New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Granulocyte-macrophage colony-stimulating factor (GM-CSF) counteracts the inhibiting effect of monocytes on natural killer (NK) cells

Contains fulltext : 22130.pdf (publisher's version ) (Open Access

Efeito da concentração espermática e do número de inseminações artificiais sobre a fertilidade de éguas inseminadas com sêmen fresco diluído Effects of sperm concentration and number of artificial inseminations on fertility of inseminated mares with diluted fresh semen

Sessenta e duas fêmeas eqüinas (tipo militar) foram distribuídas, ao acaso, em dois grupos experimentais para estudar o efeito da concentração espermática (200× 10(6) e 400× 10(6) de espermatozóides progressivamente móveis/dose inseminante) e do número de inseminações/ciclo (duas, três e quatro ou mais inseminações) sobre a fertilidade. As éguas foram rufiadas e inseminadas às segundas, quartas e sextas-feiras, a partir de um folículo de 3,0 a 3,5cm de diâmetro, com sêmen de apenas um garanhão com fertilidade comprovada, diluído para um volume inseminante de 10ml com diluidor de mínima contaminação. As taxas de concepção ao primeiro ciclo para as concentrações de 200 e 400 milhões foram de 66,7% (20/30) e 65,5% (19/29), e as taxas de concepção/ciclo, após quatro ciclos, de 52,0% (26/50) e 57,8% (26/45), respectivamente (P>0,05). As taxas de concepção ao primeiro ciclo para os grupos com duas, três e quatro ou mais inseminações/ciclo foram, respectivamente, 72,0% (18/25), 65,2% (15/23) e 54,6% (6/11), sem que se observassem diferenças entre elas (P>0,05). Após quatro ciclos, as taxas de concepção foram de 59,0% (23/39), 52,5% (21/40) e 50,0% (8/16), respectivamente, na mesma ordem de citação (P>0,05). Com base nos resultados, recomendam-se inseminações às segundas, quartas e sextas-feiras, utilizando-se a concentração de 200×10(6) SPTZ/dose inseminante, sem que haja perda da fertilidade, independente do número de inseminações/ciclo.<br>This work aimed to study the effects of spermatic concentrations (200× 10(6) and 400×10(6) spermatozoa/inseminated dose) and number of inseminations (two, three and four or more) on the fertility of 62 mares (military type). Mares were teased and inseminated on Mondays, Wednesdays and Fridays with diluted semen from only one stallion of proven fertility. The conception rates during the first cycle for the two spermatic concentrations were, respectively, 66.7%(20/30) and 65.5%(19/29) and after four cycles they were, respectively, equals to 52.0%(26/50) and 57.8%(26/45) with no difference on conception rate according to the spermatic concentrations (P>0.05). The conception rates for the first cycle after two, three and four or more inseminations were, respectively, 72.0%(18/25), 65.2%(15/23) and 54.6%(6/11) and after four cycles they were, respectively, equals to 59.0%(23/39), 52.5%(21/40) and 50.0%(8/16) with no differences on conception rates according to the number of inseminations. The results suggested that mares could be inseminated using a spermatic concentration of 200×10(6)/inseminated dose on Mondays, Wednesdays and Fridays without any loss of fertility independently of the number of inseminations/cycle