Toward deciphering the mechanistic role of variations in the Rep1 repeat site in the transcription regulation of SNCA gene.

Short structural variants-variants other than single nucleotide polymorphisms-are hypothesized to contribute to many complex diseases, possibly by modulating gene expression. However, the molecular mechanisms by which noncoding short structural variants exert their effects on gene regulation have not been discovered. Here, we study simple sequence repeats (SSRs), a common class of short structural variants. Previously, we showed that repetitive sequences can directly influence the binding of transcription factors to their proximate recognition sites, a mechanism we termed non-consensus binding. In this study, we focus on the SSR termed Rep1, which was associated with Parkinson's disease (PD) and has been implicated in the cis-regulation of the PD-risk SNCA gene. We show that Rep1 acts via the non-consensus binding mechanism to affect the binding of transcription factors from the GATA and ELK families to their specific sites located right next to the Rep1 repeat. Next, we performed an expression analysis to further our understanding regarding the GATA and ELK family members that are potentially relevant for SNCA transcriptional regulation in health and disease. Our analysis indicates a potential role for GATA2, consistent with previous reports. Our study proposes non-consensus transcription factor binding as a potential mechanism through which noncoding repeat variants could exert their pathogenic effects by regulating gene expression.

Virtual angiography for visualization and validation of computational models of aneurysm hemodynamics.

It has recently become possible to simulate aneurysmal blood flow dynamics in a patient-specific manner via the coupling of three-dimensional (3-D) X-ray angiography and cmputational fluid dynamics (CFD). Before such image-based CFD models can be used in a predictive capacity, however, it must be shown that they indeed reproduce the in vivo hemodynamic environment. Motivated by the fact that there are currently no techniques for adequately measuring complex blood velocity fields in vivo, in this paper we describe how cine X-ray angiograms may be simulated for the purpose of indirectly validating patient-sperific CFD models. Mimicking the radiological procedure, a virtual angiogram is constructed by first simulating the time-varying injection of contrast agent into a precomputed, patient-specific CFD model. A time-series of images is then constructed by simulating the attenuation of X-rays through the computed 3-D contrast-agent flow dynamics. Virtual angiographic images and residence time maps, here derived from an image-based CFD model of a giant aneurysm, are shown to be in excellent agreement wiith the corresponding clinical images and residence time maps, but only when the interaction between the quasisteady contrast agent injection and the pulsatile flow are properly accounted for. These virtual angiographic techniques pave the way for validating image-based CFD models against routinely available clinical data, and provide a means of visualizing complex, 3-D blood flow dynamics in a clinically relevant manner. They also clearly show how the contrast agent injection perturbs the noraml blood flow patterns, further highlighting the potential utility of image-based CFD as a window into the true aneurysmal hemodynamics.