Warburg-like Glycolysis and Lactate Shuttle in Mouse Decidua during Early Pregnancy.

Decidualization is an essential process of maternal endometrial stromal cells to support pregnancy. Although it is known that enhanced glucose influx is critical for decidualization, the underlying mechanism in regulating glucose metabolism in decidua remains insufficiently understood. Here, we demonstrate that aerobic glycolysis-related genes and factors are all substantially induced during decidualization, indicating the existence of Warburg-like glycolysis in decidua. In vitro, progesterone activates hypoxia-inducible factor 1α (Hif1α) and c-Myc through Pi3k-Akt signaling pathway to maintain aerobic glycolysis in decidualizing cells. Knocking down of pyruvate kinase M2 (Pkm2) attenuates the induction of decidual marker gene. Decidual formation in vivo is also impaired by glycolysis inhibitor 3-bromopyruvate. Besides, lactate exporter monocarboxylate transporter 4 (Mct4) is induced in newly formed decidual cells, whereas lactate importer Mct1 and proliferation marker Ki-67 are complementarily located in the surrounding undifferentiated cells, which are supposed to consume lactate for proliferation. Hif1α activation is required for lactate-dependent proliferation of the undifferentiated cells. Inhibition of lactate flux leads to compromised decidualization and decelerated lactate-dependent proliferation. In summary, we reveal that Warburg-like glycolysis and local lactate shuttle are activated in decidua and play important roles for supporting early pregnancy.

Effect of Aurora kinase B on polyploidy and decidualization in mouse uterus.

RESEARCH QUESTION: Decidualization is critical to the establishment of mouse normal pregnancy. The fibroblast-like stromal cells in the process form polyploid multinucleated cells. Aurora kinase B (Aurora B) has previously been shown to regulate polyploidy in various cells. However, whether Aurora B regulates the formation of decidual cell polyploidization and its regulatory mechanisms remain poorly understood. DESIGN: Establish decidualization model of mouse primary endometrial stromal cells in vitro. Construct pseudopregnancy mouse models and delayed-activation mouse models. Detect Aurora B and polyploidization related genes in mouse uteri treated by Aurora B specific inhibitor Barasertib and CPT. RESULTS: In this study, we found that Aurora B was strongly expressed in endometrial stromal cells after implantation. Additionally, Aurora B was remarkably up regulated in the stromal cells of oil-induced deciduomoa and in vitro decidualization. As an Aurora B specific inhibitor, Barasertib significantly inhibits the mRNA expression of Prl8a2, a marker of mouse decidualization. Furthermore, the protein levels of p-Plk1, Survivin and p-Cdk1 were inhibited by Barasertib. CPT-induced DNA damage suppressed Aurkb (encodes Aurora B) expression, thus resulting in polyploidization. CONCLUSION: Our data shows that Aurora B is expressed in decidual stromal cells of implantation sites and plays a key role for mouse decidualization. The protein of Plk1, Survivn, and Cdk1 may participate in formation of decidual cell polyploidization during mouse decidualization.

AIoT Used for COVID-19 Pandemic Prevention and Control.

The pandemic of COVID-19 is continuing to wreak havoc in 2021, with at least 170 million victims around the world. Healthcare systems are overwhelmed by the large-scale virus infection. Luckily, Internet of Things (IoT) is one of the most effective paradigms in the intelligent world, in which the technology of artificial intelligence (AI), like cloud computing and big data analysis, is playing a vital role in preventing the spread of the pandemic of COVID-19. AI and 5G technologies are advancing by leaps and bounds, further strengthening the intelligence and connectivity of IoT applications, and conventional IoT has been gradually upgraded to be more powerful AI + IoT (AIoT). For example, in terms of remote screening and diagnosis of COVID-19 patients, AI technology based on machine learning and deep learning has recently upgraded medical equipment significantly and has reshaped the workflow with minimal contact with patients, so medical specialists can make clinical decisions more efficiently, providing the best protection not only to patients but also to specialists themselves. This paper reviews the latest progress made in combating COVID-19 with both IoT and AI and also provides comprehensive details on how to combat the pandemic of COVID-19 as well as the technologies that may be applied in the future.

[Efficacy and side-effects of docetaxel combined with cisplatin on the treatment of local advanced esophageal cancer with concomitant radiation therapy].

OBJECTIVE: To investigate the therapeutical effect and side-effect of docetaxel combined with cisplatin (DDP) on the treatment of local advanced esophageal cancer with concomitant radiation therapy. METHODS: Ninety patients with LOCAL advanced esophageal squamous cell carcinoma were divided into two groups: (DDP + 5-Fu) group and (docetaxel + DDP) group. Chemotherapy was carried out every 4 weeks for a total of 4 courses. The radiation dose was 50.4 Gy/28FX. RESULTS: The median survival time of patients in the (DDP + 5-Fu) group was 16 months and that in (docetaxel + DDP) group was 21 months (P = 0.0278). The 3-year survival rate in the (docetaxel + DDP) group was obviously higher than that in the (DDP + 5-Fu) group (23.9% vs. 12.1%). The ORR in (docetaxel + DDP) group (84.5%) was significantly higher than that in the (DDP + 5-Fu) group (71.1%) (P = 0.025). No significant differences were observed in the incidence of side-effects in the two groups. CONCLUSIONS: The conventional dose chemotherapy of docetaxel + DDP with concomitant radiation therapy showed a better partial remission rate and long-term survival rate for the treatment of local advanced esophageal cancer than the traditional chemotherapy (DDP + 5-Fu) with concomitant radiation therapy and the side-effects are not increased.

ATP mediates the interaction between human blastocyst and endometrium.

OBJECTIVE: Embryo implantation needs a reciprocal interaction between competent embryo and receptive endometrium. Adenosine triphosphate (ATP) produced by stressed or injured cells acts as an important signalling molecule. This study aims to investigate whether adenosine triphosphate (ATP) plays an important role in the dialogue of human blastocyst-endometrium. MATERIALS AND METHODS: The concentration of lactate was analysed in culture medium from human embryos collected from in vitro fertilization patients. Extracellular ATP was measured by ATP Bioluminescent Assay Kit. Ishikawa cells and T-HESCs were treated with ATP, ATP receptor antagonist, ATP hydrolysis enzyme or inhibitors of ATP metabolic enzymes. The levels of gene expression were evaluated by real-time PCR and immunoassay. RESULTS: We showed that injured human endometrial epithelial cells could rapidly release ATP into the extracellular environment as an important signalling molecule. In addition, blastocyst-derived lactate induces the release of non-lytic ATP from human endometrial receptive epithelial cells via connexins. Extracellular ATP stimulates the secretion of IL8 from epithelial cells to promote the process of in vitro decidualization. Extracellular ATP could also directly promote the decidualization of human endometrial stromal cells via P2Y-purinoceptors. More importantly, the supernatants of injured epithelial cells clearly induce the decidualization of stromal cells in time-dependent manner. CONCLUSION: Our results suggest that ATP should play an important role in human blastocyst-endometrium dialogue for the initiation of decidualization.

Blastocyst-induced ATP release from luminal epithelial cells initiates decidualization through the P2Y2 receptor in mice.

Embryo implantation involves a sterile inflammatory reaction that is required for the invasion of the blastocyst into the decidua. Adenosine triphosphate (ATP) released from stressed or injured cells acts as an important signaling molecule to regulate many key physiological events, including sterile inflammation. We found that the amount of ATP in the uterine luminal fluid of mice increased during the peri-implantation period, and this depended on the presence of an embryo. We further showed that the release of ATP from receptive epithelial cells was likely stimulated by lactate released from the blastocyst through connexin hemichannels. The ATP receptor P2y2 was present on uterine epithelial cells during the preimplantation period and increased in the stromal cells during the time at which decidualization began. Pharmacological inhibition of P2y2 compromised decidualization and implantation. ATP-P2y2 signaling stimulated the phosphorylation of Stat3 in uterine luminal epithelial cells and the expression of early growth response 1 (Egr1) and prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as Cox-2), all of which are required for decidualization and/or implantation, in stromal cells. Short exposure to high concentrations of ATP promoted decidualization of primary stromal cells, but longer exposures or lower ATP concentrations did not. The expression of genes encoding ATP-degrading ectonucleotidases increased in the decidua during the peri-implantation period, suggesting that they may limit the duration of the ATP signal. Together, our results indicate that the blastocyst-induced release of ATP from uterine epithelial cells during the peri-implantation period may be important for the initiation of stromal cell decidualization.

Three-dimensional drivable optrode array for high-resolution neural stimulations and recordings in multiple brain regions.

The brain-computer interface (BCI) devices are of prime important for study of nervous system as well as diagnosis and treatment of neurological disorders. To meet the needs of the BCI devices in high-density integration and multi-functionalization, 3-dimensional (3D) drivable optrode array with laser diodes (LDs) coupled waveguides was developed. The unique device realizes the 3D integration of the optrodes and avoids fiber tangle and tissue heating by adopting LD coupled waveguide structure. Besides, the postoperative position adjustment of the optrode array was achieved by integrating with a 3D printed micro-drive. Most importantly, high-resolution neural stimulations and recordings were achieved for study of working memory related neural circuits in four brain regions of mice including prelimbic cortex (PrL), mediodorsal thalamic nucleus (MD), dorsal medial caudate nucleus (dmCP) and posterior motor cortex 2 (pM2). The results indicate that this novel device is promising for the research of complex neural networks.

Nucleolar stress regulation of endometrial receptivity in mouse models and human cell lines.

Embryo implantation is essential to the successful establishment of pregnancy. A previous study has demonstrated that actinomycin D (ActD) could initiate the activation of mouse delayed implantation. However, the mechanism underlying this activation remains to be elucidated. A low dose of ActD is an inducer of nucleolar stress. This study was to examine whether nucleolar stress is involved in embryo implantation. We showed that nucleolar stress occurred when delayed implantation was activated by ActD in mice. ActD treatment also stimulated the Lif-STAT3 pathway. During early pregnancy, nucleolar stress was detected in the luminal epithelial cells during the receptive phase. Blastocyst-derived lactate could induce nucleolar stress in cultured luminal epithelial cells. The inhibition of nucleophosmin1 (NPM1), which was a marker of nucleolar stress, compromised uterine receptivity and decreased the implantation rates in pregnant mice. To translate these mouse data into humans, we examined nucleolar stress in human endometrium. Our data demonstrated that ActD-induced nucleolar stress had positive effects on the embryo attachment by upregulating IL32 expression in non-receptive epithelial cells rather than receptive epithelial cells. Our data should be the first to demonstrate that nucleolar stress is present during early pregnancy and is able to induce embryo implantation in both mice and humans.

De novo synthesis of sphingolipids is essential for decidualization in mice.

Sphingolipids play multiple roles in membrane structure, signal transduction, stress responses, neural development and immune reaction. The rate of de novo synthesis pathway of sphingolipids is regulated by two key enzymes, serine palmitoyltransferase (SPT), and ketoreductase (Kds). Here, we find that the mRNA levels of three subunits of the SPT holoenzyme (Sptlc1, Sptlc2, and Ssspta) are significantly up-regulated in mouse uterine stromal cells during decidualization. The expression of Kds, which reduces 3-keto-dihydrosphingosine to dihydrosphingosine, is co-localized with Sptlc1 in mouse uteri during early pregnancy. Moreover, l-Cycloserine, a specific inhibitor of SPT, can significantly decrease the weight and number of implantation sites, and impede the decidualization process in mouse uterine stromal cells, suggesting that blockage of de novo sphingolipid synthesis may cause defective decidualization and early pregnancy loss in mice. In addition, this study also shows progesterone (P4) can stimulate the expression of both Sptlc2 and Ssspta in mouse uterus. Therefore, our study shows that de novo synthesis of sphingolipids is necessary in implantation and plays a key role in decidualization of mouse.

Direct electrodeposition of Graphene enhanced conductive polymer on microelectrode for biosensing application.

Engineering of neural interface with nanomaterials for high spatial resolution neural recording and stimulation is still hindered by materials properties and modification methods. Recently, poly(3,4-ethylene-dioxythiophene) (PEDOT) has been widely used as an electrode-tissue interface material for its good electrochemical property. However, cracks and delamination of PEDOT film under pulse stimulation are found which restrict its long-term applications. This paper develops a flexible electrochemical method about the co-deposition of graphene with PEDOT on microelectrode sites to enhance the long-term stability and improve the electrochemical properties of microelectrode. This method is unique and profound because it co-deposits graphene with PEDOT on microelectrode sites directly and avoids the harmful post reduction process. And, most importantly, significantly improved electrochemical performances of the modified microelectrodes (compared to PEDOT-GO) are demonstrated due to the large effective surface area, good conductivity and excellent mechanical property of graphene. Furthermore, the good mechanical stability of the composites is verified by ultrasonication and CV scanning tests. In-vivo acute implantation of the microelectrodes reveals the modified microelectrodes show higher recording performance than the unmodified ones. These findings suggest the composites are excellent candidates for the applications of neural interface.

The high concentration of progesterone is harmful for endometrial receptivity and decidualization.

Progesterone is required for the establishment and maintenance of mammalian pregnancy and widely used for conservative treatment of luteal phase deficiency in clinics. However, there are limited solid evidences available for the optimal timing and dose of progesterone therapy, especially for the possible adverse effects on implantation and decidualization when progesterone is administrated empirically. In our study, mouse models were used to examine effects of excess progesterone on embryo implantation and decidualization. Our data indicate that excess progesterone is not only harmful for mouse implantation, but also impairs mouse decidualization. In excess progesterone-treated mice, the impaired LIF/STAT3 pathway and dysregulated endoplasmic reticulum stress may lead to the inhibition of embryo implantation and decidualization. It is possible that the decrease in birth weight of excess progesterone-treated mice is due to a compromised embryo implantation and decidualization. Furthermore, excess progesterone compromises in vitro decidualization of human endometrial stromal cells.

The decline of pregnancy rate and abnormal uterine responsiveness of steroid hormones in aging mice.

Reproductive capacity in animals and women declines with increasing age. Although ovarian aging is considered as a main cause for the decline of pregnancy rate, whether uterine aging occurs remains unclear. Even if blastocysts are transferred from young donors to older pseudopregnant recipients, the rate of implantation is still low, suggesting the occurrence of uterine aging. In this study, we compared the pregnancy rate and the uterine responsiveness of steroid hormones in ovariectomized mice at age between 2- and 12-month-old. Compared to 2-month-old mice, there is a significant decrease of both pregnancy rate and the number of implantation sites in 12-month-old mice. In ovariectomized mice, the uterine responsiveness of steroid hormones is also significantly different between 2- and 12-month-old mice. On day 4, Muc1 and PR level in 12-month-old mice is significantly higher than that in 2-month-old mice, while Hand2 level is significantly lower in 12-month-old mice. Our data suggest that the abnormal responsiveness of steroid hormones may contribute to the decline of pregnancy rate in 12-month-old mice.

Endoplasmic reticulum stress in mouse decidua during early pregnancy.

Unfolded or misfolded protein accumulation in the endoplasmic reticulum lumen leads to endoplasmic reticulum stress (ER stress). Although it is known that ER stress is crucial for mammalian reproduction, little is known about its physiological significance and underlying mechanism during decidualization. Here we show that Ire-Xbp1 signal transduction pathway of unfolded protein response (UPR) is activated in decidual cells. The process of decidualization is compromised by ER stress inhibitor tauroursodeoxycholic acid sodium (TUDCA) and Ire specific inhibitor STF-083010 both in vivo and in vitro. A high concentration of ER stress inducer tunicamycin (TM) suppresses stromal cells proliferation and decidualization, while a lower concentration is beneficial. We further show that ER stress induces DNA damage and polyploidization in stromal cells. In conclusion, our data suggest that the GRP78/Ire1/Xbp1 signaling pathway of ER stress-UPR is activated and involved in mouse decidualization.

Non-coding RNA LINC00473 mediates decidualization of human endometrial stromal cells in response to cAMP signaling.

Decidualization is an essential step in the establishment of pregnancy. However, the functional contributions of long intergenic noncoding RNAs (LincRNAs) to decidualization have not been explored. To explore the regulation and role of LincRNAs during human decidualization, human endometrial stromal cells (HESCs) are induced to undergo in vitro decidualization by treating with estradiol-17ß, db-cAMP and medroxyprogesterone acetate. LINC00473 (LINC473) expression is highly induced in HESCs after decidual stimulus. We found that cAMP-PKA pathway regulates the expression of LINC473 through IL-11-mediated STAT3 phosphorylation. RNA interference-mediated down-regulation of LINC473 inhibits in vitro decidualization. These results suggested that LINC473 might be functionally required for human decidualization. This is the first report demonstrating the presence of LincRNA during human decidualization.

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization.

Polyploid decidual cells are specifically differentiated cells during mouse uterine decidualization. However, little is known about the regulatory mechanism and physiological significance of polyploidization in pregnancy. Here we report a novel role of E2F8 in the polyploidization of decidual cells in mice. E2F8 is highly expressed in decidual cells and regulated by progesterone through HB-EGF/EGFR/ERK/STAT3 signaling pathway. E2F8 transcriptionally suppresses CDK1, thus triggering the polyploidization of decidual cells. E2F8-mediated polyploidization is a response to stresses which are accompanied by decidualization. Interestingly, polyploidization is not detected during human decidualization with the down-regulation of E2F8, indicating differential expression of E2F8 may lead to the difference of decidual cell polyploidization between mice and humans.

Progesterone and heparin-binding epidermal growth factor-like growth factor regulate the expression of tight junction protein Claudin-3 during early pregnancy.

OBJECTIVE: To determine Claudin-3 expression and its regulatory factors during embryo implantation. DESIGN: Experimental mouse models and cell culture. SETTING: University research laboratory. ANIMAL(S): Sexually mature female CD-1 strain mice. INTERVENTION(S): Ovariectomy and treatments. MAIN OUTCOME MEASURE(S): In situ hybridization and immunohistochemistry for detecting Claudin-3 messenger RNA and protein expression in mouse uterus, respectively; Western blot for detecting protein levels; immunofluorescence for detecting Claudin-3 protein in cultured cells. RESULT(S): Claudin-3 is strongly expressed in the uterine luminal epithelium on days 3 and 4 of pregnancy, and diminished at day 5 implantation sites. Then it is expressed at secondary decidual zone on day 8. Pseudopregnant uteri have a similar expression pattern as pregnant uteri from days 1-5. Claudin-3 expression is down-regulated after delayed implantation is activated by estrogen (E) treatment. Meanwhile Claudin-3 expression is stimulated by artificial decidualization. In ovariectomized mice, P induces Claudin-3 expression in the luminal epithelium, which is abrogated by P receptor antagonist RU486. Heparin-binding-epidermal growth factor (HB-EGF) down-regulates Claudin-3 expression, but enhances transcription factor Snail expression. In human endometrial epithelial ECC-1 cells, both E and P could stimulate Claudin-3 expression, whereas HB-EGF decreases Claudin-3 and increases Snail expression. CONCLUSION(S): Claudin-3 expression in uterine luminal epithelium is stimulated by P and suppressed by HB-EGF in mice and humans.

[China's environmental load and environmental depressurization analysis].

Based on material flow accounting and related indicators, an indicator, domestic environmental load, is formulated to measure the aggregate environmental pressure of a nation. Combining this indicator with the gross national product, an indicator for environmental efficiency is derived. The domestic environmental load is then decomposed into the rebound effect caused by economic growth and the depressurization effect induced by the efficiency increase. A case study was carried out for the Chinese economy to investigate its domestic environmental load, environmental efficiency and the rebound and depressurization effects. Results show that the environmental efficiency of the Chinese economy increased during the study period with an annual rate of 5.6%, indicating that a certain degree of depressurization was achieved. However, the rebound effect caused by economic growth was much greater than the depressurization effect induced by the efficiency increase,resulting in a considerable increase in the domestic environmental load (the annual growth rate was 3.8%). The Chinese economy is characterized by high environmental pressure and it is hard to achieve absolute depressurization.

[Ecological footprint in building green university].

Ecological footprint is one of the best indexes to evaluate the level of green university. The approaches of ecological footprint are made up of compound approach and component approach. This paper introduces the basic principle and algorithm of the componential approach of ecological footprint, taking Northeastern University as an example and using this approach in the research of campus. Result show that the ecological footprint of Northeastern University 2003 was 24 787hm2, needing the productive land of ecology about 25 000hm2 support all kinds of consumption of the school and absorb the offal. The ecological efficiency of the school was 0.94cap/hm2. In the ecological footprints, the energy's footprints is the largest, it accounted for more than 2/3 of the total footprints, the next are food consumption and solid rubbish.