N6-Methyladenosine-Modified KREMEN2 Promotes Tumorigenesis and Malignant Progression of High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) remains the most lethal female cancer by far. Herein, clinical HGSOC samples had higher N6-methyladenosine (m6A) modification than normal ovarian tissue, and its dysregulation had been reported to drive aberrant transcription and translation programs. However, Kringle-containing transmembrane protein 2 (KREMEN2) and its m6A modification have not been fully elucidated in HGSOC. In this study, the data from the high-throughput messenger RNA (mRNA) sequencing of clinical samples were processed using the weighted correlation network analysis and functional enrichment analysis. Results revealed that KREMEN2 was a driver gene in the tumorigenesis of HGSOC and a potential target of m6A demethylase fat-mass and obesity-associated protein (FTO). KREMEN2 and FTO levels were upregulated and downregulated, respectively, and correlation analysis showed a significant negative correlation in HGSOC samples. Importantly, upregulated KREMEN2 was remarkably associated with lymph node metastasis, distant metastasis, peritoneal metastasis, and high International Federation of Gynecology and Obstetrics stage (Ⅲ/Ⅳ), independent of the age of patients. KREMEN2 promoted the growth of HGSOC in vitro and in vivo, which was dependent on FTO. The methylated RNA immunoprecipitation qPCR and RNA immunoprecipitation assays were performed to verify the m6A level and sites of KREMEN2. FTO overexpression significantly decreased m6A modification in the 3' and 5' untranslated regions of KREMEN2 mRNA and downregulated its expression. In addition, we found that FTO-mediated m6A modification of KREMEN2 mRNA was recognized and stabilized by the m6A reader IGF2BP1 rather than by IGF2BP2 or IGF2BP3. This study highlights the m6A modification of KREMEN2 and extends the importance of RNA epigenetics in HGSOC.

Impact of body mass index on assisted reproductive technology outcomes in patients with polycystic ovary syndrome: a meta-analysis.

The effect of obesity on pregnancy outcomes of patients with polycystic ovary syndrome (PCOS) undergoing assisted reproductive technology (ART) remains unclear. As such, a meta-analysis of recent studies was conducted to probe the effect of being overweight or obese on ART pregnancy outcomes in patients with PCOS. PubMed, Embase, MEDLINE, Scopus and Web of Science were searched from inception to 22 July 2023 without language restrictions. The main indicators were: live birth rate, clinical pregnancy rate, spontaneous abortion rate and multiple pregnancy rate. Ten studies were analysed, with a combined sample size of 247,845. Among patients with PCOS undergoing ART who were overweight or obese, the live birth rate, clinical pregnancy rate, implantation rate and number of retrieved oocytes were lower than in normal-weight patients with PCOS, and the spontaneous abortion rate was higher than in normal-weight patients with PCOS. Obese patients with PCOS undergoing ART had a lower multiple pregnancy rate and a lower number of mature oocytes compared with normal-weight patients with PCOS. The data showed that, among patients with PCOS, being overweight or obese has a negative effect on ART pregnancy outcomes. This meta-analysis may inform guidelines for pregnancy with ART, and encourage overweight or obese patients with PCOS to lose weight.

GPR65 inhibits human trophoblast cell adhesion through upregulation of MYLK and downregulation of fibronectin via cAMP-ERK signaling in a low pH environment.

BACKGROUND: Extravillous trophoblasts (EVTs) are essential cells during the formation of the placenta, with the major function of invading the maternal decidua, anchoring the developing placenta to the uterus, remodeling uterine arteries, and regulating immune responses to prevent rejection. During early pregnancy, the decidua undergoes a hypoxic and acidic microenvironment, which has been shown to participate in tumor cell migration, invasion, growth, and angiogenesis. Nevertheless, the mechanisms by which EVTs sense and respond to the acidic microenvironment, thereby executing their functions, remain poorly understood. METHODS: The effects of G protein-coupled receptor 65 (GPR65) on cell adhesion and other cellular functions were tested using JAR spheroids, mouse blastocysts, and HTR-8/SVneo cells. Specifically, we employed HTR-8/SVneo cells for gene overexpression and silencing to investigate the underlying mechanism of GPR65's impact on trophoblast cell function under acidic conditions. Additionally, villus tissue samples obtained from early pregnancy loss patients were utilized to explore the potential association between GPR65 and its related signaling pathway molecules with the disease. RESULTS: This study identified GPR65 expression widely in trophoblasts, with the highest level in EVTs. Importantly, optimal GPR65 levels are required for maintaining normal adhesion, migration, and invasion, whereas overexpression of GPR65 inhibits these functions by activating the cAMP-ERK signaling pathway, upregulating myosin light chain kinase (MYLK) and MYLK3 expression, and subsequently downregulating fibronectin. Consistently, elevated expression of GPR65, MYLK, and MYLK3 is observed in patients suffering from early pregnancy loss. CONCLUSIONS: This work offers insights into the suppressive effects of GPR65 on EVT function under acidic conditions and highlights a putative target for therapeutic intervention in early pregnancy complications. Video Abstract.

Protein glycosylation: bridging maternal-fetal crosstalk during embryo implantation†.

Infertility is a challenging health problem that affects 8-15% of couples worldwide. Establishing pregnancy requires successful embryo implantation, but about 85% of unsuccessful pregnancies are due to embryo implantation failure or loss soon after. Factors crucial for successful implantation include invasive blastocysts, receptive endometrium, invasion of trophoblast cells, and regulation of immune tolerance at the maternal-fetal interface. Maternal-fetal crosstalk, which relies heavily on protein-protein interactions, is a critical factor in implantation that involves multiple cellular communication and molecular pathways. Glycosylation, a protein modification process, is closely related to cell growth, adhesion, transport, signal transduction, and recognition. Protein glycosylation plays a crucial role in maternal-fetal crosstalk and can be divided into N-glycosylation and O-glycosylation, which are often terminated by sialylation or fucosylation. This review article examines the role of protein glycosylation in maternal-fetal crosstalk based on two transcriptome datasets from the GEO database (GSE139087 and GSE113790) and existing research, particularly in the context of the mechanism of protein glycosylation and embryo implantation. Dysregulation of protein glycosylation can lead to adverse pregnancy outcomes, such as missed abortion and recurrent spontaneous abortion, underscoring the importance of a thorough understanding of protein glycosylation in the diagnosis and treatment of female reproductive disorders. This knowledge could have significant clinical implications, leading to the development of more effective diagnostic and therapeutic approaches for these conditions.

Association of the androgens with COVID-19 prognostic outcomes: a systematic review.

OBJECTIVE: The coronavirus disease 2019 was a global public health emergency in later years (from 2020 to early 2022), and androgens have been associated with infection and prognostic outcomes. However, the relationship between low serum testosterone levels and prognostic outcomes remains inconclusive. This systematic review aimed to investigate the relationship between serum testosterone levels and prognostic outcomes in patients with COVID-19. METHODS: We searched PubMed, MEDLINE, EMBASE and Web of Science electronic databases for all literature from January 1, 2020, to September 1, 2022. In addition, we also searched literature manually. The search terms were COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), androgens, and testosterone. There were no language restrictions for retrieval. RESULTS: Our search identified 2285 articles, resulting in a full-text analysis of 16 studies, including 12 cohort studies and four case-control studies. Low serum testosterone levels were observed to be statistically associated with a higher probability of intensive care unit (ICU) admission in seven studies. In eight studies, higher hospital mortality was associated with lower serum testosterone levels. Six studies found that low serum testosterone levels were associated with a statistically significant difference in lung function impairment. Only four studies found that among living patients, those with lower serum testosterone levels had longer hospital stays. All but one of the included studies had a low risk of bias. CONCLUSIONS: Based on available data, low serum testosterone levels are associated with higher rates of ICU admission, hospital mortality, risk of lung failure, inflammatory markers, and longer hospital stays in patients with COVID-19 compared with those having normal serum testosterone levels.

Effect of COVID-19 vaccination on the outcome of in vitro fertilization: A systematic review and meta-analysis.

Background: Universal COVID-19 vaccination programs are now recommended in several countries and represent the most effective preventive measure against COVID-19. However, some reports suggest that vaccination may cause infertility or have adverse effects on pregnancy. Conflicting reports have led to vaccine hesitancy in women planning pregnancy. Purpose: To determine whether vaccination against COVID-19 affects in vitro fertilization (IVF) outcomes, we conducted a meta-analysis. Method: A systematic search was conducted using PubMed, Embase, MEDLINE, and Web of Science databases for all published literature on COVID-19 vaccines and outcomes of IVF. International Prospective Register of Systematic Reviews registration was completed on September 13, 2022 (CRD42022359771). Results: We analyzed 20 studies totaling 18,877 individual cases undergoing IVF. COVID-19 vaccination had significant effect on clinical and ongoing pregnancy rate (risk ratio (RR): 0.97; 95% confidence interval (CI): 0.94-0.99; RR: 0.93; 95% CI: 0.87-0.99). These outcomes did not differ between vaccinated and unvaccinated individuals: biochemical pregnancy rate (RR: 0.95; 95% CI: 0.88-1.03), implantation rate (RR: 1.02; 95%CI: 0.97-1.07; P = 0.41), the number of oocytes (mean difference (MD): 0.12; 95% CI: -0.65-0.88) and MII/mature oocytes recovered (MD: 0.27; 95% CI: -0.36-0.90), blastocysts rate (MD: 0.01; 95% CI: -0.04, 0.06), and fertilization rate (MD: 1.08; 95% CI: -0.57, 2.73). Conclusion: Our findings suggest that vaccination against COVID-19 does not adversely affect the biochemical pregnancy rates; number of oocytes and MII/mature oocytes obtained; implantation, blastocysts; and fertilization rates in women undergoing IVF treatment. Subgroup analysis showed that the mRNA vaccine had no statistical significance on all indexes (clinical, biochemical, or ongoing pregnancy rates; implantation, blastocysts, or fertilization rates; and the number of oocytes and MII/mature oocytes). The findings of this meta-analysis are anticipated to increase the willingness of women planning IVF treatment to receive COVID-19 vaccination and provide evidence-based medical guidance for the development and implementation of guidelines. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022359771.

Water resource carrying capacity and obstacle factors in the Yellow River basin based on the RBF neural network model.

The Yellow River basin (YRB) plays an important role in China's economic and social growth. Based on different dimensions, we adopted the radial basis function (RBF) neural network model and the obstacle degree model to examine the water resource carrying capacity (WRCC) of the YRB. From 2005 to 2020, the WRCC of the entire YRB, as well as the upstream and midstream regions, improved, but the WRCC of the downstream region remained poor, revealing spatial differences. The overall improvement in the WRCC of the Yellow River's nine provinces is good, but the WRCC of Inner Mongolia and Henan is poor, suggesting regional differences. From the standpoint of obstacle factors, the development and usage rate of surface water resources are the main challenges. In 2020, the obstacle degree of the YRB reached 87.4871%. The irrigated area rate in Gansu was the primary obstacle factor, and the obstacle degree reached 73.0238%. Qinghai's industrial aspects mostly hindered the improvement of its WRCC, with an obstacle degree of 31.36%. The results provide a theoretical reference for the high-quality development of the YRB.

Inter-regional ecological compensation in the Yellow River Basin based on the value of ecosystem services.

Ecological compensation in the Yellow River Basin aims to improve its ecological and environmental management capacity. Based on data on land-use changes in the Yellow River Basin from 2010 to 2020, this study used the equivalent factor method to assess the value of ecosystem services in the basin. This was measured at three spatial scales in the upper, middle, and lower reaches, encompassing; nine provinces and 72 cities. The priority and amount of ecological compensation were determined for the Yellow River Basin regions. Results show that (1) The total value of ecosystem services in the Yellow River Basin increased from 1798.317 billion yuan in 2010 to 1838.259 billion yuan in 2020. Grasslands had the highest total ecosystem service value in 2020, accounting for 46.11%. (2) The value of ecosystem services in the Yellow River Basin region is upstream > midstream > downstream. Qinghai Province has the highest value of ecosystem services among the nine provinces, and the level of economic development in each region is inversely correlated with the value of ecosystem services. (3) The ecosystem service value and the economic development level of the cities in the Yellow River Basin are positively and negatively correlated with the priority of ecological compensation, respectively. Among them, the cities in the upper reaches are the most urgent targets for national ecological compensation. (4) The total ecological compensation in the Yellow River Basin in 2020 was approximately 122.63 billion yuan. Further, the amount of vertical ecological compensation to be paid by the state was approximately 114.673 billion yuan, and the horizontal compensation to be borne between provinces was approximately 7.957 billion yuan. The findings of this study provide novel insights into improving ecological compensation in the Yellow River Basin regions.

Comparing Economics, Environmental Pollution and Health Efficiency in China.

As the modern economy develops rapidly, environmental pollution and human health have also been threatened. In recent years, relevant research has focused on subjects such as energy and economic, environmental pollution and health issues. Yet this has not considered the use of water resources and the impact of wastewater pollutant emissions on the economy and health. This article has combined the following factors like water consumption with wastewater discharge, pollutant concentration in sewage and local medical care expenditure and put them into the model of water resources, energy and health measurement, and a two-stage dynamic data envelopment analysis (DEA) model considering undesirable outputs is applied to 30 provinces (including autonomous regions and municipalities) to calculate the total efficiency, production efficiency and health efficiency in 2014-2017.The results show that the total efficiency values of most provinces are between 0.2 and 0.4, providing large room for improvement. Production efficiency and health efficiency have increased in recent years, but the health efficiency values of most provinces are still so low that they have dragged back the overall efficiency. The key impact indicators of different provinces are different, and each province should formulate different policies according to its own specific conditions so as to purposefully to deepen the energy, economic and medical reforms in each province, and also to promote sustainable economic development while improving health efficiency.

The gibberellin GID1-DELLA signalling module exists in evolutionarily ancient conifers.

Gibberellins (GAs) participate in controlling various aspects of basic plant growth responses. With the exception of bryophytes, GA signalling in land plants, such as lycophytes, ferns and angiosperms, is mediated via GIBBERELLIN-INSENSITIVE DWARF1 (GID1) and DELLA proteins. To explore whether this GID1-DELLA mechanism is present in pines, we cloned an orthologue (PtGID1) of Arabidopsis AtGID1a and two putative DELLA proteins (PtDPL; PtRGA) from Pinus tabuliformis, a widespread indigenous conifer species in China, and studied their recombinant proteins. PtGID1 shares with AtGID1a the conserved HSL motifs for GA binding and an N-terminal feature that are essential for interaction with DELLA proteins. Indeed, A. thaliana 35S:PtGID1 overexpressors showed a strong GA-hypersensitive phenotype compared to the wild type. Interactions between PtGID1 and PtDELLAs, but also interactions between the conifer-angiosperm counterparts (i.e. between AtGID1 and PtDELLAs and between PtGID1 and AtDELLA), were detected in vivo. This demonstrates that pine has functional GID1-DELLA components. The Δ17-domains within PtDPL and PtRGA were identified as potential interaction sites within PtDELLAs. Our results show that PtGID1 has the ability to interact with DELLA and functions as a GA receptor. Thus, a GA-GID1-DELLA signalling module also operates in evolutionarily ancient conifers.

A transcriptomics investigation into pine reproductive organ development.

The development of reproductive structures in gymnosperms is still poorly studied because of a lack of genomic information and useful genetic tools. The hermaphroditic reproductive structure derived from unisexual gymnosperms is an even less studied aspect of seed plant evolution. To extend our understanding of the molecular mechanism of hermaphroditism and the determination of sexual identity of conifer reproductive structures in general, unisexual and bisexual cones from Pinus tabuliformis were profiled for gene expression using 60K microarrays. Expression patterns of genes during progression of sexual cone development were analysed using RNA-seq. The results showed that, overall, the transcriptomes of male structures in bisexual cones were more similar to those of female cones. However, the expression of several MADS-box genes in the bisexual cones was similar to that of male cones at the more juvenile developmental stage, while despite these expression shifts, male structures of bisexual cones and normal male cones were histologically indistinguishable and cone development was continuous. This study represents a starting point for in-depth analysis of the molecular regulation of cone development and also the origin of hermaphroditism in pine.

Improving successful rate of transcranial electrical motor-evoked potentials monitoring during spinal surgery in young children.

INTRODUCTION: This prospective study was to investigate the successful rate of intraoperative motor evoked potentials (MEP) monitoring for children (<12 years old) with congenital scoliosis. MATERIALS AND METHODS: A consecutive series of 27 young children (7 girls and 20 boys; from 1 to 11 years old) between September 2007 and November 2009, were enrolled to this study. 12 patients received general anesthesia based on TIVA, induced with propofol 2-4 mg/kg and fentanyl 3-5 µg/kg followed by a continuous infusion of propofol (20-150 µg/kg/min, at mean of 71.7 µg/kg/min). The other 15 patients received combined inhalation and intravenous anesthesia, induced with sevoflurane and fentanyl 3-5 µg/kg and maintained by sevoflurane (0.5-1%). The maintenance of anaesthesia management was performed with stable physiological parameters during surgery. RESULTS: Intraoperative MEP monitoring was successfully performed in all patients, while SEP was successfully performed in 26 of 27 patients. There was no significant difference of successful rates between SEP and MEP monitoring (P > 0.05). As well, no difference in MEP successful rates was observed in two groups with different anesthetic techniques. No wake-up test and no post-operative neurological deficits occurred in this series of patients. CONCLUSION: Low dose anesthesia by either TIVA with propofol or sevoflurane-based mixture anesthesia protocol can help the intraoperative spinal cord monitoring to successfully elicit MEP and perform reliable monitoring for patients below 12 years of age.