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Contents To stably maintain pregnancy, several genes are expressed in the uterus. In particular, the endometrial expression of genes encoding growth factors appears to play a key role in maternal–foetal communication. The previous studies characterized the endometrial expression kinetics of the genes encoding epidermal growth factor (EGF), its receptor (EGFR), transforming growth factor-alpha (TGF-α), amphiregulin (Areg), heparin-binding (Hb) EGF and calbindin-D9k (CaBP-9k) in pigs during implantation. Here, we further characterized the expression patterns of these molecules during the entire porcine pregnancy. Porcine uteri were collected at pregnancy days (PD) 12, 15, 30, 60, 90 and 110 and subjected to RT-PCR. EGF and EGFR showed similar expression patterns, being highly expressed around implantation and then disappearing. TGF-α and Areg expression levels rose steadily until they peaked at PD30, after which they gradually decreased to PD12 levels. This Areg mRNA expression pattern was confirmed by real-time PCR and similar Areg protein expression patterns were observed. Immunohistochemical analysis of PD60 uteri revealed Areg in the glandular and luminal epithelial cells. Hb EGF was steadily expressed throughout the entire pregnancy, while CaBP-9k was expressed strongly on PD12, and then declined sharply on PD15 before recovering slightly for the remainder of the pregnancy. Thus, the EGF family may play a key role during implantation in pigs. In addition, CaBP-9k may help to maintain uterine quiescence during pregnancy by sequestering cytoplasmic Ca2+. [ABSTRACT FROM AUTHOR]

Transient receptor potential cation channel, subfamily V, member 6 (TRPV6) is an epithelial Ca2+ channel protein expressed in calcium-absorbing organs. Recently it was reported that TRPV6 is expressed in female reproductive organs. The present study was performed to investigate the expression and regulation of uterine and placental TRPV6 during gestation in rats. In the uterus, TRPV6 was moderately expressed at pregnancy day (P) 0 and decreased until P4. Its expression level then peaked at P5, implying that TRPV6 may be involved in embryo implantation. Around P13, uterine TRPV6 expression increased slightly a second time, and then gradually decreased until the end of pregnancy at P21. Tissue localization of TRPV6 expression was determined by immunohistochemistry methods. TRPV6 protein was detected in uterine endothelium layers and glands; however, it was not detected in uterine tissues attached to the placenta. In the placenta, TRPV6 mRNA levels increased in mid-gestation, and the tissue distribution of placental TRPV6 protein suggests that it may play a role in transferring calcium to the fetus during pregnancy. To investigate the pathway(s) mediating TRPV6 expression during pregnancy in rats and mice, steroid hormone antagonists ICI 182 780 (ICI) and RU 486 (RU) were injected prior to maximal TRPV6 expression, as anti-estrogen and anti-progesterone agents, respectively. Pregnant rats (P4 for uterine RNA preparation, P19 for placental RNA preparation) received subcutaneous injections of RU (2.5 mg per rat), ICI (0.5 mg per rat), or a combination of RU and ICI. In addition, ICR-mice at P9 were injected with RU (25 µg per mouse) and/or ICI (2 µg per mouse). We measured level of TRPV6 mRNA transcription using semi-quantitative RT-PCR and real-time PCR. Data were analyzed by nonparametric one-way analysis of variance using the Kruskal-Wallis test, followed by Dunnett''s test for multiple comparisons to vehicle. In rats, TRPV6 expression was reduced by RU treatment, and in mice ICI treatment blocked TRPV6 expression. Taken together, these results suggest that progesterone in rats and estrogen in mice act to regulate TRPV6 expression in the uterus and placenta during pregnancy. In conclusion, TRPV6 may play a role in embryo implantation in the uterus and in calcium transport between embryo and mother in the placenta. [ABSTRACT FROM AUTHOR]

Calcium Transporter 1 (CaT1), which is highly expressed in calcium-absorption organs, i.e. duodenum and kidney, is a critical mediator for calcium uptake during transcellular calcium transport. It has been shown that CaT1 gene is also expressed in the placenta and uterine smooth muscle in female reproductive organs. We previously demonstrated that uterine CaT1 mRNA is highly expressed at diestrus and tightly regulated by progesterone (P4) related to calcium homeostasis for uterine functions during the estrous cycle in rats. Thus, in the recent study, we further examined the expression of CaT1 mRNA in the uterus and placenta of rats to elucidate its role during pregnancy in these tissues. Female Sprague Dawley rats (n = 2) were employed and their pregnancy days (PD) were determined by a vaginal plug every morning; the rats were euthanized daily (PD 0 to 21). The expression of CaT1 mRNA decreased from PD 0 to 4 and highly increased on PD 5 to 10. Its increased transcripts gradually decreased at the end of pregnancy. Taken together, these results indicate that the expression level of CaT1 mRNA is regulated in the uterus of rats during pregnancy, probably via sex steroid hormones and their receptors through a complex pathway. A further study is warranted to verify relevant factors which regulate CaT1 gene and to provide further insight into its role(s) in the female reproductive tissues. [ABSTRACT FROM AUTHOR]

Implantation in mammalian species is a complex process that involves embryo apposition and attachment to the apical surface of the uterine epithelium. This process involves a variant of molecules that are not unique in themselves but play unique roles in the process of implantation. Among them, the epidermal growth factor (EGF) family, the cytokines, cell adhesion molecules, and calcium-binding proteins appear to be important in embryonic attachment. Amphireguline (Areg), its receptor (EGFR), and calbindin-D9k (CaBP-9k) were highly expressed before implantation. Thus, in the present study, using rodent and porcine models, the expression levels of Areg, EGFR, and CaBP-9k gene were analyzed in the uterus during the estrous cycle and pregnancy by means of RT-PCR to elucidate their roles in implantation. Areg and CaBP-9k were significantly up-regulated at diestrus; however, these transcripts disappeared at proestrus in mice. In addition, EGFR mRNA was primarily observed at diestrus in mice. Although CaBP-9k and EGFR transcripts of rats increased at proestrus, no Areg mRNA was observed in this model. To clarify the regulator of the mouse Areg gene, immature mice were injected with sex steroid hormones. No transcripts of Areg were detected in these models, suggesting that mouse Areg may require other puberty factors. Porcine expressions of uterine Areg, EGFR, and CaBP-9k mRNA fluctuated during pregnancy (Days 12, 15, 30, 60, 90, and 110 of pregnancy). CaBP-9k transcripts were highly expressed on Day 12 and decreased on Days 15 to 90. On Day 110, CaBP-9k mRNA was expressed as well. Areg mRNA increased on Days 12 to 30, and decreased on Days 30 to 110. EGFR transcripts were detected on Day 12 and gradually disappeared till the end of pregnancy. Uterine Areg and CaBP-9k mRNAs were regulated by progesterone (P4) in the mouse model. Areg transcripts of porcine uteri appear to be expressed after implantation, but CaBP-9k mRNA was induced before embryo attachment. Taken together, these results indicate taht uterine Areg, EGFR, and CaBP-9k are differentially regulated during pregnancy in these species, and porcine CaBP-9k could act as an important factor in implantation. A further spatial expression of these genes will contribute to the understanding of their complex molecular actions involved in embryo attachment. [ABSTRACT FROM AUTHOR]

We report here the synthesis andstructure–activity relationship(SAR) of a novel series of mammalian target of rapamycin (mTOR) kinaseinhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized forin vivo efficacy. These efforts resulted in the identification ofcompounds with excellent mTOR kinase inhibitory potency, with exquisitekinase selectivity over the related lipid kinase PI3K. The improvedPK properties of this series allowed for exploration of in vivo efficacyand ultimately the selection of CC-223 for clinical development. [ABSTRACT FROM AUTHOR]

In the case of internal gear pumps, the eccentricity of the outer rotor, which resembles a circular lobe, must be limited to a certain value in order to avoid the formation of cusps and loops; furthermore, the tip width of the inner rotor, which has a hypocycloid curve and an epicycloid curve, should not be allowed to exceed the limit value. In this study, we suggest that the tip width of the inner rotor be controlled by inserting a circular-arc curve between the hypocycloid and epicycloid curves. We also suggest that the outer rotor be designed using the closed-form equation for the inner rotor and the width correction coefficient. Thus, it is possible to design a gerotor for which there is no upper limit on the eccentricity, as in this case, undercut is prevented and there is no restriction on the tip width. We also develop an automated program for rotor design and calculation of the flow rate and flow rate irregularity. We demonstrate the superior performance of the gerotor developed in this study by analyzing the internal fluid flow using a commercial computational fluid dynamics (CFD)-code. [ABSTRACT FROM AUTHOR]

To stably maintain pregnancy, several genes are expressed in the uterus. In particular, the endometrial expression of genes encoding growth factors appears to play a key role in maternal–fetal communication. Previous studies have characterized the endometrial expression kinetics of the genes encoding epidermal growth factor (EGF), its receptor (EGFR), transforming growth factor-alpha (TGF-α), amphiregulin (Areg), heparin-binding (Hb) EGF, and calbindin-D9k (CaBP-9k) in the pig during implantation. Here, we further characterized the expression patterns of these molecules during the entire porcine pregnancy. Porcine (n = 3 per PD) were collected at pregnancy days (PD) 12, 15, 30, 60, 90, and 110 and subjected to semi-quantitative RT-PCR. The data were analyzed with a nonparametric one-way analysis of variance using the Kruskal-Wallis test, followed by Dunnett's test for multiple comparisons to the negative control. EGF and EGFR showed similar expression patterns, being highly expressed around implantation time and then disappearing. TGF-α and Areg expression levels rose steadily until they peaked at PD30, after which they gradually decreased to PD12 levels. The Areg mRNA expression pattern was confirmed by real-time PCR, and similar Areg protein expression patterns were observed. Immunohistochemical analysis of PD60 uteri revealed Areg in the glandular and luminal epithelial cells. Hb-EGF was steadily expressed throughout the entire pregnancy while CaBP-9k was expressed strongly on PD12, and then declined sharply in PD15 before recovering slightly for the remainder of the pregnancy. Thus, the EGF family may play a key role during implantation in pigs. In addition, CaBP-9k may help maintain uterine quiescence during pregnancy by sequestering cytoplasmic Ca2+. [ABSTRACT FROM AUTHOR]

The implantation of the developing blastocyst into the uterine wall is regulated by a precisely timed interplay of the ovarian hormones estrogen and progesterone, which control a set of regulatory factors that make the uterus receptive to implantation. These factors include EGF receptor (Egfr) and members of the epidermal growth factor (Egf) family, namely, EGF, heparin-binding EGF (Hbegf), transforming growth factor-alpha (Tgfa), and amphiregulin (Areg). However, the exact role(s) these factors play in pregnancy remain unclear. To address this, a group of three rats was euthanized every day from gestation day (GD) 0 through to GD21. The uterus, attached uterus (these tissues are mostly composed of stromal cells), and placenta were rapidly excised and used directly for total RNA. We used real-time PCR with the TaqMan system (Applied Biosystems, Foster City, CA, ISA) to examine the uterine expression patterns of these factors in rats during the entire pregnancy. Data were analyzed by nonparametric one-way analysis of variance using the Kruskal-Wallis test, followed by Dunnett''s test for multiple comparisons. Egf and Egfr mRNA levels increased significantly at implantation, especially on GD3 and GD6, after which their expression gradually decreased. Hbegf and Tgfa showed a modest spike of transcription around the implantation period (GD4 and GD3, respectively) but were much more strongly expressed at mid-pregnancy, which is when progesterone is secreted at high levels. Areg expression peaked strongly around implantation (GD4) and at mid-pregnancy (GD12). Treatment of pregnant rats on GD5 or GD8 with the progesterone receptor antagonist RU486 (2.5 mg per rat) blocked the expression of all of the genes on the days of treatment. Moreover, injection of immature rats with progesterone induced the uterine expression of all of the genes except Hbegf, while injection with estrogen or estrogen plus progesterone had no effect. Taken together, all genes tested may be assumed to regulate the implantation process. Moreover, Hbegf, Tgfa, and Areg may participate during mid-pregnancy. In addition, all of these activities are likely to be controlled by progesterone in the uterus of rats during pregnancy. [ABSTRACT FROM AUTHOR]

A Korean fusion energy development promotion law (FEDPL) was enacted in 2007. As a following step, a conceptual design study for a steady-state Korean fusion demonstration reactor (K-DEMO) was initiated in 2012. After the thorough 0D system analysis, the parameters of the main machine characterized by the major and minor radii of 6.8 and 2.1 m, respectively, were chosen for further study. The analyses of heating and current drives were performed for the development of the plasma operation scenarios. Preliminary results on lower hybrid and neutral beam current drive are included herein. A high performance Nb3Sn-based superconducting conductor is adopted, providing a peak magnetic field approaching 16 T with the magnetic field at the plasma centre above 7 T. Pressurized water is the prominent choice for the main coolant of K-DEMO when the balance of plant development details is considered. The blanket system adopts a ceramic pebble type breeder. Considering plasma performance, a double-null divertor is the reference configuration choice of K-DEMO. For a high availability operation, K-DEMO incorporates a design with vertical maintenance. A design concept for K-DEMO is presented together with the preliminary design parameters. [ABSTRACT FROM AUTHOR]