317 research outputs found
Selective CMP process for stacked low-k CVD oxide films
No full textS.53-58A chemical mechanical polishing process for a stacked low-k dielectric material, which is suitable for inter-metal dielectric applications, has been developed. The dielectric is deposited by CVD and composed of a methyl-doped silicon oxide (i.e., low-k Flowfill) embedded between thin SiO2 layers. A new CMP parameter is introduced, which is the removal rate selectivity between two different kinds of materials. We were able to adjust the selectivity between cap and low-k Flowfill layer in a range between 3:1 and 1:5 by tuning the slurry mixture. Different test structures were used to investigate the effect of the removal rate selectivity on the planarization efficiency of the CMP process. A higher removal rate of the low-k Flowfill layer in comparison to that of the cap layer results in a significant increase of the planarization length and a reduction of the overpolish needed to achieve planarity
A selective CMP process for stacked low-k CVD oxide films
No full textS.53-58A chemical mechanical polishing process for a stacked low-k dielectric material, which is suitable for inter-metal dielectric applications, has been developed. The dielectric is deposited by CVD and composed of a methyl-doped silicon oxide (i.e., low-k Flowfill) embedded between thin SiO2 layers. A new CMP parameter is introduced, which is the removal rate selectivity between two different kinds of materials. We were able to adjust the selectivity between cap and low-k Flowfill layer in a range between 3:1 and 1:5 by tuning the slurry mixture. Different test structures were used to investigate the effect of the removal rate selectivity on the planarisation efficiency of the CMP process. A higher removal rate of the low-k Flowfill layer in comparison to that of the cap layer results in a significant increase of-the planarisation length and a reduction of the overpolish needed to achieve planarity
Chemical mechanical polishing of low-K CVD oxide films
No full textS.461-466 : Ill., Lit.The behaviour of advanced planarisation layers (APL) deposited with Trikon's Planar 200 CVD system when subjected to chemical mechanical polishing (CMP) has been studied. The APL is a stacked layer consisting of a Flowfill layer with excellent gap-fill properties in between a PECVD base and cap layer. The standard version of the material has been found to be a high quality silicon dioxide with properties comparable to thermal oxide. The polishing behaviour of these layers is compatible with oxide CMP. In the low-k version of the material the Flowfill layer is deposited using a reaction of methyl-silane (CH3SiH3 ) and hydrogen peroxide and has a dielectric constant of about 2.9. This layer consists of a SiO2-network with methyl-groups incorporated. The C-concentration is found to be around 12 per cent. For low-k APL a standard oxide CMP process was not applicable. The removal rate is rather sensitive to the transition between cap and low-k Flowfill layer. In order to achieve a desired s electivity of 1: 1 between cap and low-k Flowfill layer some modifications of the slurry chemistry are considered. The chemical attack of the Si-CH 3 bond and the hydrophobicity of the low-k Flowfill surface play a crucial role in the process mechanism
The influence of phase II conjugation on the biological activity of flavonoids
No full textFlavonoid consumption is often correlated with a wide range of health effects, such as the prevention of cardiovascular diseases, neurodegenerative diseases, and diabetes. These effects are usually ascribed to the activity of the parent flavonoid aglycones, even though these forms of the flavonoids generally have a low systemic bioavailability. During uptake, flavonoids undergo phase II metabolism and are present in the systemic circulation nearly exclusively as conjugated metabolites. The aim of this thesis was to study the effect of conjugation on the biological activity of selected flavonoids towards different endpoints relevant for human health. To this end, conjugation with glucuronic acid was taken as the model type of conjugation because this modification is generally observed to be the most important metabolic conjugation reaction for flavonoids in man. A review of scientific literature published until early 2012 reveals that metabolic conjugation can affect the biological activity of flavonoids in different ways. Conjugation can increase, decrease, inverse or not affect the biological activity, depending on the flavonoid, the type and position of conjugation, the endpoint studied, and the assay system used. Based on the literature reviewed it is concluded that the effect of conjugation has to be studied on a case-by-case basis. As the research on the biological activity of biologically relevant flavonoid conjugates is often hampered by the generally low commercial availability and high prices of these conjugates, a simple and versatile method for the biosynthesis of metabolically relevant flavonoid conjugates is described. Using this method, relevant conjugates can be prepared from different flavonoid substrates in sufficient quantities for in vitro bioassays. Further, an efficient strategy for the identification of these flavonoid conjugates by LC-MS and 1H-NMR using MetIDB (Metabolite Identification Database), a publicly accessible database of predicted and experimental 1H-NMR spectra of flavonoids, is presented. To study the effect of conjugation on the biological activities of flavonoids, several different assay systems and endpoints were used to study the activity of different flavonoids and their conjugates. The effects of quercetin, kaempferol, and their main plasma conjugates quercetin-3-O-glucuronide and kaempferol-3-O-glucuronide (K-3G) on different endpoints related to peroxisome proliferator-activated receptor (PPAR)-γ were studied. PPAR-γ activation is reported to have positive health effects related to adipogenesis, insulin resistance and inflammation. The presented results show that the flavonoid aglycones increased PPAR-γ mediated gene expression in a stably transfected reporter gene cell line, and that glucuronidation diminished this effect. These observed increases in reporter gene expression were accompanied by increased PPAR-γ receptor-mRNA expression upon exposure to kaempferol, an effect that was also reduced by glucuronidation. Using the cell-free Microarray Assay for Real-time Coregulator-Nuclear receptor Interaction (MARCoNI) it was demonstrated that, unlike the known PPAR-γ agonist rosiglitazone, neither the flavonoid aglycones nor the conjugates are agonistic ligands of the PPAR-γ receptor. Supporting the hypothesis that the tested compounds have a different mode of action from normal LBD agonism, quercetin appeared to synergistically increase the effect of rosiglitazone in the reporter gene assay. The modes of action behind the observed effects remain to be elucidated and might include effects on protein kinase activities affecting expression of the PPAR-γ receptor, or posttranscriptional modifications of PPAR-γ. Another type of nuclear receptor known to be targeted by certain flavonoids are the estrogen receptor (ER)α- and ERβ. ERs are the main targets of estrogenic compounds, and upon their activation different transcriptional responses with opposite effects on cell proliferation and apoptosis are elicited; ERα activation stimulates cell proliferation, while ERβ activation causes apoptosis and reduces ERα mediated induction of cell proliferation. Using the MARCoNI assay, the intrinsic estrogenic effects of the two main dietary isoflavones daidzein and genistein, and their plasma conjugates daidzein-7-O-glucuronide and genistein-7-O-glucuronide on the ligand induced coregulator binding of ERα- and ERβ-LBD were studied and compared to the effect of the positive control 17β-estradiol (E2). The results show that the tested isoflavone compounds are less potent agonists of ERα- and ERβ-LBD than E2, although they modulate the LBD-coregulator interactions in a manner similar to E2. Genistein is shown to be a more potent agonist than daidzein for both receptor subtypes. While in the MARCoNI assay genistein had a strong preference for ERβ-LBD activation over ERα-LBD activation, daidzein had a slight preference for ERα-LBD activation over ERβ-LBD activation. Glucuronidation reduced the intrinsic agonistic activities of both daidzein and genistein to induce ERα-LBD and ERβ-LBD - coregulator interactions and increased their average half maximal effective concentrations (EC50s) by 8 to 4,400 times. The results presented further show that glucuronidation changed the preferential activation of genistein from ERβ-LBD to ERα-LBD and increased the preferential activation of daidzein for ERα-LBD; this is of special interest given that ERβ activation, which is counteracting the possible adverse effects of ERα activation, is considered one of the supposedly beneficial modes of action of isoflavones. Many flavonoids are reported to be inhibitors of protein kinases. To study the effect of conjugation on the inhibition of serine/threonine protein kinases by flavonoids, kaempferol and its main plasma conjugate K-3G were selected as model compounds. Protein kinases are involved in a wide range of physiological processes by controlling signaling cascades and regulating protein functions; modulation of their activities can have a wide range of biological effects. The inhibitory effects of kaempferol, K-3G, and the broad-specificity protein kinase inhibitor staurosporine on the phosphorylation activity of recombinant protein kinase A (PKA) and of a lysate prepared from the hepatocellular carcinoma cell line HepG2 were studied using a microarray platform that determines the phosphorylation of 141 putative serine/threonine phosphorylation sites derived from human proteins. The results reveal that glucuronidation reduces the intrinsic potency of kaempferol to inhibit the phosphorylation activity of PKA and HepG2 lysate on average about 16 and 3.5 times, respectively. It is shown that the inhibitory activity of K-3G in the experiments conducted was not caused by deconjugation to the aglycone. Furthermore, the results show that kaempferol and K-3G, unlike the broad-specificity protein kinase inhibitor staurosporine, did not appear to inhibit all protein kinases present in the HepG2 lysate to a similar extent, indicating that kaempferol selectively targets protein kinases, a characteristic that appeared not to be affected by glucuronidation. The fact that K-3G appeared to be only a few times less potent than kaempferol implies that K-3G does not necessarily need to be deconjugated to the aglycone to exert potential inhibitory effects on protein kinases. The results obtained in the present thesis support the conclusion that glucuronidation of flavonoids does not necessarily abolish their activity and that flavonoid glucuronides may be biologically active themselves, albeit at higher concentrations than the parent aglycones. In line with the conclusions from the earlier literature review, an updated literature review on the effect of conjugation on the biological activity of flavonoids concludes that that the effect of conjugation on the biological activity of flavonoids depends on the type and position of conjugation, the endpoint studied and the assay system used. Based on the results described and the literature reviewed in this thesis, several recommendations and perspectives for future research are formulated. Several methodological considerations are formulated that need to be taken into account when studying the biological activity of flavonoids and their conjugates to avoid confounding results. Further, the relevance of the gut microbiome for flavonoid bioactivity is highlighted, and considerations regarding the pharmacokinetics and pharmacodynamics of flavonoids in vivo are formulated. Altogether, it can be concluded that circulating flavonoid conjugates may exert biological activities themselves, and that understanding these is a prerequisite to successfully elucidate the mechanisms of action behind the biological activities linked to flavonoid consumption.</p
Physiologically based kinetic (PBK) modeling as a tool to quantify the role of gut microbial metabolism in the in vivo effects of the foodborne estrogens daidzein and zearalenone
No full textThe present thesis focuses on two food borne compounds whose toxicity may be influenced by the gut microbiota. These compounds are daidzein and zearalenone (ZEN), both known to exert estrogenic effects. The isoflavone daidzein represents an important bioactive food constituent in soy products which exerts estrogenicity due to structural similarity to the natural hormone 17β-estradiol (E2) (Niu et al., 2018). The mycotoxin zearalenone is a well-known example of a toxin produced by fungi growing on contaminated crops, showing potential estrogenicity (Drzymala et al., 2015). Both daidzein and ZEN can be metabolized by gut microbiota to metabolites with higher estrogenic potential than their parent compounds, being S-equol (Mayo et al., 2019) and α-zearalenol (α-ZEL) (Zinedine et al., 2007), respectively. Exposure to these microbial metabolites may add to the effects resulting from exposure to the respective parent compounds. The aim of the present thesis was to characterize the role of gut microbial metabolism in the toxicity of daidzein and zearalenone (ZEN) by including gut microbiota in physiologically based kinetic (PBK) models and applying these models for quantitative in vitro to in vivo extrapolations (QIVIVE). The results obtained provide proofs-of-principle for application of this novel approach methodology (NAM) for alternatives in animal testing, characterizing the consequences of the metabolism by the gut microbiota for toxicity of foodborne chemicals in the host without a need for in vivo studies in experimental animals or human intervention studies
Evolution and persistence of Arctic and Antarctic stratospheric polar vortex over the 1979 - 2021 period
No full textCe travail de thèse porte sur l'étude de l’évolution de l'intensité et de la position de la bordure du vortex en fonction de la latitude équivalente sur la période 1979 - 2021 sur 3 niveaux isentropes (675 K, 550 K et 475 K) issus des réanalyses ECMWF ERA-Interim. Une analyse des dates de formation et de rupture des vortex polaires est incluse. Le cycle solaire et dans une moindre mesure, l'oscillation quasi-biennale, l'oscillation australe El Niño et l'oscillation arctique modulent l'évolution interannuelle de l’intensité de la bordure et des dates de rupture du vortex. Dans l’HS, une augmentation à long terme de l'intensité de la bordure du vortex et des dates de rupture est observée sur la période 1979 - 1999, liée à l'augmentation du trou d'ozone en Antarctique. Après des ruptures précoces entre 1981 et 1987, des vortex plus persistants sont apparus dans l’HN au cours des années 1990. Pour les deux hémisphères, on observe une bordure du vortex plus intense et une persistance lors des années de minimum solaire (minSC). Pour l’HS, la bordure du vortex est plus intense et dure plus longtemps pour les années maxSC/wQBO que pour les années maxSC/eQBO, et est un peu plus intense durant la phase ENSO froide (cENSO). Pour l’HN, l’intensité de la bordure est plus prononcée que dans l’HS durant la phase wQBO, et il est plus intense durant les années minSC/wQBO.This PhD study focuses on the study of the evolution of the stratospheric polar vortices over the last forty years. The intensity and position of the Southern and Northern stratospheric polar vortex edge are evaluated as a function of equivalent latitude over the 1979 - 2021 period on 3 isentropic levels in the lower and middle stratosphere (675 K, 550 K and 475 K) from ECMWF ERA-Interim reanalysis. An analysis of the onset and breakup dates of the polar vortices is included. The solar cycle and to a lower extent the quasi-biennal oscillation, El Niño Southern Oscillation and the Arctic Oscillation modulate the interannual evolution of the strength of the vortex edge and the vortex breakup dates. In the SH, long-term increase of the vortex edge intensity and breakup dates is observed over the 1979 - 1999 period, linked to the increase of the Antarctic ozone hole. After early break-ups between 1981 and 1987, more persistent vortex occured in the NH during the 1990s. For both hemispheres stronger vortex edge and longer vortex duration is observed in solar minimum (minSC) years. For the SH, the vortex edge is stronger and lasts longer for maxSC/wQBO years than for maxSC/eQBO years, and is somewhat stronger during cold ENSO phase (cENSO). For the NH, the stronger vortex edge is more pronounced than in SH during the wQBO phase, and it is stronger during minSC/wQBO years
Estimating European volatile organic compound emissions using satellite observations of formaldehyde from the Ozone Monitoring Instrument
No full textEmission of non-methane Volatile Organic Compounds (VOCs) to the atmosphere
stems from biogenic and human activities, and their estimation is difficult
because of the many and not fully understood processes involved. In order to
narrow down the uncertainty related to VOC emissions, which negatively
reflects on our ability to simulate the atmospheric composition, we exploit
satellite observations of formaldehyde (HCHO), an ubiquitous oxidation
product of most VOCs, focusing on Europe. HCHO column observations from the
Ozone Monitoring Instrument (OMI) reveal a marked seasonal cycle with a
summer maximum and winter minimum. In summer, the oxidation of methane and
other long-lived VOCs supply a slowly varying background HCHO column, while
HCHO variability is dominated by most reactive VOC, primarily biogenic
isoprene followed in importance by biogenic terpenes and anthropogenic VOCs.
The chemistry-transport model CHIMERE qualitatively reproduces the temporal
and spatial features of the observed HCHO column, but display regional
biases which are attributed mainly to incorrect biogenic VOC emissions,
calculated with the Model of Emissions of Gases and Aerosol from Nature
(MEGAN) algorithm. These "bottom-up" or a-priori emissions are corrected
through a
Bayesian inversion of the OMI HCHO observations. Resulting "top-down" or
a-posteriori isoprene emissions are lower than "bottom-up" by 40% over
the Balkans
and by 20% over Southern Germany, and higher by 20% over Iberian
Peninsula, Greece and Italy.
We conclude that OMI
satellite observations of HCHO can provide a quantitative "top-down"
constraint on the European "bottom-up" VOC inventories
Influence of the gut microbiome on plasma metabolite patterns
No full textThe gut microbiome has become a burgeoning field of research and is proven to play a role in in many host physiological aspects, also contributing to the blood metabolome that is otherwise produced by tissues of the host organism. In order to increase the mechanistic understanding of how the microbiome influences its host health, there is a need to integrate knowledge of the composition of the gut microbiome with its functionality in terms of microbiota-mediated metabolic processes. The aim of this project was to obtain detailed insight in the mammalian-microbiome co-metabolism of endogenous metabolites and the extent to which the microbiome influences the plasma metabolome observed. This was achieved with the help of the MetaMap®Tox database in which the metabolome and toxicity data of more than 800 compounds are stored. To elucidate this interaction, metabolites produced by the gut microbiome in the blood of our animal model, Wistar rats, had to be determined. Therefore, antibiotics were used to modulate the microbial communities of Wistar-rats. After 28-day oral administration, metabolomics of plasma, feces, and cecum-content was done. Additionally, DNA was extracted from rat feces and the 16S subunit was sequenced to perform a core diversity analysis. Specific plasma metabolome patterns were established, and microbiome-related metabolites identified as key metabolites in MetaMap®Tox. Metabolites such as hippuric acid, indole derivates and glycerol appeared to be microbiome-derived or -associated plasma metabolites. In general, most changes were observed in metabolites belonging to the class of bile acids, complex lipids, fatty acids and related metabolites, as well as amino acids and related metabolites. Especially abrupt changes observed in the bile acid pool after antibiotic administration evidenced a strong influence of the microbiome on bile acid metabolism. In both feces and cecum-content, where almost all plasma metabolites could be determined as well, a treatment-related effect was observed, as well as only minimal, if any, differences between samples of male and female animals. The effects of the tested antibiotics, each possessing a different activity spectrum, could be separated from each other on the basis of the feces and cecum content metabolome. Largest changes were observed for the classes of lipids, bile acids and amino acids. It could also be shown that metabolome changes can be detected equally well in feces as in the cecum content, thus allowing to use a non invasive method for measurements of studies on metabolism by the gut microbiota. In conclusion, the functional microbial changes of the gut microbiome had to be assessed and the interactions between gut microbes and the host by applying metabolomics and taxonomic profiling had to be elucidated. The results of this thesis suggest that plasma and feces based metabolic profiling via a targeted analysis turned out to be a suitable tool to investigate the microbial functionality of the gut microbiome.</p
Bi-directional interactions between the gut microbiota and dietary glycation products
No full textGlycation products comprise a heterogenous group of compounds which can be formed upon thermal processing of food products and include advanced glycation end products (AGEs), such as carboxymethyllysine, and their precursors such as the Amadori product fructoselysine and α-dicarbonyl compounds like methylglyoxal, glyoxal and 3-deoxyglucosone. Besides being present in exogenous dietary sources, glycation products can also be produced endogenously inside the human body. AGEs have been associated with the development of multiple adverse health effects, such as diabetes and cardiovascular diseases, but whether exposure to exogenous dietary AGEs and their precursors contributes to these effects remains debated. In this thesis, an overview was presented of the toxicokinetics and toxicodynamics of exogenous and endogenous AGEs and their precursors which are of relevance to consider when evaluating whether exposure to exogenous dietary glycation products can contribute to the adverse health effects associated with AGEs. It was concluded that better characterization of the tested AGEs and precursors, and to distinguish between their low molecular mass (LMM) and high molecular mass (HMM) forms, as well as quantification of the exposure from endogenous formation relative to that resulting from dietary intake are all of importance to provide a definite conclusion on whether dietary exposure to glycation products can contribute to the adverse health effects associated to AGEs. In addition, it was concluded that part of the AGEs and their precursors remain unabsorbed upon dietary exposure and can reach the colon. Consequently at least part of the AGEs and their precursors can interact with the gut microbiota in a bi-directional manner. This can affect the toxicokinetics of the AGEs and their precursors but on the other hand can also result in exerted toxicodynamic effects by altering the gut microbiota composition and possibly function. The aim of this project was to characterize these interactions of the gut microbiota with selected dietary glycation products and vice versa, and to characterize inter- and intraindividual differences in gut microbial reactions using the Amadori product fructoselysine and the AGE carboxymethyllysine as model compounds. This was achieved by the application of an in vitro model where collected individual human fecal samples were incubated with the substrate of interest. Michaelis-Menten kinetic parameters could be obtained, in addition to information on metabolite formation (short chain fatty acid; SCFA). In addition to interindividual differences, intra-individual differences were quantified as well of microbial degradation of the AGE carboxymethyllysine and its precursor fructoselysine. The gut microbiota is a dynamic ecosystem and thus intraindividual temporal differences are of possible relevance for its functioning. The results revealed pronounced inter- and intraindividual variation in both carboxymethyllysine and fructoselysine degradation while the two degradation rates were not correlated (R2=0.08), showing the need to evaluate toxicokinetics for individual AGEs and precursors instead of evaluating them on a group level. In addition, multiple bacterial genera were correlated with the individuals’ carboxymethyllysine and fructoselysine degradation activities, corroborating that showing that the potential to convert fructoselysine and carboxymethyllysine may originate from multiple bacterial genera. The effect of different dietary exposures on microbial degradation was evaluated by comparing functional differences in microbial fructoselysine degradation between breast-fed (BF) and formula-fed (FF) infants, in view of their different exclusive diets and consequent different dietary fructoselysine exposures. This was done by evaluating a publicly available metagenome dataset analysis with metagenome assembled genomes (MAGs) from infant fecal samples which showed that genes involved in microbial fructoselysine degradation were present in multiple taxa in both BF and FF infant fecal samples but were higher prevalent in fecal samples from FF infants compared to the BF infants. Further collection of individual fecal samples from exclusively BF and FF infants showed that both groups were able to degrade fructoselysine anaerobically but fecal samples from the FF infants resulted in a significantly higher degradation activity compared to the BF infants. This indicated that the infant gut microbiota adapts towards dietary fructoselysine exposure. This dynamic adaptive aspect of the gut microbiota was also observed in mice which were exposed to a heated diet high in AGEs which resulted in an altered gut microbiota composition compared to mice exposed to the control diet. Exposure to the heated diet high in AGEs followed by the control diet (i.e. the switch group) showed that the altered gut microbiota composition was reversible and adapted to the dietary exposure. This reversibility was also observed for the accumulation of the tested AGEs in plasma, kidney and liver (as analyzed in their protein-bound and free form), a result that also pointed to at least partial bioavailability of the dietary AGEs and/or their precursors that appeared to be enriched in the heated chow diet.Overall, it can be concluded that the bi-directional relation of the gut microbiota with exogenous AGEs and their precursors is of relevance when evaluating their toxicokinetic and toxicodynamic characteristics. To accurately evaluate the hazards and risks of dietary exposure to AGEs and precursors, better characterization and quantification of the applied test substances and biological outcomes, and also of the exposure from endogenous formation relative to that resulting from dietary intake, are essential.  
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