An experimental and modeling study on the reactivity of extremely fuel-rich methane/dimethyl ether mixtures

Chemical reactions in stoichiometric to fuel-rich methane/dimethyl ether/air mixtures (fuel air equiva- lence ratio φ=1–20) were investigated by experiment and simulation with the focus on the conversion of methane to chemically more valuable species through partial oxidation. Experimental data from dif- ferent facilities were measured and collected to provide a large database for developing and validating a reaction mechanism for extended equivalence ratio ranges. Rapid Compression Machine ignition delay times and species profiles were collected in the temperature range between 660 and 1052 K at 10 bar and equivalence ratios of φ= 1–15. Ignition delay times and product compositions were measured in a shock tube at temperatures of 630–1500 K, pressures of 20–30 bar and equivalence ratios of φ= 2 and 10. Ad- ditionally, species concentration profiles were measured in a flow reactor at temperatures between 473 and 973 K, a pressure of 6 bar and equivalence ratios of φ= 2, 10, and 20. The extended equivalence ratio range towards extremely fuel-rich mixtures as well as the reaction-enhancing effect of dimethyl ether were studied because of their usefulness for the conversion of methane into chemically valuable species through partial oxidation at these conditions. Since existing reaction models focus only on equivalence ratios in the range of φ= 0.3–2.5, an extended chemical kinetics mechanism was developed that also covers extremely fuel-rich conditions of methane/dimethyl ether mixtures. The measured ignition delay times and species concentration profiles were compared with the predictions of the new mechanism, which is shown to predict well the ignition delay time and species concentration evolution measure- ments presented in this work. Sensitivity and reaction pathway analyses were used to identify the key reactions governing the ignition and oxidation kinetics at extremely fuel-rich conditions

In utero exposure to cigarette smoke dysregulates human fetal ovarian developmental signalling

STUDY QUESTION How does maternal cigarette smoking disturb development of the human fetal ovary?<p></p> SUMMARY ANSWER Maternal smoking increases fetal estrogen titres and dysregulates several developmental processes in the fetal ovary.<p></p> WHAT IS KNOWN ALREADY Exposure to maternal cigarette smoking during gestation reduces human fetal ovarian cell numbers, germ cell proliferation and subsequent adult fecundity.<p></p> STUDY DESIGN, SIZE, DURATION The effects of maternal cigarette smoking on the second trimester human fetal ovary, fetal endocrine signalling and fetal chemical burden were studied. A total of 105 fetuses were studied, 56 from mothers who smoked during pregnancy and 49 from those who did not.<p></p> PARTICIPANTS/MATERIALS, SETTING METHODS Ovary, liver and plasma samples were collected from electively terminated, normally progressing, second trimester human fetuses. Circulating fetal hormones, levels of 73 fetal ovarian transcripts, protein localization, density of oocytes/primordial follicles and levels of 16 polycyclic aromatic hydrocarbons (PAHs) in the fetal liver were determined.<p></p> MAIN RESULTS AND THE ROLE OF CHANCE Circulating fetal estrogen levels were very high and were increased by maternal smoking (ANOVA, P = 0.055–0.004 versus control). Smoke exposure also dysregulated (two-way ANOVA, smoking versus gestation weeks interaction, P = 0.046–0.023) four fetal ovarian genes (cytochrome P450 scc [CYP11A1], NOBOX oogenesis homeobox [NOBOX], activator of apoptosis harakiri [HRK], nuclear receptor subfamily 2, group E, member 1 [NR2E1]), shifted the ovarian Inhibin βA/inhibin α ratio (NHBA/INHA) transcript ratio in favour of activin (ANOVA, P = 0.049 versus control) and reduced the proportion of dominant-negative estrogen receptor 2 (ERβ: ESR2) isoforms in half the exposed fetuses. PAHs, ligands for the aryl hydrocarbon receptor (AHR), were increased nearly 6-fold by maternal smoking (ANOVA, P = 0.011 versus control). A fifth transcript, COUP transcription factor 1 (nuclear receptor subfamily 2, group F, member 1: NR2F1, which contains multiple AHR-binding sites), was both significantly increased (ANOVA, P = 0.026 versus control) and dysregulated by (two-way ANOVA, smoking versus gestation weeks interaction, P = 0.021) maternal smoking. NR2F1 is associated with repression of FSHR expression and smoke-exposed ovaries failed to show the normal increase in FSHR expression during the second trimester. There was a significantly higher number of DEAD (Asp-Glu-Ala-Asp) box polypeptide 4 (DDX4) VASA-positive (ANOVA, P = 0.016 versus control), but not POU domain, class 1, transcription factor 1 (POU5F1) OCT3/4-positive, oocytes in smoke-exposed fetuses and this matched with a significantly higher number of primordial follicles (ANOVA, P = 0.024 versus control).<p></p> LIMITATIONS, REASONS FOR CAUTION The effects of maternal smoking on establishment of the maximum fetal primordial follicle pool cannot be reliably studied in our population since the process is not completed until 28 weeks of gestation and normal fetuses older than 21 weeks of gestation are not available for study. Our data suggest that some fetal ovaries are affected by smoke exposure while others are not, indicating that additional studies, with larger numbers, may show more significant effects.<p></p> WIDER IMPLICATIONS OF THE FINDINGS Fetal exposure to chemicals in cigarette smoke is known to lead to reduced fecundity in women. Our study suggests, for the first time, that this occurs via mechanisms involving activation of AHR, disruption of inhibin/activin and estrogen signalling, increased exposure to estrogen and dysregulation of multiple molecular pathways in the exposed human fetal ovary. Our data also suggest that alterations in the ESR2 positive and dominant negative isoforms may be associated with reduced sensitivity of some fetuses to increased estrogens and maternal smoking

Folic acid to reduce neonatal mortality from neural tube disorders

Background Neural tube defects (NTDs) remain an important, preventable cause of mortality and morbidity. High-income countries have reported large reductions in NTDs associated with folic acid supplementation or fortification. The burden of NTDs in low-income countries and the effectiveness of folic acid fortification/supplementation are unclear

Global investigation of protein–protein interactions in yeast Saccharomyces cerevisiae using re-occurring short polypeptide sequences

Protein–protein interaction (PPI) maps provide insight into cellular biology and have received considerable attention in the post-genomic era. While large-scale experimental approaches have generated large collections of experimentally determined PPIs, technical limitations preclude certain PPIs from detection. Recently, we demonstrated that yeast PPIs can be computationally predicted using re-occurring short polypeptide sequences between known interacting protein pairs. However, the computational requirements and low specificity made this method unsuitable for large-scale investigations. Here, we report an improved approach, which exhibits a specificity of ∼99.95% and executes 16 000 times faster. Importantly, we report the first all-to-all sequence-based computational screen of PPIs in yeast, Saccharomyces cerevisiae in which we identify 29 589 high confidence interactions of ∼2 × 107 possible pairs. Of these, 14 438 PPIs have not been previously reported and may represent novel interactions. In particular, these results reveal a richer set of membrane protein interactions, not readily amenable to experimental investigations. From the novel PPIs, a novel putative protein complex comprised largely of membrane proteins was revealed. In addition, two novel gene functions were predicted and experimentally confirmed to affect the efficiency of non-homologous end-joining, providing further support for the usefulness of the identified PPIs in biological investigations

PCNA ubiquitylation ensures timely completion of unperturbed DNA replication in fission yeast

PCNA ubiquitylation on lysine 164 is required for DNA damage tolerance. In many organisms PCNA is also ubiquitylated in unchallenged S phase but the significance of this has not been established. Using Schizosaccharomyces pombe, we demonstrate that lysine 164 ubiquitylation of PCNA contributes to efficient DNA replication in the absence of DNA damage. Loss of PCNA ubiquitylation manifests most strongly at late replicating regions and increases the frequency of replication gaps. We show that PCNA ubiquitylation increases the proportion of chromatin associated PCNA and the co-immunoprecipitation of Polymerase δ with PCNA during unperturbed replication and propose that ubiquitylation acts to prolong the chromatin association of these replication proteins to allow the efficient completion of Okazaki fragment synthesis by mediating gap filling

Ibuprofen is deleterious for the development of first trimester human fetal ovary ex vivo

International audienceSTUDY QUESTION Does ibuprofen use during the first trimester of pregnancy interfere with the development of the human fetal ovary? SUMMARY ANSWER In human fetuses, ibuprofen exposure is deleterious for ovarian germ cells. WHAT IS KNOWN ALREADY In utero stages of ovarian development define the future reproductive capacity of a woman. In rodents, analgesics can impair the development of the fetal ovary leading to early onset of fertility failure. Ibuprofen, which is available over-the-counter, has been reported as a frequently consumed medication during pregnancy, especially during the first trimester when the ovarian germ cells undergo crucial steps of proliferation and differentiation. STUDY DESIGN, SIZE, DURATION Organotypic cultures of human ovaries obtained from 7 to 12 developmental week (DW) fetuses were exposed to ibuprofen at 1-100 μM for 2, 4 or 7 days. For each individual, a control culture (vehicle) was included and compared to its treated counterpart. A total of 185 individual samples were included. PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian explants were analyzed by flow cytometry, immunohistochemistry and quantitative PCR. Endpoints focused on ovarian cell number, cell death, proliferation and germ cell complement. To analyze the possible range of exposure, ibuprofen was measured in the umbilical cord blood from the women exposed or not to ibuprofen prior to termination of pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE Human ovarian explants exposed to 10 and 100 μM ibuprofen showed reduced cell number, less proliferating cells, increased apoptosis and a dramatic loss of germ cell number, regardless of the gestational age of the fetus. Significant effects were observed after 7 days of exposure to 10 μM ibuprofen. At this concentration, apoptosis was observed as early as 2 days of treatment, along with a decrease in M2A-positive germ cell number. These deleterious effects of ibuprofen were not fully rescued after 5 days of drug withdrawal. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION This study was performed in an experimental setting of human ovaries explants exposed to the drug in culture, which may not fully recapitulate the complexity of in vivo exposure and organ development. Inter-individual variability is also to be taken into account. WIDER IMPLICATIONS OF THE FINDINGS Whereas ibuprofen is currently only contra-indicated after 24 weeks of pregnancy, our results points to a deleterious effect of this drug on first trimester fetal ovaries ex vivo. These findings deserve to be considered in light of the present recommendations about ibuprofen consumption pregnancy, and reveal the urgent need for further investigations on the cellular and molecular mechanisms that underlie the effect of ibuprofen on fetal ovary development. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark

Background: Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP). Methods and Findings: Three population-based EUROCAT congenital anomaly registries- Norway (2004–2010), Wales (2000–2010) and Funen, Denmark (2000–2010)—were linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06–2.11), and the composite adverse outcome of 'anomaly or stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03–1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99–1.21). Adjusting for socio-economic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12–1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression. Conclusion: The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care