Search

HAND2 is a critical mediator of progesterone receptor signaling in endometrium. Silencing of HAND2 expression is associated with female infertility and endometrial cancers. We recently observed that lncRNA HAND2-AS1 and HAND2 are expressed coordinately in human endometrial stromal cells. To investigate involvement of HAND2-AS1 and HAND2 in pathogenesis of endometriosis, we employed immunohistochemistry, in situ hybridization, and quantitative real-time PCR to assess their expression in normal endometrium and the ectopic lesions obtained from patients with ovarian endometriosis. HAND2 promoter methylation was also monitored in these samples. Our results revealed that HAND2 and HAND2-AS1 expression levels were reduced but promoter methylation was enhanced significantly in ectopic endometrium when compared with the normal controls. Fluorescence in situ hybridization showed that HAND-AS1 is predominantly localized in the nuclei of endometrial stromal cells in contrast to the cytoplasmic distribution in epithelial cell compartment. To further investigate regulation of HAND2 expression by HAND2-AS1, HAND2-AS1 was silenced or overexpressed in human endometrial stromal cells. Our studies showed that expression levels of HAND2 and its direct target IL15 were attenuated markedly in HAND2-AS1 silenced cells but enhanced significantly in the overexpressed human endometrial stromal cells. Silencing of HAND2-AS1 also impaired endometrial stromal cell decidualization as indicated by downregulation of decidual biomarkers IGFBP1 and PRL. In addition, HAND2 promoter methylation was also enhanced upon HAND2-AS1 silencing. RNA immunoprecipitation studies further revealed that HAND2-AS1 is capable of binding to DNA methyltransferase DNMT1, indicating that HAND2-AS1 governs HAND2 expression epigenetically involving DNA methylation.

With the continuous emergence of global warming and excessive waste of resources, especially in the clothing industry, sustainable clothing has become a fast-moving consumer goods trend. As a necessity of life, clothing often sensitively reflects the fashion, the characteristics of the times and, for young people, their lifestyle. Intelligent, cultural and sustainable clothing has become the mainstream development trend of the clothing industry. Based on the theory of reasoned action, this research takes online clothing stores as the research object and constructs the effect model between e-store image, consumer attitude and intention, and verifies the impact of e-store image on consumers’ intention in the two important stages of information search and purchase. By distributing online questionnaires to consumers of online clothing stores, 823 questionnaires were finally effectively recovered. The hypothesis was verified using a multi-statistical analysis and structural equation model. The findings showed that for young consumers, in the information search stage, the three dimensions of e-store image, which are information, atmosphere and convenience, positively affect consumers’ search intention. Meanwhile, in the purchase stage, the three dimensions of e-store image, which are enjoyment, uncertainty and service, have a significant impact on consumers’ purchase intention. Particularly, consumer attitude plays a mediating role between different dimensions and intentions. According to the constructed consumer attitude model, we should propose these sustainable marketing suggestions for online clothing stores: First of all, online clothing store operators should improve the atmosphere, convenience and information image of electronic stores, establish a sustainable image, and enhance young consumer’s identity. Secondly, using multiple marketing methods, we can establish an unimpeded one-to-one interaction with young customers through the current popular live broadcast marketing, improve the enjoyment of stores, more specifically implement marketing strategies, and strengthen the sense of sustainability.

A closed-loop supply chain (CLSC) is the process of adding a reverse supply chain to the traditional forward supply chain. It has a positive effect on reducing environmental pollution, and therefore many governments have introduced relevant policies to encourage enterprises to develop CLSCs. Among them, the reward–penalty policy (RPP) for the recovery rate of waste electrical and electronic equipment (WEEE) is considered better. At the corporate level, the development of CLSCs can enhance the social responsibility awareness of the enterprise and effectively enhance the corporate image. Therefore, in order to study the decision making and recycling channel selection of CLSCs that consider corporate social responsibility (CSR) under the government’s RPP, this paper constructs a two-stage CLSC, including a manufacturer, a retailer, a third-party recycler, and the government. By adopting the Stackelberg game method, we determine the optimal results of the three models and draw a series of conclusions: (1) when the manufacturer is responsible for recycling WEEE, the profit is the largest, and it shows an increasing trend as the government’s reward–penalty coefficient increases; (2) the manufacturer recycling model enables the manufacturer to obtain the maximum CSR investment level, followed by the third-party recycler recycling model, and the smallest is the retailer recycling model; and (3) the government tends to build third-party recycling agencies, which is conducive to improving the level of contribution to GDP. The conclusion of this paper has certain management inspirations for the decision making of the enterprise and the formulation of government policies.

Efficient and low-cost remanufacturing can be achieved through process innovation. Consequently, the question of whether government subsidies for remanufacturing process innovation will stimulate improvement in this area and thus affect the closed-loop supply chain is worth discussing. To answer this question, we establish a closed-loop supply chain model consisting of a manufacturer and a retailer, taking into account both remanufacturing process innovation and government subsidy. This is done in order to explore the impact of remanufacturing process innovation on the closed-loop supply chain from the perspective of government subsidies. Moreover, the government subsidizes the manufacturer according to the improvement of remanufacturing process innovation levels. Specifically, we analyze the optimal decisions and the social welfare in two models—the benchmark model without government subsidy, and the government subsidy model. Our main findings are threefold. The optimal decisions of the two models vary with the proportion of new products’ production cost and remanufactured products’ production cost. The government subsidy for process innovation does not necessarily improve the profits of the manufacturer, the retailer, and the supply chain system. Moreover, there is a threshold; the government subsidy can hurt the retailer’s profits, and the retailer has no motivation to participate in the sale of new products when the government subsidy is below that threshold. The government subsidy for process innovation does improve overall social welfare and has a lesser environmental impact. The conclusions are also verified by numerical analysis.

Basigin (BSG) is a transmembrane glycoprotein involved in cell proliferation, angiogenesis, and tissue remodeling. BSG has been shown to be essential for male and female reproduction although little is known about its role in normal uterine function. To study the potential function of BSG in the female reproductive tract, we generated mice with conditional knockout of Bsg in uterine cells using progesterone receptor-Cre and hypothesized that BSG is required for normal pregnancy in mice. Fertility study data showed that the conditional knockout mice had significantly reduced fertility compared to controls. Ovarian function of the conditional knockout mice appeared normal with no difference in the number of superovulated oocytes collected or in serum progesterone levels between the conditional knockout and the control mice. Uterine tissues collected at various times of gestation showed increased abnormalities in implantation, decidualization, placentation, and parturition in the conditional knockout mice. Uterine cross sections on Day 5 of pregnancy showed implantation failure and abnormal uterine epithelial differentiation in a large proportion of the conditional knockout mice. There was a compromised decidual response to artificial decidualization stimuli and decreased mRNA and protein levels for decidualization genes in the uteri of the conditional knockout mice. We also observed altered protein expression of monocarboxylate transporter 1 (MCT1), as well as impaired angiogenesis in the conditional knockout uteri compared to the controls. These results support that BSG is required for successful pregnancy through its functions in implantation and decidualization. Summary sentence Loss of Bsg expression in the uterus leads to subfertility in mice due to impaired implantation and decidualization. Graphical Abstract

Chunxia Cheng,1 Xingxing Wu,2 Yu Shen,1 Quanxi Li1 1Department of Hepatobiliary Surgery, The Second People’s Hospital of Lianyungang, Liangyungang City 222023, People’s Republic of China; 2Deparment of Pediatric Surgery, The Second People’s Hospital of Lianyungang, Liangyungang City 222023, People’s Republic of ChinaCorrespondence: Quanxi Li Tel +86-13382950660Email lqx0513@163.comBackground: Hepatocellular carcinoma (HCC) is one of the most common human malignant tumors. The prognosis of HCC patients is still unsatisfying. In this study, we performed the integrated bioinformatics analysis to identify potential biomarkers and biological pathways in HCC.Methods: Gene expression profiles were obtained from the Gene Expression Omnibus database (GSE55048, GSE55758, and GSE56545) for the screening of the common differentially expressed genes (DEGs) between HCC tissues and matched non-tumor tissues. DEGs were subjected to Gene Ontology, KEGG pathway, and Reactome pathway analysis. The hub genes were identified by using protein–protein interaction (PPI) network analysis. The hub genes in HCC were further subjected to overall survival analysis of HCC patients. The hub genes were further validated by in vitro functional assays.Results: A total of 544 common differentially expressed genes were screened from three datasets. Gene Ontology, KEGG and Reactome analysis results showed that DEGs are significantly associated with the biological process of cell cycle, cell division, and DNA replication. PPI network analysis identified 20 hub genes from the DEGs. These hub genes except CENPE were all significantly up-regulated in the HCC tissues when compared to non-tumor tissues. The Kaplan–Meier survival analysis results showed that the high expression of the 20 hub genes was associated with shorter survival of the HCC patients. Further validation studies showed that knockdown of KIF14 and KIF23 both suppressed the proliferative potential, increased the caspase-3/-7 activity, up-regulated Bax expression, and promoted the invasive and migratory abilities in the HCC cells. In addition, knockdown of KIF14 and KIF23 enhanced chemosensitivity to cisplatin and sorafenib in the HCC cells. Finally, the high expression of KIF14 and KIF23 was associated with shorter progression-free survival, recurrence-free survival, and disease-specific survival of patients with HCC.Conclusion: In conclusion, the present study performed the integrated bioinformatics analysis and showed that KIF14 and KIF23 silence attenuated cell proliferation, invasion, and migration, and promoted chemosensitivity of HCC cells. KIF14 and KIF23 may serve as potential biomarkers for predicting the worse prognosis of patients with HCC.Keywords: hepatocellular carcinoma, differentially expressed genes, hub genes, KIF14, KIF23, survival analysis

Wei Wan, Yu Shen, Quanxi Li Department of Hepatobiliary Surgery, The Second People’s Hospital of Lianyungang, Liangyungang City 222023, People’s Republic of ChinaCorrespondence: Quanxi LiDepartment of Hepatobiliary Surgery, The Second People’s Hospital of Lianyungang, Liangyungang City 222023, People’s Republic of ChinaTel +86-13382950660Email 540666069@qq.comBackground: Hepatocellular carcinoma (HCC) is one of the most common human malignant tumors. The prognosis of HCC patients is still unsatisfying. Thus, it is of great importance to identify novel molecules and functional pathways associated with the pathophysiology of HCC. In this study, we performed the integrated bioinformatics analysis and experiment validation to identify novel biomarkers in the prognosis and progression of HCC.Materials and Methods: Gene expression profiles were obtained from Gene Expression Omnibus database (GSE33294) for the screening of the differentially expressed genes (DEGs) between HCC tissues and matched non-tumor tissues. The DEGs were subjected to Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Set Enrichment Analysis (GSEA). The key genes in HCC were further subjected to overall survival analysis of HCC patients. The in vitro functional studies were performed to validate the biological functions of the key gene in HCC cell progression.Results: A total of 2,334 DEGs were screened from GSE33294 dataset, including 1,120 up-regulated and 1,214 down-regulated genes. GO, KEGG and GSEA results showed that DEGs are significantly associated with the biological process of cell cycle, cell division and DNA replication. The Kaplan–Meier survival analysis results showed that the key genes from the minichromosome maintenance protein complex (MCM) family including MCM8, MCM10, MCM2, MCM3, MCM4, MCM6 and MCM7 were significantly correlated with the overall survival of the HCC patients. Further validation studies showed that MCM10 was significantly up-regulated in the HCC cell lines, and knockdown of MCM10 significantly suppressed cell proliferation as determined by the cell counting kit-8 and BrdU incorporation assays and increased the caspase-3 activity of HCC cells.Conclusion: The comprehensive bioinformatics analysis identified several key genes that were associated with the prognosis of HCC patients. The validation study results indicated that MCM10 may be an important predictor for poorer prognosis of HCC patients and may act as an oncogene to promote HCC cell progression.Keywords: hepatocellular carcinoma, GSE33294, bioinformatics, hub genes, MCM10, prognosis

It has been found that the traditionally used electromagnetic wave instruments have limitations in detection depths, as well as a lack of directionality. Therefore, those types of instruments cannot meet the needs of geo-steering applications. However, azimuth electromagnetic wave instruments have shown the ability to quickly acquire effective geo-steering information using a tilt coil design method, which can potentially provide accurate guidance for decision-making in drilling direction adjustments. In this study, a design method for an azimuth electromagnetic wave detection instrument for underground coal mining was proposed. The relationships between the structural parameters of the instrument and installation angles of the coils and the response signals were obtained in this study using simulations. Then, by choosing reasonable instrument spacings, coil installation angles, and transmitting frequencies, the detection performances of the instrument were successfully improved. Also, the basic parameter selections of the proposed logging-while-drilling azimuth electromagnetic wave logging instrument were determined to be suitable for underground coal-mining purposes. It was also found that the symmetric compensation of the instrument was sensitive to the interface responses, and the anti-symmetric compensation was sensitive to the anisotropic responses. In addition, a method of detecting the interface positions and azimuth of coal-seam interfaces using azimuth electromagnetic waves, as well as the potential for the application of the instrument for the detection of low-resistivity anomalies in coal goafs, were effectively demonstrated. The results of this study provided theoretical references for future coal-seam boundary detections and explorations, and also added insight into the development processes of coal-seam bedding.

Based on triadic reciprocal determinism, in this study, we adopted the fuzzy-set qualitative comparative analysis (fsQCA) method to conduct configuration analysis on the factors that influence the continuous use of knowledge payment platforms and explain the mechanism of the configuration effect of different influencing factors. The research included six casual variables: perceived value, platform quality, satisfaction, trust, subjective norms, and habits. Continuous use intention and continuous use behavior were used as the outcome variables. By discussing the action paths of six casual variables on two outcome variables, it is suggested that the operators of knowledge payment platforms should select different influencing factor configuration paths to improve the service and promote the continuous use of the knowledge payment platform by users.

The massive emission of carbon dioxide and other greenhouse gases has begun to threaten the survival of human beings and the balance of the Earth’s ecology. If carbon emission is left unchecked, we will face terrible consequences. Closed-loop supply chain operation is an effective way to improve economic and environmental benefits at the same time. This paper attempts to study the decision-making and recycling channel selection of CLSC under carbon allowance and carbon trading policies. This paper constructs a closed-loop supply chain consisting of a manufacturer, a retailer and a third-party recycler, and uses the Stackelberg game-theoretic method to decide variables such as the product price and recycling rate of CLSC under three recycling models. Through the analysis and comparison of the manufacturer’s profit of and the carbon emissions in different models, the following conclusions are drawn. (1) When the manufacturer recycles WEEE, the supply chain obtains the most profit. (2) When the retailer recycles WEEE, the carbon emissions of the supply chain are lowest. (3) The manufacturer tends to choose the M model, which is the manufacturer recycling model. The T model and the R model have little difference in carbon emissions. For easier management, the government prefers to choose the T model, which is the third-party recycler recycling model.

In closed-loop supply chains (CLSC), manufacturers, retailers, and recyclers perform their duties. Due to the asymmetry of information among enterprises, it is difficult for them to maximize efficiency and profits. To maximize the efficiency and profit of the CLSC, this study establishes five cooperation models of CLSC under the government‘s reward–penalty mechanism. We make decisions on wholesale prices, retail prices, transfer payment prices, and recovery rates relying on the Stackelberg game method and compare the optimal decisions. This paper analyzes the impact of the government reward-penalty mechanism on optimal decisions and how members in CLSC choose partners. We find that the government’s reward-penalty mechanism can effectively increase the recycling rate of used products and the total profit of the closed-loop supply chain. According to the calculation results of the models, under the government’s reward-penalty mechanism, the cooperation can improve the CLSC’s used products recycling capacity and profitability. In a supply chain, the more members participate in the cooperation, the higher profit the CLSC obtain. However, the cooperation mode of all members may lead to monopoly, which is not approved by government and customers.

Ample evidence suggests that environmental and occupational exposure to bisphenol A (BPA) and phthalate, two chemicals widely used in the plastics industry, disturbs homeostasis of innate immunity and causes inflammatory diseases. However, the underlying molecular mechanisms of these toxicants in the regulation of macrophage inflammatory functions remain poorly understood. In this study, we addressed the effect of chronic exposure to BPA or phthalate at levels relevant to human exposure, either in vitro or in vivo, on the inflammatory reprograming of peritoneal macrophages. Our studies revealed that BPA and phthalates adversely affected expression levels of the proinflammatory cytokines and mediators in response to lipopolysaccharide stimulation. Exposure to these toxicants also affected gene expression of scavenger receptors and phagocytic capacity of peritoneal macrophages. Our studies revealed that the epigenetic inhibitors differentially modulated target gene expression in these cells. Further analysis revealed that certain histone modification enzymes were aberrantly expressed in response to BPA or phthalate exposure, leading to alteration in the levels of H3K36 acetylation and dimethylation, two chromatin modifications that are critical for transcriptional efficacy and accuracy. Our results further revealed that silencing of H3K36-specific methyltransferase Smyd2 expression or inhibition of SMYD2 enzymatic activity attenuated H3K36 dimethylation and enhanced interleukin-6 and tumor necrosis factor-α expression but dampened the phagocytic capacity of peritoneal macrophages. In summary, our results indicate that peritoneal macrophages are vulnerable to BPA or phthalate at levels relevant to human exposure. These environmental toxicants affect phenotypic programming of macrophages via epigenetic mechanisms involving SMYD2-mediated H3K36 modification.

This study explored how individual and team-level goal orientation influence individual creativity in a work setting. By creating a cross-level theoretical framework, we tested 562 members of 81 teams currently working in various companies in China. The study analyzed the relationships between individual goal orientation, team goal orientation, and individual creativity from cross-level perspective linked by motivated information processing theory. Applying multilevel research method and hierarchical-level modeling, we found that team learning goal orientation and individual learning goal orientation influence individual creativity through different information activities at their own levels. Moreover, team learning goal orientation has a positive and team performance-avoidance goal orientation has a negative effect on individual creativity through team information exchange, while individual learning goal orientation poses a positive effect on individual creativity through individual information elaboration. In conclusion, it was indicated that team members tend to elaborate more work-related information when teams are more learning-orientated. Conversely, team members do not tend to elaborate information when their team has higher performance-avoidance goal orientation.

A trap barrier system (TBS) is widely used to manage rodents in farming areas of China. Traditional TBSs are constructed as a rectangle around crops on the principle that rodents are attracted to the enclosed trap-crop (TC) which maximizes the number of rodents captured. This study evaluated the efficiency of capturing rodents using rectangular TBS with and without a trap-crop (R-TBS + TC and R-TBS), and linear TBS (L-TBS) for rodent control in maize fields in Northeastern China. The overall number of rodents captured by R-TBS + TC and R-TBS were not significantly different, but the peak number of rodents trapped by R-TBS occurred later in time in comparison to that of R-TBS + TC. There was no difference in the community composition of the captured rodents by R-TBS and R-TBS + TC. The numbers, age structures and sex ratios of Apodemus agrarius Pallas, the rodent species most commonly trapped by R-TBS + TC and R-TBS were uniform. Thigmotactic movement of a rodent is a more likely explanation for rodent capture than the attraction of trap-crops in R-TBS. The efficacy of L-TBS in capturing rodents was not significantly different compared with R-TBS. The community composition of captured rodents and the characteristics of A. agrarius population (population size, age structures and sex ratios) trapped by R-TBS and L-TBS were similar. L-TBS could be more practical for farmers and appears to provide similar levels of rodent control compared to the traditional R-TBS in this farming system.

Quantum computing technology has reached a second renaissance in the last decade. However, in the NISQ era pointed out by John Preskill in 2018, quantum noise and decoherence, which affect the accuracy and execution effect of quantum programs, cannot be ignored and corrected by the near future NISQ computers. In order to let users more easily write quantum programs, the compiler and runtime system should consider underlying quantum hardware features such as decoherence. To address the challenges posed by decoherence, in this paper, we propose and prototype QLifeReducer to minimize the qubit lifetime in the input OpenQASM program by delaying qubits into quantum superposition. QLifeReducer includes three core modules, i.e.,the parser, parallelism analyzer and transformer. It introduces the layered bundle format to express the quantum program, where a set of parallelizable quantum operations is packaged into a bundle. We evaluate quantum programs before and after transformed by QLifeReducer on both real IBM Q 5 Tenerife and the self-developed simulator. The experimental results show that QLifeReducer reduces the error rate of a quantum program when executed on IBMQ 5 Tenerife by 11%; and can reduce the longest qubit lifetime as well as average qubit lifetime by more than 20% on most quantum workloads., To appear in TASE2019 - the 13th International Symposium on Theoretical Aspects of Software Engineering (submitted on Jan 25, 2019, and this is camera-ready version)

Endometrial stromal cells differentiate to form decidual cells in a process known as decidualization, which is critical for embryo implantation and successful establishment of pregnancy. We previously reported that bone morphogenetic protein 2 (BMP2) mediates uterine stromal cell differentiation in mice and in humans. To identify the downstream target(s) of BMP2 signaling during decidualization, we performed gene-expression profiling of mouse uterine stromal cells, treated or not treated with recombinant BMP2. Our studies revealed that expression of Msx2, a member of the mammalian Msx homeobox gene family, was markedly upregulated in response to exogenous BMP2. Interestingly, conditional ablation of Msx2 in the uterus failed to prevent a decidual phenotype, presumably because of functional compensation of Msx2 by Msx1, a closely related member of the Msx family. Indeed, in Msx2-null uteri, the level of Msx1 expression in the stromal cells was markedly elevated. When conditional, tissue-specific ablation of both Msx1 and Msx2 was accomplished in the mouse uterus, a dramatically impaired decidual response was observed. In the absence of both Msx1 and Msx2, uterine stromal cells were able to proliferate, but they failed to undergo terminal differentiation. In parallel experiments, addition of BMP2 to human endometrial stromal cell cultures led to a robust enhancement of MSX1 and MSX2 expression and stimulated the differentiation process. Attenuation of MSX1 and MSX2 expression by small interfering RNAs greatly reduced human stromal differentiation in vitro, indicating a conservation of their roles as key mediators of BMP2-induced decidualization in mice and women.

The peptide hormone prolactin (PRL) and certain members of the epidermal growth factor (EGF) family play central roles in mammary gland development and physiology, and their dysregulation has been implicated in mammary tumorigenesis. Our recent studies have revealed that the CUB and zona pellucida-like domain-containing protein 1 (CUZD1) is a critical factor for PRL-mediated activation of the transcription factor STAT5 in mouse mammary epithelium. Of note, CUZD1 controls production of a specific subset of the EGF family growth factors and consequent activation of their receptors. Here, we found that consistent with this finding, CUZD1 overexpression in non-transformed mammary epithelial HC11 cells increases their proliferation and induces tumorigenic characteristics in these cells. When introduced orthotopically in mouse mammary glands, these cells formed adenocarcinomas, exhibiting elevated levels of STAT5 phosphorylation and activation of the EGF signaling pathway. Selective blockade of STAT5 phosphorylation by pimozide, a small-molecule inhibitor, markedly reduced the production of the EGF family growth factors and inhibited PRL-induced tumor cell proliferation in vitro. Pimozide administration to mice also suppressed CUZD1-driven mammary tumorigenesis in vivo. Analysis of human MCF7 breast cancer cells indicated that CUZD1 controls the production of the same subset of EGF family members in these cells as in the mouse. Moreover, pimozide treatment reduced the proliferation of these cancer cells. Collectively, these findings indicate that overexpression of CUZD1, a regulator of growth factor pathways controlled by PRL and STAT5, promotes mammary tumorigenesis. Blockade of the STAT5 signaling pathway downstream of CUZD1 may offer a therapeutic strategy for managing these breast tumors.

The incidence of reproductive problems such as infertility and cancers in women has increased at an alarming rate, particularly in developed countries. One potential cause of the rising incidence of reproductive problems is exposure to by-products of industrialization such as man-made chemicals and additives. These man-made chemicals could mimic or interfere with reproductive hormones and their functions, therefore leading to reproductive disorders. In addition, certain populations could be more susceptible to particular types of man-made chemicals due to genetic polymorphisms. The advancement of transgenic technology in mice over the past decade has brought the field of reproductive toxicology to a critical crossroad. These genetic models create unique opportunities for reproductive toxicologists to explore questions that could never before be imagined. To take full advantage of the power of these genetic models, a basic understanding of both female reproduction and the strengths and limitations of the genetic models is necessary. It is hoped that this article will trigger interest in and promote better use of transgenic mouse models in female reproductive toxicology.

Endometriosis is a prevalent gynecological disorder in which endometrial tissue proliferates in extrauterine sites, such as the peritoneal cavity, eventually giving rise to painful, invasive lesions. Dysregulated estradiol (E) signaling has been implicated in this condition. However, the molecular mechanisms that operate downstream of E in the ectopic endometrial tissue are unknown. To investigate these mechanisms, we used a mouse model of endometriosis. Endometrial tissue from donor mice was surgically transplanted on the peritoneal surface of immunocompetent syngeneic recipient mice, leading to the establishment of cystic endometriosis-like lesions. Our studies revealed that treatment with E led to an approximately 3-fold increase in the lesion size within a week of transplantation. E also caused a concomitant stimulation in the expression of connective tissue growth factor/Cyr61/Nov (CCN1), a secreted cysteine-rich matricellular protein, in the lesions. Interestingly, CCN1 is highly expressed in human ectopic endometriotic lesions. To address its role in endometriosis, endometrial tissue from Ccn1-null donor mice was transplanted in wild-type recipient mice. The resulting ectopic lesions were reduced up to 75% in size compared with wild-type lesions due to diminished cell proliferation and cyst formation. Notably, loss of CCN1 also disrupted the development of vascular networks in the ectopic lesions and reduced the expression of several angiogenic factors, such as vascular endothelial growth factor-A and vascular endothelial growth factor-C. These results suggest that CCN1, acting downstream of E, critically controls cell proliferation and neovascularization, which support the growth and survival of endometriotic tissue at ectopic sites. Blockade of CCN1 signaling during the early stages of lesion establishment may provide a therapeutic avenue to control endometriosis.

Exploration of deep earth requires ultra deep drilling attempts on the sea or continent, which is the main goal of scientific drilling projects currently established. Uncertain geological complexity, high requirement for R&D of critical equipment as well as high demand of practical performance has to be encountered during a scientific drilling project, making it full of challenge and risks. Risk management, therefore, is critically proposed for scientific drilling projects in order to reduce the risks. However, many traditional risk assessment methods may not perform well in the project due to lack of high quality data of historical record and sufficient information. This paper, therefore, proposes a fuzzy synthetic evaluation approach for scientific drilling project risk assessment. Four criteria — probability, severity, non-detectability and worsening factor are utilized to evaluate individual and overall risks comprehensively. Linguistic terms instead of numerical values are employed to evaluate each risk normally done by experts. AHP/ANP is used to determine sensible weights of each criterion. Values of risk indices are calculated to represent the level of each risk and the overall risk. Finally, a case study on risk analysis of SinoProbe-09 project conducted in Jilin University is tested to demonstrate the procedure of the method and to validate the proposed method. Results show that the risks of the scientific drilling project can be assessed effectively and efficiently.

Environmental and occupational exposure to endocrine disrupting chemicals (EDCs) is a major threat to female reproductive health. Bisphenol A (BPA), an environmental toxicant that is commonly found in polycarbonate plastics and epoxy resins, has received much attention due to its estrogenic activity and high risk of chronic exposure in human. Whereas BPA has been linked to infertility and recurrent miscarriage in women, the impact of its exposure on uterine function during early pregnancy remains unclear. In a recent publication in Endocrinology, we demonstrated that prolonged exposure to an environmental relevant dose of BPA disrupts progesterone receptor-regulated uterine functions, thus affecting uterine receptivity for embryo implantation and decidua morphogenesis, two critical events for establishment and maintenance of early pregnancy. In particular we reported a marked impairment of progesterone receptor (PGR) expression and its downstream effector HAND2 in the uterine stromal cells in response to chronic BPA exposure. In an earlier study we have shown that HAND2 controls embryo implantation by repressing fibroblast growth factor (FGF) expression and the MAP kinase signaling pathway, thus inhibiting epithelial proliferation. Interestingly we observed that downregulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with an enhanced activation of FGFR and MAPK signaling, aberrant proliferation, and lack of uterine receptivity in the epithelium. In addition, the proliferation and differentiation of endometrial stromal cells to decidual cells, an event critical for the maintenance of early pregnancy, was severely compromised in response to BPA. This research highlight will provide an overview of our findings and discuss the potential mechanisms by which chronic BPA impairs PGR-HAND2 pathway and adversely affects implantation and the establishment of pregnancy.

Environmental and occupational exposure to bisphenol A (BPA), a chemical widely used in polycarbonate plastics and epoxy resins, has received much attention in female reproductive health due to its widespread toxic effects. Although BPA has been linked to infertility and recurrent miscarriage in women, the impact of its exposure on uterine function during early pregnancy remains unclear. In this study, we addressed the effect of prolonged exposure to an environmental relevant dose of BPA on embryo implantation and establishment of pregnancy. Our studies revealed that treatment of mice with BPA led to improper endometrial epithelial and stromal functions thus affecting embryo implantation and establishment of pregnancy. Upon further analyses, we found that the expression of progesterone receptor (PGR) and its downstream target gene, HAND2 (heart and neural crest derivatives expressed 2), was markedly suppressed in BPA-exposed uterine tissues. Previous studies have shown that HAND2 controls embryo implantation by repressing fibroblast growth factor and the MAPK signaling pathways and inhibiting epithelial proliferation. Interestingly, we observed that down-regulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with enhanced activation of fibroblast growth factor and MAPK signaling in the epithelium, thus contributing to aberrant proliferation and lack of uterine receptivity. Further, the differentiation of endometrial stromal cells to decidual cells, an event critical for the establishment and maintenance of pregnancy, was severely compromised in response to BPA. In summary, our studies revealed that chronic exposure to BPA impairs PGR-HAND2 pathway and adversely affects implantation and the establishment of pregnancy.

The progesterone receptor (PR) plays a critical role during ovulation. Mice lacking the PR gene are anovulatory due to a failure in the rupture of the preovulatory follicles. The pathways that operate downstream of PR to control ovulation are poorly understood. Using gene expression profiling, we identified peroxisome proliferator-activated receptor gamma (PPARgamma) as a target of regulation by PR in the granulosa cells of the preovulatory follicles during the ovulatory process. To investigate the function of PPARgamma during ovulation, we created a conditional knockout mouse in which this gene was deleted via Cre-Lox-mediated excision in granulosa cells. When these mutant mice were subjected to gonadotropin-induced superovulation, the preovulatory follicles failed to rupture and the number of eggs released from the mutant ovaries declined drastically. Gene expression analysis identified endothelin-2, interleukin-6, and cyclic GMP-dependent protein kinase II as novel targets of regulation by PPARgamma in the ovary. Our studies also suggested that cycloxygenase 2-derived metabolites of long-chain fatty acids function as endogenous activating ligands of PPARgamma in the preovulatory follicles. Collectively, these studies revealed that PPARgamma is a key mediator of the biological actions of PR in the granulosa cells and activation of its downstream pathways critically controls ovulation.

Endometriosis, defined as growth of the endometrial cells outside the uterus, is an inflammatory disorder that is associated with chronic pelvic pain and infertility in women of childbearing age. Although the estrogen-dependence of endometriosis is well known, the role of progesterone in development of this disease remains poorly understood. In this study, we developed a disease model in which endometriosis was induced in the peritoneal cavities of immunocompetent female mice, and maintained with exogenous estrogen. The endometriosis-like lesions that were identified at a variety of ectopic locations exhibited abundant blood supply and extensive adhesions. Histological examination revealed that these lesions had a well-organized endometrial architecture and fibrotic response, resembling those recovered from clinical patients. In addition, an extensive proliferation, inflammatory response, and loss of estrogen receptor alpha (ERα) and progesterone receptor (PR) expression were also observed in these lesions. Interestingly, administration of progesterone before, but not after, lesion induction suppressed lesion expansion and maintained ERα and PR expressions. These progesterone-pretreated lesions exhibited attenuation in KI67, CD31, and pro-inflammatory cytokine expression as well as macrophage infiltration, indicating that progesterone ameliorates endometriosis progression by inhibiting cell proliferation, inflammation and neovascularization. Our studies further showed that suppression of global DNA methylation by application of DNA methyltransferase inhibitor to female mice bearing ectopic lesions restrained lesion expansion and restored ERα and PR expression in eutopic endometrium and ectopic lesions. These results indicate that epigenetic regulation of target gene expression via DNA methylation contributes, at least in part, to progesterone resistance in endometriosis.

The endometrium acquires the ability to implant the developing embryo within a specific time window, termed the "receptive phase." During this period, the endometrium undergoes pronounced structural and functional changes induced by the ovarian steroids, estrogen and progesterone, which prepare it to be receptive to invasion by the embryo. These steroid-induced molecules, when identified, may serve as useful markers of uterine receptivity. In this article, we provide a brief description of one such molecule that has emerged as candidate marker of steroid hormone action in rats and humans during implantation.