kappa-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system.

Using the mouse delta-opioid receptor cDNA as a probe, we have isolated genomic clones encoding the human mu- and kappa-opioid receptor genes. Their organization appears similar to that of the human delta receptor gene, with exon-intron boundaries located after putative transmembrane domains 1 and 4. The kappa gene was mapped at position q11-12 in human chromosome 8. A full-length cDNA encoding the human kappa-opioid receptor has been isolated. The cloned receptor expressed in COS cells presents a typical kappa 1 pharmacological profile and is negatively coupled to adenylate cyclase. The expression of kappa-opioid receptor mRNA in human brain, as estimated by reverse transcription-polymerase chain reaction, is consistent with the involvement of kappa-opioid receptors in pain perception, neuroendocrine physiology, affective behavior, and cognition. In situ hybridization studies performed on human fetal spinal cord demonstrate the presence of the transcript specifically in lamina II of the dorsal horn. Some divergences in structural, pharmacological, and anatomical properties are noted between the cloned human and rodent receptors.

Westerschelde, Netherlands and Belgium, ca. 1799 (Image 2 of 3) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Reconnoissance du cours du Hont ou Wester Schelde (Escaut occidental) depuis Anwerpen (Anvers) jusqu'à l'embouchure, faite par ordre du Ministre de la marine et des colonies, en thermidor et fructidor, an VII, vendémiaire et brumaire, an VIII, par Beautemps-Beaupré; assisté des Cens. Daussy et Portier, et de Jh. Raoul. It was published ca. 1799. Scale [ca. 1:41,300]. Covers Westerschelde, Netherlands and Belgium, from Middelburg to Antwerp. This layer is image 2 of 3 total images of the three sheet source map, representing the center portion of the map. Map in French.The image inside the map neatline is georeferenced to the surface of the earth and fit to the RD_New (Rijksdriehoekstelsel), GCS Amersfoort coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows coastal features such as rocks, channels, points, ports, coves, islands, flats, canals, and more. Includes also selected land features such as roads, towns, fortification, drainage, land cover, selected buildings, and more. Relief shown pictorially and with hachures. Depths shown by contours and soundings. Includes "Nota" and text with insigne of the Dépôt général de la marine.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

Westerschelde, Netherlands and Belgium, ca. 1799 (Image 3 of 3) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Reconnoissance du cours du Hont ou Wester Schelde (Escaut occidental) depuis Anwerpen (Anvers) jusqu'à l'embouchure, faite par ordre du Ministre de la marine et des colonies, en thermidor et fructidor, an VII, vendémiaire et brumaire, an VIII, par Beautemps-Beaupré; assisté des Cens. Daussy et Portier, et de Jh. Raoul. It was published ca. 1799. Scale [ca. 1:41,300]. Covers Westerschelde, Netherlands and Belgium, from Middelburg to Antwerp. This layer is image 3 of 3 total images of the three sheet source map, representing the eastern portion of the map. Map in French.The image inside the map neatline is georeferenced to the surface of the earth and fit to the RD_New (Rijksdriehoekstelsel), GCS Amersfoort coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows coastal features such as rocks, channels, points, ports, coves, islands, flats, canals, and more. Includes also selected land features such as roads, towns, fortification, drainage, land cover, selected buildings, and more. Relief shown pictorially and with hachures. Depths shown by contours and soundings. Includes "Nota" and text with insigne of the Dépôt général de la marine.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

County Armàgh, Northern Ireland, United Kingdom, 1760 (Image 2 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: A topographical map of the county of Armagh to which is anex'd the plans of Newry and Armagh, by John Rocque = Carte topographique de la Province d'Armagh où se trouve les plans des villes d'Armagh et de Newry, par Jean Rocque. It was published by J. Rocque in 1760. Scale [ca. 1:41,000]. This layer is image 2 of 4 total images of the four sheet source map, representing the northeast portion of the map. Covers County Armàgh, Northern Ireland. Map in English and French. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Irish Grid (Transverse Mercator 1965 (TM-65)) coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, drainage, built-up areas and selected buildings, selected names of landowners, ground cover, and more. Relief shown by hachures and pictorially. Includes 2 insets: "A Plan of the Town of Newry" -- "A Plan of the City of Armagh".This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

County Armàgh, Northern Ireland, United Kingdom, 1760 (Image 3 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: A topographical map of the county of Armagh to which is anex'd the plans of Newry and Armagh, by John Rocque = Carte topographique de la Province d'Armagh où se trouve les plans des villes d'Armagh et de Newry, par Jean Rocque. It was published by J. Rocque in 1760. Scale [ca. 1:41,000]. This layer is image 3 of 4 total images of the four sheet source map, representing the southwest portion of the map. Covers County Armàgh, Northern Ireland. Map in English and French. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Irish Grid (Transverse Mercator 1965 (TM-65)) coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, drainage, built-up areas and selected buildings, selected names of landowners, ground cover, and more. Relief shown by hachures and pictorially. Includes 2 insets: "A Plan of the Town of Newry" -- "A Plan of the City of Armagh".This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

County Armàgh, Northern Ireland, United Kingdom, 1760 (Image 4 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: A topographical map of the county of Armagh to which is anex'd the plans of Newry and Armagh, by John Rocque = Carte topographique de la Province d'Armagh où se trouve les plans des villes d'Armagh et de Newry, par Jean Rocque. It was published by J. Rocque in 1760. Scale [ca. 1:41,000]. This layer is image 4 of 4 total images of the four sheet source map, representing the northwest portion of the map. Covers County Armàgh, Northern Ireland. Map in English and French. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Irish Grid (Transverse Mercator 1965 (TM-65)) coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, drainage, built-up areas and selected buildings, selected names of landowners, ground cover, and more. Relief shown by hachures and pictorially. Includes 2 insets: "A Plan of the Town of Newry" -- "A Plan of the City of Armagh".This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

How can we enhance our security without damaging our liberty? For a Progressive and European Rehabilitation of Sovereignty. European Policy Brief No. 41, January 2016

How can we reinforce internal security without destroying basic freedoms? This dilemma will become increasingly topical in the context of rising terrorist threats and in view of some of the responses already put in place at the national level. Many observers have pointed out the threat that these measures pose to individual freedom. But few have highlighted their relative inefficiency. Indeed, if the right to security is one of the founding reasons for political government and one of its main sources of legitimacy, can states still guarantee this basic right? This article examines this dilemma and focuses more specifically on its implications for the notion and practice of sovereignty. It also sketches a strong, but nuanced, rescue of sovereignty at the European level in order to assure individual security while, at the same time, protecting our freedoms.

Diversity of pigmentation in cultured human melanocytes is due to differences in the type as well as quantity of melanin

Cultured human melanocytes differ tremendously in visual pigmentation, and recapitulate the pigmentary phenotype of the donor's skin. This diversity arises from variation in type as well as quantity of melanin produced. Here, we measured contents of eumelanin (EM) and pheomelanin (PM) in 60 primary human melanocyte cultures (51 neonatal and nine adults), and correlated some of these values with the respective activity and protein levels of tyrosinase, and the melanocortin-1 receptor (MC1R) genotype. Melanocytes were classified into four phenotypes (L, L+, D, D+) as depicted by visual pigmentation using light microscopy, and by the pigmentary phenotype of the donor's skin. There were large differences in total melanin (TM) and EM, which increased progressively for L, L+, D and D+ melanocytes. TM content, the sum of EM and PM, showed a good correlation with TM measured spectrophotometrically, and with the activity and protein levels of tyrosinase. Log EM/PM ratio did not correlate with MC1R genotype. We conclude that: (i) EM consistently correlates with the visual phenotype; (ii) lighter melanocytes tend to be more pheomelanic in composition than darker melanocytes; (iii) in adult melanocyte cultures, EM correlates with the ethnic background of the donors (African-American > Indian > Caucasian); and (iv) MC1R loss-of-function mutations do not necessarily alter the phenotype of cultured melanocytes.

OS SINAIS NO EVANGELHO DE JOÃO: EXEGESE DE JOÃO 6.1-15

Esta dissertação analisará a recorrência do termo sinal no Quarto Evangelho, tendo como paradigma a exegese de João 6.1-15, perícope denominada como multiplicação dos pães e peixes. O texto da multiplicação dos pães e peixes se insere no Bloco dos Sinais (capítulo 1-12), o qual é marcado por sete sinais, sendo eles: o casamento de Caná (2.1-11); a cura do filho do oficial do rei (4.43-54); a cura de um paralítico de Betesda (5.1-15), a multiplicação dos pães e peixes (6.1-15); andar sobre as águas (6.16-21); cura do cego de nascença (9.1-41) e a ressurreição de Lázaro (11.1-45). A pesquisa revelou, além das peculiaridades narrativas, semióticas e hermenêuticas, próprias do Evangelho de João, que o termo sinal enquadra a narrativa, além de estruturar e proporcionar cadência para o texto joanino. Nota-se tangência e diálogo entre os sinais, de modo que a perícope de João 6.1-15 exerce papel central no Bloco da Paixão por ser um texto identitário dos leitores, bem como da comunidade joanina.

Toll-like receptor 4 signalling is neither sufficient nor required for oxidised phospholipids mediated induction of interleukin-8 expression

Toll-like receptor (TLR)-4 signalling has been shown to accelerate atherosclerosis. As oxidised phospholipids are present in atherosclerotic plaque and have been shown to modulate TLR4 signalling, we investigated the role of oxidised 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC) in the regulation of TLR 1, 2, 4 and 6 signalling. Unlike established TLR agonists, OxPAPC did not induce NF-?B-dependent gene expression in monocytic THP-1 cells, human aortic endothelial cells or TLR-deficient HEK-293 cells transfected with TLRs 1, 2, 4 or 6. OxPAPC induction of IL-8 was not blocked by the TLR4 specific antagonist Rhodobacter sphaeroides LPS in human aortic endothelial cells, though OxPAPC potently inhibited TLR4 mediated IL-8 induction in these cells. OxPAPC upregulated IL-8 production in TLR4 deficient HEK-293 cells and this was not increased following TLR4 overexpression. Lipids extracted from carotid atherectomy samples did not stimulate TLR 1, 2, 4 or 6 signalling in a HEK-293 transfection assay. TLR4 signalling does not contribute to OxPAPC induced IL-8 expression in human epithelial HEK-293, monocytic THP-1 or aortic endothelial cells. As lipids extracted from diseased human artery also induced no TLR signalling, it is likely that the TLR-activating materials contributing to atherosclerosis are not of endogenous lipid origin.

The Role of PME-1 in Cancer: Therapeutic Implication

Protein phosphatase 2A (PP2A) plays a major role in maintaining cellular signaling homeostasis in human cells by reversibly affecting the phosphorylation of a variety of proteins. Protein phosphatase methylesterase-1 (PME-1) negatively regulates PP2A activity by reversible demethylation and active site binding. Thus far, it is known that overexpression of PME-1 in human gliomas contributes to ERK pathway signaling, cell proliferation, and malignant progression. Whether PME-1-mediated PP2A inhibition promotes therapy resistance in gliomas is unknown. Specific PP2A targets regulated by PME-1 in cancers also remain elusive. Additionally, whether oncogenic function of PME-1 can be generalized to various human cancers needs to be investigated. This study demonstrated that PME-1 expression promotes kinase inhibitor resistance in glioblastoma (GBM). PME-1 silencing sensitized GBM cells to a group of clinically used indolocarbazole multikinase inhibitors (MKIs). To facilitate the quantitative evaluation of MKIs by cancer-cell specific colony formation assay, Image-J software-plugin ‘ColonyArea’ was developed. PME-1-silencing was found to reactivate specific PP2A complexes and affect PP2A-target histone deacetylase HDAC4 activity. The HDAC4 inhibition induced synthetic lethality with MKIs similar to PME-1 depletion. However, synthetic lethality by both approaches required co-expression of a pro-apoptotic protein BAD. In gliomas, PME-1 and HDAC4 expression was associated with malignant progression. Using tumor PME-1, HDAC4 and BAD expression based stratification signatures this study defined patient subgroups that are likely to respond to MKI alone or in combination with HDAC4 inhibitor therapies. In contrast to the oncogenic role of PME-1 in certain cancer types, this study established that colorectal cancer (CRC) patients with high tumor PME-1 expression display favorable prognosis. Interestingly, PME-1 regulated survival signaling did not operate in CRC cells. Summarily, this study potentiates the candidacy of PME-1 as a therapy target in gliomas, but argues against generalization of these findings to other cancers, especially CRC.

Coexistence of mcr-1 and blaNDM-1 in Escherichia coli from Venezuela

We studied the presence of the mobile colistin resistance gene mcr-1 in human, animal, and environmental Enterobacteriaceae samples from Cumana, Venezuela, that were collected in 2015. The mcr-1 gene was detected in 2/93 Escherichia coli isolates from swine (novel ST452) and human (ST19) samples that were resistant to colistin. Whole-genome sequencing and transformation experiments identified mcr-1 on an IncI2 plasmid. One of the isolates also bore the widely spread carbapenemase NDM-1. A One Health approach is necessary to further elucidate the flux of these high-risk genes.

An Analysis of Child Kidnapping in Iowa, December 1, 2013

In July 2012 the Iowa Legislative Council requested the Public Safety Advisory Board (PSAB) provide recommendations to the General Assembly relating to crimes against children. This request came in response to the high profile kidnapping of two girls and subsequent murder of one by Michael Klunder. The PSAB directed the Iowa Department of Human Rights, Division of Criminal and Juvenile Justice Planning (CJJP) to provide an analysis of child kidnapping and review of the effectiveness of Iowa kidnapping law.

Asfixia perinatal y proteína S100B

La asfixia perinatal es la principal causa de muerte en la primera semana de vida la nivel mundial, los niños que sufren esta complicación y sobreviven pueden presentar trastornos neurológicos de diferente nivel de compromiso que inciden en su desarrollo personal y social. Las cifras de muerte por este problema de salud han disminuido de manera importante, sin embargo en el reporte de la Organización Mundial de Salud (OPS) del 2010, la asfixia perinatal es causa del 29% de muertes infantiles en los países de América Latina y el Caribe 2. Es necesario conocer además la extensión del daño neurológico que sufren estos niños, con este fin se desarrolló un estudio piloto en el Hospital Universitario Mayor Mederi de Bogotá, en el cual se determinó la concentración de un marcador metabólico de daño cerebral, la proteína S100B en suero de 60 recién nacidos sanos, con el objetivo de analizar la asociación del mismo con el peso al nacer, la edad gestacional y el diagnóstico. Los resultados no mostraron diferencias significativas entre este marcador y las variables analizadas que puede asociarse al pequeño número de pacientes, sin embargo han sentado las bases para el desarrollo de un estudio que incluya varios hospitales de Bogotá y sobre todo la determinación del mismo en recién nacidos con diagnóstico de hipoxia en el período perinatal, lo cual aportará información del grado de la alteración que puedan tener a nivel cerebral y contribuya al mejor manejo evolutivo con la aplicación de medidas de intervención en estadios tempranos de la vida.

Specificity of 17 beta-oestradiol and benzo[a] pyrene oxidation by polymorphic human cytochrome P4501B1 variants substituted at residues 48, 119 and 432

1. Eight human cytochrome P4501B1 (CYP1B1) allelic variants, namely Arg(48)Ala(119)Leu(432), Arg(48)Ala(119)Val(432), Gly(48)Ala(119)Leu(432), Gly(48)Ala(119)Val(432), Arg(48)Ser(119)Leu(432), Arg(48)Ser(119)Val(432), Gly(48)Ser(119)Leu(432) and Gly(48)Ser(119)Val(432) (all with Asn(453)), were expressed in Escherichia coli together with human NADPH-P450 reductase and their catalytic specificities towards oxidation of 17 beta -oestradiol and benzo[a]pyrene were determined. 2. All of the CYP1B1 variants expressed in bacterial membranes showed Fe2+. CO versus Fe2+ difference spectra with wavelength maxima at 446 nm and they reacted with antibodies raised against recombinant human CYP1B1 in immunoblots. The ratio of expression of the reductase to CYP1B1 in these eight preparations ranged from 0.2 to 0.5. 3. CYP1B1 Arg(48) variants tended to have higher activities for 17 beta -oestradiol 4-hydroxylation than Gly(48) variants, although there were no significant variations in 17 beta -oestradiol 2-hydroxylation activity in these eight CYP1B1 variants. Interestingly, ratios of formation of 17 beta -oestradiol 4-hydroxylation to 2-hydroxylation by these CYP1B1 variants were higher in all of the Val(432) forms than the corresponding Leu(432) forms. 4. In contrast, Leu(432) forms of CYP1B1 showed higher rates of oxidation of benzo[a]pyrene (to the 7, 8-dihydoxy-7,8-dihydrodiol in the presence of epoxide hydrolase) than did the Val(432) forms. 5. These results suggest that polymorphic human CYP1B1 variants may cause some altered catalytic specificity with 17 beta -oestradiol and benzo[a]pyrene and may influence susceptibilities of individuals towards endogenous and exogenous carcinogens.