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Copyright © 2012 Elsevier Ltd All rights reserved.
Trends in Endocrinology & Metabolism, Volume 23, Issue 10, 501-508, 18 June 2012
Special Focus: Fertility and pregnancy
EG-VEGF: a key endocrine factor in placental development
Sophie Brouillet1, 2, 3, Pascale Hoffmann1, 2, 3, 4, Jean-Jacques Feige1, 2, 3, *, and Nadia Alfaidy1, 2, 3, *,
1 Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1036, Grenoble, France
2 Commissariat à l'Energie Atomique, Institut de Recherches en Technologies et Sciences pour le Vivant (iRTSV)–Biologie du Cancer et de l'Infection (BCI), Grenoble, France
3 Université Joseph Fourier, Grenoble 1, France
4 Centre Hospitalier Régional Universitaire de Grenoble, Département de Gynécologie, Obstétrique et Médecine de la Reproduction, Grenoble, France
EG-VEGF; a reproduction-associated member of the prokineticin family
In 2001, Li et al. isolated and sequenced two peptides that potently stimulate rodent gastrointestinal tract contraction, and named them prokineticins (Glossary) [1]. In the same year, LeCouter et al. identified a new peptide, highly expressed in human testis, adrenal gland, ovary, and placenta [2,3,4,5,6,7,8,9], that appeared to be a specific growth factor for endocrine gland-derived endothelial cells (EC) and lacked any effect on brain-derived capillary EC [8]. In EC isolated from steroidogenic tissues, this factor was shown to promote proliferation, survival, and chemotaxis. The protein was named EG-VEGF to reflect its similarities of action with vascular endothelial growth factor (VEGF). However, EG-VEGF and VEGF share no sequence identity. Instead, sequencing of EG-VEGF revealed complete identity to prokineticin-1 [8]. The members of the prokineticin family show differential patterns of expression and preferential sites of actions. Whereas Bv8/PROK2 is associated with the nervous system, EG-VEGF/PROK1 is associated with the reproductive tract and the endocrine organs.
Expression of EG-VEGF and its receptors in the placenta
The expression of EG-VEGF in the placenta was reported by the group of Ferrara in 2001. Subsequent work concentrated on expression of the peptide during pregnancy, with a special focus on early pregnancy, and on the decidual and placental units at term of human gestation [10,11]. EG-VEGF and its G protein-coupled receptor PROKR1 are highly expressed in human placenta and are immunolocalized to syncytiotrophoblasts (ST), cytotrophoblasts (CT), fetal endothelium, and Hofbauer cells (Ho) (Box 1) [11,12,13]. The group of Jabbour reported that EG-VEGF has a stimulatory effect on the expression of two vascular inflammation mediators, cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8). IL-8 is a potent neutrophil chemoattractant and an angiogenic factor, promoting EC chemotaxis [14], whereas COX-2 is the inducible isoform of the enzyme involved in the synthesis of prostaglandins from arachidonic acid. These data suggest that EG-VEGF may play a novel role as a mediator of the inflammatory response in the placenta, at the time of parturition.
The mature EG-VEGF protein is 86 amino acids long and is encoded by a three-exon gene (prok1) located on chromosome 1p21 (NCBI gene ID:84432). No known alternative splicing product exists. The four-exon prok2 gene (NCBI gene ID: 60675) maps to chromosome 3p13 and encodes two mature proteins, products of alternative splicing: the most active form, PROK2, lacks exon 3 and comprises 81 amino acids whereas the longer splice variant PROK2L includes all 4 exons and comprises 102 amino acids. Human EG-VEGF/PROK1 and Bv8/PROK2 have 44% amino acid identity and share two conserved features essential for their bioactivity: the N-terminal hexapeptidic signature sequence 'AVITGA' and the 10 cysteine residues engaged in five disulfide bridges [1,67,68,69,70]. PROKs are involved in numerous biological functions and are expressed in various tissues. EG-VEGF/PROK1 is particularly abundant in ovary, testis, adrenal glands, and placenta (Figure I).
The prokineticin receptors (PROKR1, PROKR2) are two G protein-coupled receptors which bind to the peptide hormones EG-VEGF and PROK2 with similar affinities [71,72]. These receptors mediate gastrointestinal smooth muscle contraction and angiogenesis. Although the prokr1 and prokr2 genes are located on two different chromosomes, they share 85% sequence identity and the proteins have the least homology at their N-termini [1,68,69,70,72]. Both PROK peptides bind both PROKRs with high affinity, in the nanomolar range. PROKR1 and PROKR2 proteins share 87% homology in their amino acid sequence, which may suggest similar activation mechanism for the two receptors; however, the final cellular response in a cell type that expresses both PROKRs depends on the repertoire of G proteins expressed by that cell type. Different signaling pathways have been reported upon prokineticin receptor activation [17,69,70,71,72]. These include calcium and cAMP mobilization, phosphoinositol turnover, mitogen-activated protein kinase and Akt phosphorylation (Figure I) [71,73,74].
During early pregnancy, placental EG-VEGF expression is dynamic throughout the first trimester [4]. At 7–8 wg (weeks of gestation), EG-VEGF expression is restricted to the ST, the endocrine unit of the placental villi and the Ho. At advanced gestational ages (9 to 12 wg), its expression is stronger in the ST and Ho, with mild expression in the CT [4]. No expression of EG-VEGF is found in the extravillous trophoblasts (EVT) (Figure 1). Placental EG-VEGF expression peaks at 8–11 wg, and then gradually decreases by the end of the first trimester of human pregnancy. Dynamic expression of local EG-VEGF is also found in serum collected from pregnant women at distinct trimesters of pregnancy. In non-pregnant women, plasma EG-VEGF levels are around 40 pg/ml and increase five-fold during the first trimester (∼200 pg/ml); these levels then gradually decrease to reach those observed in non-pregnant women by the end of the gestational period (Table 1) [15]. Elevated levels of EG-VEGF during pregnancy suggest that the placenta is a main source of EG-VEGF; this was further evidenced by the measurement of EG-VEGF in the conditioned media from ex vivo cultures of placental explants [5,16]. However, the placenta may not be the unique source of circulating EG-VEGF, especially during early pregnancy. In fact, EG-VEGF has also been shown to be highly expressed by the granulosa-derived cells of the corpus luteum (CL) during the luteal phase of the estrous cycle [3], and has been portrayed as a gonadotropin-induced gene with a role in CL formation [6,7,17].
Table 1 |
Circulating EG-VEGF (pg/ml) | Number of samples | Ref. | |||
Normal women | |||||
Non-pregnant women | 35 ± 7 | 9 | [15] | ||
First trimester of pregnancy | 225 ± 39a | 9 | [15] | ||
Second trimester of pregnancy | 73 ± 11 | 9 | [15] | ||
Third trimester of pregnancy | 77 ± 5 | 20 | [15] | ||
Preeclamptic women | |||||
Second trimester of pregnancy | 99 ± 10 | 9 | [15] | ||
Third trimester of pregnancy | 120 ± 13b | 15 | [15] | ||
PE was defined as a diastolic arterial blood pressure greater than 90mm Hg, and a systolic blood pressure greater than 140mm Hg, associated with proteinuria (more than 300mg/24h). |
a EG-VEGF levels at first trimester are significantly higher than those in non-pregnant women. b EG-VEGF levels at third trimester are significantly higher in PE patients than in normal pregnant women. |
EG-VEGF receptors, PROKR1 and PROKR2, were also detected in human placenta and their highest levels of expression were during the first part of the pregnancy. Although PROKR1 expression parallels that of EG-VEGF with a peak at 10 wg, PROKR2 expression is maintained over the first trimester but decreases gradually towards the term of the pregnancy [4,15].
Local regulators of EG-VEGF, PROKR1 and PROKR2 expression
To date, little is known about the local regulation of the EG-VEGF/PROKR system. The dynamic profile of expression of this factor and of its receptors throughout human pregnancy suggests that their expression in the placenta is finely controlled. EG-VEGF and PROKR1 are upregulated by hypoxia, a key parameter of placental development during the first trimester of pregnancy [4]. Both genes contain a functional hypoxia response element in their promoter region that binds hypoxia-inducible factor 1 (HIF-1) and mediates induction of their expressions under low oxygen tension (Figure 2). During human pregnancy, the hypoxic environment lasts throughout the first trimester. Hence, the peak of EG-VEGF and PROKR1 expression observed at 8–11 wg cannot be explained solely by regulation by oxygen tension. Other regulators might control local EG-VEGF/receptors expression in the placenta.
EG-VEGF and its receptors are finely regulated by human chorionic gonadotropin (hCG) during human pregnancy (Figure 2). In the placenta, hCG exhibits a similar temporal pattern of expression to that of EG-VEGF during the first trimester of pregnancy, and displays comparable effects on placental development [18,19]. During normal pregnancy, hCG secretion peaks at ∼8–9 wg, which concurs with the period of EG-VEGF production. Regulation of EG-VEGF production by hCG was further evidenced by the demonstration that placentas collected at 6–8 wg and treated with physiological concentrations of hCG (80–100 IU/ml) secreted five-fold more EG-VEGF than untreated placentas, which could explain the exponential increase in EG-VEGF secretion observed at this gestational period [4]. At 9–11 wg, the same concentration of hCG increased EG-VEGF secretion by only 1.5-fold, which explains the gradual decline also reported at this period of gestation [4]. Hence, the coordinated secretion of hCG and EG-VEGF suggests that some of the recently described effects of hCG on placental villi development, such as its effects on placental angiogenesis, might be mediated by EG-VEGF [20,21]. Consistent with these data, the group of Jabbour has recently shown that EG-VEGF stimulation of leukemia inhibitory factor (LIF) expression during endometrial implantation, in the baboon, is under the control of embryonic hCG [13,22].
The regulation of EG-VEGF and its receptors by hCG uncovers a new physiological regulation in which an endocrine hormone released by the ST layer acts in an autocrine manner on the same cell type to increase the expression of EG-VEGF. The effect of hCG on EG-VEGF expression is transcriptional and is mediated by a cAMP response element (CRE2) located at –383bp within the EG-VEGF promoter region. [23]. Importantly, hCG regulation of EG-VEGF expression has also been reported in the ovary [3]. The EG-VEGF promoter also contains a binding site for the steroidogenic factor-1 (SF1), a transcriptional factor that ensures steroidogenic differentiation [6,8]. Hence, it is very likely that other local hormonal regulations exist for EG-VEGF and its receptors in the placenta.
The role of EG-VEGF in the control of trophoblast invasion
Early embryonic development occurs under a low oxygen environment (∼20mm Hg, equivalent to 3% O2) that protects developing organs from the harmful effects of radical oxygen species, because the embryonic tissues express low levels of antioxidant enzymes at that developmental age [24,25]. The defensive strategy at that age is ensured by the continuous trophoblastic shell that surrounds the embryo at the uterine–placental interface and creates plugs inside the lumen of most spiral arteries [26]. The protective plugs result from the proliferation of CT cells at the tip of the anchoring placental villi. By the end of the first trimester (the end of organogenesis), there is a gradual transformation of utero-placental arteries by CT cells that invade the decidua and spiral arteries to establish the feto-maternal circulation. These CT are termed EVT. This phenomenon is concurrent with the progressive dislocation of the trophoblastic plugs [24,25]. The combination of these two closely related events allows oxygenated maternal blood to flow continuously within the intervillous space. Measurement of intervillous pO2 showed that it increases from <20mmHg (2–4% O2) before 10 wg to >50mmHg (10% O2) at 12 wg [24,25,27,28].
During pregnancy, the depth of invasion of the uterine wall by placental trophoblast cells is crucial and finely controlled. Poor invasion of maternal vessels has been correlated to both PE [29] and intrauterine growth restriction (IUGR), whereas excessive trophoblast invasion is associated with invasive mole, placenta accreta, and choriocarcinoma [30]. Consequently, subtle coordination of proliferation, differentiation and invasion of trophoblast cells is required during the early stages of placental development. Various growth factors and cytokines, such as epidermal growth factor (EGF), hepatocyte growth factor (HGF), transforming growth factor β (TGF-β), amphiregulin, insulin-like growth factor-II (IGF-II), and IL1, stimulate trophoblast differentiation towards an invasive phenotype [31,32,33]. By contrast, there are only limited data regarding possible negative regulators of trophoblast differentiation. Graham and Lala first demonstrated that TGF-β, produced primarily by the decidua, inhibits trophoblast invasion through stimulation of tissue inhibitor of metalloproteinases-1 secretion by EVTs [34]. Subsequent studies revealed that TGF-β3 inhibits trophoblast invasion, following interaction with endoglin, a component of the TGF-β receptor complex [32,33,35].
Because of its pattern of expression and its regulation by two key parameters of placental development (oxygen tension and hCG), EG-VEGF appears to be a good candidate to control trophoblast proliferation and invasion. Recent data demonstrated that EG-VEGF is a strong inhibitor of EVT migration and invasion. EG-VEGF effects on trophoblast invasion were analyzed in the placental explant model. This model is particularly relevant because the placental architecture is maintained and the tissue preserves the topology of intact villi that closely mimics the formation of anchoring villi occurring in vivo by the end of first trimester of pregnancy [15,36].
The inhibitory effects of EG-VEGF involved activation of metalloproteinases MMP-2 and MMP-9, with no effect on tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). This suggests that EG-VEGF may employ different mechanisms from those described for TGF-β and decorin to exert their anti-invasive actions in the placenta. These factors have been reported to upregulate plasminogen activator inhibitor (PAI-1) and TIMP-1 protein [37,38].
The control of EVT invasion by EG-VEGF during the critical period of embryo development suggests that this factor contributes to the villi growth under hypoxic conditions. In line with this hypothesis, EG-VEGF has been shown to increase angiogenesis within the villi during the first trimester of human pregnancy [16].
The role of EG-VEGF in placental angiogenesis
During the past decade, several studies have shed light on the angiogenic role of EG-VEGF in the reproductive organs. In the ovary and testis, EG-VEGF has been shown to influence physiological and pathological angiogenic processes [6,7,9,17,39]. The placenta is one of the most densely vascularized organs in the organism [40]. The involvement of EG-VEGF in human placental angiogenesis has been characterized, with a focus on placental microvascular endothelial cells (HPEC) that cover fetal capillaries in the chorionic villi and that ensure fetomaternal exchanges and constitute the pedestal of placental angiogenesis [16]. These results clearly established that EG-VEGF stimulates various angiogenic processes including endothelial proliferation, survival, migration, tube organization, sprouting, permeability, and paracellular transport [16]. More importantly, it has been reported that EG-VEGF has a stronger effect on HPEC sprouting and permeability than the well-established angiogenic factor VEGF [16]. On the other hand, EG-VEGF has no angiogenic effect on umbilical vein-derived macrovascular endothelial cells (HUVEC) [16]. In accordance with other studies, the concept that angiogenic factors are highly vascular bed-specific has emerged. EG-VEGF-mediated effects on HPECs have been differentially attributed to one or other type of receptor. Via PROKR1, EG-VEGF mediates HPEC proliferation, migration and sprouting, whereas PROKR2 activation by EG-VEGF mediates an increase in HPEC permeability [16]. This selectivity of effects is also found in the heart, where PROKR1 is preferentially involved in proliferation and angiogenic processes, and PROKR2 is mainly implicated in endothelial permeability [41,42,43,44]. Altogether, the effects of EG-VEGF on HPECs demonstrate that this factor is directly involved in placental angiogenesis, a process tightly linked to placental growth and fetomaternal exchanges. Hence, deregulation in EG-VEGF and/or its receptors could well be associated to vascular-associated pathologies.
Altogether, these findings imply that EG-VEGF plays an important role during human pregnancy, with multiple actions on various types of cells. EG-VEGF is produced by the ST and displays paracrine effects on EVT, EC, and villous trophoblasts that all contribute to a coordinated succession of events that ensures the success of pregnancy (Figure 3).
Role of EG-VEGF/PROKRs in PE
The dynamic profile of EG-VEGF expression throughout pregnancy, its multiple roles in the development of the chorionic villi, and its regulation by hypoxia suggest that this cytokine contributes to the success of pregnancy. Hence, inappropriate expression and/or function of EG-VEGF might contribute to major complications of pregnancy, such as recurrent pregnancy loss (RPL), ectopic pregnancies (EPs), IUGR, choriocarcinoma, and PE, which are associated with abnormal angiogenesis, as well as failures in trophoblast invasion and/or placental development.
PE, also termed gravidic toxemia, is the most common hypertensive disease of pregnancy, affecting 5–8% of all pregnancies [29] and accounting for nearly 18% of maternal deaths. Multiple theories and little agreement exist about the ultimate cause of PE. PE is also associated with adverse fetal outcomes, IUGR, placental abruption, oligohydramnios and nonreassuring fetal surveillance.
Although PE etiology is far from being fully understood, its development is thought to be primarily due to shallow invasion of the maternal decidua and spiral arteries by EVTs which creates a prolonged hypoxic environment in the placenta, and leads to the release of antiangiogenic factors by this organ [29]. Recently, improved understanding of the pathogenesis of PE suggests that blood levels of these proteins might eventually be used to predict this devastating condition. Investigations into the cause of PE development have also pointed out the potential importance of angiogenic factors and their receptors [45]. For instance, low VEGF levels or increased production of its antagonists, such as the soluble Fms-like tyrosine kinase-1 (sFlt-1, also referred to as sVEGFR-1), have been proposed as possible mediators of PE [45]. A key discovery in the field was that major PE phenotypes, such as hypertension and proteinuria, are due to an excess of sFlt-1 production by the placenta. sFlt-1 acts by neutralizing VEGF [46]. More recently, soluble endoglin, another circulating anti-angiogenic protein, was found to synergize with sFlt-1 and contribute to the pathogenesis of PE [47]. Abnormalities in these circulating angiogenic proteins are not only present during clinical PE, but also seem to antedate clinical symptoms by several weeks [48,49]. Collectively, these findings suggest that sequential angiogenic factor changes might have predictive value in PE. Therefore, current research in this field aims to discover more specific and earlier markers of the disease.
Recent findings strongly suggest that deregulation of EG-VEGF expression in the placenta might be associated with the development of PE [4,5,15,16,23]. In fact EG-VEGF fulfils many features of an early marker for PE. It is abundant in human placenta during the first trimester of pregnancy, its expression is upregulated by hypoxia, it controls trophoblast invasion, and exerts specific actions on placental EC (Figure 3) [16].
In 2004, Zheng et al. found no change in EG-VEGF mRNA levels in placentas from PE patients [50] when compared to placentas collected from term pregnancies. We have also compared the levels of EG-VEGF in sera collected from second and third trimester PE patients to age-matched controls, and found higher levels of EG-VEGF in the third trimester sera of PE patients compared to controls (Table 1) [4,5,15]. We now know that the origin of PE takes place during the first trimester of pregnancy, and any change in protein expression after the establishment of the disease is considered to be a consequence rather than a cause of the disease [51]. EG-VEGF sustained elevation in PE patients during the second and third trimester of pregnancy could be due to either a direct deregulation of EG-VEGF in the placenta, or to indirect effects of other insults that are deregulated beforehand. Both hypotheses are plausible and should be tested. A finding that might support the latter hypothesis is that EG-VEGF is upregulated by hypoxia and hCG, two factors that are tightly associated with the occurrence of PE [52,53,54,55]. Hence, hCG and/or hypoxia might contribute to the pathological maintenance of high levels of EG-VEGF, subsequently leading to EVT invasion failure. It remains to be established with a much larger cohort of pregnant women whether abnormally elevated plasma levels of EG-VEGF between 12 and 14 wg might be a good predictive marker of PE. A clinical study to determine whether EG-VEGF levels at the end of the first trimester correlates with the occurrence of placental pathologies during the second and third trimester of pregnancy will help to test the direct involvement of EG-VEGF in PE. An experimental mouse model could also conceivably test whether EG-VEGF is a cause or a consequence of PE development. Although some of the gross anatomy and physiology of mouse and human placentas are different, these two species show a similar hemochorial type of placentation and considerable histological and mechanistic similarities in placental development [56,57,58]. In gravid mice, EG-VEGF exhibits patterns and temporal profiles of expression throughout gestation equivalent to those in humans. Its highest levels of expression were found during the first 10.5 days postcoitum (dpc), corresponding to the hypoxic period of mouse placental development. EG-VEGF receptors were also found in similar cell types to those of the human placenta [5].
EG-VEGF/PROKR system as a potential actor of embryo implantation
In the endometrium, EG-VEGF expression peaks during the midluteal window of implantation, with immunolocalization to glandular epithelium, stromal and EC, myometrial vascular endothelium and smooth muscle cells [22,59,60]. Several studies demonstrated that EG-VEGF is involved in the success of endometrial implantation, and in endometrium–conceptus crosstalk during the implantation window [61]. More importantly, EG-VEGF has been identified as a new biomarker of human endometrial receptivity in the natural cycle [13,22,62]. The peptide directly regulates genes involved in implantation and increases human trophoblast cell adhesion to extracellular matrix proteins via the induction of LIF. EG-VEGF also regulates the expression of key factors of implantation, such as COX-2 and dickkhopf-1 (DKK1).
Moreover, dysregulation of EG-VEGF and its receptors has been reported in EPs [3,63], suggesting a potential role for PROKs in fallopian tube function. It has been postulated that these dysregulations could affect smooth muscle contractility in fallopian tube and embryo-tubal transport, providing a potential cause for the pathology [64,65,66]. Tubal EPs affect 1–2% of all pregnancies in Europe and the US and remain the most common cause of maternal mortality during the first trimester. Altogether, these findings suggest that dysregulated EG-VEGF/receptors system might predispose to EPs.
Concluding remarks
Screening tests for pregnancy disorders such as PE are to date unsuccessful and early biomarkers to help to minimize complications and implement therapeutic measures remain to be discovered. During the past six years, interesting data have emerged in regards to the expression, role, and regulation of EG-VEGF in normal and pathological human pregnancies. A combination of fundamental and clinical approaches now suggest that EG-VEGF might be a potential early marker for PE. However, further studies are required to determine EG-VEGF/PROKR expression levels in first trimester human pregnancy to determine whether their dysregulation might result in placental pathologies, and to evaluate their potential relevance as markers of PE, alone or in combination with other predictive tests such as Doppler ultrasound imaging of uterine arteries.
Animal models with deregulated expression of EG-VEGF are being developed to test whether this factor is a cause or consequence of the development of PE. These studies will also determine whether modulation of EG-VEGF/PROKR expression in these pathologies could be a useful therapeutic target. Future studies should also consider the contribution of this factor to the implantation process and to endometrial receptivity, aspects that represent huge challenges for reproductive medicine (Box 2). Mechanisms underlying normal and abnormal implantation are an active investigation area in clinical research with the goal of improving implantation rates after in vitro fertilization for assisted reproduction. Discovery of key factors that will improve these aspects is a current priority in the field of reproduction.
• Because EG-VEGF contributes to placental angiogenesis and development, is fetal growth restriction associated to changes in the levels of EG-VEGF and its receptors?
• Could gene polymorphisms of EG-VEGF and/or its receptors be associated with pregnancy pathologies?
• How would our knowledge gain from animal models overexpressing EG-VEGF throughout gestation? Would these animals develop symptoms of PE?
• What are the effects of pharmacological blockade of prokineticin receptors during pregnancy?
• What is the relative importance of multiple putative signaling pathways downstream of prokineticin receptors?
We thank the staff of the Department of Gynecology/Obstetrics (Prof F. Sergent) at the University Hospital of Grenoble for giving us access to human placentas. We acknowledge the following sources of funding: the INSERM (Unité 1036), University Joseph Fourier, Commissariat à l'Energie Atomique (DSV/iRTSV/BCI), the Région Rhône-Alpes (CIBLE-2008).
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52 (2009). New discoveries on the biology and detection of human chorionic gonadotropin. Reprod. Biol. Endocrinol. 7, 8. CrossRef | PubMed
53 (1999). Pathologic findings in pregnancies with unexplained increases in midtrimester maternal serum human chorionic gonadotropin levels. Am. J. Clin. Pathol. 111, 209–215. PubMed
54 (2008). Obstetrical complications associated with abnormal maternal serum markers analytes. J. Obstet. Gynaecol. Can. 30, 918–949. PubMed
55 (2009). hCG and hyperglycosylated hCG in the establishment and evolution of hemochorial placentation. J. Reprod. Immunol. 82, 112–118. CrossRef | PubMed
56 (2002). Hormones and human trophoblast differentiation: a review. Endocrine 19, 3–11. CrossRef | PubMed
57 (2001). Placental development: lessons from mouse mutants. Nat. Rev. 2, 538–548. PubMed
58 (2001). Mouse-based phenogenomics for modelling human disease. Trends Mol. Med. 7, 502–507. Abstract | Full Text | PDF (51 kb) | CrossRef | PubMed
59 (2006). Endocrine gland-derived vascular endothelial growth factor is expressed in human peri-implantation endometrium, but not in endometrial carcinoma. Endocrinology 147, 88–95. CrossRef | PubMed
60 (2010). Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss. PLoS ONE 5, e10287. PubMed
61 (2009). Identification of new biomarkers of human endometrial receptivity in the natural cycle. Hum. Reprod. 24, 198–205. CrossRef | PubMed
62 (2011). Prokineticin 1 induces Dickkopf 1 expression and regulates cell proliferation and decidualization in the human endometrium. Mol. Hum. Reprod. 17, 626–636. CrossRef | PubMed
63 (2007). Recurrent pregnancy loss: the key potential mechanisms. Trends Mol. Med. 13, 310–317. Abstract | Full Text | PDF (532 kb) | CrossRef | PubMed
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74 (2008). Prokineticin-signaling pathway. Int. J. Biochem. Cell Biol. 40, 1679–1684. CrossRef | PubMed


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Gene Expression and Biochemical Profiles in Developmental Disorders
The purpose of this protocol is to obtain, process, & characterize from the gene expression and/or biochemical viewpoints de-identified blood & cerebrospinal fluid samples from patients w/ a variety of developmental disorders. These samples, which will have been collected through research studies independently conducted by colleagues at our & other institutions, will be used by our team: (1) to supplement samples obtained from our own research studies, thereby increasing statistical power (e.g., increasing the number of Fragile X subjects) (2) to assemble comparison groups w/ other developmental disorders, which could help determine the specificity of our findings in a particular disorder (e.g., group w/ idiopathic autism to contrast findings in Fragile X syndrome). The studies to be performed w/ the aforementioned samples include a wide range of techniques, which will depend on the nature of the sample (e.g., serum levels of growth factors) & the goals of the comparison (e.g., histone profiles in idiopathic autism to be compared with those in Fragile X syndrome). The samples will be provided only with information that constitutes a "limited data set" (e.g., age, gender, IQ, medications). We expect to receive 50 samples per year for a total of 150 samples over the three year period.

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Panic Attacks (cont.) Medical Author:
Roxanne Dryden-Edwards, MD
Roxanne Dryden-Edwards, MDDr. Roxanne Dryden-Edwards is an adult, child, and adolescent psychiatrist. She is a former Chair of the Committee on Developmental Disabilities for the American Psychiatric Association, Assistant Professor of Psychiatry at Johns Hopkins Hospital in Baltimore, Maryland, and Medical Director of the National Center for Children and Families in Bethesda, Maryland. Medical Editor:
Melissa Conrad Stöppler, MD, Chief Medical Editor
Melissa Conrad Stöppler, MD, Chief Medical EditorMelissa Conrad Stöppler, MD, is a U.S. board-certified Anatomic Pathologist with subspecialty training in the fields of Experimental and Molecular Pathology. Dr. Stöppler's educational background includes a BA with Highest Distinction from the University of Virginia and an MD from the University of North Carolina. She completed residency training in Anatomic Pathology at Georgetown University followed by subspecialty fellowship training in molecular diagnostics and experimental pathology. IN THIS ARTICLE
When to Seek Medical CareFor someone who may be experiencing their first panic attack, a call to the doctor's office or 911 is warranted. The idea is to make sure that the cause of the person's distress is not a heart attack, asthma problem, endocrine emergency, or other dangerous medical condition.
Almost everyone experiencing symptoms of a panic attack needs evaluation. Unless the person has a history of having panic attacks, is otherwise healthy, and is experiencing a typical attack, they must be evaluated promptly by a doctor. The level of evaluation depends on many factors. Err on the side of safety when deciding whether to go to a hospital's emergency department.
Next Page: Must Read Articles Related to Panic Attacks
Anxiety is a feeling of apprehension, fear, or worry. Some fears and worries are justified, such as worry about a loved one. Anxiety may occur without a cause, ...learn more >>
Hyperventilation syndrome is a condition where a person hyperventilates for an unknown cause. Symptoms of hyperventilation syndrome include bloating, burping, p...learn more >>
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Panic disorder is characterized by the spontaneous and unexpected occurrence of panic attacks, the frequency of which can vary from several attacks a day to only a few attacks a year.


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The Question:I would like to know if there is any way I can find out if a friend has passed away. The only information I have is her name and hometown. We have been long time friends and I would really appreciate any help I could get from you. Thanks. The Answer:One of the best sites around for geneological research is FamilySearch, run by the Church of Jesus Christ of Latter-day Saints. They allow free searches of several databases, including the Social Security Death Index, which contains over 75,000 records. Other resources can be found in our Genealogy Guide. Good luck! —The Editors |
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Keith Groller
March 26, 2012
Advertisement |
Art Wolfe has had a lot of successful teams in his 22 seasons as the women's basketball coach at Northampton Community College. A career record of 401-162 in that span tells you that.
Wolfe hesitates to label any team as "the best," but the lifelong Allentown resident admitted that what the 2011-12 Spartans accomplished 'ranks right up there."
NCC went 20-2 in Region XIX, 25-6 overall, spent the entire season nationally-ranked, won the college's first-ever Region XIX championship and competed in the National Junior College Athletic Association tournament in Rochester, Minn.; quite a feat considering this was just the school's third season in the highly competitive NJCAA.
Wolfe was named Region XIX Coach of the Year.
"This was a great season, and even though we've had success before with our progam we've never had this kind of success at this level," Wolfe said. "What made our team special is that they had mental toughness. They just never quit.
"There were many games where we losing at halftime, but they never gave up. They came out in the second half and worked hard, especially on defense. They played really good defense. We kept most teams under 50 points."
Offensively, the team was balanced with four players — April Andrews, Tiara Aziz, DeAnna Brown and Halie Cintron — all averaging in double figures.
The highlight of the season was winning the Region XIX title with a 49-47 win over Ocean County (N.J.) College.
"That was one heck of a game," Wolfe said. "They had the ball at the end, but we did a good of pressuring the ball and they could only get off a desperation shot.
"We were seeded third going into the tournament and we had to beat Brookdale (N.J.) Community College on its homecourt in the semis just to get to the finals and then we beat Ocean County. It was quite an accomplishment."
The regional title sent NCC to Rochester, Minn., for the national tournament where the Spartans went 1-2 to finish sixth.
"It was a really nice experience for the kids in Minnesota," Wolfe said. "We received great treatment. We had nine girls on the team and for five of them it was the first time they were ever in a airplane. It was a riot. One of the girls wanted to know why the plane was going so fast down the runway.
"We were out there with seven other teams from all over the United States and these girls represented themselves, our school and the Lehigh Valley exceptionally well. They really behaved themselves and did what they were supposed to do."
What makes this story especially nice is that eight of the nine girls played high school basketball in District 11
Shana Clark (Pocono Mountain West), Kiersten Young (Pen Argyl), Alyssa Gibson (Wilson), Michelle Thomas (Dieruff), Aziz (Easton), Cintron (Allen), Andrews (Liberty) and Brown (Emmaus) are familiar faces to Lehigh Valley basketball fans. Rayna Vincent from Norristown is the other team member.
"We've always liked to get local girls here and give them an opportunity to play when no one else would," said Wolfe, who is assisted by Tara Belfield and Phil Eppolite. "We're already out beating the bushes to bring in kids for next season because will have only three returning players. We're very proud of what this group accomplished.
"We're not only the first team in school history to go to the national tournament, but I was told we are the first Region XIX team from Pennsylvania to go to nationals. I love what I do. It keeps you feeling young, even if you're really old like I am."
Parkland senior Emily Gisolfi, a key member of the Trojans state championship volleyball team, has been named an academic All-American by Prepvolleyball.com.
The Georgetown-bound Gisolfi is ranked in the top one percent of her graduating class at Parkland (sixth in a class of 721), carries a 4.81 cumulative GPA and is a member of the National Honor Society as well as the National Math, English, Spanish and Science honor societies.
She has also been a prominent member of Parkland's Honors Orchestra and Honors Chamber Orchestra. She has also been active in the community, volunteering her time for S.E.R.V.E., Parkland's community service organization and tutors other high school students in match, science and Spanish.
As for her volleyball career, she was the defensive MVP at the PIAA 3A tournament and an all-state selection.
•IUP's sophomore softball pitcher Kelly King (Bethlehem Catholic) tossed a perfect game in a 8-0 win over Lake Erie last week. King had four strikeouts, got seven outs on fly balls and 10 on groundouts.
•University of Delaware sophomore Courtney Sniscak (Parkland) placed second in the hammer at the Navy Women's Track & Field Invitational on Saturday. Her throw of 50.54 meters (or 165 feet, 10 inches) moves her into four place all-time at Delaware.
•Millersville freshman Ann Kovacs (Bethlehem Catholic) won the hammer throw with an effort of 40.30 meters at the Golden Ram Invitational. Kovacs set the school record the week before with a 45.34 meter effort at the Shamock Invitational at Coastal Carolina.
• Hartwick College's senior men's swimmer Kaird Durocher (Southern Lehigh) was part of a 200 free relay team that posted a prelim time of 1:23.73 at the NCAA Division III Championships at Indiana University last week. The time was the second-fastest in Hartwick history and earned the foursome a spot in the finals where they finished 14th with a time of 1:23.88.
Copyright © 2014, The Morning Call


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Mark Schmetzer reports:
Lakota West was picked to win the Greater Miami Conference while Sycamore was seen as a middle-of-the-pack team by conference coaches going into the season.
Tuesday night at Lakota West, it was the visiting Aviators who looked like the overwhelming favorites. Senior Mason Morgan scored a career-high 21 points and made it a double-double night with 10 rebounds as Sycamore rolled to a 61-46 win over the Firebirds.
Junior guard Mitch Hill had 10 points for Sycamore (3-2, 2-1 GMC), which led by as many as 17 points in the second half. The Aviators have something to prove, the 6-foot-6 Morgan said.
"We know we don't get any respect in the GMC," said Morgan, who scored 18 with 15 rebounds in a 77-72 GMC loss to Fairfield on Friday. "This is the year we want to show the conference that Sycamore is legit."
That's what the coaches have been saying.
"We've been talking about that this week," Sycamore coach David Moss said. "We're a couple of possessions away from being 4-0. We're a little better than our record."
Senior guard Monty Boykins was the only Lakota West player to reach double figures, finishing with 14 points. The Firebirds, the No. 5 team in the Enquirer's Division I coaches poll, set a season-low in points while shooting 34.5 percent (20-of-58) from the field during their third game in five days.
That's part of the package when you play in the GMC, coach Sean Van Winkle said, and it doesn't make it easier when games against teams such as No. 2 Lakota East are added to the schedule to help get to Ohio's new limit of 22 in the regular season. The Firebirds (3-2, 2-1) lost to the Thunderhawks, 77-73, in what actually was a non-conference game on Saturday.
"That's just what happens when you play in this conference," Van Winkle said. "We understand that and enjoy the competition, but I don't think we're playing like we need to play to contend. Right now, I think we're one of the worst teams in the conference."
Lakota West also is missing 6-1 junior guard Tyler Williams, sidelined with a left foot injury since scoring 16 points in 16 minutes during the Firebirds' season-opening win over Talawanda.
Sycamore's defense played a role in Lakota West's errant shooting, Van Winkle said.
"We haven't been shooting the ball well all year, but I'm not going to take the credit away from them," he said. "They defended us well and forced us into taking some bad shots."
The Aviators never trailed after senior forward Isaiah Brown scored to give them a 6-4 lead with 3:25 left in the first quarter.
Sycamore, which went into the game shooting 37.4 percent from the field for the season, reached 51.7 percent (15-of-29) in the first half on the way to a 32-23 halftime lead. Morgan led the Aviators with eight points, while Hill, who was averaging 6.8 points per game, scored seven.
Boykins scored eight points in the first half to help keep Lakota West in the game.
Sycamore | 15 | 18 | 15 | 13 | 61 |
Lakota West | 8 | 15 | 10 | 13 | 46 |
Sycamore (3-2, 2-1 GMC) – Hill 4 0 10, Gruden 3 2 9, Vaught 2 0 4, Farquhar 3 2 9, Brown 4 0 8, Morgan 8 5 21. Totals: 24 9 61.
Lakota West (3-2, 2-2 GMC) – Hicks 1 0 2, Capossela 1 0 3, Barnes 3 0 6, Bowling 4 0 8, Thomas 2 0 5, Boykins 7 0 14, Grove 2 4 8. Totals: 20 4 46.
Halftime: Sycamore, 33-23. 3-pointers: S 4 (Hill 2, Gruden, Farquhar), LW 2 (Capossela, Thomas).
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Matt Hirst presents "Et Cetera" (2004)
A Skateboarding video by Sidewalk - 118,004 views
The 2004 Sheffield scene video, filmed and edited by Matt Hirst. With sections from Jerome Campbell, Moggins, Jonny McNair and Mike Wright, and appearances from Danny Beall, Mark Baines, Arthur Tubb, Liam Sproat and plenty of other Sheffield based people. Massive thanks to Power Distribution and Matt Hirst.


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Fonsi Nieto: faster than the wind.
16 February 2004 | News
The battle between motorcycles and jets goes on.
In the saddle of a road-version Aprilia RSV 1000 R, the Spanish pilot challenged the acceleration of an Aviojet C-101 jet from the Aguila/Eagle squadron based in Murcia, southern Spain and the motorcycle's burst of acceleration proved faster.
The idea was originally presented by Ducati, organisers of a match-up with an Italian Airforce Starfire F104 jet that never took place.
Fonsi Nieto is now gearing up for his next challenge: victory in the 250 CC Class World Motorcycle Racing Championship.


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2013-14: Academic all-UAA.
2012-13: UAA all-academic for cross country, indoor and outdoor track & field.
2011-12: UAA all-academic for cross country, indoor and outdoor track & field.
HIGH SCHOOL: Four-year letter winner in track & field at Lyons Township High School ... Three-time all-conference track & field honoree ... Also competed in cross country and swimming for two years ... Member of the National Honor Society, Math Honor Society and Italian Honor Society ... Received academic all-conference accolades ... AP Scholar.
PERSONAL: Majoring in education ... Daughter of Raymod Ziolkowski and Gayle Simmons Ziolkowski.
© 2012 Washington University in St. Louis • One Brookings Drive • St. Louis, MO 63130 | Contact


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Leading Global Media Consultancy seek PPC pro to work on luxury car brand.
A chance to work on an iconic automotive brand! Our client is one of the top Media Agencies in the world with a reputation for cutting edge media innovation. Now they are looking to expand their PPC team due to their flagship clients increasing their Media spend.
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To find out about the wonderful role, call Chris Law at Norton Leigh – 02071833021 or email firstname.lastname@example.com


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Katy Perry and Russell Brand out in LA… separately
Katy Perry
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Katy Perry was at the premiere of her first film, the behind-the-scenes documentary Part Of Me, last night. Across town, her ex Russell Brand was also at a VIP event to celebrate the launch of his new show.
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CC: Vikings Compete at the University of MinnesotaOct. 02, 2012 10:51 AM | Author: Viking Sports Admin
The Viking Harriers travelled to Minneapolis, MN to compete in the 27th annual Roy Griak Invitational cross country meet, hosted by the University of Minnesota at the Les Bolstad Golf course. This meet proved an eye opening experience for the team, as this is one of the largest cross country meets in the nation. This meet has three separate college divisions with over thirty plus schools in each division and four hundred plus runners in each race. VCSU competed in the NCAA Division II /maroon race for both the men and women. The course featured rolling terrain with a number of sharp inclines, which in themselves where not taxing but they did have an accumulated effect in the later stages of the race. The men's distance was 8000m and the women distance was 6000m.
Jose Garcia for the third time this season led the men's squad, finishing 228th with a time of 28:35. Richard Wright followed Garcia in 246th with a time of 28:54.Freshmen Malik Jackson moved up on the team to be the Vikings third man in finishing 287th with a time of 29:36. Anna Fuka was the top finisher for the Viking women over the 6000m course in finishing 162nd with a time of 25:17. Krista Briss also ran well to finish 266th with a time of 26:32, which is a personal record. You can view full results on VCSU cross country schedule/race results page. |


text: Success Stories Helping a War Veteran Get His Life Back on TrackMervin credits Easter Seals with helping him successfully reintegrate: "Easter Seals played a big part"On July 5, 2004, during his second deployment in Iraq, Marine Cpl. Mervin Roxas was manning a machine gun atop a patrol vehicle when an improvised explosive device (IED) exploded. Three Marines died. Mervin, more fortunate, lost his left arm and shoulder, and his jaw and cheekbone were shattered. He spent 11 months at Walter Reed Army Medical Center in Washington, D.C., before being medically discharged — but his return home brought new challenges. "I had trouble transitioning back to being a civilian," he says. "I lost structure in my life, I didn't know how each day would play out, and my behavior caused misunderstandings with family and friends." There was also the challenge of suddenly living with a disability. "Learning to do things with only my right arm and getting stares and comments from strangers — I wasn't used to it. That was tough." Forced to abandon dreams of becoming a police officer, Mervin enrolled in some college courses. One day on campus, he stumbled on a job fair where Easter Seals had a booth. By that evening, he had faxed his resume to Easter Seals and soon after, he was hired as a Life Skills Coach — teaching life skills to adults with developmental disabilities. Finding a job spurred Mervin to keep moving forward. He has since run a marathon, earned his college degree and gotten married, plus he's been promoted to an Easter Seals Program Assistant. Mervin credits Easter Seals with helping him successfully reintegrate. "Easter Seals," he says, "played a big part." |


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Man who threatened freed
Suspect reportedly referred to killing Torrington students
LITCHFIELD — A Torrington man accused of threatening to kill his girlfriend in a jealous rage during which he allegedly referred to the killing of children was allowed to go free on a $10,000 bond Wednesday after his arraignment in Bantam Superior Court.
The girlfriend, according to police documents, works at Torrington High School.
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Air Quality ● Laboratory Services ● Municipal Facilities ● Waste Management ● Water Quality ● EHS Home |
LIMITED SCOPE X-RAY OPERATOR TRAINING - DIDACTIC PORTION Didactic requirements include the successful completion of three items.
1) 80-hour Didactic Course: This must be a single training program providing didactic instruction in accordance with Part 1 of Appendix H. A certificate of completion will be issued, which must be made available to the Department upon request. List of Department approved 80-hour schools 2) State Examination: This exam is administered during the 80-hour didactic instruction portion of the training. Successful completion requires a 70%. 3) 3-hour Self Study Instruction: This portion of the training includes prerequisite reading and 2 videos designed by the North Dakota Radiation Control Program. This 3-hour training supplement addresses two critical areas of the limited scope x-ray operator training requirements, the North Dakota Radiologic Health Rules and Special Pediatric Considerations. Contact :
Go to X-Ray Machines Page The Radiation Control Program pages are maintained by James Lawson, RT |
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three R's
The fundamentals of education, as in It's a terrible school; the children are not even taught the three R's. It is widely believed that Sir William Curtis, an alderman who became Lord Mayor of London, once presented a toast to the three R'sreading, riting, and rithmeticthereby betraying his illiteracy. In any event, the term was picked up by others and so used from the early 1800s on.


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West Virginia's geothermal resources could be tapped by using an enhanced geothermal system, in which fluid is pumped into the hot rock area through a pipe looped from one well bore to another.
"Basically, you would use the heat exchange process to heat a liquid, probably one with a lower boiling point than water, and use it to power a turbine," Hohn said.
"Geothermal is an extremely reliable form of energy, and it generates power 24/7, which makes it a baseload source like coal or nuclear," said David Blackwell, professor of geophysics at SMU and director of the university's Geothermal Laboratory.
Assuming only a 2 percent thermal recovery rate, West Virginia has the potential to produce nearly 19,000 megawatts of electricity from geothermal sources, according to the SMU researchers. The state currently produces about 16,300 megawatts from all sources, with coal accounting for most of the power.
"The proximity of West Virginia's large geothermal resource to East Coast population centers has the potential to enhance U.S. energy security, reduce carbon dioxide emissions, and develop high-paying clean energy jobs in West Virginia," Blackwell said.
The SMU study was conducted with funding from Google.org, the philanthropic arm of the search engine giant.
"The early West Virginia research is very promising," said Blackwell, "but we still need more information about local geological conditions to refine estimates of the magnitude, distribution and commercial significance" of the state's geothermal resources.
"We need to get a closer look at the rock types and strata in the geothermal area and learn more about their thermal conductivity," Hohn said. "We need a more precise definition of the potential that's out there. ... It's exciting, as geologists, to be able to research this. It's something you hope to be able to do over the course of your career."
More information on the SMU study is available at the West Virginia Geological and Economic Survey's Website at www.wvgs.wvnet.edu.
Reach Rick Steelhammer at rsteelham...@wvgazette.com or 304-348-5169.


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Blu-ray Review: Bones – The Complete Sixth Season
Bones: The Complete Sixth Season arrives in Blu-ray with excellent episodes and smart features.
Bones: The Complete Sixth Season arrives in Blu-ray with excellent episodes and smart features.
Bones mostly stuck to a case of the week for the finale, but with a big twist at the end.
Bones dispatched with one old enemy, while revealing another, in one of the best episodes of the series.
Bones has grown into a very comfortable, fun place. Memo to the people involved: thanks, but please Adon't be complacent.
The team is back together to save Cam, but will they stay that way?
The Bones team scatters to different countries at the end of season five!
The team goes up against their greatest adversary once more: The Gravedigger!
Booth and Brennan take on a coven of witches, and Hodgins and Angela have a heartfelt talk.
Booth and Brennan dive into the music world again and sing a great duet!
Booth and Brennan have to get to the bottom of a murder at an aquarium!


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I went to watch my alma mater play last night against Saint Aug, and I gotta say this guy is an absolute animal! He looked like Adrian Peterson out there effortlessly running all over the place.....one of the best athletes I've ever seen....Impressive. He kicks off about 75 yards through the end zone and kicks field goals too btw.... Per the daily advertiser this morning....... Fournette, who is one of the most sought after prospects in the country, put on quite the show for those in attendance as he rushed for 354 yards and three touchdowns on 28 carries to push his season totals over the 2,000 yard mark. "He's super," Hightower said. "We knew what he was coming into this game and we knew he was going to be quite the challenge for us. He was just better than us. I've seen an awful lot of great running backs in my years and I'll tell you he's as good as any of them. A lot of times we were hitting him with two, three and four guys and he didn't go down. He's got great drive. He's just a monster. He's really special."
I'm a high school official, I went watch this game friday night.......this dude is the best i have seen this year.....pretty easily too..... cougars wanted no part of him after the 1st quarter. This guy will be a very very nice pick up for whoever gets him next year...I just hope it is LSU!
I have a nephew who plays for the Cougars whom I went to watch, undersized and mean as a snake like his aunt .......anyway, he was telling me Fournette was the nicest guy, he came over to their huddle in the 4th qtr well before the game was over but it was well in hand for St. Aug and was shaking their hands, congratulating them on a hard fought game, telling them they were one of the hardest playing/well coached teams he'd ever played against, said he seemed so humble and almost ashamed of how good he is......thought that was classy of him.
How we lure him into TIGERS den will be interesting to follow. The gumps dang sure can make a hard sell for what the RB's of late have accomplished. Anyone close to him know if he/his family is an LSU fan?
I sat up next to some Saint Aug fans, one who said he drove in from Houston to watch, and asked them what the feeling was from their perspective and they all said he's all LSU's to lose, whatever that's worth.....probably not much but I liked hearing it.
With his name, he should be at LSU. Sounds like a throwback to years of lore. Malancon, Dardar, Gajan just to name a few. Add your name to that list, Mr. Fournette.
Bama hasn't come to Louisiana and gotten RB's that we wanted i don't think. Hopefully it won't happen with Mr. Fournette either.


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Panevezys hotels, Lithuania
The economy class hotel Pervaža is located half way between the two capitals-Vilnius and Riga. We have 31 rooms / 85 beds to offer. The breakfast is served in a cozy cafeteria, where also is a small kitchenette for your convenience. The meeting room that we have can fit up to 25 people. A guarded parking lot is also available. On the second floor of our building you will find a lunch cafeteria/bar, which can seat up to 50 people. |
Hotel "Romantic" is founded in the newly renewed historical flourmill in the center of Panevėžys city, on the bank of river Nevėžis. The hotel is easy to reach, near the Via Baltica road, on the half way between Vilnius and Riga. We offer our guests 39 cosy rooms with cable television, telephones, business equipment, safes, Internet, and mini bars. |
New modern and cozy hotel "SMELYNE" is in the center of Panevezys city on the bank of the river Nevezis. Hotel "SMELYNE" attaches visitors who are longing for coziness, elegance and pleasure for its exceptional attractive surroundings. This is an excellent place not only for a rest but also for those who want to held seminars, conferences and business meetings. |


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'The Greatest Bad Movies of All Time' collects the best of the worst
Film critic Phil Hall talks about his new book "The Greatest Bad Movies of All Time," in which he rounds up 100 films he considers anti-classics of cinema.
The Word: Halle Berry had a baby boy
Shiloh, Suri have new competition for world's cutest kid Hollywood High School just got another beautiful face for the class [...]
The Word: Jennifer Garner tries to enact law on paparazzi
Jennifer Garner is joining Halle Berry in pushing for a California bill that would make it illegal for paparazzi to [...]
The Word Picture Page, July 22: Comic-Con 2013
On Saturday, the big stars hit up Comic-Con.
The Word: Jimmy Kimmel and Halle Berry got hitched over the weekend (just not to each other)
Jimmy Kimmel married his comedy writer girlfriend, Molly McNearney, on Saturday in Ojai, Calif. Such bold-faced names as Matt Damon, [...]
Gossip roundup: Miley Cyrus, Justin Bieber getting friendly
Rumors have been circulating all week that Miley Cyrus and Justin Bieber are becoming more than just friends.
Gossip: Katy Perry is getting over her break-up with John Mayer
Katy Perry is reportedly turning to a very surprising source for comfort: ex-husband Russell Brand.
The Word: The Kardashian and Odom charity scandal
Oh man. This is not good. I mean, in the spectrum of not good things, this ranks pretty much at [...]
Film Review: 'The Call'
Halle Berry plays a 911 operator who fields a call from an abducted teenager (Abigail Breslin) trapped in a trunk in the new film, "The Call."
Metallic dresses ruled the Oscar red carpet
All that glitters is gold? In the case of these Oscar gowns — yes. Jessica Chastain shimmered in custom Armani [...]


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Palestinians urge boycott of Jerusalem marathon
Tuesday - 2/26/2013, 1:18pm  ET
JERUSALEM (AP) -- Palestinians are calling for a boycott of a marathon race in Jerusalem that winds through the city's eastern sector. Palestinians claim it as their capital.
The third annual Jerusalem marathon takes place Friday. Previous races have drawn thousands of runners from around the world and attracted international brands as sponsors.
In a statement Tuesday, the Palestine Liberation Organization called on marathon participants and sponsors to withdraw their support.
It says the marathon is another Israeli policy "aimed at exerting Israeli control over the occupied city." A spokesman for Jerusalem's municipality counters that the marathon is a "symbol of co-existence."
Both the Palestinians and Israel claim rights to Jerusalem. Israel captured east Jerusalem in the 1967 Mideast war and considers the whole city its capital. Israel's claim is not recognized internationally.
Copyright 2013 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.


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"What befell Newtown is not something we thought possible in any of Connecticut's beautiful towns or cities. And yet, in the midst of one of the worst days in our history, we also saw the best of our state," Gov. Dannel P. Malloy said Wednesday, Jan. 9, 2013.
Published: January 9, 2013
Gov. Dannel P. Malloy chokes back a sob as he addresses the Newtown tragedy during his State of the State address to the opening of the 2013 session of the Connecticut General Assembly at the state Capitol in Hartford Wednesday, Jan. 9, 2013.
Sean D. Elliot/The Day
Ledyard boys advance to the CIAC Class LL quarterfinals
March 13, 2014
8 Photos
Ledyard girls advance to the CIAC Class L semifinals
March 13, 2014
5 Photos
New London wins Class LL opener
March 11, 2014
8 Photos
New London advances to girls' basketball semis
March 10, 2014
6 Photos
UConn women rout Louisville 72-52 to win AAC title
March 10, 2014
15 Photos
March 9, 2014
19 Photos
ECC Boys' Swimming Championships
March 8, 2014
10 Photos
March 7, 2014
10 Photos
Future starts now for eager cadets
March 6, 2014
6 Photos
NFA falls to E.O. Smith in state tournament
March 6, 2014
10 Photos
NFA, Woodstock win at ECC boys' semifinals
March 5, 2014
11 Photos
Area Catholics observe Ash Wednesday
March 5, 2014
5 Photos


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Evolution of Friendship Groups Over Time *
*Note: This is an abbreviated Project Idea, without notes to start your background research, a specific list of materials, or a procedure for how to do the experiment. You can identify abbreviated Project Ideas by the asterisk at the end of the title. If you want a Project Idea with full instructions, please pick one without an asterisk.
This project asks the question "How do friendship groups change over time?" The results may support inferences about how "people skills" develop. What types of changes would you expect to see? Do you expect friendship groups to grow larger over time? Do you expect that individuals will belong to more, less or about the same number of friendship groups as they get older? Do you think there will be more or less exclusivity among groups (and how would you measure such a concept)? Do you expect results to be similar for boys and girls? The project requires a large group of students who have been in school together for several consecutive years. Design a survey to identify past and present friendship groups. Select one or more statistical tests for each of your hypotheses. Crunch the numbers and see if the data support or reject each hypothesis. This project involves fairly sophisticated statistical analysis. Finding a mentor with expertise in group detection statistics is highly recommended. (Doherty, 2003)Share your story with Science Buddies!
I Did This Project! Please log in and let us know how things went.Last edit date: 2013-01-10
Doherty, J., 2003. "Evolution of Friendship Groups in the Fourth through Seventh Grades," California State Science Fair Project Abstract [accessed February 1, 2006] http://www.usc.edu/CSSF/History/2003/Projects/J1707.pdf.Share your story with Science Buddies!
I Did This Project! Please log in and let us know how things went.Ask an Expert
The Ask an Expert Forum is intended to be a place where students can go to find answers to science questions that they have been unable to find using other resources. If you have specific questions about your science fair project or science fair, our team of volunteer scientists can help. Our Experts won't do the work for you, but they will make suggestions, offer guidance, and help you troubleshoot.Ask an Expert


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COLUMBIA — Jeff Finley, a local biologist with the U.S. Fish and Wildlife Service, is trying to get people to reconnect with nature. He is one of the people involved in planning to bring an outdoor education program to Columbia.
Columbia plugs into nature
Thursday, April 17, 2008 | 5:22 p.m. CDT;
updated 5:28 a.m. CDT, Monday, July 21, 2008
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Embarkation was a breeze. It took about 5 minutes. We arrived about noon and things went very smoothly. Our cabin was ready at 1pm.
The cabin was a balcony overlooking the Boardwalk. We had a great view of the aft and the diving shows. The Boardwalk gets noisy, but with the balcony door closed, there was no noise. While the balcony was nice, I think I would have preferred a regular balcony, on the outside of the ship. It was better than an inside cabin, but you can only see so much of the Boardwalk....
All of the shows we saw were very good. Hairspray was a bit long for me, 90 minutes, but it was very good. The comedy show was TOP-NOTCH! Make sure you get tickets for all shows BEFORE you sail. There were long lines at every show of people who were hoping for last minute seats. Abbacadabrra, the headliner show, was good; I am just not a real Abba fan. Come Fly with Me was also very good. We did not make it to an ice show.
The Windjammer was normal; decent food but always the same choices every meal.
Chops Grille.......absolutely grand! Best fillet I have ever tasted. I recommend Chops, just don't be in a hurry!!
Johnny Rockets for breakfast is a must. It is free breakfast. Lunch and dinner are $4.95 but not a bad meal. The Donut Shop is ok, seem to be assembly line donuts, but they are also free, so its a quick snack.
The casino is very large and the dealers are ALL very nice and friendly people. Their bar service people come by often and a beer is $4.89 plus tip. The machines are TIGHT!! I mean very tight!!
We opted for the Valet luggage option. For $20 per person, they take your bags from your room and you don't see them again until you land at your home airport. Best money I ever spent!! We were in the debarkation room at 7:45 am and at 8:05, we were inside the airport!! Smoothest I have ever seen. It was amazing how quickly we got off the ship, through customs and cabbed to the airport in Ft. Lauderdale.
The posts of call were Labadee, Costa Maya and Cozumel. Labadee was just a lay on the beach day for us. Costa Maya is a hole in the wall that should not be a stop for any cruise ship (nothing but crap shops) and Cozumel we have been to many times, so there was no reason to get off the ship.
I have nothing bad to say about this ship or this trip. The top decks do get very, very crowded on sea days. I mean VERY crowded!! So, if you want a chair in the sun, get there early!!
Our cabin steward, Rommell, was superb! At Johnny Rockets, Glenn Dais is in charge and he is a very nice man. He will make your trip!! He is all about service and he does a great job!
We only did the main dining room for one night. We just really don't like the whole "take 2 hours for dinner" thing, so we chose not to go. The food was fine, but not exactly how we wanted to spend out evenings. That was our choice and not a criticism of Oasis.
We loved this cruise and the ship. The employees are fantastic and we got what we wanted for our money; a good time and relaxation!! Thanks Oasis!!


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No Offer
Neutral Experience
I applied online and the process took 4 months - interviewed at Northrop Grumman.
Interview Details – Applied last October. Received a phone call from recruiter on March 2nd to schedule a phone interview. She said she will get back to me with confirmation.
No Offer
Neutral Experience
Interviewed at Northrop Grumman
Interview Details – Went through an email prescreen where I typed up answers to basic questions. The overall interview consisted of me sitting down with 4 employees who went around and asked me several questions. They asked what I knew about the company and how I had handled different types of situations in the past (like handling an issue working in a team). They also asked me my strengths and weaknesses. It was a basic, fair interview.
Interview Question – On a scale of 1 to 10, how competitive are you? Answer Question
Accepted Offer
Positive Experience
Easy Interview
I applied online and the process took 2 weeks - interviewed at Northrop Grumman in September 2010.
Interview Details – Easy. Manager sits down and reviews resume and ask a few other things that may pertain to the position and if you have knowledge of it. Be truthful.
Negotiation Details – They gave me an offer with was more than I expected, but was told to never accept the first offer. I asked the recruiter if that is the best they could do because of my qualifications, and she asked what I had in mind. I told her and she came back with an offer $2400 more than what I asked for. It floored me, so I accepted.
Accepted Offer
Neutral Experience
Very Easy Interview
I applied online and interviewed at Northrop Grumman.
Interview Details – My process was to be led around the building and meet people, told me what the job entailed and that was it. then wait for 2-3 for call back.
Negotiation Details – none
Accepted Offer
Neutral Experience
Difficult Interview
I applied online and the process took 6 weeks - interviewed at Northrop Grumman.
Interview Details – Interviewed with a woman on the phone and then had an in person with two hiring managers.
Interview Question – How would you describe yourself? Name a situation where you didn't get along with a teammate? Why are you the best person for the job? Answer Question
Negotiation Details – It was for an internship. No negotiation
Declined Offer
Negative Experience
Very Easy Interview
I applied online - interviewed at Northrop Grumman in August 2013.
Interview Details – two phone interviews, then an email questionaire, then put in front of customer, almost no support with how to handle the customer, no interaction with hiring manager despite several attempts which seemed to be a bother. meeting with customer was a disaster because of the lack of preparation by NG hiring manager. questions were all softball even though position was highly technical.
Interview Question – why were you let go after 24 years of top performance? View Answer
Reason for Declining – I didn't want to go thru another lay off experience like the other one
Accepted Offer
Neutral Experience
Interviewed at Northrop Grumman
Interview Details – This location is very adept at interviewing and choosing the right candidate for a position. The position was posted for a couple of weeks and a friend suggested that I apply for it. I applied and was set up for an interview in the same week. The day I interviewed they made a decision within 30 minutes to an hour afterwards and offered me the position.
Interview Question – The questions weren't difficult. I was a bit surprised and happy that I was able to answer them all. Answer Question
Negotiation Details – There was no negotiation
Accepted Offer
Negative Experience
Easy Interview
I applied online and the process took 5 months - interviewed at Northrop Grumman in October 2013.
Interview Details – Month One: Standard interview, got the job offer a few days after the interview. I pass background check. It was contingent on customer approval. I start waiting for interview with customer. Weeks go by with zero contact from recruiter.
Month Two: Recruiter disappears. No response to weekly emails and phone calls. Odd.
Month Three: I am passed to new recruiter and told project will be ramping up over months three and four. Great! But no response to email at end of month three. Not worried yet
Month Four: No response to weekly emails and phone calls asking about next steps. Voicemails left as well but no response. It's now been two months with no response and no word on what happened to 'ramp up' on accepted job offer. Unacceptable.
Month Five: I am passed to third recruiter via email. He has no idea what is going on but will check with PM. He never gets back to me. I haven't heard from him in two weeks. Shockingly he doesn't respond to email or voice mail. t guess I don't have an offer after all.
I've been in the business over 20 years and no company recruiters have ever treated me as badly as at Northrop Grumman. I guess they just don't care
At this point i don't really want to work for this company any more.
Interview Question – Tell me about a time you had a problem with a difficult customer. Answer Question
No Offer
Neutral Experience
Interviewed at Northrop Grumman
Interview Details – Applied Online, Contacted by HR, Filled out pre-interview questions. Phone Interview a few days later. Contacted by email later.
Interview Question – No difficult questions, just questions about rocket/missile modeling knowledge. Answer Question
Accepted Offer
Negative Experience
Average Interview
I applied in-person and the process took 4 months - interviewed at Northrop Grumman in December 2010.
Interview Details – Never know what to expect. Company has no standard process.
Interview Question – Tell me why you are the best candidate View Answer
We invite you to learn more about Northrop Grumman's varied businesses and our rich history of innovation. Northrop Grumman continues to manufacture some of the most cutting-edge technology and products. As a member of… — Full Overview
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Ultimate Fighting "Fistful of Dollars" – A CNBC Special highlighting the rise of the UFC. The show follows UFC fighter Rich Fanklin as he prepares for his fight with Wanderlei Silva at UFC 99.
Ortiz vs. Franklin & Henderson vs. Belfort on deck for UFC 103? : Five Ounces of Pain
That would be the best News ever


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Campground Services & Area Attractions:
Texarkana KOA, TXDescriptionThe Texarkana KOA is a celebration of the RV lifestyle. Visit the campground's unique RV art gallery! Browse for print reproductions of artwork and other collectibles. Take a stroll down Wildscape Trail, a 20-minute walk through the woods. Enjoy the area's music and art festivals or tee it up at Texarkana Golf Ranch. Stay connected with Wi-Fi access and a city-accessible location within seconds of downtown Texarkana. Enjoy big-rig sites ranging from 68 to 90 feet long!Campground Services & Area Attractions:
Getting There:GPS Info. (Latitude, Longitude):33.47083, -94.04694 33°28'15"N, 94°2'49"W From Dallas - Exit 223 and stay left on access road. Left on State Line Ave. Turn left on St. Michael Drive. Turn right into campground. From Little Rock - Exit 223. At stop light continue west across State Line Avenue on St. Micheal Drive. Turn right into campground. Contact Information:Mailing Address:Texarkana KOA500 St Micheal Drive Texarkana TX 75503 Phone Number:Information: (903)792-5521Private Campground |


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The BBC children's channel CBBC has produced a two-part documentary in its "My Life" series, following two New Foundation Scholars during their first term at Eton. The programmes will be broadcast at 5:30 pm on March 18th and 19th, and available online via BBC iPlayer after transmission (iPlayer content is not normally available outside the UK).
From the Head Master
School Diary
Entry to Eton
Public Benefit
Dates of Halves
From the Collections
Eton Video
Eton's Aims
Contact Us


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Candle Stick Which Appeared by Tora
Item Number: TA4928
The magician shows a candlestick to the audience with a candle in it. He lights the candle and then he takes the candle from the candlestick and makes it disappear.
Now he takes the empty candlestick and in a magic movement the candle appears again in the candlestick.
This trick is very easy to perform as the candle disappears and appears easily. This routine comes with a DVD that includes a performance and training sequence.
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