In vitro and in vivo pharmacological activities of 14-o-phenylpropyloxymorphone, a potent mixed mu/delta/kappa-opioid receptor agonist with reduced constipation in mice

Pain, particularly chronic pain, is still an unsolved medical condition. Central goals in pain control are to provide analgesia of adequate efficacy and to reduce complications associated with the currently available drugs. Opioids are the mainstay for the treatment of moderate to severe pain. However, opioid pain medications also cause detrimental side effects, thus highlighting the need of innovative and safer analgesics. Opioids mediate their actions via the activation of opioid receptors, with the mu-opioid receptor as the primary target for analgesia, but also for side effects. One long-standing focus of drug discovery is the pursuit for new opioids exhibiting a favorable dissociation between analgesia and adverse effects. In this study, we describe the in vitro and in vivo pharmacological profiles of the 14-O-phenylpropyl substituted analog of the mu-opioid agonist 14-O-methyloxymorphone (14-OMO). The consequence of the substitution of the 14-O-methyl in 14-OMO with a 14-O-phenylpropyl group on in vitro binding and functional activity, and in vivo behavioral properties (nociception and gastrointestinal motility) was investigated. In binding studies, 14-O-phenylpropyloxymorphone (POMO) displayed very high affinity at mu-, delta-, and kappa-opioid receptors (Ki values in nM, mu:delta:kappa = 0.073:0.13:0.30) in rodent brain membranes, with complete loss of mu-receptor selectivity compared to 14-OMO. In guinea-pig ileum and mouse vas deferens bioassays, POMO was a highly efficacious and full agonist, being more potent than 14-OMO. In the [35S]GTPγS binding assays with membranes from CHO cells expressing human opioid receptors, POMO was a potent mu/delta-receptor full agonist and a kappa-receptor partial agonist. In vivo, POMO was highly effective in acute thermal nociception (hot-plate test, AD50= 0.7 nmol/kg) in mice after subcutaneous administration, with over 70- and 9000-fold increased potency than 14-OMO and morphine, respectively. POMO-induced antinociception is mediated through the activation of the mu-opioid receptor, and it does not involve delta- and kappa-opioid receptors. In the charcoal test, POMO produced fourfold less inhibition of the gastrointestinal transit than 14-OMO and morphine. In summary, POMO emerges as a new potent mixed mu/delta/kappa-opioid receptor agonist with reduced liability to cause constipation at antinociceptive doses

Antagonism of the prokineticin system prevents and reverses allodynia and inflammation in a mouse model of diabetes

Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro- and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflammatory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflammatory events underlying disease

the heterochromatin protein 1 positively regulates euchromatic gene expression by rna binding

HP1 is a well known conserved protein involved in heterochromatin formation and gene silencing in different species including humans1-4. A general model has been proposed for heterochromatin formation and epigenetic gene silencing in different species that implies an essential role for HP1. According to the model, histone methyltransferase enzymes (HMTases) methylate the histone H3 at lysine 9 (H3-MeK9), creating selective binding sites for itself and the chromodomain of HP15. This complex is thought to form a higher order chromatin state that represses gene activity. It has also been found that HP1 plays a role in telomere capping6. Surprisingly, recent data have suggested an association of HP1 in gene activity7-10 but the nature of this interaction is still completely obscure. Here we show, that HP1 is required for positive regulation of more than one hundred euchromatic genes by its association with the corresponding RNA transcripts and by its interaction with the well known proteins DDP111, HRB87F12 and PEP13, which belong to different classes of heterogeneous nuclear ribonucleoproteins (hnRNPs) involved in RNA processing . We also found that all these hnRNP proteins also bind heterochromatin and are dominant suppressors of position effect variegation. Our data together, show novel and unexpected functions for HP1 and hnRNPs proteins. All these proteins are in fact involved in both RNA transcript processing and in heterochromatin formation. This suggests that, in general, similar epigenetic mechanisms have a significant role in the metabolism of both RNA and heterochromatin

The prokineticin receptor agonist Bv8 decreases IL-10 and IL-4 production in mice splenocytes by activating prokineticin receptor-1

<p>Abstract</p> <p>Background</p> <p>Bv8, prokineticin-1, or endocrine gland-vascular endothelial growth factor, and prokineticin-2 are recently isolated peptide agonists of two G protein-coupled receptors, prokineticin receptor-1 (PROKR 1) and PROKR 2, and have been described as affecting a number of myeloid cell functions. We evaluated the impact of Bv8 on lymphoid cells by investigating its ability to modulate T cell cytokine balance in mouse.</p> <p>Results</p> <p>The production of T-helper1 cytokines (IL-2, IFN-γ and IL-1β), the T-helper 2 cytokine IL-4, and the anti-inflammatory cytokine IL-10 by mouse splenocytes was evaluated after polyclonal stimulation or immunisation with the keyhole limpet hemocyanin protein antigen by measuring cytokine levels. When added <it>in vitro </it>to Con-A-stimulated splenocytes, Bv8 significantly increased IL-1β and decreased IL-4 and IL-10; IL-2 and IFN-γ were not affected. Similar results were obtained when Bv8 was administered <it>in vivo</it>. In KLH-immunised mice, splenocytes restimulated <it>in vitro </it>with KLH and Bv8 produced significantly smaller amounts of IL-4 and IL-10. KLH-induced IL-10 and IL-4 production was also significantly blunted in animals administered Bv8 <it>in vivo </it>at the time of KLH immunisation or two weeks later. The Bv8-induced effects were lost in mice lacking the PROKR 1 gene, thus indicating that PROKR 1 is the receptor involved in the modulation of cytokines.</p> <p>Conclusion</p> <p>These findings indicate that Bv8/prokineticin-1 is a novel modulator of lymphoid functions, and may be a suitable target for new immunopharmacological strategies.</p

Functional Changes of Retinal Ganglion Cells and Visual Pathways in Patients with Chronic Leber's Hereditary Optic Neuropathy during One Year of Follow-up.

Purpose: To assess changes of retinal ganglion cells (RGCs) and visual pathways' function in patients with Leber's hereditary optic neuropathy (LHON) during 12 months of follow-up of the chronic phase. Design: Retrospective case series. Participants: Twenty-two patients with LHON (mean age, 36.3±9.3 years) in the "chronic phase" of the disease, providing 42 eyes (LHON group) with different pathogenic mitochondrial DNA mutations (group 11778: 21 eyes; group 3460: 4 eyes; group 14484: 13 eyes; and group 14568: 4 eyes) were enrolled. Twenty-five age-similar healthy participants, providing 25 eyes, served as controls. Methods: Pattern electroretinogram (PERG) and visual evoked potentials (VEP), in response to 60ʹ and 15ʹ checks visual stimuli, were recorded at baseline in all subjects and after 6 and 12 months of follow-up in patients with LHON. At baseline, in all LHON eyes for each PERG and VEP parameter (amplitude and implicit time), the 95% confidence limit (CL) of test–retest variability was calculated. The PERG and VEP mean values observed in LHON eyes were compared (1-way analysis of variance [ANOVA]) with those of controls. During the follow-up, the PERG and VEP differences observed with respect to baseline were evaluated by ANOVA. Main Outcome Measures: Changes of individual and mean absolute values of 60ʹ and 15ʹ PERG amplitude and VEP amplitude and implicit time at each time point compared with baseline values in the LHON group. Results: At baseline, mean values of PERG and VEP parameters detected in the LHON group were significantly (P 0.01) different from baseline values. Conclusions: In our untreated patients with chronic LHON, with different specific pathogenic mutations, RGCs and visual pathways function were not significantly modified during 12 months of follow-up. This should be considered in the disease natural history when attempts for treatments are proposed in chronic LHON

Anandamide Exerts a Differential Effect on Human Placenta Before and After the Onset of Labor

The onset of labor involves the action of multiple factors and recent reports have postulated the endocannabinoid system as a new regulator of this process. Our objective was to study the role of anandamide, one of the main endocannabinoids, on the regulation of placental molecules that contribute to the onset of labor at term. Placental samples were obtained from patients with laboring vaginal deliveries and from non-laboring elective cesarean sections. Vaginal delivery placentas produced higher prostaglandins levels than cesarean section samples. Besides, no differences were observed in NOS basal activity between groups. Incubation of vaginal delivery placentas with anandamide increased prostaglandins concentration and decreased NOS activity. Antagonism of type-1cannabinoid receptor (CB1) did not alter the effect observed on NOS activity. Conversely, incubation of cesarean section placentas with anandamide reduced prostaglandins levels and enhanced NOS activity, the latter involving the participation of CB1. Furthermore, we observed a differential expression of the main components of the endocannabinoid system between placental samples, being the change in CB1 localization the most relevant finding. Our results suggest that anandamide acts as a modulator of the signals that regulate labor, exerting differential actions depending on CB1 localization in laboring or non-laboring term placentas.Fil: Accialini, Paula Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Aban, Cyntia Estefania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Etcheverry, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Negri Malbrán, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Leguizamón, Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Herlax, Vanesa Silvana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Maté, Sabina María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Farina, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Guiding neural machine translation decoding with external knowledge

© 2017 The Authors. Published by Association for Computational Linguistics. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: http://dx.doi.org/10.18653/v1/W17-4716Chatterjee, R., Negri, M., Turchi, M., Federico, M. et al. (2017) Guiding neural machine translation decoding with external knowledge. In, Proceedings of the Second Conference on Machine Translation, Volume 1: Research Papers, Bojar, O., Buck, C., Chatterjee, R., Federmann, C. et al. (eds.) Stroudsburg, PA: Association for Computational Linguistics, pp. 157-168.This work has been partially supported by the ECfunded H2020 projects QT21 (grant agreement no. 645452) and ModernMT (grant agreement no. 645487)

Translation quality and productivity: a study on rich morphology languages

© 2017 The Authors. Published by Asia-Pacific Association for Machine Translation. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: http://aamt.info/app-def/S-102/mtsummit/2017/wp-content/uploads/sites/2/2017/09/MTSummitXVI_ResearchTrack.pdfSpecia, L., Blain, F., Harris, K., Burchardt, A. et al. (2017) Translation quality and productivity: a study on rich morphology languages. In, Machine Translation Summit XVI, Vol 1. MT Research Track, Kurohashi, S., and Fung, P., Nagoya, Aichi, Japan: Asia-Pacific Association for Machine Translation, pp. 55-71.This work was supported by the QT21 project (H2020 No. 645452)

Guiding Neural Machine Translation Decoding with External Knowledge

Differentlyfromthephrase-based paradigm,neural machine translation(NMT) operates on word and sentence representations in a continuous space.This makes the decoding process not only more difficult to interpret, but also harder to influence with external knowledge. For the latter problem, effective solutions like the XML-markup used by phrase-based models to inject fixed translation options as constraints at decoding time are not yet available. We propose a “guide”mechanism that enhances an existingNMT decoder with the ability to prioritize and adequately handle translation options presented in the form of XML annotations of source words. Positive results obtained in two different translation tasks indicate the effectiveness of our approach

Mirando la universidad, desde las prácticas docentes y la formación de los alumnos

El trabajo presenta los resultados alcanzados, parcialmente, del proyecto de investigación que da título a la ponencia, cuyo objetivo es “analizar las prácticas pedagógicas universitarias en relación con los saberes que habilita la formación de grado de los alumnos”. Se focaliza en describir las prácticas docentes y las prácticas de aprendizaje estudiantil, en el proceso de formación profesional en esta institución universitaria. Integrando diversas fuentes, se ha logrado reconstruir las trayectorias académicas de los alumnos y complementariamente, se da cuenta de las percepciones que estos jóvenes detentan sobre aspectos cotidianos del cursado de la carrera como, así también, sobre su formación profesional y la significación que otorgan a su propia motivación y el contexto de enseñanza que prefieren. Se incorpora al análisis la mirada de los docentes sobre los planes de estudio y los aspectos didácticos curriculares de la asignatura que imparten