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BACKGROUND: Alzheimer's disease (AD) is a multifactorial and complex neuropathology that involves impairment of many intricate molecular mechanisms. Despite recent advances, AD pathophysiological characterization remains incomplete, which hampers the development of effective treatments. In fact, currently, there are no effective pharmacological treatments for AD. Integrative strategies such as transcription regulatory network and master regulator analyses exemplify promising new approaches to study complex diseases and may help in the identification of potential pharmacological targets. METHODS: In this study, we used transcription regulatory network and master regulator analyses on transcriptomic data of human hippocampus to identify transcription factors (TFs) that can potentially act as master regulators in AD. All expression profiles were obtained from the Gene Expression Omnibus database using the GEOquery package. A normal hippocampus transcription factor-centered regulatory network was reconstructed using the ARACNe algorithm. Master regulator analysis and two-tail gene set enrichment analysis were employed to evaluate the inferred regulatory units in AD case-control studies. Finally, we used a connectivity map adaptation to prospect new potential therapeutic interventions by drug repurposing. RESULTS: We identified TFs with already reported involvement in AD, such as ATF2 and PARK2, as well as possible new targets for future investigations, such as CNOT7, CSRNP2, SLC30A9, and TSC22D1. Furthermore, Connectivity Map Analysis adaptation suggested the repositioning of six FDA-approved drugs that can potentially modulate master regulator candidate regulatory units (Cefuroxime, Cyproterone, Dydrogesterone, Metrizamide, Trimethadione, and Vorinostat). CONCLUSIONS: Using a transcription factor-centered regulatory network reconstruction we were able to identify several potential molecular targets and six drug candidates for repositioning in AD. Our study provides further support for the use of bioinformatics tools as exploratory strategies in neurodegenerative diseases research, and also provides new perspectives on molecular targets and drug therapies for future investigation and validation in AD.

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Phylogenetic analysis of ribosomal DNA internal transcribed spacer sequences from 35 members of western American Portulacaceae plus seven Portulacaceae outgroups generally supports morphologically based interpretations of multiple intercontinental disjunctions. The data neither support nor refute monophyly of the western American group but strongly support a group comprising the western American taxa plus Phemeranthus, the only strictly American genus of the morphology-based eastern American/African group of Portulacaceae, along with the Australian genus Parakeelya. Support is strong for the monophyly of Calandrinia, Montiopsis, Lewisia, Claytonia, and Montia, along with a sister relationship of the last two. The data neither strongly support nor refute the morphologically based diagnosis of Cistanthe, but they strongly support a clade including the North American Cistanthe section Calyptridium and the South American Cistanthe sections Amarantoideae and Philippiamra. The internal transcribed spacer data fail to resolve the phylogenetic relationships among most of the western American lineages, suggesting either rapid radiation or, alternatively, erratic evolution of the internal transcribed spacer. The internal transcribed spacer and morphological evidence together suggest that in this group there have been 8-13 dispersal and colonization events across >2000 km (1 for every 15-26 extant species in this group). The internal transcribed spacer data document complex molecular evolutionary patterns, including strong substitution biases, among-site rate heterogeneity, positional bias for deamination-type substitutions, nonstationarity, and variable rates of insertion/deletion. Our phylogenetic conclusions, however, do not appear to be sensitive to these patterns.

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A formula for the standard error of Lasker's coefficient of relationship Ri derived from isonymy is proposed, and used to test for differences in relationship in two groups of pairs of spouses from the town of Quibor in Venezuela sampled one century apart. From analysis of the relationship, it was possible to attribute population growth also to immigration. Further, the study of the values of Ri showed that the surnames belonging to the male line are more frequent and stable in this population, which is characterized by a predominantly agricultural activity. From the analysis of the coefficients of relationship, the population of Quibor is also classified as patrilocal.

PIP: Lasker's coefficient of relationship has been used to measure genetic similarity between and within human populations, and to determine the temporal variation of the similarity. A formula for the standard error of Lasker's coefficient of relations Ri derived from isonomy is proposed, and used to test for differences in relationship in 2 groups of pairs of spouses from the town of Quibor in Venezuela sampled 1 century apart. Members of this studied population each have 2 surnames, differing from traditionally studied populations employing the single surname Northern European system. Quibor's 1980 population totaled 22,100, having grown rapidly from its 1940 inhabitant level of 3100. From analysis of the relationship, it was possible to attribute population growth also to immigration. Further, the study of the values of Ri showed that the surnames belonging to the male line are more frequent and stable in this predominantly agricultural population. From the analysis of the coefficients of relationship, the population of Quibor is also classified as patrilocal.

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