The impact of a human IGF-II analog ([Leu27]IGF-II) on fetal growth in a mouse model of fetal growth restriction.

Enhancing placental insulin-like growth factor (IGF) availability appears to be an attractive strategy for improving outcomes in fetal growth restriction (FGR). Our approach was the novel use of [Leu(27)]IGF-II, a human IGF-II analog that binds the IGF-II clearance receptor IGF-IIR in fetal growth-restricted (FGR) mice. We hypothesized that the impact of [Leu(27)]IGF-II infusion in C57BL/6J (wild-type) and endothelial nitric oxide synthase knockout (eNOS(-/-); FGR) mice would be to enhance fetal growth and investigated this from mid- to late gestation; 1 mg·kg(-1)·day(-1) [Leu(27)]IGF-II was delivered via a subcutaneous miniosmotic pump from E12.5 to E18.5. Fetal and placental weights recorded at E18.5 were used to generate frequency distribution curves; fetuse

In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer.

UNLABELLED: Fenofibrate, an agonist of PPAR-alpha, in doses above 25 microM, inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells. We show that these effects are potentiated by retinoic acid, an agonist of the retinoid-X-receptor. DNA content analysis shows that G1/S phase progression through the cell cycle is inhibited. Independent Component Analysis of gene microarray experiments demonstrated downregulation of Cyclin D1 (CCND1) and associated changes in cell cycle gene expression. Expression of PPAR-alpha mRNA was reduced by >75% using RNA-interference but this resulted in only minor changes in biological effects. A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth. CONCLUSION: The combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro

Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma.

Endometriosis is a common benign gynaecological condition affecting at least 10% of women of childbearing age and is characterized by pain--frequently debilitating. Although the exact prevalence is unknown, the economic burden is substantial (∼$50 billion a year in the USA alone) and it is associated with considerable morbidity. The development of endometriosis is inextricably linked to the process of menstruation and thus the models that best recapitulate the human disease are in menstruating non-human primates. However, the use of these animals is ethically challenging and very expensive. A variety of models in laboratory animals have been developed and the most recent are based on generating menstrual-like endometrial tissue that can be transferred to a recipient animal. These models are genetically manipulable and facilitate precise mechanistic studies. In addition, these models can be used to study malignant transformation in epithelial ovarian carcinoma. Epidemiological and molecular evidence indicates that endometriosis is the most plausible precursor of both clear cell and endometrioid ovarian cancer (OCCA and OEA, respectively). While this progression is rare, understanding the underlying mechanisms of transformation may offer new strategies for prevention and therapy. Our ability to pursue this is highly dependent on improved animal models but the current transgenic models, which genetically modify the ovarian surface epithelium and oviduct, are poor models of ectopic endometrial tissue. In this review we describe the various models of endometriosis and discuss how they may be applicable to developing our mechanistic understanding of OCCA and OEA.CMK was funded by a grant from CRUK (A13095). Part of the research work disclosed in this publication is funded by the Strategic Educational Pathways Scholarship (Malta) to CB. The scholarship is part-financed by the European Union-European Social Fund (ESF) under Operational Programme II-Cohesion Policy 2007-2013, "Empowering People for More Jobs and a Better Quality of Life”. JDB is supported by CRUK (A15601).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/path.465

Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development.

Early human placental and embryonic development occurs in a physiologically low oxygen environment supported by histiotrophic secretions from endometrial glands. In this study, we compare the placental metabolomic profile in the first, second and third trimesters to determine whether the energy demands are adequately met in the first trimester. We investigated whether hypoxia-inducible factors, HIF-1α and/or HIF-2α, might regulate transcription during the first trimester. First and second trimester tissue was collected using a chorionic villus sampling-like (CVS) technique. Part of each villus sample was frozen immediately and the remainder cultured under 2 or 21% O2 ± 1 mM H2O2, and ±the p38 MAPK pathway inhibitor, PD169316. Levels of HIF-1α were assessed by western blotting and VEGFA, PlGF and GLUT3 transcripts were quantified by RT-PCR. Term samples were collected from normal elective Caesarean deliveries. There were no significant differences in concentrations of ADP, NAD(+), lactate, and glucose, and in the ATP/ADP ratio, across gestational age. Neither HIF-1α nor HIF-2α could be detected in time-zero CVS samples. However, culture under any condition (2 or 21% O2 ± 1 mM H2O2) increased HIF-1α and HIF-2α. HIF-1α and HIF-2α were additionally detected in specimens retrieved after curettage. HIF-1α stabilization was accompanied by significant increases in VEGFA and GLUT3 and a decrease in PlGF mRNAs. These effects were suppressed by PD169316. In conclusion, our data suggest that first trimester placental tissues are not energetically compromised, and that HIF-1α is unlikely to play an appreciable role in regulating transcriptional activity under steady-state conditions in vivo. However, the pathway may be activated by stress conditions.This work was supported by the Wellcome Trust (084804/2/08/Z). Funding to pay the Open Access publication charges for this article was provided by theWellcome Trust.This is the final published version. It originally appeared in Molecular Human Reproduction, at http://dx.doi.org/10.1093/molehr/gau105

Microbial Reduction of U(VI) under Alkaline Conditions: Implications for Radioactive Waste Geodisposal

Although there is consensus that microorganisms significantly influence uranium speciation and mobility in the subsurface under circumneutral conditions, microbiologically mediated U(VI) redox cycling under alkaline conditions relevant to the geological disposal of cementitious intermediate level radioactive waste, remains unexplored. Here, we describe microcosm experiments that investigate the biogeochemical fate of U(VI) at pH 10–10.5, using sediments from a legacy lime working site, stimulated with an added electron donor, and incubated in the presence and absence of added Fe(III) as ferrihydrite. In systems without added Fe(III), partial U(VI) reduction occurred, forming a U(IV)-bearing non-uraninite phase which underwent reoxidation in the presence of air (O2) and to some extent nitrate. By contrast, in the presence of added Fe(III), U(VI) was first removed from solution by sorption to the Fe(III) mineral, followed by bioreduction and (bio)magnetite formation coupled to formation of a complex U(IV)-bearing phase with uraninite present, which also underwent air (O2) and partial nitrate reoxidation. 16S rRNA gene pyrosequencing showed that Gram-positive bacteria affiliated with the Firmicutes and Bacteroidetes dominated in the post-reduction sediments. These data provide the first insights into uranium biogeochemistry at high pH and have significant implications for the long-term fate of uranium in geological disposal in both engineered barrier systems and the alkaline, chemically disturbed geosphere

Determination of zeolite-group mineral compositions by electron probe microanalysis

A new protocol for the quantitative determination of zeolite-group mineral compositions by electron probe microanalysis (wavelength-dispersive spectrometry) under ambient conditions, is presented. The method overcomes the most serious challenges for this mineral group, including new confidence in the fundamentally important Si-Al ratio. Development tests were undertaken on a set of natural zeolite candidate reference samples, representing the compositional extremes of Na, K, Cs, Mg, Ca, Sr and Ba zeolites, to demonstrate and assess the extent of beam interaction effects on each oxide component for each mineral. These tests highlight the variability and impact of component mobility due to beam interaction, and show that it can be minimized with recommended operating conditions of 15 kV, 2 nA, a defocused, 20 μm spot size, and element prioritizing with the spectrometer configuration. The protocol represents a pragmatic solution that works, but provides scope for additional optimization where required. Vital to the determination of high-quality results is the attention to careful preparations and the employment of strict criteria for data reduction and quality control, including the monitoring and removal of non-zeolitic contaminants from the data (mainly Fe and clay phases). Essential quality criteria include the zeolite-specific parameters of R value (Si/(Si + Al + Fe3+), the ‘E%’ charge-balance calculation, and the weight percent of non-hydrous total oxides. When these criteria are applied in conjunction with the recommended analytical operating conditions, excellent inter-batch reproducibility is demonstrated. Application of the method to zeolites with complex solid-solution compositions is effective, enabling more precise geochemical discrimination for occurrence-composition studies. Phase validation for the reference set was conducted satisfactorily with the use of X-ray diffraction and laser-ablation inductively-coupled plasma mass spectroscopy

The Maillard reaction in traditional method sparkling wine.

The Maillard reaction between sugars and amino acids, peptides, or proteins generates a myriad of aroma compounds through complex and multi-step reaction pathways. While the Maillard has been primarily studied in the context of thermally processed foods, Maillard-associated products including thiazoles, furans, and pyrazines have been identified in aged sparkling wines, with associated bready, roasted, and caramel aromas. Sparkling wines produced in the bottle-fermented traditional method (Méthode Champenoise) have been the primary focus of studies related to Maillard-associated compounds in sparkling wine, and these wines undergo two sequential fermentations, with the second taking place in the final wine bottle. Due to the low temperature (15 ± 3°C) and low pH (pH 3-4) conditions during production and aging, we conclude that Maillard interactions may not proceed past intermediate stages. Physicochemical factors that affect the Maillard reaction are considered in the context of sparkling wine, particularly related to pH-dependent reaction pathways and existing literature pertaining to low temperature and/or low pH Maillard activity. A focus on the origins and composition of precursor species (amino acids and sugars) in sparkling wines is presented, as well as the potential role of metal ions in accelerating the Maillard reaction. Understanding the contributions of individual physicochemical factors to the Maillard reaction in sparkling wine enables a clearer understanding of reaction pathways and sensory outcomes. Advancements in analytical techniques for monitoring the Maillard reaction are also described, and important areas of future research on this topic are identified.The Brock Library Open Access Publishing Fun