[Resting-state functional magnetic resonance imaging analysis of modified electroconvulsive therapy in the treatment of major depressive disorder].

Objective: To explore the effect of modified electroconvulsive therapy (MECT) on resting-state functional connectivity (RSFC) in patients with major depressive disorder (MDD). Methods: Patients with MDD from Anhui Mental Health Center from October 2017 to May 2019 were included. Using bilateral nucleus accumbens (NAcc) as seed points, changes of RSFC were investigated before and after MECT through resting-state functional magnetic imaging (fMRI). Antidepressant effects were measured by 17 items of Hamilton Depressive Rating Scale (HDRS-17). Correlation analysis was performed between changed HRSD-17 scores and changes of functional connectivity. Results: A total of 40 MDD patients (10 males and 30 females), aged (38±11) years, who received MECT were included in the study. After MECT, patients showed increased RSFC in the right NAcc (rNAcc) and superior frontal gyrus (P<0.001), right supramarginal gyrus (P<0.001), right angular gyrus (rAG) (P= 0.017), right inferior parietal lobule (P= 0.017), left superior frontal gyrus (LSFG) (P<0.001), left middle temporal gyrus (P=0.017) and left angular gyrus (LAG) (P=0.012), respectively. The RSFC changes of rNAcc-LSFG (r=-0.454, P = 0.003), rNAcc-rAG (r=-0.437, P=0.005) and rNAcc-lAG (r=-0.383, P=0.015) were negatively correlated with the changes of HRSD-17 scores. Conclusions: MECT may alleviate major depression by regulating the functional connectivity between the rNAcc and bilateral angular gyrus and left superior frontal gyrus.

Subtype-specific inherited predisposition to pemphigus in the Chinese population.

BACKGROUND: Pemphigus is a group of rare life-threatening mucocutaneous autoimmune diseases, presenting mainly as two subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Inherited predispositions to pemphigus have long been speculated but they remain poorly understood. OBJECTIVES: To identify common and specific nongenetic and genetic factors associated with pemphigus and its subtypes in the Chinese population. METHODS: A genome-wide association study (GWAS) was performed in 496 unrelated patients with pemphigus (including 365 with PV and 104 with PF) and 1105 controls without pemphigus. RESULTS: A sex preference was observed only in PV (57·5% female) and not in PF (47·1% female). For male patients only, the mean age at diagnosis was significantly lower for PV than for PF (P < 0·001). The strongest associated single-nucleotide polymorphisms are in the human leucocyte antigen (HLA) region: rs70993900 (PV; P = 1·5 × 10-45 ) and rs9469220 (PF; P = 1·1 × 10-8 ). HLA-DQB1*05:03 ranks at the top (P = 4·7 × 10-40 ; odds ratio 12·4) in both subtypes, with significantly different risk allele frequency (RAFPV = 34·2% vs. RAFPF = 18·8% vs. RAFcontrol = 4·4%), whereas HLA-DRB1*14:01 and HLA-DRB1*04:06 are PV specific. HLA-DQB1*03:03 and HLA-DQB1*03:02 show significant subtype specificity in opposite directions. All of these associations were validated in the replication series with 147 cases of pemphigus and 604 controls. Multiple novel non-HLA susceptibility loci were also identified in the GWAS. CONCLUSIONS: This study represents the largest GWAS on pemphigus in the Chinese population published to date, and has allowed us to identify HLA haplotypes significantly shared between or specific to the two main subtypes of pemphigus.

QM/MM study of the mechanism of enzymatic limonene 1,2-epoxide hydrolysis.

Limonene 1,2-epoxide hydrolase (LEH) is completely different from those of classic epoxide hydrolases (EHs) which catalyze the hydrolysis of epoxides to vicinal diols. A novel concerted general acid catalysis step involving the Asp101-Arg99-Asp132 triad is proposed to play an important role in the mechanism. Combined quantum-mechanical/molecular-mechanical (QM/MM) calculations gave activation barriers of 16.9 and 25.1kcal/mol at the B3LYP/6-31G(d,p)//CHARMM level for nucleophilic attack on the more and less substituted epoxide carbons, respectively. Furthermore, the important roles of residues Arg99, Tyr53 and Asn55 on mutated LEH were evaluated by QM/MM-scanned energy mapping. These results may provide an explanation for site-directed mutagenesis.

QM/MM studies on the catalytic mechanism of phenylethanolamine N-methyltransferase.

Epinephrine is a naturally occurring adrenomedullary hormone that transduces environmental stressors into cardiovascular actions. As the only route in the catecholamine biosynthetic pathway, Phenylethanolamine N-methyltransferase (PNMT) catalyzes the synthesis of epinephrine. To elucidate the detailed mechanism of enzymatic catalysis of PNMT, combined quantum-mechanical/molecular-mechanical (QM/MM) calculations were performed. The calculation results reveal that this catalysis contains three elementary steps: the deprotonation of protonated norepinphrine, the methyl transferring step and deprotonation of the methylated norepinphrine. The methyl transferring step was proved to be the rate-determining step undergoing a SN2 mechanism with an energy barrier of 16.4kcal/mol. During the whole catalysis, two glutamic acids Glu185 and Glu219 were proved to be loaded with different effects according to the calculations results of the mutants. These calculation results can be used to explain the experimental observations and make a good complementarity for the previous QM study.

Receptor-based QSAR study for a series of 3,3-disubstituted-5-aryl oxindoles and 6-aryl benzimidazol-2-ones derivatives as progesterone receptor inhibitors.

Receptor-based comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of 54 progesterone receptor (PR) inhibitors. The established CoMFA model from the training set gives statistically significant results with the cross-validated q (2) of 0.534 and non-cross-validated [Formula: see text] of 0.947. The best CoMSIA model was derived by the combination of steric field and hydrophobic field with a q (2) of 0.615 and [Formula: see text] of 0.954. A test set of 18 compounds was used to validate the predictive ability of the two models. The predicted correlation coefficients [Formula: see text] are 0.681 and 0.677 for CoMFA and CoMSIA models, respectively. Based on the CoMFA maps, the key structural characters of progesterone receptor inhibitors are identified. Moreover, the binding modes of oxindoles and benzimidazol-2-ones are also given by the quantum mechanical/molecular mechanical (QM/MM) calculations. This may provide useful information for drug design.