Dynamic and distinct histone modifications facilitate human trophoblast lineage differentiation.

The placenta serves as an essential organ for fetal growth throughout pregnancy. Histone modification is a crucial regulatory mechanism involved in numerous biological processes and development. Nevertheless, there remains a significant gap in our understanding regarding the epigenetic regulations that influence trophoblast lineage differentiation, a fundamental aspect of placental development. Here, through comprehensive mapping of H3K4me3, H3K27me3, H3K9me3, and H3K27ac loci during the differentiation of trophoblast stem cells (TSCs) into syncytiotrophoblasts (STs) and extravillous trophoblasts (EVTs), we reveal dynamic reconfiguration in H3K4me3 and H3K27ac patterns that establish an epigenetic landscape conducive to proper trophoblast lineage differentiation. We observe that broad H3K4me3 domains are associated with trophoblast lineage-specific gene expression. Unlike embryonic stem cells, TSCs lack robust bivalent domains. Notably, the repression of ST- and EVT-active genes in TSCs is primarily attributed to the weak H3K4me3 signal rather than bivalent domains. We also unveil the inactivation of TSC enhancers precedes the activation of ST enhancers during ST formation. Our results provide a comprehensive global map of diverse histone modifications, elucidating the dynamic histone modifications during trophoblast lineage differentiation.

Mechanistic actions of long non-coding RNA MALAT1 within the ovary and at the feto-maternal interface.

Long non-coding RNAs (LncRNAs) are being unveiled as crucial regulators of several biological processes and pathways. Among the lncRNAs is metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), which is also known as nuclear enriched abundant transcript 2 (NEAT2). MALAT1 is highly conserved in mammals, and controls cellular processes such as proliferation, migration, invasion, angiogenesis, and apoptosis in both physiological and pathological conditions. Roles of MALAT1 in the female reproductive system are gradually getting explored. Within the ovarian micro-environment, the physiological expression of MALAT1 potentially modulates folliculogenesis while its upregulation promotes the metastasis of epithelial ovarian cancers. Interestingly, women with polycystic ovary syndrome have been shown to exhibit aberrant ovarian expression of MALAT1 and this is believed to contribute to the development of the disease. At the feto-maternal interface, MALAT1 potentially promotes trophoblast development. While its placental downregulation is linked to the pathogenesis of preeclampsia, its placental upregulation is associated with placenta increta and placenta percreta. Hence, abnormal expression of MALAT1 is a candidate molecular biomarker and therapeutic target for the treatment of these obstetric and gynecologic anomalies. To enhance a quick uncovering and detailed characterization of the mechanistic actions of MALAT1 in the female reproductive system, we have highlighted some knowledge deficits and have recommended ideal experimental models to be employed in prospective investigations.

Long noncoding RNA H19 in ovarian biology and placenta development.

As the first long noncoding RNA to be discovered, H19 has gained substantial attention as a key regulator of several biological processes and its roles in female reproductive biology are gradually getting revealed. Herein, we have summarized the current evidence regarding H19 expression pattern and involvement in the developmental and pathological processes associated with the ovary and the placenta. The findings indicate that within the ovaries, H19 is expressed in the antral and cystic atretic follicles as well as in the corpora lutea but absent in the primordial, primary, and secondary follicles. Its normal expression promotes the maturation of antral follicles and prevents their premature selection for the ovulatory journey while its aberrant induction promotes polycystic ovary syndrome development and ovarian cancer metastasis. In the placenta, H19 is highly expressed in the cytotrophoblasts and extravillous trophoblasts but weakly expressed in the syncytiotrophoblast layer and potentially controls trophoblast cell fate decisions during placenta development. Abnormal expression of H19 is observed in the placental villi of pregnancies affected by pre-eclampsia and fetal growth restriction. Therefore, dysregulated H19 is a candidate biomarker and therapeutic target for the mitigation of ovarian and placenta-associated diseases.

Long non-coding RNAs: a summary of their roles in placenta development and pathology†.

Long non-coding RNAs are cellular transcripts that have ˃200 nucleotides in length and do not code for proteins. Due to their low expression levels, long non-coding RNAs were previously considered as mere transcriptional noise. However, current evidence indicates that they regulate a myriad of biological processes such as cell proliferation, invasion, and apoptosis. Hence, their expression patterns are crucial indicators of the physiological or pathological states of cells, tissues, and organs. The utilization of long non-coding RNAs as biomarkers and therapeutic targets for the clinical management of several diseases have been suggested. Gradually, long non-coding RNAs are gaining a substantial attention in the field of feto-maternal medicine. After embryo implantation, the interactions between the trophoblast cells from the embryo and the uterus of the mother facilitate placenta development and pregnancy progression. These processes are tightly regulated, and their impairments result in pregnancy pathologies such as miscarriage and preeclampsia. Accumulating evidence implicates long non-coding RNAs in these processes. Herein, we have summarized the roles of several long non-coding RNAs in human placenta development, have proposed some mechanisms by which they participate in physiological and pathological placentation, have revealed some knowledge deficits, and have recommended ideal experimental approaches that will facilitate the clarification of the mechanistic actions of each long non-coding RNA at the feto-maternal interface during healthy and pathological pregnancies.

Bisphenol S moderately decreases the expression of syncytiotrophoblast marker genes and induces apoptosis in human trophoblast lineages.

Bisphenol S (BPS) is currently used in the manufacturing of several household equipment such as water pipes and food containers. Hence, its entrance into the human body is almost inevitable. The presence of BPS in body fluids has been reported. However, its potential toxicity, especially on human placenta development and pregnancy progression, has not been explored. In this study, we assessed the impacts of BPS on the self-renewal and differentiation potentials of placental stem cells, also known as trophoblast stem cells (TSCs), by exposing them to three different BPS concentrations during their self-renewal and differentiation into syncytiotrophoblast (ST), extravillous trophoblast (EVT), and trophoblast organoids. Interestingly, BPS treatment did not affect the stemness, cell cycle and proliferation of the TSCs but it induced apoptosis in each trophoblast lineage. BPS altered the expression of several fusion-related genes. However, this alteration did not translate into significant morphological defects in the STs and organoids. Moreover, BPS did not impair the differentiation of TSCs into EVTs. These findings suggest that the presence of BPS at the feto-maternal interface may exaggerate trophoblast apoptosis and moderately inhibit the trophoblast fusion pathway to affect placenta development and pregnancy. Our study offers valuable insights into the potential toxicity of BPS on human placenta development, emphasizing the need for epidemiological assessment of the relationship between maternal serum levels of BPS and pregnancy complications.

Maternal Hepatitis B Virus Infection and Pregnancy Outcomes of Freeze-Thaw Embryo Transfer.

This cohort study assesses the association of maternal hepatitis B virus (HBV) serostatus with pregnancy outcomes in women undergoing freeze-thaw embryo transfer (FET).

Glycyrrhizin ameliorates impaired glucose metabolism and ovarian dysfunction in a polycystic ovary syndrome mouse model.

The aim of this study was to determine the impact of glycyrrhizin, an inhibitor of high mobility group box 1, on glucose metabolic disorders and ovarian dysfunction in mice with polycystic ovary syndrome. We generated a polycystic ovary syndrome mouse model by using dehydroepiandrosterone plus high-fat diet. Glycyrrhizin (100 mg/kg) was intraperitoneally injected into the polycystic ovary syndrome mice and the effects on body weight, glucose tolerance, insulin sensitivity, estrous cycle, hormone profiles, ovarian pathology, glucolipid metabolism, and some molecular mechanisms were investigated. Increased number of cystic follicles, hormonal disorders, impaired glucose tolerance, and decreased insulin sensitivity in the polycystic ovary syndrome mice were reverted by glycyrrhizin. The increased high mobility group box 1 levels in the serum and ovarian tissues of the polycystic ovary syndrome mice were also reduced by glycyrrhizin. Furthermore, increased expressions of toll-like receptor 9, myeloid differentiation factor 88, and nuclear factor kappa B as well as reduced expressions of insulin receptor, phosphorylated protein kinase B, and glucose transporter type 4 were restored by glycyrrhizin in the polycystic ovary syndrome mice. Glycyrrhizin could suppress the polycystic ovary syndrome-induced upregulation of high mobility group box 1, several inflammatory marker genes, and the toll-like receptor 9/myeloid differentiation factor 88/nuclear factor kappa B pathways, while inhibiting the insulin receptor/phosphorylated protein kinase B/glucose transporter type 4 pathways. Hence, glycyrrhizin is a promising therapeutic agent against polycystic ovary syndrome.

Super-enhancer-associated transcription factors collaboratively regulate trophoblast-active gene expression programs in human trophoblast stem cells.

The placenta is an essential organ that supports the growth and development of the fetus during pregnancy. However, cell type-specific enhancers and transcription factors (TFs), and the mechanisms underlying the maintenance and differentiation of trophoblast stem cell (TSC) populations in the human placenta remain elusive. Here, using human TSCs as a model system, we identify 31,362 enhancers that are enriched with the motifs of previously reported TSC-pivotal TFs, including TEAD4, GATA2/3 and TFAP2C. Subsequently, we identify 580 super-enhancers (SEs) and 549 SE-associated genes. These genes are robustly expressed in the human placenta and include numerous TFs, implying that SE-associated TFs (SE-TFs) may play crucial roles in placental development. Additionally, we identify the global binding sites of five TSC-pivotal SE-TFs (FOS, GATA2, MAFK, TEAD4 and TFAP2C), revealing that they preferentially co-occupy enhancers, regulate each other and form a trophoblast-active gene regulatory network. Loss-of-function studies unveil that the five TFs promote self-renewal of TSCs by activating proliferation-associated genes while repressing developmental genes. We further reveal that the five TFs exert conserved and unique functions on placental development between humans and mice. Our study provides important insights into the roles of human TSC-pivotal TFs in regulating placenta-specific gene expression programs.

Effects of sequential cleavage and blastocyst embryo transfer on pregnancy outcomes in patients with poor ovarian response.

The management of patients with poor ovarian response (POR) remains a major challenge for fertility specialists in in vitro fertilization-embryo transfer (IVF-ET). In this retrospective cohort study, we aimed to evaluate the clinical effect of sequential transfer on pregnancy outcomes in patients with POR. A total of 3579 POR patients who underwent the first frozen embryo transfer (FET) cycle were enrolled from January 2018 to April 2021. The patients were divided into three groups according to the embryo transfer (ET) strategy adopted: a study group that included POR patients in whom a cleavage-stage embryo (day 3) and a blastocyst (day 5/6) were transferred (sequential transfer group), and two control groups in whom two cleavage-stage embryos (D3-dET group) or two blastocysts (D5/6-dET group) were transferred. The study group was matched with the control groups at a ratio of 1:4 by propensity score matching (PSM). The main pregnancy outcomes measured were the live birth rate and multiple pregnancy rate. After PSM, the live birth rate in the sequential transfer group was significantly higher than that in the D3-dET group (44.2% vs. 34.3%, P = 0.019), and was similar to that in the D5/6-dET group (44.2% vs. 45.3%; P = 0.90). In addition, there was no increase in the risk of multiple pregnancy among POR patients undergoing sequential transfer compared with both D3-dET (26.7% vs. 25.6%, P = 0.85) and D5/6-dET (26.7% vs. 28.4%, P = 0.97) groups. These findings imply that sequential transfer is an effective option for POR patients and could be utilized after careful consideration.

Role of CPXM1 in Impaired Glucose Metabolism and Ovarian Dysfunction in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS), a common female endocrinopathy associated with both reproductive and metabolic disorders, has an unclear etiology and unsatisfactory management methods. Carboxypeptidase X, M14 family member 1 (CPXM1) is a protein involved in follicular atresia, insulin production, and adipose tissue production, though its role in PCOS is not fully understood. We used a 60% high-fat diet (HFD) plus dehydroepiandrosterone (DHEA)-induced PCOS mouse model to determine the role of CPXM1 in abnormal glucose metabolism and ovarian dysfunction in PCOS. We found that serum CPXM1 concentrations were higher in PCOS mice and positively correlated with increased levels of serum testosterone and insulin. In both ovarian and adipose tissues of PCOS mice, CPXM1 mRNA and protein levels were significantly increased but GLUT4 levels were significantly decreased. Immunohistochemistry (IHC) staining of the ovary showed increased CPXM1 expression in PCOS. In addition, the protein expression of phosphorylated protein kinase B (p-Akt) was also significantly decreased in PCOS mice. Furthermore, mRNA levels of inflammatory markers such as TNF-α, IL-6, IFN-α, and IFN-γ were increased in ovarian and adipose tissues of PCOS mice. However, IRS-1, IRS-2, and INSR levels were significantly decreased. Our results indicated for the first time that abnormally high expression of CPXM1, increased adiposity, impaired glucose tolerance, and chronic low-grade inflammation may act together in a vicious cycle in the pathophysiology of PCOS. Our research suggests the possibility of CPXM1 as a potential therapeutic target for the treatment of PCOS.

EIF4G1 Is a Potential Prognostic Biomarker of Breast Cancer.

BACKGROUND: Breast cancer (BRCA) is one of the most common cancers in women worldwide and a leading cause of death from malignancy. This study was designed to identify a novel biomarker for prognosticating the survival of BRCA patients. METHODS: The prognostic potential of eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) was assessed using RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) as training cohort and validation set, respectively. The functional enrichment analysis of differentially expressed genes (DEGs) was performed. The relationship between EIF4G1 and tumor microenvironment (TME) was analyzed. Immunotherapy responses were explored by the immunophenoscores (IPS) and tumor immune dysfunction and exclusion (TIDE) score. The Connectivity Map (CMap) was used to discover potentially effective therapeutic molecules against BRCA. Immunohistochemistry (IHC) was applied to compare the protein levels of EIF4G1 in normal and cancer tissues and to verify the prognostic value of EIF4G1. RESULTS: BRCA patients with increased expression of EIF4G1 had a shorter overall survival (OS) in all cohorts and results from IHC. EIF4G1-related genes were mainly involved in DNA replication, BRCA metastasis, and the MAPK signaling pathway. Infiltration levels of CD4+-activated memory T cells, macrophages M0, macrophages M1, and neutrophils were higher in the EIF4G1 high-expression group than those in the EIF4G1 low-expression group. EIF4G1 was positively correlated with T cell exhaustion. Lower IPS was revealed in high EIF4G1 expression patients. Five potential groups of drugs against BRCA were identified. CONCLUSION: EIF4G1 might regulate the TME and affect BRCA metastasis, and it is a potential prognostic biomarker and therapeutic target for BRCA.

An Individualized Recommendation for Controlled Ovary Stimulation Protocol in Women Who Received the GnRH Agonist Long-Acting Protocol or the GnRH Antagonist Protocol: A Retrospective Cohort Study.

Background: The GnRH agonist long-acting protocol and GnRH antagonist protocol are widely used in ovarian stimulation. Which protocol eliciting higher live birth rate for IVF/ICSI patients with different ages, different ovarian reserves and different body mass index (BMI) has not been studied. However, among these protocols, the one that elicits higher live birth in IVF/ICSI patients with different ages, ovarian reserves and body mass indexes (BMI) has not been identified. Methods: This was a retrospective cohort study about 8579 women who underwent the first IVF-ET from January, 2018 to August, 2021. Propensity Score Matching (PSM) was used to improve the comparability between two protocols. Results: After PSM, significant higher live birth rates were found in the GnRH agonist long-acting protocol compared to GnRH antagonist protocol (44.04% vs. 38.32%) (p<0.001). Stratified analysis showed that for those with AMH levels between 3 ng/ml and 6 ng/ml, with BMI ≥ 24 kg/m2 and were aged ≥ 30 years old, and for those women with BMI < 24kg/m2 and were aged ≥30 years whose AMH levels were ≤ 3ng/ml, the GnRH agonist long-acting protocol was more likely to elicit live births [OR (95%CI), 2.13(1.19,3.80)], [OR (95%CI), 1.41(1.05,1.91)]. However, among women with BMI ≥ 24kg/m2 and were aged ≥30 years whose AMH levels were ≤ 3ng/ml, the GnRH agonist long-acting protocol had a lower possibility of eliciting live births [OR (95%CI), 0.54(0.32,0.90)]. Also, among women with AMH levels between 3 ng/ml and 6 ng/ml, with BMI ≥ 24 kg/m2 and with age < 30 years and for those with AMH levels between 3 ng/ml and 6 ng/ml, regardless of age, and with BMI<24kg/m2,, the possibility of live births was similar between the two protocols [OR (95%CI), 1.06(0.60,1.89)], [OR (95%CI), 1.38(0.97,1.97)], [OR (95%CI), 0.99(0.72,1.37)]. Among the women with AMH levels ≤ 3 ng/ml and with were aged < 30years, regardless of BMI, the possibility of live birth was similar between the two protocols [OR (95%CI), 1.02(0.68,1.54)], [OR (95%CI), 1.43(0.68,2.98)]. Moreover, among women with AMH levels ≥ 6ng/ml, the possibility of live birth was similar between the two protocols [OR (95%CI),1.42(0.75,2.69)], [OR (95%CI),1.02(0.19,5.35)], [OR (95%CI), 1.68(0.81,3.51)], [OR (95%CI), 0.51(0.10,2.55)]. Conclusions: The suitability of the GnRH agonist long-acting protocol or GnRH antagonist protocol to infertility patients is dependent on specific biological characteristics of the patients.

CXCL13 and CXCR5 are upregulated in PCOS mice ovaries but downregulated following metformin administration.

Polycystic ovary syndrome (PCOS) is becoming a common pathology among women, yet its pathogenesis remains enigmatic. The chemokine C-X-C motif ligand 13 (CXCL13) and its receptor type 5 (CXCR5) regulate inflammatory responses but their roles in PCOS remain unknown. Metformin is commonly administered to PCOS patients but its mechanism of action remains unclear. Thus, we aimed to determine the expression of CXCL13 and CXCR5 in the ovaries of PCOS mice and to evaluate the therapeutic effect of metformin on them. The study comprised four groups of mice: control, PCOS, PCOS plus metformin, and PCOS plus vehicle. CXCL13 and CXCR5 were found to be elevated in the ovarian tissues of the PCOS mice. Metformin reduced ovarian CXCL13 and CXCR5 expressions in the PCOS mice. Hence, CXCL13 and CXCR5 are potentially involved in PCOS pathogenesis; and metformin may help alleviate the symptoms of PCOS by inhibiting CXCL13 expression and actions.

Ovarian inflammatory mRNA profiles of a dehydroepiandrosterone plus high-fat diet-induced polycystic ovary syndrome mouse model.

RESEARCH QUESTION: What is the expression pattern of inflammatory mRNA profiles of a dehydroepiandrosterone (DHEA) plus high-fat diet (HFD)-induced polycystic ovary syndrome (PCOS) mouse model? DESIGN: RNA sequencing was performed to investigate the mRNA expression profiles in the ovarian tissues of a DHEA plus HFD-induced PCOS mouse model. Six samples were divided into two groups (control and PCOS), with three biological replicates in each group. This was followed by hierarchical clustering, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. The relative expression levels of nine inflammatory genes were validated via quantitative reverse-transcription polymerase chain reaction. RESULTS: A total of 436 genes were differentially expressed between the control and PCOS mice. Out of these, 137 genes were up-regulated while 299 genes were down-regulated. Gene ontology analysis indicated that differentially expressed mRNA were associated with T cell-mediated cytotoxicity and homocysteine metabolic processes. Pathway analysis further showed that these abnormally expressed mRNA were associated with signalling pathways, such as NF-kB signalling, tyrosine metabolism and phenylalanine metabolism. All these pathways are involved in chronic inflammation and PCOS. CONCLUSION: The differentially expressed genes are potentially involved in the inflammation that is evident in PCOS, and so could serve as therapeutic options against the disease. Nevertheless, prospective studies are needed to test this hypothesis.

Effect of artificial cycle with or without GnRH-a pretreatment on pregnancy and neonatal outcomes in women with PCOS after frozen embryo transfer: a propensity score matching study.

BACKGROUND: In frozen embryo transfer (FET), there is limited consensus on the best means of endometrial preparation in terms of the reproductive outcomes in women with polycystic ovary syndrome (PCOS). The present study aimed to compare the pregnancy and neonatal outcomes following artificial cycle FET (AC-FET) with or without gonadotropin-releasing hormone agonist (GnRH-a) pretreatment among women with PCOS. METHODS: A total of 4503 FET cycles that satisfied the inclusion criteria were enrolled in this retrospective cohort study between 2015 and 2020. The GnRH-a group received GnRH-a pretreatment while the AC-FET group did not. Propensity score matching (PSM) method and multivariate logistic regression analysis were performed to adjust for potential confounding factors. RESULTS: After PSM, women in the GnRH-a group suffered a significantly lower miscarriage rate (11.2% vs. 17.1%, P = 0.033) and a higher live birth rate (LBR) compared with those in the AC-FET group (63.1% vs. 56.8%, P = 0.043). No differences were observed in the rates of biochemical pregnancy, clinical pregnancy and ectopic pregnancy between the two groups. A higher mean gestational age at birth was observed in the GnRH-a group than in the AC-FET group (39.80 ± 2.01 vs. 38.17 ± 2.13, P = 0.009). The incidence of neonatal preterm birth (PTB) in the GnRH-a group was lower than that in the AC-FET group (7.4% vs. 14.9%, P = 0.009). Singleton newborns conceived after GnRH-a group were more likely to be small for gestational age (SGA) than those born after AC-FET group (16.4% vs. 6.8%, P = 0.009). However, no significant differences were found between the two groups in terms of mean birthweight, apgar score, the rates of macrosomia, large for gestational age and low birth weight. CONCLUSION(S): In women with PCOS who underwent AC-FET, GnRH-a pretreatment was significantly associated with a higher live birth rate and a reduced risk of neonatal PTB. However, there was a concomitant increase in the risk of developing SGA babies.

Hematobiochemical variability and predictors of new-onset and persistent postpartum preeclampsia.

Preeclampsia (PE) can occur antepartum or postpartum. When it develops de novo after childbirth, it is termed new-onset postpartum PE (NOPPE). Often, antepartum PE disappears after childbirth; however, in some women it persists after childbirth. This form of PE is termed persistent PE (PPE). Thus, there are two forms of postpartum PE: NOPPE and PPE. The pathogenesis and pathophysiology of these diseases have not been fully characterized, and whether NOPPE and PPE are different or similar pathological conditions remains unexplored. Thus, we aimed to compare the haematological and biochemical characteristics of NOPPE and PPE, predict the occurrence of new-onset PE and identify lifestyles that predispose women to postpartum PE. A total of 130 women comprising 65 normotensive postpartum women, 33 NOPPE and 32 PPE women were recruited for this hospital-based case-control study. The socio-demographic and lifestyle characteristics of the participants were obtained through well-structured questionnaires. Haematological and biochemical indices were measured using automated analysers and ELISA. The prevalence of postpartum PE was 11.9%. Dyslipidaemia (p = < 0.0001), hypomagnesaemia (p = < 0.001), elevated serum levels of ALT, AST (p = < 0.0001), sVCAM-1 (p = < 0.0001) and sFlt-1 (p = < 0.0001) were more prevalent and severe in the PPE than in the NOPPE. Sedentary lifestyle was common among both groups of hypertensive women. Elevated ALT and AST were significant predictors of NOPPE. These findings indicate that preeclampsia exists after childbirth in a high percentage of women. NOPPE and PPE are different pathological conditions that require different clinical management. Combined glucose, lipid and liver assessment could be useful in predicting postpartum PE.

A decrease in cluster of differentiation 2 expression on natural killer cells is associated with polycystic ovary syndrome but not influenced by metformin in a mouse model†.

PROBLEM: Natural killer (NK) cells from the peripheral blood and spleen represent the source from which various tissues replenish their immune cell populations. Hyperandrogenism and high interleukin-2 (IL-2) levels are factors present in polycystic ovary syndrome (PCOS). These factors and metformin, one of the commonest medications used in treating PCOS, may have an impact on NK cells. However, this is presently unknown. Here, we aimed to assess the distribution of peripheral blood and splenic NK cells and their CD2 and CD94 expression patterns in a PCOS mouse model and test whether metformin could reverse these effects. METHOD OF STUDY: Four mouse groups were designed as follows (n = 15/group): control, PCOS, PCOS plus vehicle, PCOS plus metformin. Dehydroepiandrosterone and a high-fat diet were administered to induce the PCOS mouse model. Flow cytometry was used to analyze the expressions of CD2 and CD94 on peripheral blood and splenic NK cells. RESULTS: PCOS mice had a low surface-density of CD2 on peripheral blood NK cells and a decreased percentage of CD2+ splenic NK cells. Metformin administration did not significantly influence these changes; however, it reduced the splenic NK cell counts. CONCLUSIONS: Our findings proved the association of PCOS with an altered expression of CD2 on peripheral blood and splenic NK cells and that of metformin with a lowered splenic NK cell reserve in PCOS conditions. These findings could further unlock key mechanisms in PCOS pathophysiology and in the mechanism of action of metformin, towards improving PCOS management.

LncRNA functional annotation with improved false discovery rate achieved by disease associations.

The long non-coding RNAs (lncRNAs) play critical roles in various biological processes and are associated with many diseases. Functional annotation of lncRNAs in diseases attracts great attention in understanding their etiology. However, the traditional co-expression-based analysis usually produces a significant number of false positive function assignments. It is thus crucial to develop a new approach to obtain lower false discovery rate for functional annotation of lncRNAs. Here, a novel strategy termed DAnet which combining disease associations with cis-regulatory network between lncRNAs and neighboring protein-coding genes was developed, and the performance of DAnet was systematically compared with that of the traditional differential expression-based approach. Based on a gold standard analysis of the experimentally validated lncRNAs, the proposed strategy was found to perform better in identifying the experimentally validated lncRNAs compared with the other method. Moreover, the majority of biological pathways (40%∼100%) identified by DAnet were reported to be associated with the studied diseases. In sum, the DAnet is expected to be used to identify the function of specific lncRNAs in a particular disease or multiple diseases.

The impact of bisphenol A on the placenta†.

Bisphenol A (BPA), an endocrine-disrupting chemical, is used to produce a wide variety of plastic and common house-hold items. Therefore, there is potential continual exposure to this compound. BPA exposure has been linked to certain placenta-associated obstetric complications such as preeclampsia, fetal growth restriction, miscarriage, and preterm birth. However, how BPA exposure results in these disorders remains uncertain. Hence, we have herein summarized the reported impacts of BPA on the morphology and metabolic state of the placenta and have proposed mechanisms by which BPA affects placentation, potentially leading to obstetric complications. Current findings suggest that BPA induces pathological changes in the placenta and disrupts its metabolic activities. Based on exposure concentrations, BPA can elicit apoptotic or anti-apoptotic signals in the trophoblasts, and can exaggerate trophoblast fusion while inhibiting trophoblast migration and invasion to affect pregnancy. Accordingly, the usage of BPA products by pregnant women should be minimized and less harmful alternative chemicals should be explored and employed where possible.