927 research outputs found

    The Vietnam Memorial

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    Endoplasmic reticulum stress disrupts placental morphogenesis: implications for human intrauterine growth restriction.

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    We recently reported the first evidence of placental endoplasmic reticulum (ER) stress in the pathophysiology of human intrauterine growth restriction. Here, we used a mouse model to investigate potential underlying mechanisms. Eif2s1(tm1RjK) mice, in which Ser51 of eukaryotic initiation factor 2 subunit alpha (eIF2α) is mutated, display a 30% increase in basal translation. In Eif2s1(tm1RjK) placentas, we observed increased ER stress and anomalous accumulation of glycoproteins in the endocrine junctional zone (Jz), but not in the labyrinthine zone where physiological exchange occurs. Placental and fetal weights were reduced by 15% (97 mg to 82 mg, p < 0.001) and 20% (1009 mg to 798 mg, p < 0.001), respectively. To investigate whether ER stress affects bioactivity of secreted proteins, mouse embryonic fibroblasts (MEFs) were derived from Eif2s1(tm1RjK) mutants. These MEFs exhibited ER stress, grew 50% slower, and showed reduced Akt-mTOR signalling compared to wild-type cells. Conditioned medium (CM) derived from Eif2s1(tm1RjK) MEFs failed to maintain trophoblast stem cells in a progenitor state, but the effect could be rescued by exogenous application of FGF4 and heparin. In addition, ER stress promoted accumulation of pro-Igf2 with altered glycosylation in the CM without affecting cellular levels, indicating that the protein failed to be processed after release. Igf2 is the major growth factor for placental development; indeed, activity in the Pdk1-Akt-mTOR pathways was decreased in Eif2s1(tm1RjK) placentas, indicating loss of Igf2 signalling. Furthermore, we observed premature differentiation of trophoblast progenitors at E9.5 in mutant placentas, consistent with the in vitro results and with the disproportionate development of the labyrinth and Jz seen in placentas at E18.5. Similar disproportion has been reported in the Igf2-null mouse. These results demonstrate that ER stress adversely affects placental development, and that modulation of post-translational processing, and hence bioactivity, of secreted growth factors contributes to this effect. Placental dysmorphogenesis potentially affects fetal growth through reduced exchange capacity

    Large-scale variations in ozone and polar stratospheric clouds measured with airborne lidar during formation of the 1987 ozone hole over Antarctica

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    A joint field experiment between NASA and NOAA was conducted during August to September 1987 to obtain in situ and remote measurements of key gases and aerosols from aircraft platforms during the formation of the ozone (O3) hole over Antarctica. The ER-2 (advanced U-2) and DC-8 aircraft from the NASA Ames Research Center were used in this field experiment. The NASA Langley Research Center's airborne differential absorption lidar (DIAL) system was operated from the DC-8 to obtain profiles of O3 and polar stratospheric clouds in the lower stratosphere during long-range flights over Antarctica from August 28 to September 29, 1987. The airborne DIAL system was configured to transmit simultaneously four laser wavelengths (301, 311, 622, and 1064 nm) above the DC-8 for DIAL measurements of O3 profiles between 11 to 20 km ASL (geometric altitude above sea level) and multiple wavelength aerosol backscatter measurements between 11 to 24 km ASL. A total of 13 DC-8 flights were made over Antarctica with 2 flights reaching the South Pole. Polar stratospheric clouds (PSC's) were detected in multiple thin layers in the 11 to 21 km ASL altitude range with each layer having a typical thickness of less than 1 km. Two types of PSC's were found based on aerosol backscattering ratios: predominantly water ice clouds (type 2) and clouds with scattering characteristics consistent with binary solid nitric acid/water clouds (type 1). Large-scale cross sections of O3 distributions were obtained. The data provides additional information about a potentially important transport mechanism that may influence the O3 budget inside the vortex. There is also some evidence that strong low pressure systems in the troposphere are associated with regions of lower stratospheric O3. This paper discusses the spatial and temporal variations of O3 inside and outside the polar vortex region during the development of the O3 hole and relates these data to other measurements obtained during this field experiment

    Menstrual flow as a non-invasive source of endometrial organoids.

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    Assessment of the endometrium often necessitates a biopsy, which currently involves an invasive, transcervical procedure. Here, we present an alternative technique based on deriving organoids from menstrual flow. We demonstrate that organoids can be derived from gland fragments recovered from menstrual flow. To confirm they faithfully reflect the in vivo state we compared organoids derived from paired scratch biopsies and ensuing menstrual flow from patients undergoing in vitro fertilisation (IVF). We demonstrate that the two sets of organoids share the same transcriptome signature, derivation efficiency and proliferation rate. Furthermore, they respond similarly to sex steroids and early-pregnancy hormones, with changes in morphology, receptor expression, and production of 'uterine milk' proteins that mimic those during the late-secretory phase and early pregnancy. This technique has wide-ranging impact for non-invasive investigation and personalised approaches to treatment of common gynaecological conditions, such as endometriosis, and reproductive disorders, including failed implantation after IVF and recurrent miscarriage

    Placental endoplasmic reticulum stress in gestational diabetes: the potential for therapeutic intervention with chemical chaperones and antioxidants.

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    AIMS/HYPOTHESIS: The aim of this work was to determine whether placental endoplasmic reticulum (ER) stress may contribute to the pathophysiology of gestational diabetes mellitus (GDM) and to test the efficacy of chemical chaperones and antioxidant vitamins in ameliorating that stress in a trophoblast-like cell line in vitro. METHODS: Placental samples were obtained from women suffering from GDM and from normoglycaemic controls and were frozen immediately. Women with GDM had 2 h serum glucose levels > 9.0 mmol/l following a 75 g oral glucose tolerance test and were treated with diet and insulin when necessary. Western blotting was used to assess markers of ER stress. To test the effects of hyperglycaemia on the generation of ER stress, a new trophoblast-like cell line, BeWo-NG, was generated by culturing in a physiological glucose concentration of 5.5 mmol/l (over 20 passages) before challenging with 10 or 20 mmol/l glucose. RESULTS: All GDM patients were well-controlled (HbA1c 5.86 ± 0.55% or 40.64 ± 5.85 mmol/mol, n = 11). Low-grade ER stress was observed in the placental samples, with dilation of ER cisternae and increased phosphorylation of eukaryotic initiation factor 2 subunit α. Challenge of BeWo-NG with high glucose activated the same pathways, but this was as a result of acidosis of the culture medium rather than the glucose concentration per se. Addition of chemical chaperones 4-phenylbutyrate and tauroursodeoxycholic acid and vitamins C and E ameliorated the ER stress. CONCLUSIONS/INTERPRETATION: This is the first report of placental ER stress in GDM patients. Chemical chaperones and antioxidant vitamins represent potential therapeutic interventions for GDM.This study was supported by a grant from the Wellcome Trust (084804/2/08/Z). TE-B was supported by a Newton Advanced Fellowship awarded to TE-B and GJB from the Academy of Medical Sciences, and by the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00125-016-4040-

    Diagenesis of organic matter in Las Vegas Bay and Bonelli Bay, Lake Mead

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    The interstitial water chemistry of the sediments of Las Vegas Bay and Bonelli Bay in Lake Mead has been studied as part of a comprehensive water quality study of those locations. Pore water and solid phase analyses were completed from four stations in Las Vegas Bay and two stations in Bonelli Bay. At both locations the pore water compositions and organic matter diagenesis in the sediments are dominated by sulfate reduction. This major role of sulfate reduction is unusual for lake sediments and reflects the fact that SO4 is the major anion in the lake water. In addition, gypsum (CaSO4) is a common mineral in the surrounding geological formations and appears to supply additional SO4 to the interstitial waters through dissolution. The interstitial water and solid phase analyses have been used to calculate dissolved fluxes across the sediment-water interface. The average calculated PO4 flux out of the sediments was 1.3 mg P m-2 d-1 which is comparable with literature values of 1.2 to 9.6 mg P m-2 d-1 for aerobic water column conditions in rivers and lakes. The rate of burial of organic carbon averages about 6.2 kg m-2 yr-1. Our calculations suggest that this is about four times the loss due to decomposition of organic carbon by 02 and SO4. The extent of SO4 reduction was much more extensive in the sediments of Las Vegas Bay than Bonelli Bay and probably reflects a greater amount of utilizable organic carbon in the former observation
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