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Salomonis N.,Cincinnati Childrens Hospital Medical Center Research Foundation
Pediatric Research | Year: 2014

Sudden infant death syndrome (SIDS) remains one of the primary causes of infant mortality in developed countries. Although the causes of SIDS remain largely inconclusive, some of the most informative associations implicate molecular, genetic, anatomical, physiological, and environmental (i.e., infant sleep) factors. Thus, a comprehensive and evolving systems-level model is required to understand SIDS susceptibility. Such models, by being powerful enough to uncover indirect associations, could be used to expand our list of candidate targets for in-depth analysis. We present an integrated WikiPathways model for SIDS susceptibility that includes associated cell systems, signaling pathways, genetics, and animal phenotypes. Experimental and literature-based gene-regulatory data have been integrated into this model to identify intersecting upstream control elements and associated interactions. To expand this pathway model, we performed a comprehensive analysis of existing proteomics data from brainstem samples of infants with SIDS. From this analysis, we discovered changes in the expression of several proteins linked to known SIDS pathologies, including factors involved in glial cell production, hypoxia regulation, and synaptic vesicle release, in addition to interactions with annotated SIDS markers. Our results highlight new targets for further consideration that further enrich this pathway model, which, over time, can improve as a wiki-based, community curation project. Copyright © 2014 International Pediatric Research Foundation, Inc.

Hsieh Y.-W.,Cincinnati Childrens Hospital Medical Center Research Foundation | Chang C.,Cincinnati Childrens Hospital Medical Center Research Foundation | Chuang C.-F.,Cincinnati Childrens Hospital Medical Center Research Foundation
PLoS Genetics | Year: 2012

The Caenorhabditis elegans left and right AWC olfactory neurons communicate to establish stochastic asymmetric identities, AWCON and AWCOFF, by inhibiting a calcium-mediated signaling pathway in the future AWCON cell. NSY-4/claudin-like protein and NSY-5/innexin gap junction protein are the two parallel signals that antagonize the calcium signaling pathway to induce the AWCON fate. However, it is not known how the calcium signaling pathway is downregulated by nsy-4 and nsy-5 in the AWCON cell. Here we identify a microRNA, mir-71, that represses the TIR-1/Sarm1 adaptor protein in the calcium signaling pathway to promote the AWCON identity. Similar to tir-1 loss-of-function mutants, overexpression of mir-71 generates two AWCON neurons. tir-1 expression is downregulated through its 3′ UTR in AWCON, in which mir-71 is expressed at a higher level than in AWCOFF. In addition, mir-71 is sufficient to inhibit tir-1 expression in AWC through the mir-71 complementary site in the tir-1 3′ UTR. Our genetic studies suggest that mir-71 acts downstream of nsy-4 and nsy-5 to promote the AWCON identity in a cell autonomous manner. Furthermore, the stability of mature mir-71 is dependent on nsy-4 and nsy-5. Together, these results provide insight into the mechanism by which nsy-4 and nsy-5 inhibit calcium signaling to establish stochastic asymmetric AWC differentiation. © 2012 Hsieh et al.

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