Polyglutamine Induced Misfolding of Huntingtin Exon1 is Modulated by the Flanking Sequences

Polyglutamine (polyQ) expansion in exon1 (XN1) of the huntingtin protein is linked to Huntington's disease. When the number of glutamines exceeds a threshold of approximately 36–40 repeats, XN1 can readily form amyloid aggregates similar to those associated with disease. Many experiments suggest that misfolding of monomeric XN1 plays an important role in the length-dependent aggregation. Elucidating the misfolding of a XN1 monomer can help determine the molecular mechanism of XN1 aggregation and potentially help develop strategies to inhibit XN1 aggregation. The flanking sequences surrounding the polyQ region can play a critical role in determining the structural rearrangement and aggregation mechanism of XN1. Few experiments have studied XN1 in its entirety, with all flanking regions. To obtain structural insights into the misfolding of XN1 toward amyloid aggregation, we perform molecular dynamics simulations on monomeric XN1 with full flanking regions, a variant missing the polyproline regions, which are hypothesized to prevent aggregation, and an isolated polyQ peptide (Qn). For each of these three constructs, we study glutamine repeat lengths of 23, 36, 40 and 47. We find that polyQ peptides have a positive correlation between their probability to form a β-rich misfolded state and their expansion length. We also find that the flanking regions of XN1 affect its probability to^x_page_count=28 form a β-rich state compared to the isolated polyQ. Particularly, the polyproline regions form polyproline type II helices and decrease the probability of the polyQ region to form a β-rich state. Additionally, by lengthening polyQ, the first N-terminal 17 residues are more likely to adopt a β-sheet conformation rather than an α-helix conformation. Therefore, our molecular dynamics study provides a structural insight of XN1 misfolding and elucidates the possible role of the flanking sequences in XN1 aggregation

Novel Feature for Catalytic Protein Residues Reflecting Interactions with Other Residues

Owing to their potential for systematic analysis, complex networks have been widely used in proteomics. Representing a protein structure as a topology network provides novel insight into understanding protein folding mechanisms, stability and function. Here, we develop a new feature to reveal correlations between residues using a protein structure network. In an original attempt to quantify the effects of several key residues on catalytic residues, a power function was used to model interactions between residues. The results indicate that focusing on a few residues is a feasible approach to identifying catalytic residues. The spatial environment surrounding a catalytic residue was analyzed in a layered manner. We present evidence that correlation between residues is related to their distance apart most environmental parameters of the outer layer make a smaller contribution to prediction and ii catalytic residues tend to be located near key positions in enzyme folds. Feature analysis revealed satisfactory performance for our features, which were combined with several conventional features in a prediction model for catalytic residues using a comprehensive data set from the Catalytic Site Atlas. Values of 88.6 for sensitivity and 88.4 for specificity were obtained by 10fold crossvalidation. These results suggest that these features reveal the mutual dependence of residues and are promising for further study of structurefunction relationship

Utilization of CT scanning associated with complex spine surgery

BACKGROUND: Due to the risk associated with exposure to ionizing radiation, there is an urgent need to identify areas of CT scanning overutilization. While increased use of diagnostic spinal imaging has been documented, no previous research has estimated the magnitude of follow-up imaging used to evaluate the postoperative spine. METHODS: This retrospective cohort study quantifies the association between spinal surgery and CT utilization. An insurance database (Humana, Inc.) with ≈ 19 million enrollees was employed, representing 8 consecutive years (2007–2014). Surgical and imaging procedures were captured by anatomic-specific CPT codes. Complex surgeries included all cervical, thoracic and lumbar instrumented spine fusions. Simple surgeries included discectomy and laminectomy. Imaging was restricted to CT and MRI. Postoperative imaging frequency extended to 5-years post-surgery. RESULTS: There were 140,660 complex spinal procedures and 39,943 discectomies and 49,889 laminectomies. MRI was the predominate preoperative imaging modality for all surgical procedures (median: 80%; range: 73–82%). Postoperatively, CT prevalence following complex procedures increased more than two-fold from 6 months (18%) to 5 years (≥40%), and patients having a postoperative CT averaged two scans. For simple procedures, the prevalence of postoperative CT scanning never exceeded 30%. CONCLUSIONS: CT scanning is used frequently for follow-up imaging evaluation following complex spine surgery. There is emerging evidence of an increased cancer risk due to ionizing radiation exposure with CT. In the setting of complex spine surgery, actions to mitigate this risk should be considered and include reducing nonessential scans, using the lowest possible radiation dose protocols, exerting greater selectivity in monitoring the developing fusion construct, and adopting non-ferromagnetic implant biomaterials that facilitate MRI postoperatively. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12891-017-1420-9) contains supplementary material, which is available to authorized users