Purpose: This study aims to identify genetic causes of female infertility associated with recurrent failure of assisted reproductive technology (ART) characterized by embryonic developmental arrest. Methods: We recruited infertile patients from two consanguineous families from the Reproductive Medicine Center of Guizhou Provincial People’s Hospital. Peripheral blood was collected for genomic DNA extraction. Two affected individuals and their family members were performed with whole-exome sequencing and Sanger validation in order to identify possible causative genes. For further analyzing the effect of splicing mutation on mRNA integrity in vivo, TLE6 cDNA from the peripheral blood lymphocyte of the affected individual was sequenced. In addition, the possible impact of the pathogenic mutation on the structure and function of the protein were also assessed. Results: Two novel homozygous mutations in the peptidylarginine deiminase type VI (PADI6) and the transducin-like enhancer of split 6 (TLE6) genes were identified in the two families. One patient carried the frameshift deletion mutation c.831_832del:p.S278Pfs^*59 of the PADI6 gene and the other patient carried the splicing mutation c.1245-2 A>G of the TLE6 gene. The analysis of the mRNA from the proband’s peripheral blood leukocytes confirmed aberrant splicing. Conclusions: Our findings expand the mutational spectrum of PADI6 and TLE6 associated with embryonic developmental arrest and deepen our understanding of the genetic causes of infertility with recurrent ART failure.

Alterations in messenger RNAs (mRNAs) of protein-coding genes can influence the malignant behaviors of acute lymphoblastic leukemia (ALL) cells. According to the prediction from The Cancer Genome Atlas (TCGA) database, we discovered that glutathione peroxidase 1 (GPX1) was up-regulated in acute myeloid leukemia (LAML) tissues, which pushed us to explore the feasible role and its related modulatory mechanism of GPX1 in ALL. In this research, we first proved the high expression of GPX1 in ALL cells compared with normal cells. Functional assays further revealed that the proliferation was obstructed and the apoptosis was facilitated in ALL cells with silenced GPX1. Then, both miR-491-5p and miR-214-3p that were down-regulated in ALL cells were affirmed to target GPX1. Subsequently, VPS9D1 antisense RNA 1 (VPS9D1-AS1) was recognized as the upstream regulator of miR-491-5p-miR-214-3p/GPX1 axis in a competing endogenous RNA (ceRNA) model. Importantly, we proved that VPS9D1-AS1 served as a tumor promoter in ALL through elevating GPX1. In conclusion, VPS9D1-AS1 contributed to ALL cell proliferation through miR-491-5p-miR-214-3p/GPX1 axis, hinting an optional choice for the treatment of ALL.

Ultrasound strain imaging has been proposed to quantitatively assess myocardial contractility. Cross-correlation- based 2-D speckle tracking (ST) and auto-correlation-based tissue Doppler imaging (TDI) [often called Doppler tissue imaging (DTI)] are competitive ultrasound techniques for this application. Compared with 2-D ST, TDI, as a 1-D method, is sensitive to beam angle and suffers from low strain signal-to-noise ratio because a high pulse repetition frequency is required to avoid aliasing in velocity estimation. In addition, ST and TDI are fundamentally different in the way that physical parameters such as the mechanical strain are derived, resulting in different estimation accuracy and interpretation. In this study, we directly compared the accuracy of TDI and 2-D ST estimates of instantaneous axial normal strain and accumulated axial normal strain using a simulated heart. We then used an isolated rabbit heart model of acute ischemia produced by left descending anterior artery ligation to evaluate the performance of the two methods in detecting abnormal motion. Results showed that instantaneous axial normal strains derived using TDI (0.36% error) were less accurate with larger variance than those derived from 2-D ST (0.08% error) given the same spatial resolution. In addition to poorer accuracy, accumulated axial normal strain estimates derived using TDI suffered from bias, because the accumulation method for TDI cannot trace along the actual tissue displacement path. Finally, we demonstrated the advantage 2-D ST has over TDI to reduce dependency on beam angle for lesion detection by estimating strains based on the principal stretches and their corresponding principal axes.