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

The blast behaviour of fiber reinforced thermoplastic laminates

This article presents the results of a series of blast tests on a carbon fiber-reinforced poly-ether-imide (PEI) and a glass fiber-reinforced PEI composite. Initially, the fracture properties of the two composite systems were characterized through a series of flexural and interlaminar fracture tests. Blast testing was then undertaken on a ballistic pendulum facility, capable of measuring the impulse imparted by the plastic explosive. Delamination, localized fiber buckling, fiber fracture, and shear failure at the boundary of the clamped plates were identified as the primary failure mechanisms in the laminates, with their severity depending on the panel thickness and the applied impulse. Delamination was very localized along the center plane of the laminate, a reflection of the very high interlaminar fracture toughness of these composites. The critical impulse for rear surface fiber fracture has been found to increase rapidly with laminate thickness for the range of panels considered here. The impulses associated with the onset of rear-surface fiber fracture and complete failure of the target were similar, suggesting that rear surface fiber fracture is a pre-cursor to complete failure in these laminates. Limited tests on the glass fiber-reinforced PEI system showed that it offers a superior blast resistance to its carbon fiber counterpart

Influência do dano físico na fisiologia pós-colheita de folhas de taioba

Folhas de taioba danificadas fisicamente tornam-se amarelas e escuras na região do dano. Assim, o objetivo deste trabalho foi avaliar o efeito do dano físico sobre o metabolismo pós-colheita de folhas de taioba. Para esse fim, avaliou-se o teor de clorofila e o acúmulo de compostos fenólicos solúveis em discos foliares de taioba que continham furos realizados com uma agulha em um dos lados da folha, simulando os danos sofridos no campo e transporte. O lado não danificado foi usado como tratamento controle. Para a avaliação da produção de etileno e CO2, discos foliares danificados e intactos foram infiltrados com ácido 1-carboxílico-1-aminociclopropano (ACC) ou com água desionizada. Houve acentuada queda de clorofila nas primeiras 24 horas após a colheita, porém, o dano físico não estimulou a degradação da clorofila ou elevação da produção de etileno. Entretanto, nos discos foliares danificados e infiltrados com ACC, houve aumento transiente na produção de etileno após 4 horas da realização do dano. Essa resposta demonstra que a enzima ACC sintase não é estimulada pelo dano e a enzima ACC oxidase tem sua atividade aumentada apenas por um curto período. Em contrapartida, as folhas danificadas tiveram maior acúmulo de compostos fenólicos e elevada taxa respiratória

Metabolic engineering of β-oxidation in Penicillium chrysogenum for improved semi-synthetic cephalosporin biosynthesis

Industrial production of semi-synthetic cephalosporins by Penicillium chrysogenum requires supplementation of the growth media with the side-chain precursor adipic acid. In glucose-limited chemostat cultures of P. chrysogenum, up to 88% of the consumed adipic acid was not recovered in cephalosporin-related products, but used as an additional carbon and energy source for growth. This low efficiency of side-chain precursor incorporation provides an economic incentive for studying and engineering the metabolism of adipic acid in P. chrysogenum. Chemostat-based transcriptome analysis in the presence and absence of adipic acid confirmed that adipic acid metabolism in this fungus occurs via β-oxidation. A set of 52 adipate-responsive genes included six putative genes for acyl-CoA oxidases and dehydrogenases, enzymes responsible for the first step of β-oxidation. Subcellular localization of the differentially expressed acyl-CoA oxidases and dehydrogenases revealed that the oxidases were exclusively targeted to peroxisomes, while the dehydrogenases were found either in peroxisomes or in mitochondria. Deletion of the genes encoding the peroxisomal acyl-CoA oxidase Pc20g01800 and the mitochondrial acyl-CoA dehydrogenase Pc20g07920 resulted in a 1.6- and 3.7-fold increase in the production of the semi-synthetic cephalosporin intermediate adipoyl-6-APA, respectively. The deletion strains also showed reduced adipate consumption compared to the reference strain, indicating that engineering of the first step of β-oxidation successfully redirected a larger fraction of adipic acid towards cephalosporin biosynthesis.