Genetic Polymorphisms of the TYMS Gene Are Not Associated with Congenital Cardiac Septal Defects in a Han Chinese Population

Background: Clinical research indicates that periconceptional administration of folic acid can reduce the occurrence of congenital cardiac septal defects (CCSDs). The vital roles of folate exhibits in three ways: the unique methyl donor for DNA expression regulation, the de novo biosynthesis of purine and pyrimidine for DNA construction, and the serum homocysteine removal. Thymidylate synthase (TYMS) is the solo catalysis enzyme for the de novo synthesis of dTMP, which is the essential precursor of DNA biosynthesis and repair process. To examine the role of TYMS in Congenital Cardiac Septal Defects (CCSDs) risk, we investigated whether genetic polymorphisms in the TYMS gene associated with the CCSDs in a Han Chinese population. Method: Polymorphisms in the noncoding region of TYMS were identified via direct sequencing in 32 unrelated individuals composed of half CCSDs and half control subjects. Nine SNPs and two insertion/deletion polymorphisms were genotyped from two independent case-control studies involving a total of 529 CCSDs patients and 876 healthy control participants. The associations were examined by both single polymorphism and haplotype tests using logistic regression. Result: We found that TYMS polymorphisms were not related to the altered CCSDs risk, and even to the changed risk of VSDs subgroup, when tested in both studied groups separately or in combination. In the haplotype analysis, there were no haplotypes significantly associated with risks for CCSDs either. Conclusion: Our results show no association between common genetic polymorphisms of the regulatory region of th

Trachoma prevalence in rural primary school children, Gansu Province

AIM: To make a survey on people suffering trachoma in Gansu province, and to provide evidence for developing trachoma control and prevention therapy.METHODS: We chose the zone on the basis of relative information. Provincial Office of Blindness Prevention carried out the survey in 3 counties including Tange Township of Wushan, Xiqu Township of Minqin and Hulinjia Township of Jishishan from October 14, 2013 to November 23, 2013. One hundred and fifty primary school students were selected, including 72 boys and 78 girls aging from 5a to 10a with the average age of 7.5y. The targeted students received the fast trachoma assessment by the adoption of simplified trachoma classification system which was recommended by the World Health Organization. RESULTS: No case of active trachoma, trachomatous trichiasis and corneal disease were examined among 150 students. CONCLUSION: The rate of trachoma is low in Gansu province. But we still cannot get the conclusion that there is no epidemic of trachoma in Gansu. And we need to further expand the survey scope to correctly assess the trachoma case and to provide reliable evidence for trachoma prevention and control

PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations

The anti-PD-L1 monoclonal antibody (mAb) targeting PD-1/PD-L1 immune checkpoint has achieved outstanding results in clinical application and has become one of the most popular anti-cancer drugs. The mechanism of molecular recognition and inhibition of PD-L1 mAbs is not yet clear, which hinders the subsequent antibody design and modification. In this work, the trajectories of PD-1/PD-L1 and nanobody/PD-L1 complexes were obtained via comparative molecular dynamics simulations. Then, a series of physicochemical parameters including hydrogen bond, dihedral angle distribution, pKa value and binding free energy, and so forth, were all comparatively analyzed to investigate the recognition difference between PD-L1 and PD-1 and nanobody. Both LR113 (the amino acid residues in PD-L1 are represented by the lower left sign of L) and LR125 residues of PD-L1 undergo significant conformational change after association with mAbs, which dominates a strong electrostatic interaction. Solvation effect analysis revealed that solvent-water enhanced molecular recognition between PD-L1 and nanobody. By combining the analyses of the time-dependent root mean squared fluctuation (RMSF), free energy landscape, clustering and energy decomposition, the potential inhibition mechanism was proposed that the nanobody competitively and specifically bound to the β-sheet groups of PD-L1, reduced the PD-L1’s flexibility and finally blocked the formation of PD-1/PD-L1 complex. Based on the simulation results, site-directed mutagenesis of ND99 (the amino acid residues in Nano are displayed by the lower left sign of N) and NQ116 in the nanobody may be beneficial for improving antibody activity. This work offers some structural guidance for the design and modification of anticancer mAbs based on the structure of the PD-1/PD-L1 complex

<i>TYMS</i> haplotype analysis of combined group.

<p>*Adjusted by age and gender;</p>$<p>P value for difference in haplotypes distributions between case and control subjects;</p>#<p>The sum of other rare haplotypes.</p

Demographic characteristics in CCSDs cases and controls.

<p>*All comparisons by 2-side χ2 test. Date shown in the table is means (±SEM).</p

The allelic and genotype frequency of the <i>TYMS</i> polymorphisms in CCSD patients and controls.

<p>*MAF, minor allele frequency from HapMap database for CHB population.</p>$<p>P value for difference in genotypes distributions between case and control subjects.</p>&<p>P value for Hardy-Weinberg equilibrium test in the control subjects. Additional detailed genotype frequencies is present in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031644#pone.0031644.s002" target="_blank">Table S2</a>.</p>#<p>Not available in dbSNP database.</p