Alzheimer’s disease is the fourth biggest killer in developed countries. Amyloid precursor protein (APP) plays a central role in the development of the disease, through the generation of a peptide ...called Aβ by proteolysis of the precursor protein. APP can function as a metalloprotein and modulate copper transport via its extracellular copper binding domain (CuBD). Copper binding to this domain has been shown to reduce Aβ levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease. We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD. The structures provide a mechanism by which CuBD could readily transfer copper ions to other proteins. Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in Aβ production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer’s disease.
China's century of revolutionary change has been heard as much as seen, and nowhere is this more evident than in an auditory history of the modern Chinese poem. From Lu Xun's seminal writings on ...literature to a recitation renaissance in urban centers today, poetics meets politics in the sounding voice of poetry. Supported throughout by vivid narration and accessible analysis,Voices in Revolutionoffers a literary history of modern China that makes the case for the importance of the auditory dimension of poetry in national, revolutionary, and postsocialist culture.
Crespi brings the past to life by first examining the ideological changes to poetic voice during China's early twentieth-century transition from empire to nation. He then traces the emergence of the spoken poem from the May Fourth period to the present, including its mobilization during the Anti-Japanese War, its incorporation into the student protest repertoire during China's civil war, its role as a conflicted voice of Mao-era revolutionary passion, and finally its current adaptation to the cultural life of China's party-guided market economy.
Voices in Revolutionalters the way we read by moving poems off the page and into the real time and space of literary activity. To all readers it offers an accessible yet conceptually fresh and often dramatic narration of China's modern literary experience. Specialists will appreciate the book's inclusion of noncanonical texts as well as its innovative interdisciplinary approach.
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Solanezumab (Eli Lilly) and crenezumab (Genentech) are the leading clinical antibodies targeting Amyloid-β (Aβ) to be tested in multiple Phase III clinical trials for the prevention of Alzheimer's ...disease in at-risk individuals. Aβ capture by these clinical antibodies is explained here with the first reported mid-region Aβ-anti-Aβ complex crystal structure. Solanezumab accommodates a large Aβ epitope (960 Å(2) buried interface over residues 16 to 26) that forms extensive contacts and hydrogen bonds to the antibody, largely via main-chain Aβ atoms and a deeply buried Phe19-Phe20 dipeptide core. The conformation of Aβ captured is an intermediate between observed sheet and helical forms with intramolecular hydrogen bonds stabilising residues 20-26 in a helical conformation. Remarkably, Aβ-binding residues are almost perfectly conserved in crenezumab. The structure explains the observed shared cross reactivity of solanezumab and crenezumab with proteins abundant in plasma that exhibit this Phe-Phe dipeptide.
•GBS is a powerful tool to study simultaneously traits and diseases in large samples.•GBS shows a high degree of accuracy.•Higher numbers of SNPs are needed to exclude a false progeny in inbred ...dogs.•Most genetic conditions were monomorphic in a specific breed or breed group.•Validation of GBS results for genetic disorders showed 94–100% concordance.
Next-generation sequencing (NGS) technologies have enabled the identification of many causal variants of genetic disorders, the development of parentage tests and the analysis of multiple traits in domestic animals. In this study, we evaluated the performance of a Canine Targeted Genotyping-by-Sequencing (GBS) custom panel (Thermo Fisher Scientific, Waltham, Ma, USA) in a cohort of 95 dog DNA samples, comprising 76 Doberman Pinschers and 19 Toy Poodles from Argentina. The used panel included 383 targets (228 parentage SNVs, 137 genetic disorder markers and 18 trait markers). While paternity analysis showed correct duo (97.4%; LOD > 2.98E+13) and trio (100%; LOD > 2.20E+15) parentage assignment, the panel resulted still insufficient for excluding close relatives in inbred populations. In this sense, close relatives were wrongly assigned as parents in 12.6% of duos and 0.3% of trios. We detected 17 polymorphic markers (genetic disorders, n = 4; hair type, n = 3; coat color, n = 10) and estimated their allele frequencies in the studied breeds. The accuracy of targeted GBS results were evaluated for three markers that were associated with Progressive rod-cone degeneration, von Willebrand disease type 1 and dilated cardiomyopathy by pyrosequencing and Sanger sequencing genotyping, showing 94–100% concordance among assays. The targeted GBS custom panel resulted cost-effective strategy to study the prevalence of genetic disorders and traits in a large number of samples and to analyze genetic interactions between previously reported variants. Once assays based on AgriSeq technology were standardized, their uses are a good strategy for large-scale routine genetic evaluation of animal populations.
This paper provides novel empirical evidence on productivity growth in the manufacturing sector in Chile, Colombia, Mexico and Peru. Relying on plant-level data, we first decompose productivity and ...productivity growth into plant-level growth and market allocation forces. While the average productivity of the survivors is higher than the overall contribution of reallocation forces, during recessions the inverse is true and reallocation gives a positive, albeit small, contribution to aggregate productivity growth. Next we analyze how policy measures can determine allocative efficiency levels and growth, and find important scope for action on education, financial regulation, and structural reforms.
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