3D Structure Prediction of TAS2R38 Bitter Receptors Bound to Agonists Phenylthiocarbamide (PTC) and 6-n-Propylthiouracil (PROP)

The G protein-coupled receptor (GPCR) TAS2R38 is a bitter taste receptor that can respond to bitter compounds such as phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). This receptor was chosen because its four haplotypes (based on three residue site polymorphism) hTAS2R38_PAV, hTAS2R38_AVI, hTAS2R38_AAI, and hTAS2R38_PVV are known to have dramatically different responses to PTC and PROP. We aimed to identify the protein–ligand interaction features that determine whether the bitter taste signal from this receptor is sent to the cortex. To do this we predicted the 3D structures of the TAS2R38 bitter taste receptor using our new BiHelix and SuperBiHelix Monte Carlo methods (No experimental determinations of the 3D structure have been reported for any taste receptors.). We find that residue 262 (2nd position in the polymorphism) is involved in the interhelical hydrogen bond network stabilizing the GPCR structure in tasters (hTAS2R38_PAV, hTAS2R38_AAI, and hTAS2R38_PVV), while it is not in the nontaster (hTAS2R38_AVI). This suggests that the hydrogen bond interactions between TM3 and TM6 or between TM5 and TM6 may play a role in activating this GPCR. To further validate these structures, we used the DarwinDock method to predict the binding sites and 3D structures for PTC and PROP bound to hTAS2R38_PAV, hTAS2R38_AVI, hTAS2R38_AAI, and hTAS2R38_PVV, respectively. Our results show that PTC and PROP can form H-bonds with the backbone of residue 262 in the tasters (hTAS2R38_PAV, hTAS2R38_AAI, and hTAS2R38_PVV) but not in the nontaster (hTAS2R38_AVI). Thus it appears that the hydrogen bond interaction between TM3 and TM6 may activate the receptor to pass the ligand binding signal to intracellular processes and that the H-bond between agonists and residue 262 in tasters is involved in the bitter tasting. This is in agreement with experimental observations, providing validation of the predicted ligand-protein complexes and also a potential activation mechanism for the TAS2R38 receptor

Records of CMAP from Control Group (A), Transection Group (B) and Bridge Group (C) rabbit showing both distal latency (dLAT) and amplitude 20 weeks after surgery.

<p>The stimulator electrode was place on the intact VN in Control Group, the proximal end of the transected VN in the Transection Group, and the VN rostral to the anastomosed site in the Bridge Group. <b>D</b>, Comparison of dLAT. <b>E</b>, Comparison of amplitude. The error bars indicate standard deviation (SD). * p<0.001 vs. control group; # p<0.001 vs. Transected Group; ## p<0.05 vs. Transected Group</p

Is Anterior Cervical Discectomy and Fusion Superior to Corpectomy and Fusion for Treatment of Multilevel Cervical Spondylotic Myelopathy? A Systemic Review and Meta-Analysis

<div><p>Objective</p><p>Both anterior cervical discectomy with fusion (ACDF) and anterior cervical corpectomy with fusion (ACCF) are used to treat cervical spondylotic myelopathy (CSM), however, there is considerable controversy as to whether ACDF or ACCF is the optimal treatment for this condition. To compare the clinical outcomes, complications, and surgical trauma between ACDF and ACCF for the treatment of CSM, we conducted a meta-analysis.</p><p>Methods</p><p>We conducted a comprehensive search in MEDLINE, EMBASE, PubMed, Google Scholar and Cochrane databases, searching for relevant controlled trials up to July 2013 that compared ACDF and ACCF for the treatment of CSM. We performed title and abstract screening and full-text screening independently and in duplicate. A random effects model was used for heterogeneous data; otherwise, a fixed effect model was used to pool data, using mean difference (MD) for continuous outcomes and odds ratio (OR) for dichotomous outcomes.</p><p>Results</p><p>Of 2157 citations examined, 15 articles representing 1372 participants were eligible. Overall, there were significant differences between the two treatment groups for hospital stay (M = −5.60, 95% CI = −7.09 to −4.11), blood loss (MD = −151.35, 95% CI = −253.22 to −49.48), complications (OR = 0.50, 95% CI = 0.35 to 0.73) and increased lordosis of C2–C7 (MD = 3.70, 95% CI = 0.96 to 6.45) and fusion segments angles (MD = 3.38, 95% CI = 2.54 to 4.22). However, there were no significant differences in the operation time (MD = −9.34, 95% CI = −42.99 to 24.31), JOA (MD = 0.24, 95% CI = −0.10 to 0.57), VAS (MD = −0.06, 95% CI = −0.81 to 0.70), NDI (MD = −1.37, 95% CI  = −3.17 to 0.43), Odom criteria (OR = 0.88, 95% CI = 0.60 to 1.30) or fusion rate (OR = 1.17, 95% CI = 0.34 to 4.11).</p><p>Conclusions</p><p>Based on this meta-analysis, although complications and increased lordosis are significantly better in the ACDF group, there is no strong evidence to support the routine use of ACDF over ACCF in CSM.</p></div

Schematic showing the surgical preparations in the three groups.

<p><b>A.</b> Control Group: Both VN and PN were intact. <b>B.</b> Transection Group: Both VN and PN were transected. <b>C.</b> Bridge group: The proximal end of VN was anastomosed to the distal end of the PN.</p

Additional file 1: Table S1. of In silico region of difference (RD) analysis of Mycobacterium tuberculosis complex from sequence reads using RD-Analyzer

Informative RD for MTC analysis and its characteristics. (XLS 25 kb