Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding

Cellular prion protein (PrPC) is a glycosyl-phosphatidylinositol¿anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrPSC) induces transmissible spongiform encephalopathies. In contrast, PrPC has a number of physiological functions in several neural processes. Several lines of evidence implicate PrPC in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrPC has been implicated in the inhibition of N-methyl-D-aspartic acid (NMDA)¿mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnpo/oJnk3o/o mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrPC-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrPC with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6¿PSD-95 interaction after KA injections was favored by the absence of PrPC. Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrPC against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.

Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding

Cellular prion protein (PrPC) is a glycosyl-phosphatidylinositol¿anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrPSC) induces transmissible spongiform encephalopathies. In contrast, PrPC has a number of physiological functions in several neural processes. Several lines of evidence implicate PrPC in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrPC has been implicated in the inhibition of N-methyl-D-aspartic acid (NMDA)¿mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnpo/oJnk3o/o mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrPC-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrPC with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6¿PSD-95 interaction after KA injections was favored by the absence of PrPC. Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrPC against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.

A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease.

The postsynaptic density protein PSD-95 is a major element of synapses. PSD-95 is involved in aging, Alzheimer's disease (AD) and numerous psychiatric disorders. However, contradictory data about PSD-95 expression in aging and AD have been reported. Indeed in AD versus control brains PSD-95 varies according to regions, increasing in the frontal cortex, at least in a primary stage, and decreasing in the temporal cortex. In contrast, in transgenic mouse models of aging and AD PSD-95 expression is decreased, in behaviorally aged impaired versus unimpaired rodents it can decrease or increase and finally, it is increased in rodents grown in enriched environments. Different factors explain these contradictory results in both animals and humans, among others concomitant psychiatric endophenotypes, such as depression. The possible involvement of PSD-95 in reactive and/or compensatory mechanisms during AD progression is underscored, at least before the occurrence of important synaptic elimination. Thus, in AD but not in AD transgenic mice, enhanced expression might precede the diminution commonly observed in advanced aging. A two-compartments cell model, separating events taking place in cell bodies and synapses, is presented. Overall these data suggest that AD research will progress by untangling pathological from protective events, a prerequisite for effective therapeutic strategies.

Friday Facts, April 1, 2011, Vol. 95

Bureau of Nutrition and Health Promotion part of the Iowa Department of Public Health produces of weekly newsletter about the Iowa WIC Program for the State of Iowa citizen.

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Euroopan yhteisöjen tuomioistuimen tuomio 17.11.1998 asiassa C-391/95 (Van Uden) : Brysselin yleissopimus - välityslauseke - ennakkona maksettava maksu - väliaikaisten toimenpiteiden käsite

Ratkaisu koskee Brysselin yleissopimuksen 24 artiklaan perustuvaa tuomioistuimen toimivaltaa turvaamistoimiasiassa

[Collection de cartes postales classées méthodiquement pour l'enseignement de la géographie, Paris, F. Nathan, s.d. (1928), offert par l'éditeur. 353 cartes postales en 15 paquets. 1. Généralités, définitions principales (1-25) 2. Ports de commerce, de pêche, militaires, fluviaux (26-50) 3. Pêches et industries diverses (51-75) 4. Relief du sol (76-95) 5. Communications en montagne (96-119) 6. Histoire d'un fleuve (120-139) 7. Phénomènes dus à l'érosion (140-159) 8. Voies de communication (160-179) 9. Paris (180-204) 10. Algérie (205-228) 11. Tunisie (229-253) 12. Maroc (254-278) 13. A.O.F. et A.E.F. (279-303) 14. Madagascar (304-328) 15. Indochine (329-353)]

Donateur : Nathan, Fernand (1858-1947)

Caracterización meteorológica de las camapañas estivales 1994-95 y 1995-96, en la isla Livingston (Shetland del Sur).

En este trabajo se presenta el análisis de los datos de temperatura, radiación global, radiación difusa y humedad relativa, simultáneos, registrados en la isla Livingston durante las campañas de verano de 1994-95 y 1995-96. Los datos corresponden a dos estaciones, una instalada en la Base Antártica Española Juan Carlos I y otra instalada sobre el Glaciar Johnsons. Se ha establecido la correlación de las variables medidas en la Base con las obtenidas en el glaciar. A su vez, los resultados obtenidos permiten calcular por regresión los correspondientes al glaciar, en las campañas donde no se obtuvieron datos in situ. También, se caracterizan las evoluciones medias diarias de la temperatura, radiación y humedad mediante modelos periódicos. Por último se estudian la relación de la temperatura y nubosidad con respecto a la velocidad y dirección del viento. Algunos de los resultados obtenidos se han comparado con éxito con los obtenidos a partir de los registros de la base antrática de Bellingshausen.

A Laboratory Evaluation of Tungsten Carbide Inserts for Snowplow Blades, MLR-95-6, 1996

Tungsten carbide used in snowplow blades was studied from three manufacturers. The carbides were measured for common industry properties including specific gravity and hardness. In addition, an abrasion resistance was performed. There was no significant difference found in abrasion resistance between the Kenametal and the Valk carbides. The Bucyrus carbides showed improved abrasion resistance, but were outside industry specifications for specific gravity.

Minimum VMA in HMA Based on Gradation and Volumetric Properties, MLR-95-7, 1996

The use of voids in the mineral aggregate (VMA) criteria for proper mix design of hot mix asphalt (HMA) mixtures is a time honored and fairly successful tool. Recent developments in the field of asphalt mix design have encouraged the use of mixtures with a coarse aggregate structure to resist the affect of heavy traffic loads. By using the equations presented, which account for both aggregate gradation and the volumetric properties of the materials, the mix designer is able to judge the proper VMA requirement for each unique blend of materials. By applying the new equations, the most economical mix may be selected without great risk of reduced durability. Supporting data from field application is presented to illustrate the use of the equations.

Structural Analysis of Aggregate Blends Using the SHRP Gyratory Compactor, MLR-95-8, 1996

The Iowa Department of Transportation (IDOT) received a Strategic Highway Research Program (SHRP) gyratory compactor in December 1994. Since then IDOT has been studying the ability of the compactor to analyze fundamental properties of aggregates such as shape, texture, and gradation by studying the volumetrics of the aggregate blends under a standard load using the SHRP gyratory compactor. This method of analyzing the volumetrics of aggregate blends is similar to SHRP's fine aggregate angularity procedure, which analyzes void levels in noncompacted aggregate blends, which in turn can be used to evaluate the texture or shape of aggregates, what SHRP refers to as angularity. Research is showing that by splitting the aggregate blend on the 2.36-mm (#8) sieve and analyzing the volumetrics or angularity of the separated blend, important fundamental properties can be determined. Most important is structure (the degree and location of aggregate interlock). In addition, analysis of the volumes of the coarse and fine portions can predict the voids in the mineral aggregate and the desired asphalt content. By predicting these properties, it can be determined whether the combined aggregate blend, when mixed with asphalt cement, will produce a mix with structural adequacy to carry the designed traffic load.

Vibration Study for Consolidation of Portland Cement Concrete, MLR-95-4, 1999

The Iowa Department of Transportation has noticed an increase in the occurrence of excessively vibrated portland cement concrete (PCC) pavements. The overconsolidation of PCC pavements can be observed in several sections of PCC highways across the state of Iowa. Also, excessive vibration is believed to be a factor in the premature deterioration of several pavements in Iowa. To address the problem of excessive vibration, a research project was conducted to document the vibratory practices of PCC slipform paving in Iowa and determine the effect of vibration on the air content of pavement. The primary factors studied were paver speed, vibrator frequency, and air content relative to the location of the vibrator. The study concluded that the Iowa Department of Transportation specification of 5000 and 8000 vibrations per minute (vpm) for slipform pavers is effective for normal paver speeds observed on the three test paving projects. Excessive vibration was clearly identified on one project where a vibrator frequency was found to be 12,000 vpm. When the paver speed was reduced to half the normal speed, hard air contents indicated that excessive vibration was beginning to occur in the localized area immediately surrounding the vibrator at a frequency of 8000 vpm. Analysis of variance testing indicated many variables and interactions to be significant at a 95% confidence level; however, the variables and interactions that were found to be significant varied from project to project. This affirms the complexity of the process for consolidating PCC.

Vibration Study for Consolidation of Portland Cement Concrete, Preprint, MLR-95-4, 1997

The Iowa Department of Transportation has discovered an increase in the occurrence of excessively vibrated portland cement concrete (PCC) pavements. The overconsolidation of PCC pavements has been observed in several projects across the state. Overconsolidation is also believed to be a factor in acceleration of premature deterioration of at least two pavement projects in Iowa. To address the problem, a research project in 1995 documented the vibratory practices of PCC slipform paving in Iowa in order to determine the effect of vibration on consolidation and air content of pavement. Paver speed, vibrator frequency, and air content relative to the location of the vibrator were studied. The study concluded that the Iowa Department of Transportation specification of 5,000 to 8,000 vibrations per minute (vpm) for slipform pavers is effective for normal paver speeds on the three projects that were examined. Excessive vibration was clearly identified on one project where a vibrator frequency of 12,000 vpm was discovered. When the paver speed was reduced to half the normal speed, hard air contents indicate that excessive vibration was beginning to occur in the localized area immediately surrounding the vibrator at a frequency of 8,000 vpm. The study also indicates that the radius of influence of the vibrators is smaller than has been claimed.