mor binding site result in changes of promoter activity in vivo. These mutations are located at the junction between a rigid T-tract and adjacent, potentially deformable G + C-rich DNA segment, suggesting that deformation of the spacer region may play a role in the transcriptional activation of Pm. This prediction was tested by using dimethyl sulfate and potassium permanganate footprinting analyses. Helical distortion involving strand separation was detected at positions -32 to -34, close to the predicted interface between Mor and RNAP. Promoter mutants in which this distortion was not detected exhibited a lack of melting in the -12 to -1 region and reduced promoter activity in vivo. We propose that complexes containing the distortion represent stressed intermediates rather than stable open complexes and thus can be envisaged as a transition state in the kinetic pathway of Pm activation in which stored torsional energy could be used to facilitate melting around the transcription start point. Images Fig. 2 Fig. 3 Fig. 4 PMID:8790343

Increased mortality odds ratio of male liver cancer in a community contaminated by chlorinated hydrocarbons in groundwater

PubMed Central

Lee, L; Chung, C; Ma, Y; Wang, G; Chen, P; Hwang, Y; Wang, J

2003-01-01

Aims: To investigate the association between cancer mortality risk and exposure to chlorinated hydrocarbons in groundwater of a downstream community near a contaminated site. Methods: Death certificates inclusive for the years 1966–97 were collected from two villages in the vicinity of an electronics factory operated between 1970 and 1992. These two villages were classified into the downstream (exposed) village and the upstream (unexposed) according to groundwater flow direction. Exposure classification was validated by the contaminant levels in 49 residential wells measured with gas chromatography/mass spectrometry. Mortality odds ratios (MORs) for cancer were calculated with cardiovascular-cerebrovascular diseases as the reference diseases. Multiple logistic regressions were performed to estimate the effects of exposure and period after adjustment for age. Results: Increased MORs were observed among males for all cancer, and liver cancer for the periods after 10 years of latency, namely, 1980–89, and 1990–97. Adjusted MOR for male liver cancer was 2.57 (95% confidence interval 1.21 to 5.46) with a significant linear trend for the period effect. Conclusion: The results suggest a link between exposure to chlorinated hydrocarbons and male liver cancer risk. However, the conclusion is limited by lack of individual information on groundwater exposure and potential confounding factors. PMID:12709523

Noble metals in mid-ocean ridge volcanism: A significant fractionation of gold with respect to platinum group metals

NASA Technical Reports Server (NTRS)

Crocket, James H.

1988-01-01

Hydrothermal precipitates, black smoker particulate, and massive sulphide dredge samples from the Explorer Ridge on the Juan de Fuca Plate and the TAG hydrothermal area on the Mid-Atlantic Ridge were analyzed for selected noble metals including Au, Ir and Pd by radiochemical neutron activation analysis. The preliminary results indicate that gold contents may reach the ppm range although values in the neighborhood of 100 to 200 ppb are more typical. The platinum group elements (PGE) represented by Ir and Pd are typically less than 0.02 ppb and less than 2 ppb respectively. These abundances represent a significant enrichment of gold relative to the PGE in comparison with average noble metal abundances in mid-ocean ridge basalts (MORB). A partial explanation of this distinctive fractionation can be found in the concepts of sulfur-saturation of basic magma in mid-ocean ridge (MOR) settings, and the origin of MOR hydrothermal fluids. Experimental and petrological data suggest that MORBs are sulfur-saturated at the time of magma generation and that an immiscible sulfide component remains in the mantle residue. Hence, MORBs are noble metal-poor, particularly with respect to PGE. Consequently, black smoker fluids can be expected to reflect the low Ir and Pd contents of the rock column. The average Au content of MORB is 1.3 ppb, and so the rock column is not significantly enriched in Au. The generation of fluids which precipitate solids with 200 ppb Au is apparently dependent on highly efficient fluid chemistry to mobilize Au from the rock column, high Au solubility in seawater hydrothermal fluids and efficient precipitation mechanisms to coprecipitate Au on Fe, Zn and Cu sulfides. Significant differences in these parameters appear to be the ultimate cause of the strong Au-PGE fractionation in the MOR setting. It does not appear from the current data base that MOR hydrothermal fluids are significant contributors to the Ir enrichment seen in Cretaceous-Tertiary boundary sediments.

Risk factors for headache in the UK military: cross-sectional and longitudinal analyses.

PubMed

Rona, Roberto J; Jones, Margaret; Goodwin, Laura; Hull, Lisa; Wessely, Simon

2013-05-01

To assess the importance of service demographic, mental disorders, and deployment factors on headache severity and prevalence, and to assess the impact of headache on functional impairment. There is no information on prevalence and risk factors of headache in the UK military. Recent US reports suggest that deployment, especially a combat role, is associated with headache. Such an association may have serious consequences on personnel during deployment. A survey was carried out between 2004 and 2006 (phase 1) and again between 2007 and 2009 (phase 2) of randomly selected UK military personnel to study the health consequences of the Iraq and Afghanistan wars. This study is based on those who participated in phase 2 and includes cross-sectional and longitudinal analyses. Headache severity in the last month and functional impairment at phase 2 were the main outcomes. Forty-six percent complained of headache in phase 2, half of whom endorsed moderate or severe headache. Severe headache was strongly associated with probable post-traumatic stress disorder (multinomial odds ratio [MOR] 9.6, 95% confidence interval [CI] 6.4-14.2), psychological distress (MOR 6.15, 95% CI 4.8-7.9), multiple physical symptoms (MOR 18.2, 95% CI 13.4-24.6) and self-reported mild traumatic brain injury (MOR 3.5, 95% CI 1.4-8.6) after adjustment for service demographic factors. Mild headache was also associated with these variables but at a lower level. Moderate and severe headache were associated with functional impairment, but the association was partially explained by mental disorders. Mental ill health was also associated with reporting moderate and severe headache at both phase 1 and phase 2. Deployment and a combat role were not associated with headache. Moderate and severe headache are common in the military and have an impact on functional impairment. They are more strongly associated with mental disorders than with mild traumatic brain injury. © 2013 American Headache Society.

Changes in Receipt of Cancer Screening in Medicare Beneficiaries Following the Affordable Care Act

PubMed Central

Kou, Tzuyung D.; Schluchter, Mark D.; Dor, Avi; Koroukian, Siran M.

2016-01-01

Background: The Affordable Care Act (ACA) removed copayments for screening mammography and colonoscopy in Medicare beneficiaries, but its clinical impact is unknown. Methods: Using a 5% random sample of Medicare claims from 2009 through 2012 in individuals age 70 years or older who were due for screening, we examined claims for screening mammography and screening or surveillance colonoscopy for two years prior to ACA (2009–2010) and two years post-ACA (2011–2012). Receipt of the procedures at the patient level was compared across years using generalized estimating equations. Statistical tests were two-sided. Results: Compared with 2009, we found an increase in mammography uptake during the ACA coverage period, with multivariable odds ratios (MOR) of 1.22 (95% confidence interval [CI] = 1.20 to 1.25, P < .001) for 2011 and 1.17 (95% CI = 1.15 to 1.20, P < .001) for 2012 and less change in 2010 (OR = 1.03, 95% CI = 1.01 to 1.05, P = .01). In contrast to mammography, uptake of screening or surveillance colonoscopy decreased in 2012 (MOR = 0.95, 95% CI = 0.92 to 0.98, P = .002) compared with 2009, with no change in 2010 (MOR = 1.01, 95% CI = 0.99 to 1.04, P = .47) or 2011 (MOR = 1.01, 95% CI = 0.99 to 1.04, P = .34). Other factors associated with procedure receipt included younger age and prior preventive health visits. In an analysis restricted to patients age 70 to 74 years, colonoscopy use increased slightly in 2011 but was unchanged in 2012, and the findings by year for mammography were consistent with the main analysis. Conclusions: Following ACA implementation with concomitant reduction in out-of-pocket expenditures, there was a statistically significant increment in mammography uptake but not colonoscopy. This suggests that affordability is a necessary but not sufficient facilitator of preventive services. PMID:26640244

Changes in Receipt of Cancer Screening in Medicare Beneficiaries Following the Affordable Care Act.

PubMed

Cooper, Gregory S; Kou, Tzuyung D; Schluchter, Mark D; Dor, Avi; Koroukian, Siran M

2016-05-01

The Affordable Care Act (ACA) removed copayments for screening mammography and colonoscopy in Medicare beneficiaries, but its clinical impact is unknown. Using a 5% random sample of Medicare claims from 2009 through 2012 in individuals age 70 years or older who were due for screening, we examined claims for screening mammography and screening or surveillance colonoscopy for two years prior to ACA (2009-2010) and two years post-ACA (2011-2012). Receipt of the procedures at the patient level was compared across years using generalized estimating equations. Statistical tests were two-sided. Compared with 2009, we found an increase in mammography uptake during the ACA coverage period, with multivariable odds ratios (MOR) of 1.22 (95% confidence interval [CI] = 1.20 to 1.25, P < .001) for 2011 and 1.17 (95% CI = 1.15 to 1.20, P < .001) for 2012 and less change in 2010 (OR = 1.03, 95% CI = 1.01 to 1.05, P = .01). In contrast to mammography, uptake of screening or surveillance colonoscopy decreased in 2012 (MOR = 0.95, 95% CI = 0.92 to 0.98, P = .002) compared with 2009, with no change in 2010 (MOR = 1.01, 95% CI = 0.99 to 1.04, P = .47) or 2011 (MOR = 1.01, 95% CI = 0.99 to 1.04, P = .34). Other factors associated with procedure receipt included younger age and prior preventive health visits. In an analysis restricted to patients age 70 to 74 years, colonoscopy use increased slightly in 2011 but was unchanged in 2012, and the findings by year for mammography were consistent with the main analysis. Following ACA implementation with concomitant reduction in out-of-pocket expenditures, there was a statistically significant increment in mammography uptake but not colonoscopy. This suggests that affordability is a necessary but not sufficient facilitator of preventive services. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Differences in adults' health and health behaviour between 16 European urban areas and the associations with socio-economic status and physical and social environment.

PubMed

de Gelder, Rianne; Koster, Emmy M; van Buren, Laurens P; van Ameijden, Erik J C; Harrison, Annie; Birt, Christopher A; Verma, Arpana

2017-05-01

With a growing proportion of the European population living in urban areas (UAs), exploring health in urban areas becomes increasingly important. The objective of this study is to assess the magnitude of differences in health and health behaviour between adults living in urban areas (UAs) across Europe. We also explored whether and to what extent such differences can be explained by socio-economic status (SES) and physical or social environment. Data were obtained from a cross-sectional questionnaire survey, performed between as part of the European Urban Health Indicator System Part 2 (EURO-URHIS 2) project. Using multi-level logistic regression analysis, UA differences in psychological distress, self-assessed health, overweight and obesity, daily smoking, binge drinking and physical exercise were assessed. Median Odds Ratios (MORs) were calculated to estimate the extent to which the observed variance is attributable to UA, individual-level SES (measured by perceived financial strains, education level and employment status) and/or characteristics of physical and social environment. The dataset included 14 022 respondents in 16 UAs within 9 countries. After correction for age and gender, all MORs, except that for daily smoking, indicated statistically significant UA health differences. SES indicators (partly) explained UA differences in psychological distress, decreasing the MOR from 1.43 [95% credible interval (Cr.I.) 1.27-1.67, baseline model], to 1.25 (95% Cr.I. 1.14-1.40, SES model): a reduction of 42%. Accounting for the quality of green areas reduced the MOR for psychological distress by an additional 40%, to 1.15 (95% Cr.I. 1.05-1.28). Our study showed large differences in health and health behaviour between European UAs. Reducing socio-economic disadvantage and improving the quality of the neighbourhood's green spaces may reduce UA differences in psychological distress. © The Author 2016. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

Weak Lensing by Galaxy Clusters: from Pixels to Cosmology

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

Gruen, Daniel

The story of the origin and evolution of our Universe is told, equivalently, by space-time itself and by the structures that grow inside of it. Clusters of galaxies are the frontier of bottom-up structure formation. They are the most massive objects to have collapsed at the present epoch. By that virtue, their abundance and structural parameters are highly sensitive to the composition and evolution of the Universe. The most common probe of cluster cosmology, abundance, uses samples of clusters selected by some observable. Applying a mass-observable relation (MOR), cosmological parameters can be constrained by comparing the sample to predicted clustermore » abundances as a function of observable and redshift. Arguably, however, cluster probes have not yet entered the era of per cent level precision cosmology. The primary reason for this is our imperfect understanding of the MORs. The overall normalization, the slope of mass vs. observable, the redshift evolution, and the degree and correlation of intrinsic scatters of observables at fixed mass have to be constrained for interpreting abundances correctly. Mass measurement of clusters by means of the differential deflection of light from background sources in their gravitational field, i.e. weak lensing, is a powerful approach for achieving this. This thesis presents new methods for and scientific results of weak lensing measurements of clusters of galaxies. The former include, on the data reduction side, (i) the correction of CCD images for non-linear effects due to the electric fields of accumulated charges and (ii) a method for masking artifact features in sets of overlapping images of the sky by comparison to the median image. Also, (iii) I develop a method for the selection of background galaxy samples based on their color and apparent magnitude that includes a new correction for contamination with cluster member galaxies. The main scientific results are the following. (i) For the Hubble Frontier Field cluster RXC J2248.7--4431 our lensing analysis constrains mass and concentration of the cluster halo and we confirm the large mass predicted by X-ray and Sunyaev-Zel’dovich (SZ) observations. The study of cluster members shows the relation of galaxy morphology to luminosity and environment. (ii) Our lensing mass measurements for 12 clusters are consistent with X-ray masses derived under the assumption of hydrostatic equilibrium of the intra-cluster gas. We confirm the MORs derived by the South Pole Telescope collaboration for the detection significance of the cluster SZ signal in their survey. We find discrepancies, however, with the Planck SZ MOR. We hypothesize that these are related either to a shallower slope of the MOR or a size-, redshift- or noise-dependent bias in SZ signal extraction. (iii) Finally, using a combination of simulations and theoretical models for the variation of cluster profiles at fixed mass, we find that the latter is a significant contribution to the uncertainty of cluster lensing mass measurements. A cosmic variance model, such as the one we develop, is necessary for MOR constraints to be accurate at the level required for future surveys.« less

Surface tailored single walled carbon nanotubes as catalyst support for direct methanol fuel cell

NASA Astrophysics Data System (ADS)

Kireeti, Kota V. M. K.; Jha, Neetu

2017-10-01

A strategy for tuning the surface property of Single Walled Carbon Nanotubes (SWNTs) for enhanced methanol oxidation reaction (MOR) and oxygen reduction reaction (ORR) along with methanol tolerance is presented. The surface functionality is tailored using controlled acid and base treatment. Acid treatment leads to the attachment of carboxylic carbon (CC) fragments to SWNT making it hydrophilic (P3-SWNT). Base treatment of P3-SWNT with 0.05 M NaOH reduces the CCs and makes it hydrophobic (P33-SWNT). Pt catalyst supported on the P3-SWNT possesses enhanced MOR whereas that supported on P33-SWNT not only enhances ORR kinetics but also possess good tolerance towards methanol oxidation as verified by the electrochemical technique.

Effect of paleoseawater composition on hydrothermal exchange in midocean ridges

NASA Astrophysics Data System (ADS)

Antonelli, Michael A.; Pester, Nicholas J.; Brown, Shaun T.; DePaolo, Donald J.

2017-11-01

Variations in the Mg, Ca, Sr, and SO4 concentrations of paleoseawater can affect the chemical exchange between seawater and oceanic basalt in hydrothermal systems at midocean ridges (MOR). We present a model for evaluating the nature and magnitude of these previously unappreciated effects, using available estimates of paleoseawater composition over Phanerozoic time as inputs and 87Sr/86Sr of ophiolite epidosites and epidote-quartz veins as constraints. The results suggest that modern hydrothermal fluids are not typical due to low Ca and Sr relative to Mg and SO4 in modern seawater. At other times during the last 500 million years, particularly during the Cretaceous and Ordovician, hydrothermal fluids had more seawater-derived Sr and Ca, a prediction that is supported by Sr isotope data. The predicted 87Sr/86Sr of vent fluids varies cyclically in concert with ocean chemistry, with some values much higher than the modern value of ˜0.7037. The seawater chemistry effects can be expressed in terms of the transfer efficiency of basaltic Ca and Sr to seawater in hydrothermal systems, which varies by a factor of ˜1.6 over the Phanerozoic, with minima when seawater Mg and SO4 are low. This effect provides a modest negative feedback on seawater composition and 87Sr/86Sr changes. For the mid-Cretaceous, the low 87Sr/86Sr of seawater requires either exceptionally large amounts of low-temperature exchange with oceanic crust or that the weathering flux of continentally derived Sr was especially small. The model also has implications for MOR hydrothermal systems in the Precambrian, when low-seawater SO4 could help explain low seawater 87Sr/86Sr.

Undertreatment of acute pain (oligoanalgesia) and medical practice variation in prehospital analgesia of adult trauma patients: a 10 yr retrospective study.

PubMed

Albrecht, E; Taffe, P; Yersin, B; Schoettker, P; Decosterd, I; Hugli, O

2013-01-01

Prehospital oligoanalgesia is prevalent among trauma victims, even when the emergency medical services team includes a physician. We investigated if not only patients' characteristics but physicians' practice variations contributed to prehospital oligoanalgesia. Patient records of conscious adult trauma victims transported by our air rescue helicopter service over 10 yr were reviewed retrospectively. Oligoanalgesia was defined as a numeric rating scale (NRS) >3 at hospital admission. Multilevel logistic regression analysis was used to predict oligoanalgesia, accounting first for patient case-mix, and then physician-level clustering. The intraclass correlation was expressed as the median odds ratio (MOR). A total of 1202 patients and 77 physicians were included in the study. NRS at the scene was 6.9 (1.9). The prevalence of oligoanalgesia was 43%. Physicians had a median of 5.7 yr (inter-quartile range: 4.2-7.5) of post-graduate training and 27% were female. In our multilevel analysis, significant predictors of oligoanalgesia were: no analgesia [odds ratio (OR) 8.8], National Advisory Committee for Aeronautics V on site (OR 4.4), NRS on site (OR 1.5 per additional NRS unit >4), female physician (OR 2.0), and years of post-graduate experience [>4.0 to ≤5.0 (OR 1.3), >3.0 to ≤4.0 (OR 1.6), >2.0 to ≤3.0 (OR 2.6), and ≤2.0 yr (OR 16.7)]. The MOR was 2.6, and was statistically significant. Physicians' practice variations contributed to oligoanalgesia, a factor often overlooked in analyses of prehospital pain management. Further exploration of the sources of these variations may provide innovative targets for quality improvement programmes to achieve consistent pain relief for trauma victims.

Effect of paleoseawater composition on hydrothermal exchange in midocean ridges

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

Antonelli, Michael A.; Pester, Nicholas J.; Brown, Shaun T.

Variations in the Mg, Ca, Sr, and SO 4 concentrations of paleoseawater can affect the chemical exchange between seawater and oceanic basalt in hydrothermal systems at midocean ridges (MOR). Here, we present a model for evaluating the nature and magnitude of these previously unappreciated effects, using available estimates of paleoseawater composition over Phanerozoic time as inputs and 87Sr/ 86Sr of ophiolite epidosites and epidote-quartz veins as constraints. The results suggest that modern hydrothermal fluids are not typical due to low Ca and Sr relative to Mg and SO 4 in modern seawater. At other times during the last 500 millionmore » years, particularly during the Cretaceous and Ordovician, hydrothermal fluids had more seawater-derived Sr and Ca, a prediction that is supported by Sr isotope data. The predicted 87Sr/ 86Sr of vent fluids varies cyclically in concert with ocean chemistry, with some values much higher than the modern value of ~0.7037. The seawater chemistry effects can be expressed in terms of the transfer efficiency of basaltic Ca and Sr to seawater in hydrothermal systems, which varies by a factor of ~1.6 over the Phanerozoic, with minima when seawater Mg and SO 4 are low. This effect provides a modest negative feedback on seawater composition and 87Sr/ 86Sr changes. For the mid-Cretaceous, the low 87Sr/ 86Sr of seawater requires either exceptionally large amounts of low-temperature exchange with oceanic crust or that the weathering flux of continentally derived Sr was especially small. Lastly, the model also has implications for MOR hydrothermal systems in the Precambrian, when low-seawater SO 4 could help explain low seawater 87Sr/ 86Sr.« less

Effect of paleoseawater composition on hydrothermal exchange in midocean ridges

DOE PAGES

Antonelli, Michael A.; Pester, Nicholas J.; Brown, Shaun T.; ...

2017-11-06

Variations in the Mg, Ca, Sr, and SO 4 concentrations of paleoseawater can affect the chemical exchange between seawater and oceanic basalt in hydrothermal systems at midocean ridges (MOR). Here, we present a model for evaluating the nature and magnitude of these previously unappreciated effects, using available estimates of paleoseawater composition over Phanerozoic time as inputs and 87Sr/ 86Sr of ophiolite epidosites and epidote-quartz veins as constraints. The results suggest that modern hydrothermal fluids are not typical due to low Ca and Sr relative to Mg and SO 4 in modern seawater. At other times during the last 500 millionmore » years, particularly during the Cretaceous and Ordovician, hydrothermal fluids had more seawater-derived Sr and Ca, a prediction that is supported by Sr isotope data. The predicted 87Sr/ 86Sr of vent fluids varies cyclically in concert with ocean chemistry, with some values much higher than the modern value of ~0.7037. The seawater chemistry effects can be expressed in terms of the transfer efficiency of basaltic Ca and Sr to seawater in hydrothermal systems, which varies by a factor of ~1.6 over the Phanerozoic, with minima when seawater Mg and SO 4 are low. This effect provides a modest negative feedback on seawater composition and 87Sr/ 86Sr changes. For the mid-Cretaceous, the low 87Sr/ 86Sr of seawater requires either exceptionally large amounts of low-temperature exchange with oceanic crust or that the weathering flux of continentally derived Sr was especially small. Lastly, the model also has implications for MOR hydrothermal systems in the Precambrian, when low-seawater SO 4 could help explain low seawater 87Sr/ 86Sr.« less

Alterations in opioid inhibition cause widespread nociception but do not affect anxiety-like behavior in oral cancer mice.

PubMed

Ye, Yi; Bernabé, Daniel G; Salvo, Elizabeth; Viet, Chi T; Ono, Kentaro; Dolan, John C; Janal, Malvin; Aouizerat, Brad E; Miaskowski, Christine; Schmidt, Brian L

2017-11-05

Widespread pain and anxiety are commonly reported in cancer patients. We hypothesize that cancer is accompanied by attenuation of endogenous opioid-mediated inhibition, which subsequently causes widespread pain and anxiety. To test this hypothesis we used a mouse model of oral squamous cell carcinoma (SCC) in the tongue. We found that mice with tongue SCC exhibited widespread nociceptive behaviors in addition to behaviors associated with local nociception that we reported previously. Tongue SCC mice exhibited a pattern of reduced opioid receptor expression in the spinal cord; intrathecal administration of respective mu (MOR), delta (DOR), and kappa (KOR) opioid receptor agonists reduced widespread nociception in mice, except for the fail flick assay following administration of the MOR agonist. We infer from these findings that opioid receptors contribute to widespread nociception in oral cancer mice. Despite significant nociception, mice with tongue SCC did not differ from sham mice in anxiety-like behaviors as measured by the open field assay and elevated maze. No significant differences in c-Fos staining were found in anxiety-associated brain regions in cancer relative to control mice. No correlation was found between nociceptive and anxiety-like behaviors. Moreover, opioid receptor agonists did not yield a statistically significant effect on behaviors measured in the open field and elevated maze in cancer mice. Lastly, we used an acute cancer pain model (injection of cancer supernatant into the mouse tongue) to test whether adaptation to chronic pain is responsible for the absence of greater anxiety-like behavior in cancer mice. No changes in anxiety-like behavior were observed in mice with acute cancer pain. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Current Research on Opioid Receptor Function

PubMed Central

Feng, Yuan; He, Xiaozhou; Yang, Yilin; Chao, Dongman; Lazarus, Lawrence H.; Xia, Ying

2012-01-01

The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The up-regulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and anti-oxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article is to review the recent work done on opioids and their receptor functions. It shall provide an informative reference for better understanding the opioid system and further elucidation of the opioid receptor function from a physiological and pharmacological point of view. PMID:22204322

Development of an Ultrasonic Resonator for Ballast Water Disinfection

NASA Astrophysics Data System (ADS)

Osman, Hafiiz; Lim, Fannon; Lucas, Margaret; Balasubramaniam, Prakash

Ultrasonic disinfection involves the application of low-frequency acoustic energy in a water body to induce cavitation. The implosion of cavitation bubbles generates high speed microjets >1 km/s, intense shock wave >1 GPa, localized hot spots >1000 K, and free-radicals, resulting in cell rupture and death of micro-organisms and pathogens. Treatment of marine ballast water using power ultrasonics is an energy-intensive process. Compared with other physical treatment methods such as ultraviolet disinfection, ultrasonic disinfection require 2 to 3 orders of magnitude more energy to achieve similar rate of micro-organism mortality. Current technology limits the amount of acoustic energy that can be transferred per unit volume of fluid and presents challenges when it comes to high-flow applications. Significant advancements in ultrasonic processing technology are needed before ultrasound can be recognized as a viable alternative disinfection method. The ultrasonic resonator has been identified as one of the areas of improvement that can potentially contribute to the overall performance of an ultrasonic disinfection system. The present study focuses on the design of multiple-orifice resonators (MOR) for generating a well-distributed cavitation field. Results show that the MOR resonator offers significantly larger vibrational surface area to mass ratio. In addition, acoustic pressure measurements indicate that the MOR resonators are able to distribute the acoustic energy across a larger surface area, while generating 2-4 times higher pressures than existing ultrasonic probes.

CuPt and CuPtRu Nanostructures for Ammonia Oxidation Reaction

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

Manso, R H.; Song, L.; Liang, Z.

Liquid fuels, such as methanol, ethanol, and ammonia, are attractive alternative to hydrogen for fuel cells due to their lower costs for storage and distribution. However, lack of sufficiently active catalysts for their oxidation reactions is a roadblock. Our previous study found that Pt 3Cu nanodendrites yielded higher activity and durability than Pt nanoparticles for methanol oxidation reaction (MOR) in acid. In this study, we synthesized two types of nanostructures of CuPt and CuPtRu catalysts via seed-mediated growth of Pt and Ru on Cu and tested their performance for ammonia oxidation reaction (AOR) in alkaline solution. Unlike for MOR, themore » nanodendrites do not promote AOR activity - CuPt performs similar to Pt and CuPtRu is less active than Pt. Interestingly, the AOR peak current is increased by 64% on CuPt nanowires and 330% on CuPtRu nanowires as compared to Pt nanoparticles. These results suggest that AOR prefers extended surface on long nanowires, distinctly differing from MOR. This can be contributed to two factors: NH 3 oxidization to N 2 involves dimerization of two N-containing intermediates to form the N-N bond and diffusion batters for adsorbed intermediates are generally lower on terrace than at low-coordination sites. This demonstrated strong effect of surface morphology will be further studied and utilized in developing advanced AOR nanocatalysts.« less

CuPt and CuPtRu Nanostructures for Ammonia Oxidation Reaction

DOE PAGES

Manso, R H.; Song, L.; Liang, Z.; ...

2018-04-01

Liquid fuels, such as methanol, ethanol, and ammonia, are attractive alternative to hydrogen for fuel cells due to their lower costs for storage and distribution. However, lack of sufficiently active catalysts for their oxidation reactions is a roadblock. Our previous study found that Pt 3Cu nanodendrites yielded higher activity and durability than Pt nanoparticles for methanol oxidation reaction (MOR) in acid. In this study, we synthesized two types of nanostructures of CuPt and CuPtRu catalysts via seed-mediated growth of Pt and Ru on Cu and tested their performance for ammonia oxidation reaction (AOR) in alkaline solution. Unlike for MOR, themore » nanodendrites do not promote AOR activity - CuPt performs similar to Pt and CuPtRu is less active than Pt. Interestingly, the AOR peak current is increased by 64% on CuPt nanowires and 330% on CuPtRu nanowires as compared to Pt nanoparticles. These results suggest that AOR prefers extended surface on long nanowires, distinctly differing from MOR. This can be contributed to two factors: NH 3 oxidization to N 2 involves dimerization of two N-containing intermediates to form the N-N bond and diffusion batters for adsorbed intermediates are generally lower on terrace than at low-coordination sites. This demonstrated strong effect of surface morphology will be further studied and utilized in developing advanced AOR nanocatalysts.« less

The association between irregular menstruations and acne with asthma and atopy phenotypes.

PubMed

Galobardes, Bruna; Patel, Sumaiya; Henderson, John; Jeffreys, Mona; Smith, George Davey

2012-10-15

Earlier menarche and irregular periods, among other markers of sex-hormone levels, have been associated with a higher risk of asthma and allergic diseases. This has suggested an etiologic role of sex hormones in the development of these conditions. The authors investigated the association of age at menarche, irregular periods, duration of menstruation, and acne with reported medical history of asthma and/or atopy (hay fever and/or eczema/urticaria) in a historical cohort of students born before the rise in asthma prevalence in the United Kingdom and attending university in 1948-1968. Finding consistent associations in a cohort that has experienced different life-course exposures and has different confounding structure can help to identify causal associations. In the Glasgow Alumni Cohort, irregular periods were associated with atopic asthma (multinomial odds ratio (MOR) = 2.79, 95% confidence interval (CI): 1.33, 5.83) and atopy alone (MOR = 1.40, 95% CI: 1.06, 1.84) but not with nonatopic asthma (MOR = 1.02, 95% CI: 0.45, 2.30), compared with students reporting no asthma and no atopy. The authors found no association with acne, a marker of high testosterone levels, that they hypothesized could point to polycystic ovary syndrome underpinning these associations. In summary, the authors found evidence for a potentially etiologic role of irregular menstruations with some specific asthma phenotypes, namely, atopic asthma and atopy, but not with nonatopic asthma.

Substance P analogs displace sigma binding differentially in the brain and spinal cord of the adult mouse.

PubMed

Mousseau, D D; Larson, A A

1994-09-01

We have previously observed similarities in the behavioral effects produced by the NH2-terminus of the undecapeptide substance P (SP) and by 1,3-di(2-tolyl)-guanidine (DTG) in the adult mouse. The present series of experiments indicate differences in the rank-order of potency of sigma ligands [DTG; haloperidol (HAL)], SP analogs [SP; SP(1-7); SP(5-11); [D-Pro2, D-Phe7]-SP(1-7) (D-SP(1-7))] and miscellaneous compounds [morphine (MOR), naloxone (NAL)] at competing for [3H]-DTG binding sites in the mouse brain and spinal cord in vitro: Brain; DTG = HAL > SP = MOR = NAL > SP(1-7) > D-SP(1-7) > SP(5-11): Spinal cord; DTG = HAL > SP(1-7) = MOR = NAL > SP > D-SP(1-7) = SP(5-11). The observed difference in the rank-order potencies of the displacing ligands at these same binding sites supports the notion of two distinct populations of sigma binding sites in these tissues in the adult mouse. Given the low (micromolar) potency of SP analogs at displacing [3H]-DTG binding in the present series of experiments, it is unlikely that the similar behavioral effects we have previously observed elicited by SP(1-7) and DTG in the adult mouse are a result of a direct action of SP(1-7) at the sigma binding site.

Quasi-zero-dimensional cobalt-doped CeO2 dots on Pd catalysts for alcohol electro-oxidation with enhanced poisoning-tolerance.

PubMed

Tan, Qiang; Zhu, Haiyan; Guo, Shengwu; Chen, Yuanzhen; Jiang, Tao; Shu, Chengyong; Chong, Shaokun; Hultman, Benjamin; Liu, Yongning; Wu, Gang

2017-08-31

Deactivation of an anode catalyst resulting from the poisoning of CO ad -like intermediates is one of the major problems for methanol and ethanol electro-oxidation reactions (MOR & EOR), and remains a grand challenge towards achieving high performance for direct alcohol fuel cells (DAFCs). Herein, we report a new approach for the preparation of ultrafine cobalt-doped CeO 2 dots (Co-CeO 2 , d = 3.6 nm), which can be an effective anti-poisoning promoter for Pd catalysts towards MOR and EOR in alkaline media. Compared to Pd/CeO 2 and pure Pd, the hybrid Pd/Co-CeO 2 nanocomposite catalyst exhibited a much enhanced activity and remarkable anti-poisoning ability for both MOR and EOR. The nanocomposite catalyst showed much higher mass activity (4×) than a state-of-the-art PtRu catalyst. The promotional mechanism was elucidated using extensive characterization and density-functional theory (DFT). A bifunctional effect of the Co-CeO 2 dots was discovered to be due to (i) an enhanced electronic interaction between Co-CeO 2 and Pd dots and (ii) the increased oxygen storage capacity of Co-CeO 2 dots to facilitate the oxidation of CO ad . Therefore, the Pd/Co-CeO 2 nanocomposite appears to be a promising catalyst for advanced DAFCs with low cost and high performance.

Kinetic preference for the 3'-5'-linked dimer in the reaction of guanosine 5'-phosphorylmorpholinamide with deoxyguanosine 5'-phosphoryl-2-methylimidazolide as a function of poly(C) concentration

NASA Technical Reports Server (NTRS)

Kanavarioti, A.

1998-01-01

The formation of the internucleotide bond in diguanylate synthesis was studied in aqueous solution at pH 8 and 0.2 M Mg2+ in the presence and absence of polycytidylate, poly(C). The investigation was simplified by using guanosine 5'-phosphorylmorpholinamide, mor-pG, which can act only as a nucleophile, and deoxyguanosine 5'-phosphoryl-2-methylimidazolide, 2-MeImpdG, which can act only as an electrophile. The time-dependent product distribution was monitored by high-performance liquid chromatography (HPLC) and liquid chromatography mass spectrometry (LC/MS). In the absence of poly(C) the reaction between mor-pG and 2-MeImpdG yielded small amounts of the dimer mor-pGpdG with a regioselectivity of 2'-5':3'-5' = 3.5. In the presence of poly(C) dimer yields increased and a reversal in regioselectivity occurred; both effects were in proportion to the concentration of the polymer. The results can be quantitatively explained with the proposition that poly(C), acting as the template, catalyzes the reaction between template-bound monomers by about a factor of 4-5 over the reaction in solution and yields dimers with a regioselectivity of 2'-5':3'-5' approximately 0.33. These findings illustrate the intrinsic preference of guanosine monomers to correctly self-assemble on the appropriate template.

Spiritual assessment of patients with cancer: the moral authority, vocational, aesthetic, social, and transcendent model.

PubMed

Skalla, Karen; McCoy, J Patrick

2006-07-01

To explore the nature of spiritual care in patients with cancer and discuss the Moral Authority, Vocational, Aesthetic, Social, and Transcendent (Mor-VAST) Model, a new theoretical model for assessment. Published articles, online references. Discussions regarding spirituality often do not occur for a variety of reasons but may affect physical and spiritual health of an individual. Assessment of spirituality should be an integral part of cancer care. The Mor-VAST model can assist clinicians in discussing spirituality. Nurses should be aware of resources for referral to chaplaincy, but they can be a part of the process of spiritual support. Educational opportunities are available for nurses who wish to address their own spirituality so they can address spirituality comfortably and confidently with their patients.

Reaction of seawater with fresh mid-ocean ridge gabbro creates ';atypical' REE pattern and high REE fluid fluxes: Experiments at 425 and 475 °C, 400 and 1000 bar

NASA Astrophysics Data System (ADS)

Beermann, O.; Garbe-Schönberg, D.; Holzheid, A. D.

2013-12-01

High-temperature MOR hydrothermalism significantly affects ocean chemistry. The Sisters Peak (SP) hydrothermal field at 5°S on the slow-spreading Mid-Atlantic Ridge (MAR) emanates fluids >400°C [1] that have high concentrations of H2, transition metals, and rare earth elements (REE) exhibiting ';atypical' REE pattern characterized by depletions of LREE and HREE relative to MREE and no Eu anomaly [2]. This is in contrast to the ';typical' LREE enrichment and strong positive Eu anomaly known from many MOR vent fluids observed world-wide [e.g., 3]. Besides temperature, the seawater-to-rock ratio (w/r ratio) has significant control on the fluid chemistry [e.g., 4, 5]. To understand how vent fluid REE-signatures are generated during water-rock interaction processes we reacted unaltered gabbro with natural bottom seawater at 425 °C and 400 bar and at 425 and 475 °C at 1000 bar at variable w/r (mass) ratios ranging from 0.5-10 by using cold seal pressure vessels (CSPV). The run durations varied from 3-72 h. Reacted fluids were analysed for major and trace elements by ICP-OES and ICP-MS. In our experiments, ';atypical' REE fluid pattern similar to those of SP fluids were obtained at high w/r ratio (5 and 10) that might be characteristic for focused fluid-flow along e.g., detachment faults at slow-spreading MOR [6]. In contrast, more ';typical'-like REE pattern with elevated LREE and slightly positive Eu anomalies have been reproduced at low w/r ratio (0.5-1). Results of numerical simulations imply that strong positive Eu anomalies of fluids and altered gabbro from high temperature MOR hydrothermal systems can be created by intense rock leaching processes at high w/r ratio (5-10). This suggests that hydrothermal circulation through the ocean crust creates ';typical' REE fluid pattern with strong positive Eu anomalies if seawater reacts with gabbroic host rock that has been already leached in REE at high fluid fluxes. Simulations of the temporal chemical evolution of high temperature MOR hydrothermal systems reveal that rock and fluid REE contents can rapidly decrease within several months particularly at high fluid fluxes. In contrast, the reaction with ';fresh', unaltered rock is evident from the high REE concentration of SP fluids. Both, fluid access to fresh rock and the fluid flux should therefore significantly control chemical fluxes to the ocean. Thus, high chemical fluxes can be expected in particular from early stage high-temperature MOR hydrothermal systems that are assumed to be not uncommon along the slow-spreading MAR. [1] Koschinsky A., Garbe-Schönberg D., Sander S., Schmidt K., Gennerich H.-H., and Strauss H. (2008) Geology 36, 615-618. [2] Schmidt K., Garbe-Schönberg D., Bau M., and Koschinsky A. (2010) Geochim. Cosmochim. Acta 74, 4058-4077. [3] Douville E., Bienvenu P., Charlou J. L., Donval J. P., Fouquet Y., Appriou P., and Gamo T. (1999). Geochim. Cosmochim. Acta 63, 627-643. [4] Seyfried [Jr.] W. E. and Bischoff J. L. (1977) Earth. Planet. Sci. Lett. 34, 71-77. [5] Hajash A. and Chandler G. W. (1981) Contrib. Mineral. Petrol. 78, 240-254. [6] McCaig A.M. and Harris M. (2012) Geology 40, 367-370.

Climate Action Program at Caltrans.

DOT National Transportation Integrated Search

2006-12-01

Greenhouse gas (GHG) emissions and the related subject of global climate change are : emerging as critical issues for the transportation community. The California Department : of Transportation (Department) recognizes the significance of cleaner, mor...

Evolution of spreading rate and H2 production by serpentinization at mid-ocean ridges from 200 Ma to Present

NASA Astrophysics Data System (ADS)

Andreani, M.; García del Real, P.; Daniel, I.; Wright, N.; Coltice, N.

2017-12-01

Mid-oceanic ridge (MOR) spreading rate spatially varies today from 20 to 200 mm/yr and geological records attest of important temporal variations, at least during the past 200 My. The spreading rate has a direct impact on the mechanisms accomodating extension (magmatic vs tectonic), hence on the nature of the rocks forming the oceanic lithosphere. The latter is composed of variable amount of magmatic and mantle rocks, that dominate at fast and (ultra-) slow spreading ridges, respectively. Serpentinization of mantle rocks contributes to global fluxes and notably to those of hydrogen and carbon by providing a pathways for dihydrogen (H2) production, carbone storage by mineralization, and carbon reduction to CH4 and possibly complex organic compounds. Quantification of the global chemical impact of serpentinization through geological time requires a coupling of geochemical parameters with plate-tectonic reconstructions. Here we quantify serpentinization extent and concurrent H2 production at MOR from the Jurassic (200 Ma) to present day (0 Ma). We coupled mean values of relevant petro-chemical parameters such as the proportion of mantle rocks, initial iron in olivine, iron redox state in serpentinites, % of serpentinization to high-resolution models of plate motion within the GPlates infrastructure to estimate the lengths in 1 Myr intervals for the global MOR plate boundary (spreading and transform components), and spreading ridges as a function of their rate. The model sensitivity to selected parameters has been tested. The results show that fragmentation of Pangea resulted in elevated H2 rates (>1012 to 1013 mol/yr) starting at 160 Ma compared to Late Mesozoic (<160 Ma) rates (<1011-1012 mol/yr). From 160 Ma to present, the coupled opening of the Atlantic and Indian oceans as well as the variation in spreading rates maintained H2 generation in the 1012 mol/yr level, but with significant excursions mainly related to the length of ultra-slow spreading segments. For the first time, this model offers a framework toward flux modeling at MOR through time. The model can be further implemented by adding supplementary geochemical parameters or serve other geochemical issues.

Effects of body formulation and firing temperature to properties of ceramic tile incorporated with electric arc furnace (EAF) slag waste

NASA Astrophysics Data System (ADS)

Sharif, Nurulakmal Mohd; Lim, Chi Yang; Teo, Pao Ter; Seman, Anasyida Abu

2017-07-01

Significant quantities of sludge and slag are generated as waste materials or by-products from steel industries. One of the by-products is Electric Arc Furnace (EAF) steel slag which consists of oxides such as CaO, Al2O3 and FeO. This makes it possible for slag to partially replace the raw materials in ceramic tile production. In our preliminary assessment of incorporating the EAF slag into ceramic tile, it was revealed that at fixed firing temperature of 1150°C, the tile of composition 40 wt.% EAF slag - 60 wt.% ball clay has comparable properties with commercial ceramic tile. Thus, this current study would focus on effects of body formulation (different weight percentages of K-feldspar and silica) and different firing temperatures to properties of EAF slag added ceramic tile. EAF slag from Southern Steel Berhad (SSB) was crushed into micron size (EAF slag content was 40 wt.%) and milled with ball clay, K-feldspar and silica before compacted and fired at 1125°C and 1150°C. The EAF slag added tile was characterized in terms of water absorption, apparent porosity, bulk density, modulus of rupture (MOR) and phase analysis via X-ray diffraction (XRD). The composition of 40 wt.% EAF slag - 30 wt.% ball clay - 10 wt.% K-feldspar - 20 wt.% silica (10F_20S), fired at 1150°C showed the lowest water absorption, apparent porosity and highest bulk density due to enhancement of densification process during firing. However, the same composition of ceramic tile (10F_20S) had the highest MOR at lower firing temperature of 1125°C, contributed by presence of the highest total amount of anorthite and wollastonite reinforcement crystalline phases (78.40 wt.%) in the tile. Overall, both the water absorption and MOR of all ceramic tiles surpassed the requirement regulated by MS ISO 13006:2014 Standard (Annex G: Dry-pressed ceramic tile with low water absorption, Eb ≤ 0.50 % and minimum MOR of 35 MPa).

Long-term effects of interprofessional biopsychosocial rehabilitation for adults with chronic non-specific low back pain: a multicentre, quasi-experimental study.

PubMed

Semrau, Jana; Hentschke, Christian; Buchmann, Jana; Meng, Karin; Vogel, Heiner; Faller, Hermann; Bork, Hartmut; Pfeifer, Klaus

2015-01-01

Improvement of the long-term effectiveness of multidisciplinary ortho-paedic rehabilitation (MOR) in the management of chronic non-specific low back pain (CLBP) remains a central issue for health care in Germany. We developed an interprofessional and interdisciplinary, biopsychosocial rehabilitation concept named "PASTOR" to promote self-management in adults with CLBP and compared its effectiveness with the current model of MOR. A multicentre quasi-experimental study with three measurement time points was implemented. 680 adults aged 18 to 65 with CLBP were assed for eligibil-ity in three inpatient rehabilitation centres in Germany. At first the effects of the MOR, with a total extent of 48 hours (control group), were assessed. Thereafter, PASTOR was implemented and evaluated in the same centres (intervention group). It consisted of six interprofessional modules, which were provided on 12 days in fixed groups, with a total extent of 48 hours. Participants were assessed with self-report measures at baseline, discharge, and 12 months for functional ability (primary outcome) using the Hannover Functional Ability Questionnaire (FFbH-R) and vari-ous secondary outcomes (e.g. pain, health status, physical activity, pain coping, pain-related cognitions). In total 536 participants were consecutively assigned to PASTOR (n=266) or MOR (n=270). At 12 months, complete data of 368 participants was available. The adjusted between-group difference in the FFbH-R at 12 months was 6.58 (95% CI 3.38 to 9.78) using complete data and 3.56 (95% CI 0.45 to 6.67) using available da-ta, corresponding to significant small-to-medium effect sizes of d=0.42 (p<0.001) and d=0.10 (p=0.025) in favour of PASTOR. Further improvements in secondary out-comes were also observed in favour of PASTOR. The interprofessional and interdisciplinary, biopsychosocial rehabilita-tion program PASTOR shows some improvements of the long-term effectiveness of inpatient rehabilitation in the management of adults with CLBP. Further insights into mechanisms of action of complex intervention programs are required. ClinicalTrials.gov NCT02056951.

Magma ascent and lava flow emplacement rates during the 2011 Axial Seamount eruption based on CO2 degassing

NASA Astrophysics Data System (ADS)

Jones, M. R.; Soule, S. A.; Gonnermann, H. M.; Le Roux, V.; Clague, D. A.

2018-07-01

Quantitative metrics for eruption rates at mid-ocean ridges (MORs) would improve our understanding of the structure and formation of the uppermost oceanic crust and would provide a means to link volcanic processes with the conditions of the underlying magmatic system. However, these metrics remain elusive because no MOR eruptions have been directly observed. The possibility of disequilibrium degassing in mid-ocean ridge basalts (MORB), due to high eruptive depressurization rates, makes the analysis of volatile concentrations in MORB glass a promising method for evaluating eruption rates. In this study, we estimate magma ascent and lava flow emplacement rates during the 2011 eruption of Axial Seamount based on numerical modeling of diffusion-controlled bubble growth and new measurements of dissolved volatiles, vesicularity, and vesicle size distributions in erupted basalts. This dataset provides a unique view of the variability in magma ascent (∼0.02-1.2 m/s) and lava flow rates (∼0.1-0.7 m/s) during a submarine MOR eruption based on 50 samples collected from a >10 km long fissure system and three individual lava flow lobes. Samples from the 2011 eruption display an unprecedented range in dissolved CO2 concentrations, nearly spanning the full range observed on the global MOR system. The variable vesicularity and dissolved CO2 concentrations in these samples can be explained by differences in the extent of degassing, dictated by flow lengths and velocities during both vertical ascent and horizontal flow along the seafloor. Our results document, for the first time, the variability in magma ascent rates during a submarine eruption (∼0.02-1.2 m/s), which spans the global range previously proposed based on CO2 degassing. The slowest ascent rates are associated with hummocky flows while faster ascent rates produce channelized sheet flows. This study corroborates degassing-based models for eruption rates using comparisons with independent methods and documents the relationship between eruption dynamics, magma ascent rates, and the morphology of eruptive products. Globally, this approach allows interrogation of the processes that govern mid-ocean ridge eruptions and influence the formation of the oceanic crust.

Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics.

PubMed

Schmid, Cullen L; Kennedy, Nicole M; Ross, Nicolette C; Lovell, Kimberly M; Yue, Zhizhou; Morgenweck, Jenny; Cameron, Michael D; Bannister, Thomas D; Bohn, Laura M

2017-11-16

Biased agonism has been proposed as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit βarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compounds spanning a wide range of signaling bias. We find that βarrestin-biased compounds, such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression. Copyright © 2017 Elsevier Inc. All rights reserved.

Radial basis function network learns ceramic processing and predicts related strength and density

NASA Technical Reports Server (NTRS)

Cios, Krzysztof J.; Baaklini, George Y.; Vary, Alex; Tjia, Robert E.

1993-01-01

Radial basis function (RBF) neural networks were trained using the data from 273 Si3N4 modulus of rupture (MOR) bars which were tested at room temperature and 135 MOR bars which were tested at 1370 C. Milling time, sintering time, and sintering gas pressure were the processing parameters used as the input features. Flexural strength and density were the outputs by which the RBF networks were assessed. The 'nodes-at-data-points' method was used to set the hidden layer centers and output layer training used the gradient descent method. The RBF network predicted strength with an average error of less than 12 percent and density with an average error of less than 2 percent. Further, the RBF network demonstrated a potential for optimizing and accelerating the development and processing of ceramic materials.

Dendritic Core-Frame and Frame Multimetallic Rhombic Dodecahedra: A Comparison Study of Composition and Structure Effects on Electrocatalysis of Methanol Oxidation

DOE PAGES

Mathurin, Leanne E.; Tao, Jing; Xin, Huolin; ...

2017-11-03

The composition and structure of multimetallic nanostructures can be tailored to enhance electrocatalytic properties. This work reports a seed-mediated synthesis of novel multimetallic dendritic core-frame and frame nanostructures with a rhombic dodecahedral shape for enhanced methanol oxidation reaction (MOR). The synthesis involves in situ formation of Cu seeds and the subsequent selective deposition of Pt and Ru on the edges and vertices of the Cu seeds to generate CuPt and CuPtRu dendritic core-frame nanostructures. The core-frame nanostructures undergo a post acetic acid etching process to form the frame nanostructures. While transmission electron microscopy reveals the morphology and elemental distribution ofmore » the nanostructures, X-ray diffraction patterns confirm the alloy compositions of dendritic frames for both the core-frame and frame nanostructures. Compared to the bimetallic CuPt nanostructures, the trimetallic CuPtRu nanostructures lower the onset potential and completely suppress the peak current in the reverse scan for MOR. The CuPtRu alloyed frame nanostructures are the best to prevent Ru leaching compared to the CuPtRu core-frame nanostructures and PtRu catalysts. X-ray photoelectron spectroscopy reveals that all three elements become more electron rich in the frame nanostructures. Thus, further refining the composition ratio of the CuPtRu alloyed dendritic frame nanostructures can lead to more efficient catalysts at a lower cost for MOR.« less

Cation hydrolysis and the regulation of trace metal composition in seawater

NASA Astrophysics Data System (ADS)

Kumar, M. Dileep

1987-08-01

Thermodynamic calculations have been performed for cation hydrolysis, including temperatures from 2°C to the high values of significance near Mid-Oceanic Ridge Systems (MORS). Eighteen elements with wide range of residence times ( t) in seawater (Mn, Th, Al, Bi, Ce, Co, Cr(III), Fe, Nd, Pb, Sc, Sm, Ag, Cd, Cu, Hg, Ni and Zn) have been considered. A model for the regulation of trace metal composition in seawater by cation hydrolytic processes, including those at MORS, is presented. Results show an increase in the abundance of neutral metal hydroxyl species with increase in temperature. During hydrothermal mixing, as the temperature increases, transformation from lower positive hydroxyl complexes to higher or neutral complexes would occur for Cd, Ce, Co, Cr(III), Cu, Mn, Nd, Ni, Pb, Sm and Zn. pH values for adsorption of the metal ion onto solid surfaces have direct relation with pH values of hydrolysis. Co, Mn and Pb could be oxidized to higher states (at Mn-oxide surfaces) that would occur even at MORS. Ce can also be oxidized at 25°C. Solubility calculations show that Al, Bi, Cr(III), Sc, Fe and Th are saturated while Ce, Nd and Sm are not with respect to their oxyhydroxide solids at their concentrations in seawater at 25°C. Cu, Hg, Ni and Zn reach saturation equilibrium at 250°C, whereas Co, Mn and Pb exhibit unsaturation. The results suggest an increase in scavenging capacity of a cation with rise in temperature.

Natural lead concentrations in pristine boreal forest soils and past pollution trends: A reference for critical load models

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

Bindler, R.; Braennvall, M.L.; Renberg, I.

1999-10-01

Knowledge of natural, prepollution concentrations of heavy metals in forest soils and temporal trends of soil pollution are essential for understanding present-day pollution and for establishing realistic goals for reductions of atmospheric pollution deposition. Soils not exposed to deposition of atmospheric pollution no longer exist and, for example, present lead (Pb) pollution conditions in northern European soils are a consequence of nearly 4,000 years of atmospheric pollution. The authors use analyses of Pb concentrations and stable Pb isotopes ({sup 206}Pb/{sup 207}Pb ratios) of ombrotrophic peat and forest soils from southern Sweden and a model for Pb cycling in forest soilsmore » to derive an estimate for the prepollution concentration of Pb in the mor layer of boreal forest soils and to back-calculate Pb concentrations for the last 5,500 years. While the present-day concentrations of the mor layer are typically 40--100 {micro}g g{sup {minus}1} (0.25--1.0 g m{sup {minus}2}), Pb concentrations of pristine forest mor layers in Sweden were quite low, {le}0.1 {micro}g g{sup {minus}1} ({le}1 mg m{sup {minus}2}). Large-scale atmospheric pollution from the Greek and Roman cultures increased Pb concentrations to about 1 {micro}g g{sup {minus}1}. Lead (Pb) concentrations increased to about 4 {micro}g g{sup {minus}1} following the increase of metal production and atmospheric pollution in Medieval Europe.« less

Dendritic Core-Frame and Frame Multimetallic Rhombic Dodecahedra: A Comparison Study of Composition and Structure Effects on Electrocatalysis of Methanol Oxidation

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

Mathurin, Leanne E.; Tao, Jing; Xin, Huolin

The composition and structure of multimetallic nanostructures can be tailored to enhance electrocatalytic properties. This work reports a seed-mediated synthesis of novel multimetallic dendritic core-frame and frame nanostructures with a rhombic dodecahedral shape for enhanced methanol oxidation reaction (MOR). The synthesis involves in situ formation of Cu seeds and the subsequent selective deposition of Pt and Ru on the edges and vertices of the Cu seeds to generate CuPt and CuPtRu dendritic core-frame nanostructures. The core-frame nanostructures undergo a post acetic acid etching process to form the frame nanostructures. While transmission electron microscopy reveals the morphology and elemental distribution ofmore » the nanostructures, X-ray diffraction patterns confirm the alloy compositions of dendritic frames for both the core-frame and frame nanostructures. Compared to the bimetallic CuPt nanostructures, the trimetallic CuPtRu nanostructures lower the onset potential and completely suppress the peak current in the reverse scan for MOR. The CuPtRu alloyed frame nanostructures are the best to prevent Ru leaching compared to the CuPtRu core-frame nanostructures and PtRu catalysts. X-ray photoelectron spectroscopy reveals that all three elements become more electron rich in the frame nanostructures. Thus, further refining the composition ratio of the CuPtRu alloyed dendritic frame nanostructures can lead to more efficient catalysts at a lower cost for MOR.« less

Synthesis of mixed MOR/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration.

PubMed

Perlikowska, Renata; Piekielna, Justyna; Gentilucci, Luca; De Marco, Rossella; Cerlesi, Maria Camilla; Calo, Girolamo; Artali, Roberto; Tömböly, Csaba; Kluczyk, Alicja; Janecka, Anna

2016-02-15

Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endomorphin-2 (EM-2), which shows high affinity to the μ-opioid receptor (MOR) and a very strong antinociceptive activity in mice was used as a parent compound for the structure-activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the more extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar MOR and nanomolar κ-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible for the different pharmacological profiles of position 3- versus position 4-modified analogs. Copyright © 2015. Published by Elsevier Masson SAS.

Aversive learning of odor-heat associations in ants.

PubMed

Desmedt, Lucie; Baracchi, David; Devaud, Jean-Marc; Giurfa, Martin; d'Ettorre, Patrizia

2017-12-15

Ants have recently emerged as useful models for the study of olfactory learning. In this framework, the development of a protocol for the appetitive conditioning of the maxilla-labium extension response (MaLER) provided the possibility of studying Pavlovian odor-food learning in a controlled environment. Here we extend these studies by introducing the first Pavlovian aversive learning protocol for harnessed ants in the laboratory. We worked with carpenter ants Camponotus aethiops and first determined the capacity of different temperatures applied to the body surface to elicit the typical aversive mandible opening response (MOR). We determined that 75°C is the optimal temperature to induce MOR and chose the hind legs as the stimulated body region because of their high sensitivity. We then studied the ability of ants to learn and remember odor-heat associations using 75°C as the unconditioned stimulus. We studied learning and short-term retention after absolute (one odor paired with heat) and differential conditioning (a punished odor versus an unpunished odor). Our results show that ants successfully learn the odor-heat association under a differential-conditioning regime and thus exhibit a conditioned MOR to the punished odor. Yet, their performance under an absolute-conditioning regime is poor. These results demonstrate that ants are capable of aversive learning and confirm previous findings about the different attentional resources solicited by differential and absolute conditioning in general. © 2017. Published by The Company of Biologists Ltd.

Genetic Algorithm-Guided, Adaptive Model Order Reduction of Flexible Aircrafts

NASA Technical Reports Server (NTRS)

Zhu, Jin; Wang, Yi; Pant, Kapil; Suh, Peter; Brenner, Martin J.

2017-01-01

This paper presents a methodology for automated model order reduction (MOR) of flexible aircrafts to construct linear parameter-varying (LPV) reduced order models (ROM) for aeroservoelasticity (ASE) analysis and control synthesis in broad flight parameter space. The novelty includes utilization of genetic algorithms (GAs) to automatically determine the states for reduction while minimizing the trial-and-error process and heuristics requirement to perform MOR; balanced truncation for unstable systems to achieve locally optimal realization of the full model; congruence transformation for "weak" fulfillment of state consistency across the entire flight parameter space; and ROM interpolation based on adaptive grid refinement to generate a globally functional LPV ASE ROM. The methodology is applied to the X-56A MUTT model currently being tested at NASA/AFRC for flutter suppression and gust load alleviation. Our studies indicate that X-56A ROM with less than one-seventh the number of states relative to the original model is able to accurately predict system response among all input-output channels for pitch, roll, and ASE control at various flight conditions. The GA-guided approach exceeds manual and empirical state selection in terms of efficiency and accuracy. The adaptive refinement allows selective addition of the grid points in the parameter space where flight dynamics varies dramatically to enhance interpolation accuracy without over-burdening controller synthesis and onboard memory efforts downstream. The present MOR framework can be used by control engineers for robust ASE controller synthesis and novel vehicle design.

LANDSAT-D Mission Operations Review (MOR)

NASA Technical Reports Server (NTRS)

1982-01-01

The integrated LANDSAT-D systems operation plan is presented and discussed with respect to functional elements, personnel, and procedures. Specifically, a review of the LANDSAT-D program, mission requirements and management, and flight operations is given.

Settlement at culverts.

DOT National Transportation Integrated Search

1984-05-01

Past construction methods have resulted in the need for leveling : wedges of asphaltic cement concrete or mud jacking at locations where a : reinforced concrete box culvert was replaced with a pipe culvert . : With the restraint of limited funds, mor...

National positioning, navigation, and timing architecture : implementation plan.

DOT National Transportation Integrated Search

2010-04-01

The Assistant Secretary of Defense for Networks and Information Integration (ASD/NII) and the : Under Secretary of Transportation for Policy (UST/P) sponsored a National Positioning, : Navigation, and Timing (PNT) Architecture Study to provide mor...

GEM-TREND: a web tool for gene expression data mining toward relevant network discovery

PubMed Central

Feng, Chunlai; Araki, Michihiro; Kunimoto, Ryo; Tamon, Akiko; Makiguchi, Hiroki; Niijima, Satoshi; Tsujimoto, Gozoh; Okuno, Yasushi

2009-01-01

Background DNA microarray technology provides us with a first step toward the goal of uncovering gene functions on a genomic scale. In recent years, vast amounts of gene expression data have been collected, much of which are available in public databases, such as the Gene Expression Omnibus (GEO). To date, most researchers have been manually retrieving data from databases through web browsers using accession numbers (IDs) or keywords, but gene-expression patterns are not considered when retrieving such data. The Connectivity Map was recently introduced to compare gene expression data by introducing gene-expression signatures (represented by a set of genes with up- or down-regulated labels according to their biological states) and is available as a web tool for detecting similar gene-expression signatures from a limited data set (approximately 7,000 expression profiles representing 1,309 compounds). In order to support researchers to utilize the public gene expression data more effectively, we developed a web tool for finding similar gene expression data and generating its co-expression networks from a publicly available database. Results GEM-TREND, a web tool for searching gene expression data, allows users to search data from GEO using gene-expression signatures or gene expression ratio data as a query and retrieve gene expression data by comparing gene-expression pattern between the query and GEO gene expression data. The comparison methods are based on the nonparametric, rank-based pattern matching approach of Lamb et al. (Science 2006) with the additional calculation of statistical significance. The web tool was tested using gene expression ratio data randomly extracted from the GEO and with in-house microarray data, respectively. The results validated the ability of GEM-TREND to retrieve gene expression entries biologically related to a query from GEO. For further analysis, a network visualization interface is also provided, whereby genes and gene annotations are dynamically linked to external data repositories. Conclusion GEM-TREND was developed to retrieve gene expression data by comparing query gene-expression pattern with those of GEO gene expression data. It could be a very useful resource for finding similar gene expression profiles and constructing its gene co-expression networks from a publicly available database. GEM-TREND was designed to be user-friendly and is expected to support knowledge discovery. GEM-TREND is freely available at . PMID:19728865

GEM-TREND: a web tool for gene expression data mining toward relevant network discovery.

PubMed

Feng, Chunlai; Araki, Michihiro; Kunimoto, Ryo; Tamon, Akiko; Makiguchi, Hiroki; Niijima, Satoshi; Tsujimoto, Gozoh; Okuno, Yasushi

2009-09-03

DNA microarray technology provides us with a first step toward the goal of uncovering gene functions on a genomic scale. In recent years, vast amounts of gene expression data have been collected, much of which are available in public databases, such as the Gene Expression Omnibus (GEO). To date, most researchers have been manually retrieving data from databases through web browsers using accession numbers (IDs) or keywords, but gene-expression patterns are not considered when retrieving such data. The Connectivity Map was recently introduced to compare gene expression data by introducing gene-expression signatures (represented by a set of genes with up- or down-regulated labels according to their biological states) and is available as a web tool for detecting similar gene-expression signatures from a limited data set (approximately 7,000 expression profiles representing 1,309 compounds). In order to support researchers to utilize the public gene expression data more effectively, we developed a web tool for finding similar gene expression data and generating its co-expression networks from a publicly available database. GEM-TREND, a web tool for searching gene expression data, allows users to search data from GEO using gene-expression signatures or gene expression ratio data as a query and retrieve gene expression data by comparing gene-expression pattern between the query and GEO gene expression data. The comparison methods are based on the nonparametric, rank-based pattern matching approach of Lamb et al. (Science 2006) with the additional calculation of statistical significance. The web tool was tested using gene expression ratio data randomly extracted from the GEO and with in-house microarray data, respectively. The results validated the ability of GEM-TREND to retrieve gene expression entries biologically related to a query from GEO. For further analysis, a network visualization interface is also provided, whereby genes and gene annotations are dynamically linked to external data repositories. GEM-TREND was developed to retrieve gene expression data by comparing query gene-expression pattern with those of GEO gene expression data. It could be a very useful resource for finding similar gene expression profiles and constructing its gene co-expression networks from a publicly available database. GEM-TREND was designed to be user-friendly and is expected to support knowledge discovery. GEM-TREND is freely available at http://cgs.pharm.kyoto-u.ac.jp/services/network.

Neighboring Genes Show Correlated Evolution in Gene Expression

PubMed Central

Ghanbarian, Avazeh T.; Hurst, Laurence D.

2015-01-01

When considering the evolution of a gene’s expression profile, we commonly assume that this is unaffected by its genomic neighborhood. This is, however, in contrast to what we know about the lack of autonomy between neighboring genes in gene expression profiles in extant taxa. Indeed, in all eukaryotic genomes genes of similar expression-profile tend to cluster, reflecting chromatin level dynamics. Does it follow that if a gene increases expression in a particular lineage then the genomic neighbors will also increase in their expression or is gene expression evolution autonomous? To address this here we consider evolution of human gene expression since the human-chimp common ancestor, allowing for both variation in estimation of current expression level and error in Bayesian estimation of the ancestral state. We find that in all tissues and both sexes, the change in gene expression of a focal gene on average predicts the change in gene expression of neighbors. The effect is highly pronounced in the immediate vicinity (<100 kb) but extends much further. Sex-specific expression change is also genomically clustered. As genes increasing their expression in humans tend to avoid nuclear lamina domains and be enriched for the gene activator 5-hydroxymethylcytosine, we conclude that, most probably owing to chromatin level control of gene expression, a change in gene expression of one gene likely affects the expression evolution of neighbors, what we term expression piggybacking, an analog of hitchhiking. PMID:25743543

REGIONAL CARDIAC BLOOD FLOW WITH AIR PARTICLE EXPOSURE

EPA Science Inventory

This proposal offers the unique application of novel techniques to improve understanding of the mechanisms whereby ambient particulate exerts deleterious influences on the heart and circulation. Enhanced ischemia has broad implications for cardiac morbidity and mor...

Image quality, meteorological optical range, and fog particulate number evaluation using the Sandia National Laboratories fog chamber

DOE PAGES

Birch, Gabriel C.; Woo, Bryana L.; Sanchez, Andres L.; ...

2017-08-24

The evaluation of optical system performance in fog conditions typically requires field testing. This can be challenging due to the unpredictable nature of fog generation and the temporal and spatial nonuniformity of the phenomenon itself. We describe the Sandia National Laboratories fog chamber, a new test facility that enables the repeatable generation of fog within a 55 m×3 m×3 m (L×W×H) environment, and demonstrate the fog chamber through a series of optical tests. These tests are performed to evaluate system image quality, determine meteorological optical range (MOR), and measure the number of particles in the atmosphere. Relationships between typical opticalmore » quality metrics, MOR values, and total number of fog particles are described using the data obtained from the fog chamber and repeated over a series of three tests.« less

Image quality, meteorological optical range, and fog particulate number evaluation using the Sandia National Laboratories fog chamber

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

Birch, Gabriel C.; Woo, Bryana L.; Sanchez, Andres L.

The evaluation of optical system performance in fog conditions typically requires field testing. This can be challenging due to the unpredictable nature of fog generation and the temporal and spatial nonuniformity of the phenomenon itself. We describe the Sandia National Laboratories fog chamber, a new test facility that enables the repeatable generation of fog within a 55 m×3 m×3 m (L×W×H) environment, and demonstrate the fog chamber through a series of optical tests. These tests are performed to evaluate system image quality, determine meteorological optical range (MOR), and measure the number of particles in the atmosphere. Relationships between typical opticalmore » quality metrics, MOR values, and total number of fog particles are described using the data obtained from the fog chamber and repeated over a series of three tests.« less

Effect of carbon fiber addition on the electromagnetic shielding properties of carbon fiber/polyacrylamide/wood based fiberboards

NASA Astrophysics Data System (ADS)

Dang, Baokang; Chen, Yipeng; Yang, Ning; Chen, Bo; Sun, Qingfeng

2018-05-01

Carbon fiber (CF) reinforced polyacrylamide/wood fiber composite boards are fabricated by mechanical grind-assisted hot-pressing, and are used for electromagnetic interference (EMI) shielding. CF with an average diameter of 150 nm is distributed on wood fiber, which is then encased by polyacrylamide. The CF/polyacrylamide/wood fiber (CPW) composite exhibits an optimal EMI shielding effectiveness (SE) of 41.03 dB compared to that of polyacrylamide/wood fiber composite (0.41 dB), which meets the requirements of commercial merchandise. Meanwhile, the CPW composite also shows high mechanical strength. The maximum modulus of rupture (MOR) and modulus of elasticity (MOE) of CPW composites are 39.52 MPa and 5823.15 MPa, respectively. The MOR and MOE of CPW composites increased by 38% and 96%, respectively, compared to that of polyacrylamide/wood fiber composite (28.64 and 2967.35 MPa).

Social touch modulates endogenous μ-opioid system activity in humans.

PubMed

Nummenmaa, Lauri; Tuominen, Lauri; Dunbar, Robin; Hirvonen, Jussi; Manninen, Sandra; Arponen, Eveliina; Machin, Anna; Hari, Riitta; Jääskeläinen, Iiro P; Sams, Mikko

2016-09-01

In non-human primates, opioid-receptor blockade increases social grooming, and the endogenous opioid system has therefore been hypothesized to support maintenance of long-term relationships in humans as well. Here we tested whether social touch modulates opioidergic activation in humans using in vivo positron emission tomography (PET). Eighteen male participants underwent two PET scans with [11C]carfentanil, a ligand specific to μ-opioid receptors (MOR). During the social touch scan, the participants lay in the scanner while their partners caressed their bodies in a non-sexual fashion. In the baseline scan, participants lay alone in the scanner. Social touch triggered pleasurable sensations and increased MOR availability in the thalamus, striatum, and frontal, cingulate, and insular cortices. Modulation of activity of the opioid system by social touching might provide a neurochemical mechanism reinforcing social bonds between humans. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of the ability of calcite, bentonite and barite to enhance oil dispersion under arctic conditions.

PubMed

Jézéquel, Ronan; Receveur, Justine; Nedwed, Tim; Le Floch, Stéphane

2018-02-01

A test program was conducted at laboratory and pilot scale to assess the ability of clays used in drilling mud (calcite, bentonite and barite) to create oil-mineral aggregates and disperse crude oil under arctic conditions. Laboratory tests were performed in order to determine the most efficient conditions (type of clay, MOR (Mineral/Oil Ratio), mixing energy) for OMA (Oil Mineral Aggregate) formation. The dispersion rates of four crude oils were assessed at two salinities. Dispersion was characterized in terms of oil concentration in the water column and median OMA size. Calcite appeared to be the best candidate at a MOR of 2:5. High mixing energy was required to initiate OMA formation and low energy was then necessary to prevent the OMAs from resurfacing. Oil dispersion using Corexit 9500 was compared with oil dispersion using mineral fines. Copyright © 2017 Elsevier Ltd. All rights reserved.

Endogenous opioids regulate moment-to-moment neuronal communication and excitability.

PubMed

Winters, Bryony L; Gregoriou, Gabrielle C; Kissiwaa, Sarah A; Wells, Oliver A; Medagoda, Danashi I; Hermes, Sam M; Burford, Neil T; Alt, Andrew; Aicher, Sue A; Bagley, Elena E

2017-03-22

Fear and emotional learning are modulated by endogenous opioids but the cellular basis for this is unknown. The intercalated cells (ITCs) gate amygdala output and thus regulate the fear response. Here we find endogenous opioids are released by synaptic stimulation to act via two distinct mechanisms within the main ITC cluster. Endogenously released opioids inhibit glutamate release through the δ-opioid receptor (DOR), an effect potentiated by a DOR-positive allosteric modulator. Postsynaptically, the opioids activate a potassium conductance through the μ-opioid receptor (MOR), suggesting for the first time that endogenously released opioids directly regulate neuronal excitability. Ultrastructural localization of endogenous ligands support these functional findings. This study demonstrates a new role for endogenously released opioids as neuromodulators engaged by synaptic activity to regulate moment-to-moment neuronal communication and excitability. These distinct actions through MOR and DOR may underlie the opposing effect of these receptor systems on anxiety and fear.

Effect of carbon fiber addition on the electromagnetic shielding properties of carbon fiber/polyacrylamide/wood based fiberboards.

PubMed

Dang, Baokang; Chen, Yipeng; Yang, Ning; Chen, Bo; Sun, Qingfeng

2018-05-11

Carbon fiber (CF) reinforced polyacrylamide/wood fiber composite boards are fabricated by mechanical grind-assisted hot-pressing, and are used for electromagnetic interference (EMI) shielding. CF with an average diameter of 150 nm is distributed on wood fiber, which is then encased by polyacrylamide. The CF/polyacrylamide/wood fiber (CPW) composite exhibits an optimal EMI shielding effectiveness (SE) of 41.03 dB compared to that of polyacrylamide/wood fiber composite (0.41 dB), which meets the requirements of commercial merchandise. Meanwhile, the CPW composite also shows high mechanical strength. The maximum modulus of rupture (MOR) and modulus of elasticity (MOE) of CPW composites are 39.52 MPa and 5823.15 MPa, respectively. The MOR and MOE of CPW composites increased by 38% and 96%, respectively, compared to that of polyacrylamide/wood fiber composite (28.64 and 2967.35 MPa).

A TALE-inspired computational screen for proteins that contain approximate tandem repeats.

PubMed

Perycz, Malgorzata; Krwawicz, Joanna; Bochtler, Matthias

2017-01-01

TAL (transcription activator-like) effectors (TALEs) are bacterial proteins that are secreted from bacteria to plant cells to act as transcriptional activators. TALEs and related proteins (RipTALs, BurrH, MOrTL1 and MOrTL2) contain approximate tandem repeats that differ in conserved positions that define specificity. Using PERL, we screened ~47 million protein sequences for TALE-like architecture characterized by approximate tandem repeats (between 30 and 43 amino acids in length) and sequence variability in conserved positions, without requiring sequence similarity to TALEs. Candidate proteins were scored according to their propensity for nuclear localization, secondary structure, repeat sequence complexity, as well as covariation and predicted structural proximity of variable residues. Biological context was tentatively inferred from co-occurrence of other domains and interactome predictions. Approximate repeats with TALE-like features that merit experimental characterization were found in a protein of chestnut blight fungus, a eukaryotic plant pathogen.

A TALE-inspired computational screen for proteins that contain approximate tandem repeats

PubMed Central

Krwawicz, Joanna

2017-01-01

TAL (transcription activator-like) effectors (TALEs) are bacterial proteins that are secreted from bacteria to plant cells to act as transcriptional activators. TALEs and related proteins (RipTALs, BurrH, MOrTL1 and MOrTL2) contain approximate tandem repeats that differ in conserved positions that define specificity. Using PERL, we screened ~47 million protein sequences for TALE-like architecture characterized by approximate tandem repeats (between 30 and 43 amino acids in length) and sequence variability in conserved positions, without requiring sequence similarity to TALEs. Candidate proteins were scored according to their propensity for nuclear localization, secondary structure, repeat sequence complexity, as well as covariation and predicted structural proximity of variable residues. Biological context was tentatively inferred from co-occurrence of other domains and interactome predictions. Approximate repeats with TALE-like features that merit experimental characterization were found in a protein of chestnut blight fungus, a eukaryotic plant pathogen. PMID:28617832

Identification of Human HK Genes and Gene Expression Regulation Study in Cancer from Transcriptomics Data Analysis

PubMed Central

Zhang, Zhang; Liu, Jingxing; Wu, Jiayan; Yu, Jun

2013-01-01

The regulation of gene expression is essential for eukaryotes, as it drives the processes of cellular differentiation and morphogenesis, leading to the creation of different cell types in multicellular organisms. RNA-Sequencing (RNA-Seq) provides researchers with a powerful toolbox for characterization and quantification of transcriptome. Many different human tissue/cell transcriptome datasets coming from RNA-Seq technology are available on public data resource. The fundamental issue here is how to develop an effective analysis method to estimate expression pattern similarities between different tumor tissues and their corresponding normal tissues. We define the gene expression pattern from three directions: 1) expression breadth, which reflects gene expression on/off status, and mainly concerns ubiquitously expressed genes; 2) low/high or constant/variable expression genes, based on gene expression level and variation; and 3) the regulation of gene expression at the gene structure level. The cluster analysis indicates that gene expression pattern is higher related to physiological condition rather than tissue spatial distance. Two sets of human housekeeping (HK) genes are defined according to cell/tissue types, respectively. To characterize the gene expression pattern in gene expression level and variation, we firstly apply improved K-means algorithm and a gene expression variance model. We find that cancer-associated HK genes (a HK gene is specific in cancer group, while not in normal group) are expressed higher and more variable in cancer condition than in normal condition. Cancer-associated HK genes prefer to AT-rich genes, and they are enriched in cell cycle regulation related functions and constitute some cancer signatures. The expression of large genes is also avoided in cancer group. These studies will help us understand which cell type-specific patterns of gene expression differ among different cell types, and particularly for cancer. PMID:23382867

Neighboring Genes Show Correlated Evolution in Gene Expression.

PubMed

Ghanbarian, Avazeh T; Hurst, Laurence D

2015-07-01

When considering the evolution of a gene's expression profile, we commonly assume that this is unaffected by its genomic neighborhood. This is, however, in contrast to what we know about the lack of autonomy between neighboring genes in gene expression profiles in extant taxa. Indeed, in all eukaryotic genomes genes of similar expression-profile tend to cluster, reflecting chromatin level dynamics. Does it follow that if a gene increases expression in a particular lineage then the genomic neighbors will also increase in their expression or is gene expression evolution autonomous? To address this here we consider evolution of human gene expression since the human-chimp common ancestor, allowing for both variation in estimation of current expression level and error in Bayesian estimation of the ancestral state. We find that in all tissues and both sexes, the change in gene expression of a focal gene on average predicts the change in gene expression of neighbors. The effect is highly pronounced in the immediate vicinity (<100 kb) but extends much further. Sex-specific expression change is also genomically clustered. As genes increasing their expression in humans tend to avoid nuclear lamina domains and be enriched for the gene activator 5-hydroxymethylcytosine, we conclude that, most probably owing to chromatin level control of gene expression, a change in gene expression of one gene likely affects the expression evolution of neighbors, what we term expression piggybacking, an analog of hitchhiking. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Endomorphins potentiate acid-sensing ion channel currents and enhance the lactic acid-mediated increase in arterial blood pressure: effects amplified in hindlimb ischaemia.

PubMed

Farrag, Mohamed; Drobish, Julie K; Puhl, Henry L; Kim, Joyce S; Herold, Paul B; Kaufman, Marc P; Ruiz-Velasco, Victor

2017-12-01

Chronic limb ischaemia, characterized by inflammatory mediator release and a low extracellular pH, leads to acid-sensing ion channel (ASIC) activation and reflexively increases mean arterial pressure; endomorphin release is also increased under inflammatory conditions. We examined the modulation of ASIC currents by endomorphins in sensory neurons from rats with freely perfused and ligated femoral arteries: peripheral artery disease (PAD) model. Endomorphins potentiated sustained ASIC currents in both groups of dorsal root ganglion neurons, independent of mu opioid receptor stimulation or G protein activation. Intra-arterial administration of lactic acid (to simulate exercising muscle and evoke a pressor reflex), endomorphin-2 and naloxone resulted in a significantly greater pressor response than lactic acid alone, while administration of APETx2 inhibited endomorphin's enhancing effect in both groups. These results suggest a novel role for endomorphins in modulating ASIC function to effect lactic acid-mediated reflex increase in arterial pressure in patients with PAD. Chronic muscle ischaemia leads to accumulation of lactic acid and other inflammatory mediators with a subsequent drop in interstitial pH. Acid-sensing ion channels (ASICs), expressed in thin muscle afferents, sense the decrease in pH and evoke a pressor reflex known to increase mean arterial pressure. The naturally occurring endomorphins are also released by primary afferents under ischaemic conditions. We examined whether high affinity mu opioid receptor (MOR) agonists, endomorphin-1 (E-1) and -2 (E-2), modulate ASIC currents and the lactic acid-mediated pressor reflex. In rat dorsal root ganglion (DRG) neurons, exposure to E-2 in acidic solutions significantly potentiated ASIC currents when compared to acidic solutions alone. The potentiation was significantly greater in DRG neurons isolated from rats whose femoral arteries were ligated for 72 h. Sustained ASIC current potentiation was also observed in neurons pretreated with pertussis toxin, an uncoupler of G proteins and MOR. The endomorphin-mediated potentiation was a result of a leftward shift of the activation curve to higher pH values and a slight shift of the inactivation curve to lower pH values. Intra-arterial co-administration of lactic acid and E-2 led to a significantly greater pressor reflex than lactic acid alone in the presence of naloxone. Finally, E-2 effects were inhibited by pretreatment with the ASIC3 blocker APETx2 and enhanced by pretreatment with the ASIC1a blocker psalmotoxin-1. These findings have uncovered a novel role of endomorphins by which the opioids can enhance the lactic acid-mediated reflex increase in arterial pressure that is MOR stimulation-independent and APETx2-sensitive. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Prolonged university outbreak of meningococcal disease associated with a serogroup B strain rarely seen in the United States.

PubMed

Mandal, Sema; Wu, Henry M; MacNeil, Jessica R; Machesky, Kimberly; Garcia, Jocelyn; Plikaytis, Brian D; Quinn, Kim; King, Larry; Schmink, Susanna E; Wang, Xin; Mayer, Leonard W; Clark, Thomas A; Gaskell, James R; Messonnier, Nancy E; DiOrio, Mary; Cohn, Amanda C

2013-08-01

College students living in residential halls are at increased risk of meningococcal disease. Unlike that for serogroups prevented by quadrivalent meningococcal vaccines, public health response to outbreaks of serogroup B meningococcal disease is limited by lack of a US licensed vaccine. In March 2010, we investigated a prolonged outbreak of serogroup B disease associated with a university. In addition to case ascertainment, molecular typing of isolates was performed to characterize the outbreak. We conducted a matched case-control study to examine risk factors for serogroup B disease. Five controls per case, matched by college year, were randomly selected. Participants completed a risk factor questionnaire. Data were analyzed using conditional logistic regression. Between January 2008 and November 2010, we identified 13 meningococcal disease cases (7 confirmed, 4 probable, and 2 suspected) involving 10 university students and 3 university-linked persons. One student died. Ten cases were determined to be serogroup B. Isolates from 6 confirmed cases had an indistinguishable pulsed-field gel electrophoresis pattern and belonged to sequence type 269, clonal complex 269. Factors significantly associated with disease were Greek society membership (matched odds ratio [mOR], 15.0; P = .03), >1 kissing partner (mOR, 13.66; P = .03), and attending bars (mOR, 8.06; P = .04). The outbreak was associated with a novel serogroup B strain (CC269) and risk factors were indicative of increased social mixing. Control measures were appropriate but limited by lack of vaccine. Understanding serogroup B transmission in college and other settings will help inform use of serogroup B vaccines currently under consideration for licensure.

Sexual behavior and sex-associated environmental cues activate the mesolimbic system in male rats.

PubMed

Balfour, Margaret E; Yu, Lei; Coolen, Lique M

2004-04-01

The mesolimbic system plays an important role in the regulation of both pathological behaviors such as drug addiction and normal motivated behaviors such as sexual behavior. The present study investigated the mechanism by which this system is endogenously activated during sexual behavior. Specifically, the effects of sexual experience and sex-related environmental cues on the activation of several components of the mesolimbic system were studied. The mesolimbic system consists of a dopaminergic projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Previous studies suggest that these neurons are under tonic inhibition by local GABA interneurons, which are in turn modulated by mu opioid receptor (MOR) ligands. To test the hypothesis that opioids are acting in the VTA during sexual behavior, visualization of MOR internalization in VTA was used as a marker for ligand-induced activation of the receptor. Significant increases in MOR internalization were observed following copulation or exposure to sex-related environmental cues. The next goal was to determine if sexual behavior activates dopamine neurons in the VTA, using tyrosine hydroxylase as a marker for dopaminergic neurons and Fos-immunoreactivity as a marker for neuronal activation. Significant increases in the percentage of activated dopaminergic neurons were observed following copulation or exposure to sex-related environmental cues. In addition, mating and sex-related cues activated a large population of nondopaminergic neurons in VTA as well as neurons in both the NAc Core and Shell. Taken together, our results provide functional neuroanatomical evidence that the mesolimbic system is activated by both sexual behavior and exposure to sex-related environmental cues.

Stability of bound species during alkene reactions on solid acids

NASA Astrophysics Data System (ADS)

Sarazen, Michele L.; Iglesia, Enrique

2017-05-01

This study reports the thermodynamics of bound species derived from ethene, propene, n-butene, and isobutene on solid acids with diverse strength and confining voids. Density functional theory (DFT) and kinetic data indicate that covalently bound alkoxides form C-C bonds in the kinetically relevant step for dimerization turnovers on protons within TON (0.57 nm) and MOR (0.67 nm) zeolitic channels and on stronger acids HPW (polyoxometalate clusters on silica). Turnover rates for mixed alkenes give relative alkoxide stabilities; the respective adsorption constants are obtained from in situ infrared spectra. Tertiary alkoxides (from isobutene) within larger voids (MOR, HPW) are more stable than less substituted isomers but are destabilized within smaller concave environments (TON) because framework distortions are required to avoid steric repulsion. Adsorption constants are similar on MOR and HPW for each alkoxide, indicating that binding is insensitive to acid strength for covalently bound species. DFT-derived formation free energies for alkoxides with different framework attachments and backbone length/structure agree with measurements when dispersion forces, which mediate stabilization by confinement in host-guest systems, are considered. Theory reveals previously unrecognized framework distortions that balance the C-O bond lengths required for covalency with host-guest distances that maximize van der Waals contacts. These distortions, reported here as changes in O-atom locations and dihedral angles, become stronger for larger, more substituted alkoxides. The thermodynamic properties reported here for alkoxides and acid hosts differing in size and conjugate-anion stability are benchmarked against DFT-derived free energies; their details are essential to design host-guest pairs that direct alkoxide species toward specific products.

Tailoring the composition of ultrathin, ternary alloy PtRuFe nanowires for the methanol oxidation reaction and formic acid oxidation reaction

DOE PAGES

Scofield, Megan E.; Koenigsmann, Christopher; Wang, Lei; ...

2014-11-25

In the search for alternatives to conventional Pt electrocatalysts, we have synthesized ultrathin, ternary PtRuFe nanowires (NW), possessing different chemical compositions in order to probe their CO tolerance as well as electrochemical activity as a function of composition for both (i) the methanol oxidation reaction (MOR) and (ii) the formic acid oxidation reaction (FAOR). As-prepared ‘multifunctional’ ternary NW catalysts exhibited both higher MOR and FAOR activity as compared with binary Pt₇Ru₃ NW, monometallic Pt NW, and commercial catalyst control samples. In terms of synthetic novelty, we utilized a sustainably mild, ambient wet-synthesis method never previously applied to the fabrication ofmore » crystalline, pure ternary systems in order to fabricate ultrathin, homogeneous alloy PtRuFe NWs with a range of controlled compositions. Thus, these NWs were subsequently characterized using a suite of techniques including XRD, TEM, SAED, and EDAX in order to verify not only the incorporation of Ru and Fe into the Pt lattice but also their chemical homogeneity, morphology, as well as physical structure and integrity. Lastly, these NWs were electrochemically tested in order to deduce the appropriateness of conventional explanations such as (i) the bi-functional mechanism as well as (ii) the ligand effect to account for our MOR and FAOR reaction data. Specifically, methanol oxidation appears to be predominantly influenced by the Ru content, whereas formic acid oxidation is primarily impacted by the corresponding Fe content within the ternary metal alloy catalyst itself.« less

Eye hyperdeviation in mouse cerebellar mutants is comparable to the gravity-dependent component of human downbeat nystagmus.

PubMed

Stahl, John S; Oommen, Brian S

2008-01-01

Humans with cerebellar degeneration commonly exhibit downbeat nystagmus (DBN). DBN has gravity-independent and -dependent components, and the latter has been proposed to reflect hyperactive tilt maculo-ocular reflexes (tilt-MOR). Mice with genetically determined cerebellar ataxia do not exhibit DBN, but they do exhibit tonic hyperdeviation of the eyes, which we have proposed to be the DBN equivalent. As such, the tilt-MOR might be predicted to be hyperactive in these mutant mice. We measured the tilt-MOR in 10 normal C57BL/6 mice and in 6 tottering, a mutant exhibiting ataxia and ocular motor abnormalities due to mutation of the P/Q calcium channel. Awake mice were placed in body orientations spanning 360 degrees about the pitch axis. The absolute, equilibrium vertical angular deviations of one eye were measured using infrared videooculography. In both strains, eye elevation varied quasi-sinusoidally with tilt angle in the range of 90 degrees nose-up to 90 degrees nose-down. Beyond this range the eye returned to a neutral position. Deviation over +/-30 degrees of tilt was an approximately linear function of the projection of the gravity vector into the animal's horizontal plane, and can thus be summarized by its slope (sensitivity). Sensitivity measured 14.9 degrees/g for C57BL/6 and 20.3 degrees/g for tottering, a statistically significant difference. Thus the pitch otolithic reflex of the ataxic mutants is hyperactive relative to controls and could explain tonic hyperdeviation of the eyes, consistent with the idea that the tonic hyperdeviation is analogous to DBN.

Kinematics and dynamics of the East Pacific Rise linked to a stable, deep-mantle upwelling

PubMed Central

Rowley, David B.; Forte, Alessandro M.; Rowan, Christopher J.; Glišović, Petar; Moucha, Robert; Grand, Stephen P.; Simmons, Nathan A.

2016-01-01

Earth’s tectonic plates are generally considered to be driven largely by negative buoyancy associated with subduction of oceanic lithosphere. In this context, mid-ocean ridges (MORs) are passive plate boundaries whose divergence accommodates flow driven by subduction of oceanic slabs at trenches. We show that over the past 80 million years (My), the East Pacific Rise (EPR), Earth’s dominant MOR, has been characterized by limited ridge-perpendicular migration and persistent, asymmetric ridge accretion that are anomalous relative to other MORs. We reconstruct the subduction-related buoyancy fluxes of plates on either side of the EPR. The general expectation is that greater slab pull should correlate with faster plate motion and faster spreading at the EPR. Moreover, asymmetry in slab pull on either side of the EPR should correlate with either ridge migration or enhanced plate velocity in the direction of greater slab pull. Based on our analysis, none of the expected correlations are evident. This implies that other forces significantly contribute to EPR behavior. We explain these observations using mantle flow calculations based on globally integrated buoyancy distributions that require core-mantle boundary heat flux of up to 20 TW. The time-dependent mantle flow predictions yield a long-lived deep-seated upwelling that has its highest radial velocity under the EPR and is inferred to control its observed kinematics. The mantle-wide upwelling beneath the EPR drives horizontal components of asthenospheric flows beneath the plates that are similarly asymmetric but faster than the overlying surface plates, thereby contributing to plate motions through viscous tractions in the Pacific region. PMID:28028535

Kinematics and dynamics of the East Pacific Rise linked to a stable, deep-mantle upwelling.

PubMed

Rowley, David B; Forte, Alessandro M; Rowan, Christopher J; Glišović, Petar; Moucha, Robert; Grand, Stephen P; Simmons, Nathan A

2016-12-01

Earth's tectonic plates are generally considered to be driven largely by negative buoyancy associated with subduction of oceanic lithosphere. In this context, mid-ocean ridges (MORs) are passive plate boundaries whose divergence accommodates flow driven by subduction of oceanic slabs at trenches. We show that over the past 80 million years (My), the East Pacific Rise (EPR), Earth's dominant MOR, has been characterized by limited ridge-perpendicular migration and persistent, asymmetric ridge accretion that are anomalous relative to other MORs. We reconstruct the subduction-related buoyancy fluxes of plates on either side of the EPR. The general expectation is that greater slab pull should correlate with faster plate motion and faster spreading at the EPR. Moreover, asymmetry in slab pull on either side of the EPR should correlate with either ridge migration or enhanced plate velocity in the direction of greater slab pull. Based on our analysis, none of the expected correlations are evident. This implies that other forces significantly contribute to EPR behavior. We explain these observations using mantle flow calculations based on globally integrated buoyancy distributions that require core-mantle boundary heat flux of up to 20 TW. The time-dependent mantle flow predictions yield a long-lived deep-seated upwelling that has its highest radial velocity under the EPR and is inferred to control its observed kinematics. The mantle-wide upwelling beneath the EPR drives horizontal components of asthenospheric flows beneath the plates that are similarly asymmetric but faster than the overlying surface plates, thereby contributing to plate motions through viscous tractions in the Pacific region.

Increased impulsive action in rats: effects of morphine in a short and long fixed-delay response inhibition task.

PubMed

Mahoney, Megan K; Silveira, Mason M; Olmstead, Mary C

2013-12-01

Impulsive action is mediated through several neurochemical systems, although it is not clear which role each of these plays in the inability to withhold inappropriate responses. Manipulations of the opioid system alter impulsive action in rodents, although the effects are not consistent across tasks. Previously, we speculated that these discrepancies reflect differences in the cognitive mechanisms that control responding in each task. We investigated whether the effect of morphine, a mu opioid receptor (MOR) agonist, on impulsive action depends on the ability of the subjects to time the interval during which they must inhibit a response. Male Long-Evans rats were trained in a response inhibition (RI) task to withhold responding for sucrose during a 4- or 60-s delay; impulsive action was assessed as increased responding during the delay. The rats were tested following an injection of morphine (0, 1, 3, 6 mg/kg). In a subsequent experiment, the effects of morphine (6 mg/kg) plus the MOR antagonist naloxone (0, 0.3, 1, 3 mg/kg) were investigated. Morphine increased impulsive action, but had different effects in the two conditions: the drug increased the proportion of premature responses as the 4-s interval progressed and produced a general increase in responding across the 60-s interval. Naloxone blocked all morphine-induced effects. The finding that morphine increases impulsive action in a fixed-delay RI task contrasts with our previous evidence which shows no effect in the same task with a variable delay. Thus, MORs disrupt impulsive action only when rats can predict the delay to respond.

The effects of kratom on restraint-stress-induced analgesia and its mechanisms of action.

PubMed

Vázquez López, José Luis; Schild, Lorenz; Günther, Thomas; Schulz, Stefan; Neurath, Hartmud; Becker, Axel

2017-06-09

Mitragyna speciosa and its extracts are called kratom (dried leaves, extract). They contain several alkaloids with an affinity for different opioid receptors. They are used in traditional medicine for the treatment of different diseases, as a substitute by opiate addicts, and to mitigate opioid withdrawal symptoms. Apart from their medical properties, they are used to enhance physical endurance and as a means of overcoming stress. The aim of this study was to determine the mechanisms underlying the effects of kratom on restraint-stress-induced analgesia which occurs during or following exposure to a stressful or fearful stimulus. To gain further insights into the action of kratom on stress, we conducted experiments using restraint stress as a test system and stress-induced analgesia as a test parameter. Using transgenic mu opioid-receptor (MOR) deficient mice, we studied the involvement of this receptor type. We used nor-binaltorphimine (BNT), an antagonist at kappa opioid receptors (KOR), to study functions of this type of receptor. Membrane potential assay was also employed to measure the intrinsic activity of kratom in comparison to U50,488, a highly selective kappa agonist. Treatment with kratom diminished stress-induced analgesia in wildtype and MOR knockout animals. Pretreatment of MOR deficient mice with BNT resulted in similar effects. In comparison to U50,488, kratom exhibited negligible intrinsic activity at KOR alone. The results suggest that the use of kratom as a pharmacological tool to mitigate withdrawal symptoms is related to its action on KOR. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Adenosine-A1 Receptor Agonist Induced Hyperalgesic Priming Type II

PubMed Central

Araldi, Dioneia; Ferrari, Luiz F.; Levine, Jon D.

2016-01-01

We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin acetate salt) induces a model of the transition to chronic pain that we have termed Type II hyperalgesic priming. Similar to Type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E2 (PGE2). However, Type II hyperalgesic priming differs from Type I in being rapidly induced, protein kinase A (PKA), rather than PKCε dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent. We report that as with the repeated injection of a MOR agonist, the repeated administration of an agonist at the A1-adenosine receptor, also a Gi-protein coupled receptor, N6-Cyclopentyladenosine (CPA), also produces priming similar to DAMGO-induced Type II hyperalgesic priming. In this study we demonstrate that priming induced by repeated exposure to this A1-adenosine receptor agonist shares the same mechanisms as MOR-agonist induced priming. However, the prolongation of PGE2 hyperalgesia induced by repeated administration of CPA depends on G-protein αi subunit activation, differently from DAMGO-induced Type II priming, in which it depends on the β/γ subunit. These data implicate a novel form of Gi-protein signaling pathway in the Type II hyperalgesic priming induced by repeated administration of an agonist at A1-adenosine receptor to the peripheral terminal of the nociceptor. PMID:26588695

Quality improvement of laminated board made from oil palm trunk at various outer layer using phenol formaldehyde adhesive

NASA Astrophysics Data System (ADS)

Hartono, R.; Sucipto, T.

2018-02-01

Characteristic of laminated board from oil palm trunk (OPT) is very low in quality. The effort to improved it’s quality done by using the outer layer from high density wood. The purpose of this experiment was to analyzed the effects of the outer layer on physical and mechanical properties of OPT and to obtain optimum treatment to fulfills JAS 234:2003. All of laminated board was made of 3 layers, and for the middle layer was made by densified-OPT. Then for the outer layer was made of sengon and meranti wood. The sample size was 5 cm (width) × 3 cm (thick) × 45 cm (length). The various outer layer of laminated board were A (OPT/densified OPT/OPT); B (Sengon/densified OPT/OPT); C (Sengon/densified OPT/sengon); D (Meranti/densified OPT/OPT) and E (Meranti/densified OPT/meranti). The results showed that the moisture content, density, thickness swelling, delamination, MOR and MOE were 6.10-8.48%; 0.40-0.63 g/cm3; 6.43-13.20%; 0%; 168.79-438.29 kg/cm2 and 30115-100454 kg/cm2, respectively. The moisture content and delamination fulfills JAS 234:2003, while density and thickness swelling did not fulfill standard. Whereas for MOR and MOE value, only type D and E that fulfill standard. There are strongth relationship between density and mechanical properties, such as MOR and MOE value. The optimum treatment in this reseach to made laminated board made from OPT was type D that using the meranti as outer layer.

Enhanced methanol electro-oxidation reaction on Pt-CoOx/MWCNTs hybrid electro-catalyst

NASA Astrophysics Data System (ADS)

Nouralishahi, Amideddin; Rashidi, Ali Morad; Mortazavi, Yadollah; Khodadadi, Abbas Ali; Choolaei, Mohammadmehdi

2015-04-01

The electro-catalytic behavior of Pt-CoOx/MWCNTs in methanol electro-oxidation reaction (MOR) is investigated and compared to that of Pt/MWCNTs. The electro-catalysts were synthesized by an impregnation method using NaBH4 as the reducing agent. The morphological and physical characteristics of samples are examined by XRD, TEM, ICP and EDS techniques. In the presence of CoOx, Pt nanoparticles were highly distributed on the support with an average particle size of 2 nm, an obvious decrease from 5.1 nm for Pt/MWCNTs. Cyclic voltammetry, CO-stripping, Chronoamperometry, and electrochemical impedance spectroscopy (EIS) measurements are used to study the electrochemical behavior of the electro-catalysts. The results revealed a considerable enhancement in the oxidation kinetics of COads on Pt active sites by the participation of CoOx. Compared to Pt/MWCNTs, Pt-CoOx/MWCNTs sample has a larger electrochemical active surface area (ECSA) and higher electro-catalytic activity and stability toward methanol electro-oxidation. According to the results of cyclic voltammetry, the forward anodic peak current density enhances more than 89% at the optimum atomic ratio of Pt:Co = 2:1. Furthermore, inclusion of cobalt oxide species causes the onset potential of methanol electro-oxidation reaction to shift 84 mV to negative values compared to that on Pt/MWCNTs. Based on EIS data, dehydrogenation of methanol is the rate-determining step of MOR on both Pt/MWCNTs and Pt-CoOx/MWCNTs, at small overpotentials. However, at higher overpotentials, the oxidation of adsorbed oxygen-containing groups controls the total rate of MOR process.

Application of community phylogenetic approaches to understand gene expression: differential exploration of venom gene space in predatory marine gastropods.

PubMed

Chang, Dan; Duda, Thomas F

2014-06-05

Predatory marine gastropods of the genus Conus exhibit substantial variation in venom composition both within and among species. Apart from mechanisms associated with extensive turnover of gene families and rapid evolution of genes that encode venom components ('conotoxins'), the evolution of distinct conotoxin expression patterns is an additional source of variation that may drive interspecific differences in the utilization of species' 'venom gene space'. To determine the evolution of expression patterns of venom genes of Conus species, we evaluated the expression of A-superfamily conotoxin genes of a set of closely related Conus species by comparing recovered transcripts of A-superfamily genes that were previously identified from the genomes of these species. We modified community phylogenetics approaches to incorporate phylogenetic history and disparity of genes and their expression profiles to determine patterns of venom gene space utilization. Less than half of the A-superfamily gene repertoire of these species is expressed, and only a few orthologous genes are coexpressed among species. Species exhibit substantially distinct expression strategies, with some expressing sets of closely related loci ('under-dispersed' expression of available genes) while others express sets of more disparate genes ('over-dispersed' expression). In addition, expressed genes show higher dN/dS values than either unexpressed or ancestral genes; this implies that expression exposes genes to selection and facilitates rapid evolution of these genes. Few recent lineage-specific gene duplicates are expressed simultaneously, suggesting that expression divergence among redundant gene copies may be established shortly after gene duplication. Our study demonstrates that venom gene space is explored differentially by Conus species, a process that effectively permits the independent and rapid evolution of venoms in these species.

Genomic and proteomic characterization of SuMu, a Mu-like bacteriophage infecting Haemophilus parasuis

PubMed Central

2012-01-01

Background Haemophilus parasuis, the causative agent of Glässer’s disease, is prevalent in swine herds and clinical signs associated with this disease are meningitis, polyserositis, polyarthritis, and bacterial pneumonia. Six to eight week old pigs in segregated early weaning herds are particularly susceptible to the disease. Insufficient colostral antibody at weaning or the mixing of pigs with heterologous virulent H. parasuis strains from other farm sources in the nursery or grower-finisher stage are considered to be factors for the outbreak of Glässer’s disease. Previously, a Mu-like bacteriophage portal gene was detected in a virulent swine isolate of H. parasuis by nested polymerase chain reaction. Mu-like bacteriophages are related phyologenetically to enterobacteriophage Mu and are thought to carry virulence genes or to induce host expression of virulence genes. This study characterizes the Mu-like bacteriophage, named SuMu, isolated from a virulent H. parasuis isolate. Results Characterization was done by genomic comparison to enterobacteriophage Mu and proteomic identification of various homologs by mass spectrometry. This is the first report of isolation and characterization of this bacteriophage from the Myoviridae family, a double-stranded DNA bacteriophage with a contractile tail, from a virulent field isolate of H. parasuis. The genome size of bacteriophage SuMu was 37,151 bp. DNA sequencing revealed fifty five open reading frames, including twenty five homologs to Mu-like bacteriophage proteins: Nlp, phage transposase-C-terminal, COG2842, Gam-like protein, gp16, Mor, peptidoglycan recognition protein, gp29, gp30, gpG, gp32, gp34, gp36, gp37, gpL, phage tail tube protein, DNA circulation protein, gpP, gp45, gp46, gp47, COG3778, tail fiber protein gp37-C terminal, tail fiber assembly protein, and Com. The last open reading frame was homologous to IS1414. The G + C content of bacteriophage SuMu was 41.87% while its H. parasuis host genome’s G + C content was 39.93%. Twenty protein homologs to bacteriophage proteins, including 15 structural proteins, one lysogeny-related and one lysis-related protein, and three DNA replication proteins were identified by mass spectrometry. One of the tail proteins, gp36, may be a virulence-related protein. Conclusions Bacteriophage SuMu was characterized by genomic and proteomic methods and compared to enterobacteriophage Mu. PMID:22823751

Genomic and proteomic characterization of SuMu, a Mu-like bacteriophage infecting Haemophilus parasuis.

PubMed

Zehr, Emilie S; Tabatabai, Louisa B; Bayles, Darrell O

2012-07-23

Haemophilus parasuis, the causative agent of Glässer's disease, is prevalent in swine herds and clinical signs associated with this disease are meningitis, polyserositis, polyarthritis, and bacterial pneumonia. Six to eight week old pigs in segregated early weaning herds are particularly susceptible to the disease. Insufficient colostral antibody at weaning or the mixing of pigs with heterologous virulent H. parasuis strains from other farm sources in the nursery or grower-finisher stage are considered to be factors for the outbreak of Glässer's disease. Previously, a Mu-like bacteriophage portal gene was detected in a virulent swine isolate of H. parasuis by nested polymerase chain reaction. Mu-like bacteriophages are related phyologenetically to enterobacteriophage Mu and are thought to carry virulence genes or to induce host expression of virulence genes. This study characterizes the Mu-like bacteriophage, named SuMu, isolated from a virulent H. parasuis isolate. Characterization was done by genomic comparison to enterobacteriophage Mu and proteomic identification of various homologs by mass spectrometry. This is the first report of isolation and characterization of this bacteriophage from the Myoviridae family, a double-stranded DNA bacteriophage with a contractile tail, from a virulent field isolate of H. parasuis. The genome size of bacteriophage SuMu was 37,151 bp. DNA sequencing revealed fifty five open reading frames, including twenty five homologs to Mu-like bacteriophage proteins: Nlp, phage transposase-C-terminal, COG2842, Gam-like protein, gp16, Mor, peptidoglycan recognition protein, gp29, gp30, gpG, gp32, gp34, gp36, gp37, gpL, phage tail tube protein, DNA circulation protein, gpP, gp45, gp46, gp47, COG3778, tail fiber protein gp37-C terminal, tail fiber assembly protein, and Com. The last open reading frame was homologous to IS1414. The G + C content of bacteriophage SuMu was 41.87% while its H. parasuis host genome's G + C content was 39.93%. Twenty protein homologs to bacteriophage proteins, including 15 structural proteins, one lysogeny-related and one lysis-related protein, and three DNA replication proteins were identified by mass spectrometry. One of the tail proteins, gp36, may be a virulence-related protein. Bacteriophage SuMu was characterized by genomic and proteomic methods and compared to enterobacteriophage Mu.

LANDSAT-D Mission Operations Review (MOR)

NASA Technical Reports Server (NTRS)

1982-01-01

Portions of the LANDSAT-D systems operation plan are presented. An overview of the data processing operations, logistics and other operations support, prelaunch and post-launch activities, thematic mapper operations during the scrounge period, and LANDSAT-D performance evaluation is given.

Mid-Ocean Ridge Melt Supply and Glacial Cycles: A 3D EPR Study of Crustal Thickness, Layer 2A, and Bathymetry

NASA Astrophysics Data System (ADS)

Boulahanis, B.; Aghaei, O.; Carbotte, S. M.; Huybers, P. J.; Langmuir, C. H.; Nedimovic, M. R.; Carton, H. D.; Canales, J. P.

2017-12-01

Recent studies suggest that eustatic sea level fluctuations induced by glacial cycles in the Pleistocene may influence mantle-melting and volcanic eruptions at mid-ocean ridges (MOR), with models predicting variation in oceanic crustal thickness linked to sea level change. Previous analyses of seafloor bathymetry as a proxy for crustal thickness show significant spectral energy at frequencies linked to Milankovitch cycles of 1/23, 1/41, and 1/100 ky-1, however the effects of faulting in seafloor relief and its spectral characteristics are difficult to separate from climatic signals. Here we investigate the hypothesis of climate driven periodicity in MOR magmatism through spectral analysis, time series comparisons, and statistical characterization of bathymetry data, seismic layer 2A thickness (as a proxy for extrusive volcanism), and seafloor-to-Moho thickness (as a proxy for total magma production). We utilize information from a three-dimensional multichannel seismic study of the East Pacific Rise and its flanks from 9°36`N to 9°57`N. We compare these datasets to the paleoclimate "LR04" benthic δ18O stack. The seismic dataset covers 770 km2 and provides resolution of Moho for 92% of the imaged region. This is the only existing high-resolution 3-D image across oceanic crust, making it ideal for assessing the possibility that glacial cycles modulate magma supply at fast spreading MORs. The layer 2A grid extends 9 km (170 ky) from the ridge axis, while Moho imaging extends to a maximum of 16 km (310 ky). Initial results from the East Pacific Rise show a relationship between sea level and both crustal thickness and sea floor depth, consistent with the hypothesis that magma supply to MORs may be modulated by glacial cycles. Analysis of crustal thickness and bathymetry data reveals spectral peaks at Milankovitch frequencies of 1/100 ky-1 and 1/41 ky-1 where datasets extend sufficiently far from the ridge. The layer 2A grid does not extend sufficiently far from the ridge to be conclusive. Correlations between sea level and crustal thickness suggest a lag of 65 ky between sea level forcing and crustal thickness response. A further lag of 25 ky is observed between crustal thickness variations and seafloor depth change, which we attribute to the finite width of the crustal formation zone.

The otolithic contribution to vertical ocular stability in the cat.

PubMed

Pettorossi, V E; Draicchio, F; Ferraresi, A; Bruni, R

1994-10-01

In cats, horizontal (HVOR) and vertical (VVOR) vestibulo-ocular reflexes were studied alone and combined with optokinetic stimulation. The upright VVOR (VVOR O degree) only showed higher gain and smaller phase lead compared to those of HVOR at frequencies below 0.05 Hz. The addition of optokinetic stimulation to the vestibular stimulation increased the gain of the horizontal and vertical ocular responses close to 1. VVOR was also studied in side down position (VVOR 90 degrees). In VVOR 90 degrees the ocular responses were asymmetric. The downward directed eye responses of VVOR 90 degrees showed lower gain and greater phase lead compared to those of VVOR 0 degree for the whole range of tested frequencies (0.01-0.4 Hz), while the upward eye responses only showed a lower gain at the lower range of frequencies tested. In the light the gain of VVOR 90 degrees increased, but the gain of downward directed eye responses was consistently lower than 1 at lower frequencies. The higher gain of the VVOR 0 degree compared to the VVOR 90 degrees and HVOR was attributed to the maculo-ocular reflex (MOR) evoked by the gravity modulation of the otolithic receptors, when the animals were oscillated in the pitch plane. The MOR was isolated from the VVOR 0 degree by plugging all semicircular canals. At very low frequencies the gain of the MOR was 0.3-0.35 and the phase was close to 0 degree. This reflex showed a progressive gain decrease and phase lag by increasing the stimulation frequencies. This suggests a low pass filtering process of the otolithic signal. Furthermore in plugged animals the asymmetry of the vertical optokinetic responses was reduced by adding the MOR. The quick phases (QPs) of the vestibular responses were also different depending upon the stimulation plane. The QPs of VVOR 0 degree were smaller and more delayed than those of HVOR and VVOR 90 degrees. In conclusion the main effects observed during otolithic coactivation in the VVOR 0 of the cat are: 1) the enhancement of gain and reduction of phase lead at low frequency vestibular stimulation, resulting in similar vertical and horizontal gaze stability; 2) the equalization of the upward and downward responses of both vestibulo-ocular and optokinetic responses; 3) the reduction of the amplitude and frequency of vertical quick phases.

FARO server: Meta-analysis of gene expression by matching gene expression signatures to a compendium of public gene expression data.

PubMed

Manijak, Mieszko P; Nielsen, Henrik B

2011-06-11

Although, systematic analysis of gene annotation is a powerful tool for interpreting gene expression data, it sometimes is blurred by incomplete gene annotation, missing expression response of key genes and secondary gene expression responses. These shortcomings may be partially circumvented by instead matching gene expression signatures to signatures of other experiments. To facilitate this we present the Functional Association Response by Overlap (FARO) server, that match input signatures to a compendium of 242 gene expression signatures, extracted from more than 1700 Arabidopsis microarray experiments. Hereby we present a publicly available tool for robust characterization of Arabidopsis gene expression experiments which can point to similar experimental factors in other experiments. The server is available at http://www.cbs.dtu.dk/services/faro/.

Digital gene expression analysis of the zebra finch genome

PubMed Central

2010-01-01

Background In order to understand patterns of adaptation and molecular evolution it is important to quantify both variation in gene expression and nucleotide sequence divergence. Gene expression profiling in non-model organisms has recently been facilitated by the advent of massively parallel sequencing technology. Here we investigate tissue specific gene expression patterns in the zebra finch (Taeniopygia guttata) with special emphasis on the genes of the major histocompatibility complex (MHC). Results Almost 2 million 454-sequencing reads from cDNA of six different tissues were assembled and analysed. A total of 11,793 zebra finch transcripts were represented in this EST data, indicating a transcriptome coverage of about 65%. There was a positive correlation between the tissue specificity of gene expression and non-synonymous to synonymous nucleotide substitution ratio of genes, suggesting that genes with a specialised function are evolving at a higher rate (or with less constraint) than genes with a more general function. In line with this, there was also a negative correlation between overall expression levels and expression specificity of contigs. We found evidence for expression of 10 different genes related to the MHC. MHC genes showed relatively tissue specific expression levels and were in general primarily expressed in spleen. Several MHC genes, including MHC class I also showed expression in brain. Furthermore, for all genes with highest levels of expression in spleen there was an overrepresentation of several gene ontology terms related to immune function. Conclusions Our study highlights the usefulness of next-generation sequence data for quantifying gene expression in the genome as a whole as well as in specific candidate genes. Overall, the data show predicted patterns of gene expression profiles and molecular evolution in the zebra finch genome. Expression of MHC genes in particular, corresponds well with expression patterns in other vertebrates. PMID:20359325

A novel approach for human whole transcriptome analysis based on absolute gene expression of microarray data.

PubMed

Bikel, Shirley; Jacobo-Albavera, Leonor; Sánchez-Muñoz, Fausto; Cornejo-Granados, Fernanda; Canizales-Quinteros, Samuel; Soberón, Xavier; Sotelo-Mundo, Rogerio R; Del Río-Navarro, Blanca E; Mendoza-Vargas, Alfredo; Sánchez, Filiberto; Ochoa-Leyva, Adrian

2017-01-01

In spite of the emergence of RNA sequencing (RNA-seq), microarrays remain in widespread use for gene expression analysis in the clinic. There are over 767,000 RNA microarrays from human samples in public repositories, which are an invaluable resource for biomedical research and personalized medicine. The absolute gene expression analysis allows the transcriptome profiling of all expressed genes under a specific biological condition without the need of a reference sample. However, the background fluorescence represents a challenge to determine the absolute gene expression in microarrays. Given that the Y chromosome is absent in female subjects, we used it as a new approach for absolute gene expression analysis in which the fluorescence of the Y chromosome genes of female subjects was used as the background fluorescence for all the probes in the microarray. This fluorescence was used to establish an absolute gene expression threshold, allowing the differentiation between expressed and non-expressed genes in microarrays. We extracted the RNA from 16 children leukocyte samples (nine males and seven females, ages 6-10 years). An Affymetrix Gene Chip Human Gene 1.0 ST Array was carried out for each sample and the fluorescence of 124 genes of the Y chromosome was used to calculate the absolute gene expression threshold. After that, several expressed and non-expressed genes according to our absolute gene expression threshold were compared against the expression obtained using real-time quantitative polymerase chain reaction (RT-qPCR). From the 124 genes of the Y chromosome, three genes (DDX3Y, TXLNG2P and EIF1AY) that displayed significant differences between sexes were used to calculate the absolute gene expression threshold. Using this threshold, we selected 13 expressed and non-expressed genes and confirmed their expression level by RT-qPCR. Then, we selected the top 5% most expressed genes and found that several KEGG pathways were significantly enriched. Interestingly, these pathways were related to the typical functions of leukocytes cells, such as antigen processing and presentation and natural killer cell mediated cytotoxicity. We also applied this method to obtain the absolute gene expression threshold in already published microarray data of liver cells, where the top 5% expressed genes showed an enrichment of typical KEGG pathways for liver cells. Our results suggest that the three selected genes of the Y chromosome can be used to calculate an absolute gene expression threshold, allowing a transcriptome profiling of microarray data without the need of an additional reference experiment. Our approach based on the establishment of a threshold for absolute gene expression analysis will allow a new way to analyze thousands of microarrays from public databases. This allows the study of different human diseases without the need of having additional samples for relative expression experiments.

Differential gene expression analysis in glioblastoma cells and normal human brain cells based on GEO database.

PubMed

Wang, Anping; Zhang, Guibin

2017-11-01

The differentially expressed genes between glioblastoma (GBM) cells and normal human brain cells were investigated to performed pathway analysis and protein interaction network analysis for the differentially expressed genes. GSE12657 and GSE42656 gene chips, which contain gene expression profile of GBM were obtained from Gene Expression Omniub (GEO) database of National Center for Biotechnology Information (NCBI). The 'limma' data packet in 'R' software was used to analyze the differentially expressed genes in the two gene chips, and gene integration was performed using 'RobustRankAggreg' package. Finally, pheatmap software was used for heatmap analysis and Cytoscape, DAVID, STRING and KOBAS were used for protein-protein interaction, Gene Ontology (GO) and KEGG analyses. As results: i) 702 differentially expressed genes were identified in GSE12657, among those genes, 548 were significantly upregulated and 154 were significantly downregulated (p<0.01, fold-change >1), and 1,854 differentially expressed genes were identified in GSE42656, among the genes, 1,068 were significantly upregulated and 786 were significantly downregulated (p<0.01, fold-change >1). A total of 167 differentially expressed genes including 100 upregulated genes and 67 downregulated genes were identified after gene integration, and the genes showed significantly different expression levels in GBM compared with normal human brain cells (p<0.05). ii) Interactions between the protein products of 101 differentially expressed genes were identified using STRING and expression network was established. A key gene, called CALM3, was identified by Cytoscape software. iii) GO enrichment analysis showed that differentially expressed genes were mainly enriched in 'neurotransmitter:sodium symporter activity' and 'neurotransmitter transporter activity', which can affect the activity of neurotransmitter transportation. KEGG pathway analysis showed that the differentially expressed genes were mainly enriched in 'protein processing in endoplasmic reticulum', which can affect protein processing in endoplasmic reticulum. The results showed that: i) 167 differentially expressed genes were identified from two gene chips after integration; and ii) protein interaction network was established, and GO and KEGG pathway analyses were successfully performed to identify and annotate the key gene, which provide new insights for the studies on GBN at gene level.

Discovery and validation of a glioblastoma co-expressed gene module

PubMed Central

Dunwoodie, Leland J.; Poehlman, William L.; Ficklin, Stephen P.; Feltus, Frank Alexander

2018-01-01

Tumors exhibit complex patterns of aberrant gene expression. Using a knowledge-independent, noise-reducing gene co-expression network construction software called KINC, we created multiple RNAseq-based gene co-expression networks relevant to brain and glioblastoma biology. In this report, we describe the discovery and validation of a glioblastoma-specific gene module that contains 22 co-expressed genes. The genes are upregulated in glioblastoma relative to normal brain and lower grade glioma samples; they are also hypo-methylated in glioblastoma relative to lower grade glioma tumors. Among the proneural, neural, mesenchymal, and classical glioblastoma subtypes, these genes are most-highly expressed in the mesenchymal subtype. Furthermore, high expression of these genes is associated with decreased survival across each glioblastoma subtype. These genes are of interest to glioblastoma biology and our gene interaction discovery and validation workflow can be used to discover and validate co-expressed gene modules derived from any co-expression network. PMID:29541392

Discovery and validation of a glioblastoma co-expressed gene module.

PubMed

Dunwoodie, Leland J; Poehlman, William L; Ficklin, Stephen P; Feltus, Frank Alexander

2018-02-16

Tumors exhibit complex patterns of aberrant gene expression. Using a knowledge-independent, noise-reducing gene co-expression network construction software called KINC, we created multiple RNAseq-based gene co-expression networks relevant to brain and glioblastoma biology. In this report, we describe the discovery and validation of a glioblastoma-specific gene module that contains 22 co-expressed genes. The genes are upregulated in glioblastoma relative to normal brain and lower grade glioma samples; they are also hypo-methylated in glioblastoma relative to lower grade glioma tumors. Among the proneural, neural, mesenchymal, and classical glioblastoma subtypes, these genes are most-highly expressed in the mesenchymal subtype. Furthermore, high expression of these genes is associated with decreased survival across each glioblastoma subtype. These genes are of interest to glioblastoma biology and our gene interaction discovery and validation workflow can be used to discover and validate co-expressed gene modules derived from any co-expression network.

Unit costs of medium and heavy truck crashes.

DOT National Transportation Integrated Search

2008-03-01

This study provides the latest estimates of unit costs for highway crashes involving medium/heavy trucks by severity. Based on the latest data available, the estimated cost of police-reported crashes involving trucks with a gross weight rating of mor...

Morphine induces albuminuria by compromising podocyte integrity.

PubMed

Lan, Xiqian; Rai, Partab; Chandel, Nirupama; Cheng, Kang; Lederman, Rivka; Saleem, Moin A; Mathieson, Peter W; Husain, Mohammad; Crosson, John T; Gupta, Kalpna; Malhotra, Ashwani; Singhal, Pravin C

2013-01-01

Morphine has been reported to accelerate the progression of chronic kidney disease. However, whether morphine affects slit diaphragm (SD), the major constituent of glomerular filtration barrier, is still unclear. In the present study, we examined the effect of morphine on glomerular filtration barrier in general and podocyte integrity in particular. Mice were administered either normal saline or morphine for 72 h, then urine samples were collected and kidneys were subsequently isolated for immunohistochemical studies and Western blot. For in vitro studies, human podocytes were treated with morphine and then probed for the molecular markers of slit diaphragm. Morphine-receiving mice displayed a significant increase in albuminuria and showed effacement of podocyte foot processes. In both in vivo and in vitro studies, the expression of synaptopodin, a molecular marker for podocyte integrity, and the slit diaphragm constituting molecules (SDCM), such as nephrin, podocin, and CD2-associated protein (CD2AP), were decreased in morphine-treated podocytes. In vitro studies indicated that morphine modulated podocyte expression of SDCM through opiate mu (MOR) and kappa (KOR) receptors. Since morphine also enhanced podocyte oxidative stress, the latter seems to contribute to decreased SDCM expression. In addition, AKT, p38, and JNK pathways were involved in morphine-induced down regulation of SDCM in human podocytes. These findings demonstrate that morphine has the potential to alter the glomerular filtration barrier by compromising the integrity of podocytes.

Gender-Specific Gene Expression in Post-Mortem Human Brain: Localization to Sex Chromosomes

PubMed Central

Vawter, Marquis P; Evans, Simon; Choudary, Prabhakara; Tomita, Hiroaki; Meador-Woodruff, Jim; Molnar, Margherita; Li, Jun; Lopez, Juan F; Myers, Rick; Cox, David; Watson, Stanley J; Akil, Huda; Jones, Edward G; Bunney, William E

2011-01-01

Gender differences in brain development and in the prevalence of neuropsychiatric disorders such as depression have been reported. Gender differences in human brain might be related to patterns of gene expression. Microarray technology is one useful method for investigation of gene expression in brain. We investigated gene expression, cell types, and regional expression patterns of differentially expressed sex chromosome genes in brain. We profiled gene expression in male and female dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum using the Affymetrix oligonucleotide microarray platform. Differentially expressed genes between males and females on the Y chromosome (DBY, SMCY, UTY, RPS4Y, and USP9Y) and X chromosome (XIST) were confirmed using real-time PCR measurements. In situ hybridization confirmed the differential expression of gender-specific genes and neuronal expression of XIST, RPS4Y, SMCY, and UTY in three brain regions examined. The XIST gene, which silences gene expression on regions of the X chromosome, is expressed in a subset of neurons. Since a subset of neurons express gender-specific genes, neural subpopulations may exhibit a subtle sexual dimorphism at the level of differences in gene regulation and function. The distinctive pattern of neuronal expression of XIST, RPS4Y, SMCY, and UTY and other sex chromosome genes in neuronal subpopulations may possibly contribute to gender differences in prevalence noted for some neuropsychiatric disorders. Studies of the protein expression of these sex- chromosome-linked genes in brain tissue are required to address the functional consequences of the observed gene expression differences. PMID:14583743

Gene expression variability in human hepatic drug metabolizing enzymes and transporters.

PubMed

Yang, Lun; Price, Elvin T; Chang, Ching-Wei; Li, Yan; Huang, Ying; Guo, Li-Wu; Guo, Yongli; Kaput, Jim; Shi, Leming; Ning, Baitang

2013-01-01

Interindividual variability in the expression of drug-metabolizing enzymes and transporters (DMETs) in human liver may contribute to interindividual differences in drug efficacy and adverse reactions. Published studies that analyzed variability in the expression of DMET genes were limited by sample sizes and the number of genes profiled. We systematically analyzed the expression of 374 DMETs from a microarray data set consisting of gene expression profiles derived from 427 human liver samples. The standard deviation of interindividual expression for DMET genes was much higher than that for non-DMET genes. The 20 DMET genes with the largest variability in the expression provided examples of the interindividual variation. Gene expression data were also analyzed using network analysis methods, which delineates the similarities of biological functionalities and regulation mechanisms for these highly variable DMET genes. Expression variability of human hepatic DMET genes may affect drug-gene interactions and disease susceptibility, with concomitant clinical implications.

A novel approach for human whole transcriptome analysis based on absolute gene expression of microarray data

PubMed Central

Bikel, Shirley; Jacobo-Albavera, Leonor; Sánchez-Muñoz, Fausto; Cornejo-Granados, Fernanda; Canizales-Quinteros, Samuel; Soberón, Xavier; Sotelo-Mundo, Rogerio R.; del Río-Navarro, Blanca E.; Mendoza-Vargas, Alfredo; Sánchez, Filiberto

2017-01-01

Background In spite of the emergence of RNA sequencing (RNA-seq), microarrays remain in widespread use for gene expression analysis in the clinic. There are over 767,000 RNA microarrays from human samples in public repositories, which are an invaluable resource for biomedical research and personalized medicine. The absolute gene expression analysis allows the transcriptome profiling of all expressed genes under a specific biological condition without the need of a reference sample. However, the background fluorescence represents a challenge to determine the absolute gene expression in microarrays. Given that the Y chromosome is absent in female subjects, we used it as a new approach for absolute gene expression analysis in which the fluorescence of the Y chromosome genes of female subjects was used as the background fluorescence for all the probes in the microarray. This fluorescence was used to establish an absolute gene expression threshold, allowing the differentiation between expressed and non-expressed genes in microarrays. Methods We extracted the RNA from 16 children leukocyte samples (nine males and seven females, ages 6–10 years). An Affymetrix Gene Chip Human Gene 1.0 ST Array was carried out for each sample and the fluorescence of 124 genes of the Y chromosome was used to calculate the absolute gene expression threshold. After that, several expressed and non-expressed genes according to our absolute gene expression threshold were compared against the expression obtained using real-time quantitative polymerase chain reaction (RT-qPCR). Results From the 124 genes of the Y chromosome, three genes (DDX3Y, TXLNG2P and EIF1AY) that displayed significant differences between sexes were used to calculate the absolute gene expression threshold. Using this threshold, we selected 13 expressed and non-expressed genes and confirmed their expression level by RT-qPCR. Then, we selected the top 5% most expressed genes and found that several KEGG pathways were significantly enriched. Interestingly, these pathways were related to the typical functions of leukocytes cells, such as antigen processing and presentation and natural killer cell mediated cytotoxicity. We also applied this method to obtain the absolute gene expression threshold in already published microarray data of liver cells, where the top 5% expressed genes showed an enrichment of typical KEGG pathways for liver cells. Our results suggest that the three selected genes of the Y chromosome can be used to calculate an absolute gene expression threshold, allowing a transcriptome profiling of microarray data without the need of an additional reference experiment. Discussion Our approach based on the establishment of a threshold for absolute gene expression analysis will allow a new way to analyze thousands of microarrays from public databases. This allows the study of different human diseases without the need of having additional samples for relative expression experiments. PMID:29230367

Modelling uncertain paternity to address differential pedigree accuracy

USDA-ARS?s Scientific Manuscript database

The objective was to implement uncertain parentage models to account for differences in daughter pedigree accuracy. Elite sires have nearly all daughters genotyped resulting in correct paternity assignment. Bulls of lesser genetic merit have fewer daughters genotyped creating the possibility for mor...

Integration of DNA barcoding approaches into aquatic bioassessments

EPA Science Inventory

The Clean Water Act directs states to protect water resources by developing criteria based in part on biological assessments of natural aquatic ecosystems. Current protocols can be limited by the availability of taxonomic expertise and concerns about precision and accuracy in mor...

REPRODUCTIVE AND DEVELOPMENTAL PHARMACOKINETIC AND MECHANISTIC RESEARCH

EPA Science Inventory

In 1993, an expert panel convened by the EPA and the International Life Sciences Institute (ILSI) decided that: 1) screening studies should be implemented to fill critical data gaps; 2) fertility assessments should be enhanced; and 3) biomarkers of effect should be developed. Mor...

Accelerated Evolution of Developmentally Biased Genes in the Tetraphenic Ant Cardiocondyla obscurior.

PubMed

Schrader, Lukas; Helanterä, Heikki; Oettler, Jan

2017-03-01

Plastic gene expression underlies phenotypic plasticity and plastically expressed genes evolve under different selection regimes compared with ubiquitously expressed genes. Social insects are well-suited models to elucidate the evolutionary dynamics of plastic genes for their genetically and environmentally induced discrete polymorphisms. Here, we study the evolution of plastically expressed genes in the ant Cardiocondyla obscurior-a species that produces two discrete male morphs in addition to the typical female polymorphism of workers and queens. Based on individual-level gene expression data from 28 early third instar larvae, we test whether the same evolutionary dynamics that pertain to plastically expressed genes in adults also pertain to genes with plastic expression during development. In order to quantify plasticity of gene expression over multiple contrasts, we develop a novel geometric measure. For genes expressed during development, we show that plasticity of expression is positively correlated with evolutionary rates. We furthermore find a strong correlation between expression plasticity and expression variation within morphs, suggesting a close link between active and passive plasticity of gene expression. Our results support the notion of relaxed selection and neutral processes as important drivers in the evolution of adaptive plasticity. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Analysis of multiplex gene expression maps obtained by voxelation.

PubMed

An, Li; Xie, Hongbo; Chin, Mark H; Obradovic, Zoran; Smith, Desmond J; Megalooikonomou, Vasileios

2009-04-29

Gene expression signatures in the mammalian brain hold the key to understanding neural development and neurological disease. Researchers have previously used voxelation in combination with microarrays for acquisition of genome-wide atlases of expression patterns in the mouse brain. On the other hand, some work has been performed on studying gene functions, without taking into account the location information of a gene's expression in a mouse brain. In this paper, we present an approach for identifying the relation between gene expression maps obtained by voxelation and gene functions. To analyze the dataset, we chose typical genes as queries and aimed at discovering similar gene groups. Gene similarity was determined by using the wavelet features extracted from the left and right hemispheres averaged gene expression maps, and by the Euclidean distance between each pair of feature vectors. We also performed a multiple clustering approach on the gene expression maps, combined with hierarchical clustering. Among each group of similar genes and clusters, the gene function similarity was measured by calculating the average gene function distances in the gene ontology structure. By applying our methodology to find similar genes to certain target genes we were able to improve our understanding of gene expression patterns and gene functions. By applying the clustering analysis method, we obtained significant clusters, which have both very similar gene expression maps and very similar gene functions respectively to their corresponding gene ontologies. The cellular component ontology resulted in prominent clusters expressed in cortex and corpus callosum. The molecular function ontology gave prominent clusters in cortex, corpus callosum and hypothalamus. The biological process ontology resulted in clusters in cortex, hypothalamus and choroid plexus. Clusters from all three ontologies combined were most prominently expressed in cortex and corpus callosum. The experimental results confirm the hypothesis that genes with similar gene expression maps might have similar gene functions. The voxelation data takes into account the location information of gene expression level in mouse brain, which is novel in related research. The proposed approach can potentially be used to predict gene functions and provide helpful suggestions to biologists.

Co-expression network analysis of duplicate genes in maize (Zea mays L.) reveals no subgenome bias.

PubMed

Li, Lin; Briskine, Roman; Schaefer, Robert; Schnable, Patrick S; Myers, Chad L; Flagel, Lex E; Springer, Nathan M; Muehlbauer, Gary J

2016-11-04

Gene duplication is prevalent in many species and can result in coding and regulatory divergence. Gene duplications can be classified as whole genome duplication (WGD), tandem and inserted (non-syntenic). In maize, WGD resulted in the subgenomes maize1 and maize2, of which maize1 is considered the dominant subgenome. However, the landscape of co-expression network divergence of duplicate genes in maize is still largely uncharacterized. To address the consequence of gene duplication on co-expression network divergence, we developed a gene co-expression network from RNA-seq data derived from 64 different tissues/stages of the maize reference inbred-B73. WGD, tandem and inserted gene duplications exhibited distinct regulatory divergence. Inserted duplicate genes were more likely to be singletons in the co-expression networks, while WGD duplicate genes were likely to be co-expressed with other genes. Tandem duplicate genes were enriched in the co-expression pattern where co-expressed genes were nearly identical for the duplicates in the network. Older gene duplications exhibit more extensive co-expression variation than younger duplications. Overall, non-syntenic genes primarily from inserted duplications show more co-expression divergence. Also, such enlarged co-expression divergence is significantly related to duplication age. Moreover, subgenome dominance was not observed in the co-expression networks - maize1 and maize2 exhibit similar levels of intra subgenome correlations. Intriguingly, the level of inter subgenome co-expression was similar to the level of intra subgenome correlations, and genes from specific subgenomes were not likely to be the enriched in co-expression network modules and the hub genes were not predominantly from any specific subgenomes in maize. Our work provides a comprehensive analysis of maize co-expression network divergence for three different types of gene duplications and identifies potential relationships between duplication types, duplication ages and co-expression consequences.

A national outbreak of Salmonella serotype Tennessee infections from contaminated peanut butter: a new food vehicle for salmonellosis in the United States.

PubMed

Sheth, Anandi N; Hoekstra, Mike; Patel, Nehal; Ewald, Gwen; Lord, Cathy; Clarke, Carmen; Villamil, Elizabeth; Niksich, Katherine; Bopp, Cheryl; Nguyen, Thai-An; Zink, Donald; Lynch, Michael

2011-08-01

Salmonella serotype Tennessee is a rare cause of the estimated 1 million cases of salmonellosis occurring annually in the United States. In January 2007, we began investigating a nationwide increase in Salmonella Tennessee infections. We defined a case as Salmonella Tennessee infection in a patient whose isolate demonstrated 1 of 3 closely related pulsed-field gel electrophoresis patterns and whose illness began during the period 1 August 2006 through 31 July 2007. We conducted a case-control study in 22 states and performed laboratory testing of foods and environmental samples. We identified 715 cases in 48 states; 37% of isolates were from urine specimens. Illness was associated with consuming peanut butter more than once a week (matched odds ratio [mOR], 3.5 [95% confidence interval {95% CI}, 1.4-9.9]), consuming Brand X peanut butter (mOR, 12.1 [95% CI, 3.6-66.3]), and consuming Brand Y peanut butter (mOR, 9.1 [95% CI, 1.0-433]). Brands X and Y were produced in 1 plant, which ceased production and recalled products on 14 February 2007. Laboratories isolated outbreak strains of Salmonella Tennessee from 34 Brands X and Y peanut butter jars and 2 plant environmental samples. This large, widespread outbreak of salmonellosis is the first linked to peanut butter in the United States; a nationwide recall resulted in outbreak control. Environmental contamination in the peanut butter plant likely caused this outbreak. This outbreak highlights the risk of salmonellosis from heat-processed foods of nonanimal origin previously felt to be low risk for Salmonella contamination.

The Effect of Arc Proximity on Hydrothermal Activity Along Spreading Centers: New Evidence From the Mariana Back Arc (12.7°N-18.3°N)

NASA Astrophysics Data System (ADS)

Baker, Edward T.; Walker, Sharon L.; Resing, Joseph A.; Chadwick, William W.; Merle, Susan G.; Anderson, Melissa O.; Butterfield, David A.; Buck, Nathan J.; Michael, Susanna

2017-11-01

Back-arc spreading centers (BASCs) form a distinct class of ocean spreading ridges distinguished by steep along-axis gradients in spreading rate and by additional magma supplied through subduction. These characteristics can affect the population and distribution of hydrothermal activity on BASCs compared to mid-ocean ridges (MORs). To investigate this hypothesis, we comprehensively explored 600 km of the southern half of the Mariana BASC. We used water column mapping and seafloor imaging to identify 19 active vent sites, an increase of 13 over the current listing in the InterRidge Database (IRDB), on the bathymetric highs of 7 of the 11 segments. We identified both high and low (i.e., characterized by a weak or negligible particle plume) temperature discharge occurring on segment types spanning dominantly magmatic to dominantly tectonic. Active sites are concentrated on the two southernmost segments, where distance to the adjacent arc is shortest (<40 km), spreading rate is highest (>48 mm/yr), and tectonic extension is pervasive. Re-examination of hydrothermal data from other BASCs supports the generalization that hydrothermal site density increases on segments <90 km from an adjacent arc. Although exploration quality varies greatly among BASCs, present data suggest that, for a given spreading rate, the mean spatial density of hydrothermal activity varies little between MORs and BASCs. The present global database, however, may be misleading. On both BASCs and MORs, the spatial density of hydrothermal sites mapped by high-quality water-column surveys is 2-7 times greater than predicted by the existing IRDB trend of site density versus spreading rate.

Kinematics and dynamics of the East Pacific Rise linked to a stable, deep-mantle upwelling [Kinematics and dynamics of the East Pacific Rise linked to whole mantel convective motions

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

Rowley, David B.; Forte, Alessandro M.; Rowan, Christopher J.

Earth’s tectonic plates are generally considered to be driven largely by negative buoyancy associated with subduction of oceanic lithosphere. In this context, mid-ocean ridges (MORs) are passive plate boundaries whose divergence accommodates flow driven by subduction of oceanic slabs at trenches. We show that over the past 80 million years (My), the East Pacific Rise (EPR), Earth’s dominant MOR, has been characterized by limited ridge-perpendicular migration and persistent, asymmetric ridge accretion that are anomalous relative to other MORs. We reconstruct the subduction-related buoyancy fluxes of plates on either side of the EPR. The general expectation is that greater slab pullmore » should correlate with faster plate motion and faster spreading at the EPR. Moreover, asymmetry in slab pull on either side of the EPR should correlate with either ridge migration or enhanced plate velocity in the direction of greater slab pull. Based on our analysis, none of the expected correlations are evident. This implies that other forces significantly contribute to EPR behavior. We explain these observations using mantle flow calculations based on globally integrated buoyancy distributions that require core-mantle boundary heat flux of up to 20 TW. The time-dependent mantle flow predictions yield a long-lived deep-seated upwelling that has its highest radial velocity under the EPR and is inferred to control its observed kinematics. Lastly, the mantle-wide upwelling beneath the EPR drives horizontal components of asthenospheric flows beneath the plates that are similarly asymmetric but faster than the overlying surface plates, thereby contributing to plate motions through viscous tractions in the Pacific region.« less

The New Substance Abuse and Mental Health Services Administration Oral Fluid Cutoffs for Cocaine and Heroin-Related Analytes Applied to an Addiction Medicine Setting: Important, Unanticipated Findings with LC-MS/MS.

PubMed

Flood, James G; Khaliq, Tahira; Bishop, Kenneth A; Griggs, David A

2016-05-01

We implemented oral fluid (OF) as an alternative specimen type to urine for detection of cocaine (COC) and opiate abuse in outpatient addiction medicine clinics. We implemented a 2-μg/L limit of quantification OF LC-MS/MS assay and compiled and reviewed all findings from a 22-month collection period for COC, benzoylecgonine (BZE), codeine (COD), 6-acetylmorphine (MAM), and morphine (MOR). We also compared the results of our clinical samples at different OF cutoffs and analytes specified in the new 2015 SAMHSA OF guidelines. Of 3608 OF samples, COC and BZE were positive in 593 and 508, respectively. COC or BZE was positive in 662 samples. Importantly and unexpectedly, 154 samples were COC positive and BZE negative, with 125 having COC 2.0-7.9 μg/L. A simulation with the new guideline cutoffs confirmed 65% (430 of 662) of all COC- or BZE-positive data set samples. Similarly, the new guidelines confirmed 44% (263 of 603) of data set samples positive for MOR or COD. Simulation found that the new, lower MAM guideline cutoffs detected 89% of the 382 MAM-positive samples in the data set, 104 of which the new guidelines had identified as negative for MOR and COD. COC (not BZE) is the dominant low-concentration OF analyte in an addiction medicine setting. This information will aid OF test interpretation. It also illustrates the importance of the 2015 guideline's new immunoassay cross-reactivity requirements and the likely improvement in detection of heroin use stemming from the new, lower MAM cutoffs. © 2016 American Association for Clinical Chemistry.

Kinematics and dynamics of the East Pacific Rise linked to a stable, deep-mantle upwelling [Kinematics and dynamics of the East Pacific Rise linked to whole mantel convective motions

DOE PAGES

Rowley, David B.; Forte, Alessandro M.; Rowan, Christopher J.; ...

2016-12-23

Earth’s tectonic plates are generally considered to be driven largely by negative buoyancy associated with subduction of oceanic lithosphere. In this context, mid-ocean ridges (MORs) are passive plate boundaries whose divergence accommodates flow driven by subduction of oceanic slabs at trenches. We show that over the past 80 million years (My), the East Pacific Rise (EPR), Earth’s dominant MOR, has been characterized by limited ridge-perpendicular migration and persistent, asymmetric ridge accretion that are anomalous relative to other MORs. We reconstruct the subduction-related buoyancy fluxes of plates on either side of the EPR. The general expectation is that greater slab pullmore » should correlate with faster plate motion and faster spreading at the EPR. Moreover, asymmetry in slab pull on either side of the EPR should correlate with either ridge migration or enhanced plate velocity in the direction of greater slab pull. Based on our analysis, none of the expected correlations are evident. This implies that other forces significantly contribute to EPR behavior. We explain these observations using mantle flow calculations based on globally integrated buoyancy distributions that require core-mantle boundary heat flux of up to 20 TW. The time-dependent mantle flow predictions yield a long-lived deep-seated upwelling that has its highest radial velocity under the EPR and is inferred to control its observed kinematics. Lastly, the mantle-wide upwelling beneath the EPR drives horizontal components of asthenospheric flows beneath the plates that are similarly asymmetric but faster than the overlying surface plates, thereby contributing to plate motions through viscous tractions in the Pacific region.« less

International outbreak of Salmonella Oranienburg due to German chocolate.

PubMed

Werber, Dirk; Dreesman, Johannes; Feil, Fabian; van Treeck, Ulrich; Fell, Gerhard; Ethelberg, Steen; Hauri, Anja M; Roggentin, Peter; Prager, Rita; Fisher, Ian S T; Behnke, Susanne C; Bartelt, Edda; Weise, Ekkehard; Ellis, Andrea; Siitonen, Anja; Andersson, Yvonne; Tschäpe, Helmut; Kramer, Michael H; Ammon, Andrea

2005-02-03

This report describes a large international chocolate-associated Salmonella outbreak originating from Germany. We conducted epidemiologic investigations including a case-control study, and food safety investigations. Salmonella (S.) Oranienburg isolates were subtyped by the use of pulsed-field gel electrophoresis (PFGE). From 1 October 2001 through 24 March 2002, an estimated excess of 439 S. Oranienburg notifications was registered in Germany. Simultaneously, an increase in S. Oranienburg infections was noted in other European countries in the Enter-net surveillance network. In a multistate matched case-control study in Germany, daily consumption of chocolate (matched odds ratio [MOR]: 4.8; 95% confidence interval [CI]: 1.3-26.5), having shopped at a large chain of discount grocery stores (MOR: 4.2; CI: 1.2-23.0), and consumption of chocolate purchased there (MOR: 5.0; CI: 1.1-47.0) were associated with illness. Subsequently, two brands from the same company, one exclusively produced for that chain, tested positive for S. Oranienburg. In two other European countries and in Canada chocolate from company A was ascertained that also contained S. Oranienburg. Isolates from humans and from chocolates had indistinguishable PFGE profiles. No source or point of contamination was identified. Epidemiological identification of chocolate as a vehicle of infections required two months, and was facilitated by proxy measures. Despite the use of improved production technologies, the chocolate industry continues to carry a small risk of manufacturing Salmonella-containing products. Particularly in diffuse outbreak-settings, clear associations with surrogates of exposure should suffice to trigger public health action. Networks such as Enter-net have become invaluable for facilitating rapid and appropriate management of international outbreaks.

Evaluation of injectable anaesthesia with five medetomidine-midazolam based combinations in Egyptian fruit bats ( Rousettus aegyptiacus).

PubMed

Tuval, Avishag; Las, Liora; Shilo-Benjamini, Yael

2018-01-01

Egyptian fruit bats are increasingly used as model animals in neuroscience research. Our aim was to characterize suitable injectable anaesthesia for this species, possibly replacing inhalant anaesthesia, thus minimizing occupational health hazards. Eight bats were randomly assigned by a crossover design for subcutaneously administered combinations of medetomidine-midazolam with: saline (MM-Sal), ketamine (MM-Ket), fentanyl (MM-Fen), morphine (MM-Mor), or butorphanol (MM-But). The anaesthetic depth and vital signs were monitored at baseline and every 10 min until bats recovered. If after 180 min the bats did not recover, atipamezole was administered. Mean induction times were 7-11.5 min with all combinations. Twitching during induction was common. All combinations produced anaesthesia, with significantly decreased heart rate (from 400 to 200 bpm) and respiratory rate (from 120-140 to 36-65 rpm). Arrhythmia and irregular breathing patterns occurred. MM-Fen, MM-Mor, and MM-But depressed respiration significantly more than MM-Sal. Time to first movement with MM-Ket and MM-But lasted significantly longer than with MM-Sal. Recovery time was significantly shorter in the MM-Sal (88 min) in comparison to all other treatments, and it was significantly longer in the MM-But (159 min), with atipamezole administered to four of the eight bats. In conclusion, all five anaesthetic protocols are suitable for Egyptian fruit bats; MM-Ket produces long anaesthesia and minimal respiratory depression, but cannot be antagonized completely. MM-Fen, MM-Mor, and MM-But depress respiration, but are known to produce good analgesia, and can be fully antagonized. Administration of atipamezole following the use of MM-But in Egyptian fruit bats is recommended.

Lack of synergistic interaction between the two mechanisms of action of tapentadol in gastrointestinal transit.

PubMed

Cowan, A; Raffa, R B; Tallarida, C S; Tallarida, R J; Christoph, T; Schröder, W; Tzschentke, T M

2014-09-01

A multi-mechanistic approach offers potential enhancement of analgesic efficacy, but therapeutic gain could be offset by an increase in adverse events. The centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines μ-opioid receptor (MOR) agonism and neuronal noradrenaline reuptake inhibition (NRI), both of which contribute to its analgesic effects. Previously, isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated pronounced synergistic interaction between the two mechanisms of action of tapentadol in two models of antinociception (low-intensity tail-flick and spinal nerve ligation). The present study investigated the nature of interaction of the two mechanisms on a surrogate measure for gastrointestinal adverse effect (inhibition of gastrointestinal transit). Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid receptor antagonist, naloxone, or the α2 -adrenoceptor antagonist, yohimbine, to reveal the effect of tapentadol based upon MOR agonism, NRI, and combined mechanisms. The dose-effect curve of tapentadol was shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Analysis revealed a simple additive interaction between the two mechanisms on this endpoint, in contrast to the synergistic interaction previously demonstrated for antinociception. We believe this is the first published evaluation of mechanistic interaction for a surrogate measure of adverse effect of a single compound with two mechanisms of action, and the results suggest that there is a greater separation between the analgesic and gastrointestinal effects of tapentadol than expected based upon its analgesic efficacy. © 2014 European Pain Federation - EFIC®

Residues W320 and Y328 within the binding site of the μ-opioid receptor influence opiate ligand bias.

PubMed

Hothersall, J Daniel; Torella, Rubben; Humphreys, Sian; Hooley, Monique; Brown, Alastair; McMurray, Gordon; Nickolls, Sarah A

2017-05-15

The development of G protein-biased agonists for the μ-opioid receptor (MOR) offers a clear drug discovery rationale for improved analgesia and reduced side-effects of opiate pharmacotherapy. However, our understanding of the molecular mechanisms governing ligand bias is limited, which hinders our ability to rationally design biased compounds. We have investigated the role of MOR binding site residues W320 and Y328 in controlling bias, by receptor mutagenesis. The pharmacology of a panel of ligands in a cAMP and a β-arrestin2 assay were compared between the wildtype and mutated receptors, with bias factors calculated by operational analysis using ΔΔlog(τ/K A ) values. [ 3 H]diprenorphine competition binding was used to estimate affinity changes. Introducing the mutations W320A and Y328F caused changes in pathway bias, with different patterns of change between ligands. For example, DAMGO increased relative β-arrestin2 activity at the W320A mutant, whilst its β-arrestin2 response was completely lost at Y328F. In contrast, endomorphin-1 gained activity with Y328F but lost activity at W320A, in both pathways. For endomorphin-2 there was a directional shift from cAMP bias at the wildtype towards more β-arrestin2 bias at W320A. We also observe clear uncoupling between mutation-driven changes in function and binding affinity. These findings suggest that the mutations influenced the balance of pathway activation in a ligand-specific manner, thus identifying residues in the MOR binding pocket that govern ligand bias. This increases our understanding of how ligand/receptor binding interactions can be translated into agonist-specific pathway activation. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Alcohol-induced sedation and synergistic interactions between alcohol and morphine: A key mechanistic role for Toll-Like Receptors and MyD88-dependent signalling

PubMed Central

Corrigan, Frances; Wu, Yue; Tuke, Jonathan; Coller, Janet K.; Rice, Kenner C.; Diener, Kerrilyn R.; Hayball, John D.; Watkins, Linda R.; Somogyi, Andrew A.; Hutchinson, Mark R.

2015-01-01

Increasing evidence demonstrates induction of proinflammatory Toll-like receptor (TLR) 2 and TLR4 signaling by morphine and, TLR4 signaling by alcohol; thus indicating a common site of drug action and a potential novel innate immune-dependent hypothesis for opioid and alcohol drug interactions. Hence, the current study aimed to assess the role of TLR2, TLR4, MyD88 (as a critical TLR-signalling participant), NF-κB, Interleukin-1β (IL-1β; as a downstream proinflammatory effector molecule) and the µ opioid receptor (MOR; as a classical site for morphine action) in acute alcohol-induced sedation (4.5 g/kg) and alcohol (2.5 g/kg) interaction with morphine (5 mg/kg) by assessing the loss of righting reflex (LORR) as a measure of sedation. Wild-type male Balb/c mice and matched genetically-deficient TLR2, TLR4, and MyD88 strains were utilized, together with pharmacological manipulation of MOR, NF-κB, TLR4 and Interleukin-1β. Alcohol induced significant LORR in wild-type mice; this was halved by MyD88 and TLR4 deficiency, and surprisingly nearly completely eliminated by TLR2 deficiency. In contrast, the interaction between morphine and alcohol was found to be MOR-, NF-κB-, TLR2- and MyD88-dependent, but did not involve TLR4 or Interleukin-1β. Morphine-alcohol interactions caused acute elevations in microglial cell counts and NF-κB-p65 positive cells in the motor cortex in concordance with wild-type and TLR2 deficient mouse behavioral data, implicating neuroimmunopharmacological signaling as a pivotal mechanism in this clinically problematic drug-drug interaction. PMID:25542736

Profiling soil microbial communities with next-generation sequencing: the influence of DNA kit selection and technician technical expertise.

PubMed

Soliman, Taha; Yang, Sung-Yin; Yamazaki, Tomoko; Jenke-Kodama, Holger

2017-01-01

Structure and diversity of microbial communities are an important research topic in biology, since microbes play essential roles in the ecology of various environments. Different DNA isolation protocols can lead to data bias and can affect results of next-generation sequencing. To evaluate the impact of protocols for DNA isolation from soil samples and also the influence of individual handling of samples, we compared results obtained by two researchers (R and T) using two different DNA extraction kits: (1) MO BIO PowerSoil ® DNA Isolation kit (MO_R and MO_T) and (2) NucleoSpin ® Soil kit (MN_R and MN_T). Samples were collected from six different sites on Okinawa Island, Japan. For all sites, differences in the results of microbial composition analyses (bacteria, archaea, fungi, and other eukaryotes), obtained by the two researchers using the two kits, were analyzed. For both researchers, the MN kit gave significantly higher yields of genomic DNA at all sites compared to the MO kit (ANOVA; P  < 0.006). In addition, operational taxonomic units for some phyla and classes were missed in some cases: Micrarchaea were detected only in the MN_T and MO_R analyses; the bacterial phylum Armatimonadetes was detected only in MO_R and MO_T; and WIM5 of the phylum Amoebozoa of eukaryotes was found only in the MO_T analysis. Our results suggest the possibility of handling bias; therefore, it is crucial that replicated DNA extraction be performed by at least two technicians for thorough microbial analyses and to obtain accurate estimates of microbial diversity.

International outbreak of Salmonella Oranienburg due to German chocolate

PubMed Central

Werber, Dirk; Dreesman, Johannes; Feil, Fabian; van Treeck, Ulrich; Fell, Gerhard; Ethelberg, Steen; Hauri, Anja M; Roggentin, Peter; Prager, Rita; Fisher, Ian ST; Behnke, Susanne C; Bartelt, Edda; Weise, Ekkehard; Ellis, Andrea; Siitonen, Anja; Andersson, Yvonne; Tschäpe, Helmut; Kramer, Michael H; Ammon, Andrea

2005-01-01

Background This report describes a large international chocolate-associated Salmonella outbreak originating from Germany. Methods We conducted epidemiologic investigations including a case-control study, and food safety investigations. Salmonella (S.) Oranienburg isolates were subtyped by the use of pulsed-field gel electrophoresis (PFGE). Results From 1 October 2001 through 24 March 2002, an estimated excess of 439 S. Oranienburg notifications was registered in Germany. Simultaneously, an increase in S. Oranienburg infections was noted in other European countries in the Enter-net surveillance network. In a multistate matched case-control study in Germany, daily consumption of chocolate (matched odds ratio [MOR]: 4.8; 95% confidence interval [CI]: 1.3–26.5), having shopped at a large chain of discount grocery stores (MOR: 4.2; CI: 1.2–23.0), and consumption of chocolate purchased there (MOR: 5.0; CI: 1.1–47.0) were associated with illness. Subsequently, two brands from the same company, one exclusively produced for that chain, tested positive for S. Oranienburg. In two other European countries and in Canada chocolate from company A was ascertained that also contained S. Oranienburg. Isolates from humans and from chocolates had indistinguishable PFGE profiles. No source or point of contamination was identified. Epidemiological identification of chocolate as a vehicle of infections required two months, and was facilitated by proxy measures. Conclusions Despite the use of improved production technologies, the chocolate industry continues to carry a small risk of manufacturing Salmonella-containing products. Particularly in diffuse outbreak-settings, clear associations with surrogates of exposure should suffice to trigger public health action. Networks such as Enter-net have become invaluable for facilitating rapid and appropriate management of international outbreaks. PMID:15691371

Is physician adherence to prescription guidelines a general trait of health care practices or dependent on drug type?--a multilevel logistic regression analysis in South Sweden.

PubMed

Ohlsson, Henrik; Merlo, Juan

2009-08-01

Therapeutic traditions at health care practices (HCPs) influence physicians' adherence to prescription guidelines for specific drugs, however, it is not known if such traditions affect all kinds of prescriptions or only specific types of drug. Our goal was to determine whether adherence to prescription guidelines is a common trait of HCPs or dependent on drug type. We fitted separate multi-level logistic regression models to all patients in the Skåne region who received a prescription for a statin drug (ATC: C10AA, n = 6232), an agent acting on the renin-angiotensin system (ATC: C09, n = 7222) or a proton pump inhibitor (ATC: A02BC, n = 11 563) at 198 HCPs from July 2006 to December 2006. There was a high clustering of adherence to prescription guidelines at HCPs for the different drug types (MOR(agents acting on the renin-angiotensin system) = 4.72 [95% CI: 3.90-5.92], MOR(Statins) = 2.71 [95% CI: 2.23-3.39] and MOR(Proton pump inhibitors) = 2.16 [95% CI: 1.95-2.45]). Compared with HCPs with low adherence to guidelines in two drug types, those HCPs with the highest level of adherence for these two drug types also showed a higher probability of adherence for the third drug type. Physicians' decisions to follow prescription guidelines seem to be influenced by therapeutic traditions at the HCP. Moreover, these therapeutic traditions seem to affect all kinds of prescriptions. This information can be used as basis for interventions to support rational and cost-effective medication use. Copyright 2009 John Wiley & Sons, Ltd.

Tissue Non-Specific Genes and Pathways Associated with Diabetes: An Expression Meta-Analysis.

PubMed

Mei, Hao; Li, Lianna; Liu, Shijian; Jiang, Fan; Griswold, Michael; Mosley, Thomas

2017-01-21

We performed expression studies to identify tissue non-specific genes and pathways of diabetes by meta-analysis. We searched curated datasets of the Gene Expression Omnibus (GEO) database and identified 13 and five expression studies of diabetes and insulin responses at various tissues, respectively. We tested differential gene expression by empirical Bayes-based linear method and investigated gene set expression association by knowledge-based enrichment analysis. Meta-analysis by different methods was applied to identify tissue non-specific genes and gene sets. We also proposed pathway mapping analysis to infer functions of the identified gene sets, and correlation and independent analysis to evaluate expression association profile of genes and gene sets between studies and tissues. Our analysis showed that PGRMC1 and HADH genes were significant over diabetes studies, while IRS1 and MPST genes were significant over insulin response studies, and joint analysis showed that HADH and MPST genes were significant over all combined data sets. The pathway analysis identified six significant gene sets over all studies. The KEGG pathway mapping indicated that the significant gene sets are related to diabetes pathogenesis. The results also presented that 12.8% and 59.0% pairwise studies had significantly correlated expression association for genes and gene sets, respectively; moreover, 12.8% pairwise studies had independent expression association for genes, but no studies were observed significantly different for expression association of gene sets. Our analysis indicated that there are both tissue specific and non-specific genes and pathways associated with diabetes pathogenesis. Compared to the gene expression, pathway association tends to be tissue non-specific, and a common pathway influencing diabetes development is activated through different genes at different tissues.

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

PubMed

Hurst, Laurence D; Ghanbarian, Avazeh T; Forrest, Alistair R R; Huminiecki, Lukasz

2015-12-01

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution.

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome

PubMed Central

Hurst, Laurence D.; Ghanbarian, Avazeh T.; Forrest, Alistair R. R.; Huminiecki, Lukasz

2015-01-01

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X’s gene content, gene expression, and evolution. PMID:26685068

Validating internal controls for quantitative plant gene expression studies.

PubMed

Brunner, Amy M; Yakovlev, Igor A; Strauss, Steven H

2004-08-18

Real-time reverse transcription PCR (RT-PCR) has greatly improved the ease and sensitivity of quantitative gene expression studies. However, accurate measurement of gene expression with this method relies on the choice of a valid reference for data normalization. Studies rarely verify that gene expression levels for reference genes are adequately consistent among the samples used, nor compare alternative genes to assess which are most reliable for the experimental conditions analyzed. Using real-time RT-PCR to study the expression of 10 poplar (genus Populus) housekeeping genes, we demonstrate a simple method for determining the degree of stability of gene expression over a set of experimental conditions. Based on a traditional method for analyzing the stability of varieties in plant breeding, it defines measures of gene expression stability from analysis of variance (ANOVA) and linear regression. We found that the potential internal control genes differed widely in their expression stability over the different tissues, developmental stages and environmental conditions studied. Our results support that quantitative comparisons of candidate reference genes are an important part of real-time RT-PCR studies that seek to precisely evaluate variation in gene expression. The method we demonstrated facilitates statistical and graphical evaluation of gene expression stability. Selection of the best reference gene for a given set of experimental conditions should enable detection of biologically significant changes in gene expression that are too small to be revealed by less precise methods, or when highly variable reference genes are unknowingly used in real-time RT-PCR experiments.

FLOW SIMULATION IN THE HUMAN UPPER RESPIRATORY TRACT

EPA Science Inventory

ABSTRACT

Computer simulations of airflow patterns within the human upper respiratory tract (URT) are presented. The URT model includes airways of the head (nasal and oral), throat (pharyngeal and laryngeal), and lungs (trachea and main bronchi). The head and throat mor...

SIMULATED CHANGES IN RUNOFF AND SEDIMENT IN DEVELOPING AREAS NEAR BENSON, ARIZONA

EPA Science Inventory

Residential and commercial development is occurring with unprecedented speed throughout the American Southwest. It is projected that from 1995 to 2025, the population in the six Southwestern states of California, Nevada, Arizona, New Mexico, Utah and Colorado will increase by mor...

NUSC Technical Volunteer Service (TVS).

DTIC Science & Technology

1982-12-12

unique evaporator wastewater recycling methods. In this system, water, electroplating metals, and waste heat can all be reused. More information on...lore, leqnd, and trivia to make the ir oject mor, Int: resting. if you scrved aboard the Nautii :, or know someone who did, and have interesting

RELEVANCE OF VISUAL EFFECTS OF VOLATILE ORGANIC COMPOUNDS TO HUMAN HEALTH RISK ASSESSMENT

EPA Science Inventory

Traditional measures of neurotoxicity have included assessment of sensory, cognitive, and motor function. Visual system function and the neurobiological substrates are well characterized across species. Dysfunction in the visual system may be specific or may be surrogate for mor...

Axioms Altered With Research

DTIC Science & Technology

2012-08-01

antimicrobials (eg, imipenem ) at the time of initial care to assist in the control of wound infection. To better understand the role of Acinetobacter in wound... imipenem ) were used during initial surgical care in Iraq and Af- ghanistan. Finally, continued re- search into the morbidity and mor- tality of

General statistics of stochastic process of gene expression in eukaryotic cells.

PubMed Central

Kuznetsov, V A; Knott, G D; Bonner, R F

2002-01-01

Thousands of genes are expressed at such very low levels (< or =1 copy per cell) that global gene expression analysis of rarer transcripts remains problematic. Ambiguity in identification of rarer transcripts creates considerable uncertainty in fundamental questions such as the total number of genes expressed in an organism and the biological significance of rarer transcripts. Knowing the distribution of the true number of genes expressed at each level and the corresponding gene expression level probability function (GELPF) could help resolve these uncertainties. We found that all observed large-scale gene expression data sets in yeast, mouse, and human cells follow a Pareto-like distribution model skewed by many low-abundance transcripts. A novel stochastic model of the gene expression process predicts the universality of the GELPF both across different cell types within a multicellular organism and across different organisms. This model allows us to predict the frequency distribution of all gene expression levels within a single cell and to estimate the number of expressed genes in a single cell and in a population of cells. A random "basal" transcription mechanism for protein-coding genes in all or almost all eukaryotic cell types is predicted. This fundamental mechanism might enhance the expression of rarely expressed genes and, thus, provide a basic level of phenotypic diversity, adaptability, and random monoallelic expression in cell populations. PMID:12136033

The changes of gene expression profiling between segmental vitiligo, generalized vitiligo and healthy individual.

PubMed

Wang, Ping; Li, Yong; Nie, Huiqiong; Zhang, Xiaoyan; Shao, Qiongyan; Hou, Xiuli; Xu, Wen; Hong, Weisong; Xu, Aie

2016-10-01

Vitiligo is a common acquired depigmentation skin disease characterized by loss or dysfunction of melanocytes within the skin lesion, but its pathologenesis is far from lucid. The gene expression profiling of segmental vitiligo (SV) and generalized vitiligo (GV) need further investigation. To better understanding the common and distinct factors, especially in the view of gene expression profile, which were involved in the diseases development and maintenance of segmental vitiligo (SV) and generalized vitiligo (GV). Peripheral bloods were collected from SV, GV and healthy individual (HI), followed by leukocytes separation and total RNA extraction. The high-throughput whole genome expression microarrays were used to assay the gene expression profiles between HI, SV and GV. Bioinformatics tools were employed to annotated the biological function of differently expressed genes. Quantitative PCR assay was used to validate the gene expression of array. Compared to HI, 239 over-expressed genes and 175 down-expressed genes detected in SV, 688 over-expressed genes and 560 down-expressed genes were found in GV, following the criteria of log2 (fold change)≥0.585 and P value<0.05. In these differently expressed genes, 60 over-expressed genes and 60 down-expressed genes had similar tendency in SV and GV. Compared to SV, 223 genes were up regulated and 129 genes were down regulated in GV. In the SV with HI as control, the differently expressed genes were mainly involved in the adaptive immune response, cytokine-cytokine receptor interaction, chemokine signaling, focal adhesion and sphingolipid metabolism. The differently expressed genes between GV and HI were mainly involved in the innate immune, autophagy, apoptosis, melanocyte biology, ubiquitin mediated proteolysis and tyrosine metabolism, which was different from SV. While the differently expressed genes between SV and GV were mainly involved in the metabolism pathway of purine, pyrimidine, glycolysis and sphingolipid. Above results suggested that they not only shared part bio-process and signal pathway, but more important, they utilized different biological mechanism in their pathogenesis and maintenance. Our results provide a comprehensive view on the gene expression profiling change between SV and GV especially in the side of leukocytes, and may facilitate the future study on their molecular mechanism and theraputic targets. Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Music Taste Groups and Problem Behavior.

PubMed

Mulder, Juul; Bogt, Tom Ter; Raaijmakers, Quinten; Vollebergh, Wilma

2007-04-01

Internalizing and externalizing problems differ by musical tastes. A high school-based sample of 4159 adolescents, representative of Dutch youth aged 12 to 16, reported on their personal and social characteristics, music preferences and social-psychological functioning, measured with the Youth Self-Report (YSR). Cluster analysis on their music preferences revealed six taste groups: Middle-of-the-road (MOR) listeners, Urban fans, Exclusive Rock fans, Rock-Pop fans, Elitists, and Omnivores. A seventh group of musically Low-Involved youth was added. Multivariate analyses revealed that when gender, age, parenting, school, and peer variables were controlled, Omnivores and fans within the Exclusive Rock groups showed relatively high scores on internalizing YSR measures, and social, thought and attention problems. Omnivores, Exclusive Rock, Rock-Pop and Urban fans reported more externalizing problem behavior. Belonging to the MOR group that highly appreciates the most popular, chart-based pop music appears to buffer problem behavior. Music taste group membership uniquely explains variance in both internalizing and externalizing problem behavior.

Transformation toughened ceramics for the heavy duty diesel engine technology program, phase 2

NASA Technical Reports Server (NTRS)

Musikant, S.; Samanta, S. C.; Architetto, P.; Feingold, E.

1985-01-01

The objective of this program is to develop an insulating structural ceramic for application in a heavy duty adiabatic diesel engine. The approach is to employ transformation toughening (TT) by additions of zirconia-hafnia solid solution (ZHSS). The feasibility of using ZHSS as a toughening agent in mullite and alumina has been demonstrated in Phase 1 of this work. Based on Phase 1 results, a decision was made to concentrate the Phase 2 effort on process optimization of the TT mullite. A strong factor in that decision was the low thermal conductivity and high thermal shock resistance of the mullite. Results of the Phase 2 effort indicate that optimum toughening of mullite by additions of ZHSS is difficult to achieve due to apparent sensitivity to morphology. The 48 ksi room temperature modulus-of-rupture (MOR) achieved in selected specimens is approximately 50% of the original strength target. The MOR deteriorated to 34 ksi at 800 C.

Unexpected opioid activity profiles of analogues of the novel peptide kappa opioid receptor ligand CJ-15,208.

PubMed

Aldrich, Jane V; Kulkarni, Santosh S; Senadheera, Sanjeewa N; Ross, Nicolette C; Reilley, Kate J; Eans, Shainnel O; Ganno, Michelle L; Murray, Thomas F; McLaughlin, Jay P

2011-09-05

An alanine scan was performed on the novel κ opioid receptor (KOR) peptide ligand CJ-15,208 to determine which residues contribute to the potent in vivo agonist activity observed for the parent peptide. These cyclic tetrapeptides were synthesized by a combination of solid-phase peptide synthesis of the linear precursors, followed by cyclization in solution. Like the parent peptide, each of the analogues exhibited agonist activity and KOR antagonist activity in an antinociceptive assay in vivo. Unlike the parent peptide, the agonist activity of the potent analogues was mediated predominantly, if not exclusively, by μ opioid receptors (MOR). Thus analogues 2 and 4, in which one of the phenylalanine residues was replaced by alanine, exhibited both potent MOR agonist activity and KOR antagonist activity in vivo. These peptides represent novel lead compounds for the development of peptide-based opioid analgesics. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cancer mortality among Brazilian dentists.

PubMed

Koifman, Sergio; Malhão, Thainá Alves; Pinto de Oliveira, Gisele; de Magalhães Câmara, Volney; Koifman, Rosalina Jorge; Meyer, Armando

2014-11-01

Previous studies have variably shown excess risks of elected cancers among dentists. National Brazilian mortality data were used to obtain mortality patterns among dentists between 1996 and 2004. Cancer mortality odds ratios (MORs) and cancer proportional mortality ratios for all cancer sites were calculated, using the general population and physicians and lawyers as comparison groups. Female dentists from both age strata showed higher risks for breast, colon-rectum, lung, brain, and non-Hodgkin lymphoma. Compared to physicians and lawyers, higher MOR estimates were observed for brain cancer among female dentists 20-49 yr. Among male dentists, higher cancer mortality was found for colon-rectum, pancreas, lung, melanoma, and non-Hodgkin lymphoma. Higher risk estimates for liver, prostate, bladder, brain, multiple myeloma and leukemia were observed among 50-79 yr old male dentists. If confirmed, these results indicate the need for limiting occupational exposures among dentists in addition to establishing screening programs to achieve early detection of selected malignant tumors. © 2014 Wiley Periodicals, Inc.

Synthesis of iboga-like isoquinuclidines: Dual opioid receptors agonists having antinociceptive properties.

PubMed

Banerjee, Tuhin Suvro; Paul, Sibasish; Sinha, Surajit; Das, Sumantra

2014-11-01

Some novel iboga-analogues consisting of benzofuran moiety and dehydroisoquinuclidine ring connected by -CH2-, (CH2)2 and (CH2)3 linkers have been synthesized with the view to develop potential antinociceptive drugs. The compounds 14 and 21 showed binding at the μ-opioid receptor (MOR), while the compound 11a exhibited dual affinities at both MOR and κ-opioid receptor (KOR). MAP kinase activation indicated all three compounds have opioid agonistic properties. The presence of a double bond and endo-methylcarboxylate group in the dehydroisoquinuclidine ring and the benzofuran and methylene spacer appeared to be essential for opioid receptor binding. Further studies demonstrated 11a caused significant antinociception in mice in the hot-plate test which was comparable to that produced by morphine. The compound 11a was also found to be nontremorigenic unlike various iboga congeners. This study identifies a new pharmacophore which may lead to the development of suitable substitute of morphine in the treatment of pain. Copyright © 2014 Elsevier Ltd. All rights reserved.

The bifunctional μ opioid agonist/antioxidant [Dmt(1)]DALDA is a superior analgesic in an animal model of complex regional pain syndrome-type i.

PubMed

Schiller, Peter W; Nguyen, Thi M-D; Saray, Amy; Poon, Annie Wing Hoi; Laferrière, André; Coderre, Terence J

2015-11-18

Reactive oxygen species (ROS) play an important role in the development of complex regional pain syndrome-Type I (CRPS-I), as also demonstrated with the chronic post ischemia pain (CPIP) animal model of CRPS-I. We show that morphine and the antioxidant N-acetylcysteine (NAC) act synergistically to reduce mechanical allodynia in CPIP rats. The tetrapeptide amide [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) is a potent and selective μ opioid receptor (MOR) agonist with favorable pharmacokinetic properties and with antioxidant activity due to its N-terminal Dmt (2',6'-dimethyltyrosine) residue. In the CPIP model, [Dmt(1)]DALDA was 15-fold more potent than morphine in reversing mechanical allodynia and 4.5-fold more potent as analgesic in the heat algesia test. The results indicate that bifunctional compounds with MOR agonist/antioxidant activity have therapeutic potential for the treatment of CRPS-I.

Identification of reference genes in human myelomonocytic cells for gene expression studies in altered gravity.

PubMed

Thiel, Cora S; Hauschild, Swantje; Tauber, Svantje; Paulsen, Katrin; Raig, Christiane; Raem, Arnold; Biskup, Josefine; Gutewort, Annett; Hürlimann, Eva; Unverdorben, Felix; Buttron, Isabell; Lauber, Beatrice; Philpot, Claudia; Lier, Hartwin; Engelmann, Frank; Layer, Liliana E; Ullrich, Oliver

2015-01-01

Gene expression studies are indispensable for investigation and elucidation of molecular mechanisms. For the process of normalization, reference genes ("housekeeping genes") are essential to verify gene expression analysis. Thus, it is assumed that these reference genes demonstrate similar expression levels over all experimental conditions. However, common recommendations about reference genes were established during 1 g conditions and therefore their applicability in studies with altered gravity has not been demonstrated yet. The microarray technology is frequently used to generate expression profiles under defined conditions and to determine the relative difference in expression levels between two or more different states. In our study, we searched for potential reference genes with stable expression during different gravitational conditions (microgravity, normogravity, and hypergravity) which are additionally not altered in different hardware systems. We were able to identify eight genes (ALB, B4GALT6, GAPDH, HMBS, YWHAZ, ABCA5, ABCA9, and ABCC1) which demonstrated no altered gene expression levels in all tested conditions and therefore represent good candidates for the standardization of gene expression studies in altered gravity.

Adaptation of Musca domestica L. Field Population to Laboratory Breeding Causes Transcriptional Alterations

PubMed Central

Højland, Dorte H.; Jensen, Karl-Martin Vagn; Kristensen, Michael

2014-01-01

Background The housefly, Musca domestica, has developed resistance to most insecticides applied for its control. Expression of genes coding for detoxification enzymes play a role in the response of the housefly when encountered by a xenobiotic. The highest level of constitutive gene expression of nine P450 genes was previously found in a newly-collected susceptible field population in comparison to three insecticide-resistant laboratory strains and a laboratory reference strain. Results We compared gene expression of five P450s by qPCR as well as global gene expression by RNAseq in the newly-acquired field population (845b) in generation F1, F13 and F29 to test how gene expression changes following laboratory adaption. Four (CYP6A1, CYP6A36, CYP6D3, CYP6G4) of five investigated P450 genes adapted to breeding by decreasing expression. CYP6D1 showed higher female expression in F29 than in F1. For males, about half of the genes accessed in the global gene expression were up-regulated in F13 and F29 in comparison with the F1 population. In females, 60% of the genes were up-regulated in F13 in comparison with F1, while 33% were up-regulated in F29. Forty potential P450 genes were identified. In most cases, P450 gene expression was decreased in F13 flies in comparison with F1. Gene expression then increased from F13 to F29 in males and decreased further in females. Conclusion The global gene expression changes massively during adaptation to laboratory breeding. In general, global expression decreased as a result of laboratory adaption in males, while female expression was not unidirectional. Expression of P450 genes was in general down-regulated as a result of laboratory adaption. Expression of hexamerin, coding for a storage protein was increased, while gene expression of genes coding for amylases decreased. This suggests a major impact of the surrounding environment on gene response to xenobiotics and genetic composition of housefly strains. PMID:24489682

An RNA-Seq based gene expression atlas of the common bean.

PubMed

O'Rourke, Jamie A; Iniguez, Luis P; Fu, Fengli; Bucciarelli, Bruna; Miller, Susan S; Jackson, Scott A; McClean, Philip E; Li, Jun; Dai, Xinbin; Zhao, Patrick X; Hernandez, Georgina; Vance, Carroll P

2014-10-06

Common bean (Phaseolus vulgaris) is grown throughout the world and comprises roughly 50% of the grain legumes consumed worldwide. Despite this, genetic resources for common beans have been lacking. Next generation sequencing, has facilitated our investigation of the gene expression profiles associated with biologically important traits in common bean. An increased understanding of gene expression in common bean will improve our understanding of gene expression patterns in other legume species. Combining recently developed genomic resources for Phaseolus vulgaris, including predicted gene calls, with RNA-Seq technology, we measured the gene expression patterns from 24 samples collected from seven tissues at developmentally important stages and from three nitrogen treatments. Gene expression patterns throughout the plant were analyzed to better understand changes due to nodulation, seed development, and nitrogen utilization. We have identified 11,010 genes differentially expressed with a fold change ≥ 2 and a P-value < 0.05 between different tissues at the same time point, 15,752 genes differentially expressed within a tissue due to changes in development, and 2,315 genes expressed only in a single tissue. These analyses identified 2,970 genes with expression patterns that appear to be directly dependent on the source of available nitrogen. Finally, we have assembled this data in a publicly available database, The Phaseolus vulgaris Gene Expression Atlas (Pv GEA), http://plantgrn.noble.org/PvGEA/ . Using the website, researchers can query gene expression profiles of their gene of interest, search for genes expressed in different tissues, or download the dataset in a tabular form. These data provide the basis for a gene expression atlas, which will facilitate functional genomic studies in common bean. Analysis of this dataset has identified genes important in regulating seed composition and has increased our understanding of nodulation and impact of the nitrogen source on assimilation and distribution throughout the plant.

Analysis of bHLH coding genes using gene co-expression network approach.

PubMed

Srivastava, Swati; Sanchita; Singh, Garima; Singh, Noopur; Srivastava, Gaurava; Sharma, Ashok

2016-07-01

Network analysis provides a powerful framework for the interpretation of data. It uses novel reference network-based metrices for module evolution. These could be used to identify module of highly connected genes showing variation in co-expression network. In this study, a co-expression network-based approach was used for analyzing the genes from microarray data. Our approach consists of a simple but robust rank-based network construction. The publicly available gene expression data of Solanum tuberosum under cold and heat stresses were considered to create and analyze a gene co-expression network. The analysis provide highly co-expressed module of bHLH coding genes based on correlation values. Our approach was to analyze the variation of genes expression, according to the time period of stress through co-expression network approach. As the result, the seed genes were identified showing multiple connections with other genes in the same cluster. Seed genes were found to be vary in different time periods of stress. These analyzed seed genes may be utilized further as marker genes for developing the stress tolerant plant species.

Validating internal controls for quantitative plant gene expression studies

PubMed Central

Brunner, Amy M; Yakovlev, Igor A; Strauss, Steven H

2004-01-01

Background Real-time reverse transcription PCR (RT-PCR) has greatly improved the ease and sensitivity of quantitative gene expression studies. However, accurate measurement of gene expression with this method relies on the choice of a valid reference for data normalization. Studies rarely verify that gene expression levels for reference genes are adequately consistent among the samples used, nor compare alternative genes to assess which are most reliable for the experimental conditions analyzed. Results Using real-time RT-PCR to study the expression of 10 poplar (genus Populus) housekeeping genes, we demonstrate a simple method for determining the degree of stability of gene expression over a set of experimental conditions. Based on a traditional method for analyzing the stability of varieties in plant breeding, it defines measures of gene expression stability from analysis of variance (ANOVA) and linear regression. We found that the potential internal control genes differed widely in their expression stability over the different tissues, developmental stages and environmental conditions studied. Conclusion Our results support that quantitative comparisons of candidate reference genes are an important part of real-time RT-PCR studies that seek to precisely evaluate variation in gene expression. The method we demonstrated facilitates statistical and graphical evaluation of gene expression stability. Selection of the best reference gene for a given set of experimental conditions should enable detection of biologically significant changes in gene expression that are too small to be revealed by less precise methods, or when highly variable reference genes are unknowingly used in real-time RT-PCR experiments. PMID:15317655

Characterization of basal gene expression trends over a diurnal cycle in Xiphophorus maculatus skin, brain and liver.

PubMed

Lu, Yuan; Reyes, Jose; Walter, Sean; Gonzalez, Trevor; Medrano, Geraldo; Boswell, Mikki; Boswell, William; Savage, Markita; Walter, Ronald

2018-06-01

Evolutionarily conserved diurnal circadian mechanisms maintain oscillating patterns of gene expression based on the day-night cycle. Xiphophorus fish have been used to evaluate transcriptional responses after exposure to various light sources and it was determined that each source incites distinct genetic responses in skin tissue. However, basal expression levels of genes that show oscillating expression patterns in day-night cycle, may affect the outcomes of such experiments, since basal gene expression levels at each point in the circadian path may influence the profile of identified light responsive genes. Lack of knowledge regarding diurnal fluctuations in basal gene expression patterns may confound the understanding of genetic responses to external stimuli (e.g., light) since the dynamic nature of gene expression implies animals subjected to stimuli at different times may be at very different stages within the continuum of genetic homeostasis. We assessed basal gene expression changes over a 24-hour period in 200 select Xiphophorus gene targets known to transcriptionally respond to various types of light exposure. We identified 22 genes in skin, 36 genes in brain and 28 genes in liver that exhibit basal oscillation of expression patterns. These genes, including known circadian regulators, produced the expected expression patterns over a 24-hour cycle when compared to circadian regulatory genes identified in other species, especially human and other vertebrate animal models. Our results suggest the regulatory network governing diurnal oscillating gene expression is similar between Xiphophorus and other vertebrates for the three Xiphophorus organs tested. In addition, we were able to categorize light responsive gene sets in Xiphophorus that do, and do not, exhibit circadian based oscillating expression patterns. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of Reference Genes in Human Myelomonocytic Cells for Gene Expression Studies in Altered Gravity

PubMed Central

Thiel, Cora S.; Hauschild, Swantje; Tauber, Svantje; Paulsen, Katrin; Raig, Christiane; Raem, Arnold; Biskup, Josefine; Gutewort, Annett; Hürlimann, Eva; Philpot, Claudia; Lier, Hartwin; Engelmann, Frank; Layer, Liliana E.

2015-01-01

Gene expression studies are indispensable for investigation and elucidation of molecular mechanisms. For the process of normalization, reference genes (“housekeeping genes”) are essential to verify gene expression analysis. Thus, it is assumed that these reference genes demonstrate similar expression levels over all experimental conditions. However, common recommendations about reference genes were established during 1 g conditions and therefore their applicability in studies with altered gravity has not been demonstrated yet. The microarray technology is frequently used to generate expression profiles under defined conditions and to determine the relative difference in expression levels between two or more different states. In our study, we searched for potential reference genes with stable expression during different gravitational conditions (microgravity, normogravity, and hypergravity) which are additionally not altered in different hardware systems. We were able to identify eight genes (ALB, B4GALT6, GAPDH, HMBS, YWHAZ, ABCA5, ABCA9, and ABCC1) which demonstrated no altered gene expression levels in all tested conditions and therefore represent good candidates for the standardization of gene expression studies in altered gravity. PMID:25654098

Life-cycle and growth-phase-dependent regulation of the ubiquitin genes of Trypanosoma cruzi.

PubMed

Manning-Cela, Rebeca; Jaishankar, Sobha; Swindle, John

2006-07-01

Trypanosoma cruzi, the causative agent of Chagas disease, exhibits a complex life cycle that is accompanied by the stage-specific gene expression. At the molecular level, very little is known about gene regulation in trypanosomes. Complex gene organizations coupled with polycistronic transcription units make the analysis of regulated gene expression difficult in trypanosomes. The ubiquitin genes of T. cruzi are a good example of this complexity. They are organized as a single cluster containing five ubiquitin fusion (FUS) and five polyubiquitin (PUB) genes that are polycistronically transcribed but expressed differently in response to developmental and environmental changes. Gene replacements were used to study FUS and PUB gene expression at different stages of growth and at different points in the life cycle of T. cruzi. Based on the levels of reporter gene expression, it was determined that FUS1 expression was downregulated as the parasites approached stationary phase, whereas PUB12.5 polyubiquitin gene expression increased. Conversely, FUS1 expression increases when epimastigotes and amastigotes differentiate into trypomastigotes, whereas the expression of PUB12.5 decreases when epimastigotes differentiate into amastigotes and trypomastigotes. Although the level of CAT activity in logarithmic growing epimastigotes is six- to seven-fold higher when the gene was expressed from the FUS1 locus than when expressed from the PUB12.5 locus, the rate of transcription from the two loci was the same implying that post-transcriptional mechanisms play a dominant role in the regulation of gene expression.

TMBP200, a XMAP215 homologue of tobacco BY-2 cells, has an essential role in plant mitosis.

PubMed

Yasuhara, Hiroki; Oe, Yuki

2011-07-01

TMBP200 from tobacco BY-2 cells is a member of the highly conserved family of microtubule-associated proteins that includes Xenopus XMAP215, human TOGp, and Arabidopsis MOR1/GEM1. XMAP215 homologues have an essential role in spindle assembly and function in animals and yeast, but their role in plant mitosis is not fully clarified. Here, we show by immunoblot analysis that TMBP200 levels in synchronously cultured BY-2 cells increased when the cells entered mitosis, thus indicating that TMBP200 plays an important role in mitosis in tobacco. To investigate the role of TMBP200 in mitosis, we employed inducible RNA interference to silence TMBP200 expression in BY-2 cells. The resulting depletion of TMBP200 caused severe defects in bipolar spindle formation and resulted in the appearance of multinucleated cells with variable-sized nuclei. This finding indicates that TMBP200 has an essential role in bipolar spindle formation and function.

Gene expression changes with age in skin, adipose tissue, blood and brain.

PubMed

Glass, Daniel; Viñuela, Ana; Davies, Matthew N; Ramasamy, Adaikalavan; Parts, Leopold; Knowles, David; Brown, Andrew A; Hedman, Asa K; Small, Kerrin S; Buil, Alfonso; Grundberg, Elin; Nica, Alexandra C; Di Meglio, Paola; Nestle, Frank O; Ryten, Mina; Durbin, Richard; McCarthy, Mark I; Deloukas, Panagiotis; Dermitzakis, Emmanouil T; Weale, Michael E; Bataille, Veronique; Spector, Tim D

2013-07-26

Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age. Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues. Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.

DIFFERENTIATING MECHANISMS OF REACTIVE CHEMICAL TOXICITY IN ISOLATED TROUT HEPATOCYTES

EPA Science Inventory

The toxicity of four quinones, 2,3-dimethoxy-1,4-naphthoquinone (DMONQ), 2-methyl 1,4-naphthoquinone (MNQ ),1,4-naphthoquinone (NQ), and 1,4-benzoquinone (BQ), which redox cycle or arlyate in mammalian cells, was determined in isolated trout (Oncorhynchus mykiss) hepatocytes. Mor...

Instrumental texture characteristics of broiler pectoralis major with the woody breast condition

USDA-ARS?s Scientific Manuscript database

The objective was to characterize texture properties of raw and cooked broiler fillets (pectoralis major) with the woody breast condition (WBC) using instrumental texture techniques Meullenet-Owens Razor Shear (MORS) and texture profile analysis (TPA). Deboned (3 h postmortem) broiler fillets were c...

Electrospun nanofibers of poly(vinyl alcohol)reinforced with cellulose nanofibrils

USDA-ARS?s Scientific Manuscript database

In this work, nanofibers of poly(vinyl alcohol) (PVA) reinforced with cellulose nanofibrils (CnF) were produced by electrospinning. The effects of applied voltage, polymer concentration and injection rate, tip-to-collector distance (TCD), rotation speed of the collector, and relative humidity on mor...

LINKING INDIVIDUAL-LEVEL RESPONSES AND POPULATION-LEVEL CONSEQUENCES

EPA Science Inventory

The protection of populations is at the heart of ecological risk assessment, yet most studies measure effects on individuals. In this chapter, we outline the need to enhance our ability to project and interpret the effect of stressors on natural populations and to manage risk mor...

Differential expression profiles and pathways of genes in sugarcane leaf at elongation stage in response to drought stress

PubMed Central

Li, Changning; Nong, Qian; Solanki, Manoj Kumar; Liang, Qiang; Xie, Jinlan; Liu, Xiaoyan; Li, Yijie; Wang, Weizan; Yang, Litao; Li, Yangrui

2016-01-01

Water stress causes considerable yield losses in sugarcane. To investigate differentially expressed genes under water stress, a pot experiment was performed with the sugarcane variety GT21 at three water-deficit levels (mild, moderate, and severe) during the elongation stage and gene expression was analyzed using microarray technology. Physiological parameters of sugarcane showed significant alterations in response to drought stress. Based on the expression profile of 15,593 sugarcane genes, 1,501 (9.6%) genes were differentially expressed under different water-level treatments; 821 genes were upregulated and 680 genes were downregulated. A gene similarity analysis showed that approximately 62.6% of the differentially expressed genes shared homology with functional proteins. In a Gene Ontology (GO) analysis, 901 differentially expressed genes were assigned to 36 GO categories. Moreover, 325 differentially expressed genes were classified into 101 pathway categories involved in various processes, such as the biosynthesis of secondary metabolites, ribosomes, carbon metabolism, etc. In addition, some unannotated genes were detected; these may provide a basis for studies of water-deficit tolerance. The reliability of the observed expression patterns was confirmed by RT-PCR. The results of this study may help identify useful genes for improving drought tolerance in sugarcane. PMID:27170459

Tobacco smoking in Mongolia: findings of a national knowledge, attitudes and practices study.

PubMed

Demaio, Alessandro R; Nehme, Jessica; Otgontuya, Dugee; Meyrowitsch, Dan Wolf; Enkhtuya, Palam

2014-02-28

In 2009, 48% of males aged 15 or over in Mongolia consumed tobacco, placing Mongolia among the countries with the highest prevalence of male smokers in the world. Importantly, tobacco use is one of the four major risk factors contributing to the global burden of non-communicable diseases (NCDs) - the leading cause of mortality in Mongolia. However, the knowledge, attitudes and practices of the Mongolian population with regards to smoking are largely unmeasured. In this context, a national NCDs knowledge, attitudes and practices survey focusing, among other things, on NCD risk factors was implemented in Mongolia in late 2010 to complement the previous WHO STEPwise approach to Surveillance Survey (STEPS) findings from 2009. This publication explores the smoking-related findings of the Knowledge, Attitudes and Practices Survey (KAPS). A nationally representative sample size was calculated using methodologies aligned with the WHO STEPS surveys. As a result, 3450 people from across Mongolia were selected using a multi-stage, random cluster sampling method from permanent residents aged between 15 and 64 years. The KAP survey questionnaire was interviewer-administered on a door-to-door basis. In Mongolia at 2010, 46.3% of males and 6.8% of females were smokers. This practice was especially dominant among males and urban dwellers (MOR 2.2), and more so among the middle-aged (45-54) (MOR 2.1) while still displaying a high prevalence among Mongolian youth (15.5%). The probability of smoking was independent of the level of education. Although the level of awareness of the health hazards related to tobacco smoking was generally very high in the population, this was influenced by the level of education as more people with a primary and secondary level of education believed that smoking at least one pack of cigarette per day was required to harm one's health (MOR 5.8 for primary education and 2.5 for secondary). Finally, this knowledge did not necessarily translate into a behavioural outcome as 15.5% of the population did not object to people smoking in their house, and especially so among males (MOR 4.1). The findings of this KAP survey corroborate the 2009 WHO STEPS Survey findings with regards to the prevalence of tobacco smoking in Mongolia. It identifies males, urban dwellers and Mongolian youth as groups that should be targeted by public health measures on tobacco consumption, while keeping in mind that higher levels of awareness of the harms caused by tobacco smoking do not necessarily translate into behavioural changes.

GSEH: A Novel Approach to Select Prostate Cancer-Associated Genes Using Gene Expression Heterogeneity.

PubMed

Kim, Hyunjin; Choi, Sang-Min; Park, Sanghyun

2018-01-01

When a gene shows varying levels of expression among normal people but similar levels in disease patients or shows similar levels of expression among normal people but different levels in disease patients, we can assume that the gene is associated with the disease. By utilizing this gene expression heterogeneity, we can obtain additional information that abets discovery of disease-associated genes. In this study, we used collaborative filtering to calculate the degree of gene expression heterogeneity between classes and then scored the genes on the basis of the degree of gene expression heterogeneity to find "differentially predicted" genes. Through the proposed method, we discovered more prostate cancer-associated genes than 10 comparable methods. The genes prioritized by the proposed method are potentially significant to biological processes of a disease and can provide insight into them.

Circular RNA and gene expression profiles in gastric cancer based on microarray chip technology.

PubMed

Sui, Weiguo; Shi, Zhoufang; Xue, Wen; Ou, Minglin; Zhu, Ying; Chen, Jiejing; Lin, Hua; Liu, Fuhua; Dai, Yong

2017-03-01

The aim of the present study was to screen gastric cancer (GC) tissue and adjacent tissue for differences in mRNA and circular (circRNA) expression, to analyze the differences in circRNA and mRNA expression, and to investigate the circRNA expression in gastric carcinoma and its mechanism. circRNA and mRNA differential expression profiles generated using Agilent microarray technology were analyzed in the GC tissues and adjacent tissues. qRT-PCR was used to verify the differential expression of circRNAs and mRNAs according to the interactions between circRNAs and miRNAs as well as the possible existence of miRNA and mRNA interactions. We found that: i) the circRNA expression profile revealed 1,285 significant differences in circRNA expression, with circRNA expression downregulated in 594 samples and upregulated in 691 samples via interactions with miRNAs. The qRT-PCR validation experiments showed that hsa_circRNA_400071, hsa_circRNA_000543 and hsa_circRNA_001959 expression was consistent with the microarray analysis results. ii) 29,112 genes were found in the GC tissues and adjacent tissues, including 5,460 differentially expressed genes. Among them, 2,390 differentially expressed genes were upregulated and 3,070 genes were downregulated. Gene Ontology (GO) analysis of the differentially expressed genes revealed these genes involved in biological process classification, cellular component classification and molecular function classification. Pathway analysis of the differentially expressed genes identified 83 significantly enriched genes, including 28 upregulated genes and 55 downregulated genes. iii) 69 differentially expressed circRNAs were found that might adsorb specific miRNAs to regulate the expression of their target gene mRNAs. The conclusions are: i) differentially expressed circRNAs had corresponding miRNA binding sites. These circRNAs regulated the expression of target genes through interactions with miRNAs and might become new molecular biomarkers for GC in the future. ii) Differentially expressed genes may be involved in the occurrence of GC via a variety of mechanisms. iii) CD44, CXXC5, MYH9, MALAT1 and other genes may have important implications for the occurrence and development of GC through the regulation, interaction, and mutual influence of circRNA-miRNA-mRNA via different mechanisms.

A P-Norm Robust Feature Extraction Method for Identifying Differentially Expressed Genes

PubMed Central

Liu, Jian; Liu, Jin-Xing; Gao, Ying-Lian; Kong, Xiang-Zhen; Wang, Xue-Song; Wang, Dong

2015-01-01

In current molecular biology, it becomes more and more important to identify differentially expressed genes closely correlated with a key biological process from gene expression data. In this paper, based on the Schatten p-norm and Lp-norm, a novel p-norm robust feature extraction method is proposed to identify the differentially expressed genes. In our method, the Schatten p-norm is used as the regularization function to obtain a low-rank matrix and the Lp-norm is taken as the error function to improve the robustness to outliers in the gene expression data. The results on simulation data show that our method can obtain higher identification accuracies than the competitive methods. Numerous experiments on real gene expression data sets demonstrate that our method can identify more differentially expressed genes than the others. Moreover, we confirmed that the identified genes are closely correlated with the corresponding gene expression data. PMID:26201006

A P-Norm Robust Feature Extraction Method for Identifying Differentially Expressed Genes.

PubMed

Liu, Jian; Liu, Jin-Xing; Gao, Ying-Lian; Kong, Xiang-Zhen; Wang, Xue-Song; Wang, Dong

2015-01-01

In current molecular biology, it becomes more and more important to identify differentially expressed genes closely correlated with a key biological process from gene expression data. In this paper, based on the Schatten p-norm and Lp-norm, a novel p-norm robust feature extraction method is proposed to identify the differentially expressed genes. In our method, the Schatten p-norm is used as the regularization function to obtain a low-rank matrix and the Lp-norm is taken as the error function to improve the robustness to outliers in the gene expression data. The results on simulation data show that our method can obtain higher identification accuracies than the competitive methods. Numerous experiments on real gene expression data sets demonstrate that our method can identify more differentially expressed genes than the others. Moreover, we confirmed that the identified genes are closely correlated with the corresponding gene expression data.

Genetic and epigenetic architecture of sex-biased expression in the jewel wasps Nasonia vitripennis and giraulti

PubMed Central

Wang, Xu; Werren, John H.; Clark, Andrew G.

2015-01-01

There is extraordinary diversity in sexual dimorphism (SD) among animals, but little is known about its epigenetic basis. To study the epigenetic architecture of SD in a haplodiploid system, we performed RNA-seq and whole-genome bisulfite sequencing of adult females and males from two closely related parasitoid wasps, Nasonia vitripennis and Nasonia giraulti. More than 75% of expressed genes displayed significantly sex-biased expression. As a consequence, expression profiles are more similar between species within each sex than between sexes within each species. Furthermore, extremely male- and female-biased genes are enriched for totally different functional categories: male-biased genes for key enzymes in sex-pheromone synthesis and female-biased genes for genes involved in epigenetic regulation of gene expression. Remarkably, just 70 highly expressed, extremely male-biased genes account for 10% of all transcripts in adult males. Unlike expression profiles, DNA methylomes are highly similar between sexes within species, with no consistent sex differences in methylation found. Therefore, methylation changes cannot explain the extensive level of sex-biased gene expression observed. Female-biased genes have smaller sequence divergence between species, higher conservation to other hymenopterans, and a broader expression range across development. Overall, female-biased genes have been recruited from genes with more conserved and broadly expressing “house-keeping” functions, whereas male-biased genes are more recently evolved and are predominately testis specific. In summary, Nasonia accomplish a striking degree of sex-biased expression without sex chromosomes or epigenetic differences in methylation. We propose that methylation provides a general signal for constitutive gene expression, whereas other sex-specific signals cause sex-biased gene expression. PMID:26100871

Extent and character of circadian gene expression in Drosophila melanogaster: identification of twenty oscillating mRNAs in the fly head.

PubMed

Van Gelder, R N; Bae, H; Palazzolo, M J; Krasnow, M A

1995-12-01

Although mRNAs expressed with a circadian rhythm have been isolated from many species, the extent and character of circadianly regulated gene expression is unknown for any animal. In Drosophila melanogaster, only the period (per) gene, an essential component of the circadian pacemaker, is known to show rhythmic mRNA expression. Recent work suggests that the encoded Per protein controls its own transcription by an autoregulatory feedback loop. Per might also control the rhythmic expression of other genes to generate circadian behavior and physiology. The goals of this work were to evaluate the extent and character of circadian control of gene expression in Drosophila, and to identify genes dependent on per for circadian expression. A large collection of anonymous, independent cDNA clones was used to screen for transcripts that are rhythmically expressed in the fly head. 20 of the 261 clones tested detected mRNAs with a greater than two-fold daily change in abundance. Three mRNAs were maximally expressed in the morning, whereas 17 mRNAs were most abundant in the evening--when per mRNA is also maximally expressed (but when the flies are inactive). Further analysis of the three 'morning' cDNAs showed that each has a unique dependence on the presence of a light-dark cycle, on timed feeding, and on the function of the per gene for its oscillation. These dependencies were different from those determined for per and for a novel 'evening' gene. Sequence analysis indicated that all but one of the 20 cDNAs identified previously uncloned genes. Diurnal control of gene expression is a significant but limited phenomenon in the fly head, which involves many uncharacterized genes. Diurnal control is mediated by multiple endogenous and exogenous mechanisms, even at the level of individual genes. A subset of circadianly expressed genes are predominantly or exclusively dependent on per for their rhythmic expression. The per gene can therefore influence the expression of genes other than itself, but for many rhythmically expressed genes, per functions in conjunction with external inputs to control their daily expression patterns.

Polycistronic gene expression in Aspergillus niger.

PubMed

Schuetze, Tabea; Meyer, Vera

2017-09-25

Genome mining approaches predict dozens of biosynthetic gene clusters in each of the filamentous fungal genomes sequenced so far. However, the majority of these gene clusters still remain cryptic because they are not expressed in their natural host. Simultaneous expression of all genes belonging to a biosynthetic pathway in a heterologous host is one approach to activate biosynthetic gene clusters and to screen the metabolites produced for bioactivities. Polycistronic expression of all pathway genes under control of a single and tunable promoter would be the method of choice, as this does not only simplify cloning procedures, but also offers control on timing and strength of expression. However, polycistronic gene expression is a feature not commonly found in eukaryotic host systems, such as Aspergillus niger. In this study, we tested the suitability of the viral P2A peptide for co-expression of three genes in A. niger. Two genes descend from Fusarium oxysporum and are essential to produce the secondary metabolite enniatin (esyn1, ekivR). The third gene (luc) encodes the reporter luciferase which was included to study position effects. Expression of the polycistronic gene cassette was put under control of the Tet-On system to ensure tunable gene expression in A. niger. In total, three polycistronic expression cassettes which differed in the position of luc were constructed and targeted to the pyrG locus in A. niger. This allowed direct comparison of the luciferase activity based on the position of the luciferase gene. Doxycycline-mediated induction of the Tet-On expression cassettes resulted in the production of one long polycistronic mRNA as proven by Northern analyses, and ensured comparable production of enniatin in all three strains. Notably, gene position within the polycistronic expression cassette matters, as, luciferase activity was lowest at position one and had a comparable activity at positions two and three. The P2A peptide can be used to express at least three genes polycistronically in A. niger. This approach can now be applied to heterologously express entire secondary metabolite gene clusters polycistronically or to co-express any genes of interest in equimolar amounts.

Intracellular high cholesterol content disorders the clock genes, apoptosis-related genes and fibrinolytic-related genes rhythmic expressions in human plaque-derived vascular smooth muscle cells.

PubMed

Lin, Changpo; Tang, Xiao; Xu, Lirong; Qian, Ruizhe; Shi, Zhenyu; Wang, Lixin; Cai, Tingting; Yan, Dong; Fu, Weiguo; Guo, Daqiao

2017-07-10

The clock genes are involved in regulating cardiovascular functions, and their expression disorders would lead to circadian rhythm disruptions of clock-controlled genes (CCGs), resulting in atherosclerotic plaque formation and rupture. Our previous study revealed the rhythmic expression of clock genes were attenuated in human plaque-derived vascular smooth muscle cells (PVSMCs), but failed to detect the downstream CCGs expressions and the underlying molecular mechanism. In this study, we examined the difference of CCGs rhythmic expression between human normal carotid VSMCs (NVSMCs) and PVSMCs. Furthermore, we compared the cholesterol and triglycerides levels between two groups and the link to clock genes and CCGs expressions. Seven health donors' normal carotids and 19 carotid plaques yielded viable cultured NVSMCs and PVSMCs. The expression levels of target genes were measured by quantitative real-time PCR and Western-blot. The intracellular cholesterol and triglycerides levels were measured by kits. The circadian expressions of apoptosis-related genes and fibrinolytic-related genes were disordered. Besides, the cholesterol levels were significant higher in PVSMCs. After treated with cholesterol or oxidized low density lipoprotein (ox-LDL), the expressions of clock genes were inhibited; and the rhythmic expressions of clock genes, apoptosis-related genes and fibrinolytic-related genes were disturbed in NVSMCs, which were similar to PVSMCs. The results suggested that intracellular high cholesterol content of PVSMCs would lead to the disorders of clock genes and CCGs rhythmic expressions. And further studies should be conducted to demonstrate the specific molecular mechanisms involved.

Double-filter identification of vascular-expressed genes using Arabidopsis plants with vascular hypertrophy and hypotrophy.

PubMed

Ckurshumova, Wenzislava; Scarpella, Enrico; Goldstein, Rochelle S; Berleth, Thomas

2011-08-01

Genes expressed in vascular tissues have been identified by several strategies, usually with a focus on mature vascular cells. In this study, we explored the possibility of using two opposite types of altered tissue compositions in combination with a double-filter selection to identify genes with a high probability of vascular expression in early organ primordia. Specifically, we generated full-transcriptome microarray profiles of plants with (a) genetically strongly reduced and (b) pharmacologically vastly increased vascular tissues and identified a reproducible cohort of 158 transcripts that fulfilled the dual requirement of being underrepresented in (a) and overrepresented in (b). In order to assess the predictive value of our identification scheme for vascular gene expression, we determined the expression patterns of genes in two unbiased subsamples. First, we assessed the expression patterns of all twenty annotated transcription factor genes from the cohort of 158 genes and found that seventeen of the twenty genes were preferentially expressed in leaf vascular cells. Remarkably, fifteen of these seventeen vascular genes were clearly expressed already very early in leaf vein development. Twelve genes with published leaf expression patterns served as a second subsample to monitor the representation of vascular genes in our cohort. Of those twelve genes, eleven were preferentially expressed in leaf vascular tissues. Based on these results we propose that our compendium of 158 genes represents a sample that is highly enriched for genes expressed in vascular tissues and that our approach is particularly suited to detect genes expressed in vascular cell lineages at early stages of their inception. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Increased gene expression noise in human cancers is correlated with low p53 and immune activities as well as late stage cancer.

PubMed

Han, Rongfei; Huang, Guanqun; Wang, Yejun; Xu, Yafei; Hu, Yueming; Jiang, Wenqi; Wang, Tianfu; Xiao, Tian; Zheng, Duo

2016-11-01

Gene expression in metazoans is delicately organized. As genetic information transmits from DNA to RNA and protein, expression noise is inevitably generated. Recent studies begin to unveil the mechanisms of gene expression noise control, but the changes of gene expression precision in pathologic conditions like cancers are unknown. Here we analyzed the transcriptomic data of human breast, liver, lung and colon cancers, and found that the expression noise of more than 74.9% genes was increased in cancer tissues as compared to adjacent normal tissues. This suggested that gene expression precision controlling collapsed during cancer development. A set of 269 genes with noise increased more than 2-fold were identified across different cancer types. These genes were involved in cell adhesion, catalytic and metabolic functions, implying the vulnerability of deregulation of these processes in cancers. We also observed a tendency of increased expression noise in patients with low p53 and immune activity in breast, liver and lung caners but not in colon cancers, which indicated the contributions of p53 signaling and host immune surveillance to gene expression noise in cancers. Moreover, more than 53.7% genes had increased noise in patients with late stage than early stage cancers, suggesting that gene expression precision was associated with cancer outcome. Together, these results provided genomic scale explorations of gene expression noise control in human cancers.

[Differential expression genes of bone tissues surrounding implants in diabetic rats by gene chip].

PubMed

Wang, Xin-xin; Ma, Yue; Li, Qing; Jiang, Bao-qi; Lan, Jing

2012-10-01

To compare mRNA expression profiles of bone tissues surrounding implants between normal rats and rats with diabetes using microarray technology. Six Wistar rats were randomly selected and divided into normal model group and diabetic group. Diabetic model condition was established by injecting Streptozotocin into peritoneal space. Titanium implants were implanted into the epiphyseal end of the rats' tibia. Bone tissues surrounding implant were harvested and sampled after 3 months to perform comprehensive RNA gene expression profiling, including 17983 for genome-wide association study.GO analysis was used to compare different gene expression and real-time PCR was used to confirm the results on core samples. The results indicated that there were 1084 differential gene expression. In the diabetic model, there were 352 enhanced expression genes, 732 suppressed expression genes. GO analysis involved 1154 different functional type. Osteoblast related gene expressions in bone tissue samples of diabetic rats were decreased, and lipid metabolism pathway related gene expression was increased.

Gene Architectures that Minimize Cost of Gene Expression.

PubMed

Frumkin, Idan; Schirman, Dvir; Rotman, Aviv; Li, Fangfei; Zahavi, Liron; Mordret, Ernest; Asraf, Omer; Wu, Song; Levy, Sasha F; Pilpel, Yitzhak

2017-01-05

Gene expression burdens cells by consuming resources and energy. While numerous studies have investigated regulation of expression level, little is known about gene design elements that govern expression costs. Here, we ask how cells minimize production costs while maintaining a given protein expression level and whether there are gene architectures that optimize this process. We measured fitness of ∼14,000 E. coli strains, each expressing a reporter gene with a unique 5' architecture. By comparing cost-effective and ineffective architectures, we found that cost per protein molecule could be minimized by lowering transcription levels, regulating translation speeds, and utilizing amino acids that are cheap to synthesize and that are less hydrophobic. We then examined natural E. coli genes and found that highly expressed genes have evolved more forcefully to minimize costs associated with their expression. Our study thus elucidates gene design elements that improve the economy of protein expression in natural and heterologous systems. Copyright © 2017 Elsevier Inc. All rights reserved.

Transcriptome sequencing of Eucalyptus camaldulensis seedlings subjected to water stress reveals functional single nucleotide polymorphisms and genes under selection

PubMed Central

2012-01-01

Background Water stress limits plant survival and production in many parts of the world. Identification of genes and alleles responding to water stress conditions is important in breeding plants better adapted to drought. Currently there are no studies examining the transcriptome wide gene and allelic expression patterns under water stress conditions. We used RNA sequencing (RNA-seq) to identify the candidate genes and alleles and to explore the evolutionary signatures of selection. Results We studied the effect of water stress on gene expression in Eucalyptus camaldulensis seedlings derived from three natural populations. We used reference-guided transcriptome mapping to study gene expression. Several genes showed differential expression between control and stress conditions. Gene ontology (GO) enrichment tests revealed up-regulation of 140 stress-related gene categories and down-regulation of 35 metabolic and cell wall organisation gene categories. More than 190,000 single nucleotide polymorphisms (SNPs) were detected and 2737 of these showed differential allelic expression. Allelic expression of 52% of these variants was correlated with differential gene expression. Signatures of selection patterns were studied by estimating the proportion of nonsynonymous to synonymous substitution rates (Ka/Ks). The average Ka/Ks ratio among the 13,719 genes was 0.39 indicating that most of the genes are under purifying selection. Among the positively selected genes (Ka/Ks > 1.5) apoptosis and cell death categories were enriched. Of the 287 positively selected genes, ninety genes showed differential expression and 27 SNPs from 17 positively selected genes showed differential allelic expression between treatments. Conclusions Correlation of allelic expression of several SNPs with total gene expression indicates that these variants may be the cis-acting variants or in linkage disequilibrium with such variants. Enrichment of apoptosis and cell death gene categories among the positively selected genes reveals the past selection pressures experienced by the populations used in this study. PMID:22853646

Functional clustering of time series gene expression data by Granger causality

PubMed Central

2012-01-01

Background A common approach for time series gene expression data analysis includes the clustering of genes with similar expression patterns throughout time. Clustered gene expression profiles point to the joint contribution of groups of genes to a particular cellular process. However, since genes belong to intricate networks, other features, besides comparable expression patterns, should provide additional information for the identification of functionally similar genes. Results In this study we perform gene clustering through the identification of Granger causality between and within sets of time series gene expression data. Granger causality is based on the idea that the cause of an event cannot come after its consequence. Conclusions This kind of analysis can be used as a complementary approach for functional clustering, wherein genes would be clustered not solely based on their expression similarity but on their topological proximity built according to the intensity of Granger causality among them. PMID:23107425

Global gene expression analyses of hematopoietic stem cell-like cell lines with inducible Lhx2 expression

PubMed Central

Richter, Karin; Wirta, Valtteri; Dahl, Lina; Bruce, Sara; Lundeberg, Joakim; Carlsson, Leif; Williams, Cecilia

2006-01-01

Background Expression of the LIM-homeobox gene Lhx2 in murine hematopoietic cells allows for the generation of hematopoietic stem cell (HSC)-like cell lines. To address the molecular basis of Lhx2 function, we generated HSC-like cell lines where Lhx2 expression is regulated by a tet-on system and hence dependent on the presence of doxycyclin (dox). These cell lines efficiently down-regulate Lhx2 expression upon dox withdrawal leading to a rapid differentiation into various myeloid cell types. Results Global gene expression of these cell lines cultured in dox was compared to different time points after dox withdrawal using microarray technology. We identified 267 differentially expressed genes. The majority of the genes overlapping with HSC-specific databases were those down-regulated after turning off Lhx2 expression and a majority of the genes overlapping with those defined as late progenitor-specific genes were the up-regulated genes, suggesting that these cell lines represent a relevant model system for normal HSCs also at the level of global gene expression. Moreover, in situ hybridisations of several genes down-regulated after dox withdrawal showed overlapping expression patterns with Lhx2 in various tissues during embryonic development. Conclusion Global gene expression analysis of HSC-like cell lines with inducible Lhx2 expression has identified genes putatively linked to self-renewal / differentiation of HSCs, and function of Lhx2 in organ development and stem / progenitor cells of non-hematopoietic origin. PMID:16600034

Integrated analysis of gene expression and methylation profiles of 48 candidate genes in breast cancer patients.

PubMed

Li, Zibo; Heng, Jianfu; Yan, Jinhua; Guo, Xinwu; Tang, Lili; Chen, Ming; Peng, Limin; Wu, Yepeng; Wang, Shouman; Xiao, Zhi; Deng, Zhongping; Dai, Lizhong; Wang, Jun

2016-11-01

Gene-specific methylation and expression have shown biological and clinical importance for breast cancer diagnosis and prognosis. Integrated analysis of gene methylation and gene expression may identify genes associated with biology mechanism and clinical outcome of breast cancer and aid in clinical management. Using high-throughput microfluidic quantitative PCR, we analyzed the expression profiles of 48 candidate genes in 96 Chinese breast cancer patients and investigated their correlation with gene methylation and associations with breast cancer clinical parameters. Breast cancer-specific gene expression alternation was found in 25 genes with significant expression difference between paired tumor and normal tissues. A total of 9 genes (CCND2, EGFR, GSTP1, PGR, PTGS2, RECK, SOX17, TNFRSF10D, and WIF1) showed significant negative correlation between methylation and gene expression, which were validated in the TCGA database. Total 23 genes (ACADL, APC, BRCA2, CADM1, CAV1, CCND2, CST6, EGFR, ESR2, GSTP1, ICAM5, NPY, PGR, PTGS2, RECK, RUNX3, SFRP1, SOX17, SYK, TGFBR2, TNFRSF10D, WIF1, and WRN) annotated with potential TFBSs in the promoter regions showed negative correlation between methylation and expression. In logistics regression analysis, 31 of the 48 genes showed improved performance in disease prediction with combination of methylation and expression coefficient. Our results demonstrated the complex correlation and the possible regulatory mechanisms between DNA methylation and gene expression. Integration analysis of methylation and expression of candidate genes could improve performance in breast cancer prediction. These findings would contribute to molecular characterization and identification of biomarkers for potential clinical applications.

Genome-wide profiling identifies a subset of methamphetamine (METH)-induced genes associated with METH-induced increased H4K5Ac binding in the rat striatum

PubMed Central

2013-01-01

Background METH is an illicit drug of abuse that influences gene expression in the rat striatum. Histone modifications regulate gene transcription. Methods We therefore used microarray analysis and genome-scale approaches to examine potential relationships between the effects of METH on gene expression and on DNA binding of histone H4 acetylated at lysine 4 (H4K5Ac) in the rat dorsal striatum of METH-naïve and METH-pretreated rats. Results Acute and chronic METH administration caused differential changes in striatal gene expression. METH also increased H4K5Ac binding around the transcriptional start sites (TSSs) of genes in the rat striatum. In order to relate gene expression to histone acetylation, we binned genes of similar expression into groups of 100 genes and proceeded to relate gene expression to H4K5Ac binding. We found a positive correlation between gene expression and H4K5Ac binding in the striatum of control rats. Similar correlations were observed in METH-treated rats. Genes that showed acute METH-induced increased expression in saline-pretreated rats also showed METH-induced increased H4K5Ac binding. The acute METH injection caused similar increases in H4K5Ac binding in METH-pretreated rats, without affecting gene expression to the same degree. Finally, genes that showed METH-induced decreased expression exhibited either decreases or no changes in H4K5Ac binding. Conclusion Acute METH injections caused increased gene expression of genes that showed increased H4K5Ac binding near their transcription start sites. PMID:23937714

Genome-wide profiling identifies a subset of methamphetamine (METH)-induced genes associated with METH-induced increased H4K5Ac binding in the rat striatum.

PubMed

Cadet, Jean Lud; Jayanthi, Subramaniam; McCoy, Michael T; Ladenheim, Bruce; Saint-Preux, Fabienne; Lehrmann, Elin; De, Supriyo; Becker, Kevin G; Brannock, Christie

2013-08-12

METH is an illicit drug of abuse that influences gene expression in the rat striatum. Histone modifications regulate gene transcription. We therefore used microarray analysis and genome-scale approaches to examine potential relationships between the effects of METH on gene expression and on DNA binding of histone H4 acetylated at lysine 4 (H4K5Ac) in the rat dorsal striatum of METH-naïve and METH-pretreated rats. Acute and chronic METH administration caused differential changes in striatal gene expression. METH also increased H4K5Ac binding around the transcriptional start sites (TSSs) of genes in the rat striatum. In order to relate gene expression to histone acetylation, we binned genes of similar expression into groups of 100 genes and proceeded to relate gene expression to H4K5Ac binding. We found a positive correlation between gene expression and H4K5Ac binding in the striatum of control rats. Similar correlations were observed in METH-treated rats. Genes that showed acute METH-induced increased expression in saline-pretreated rats also showed METH-induced increased H4K5Ac binding. The acute METH injection caused similar increases in H4K5Ac binding in METH-pretreated rats, without affecting gene expression to the same degree. Finally, genes that showed METH-induced decreased expression exhibited either decreases or no changes in H4K5Ac binding. Acute METH injections caused increased gene expression of genes that showed increased H4K5Ac binding near their transcription start sites.

Evaluating the consistency of gene sets used in the analysis of bacterial gene expression data.

PubMed

Tintle, Nathan L; Sitarik, Alexandra; Boerema, Benjamin; Young, Kylie; Best, Aaron A; Dejongh, Matthew

2012-08-08

Statistical analyses of whole genome expression data require functional information about genes in order to yield meaningful biological conclusions. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) are common sources of functionally grouped gene sets. For bacteria, the SEED and MicrobesOnline provide alternative, complementary sources of gene sets. To date, no comprehensive evaluation of the data obtained from these resources has been performed. We define a series of gene set consistency metrics directly related to the most common classes of statistical analyses for gene expression data, and then perform a comprehensive analysis of 3581 Affymetrix® gene expression arrays across 17 diverse bacteria. We find that gene sets obtained from GO and KEGG demonstrate lower consistency than those obtained from the SEED and MicrobesOnline, regardless of gene set size. Despite the widespread use of GO and KEGG gene sets in bacterial gene expression data analysis, the SEED and MicrobesOnline provide more consistent sets for a wide variety of statistical analyses. Increased use of the SEED and MicrobesOnline gene sets in the analysis of bacterial gene expression data may improve statistical power and utility of expression data.

Validation of housekeeping genes as an internal control for gene expression studies in Giardia lamblia using quantitative real-time PCR.

PubMed

Marcial-Quino, Jaime; Fierro, Francisco; De la Mora-De la Mora, Ignacio; Enríquez-Flores, Sergio; Gómez-Manzo, Saúl; Vanoye-Carlo, America; Garcia-Torres, Itzhel; Sierra-Palacios, Edgar; Reyes-Vivas, Horacio

2016-04-25

The analysis of transcript levels of specific genes is important for understanding transcriptional regulation and for the characterization of gene function. Real-time quantitative reverse transcriptase PCR (RT-qPCR) has become a powerful tool to quantify gene expression. The objective of this study was to identify reliable housekeeping genes in Giardia lamblia. Twelve genes were selected for this purpose, and their expression was analyzed in the wild type WB strain and in two strains with resistance to nitazoxanide (NTZ) and metronidazole (MTZ), respectively. RefFinder software analysis showed that the expression of the genes is different in the three strains. The integrated data from the four analyses showed that the NADH oxidase (NADH) and aldolase (ALD) genes were the most steadily expressed genes, whereas the glyceraldehyde-3-phosphate dehydrogenase gene was the most unstable. Additionally, the relative expression of seven genes were quantified in the NTZ- and MTZ-resistant strains by RT-qPCR, using the aldolase gene as the internal control, and the results showed a consistent differential pattern of expression in both strains. The housekeeping genes found in this work will facilitate the analysis of mRNA expression levels of other genes of interest in G. lamblia. Copyright © 2016 Elsevier B.V. All rights reserved.

Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter.

PubMed

Su, Zhao-Zhong; Sarkar, Devanand; Emdad, Luni; Duigou, Gregory J; Young, Charles S H; Ware, Joy; Randolph, Aaron; Valerie, Kristoffer; Fisher, Paul B

2005-01-25

One impediment to effective cancer-specific gene therapy is the rarity of regulatory sequences targeting gene expression selectively in tumor cells. Although many tissue-specific promoters are recognized, few cancer-selective gene promoters are available. Progression-elevated gene-3 (PEG-3) is a rodent gene identified by subtraction hybridization that displays elevated expression as a function of transformation by diversely acting oncogenes, DNA damage, and cancer cell progression. The promoter of PEG-3, PEG-Prom, displays robust expression in a broad spectrum of human cancer cell lines with marginal expression in normal cellular counterparts. Whereas GFP expression, when under the control of a CMV promoter, is detected in both normal and cancer cells, when GFP is expressed under the control of the PEG-Prom, cancer-selective expression is evident. Mutational analysis identifies the AP-1 and PEA-3 transcription factors as primary mediators of selective, cancer-specific expression of the PEG-Prom. Synthesis of apoptosis-inducing genes, under the control of the CMV promoter, inhibits the growth of both normal and cancer cells, whereas PEG-Prom-mediated expression of these genes kills only cancer cells and spares normal cells. The efficacy of the PEG-Prom as part of a cancer gene therapeutic regimen is further documented by in vivo experiments in which PEG-Prom-controlled expression of an apoptosis-inducing gene completely inhibited prostate cancer xenograft growth in nude mice. These compelling observations indicate that the PEG-Prom, with its cancer-specific expression, provides a means of selectively delivering genes to cancer cells, thereby providing a crucial component in developing effective cancer gene therapies.

Evaluation of Allelic Expression of Imprinted Genes in Adult Human Blood

PubMed Central

Frost, Jennifer M.; Monk, Dave; Stojilkovic-Mikic, Taita; Woodfine, Kathryn; Chitty, Lyn S.; Murrell, Adele; Stanier, Philip; Moore, Gudrun E.

2010-01-01

Background Imprinted genes are expressed from only one allele in a parent-of-origin dependent manner. Loss of imprinted (LOI) expression can result in a variety of human disorders and is frequently reported in cancer. Biallelic expression of imprinted genes in adult blood has been suggested as a useful biomarker and is currently being investigated in colorectal cancer. In general, the expression profiles of imprinted genes are well characterised during human and mouse fetal development, but not in human adults. Methodology/Principal Findings We investigated quantitative expression of 36 imprinted genes in adult human peripheral blood leukocytes obtained from healthy individuals. Allelic expression was also investigated in B and T lymphocytes and myeloid cells. We found that 21 genes were essentially undetectable in adult blood. Only six genes were demonstrably monoallelic, and most importantly, we found that nine genes were either biallelic or showed variable expression in different individuals. Separated leukocyte populations showed the same expression patterns as whole blood. Differential methylation at each of the imprinting control loci analysed was maintained, including regions that contained biallelically expressed genes. This suggests in some cases methylation has become uncoupled from its role in regulating gene expression. Conclusions/Significance We conclude that only a limited set of imprinted genes, including IGF2 and SNRPN, may be useful for LOI cancer biomarker studies. In addition, blood is not a good tissue to use for the discovery of new imprinted genes. Finally, lymphocyte DNA methylation status in the adult may not always be a reliable indicator of monoallelic gene expression. PMID:21042416