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Early pregnancy loss (EPL) is a common event worldwide. Previous studies show that mitochondrial DNA (mtDNA) copy number (CN) is associated with semen parameters and preimplantation embryo viability, indicating the predictive potential of mtDNA CN for ongoing pregnancy outcomes. However, no relevant study has assessed the relationship between mtDNA CN and EPL. Thus, we aimed to determine whether mtDNA CN and mtDNA 4977-bp deletion rate (DR) in chorionic villous tissue are associated with EPL. Chorionic villous tissue total DNA was extracted from 75 EPL cases and 75 healthy controls. Chromosomal analysis was conducted using copy number variation (CNV) sequencing. The mtDNA CN and DR were measured in samples without pathogenic CNVs. The association between mtDNA CN or DR and EPL risk were estimated using logistic regression. The EPL group had a significantly different mtDNA CN (P 0.001) and DR (P = 0.005) compared to the control group. Both biomarkers were independent risk factors for EPL (CN odds ratio 1.71, 95% confidence interval 1.17 to 2.49, P = 0.005; DR odds ratio 1.07, 95% confidence interval 1.02 to 1.12, P = 0.006). These results suggest that higher mtDNA CN and DR levels are strongly associated with EPL and represent independent risk factors for EPL. Further studies validating these findings and exploring the underlying biological mechanisms are warranted.

Objective To study the effect of aging on ovarian circadian rhythm. Design Human and animal study. Setting University hospital and research laboratory. Patients/animals Human granulosa cells were obtained by follicular aspiration from women undergoing in vitro fertilization (IVF), and ovarian and liver tissues were obtained from female C57BL/6 mice. Intervention(s) None. Main outcome measure(s) Expression of circadian genes in young and older human granulosa cells and circadian rhythm in ovaries and livers of young and older mice. Result(s) All examined circadian clock genes in human granulosa cells showed a downward trend in expression with aging, and their mRNA expression levels were negatively correlated with age (P P Conclusion(s) Lower ovarian reserve in older women is partially due to ovarian circadian dysrhythmia as a result of aging.

Background Except for sperm parameters (sperm concentration, motility, and morphology), sperm mitochondria DNA copy number (mtDNA-CN), DNA fragmentation index (DFI), and reactive oxygen species (ROS) content are essential characteristics for sperm function. However, the roles of these measurements in embryo development and pregnancy outcomes are still unclear. Methods Semen samples of 402 participants were collected. Sperm parameters, including sperm morphology, concentration, and motility, were analyzed by a computer-assisted sperm analysis system. MtDNA-CN, DFI, and ROS levels were measured using remained sperms through quantitative polymerase chain reaction method, sperm chromatin structure assay and Reactive Oxygen Species Assay Kit, respectively. The assisted reproductive technology (ART) treatments, including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), were performed in 126 couples of these participants. Results In 402 semen samples, elevated mtDNA-CN and DFI were associated with poor seminal quality. In 126 couples conducted ART, only mtDNA-CN was negatively correlated with fertilization rate in ART cases. However, it was not significant after adjusting male age, female age, seminal quality, and ART strategy. With regard to pregnancy outcomes, none of sperm mtDNA-CN, ROS and DFI was associated with clinical pregnancy rate in 79 cases transferred embryos. Conclusions Increased mtDNA-CN and DFI in sperms jointly contributed to poor seminal quality. However, none of sperm mtDNA-CN, ROS/MS and DFI were associated with clinical outcomes in ART.

Substantial evidence now suggests an association between the FMR1 genotype and female fertility. The aim of this study was to determine whether a high normal FMR1 allele (35-54 repeats) affects in vitro fertilization (IVF) outcomes in Chinese women. A total of 120 women with 210 IVF cycles were retrospectively recruited in this study. The patients were divided into two groups based on the FMR1 repeat lengths at allele 2 (normal repeat group:35 repeats; high repeat group: 35-54 repeats). The observed primary outcomes were the clinical pregnancy rate and live birth rate. No associations were observed between the high normal FMR1 allele and lower clinical pregnancy rate or live birth rate after adjusting for maternal age, education, work status, duration of infertility and number of embryos transferred (aOR 0.633, 95% CI 0.249-1.601, p = 0.337; aOR 0.325, 95% CI 0.094-1.118, p = 0.075; respectively). However, after additionally adjusting for anti-Müllerian hormone (AMH) level, there was a weak but significant association between high normal sized CGG repeats and a lower live birth rate (aOR 0.218, 95% CI 0.057-0.836, p = 0.026). The rate of available embryos showed a decreasing trend in patients with a high normal FMR1 allele, although the difference was not statistically significant after adjusting for maternal age, education, work status, duration of infertility and AMH level (aOR 0.905, 95% CI 0.810-1.011, p = 0.078). Furthermore, the number of CGG repeats in either allele was not associated with the live birth rate after adjusting for all confounding factors (aOR 0.832, 95% CI 0.677-1.023, p = 0.081; aOR 0.865, 95% CI 0.651-1.148, p = 0.315; respectively). In addition, no significant differences were found in the rates of good-quality embryos (p = 0.263), miscarriage (p = 0.861) or cycle cancellation (p = 0.295) between the groups. Taken together, in the Chinese population, individuals with high normal sized CGG repeats on the FMR1 gene have a higher risk of reduced live birth rates in childbearing age. Therefore, we recommend enhanced screening for fragile X syndrome in women of childbearing age in China. This study also suggests that the association between the FMR1 genotype and fertility in Chinese women merits further research.

Background: Preimplantation genetic testing for aneuploidies (PGT-A) is widely used in women of advanced maternal age (AMA). However, the effectiveness remains controversial. Method: We conducted a comprehensive literature review comparing outcomes of IVF with or without PGT-A in women of AMA in PubMed, Embase, and the Cochrane Central Register of Controlled Trials in January 2021. All included trials met the criteria that constituted a randomized controlled trial for PGT-A involving women of AMA (≥35 years). Reviews, conference abstracts, and observational studies were excluded. The primary outcome was the live birth rate in included random control trials (RCTs). Results: Nine randomized controlled trials met our inclusion criteria. For techniques of genetic analysis, three trials (270 events) performed with comprehensive chromosomal screening showed that the live birth rate was significantly higher in the women randomized to IVF/ICSI with PGT-A (RR = 1.30, 95% CI 1.03–1.65), which was not observed in six trials used with FISH as well as all nine trials. For different stages of embryo biopsy, only the subgroup of blastocyst biopsy showed a higher live birth rate in women with PGT-A (RR = 1.36, 95% CI 1.04–1.79). Conclusion: The application of comprehensive chromosome screening showed a beneficial effect of PGT-A in women of AMA compared with FISH. Moreover, blastocyst biopsy seemed to be associated with a better outcome than polar body biopsy and cleavage-stage biopsy.

Increasing evidence demonstrates the crucial regulatory functions of circular RNAs in different cancer types. The major aim of the current study was to establish functions of circPIP5K1A during ovarian cancer. Our results showed an increased expression of circPIP5K1A in both ovarian cancers and cell lines, which was associated with poor prognosis. In functional analyses, downregulation of circPIP5K1A suppressed ovarian cancer cell migration, proliferation, and invasion in vitro. The miR-661 was indicated as a target of circPIP5K1A and insulin-like growth factor-binding protein 5 (IGFBP5) as a target of miR-661. circPIP5K1A silencing triggered downregulation of IGFBP5 through inducing an increase in miR-66 levels, as determined by the luciferase reporter assay. Data from cell counting kit-8, colony formation, wound healing, and Transwell assays showed that overexpression of IGFBP5 effectively reversed the circPIP5K1A depletion effects. The results collectively indicated that circPIP5K1A contributed to ovarian cancer progression via targeting the miR-661/IGFBP5 axis, supporting its utility as a candidate target for therapy of the disease.

The number of children born after assisted reproductive technology (ART) is accumulating rapidly, and the health problems of the children are extensively concerned. This study aims to evaluate whether ART procedures alter behaviours in male offspring. Mouse models were utilized to establish three groups of offspring conceived by natural conception (NC), in vitro fertilization and embryo transfer (IVF-ET), and frozen-thawed embryo transfer (IVF-FET), respectively. A battery of behaviour experiments for evaluating anxiety and depression levels, including the open field test (OFT), elevated plus maze (EPM) test, light/dark transition test (L/DTT), tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT) was carried out. Aged (18 months old), but not young (3 months old), male offspring in the IVF-ET and IVF-FET groups, compared with those in the NC group, exhibited increased anxiety and depression-like behaviours. The protein expression levels of three neurotrophins in PFC or hippocampus in aged male offspring from the IVF-ET and IVF-FET groups reduced at different extent, in comparison to NC group. RNA sequencing (RNA-Seq) was performed in the hippocampus of 18 months old offspring to further explore the gene expression profile changes in the three groups. KEGG analyses revealed the coexisted pathways, such as PI3K-Akt signalling pathway, which potentially reflected the similarity and divergence in anxiety and depression between the offspring conceived by IVF-ET and IVF-FET. Our research suggested the adverse effects of advanced age on the psychological health of children born after ART should be highlighted in the future.

Background PCOS is a common worldwide endocrine disorder. We aimed to examine the associations of two mtDNA biomarkers in the peripheral blood, mtDNA CN and mtDNA4977 DR, with PCOS in a clinical setting.Methods We performed a study involving 263 women with PCOS and 326 age-matched controls between January 2016 and December 2018. The mtDNA CN and mtDNA4977 DR were measured via a multiplex probe-based qPCR. The associations of mtDNA CN and mtDNA DR with the risk of PCOS were estimated by logistic regression.Results In the analysis between mtDNA biomarkers and PCOS, the mtDNA CN (P = 0.003) and mtDNA4977 DR (P < 0.001) levels in PCOS patients were significantly higher than those in the controls. After adjusting for BMI, LH/FSH, and T, only higher mtDNA4977 DR was associated with PCOS (odds ratio 1.053, 95% confidence interval 1.024 to 1.083, P < 0.001). The linear dose-response trends of mtDNA4977 DR were also supported by the quartile analyses.Conclusions Multivariable models suggest that mtDNA4977 DR levels are strongly associated with PCOS and represent an independent risk factor for PCOS. Future investigation of the utility of mtDNA as a biomarker for PCOS is warranted.

Kabuki syndrome (KS) is a rare congenital mental retardation condition characterized by facial dysmorphia, visceral and skeletal malformations, and developmental delay. The integrated phenotype and genotype-based prioritization is critical for diagnoses of genetic diseases. In this study, a Chinese woman, presenting with characteristic facial features of KS, came for pre-pregnancy consultation. We aimed to clarify the diagnosis and provide pre-pregnancy genetic counseling. Facial dysmorphology analysis and next-generation sequencing-based multigene panel approach were used to identify candidate syndromes and causative variants, respectively. The candidate variant was verified by Sanger sequencing. We identified a novel de novo KDM6A pathogenic variant (c.3521G>A) in the woman, which was in line with the Face2Gene analysis result. Peripheral blood RNA assay showed that the variant transcript underwent the nonsense-mediated mRNA decay and led to subsequent haploinsufficiency of KDM6A. Our study provides the genetic diagnosis method for KS type 2 and identifies the first KDM6A point variant in Chinese patient. Key words: facial analysis; Kabuki syndrome type 2; RNA assay; targeted sequencing

To investigate the effect of basal hormone levels including follicle stimulating hormone (FSH) and estradiol (E2) and age on the pregnancy outcomes in women undergoing in vitro fertilization and embryo transfer (IVF-ET), we designed a retrospective cohort analysis and collected information of patients undergoing IVF between January 2014 and April 2017. We found that young women had much better pregnancy outcomes than older women regardless of the hormone levels. The pregnancy outcomes declined in young women with high basal E2, even though they had normal FSH. Older women with higher FSH had a worse outcome of pregnancy, especially with increased E2 level. The results suggest that a combination of FSH, E2 and age could effectively predict the pregnancy outcome for women undergoing IVF-ET, and we should encourage infertile women with diminished ovarian reserve, especially young infertile women, to try the assisted reproduction as early as possible. After 40-yearold, the cost-benefit ratio should be considered according to the ovarian function.

Endometriosis is a condition which involves the presence of uterine stroma and glands outside of the uterine cavity and represents one of the most prevalent disorders of the female reproductive tract. The key symptom of endometriosis is pain, including dysmenorrhea, deep dyspareunia, and chronic pelvic pain. As such, endometriosis has significant economic consequences within the healthcare system and can influence the daily quality of life in affected patients. However, the pathophysiology of this disease and the mechanisms in which this condition generates pain are very unclear. This study, involving 30 women with endometriosis and 28 controls without endometriosis, aimed to investigate relative levels of estrogen receptor alpha (ERα) splice variants in the endometrium of women with and without endometriosis and investigate potential links to the severity of pain. Wild type (wt)-ERα was dominantly expressed in human endometrium while the expression of ERα-del.4, ERα-del.7, and ERα-del.3,4 was significantly reduced in endometriosis patients compared with healthy patients (p < 0.05). Furthermore, the relative ratios of wtERα:ERα-del.4, and wtERα:ERα-del.3,4 were associated with the severity of pain in endometriosis patients (p < 0.05). Consequently, analyzing differences in the relative levels of four types of ERα splice variant in the endometrium of patients with endometriosis may help in the development of endometriosis-targeted treatment and the development of appropriate therapies.

Hydrothermal liquefaction of rice husk was investigated in a 10-ml stainless steel micro-reactor. Without catalyst, the bio-crude yields are in the range of 11.8–23.8 wt%, depending on temperature, reaction time, and water/rice husk mass ratio. With catalysts, the bio-crude yields are obviously increased and the highest bio-crude yield of 32.5 wt% is obtained with La2O3 catalyst at 300°C for 10 min and a water/rice husk mass ratio of 5. The elemental analysis shows that the oxygen contents of bio-crude are significantly decreased by La2O3 and Dy2O3 catalysts, respectively. The highest higher heating value (31.78 MJ/kg) of bio-crude is obtained with La2O3 catalyst, which is obviously higher than that of the raw material (16.19 MJ/kg). Energy balance results show that La2O3 and Dy2O3 catalysts have a beneficial effect on energy recovery and energy consumption ratio. Gas chromatography-mass spectrometry and Fourier transform-infrared analysis show that La2O3 and Dy2O3 decrease the contents of phenols and aci...

In this paper, it is proved that any system of L-simple (L≥1) of nonlinear partial differential equations is unstable.

The distributed simulation system interoperation can be divided into six levels. Interactive data encryption can be completed in each level, lead to six encryption strategies: data field encryption, data package encryption, program module encryption, simulation application encryption, simulation node encryption, and simulation system encryption. There are four basic Encryption/decryption realization modes: serial modes with software or hardware realization, parallel modes based on embedded processor or FPGA/ASIC system. Large and Complex distributed simulation system may employ one or several encryption strategies and realization modes.

Adenosine monophosphate-activated protein kinase (AMPK) acts as a major sensor of cellular energy status in cancers and is critically involved in cell sensitivity to anticancer agents. Here, we showed that AMPK was inactivated in lymphoma and related to the upregulation of the mammalian target of rapamycin (mTOR) pathway. AMPK activator metformin potentially inhibited the growth of B- and T-lymphoma cells. Strong antitumor effect was also observed on primary lymphoma cells while sparing normal hematopoiesis ex vivo. Metformin-induced AMPK activation was associated with the inhibition of the mTOR signaling without involving AKT. Moreover, lymphoma cell response to the chemotherapeutic agent doxorubicin and mTOR inhibitor temsirolimus was significantly enhanced when co-treated with metformin. Pharmacologic and molecular knock-down of AMPK attenuated metformin-mediated lymphoma cell growth inhibition and drug sensitization. In vivo, metformin induced AMPK activation, mTOR inhibition and remarkably blocked tumor growth in murine lymphoma xenografts. Of note, metformin was equally effective when given orally. Combined treatment of oral metformin with doxorubicin or temsirolimus triggered lymphoma cell autophagy and functioned more efficiently than either agent alone. Taken together, these data provided first evidence for the growth-inhibitory and drug-sensitizing effect of metformin on lymphoma. Selectively targeting mTOR pathway through AMPK activation may thus represent a promising new strategy to improve treatment of lymphoma patients.