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

Providing built-in keyword search capabilities in RDBMS

A common approach to performing keyword search over relational databases is to find the minimum Steiner trees in database graphs transformed from relational data. These methods, however, are rather expensive as the minimum Steiner tree problem is known to be NP-hard. Further, these methods are independent of the underlying relational database management system (RDBMS), thus cannot benefit from the capabilities of the RDBMS. As an alternative, in this paper we propose a new concept called Compact Steiner Tree (CSTree), which can be used to approximate the Steiner tree problem for answering top-k keyword queries efficiently. We propose a novel structure-aware index, together with an effective ranking mechanism for fast, progressive and accurate retrieval of top-k highest ranked CSTrees. The proposed techniques can be implemented using a standard relational RDBMS to benefit from its indexing and query-processing capability. We have implemented our techniques in MYSQL, which can provide built-in keyword-search capabilities using SQL. The experimental results show a significant improvement in both search efficiency and result quality comparing to existing state-of-the-art approaches

Interplay of IKK/NF-κB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder associated with dystrophin deficiency that results in chronic inflammation and severe skeletal muscle degeneration. In DMD mouse models and patients, we find that IκB kinase/NF-κB (IKK/NF-κB) signaling is persistently elevated in immune cells and regenerative muscle fibers. Ablation of 1 allele of the p65 subunit of NF-κB was sufficient to improve pathology in mdx mice, a model of DMD. In addition, conditional deletion of IKKβ in mdx mice elucidated that NF-κB functions in activated macrophages to promote inflammation and muscle necrosis and in skeletal muscle fibers to limit regeneration through the inhibition of muscle progenitor cells. Furthermore, specific pharmacological inhibition of IKK resulted in improved pathology and muscle function in mdx mice. Collectively, these results underscore the critical role of NF-κB in the progression of muscular dystrophy and suggest the IKK/NF-κB signaling pathway as a potential therapeutic target for DMD

African Americans and U.S. Politics: The Gradual Progress of Black Women in Political Representation

African American, U.S. politics, Gender representation, Political participation,