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•Four protein emulsions with varied nano and microstructures were prepared.•They were submitted to in vitro gastro-intestinal digestions (Infogest protocol)•Gastro-intestinal ...hydrolyses of both lipids and proteins were assessed by pH-stat.•Orlistat can be used to distinguish pancreatic hydrolysis of proteins and lipids.•Main influencing factors were the bulk phase physical state and oil droplet sizes.
This study describes an experimental design, based on pH-stat, to rapidly screen and assess food formulation effects on the degrees of hydrolysis (DH) of both proteins and lipids throughout in vitro gastro-intestinal digestions. This approach was used to quantitatively compare and hierarchize key structure parameters of protein emulsions. Six matrices (15 wt% whey proteins, 0 or 10 wt% oil), each differing by at least one structure characteristic, were studied. The physical state of the bulk and the oil droplet size were the major structural levers to modulate the hydrolysis of proteins (final DH between 51.7 and 58.3%) and lipids (final DH between 46.9 and 72.7%), with non-trivial interplays between proteolysis and lipolysis. Additionally, pH-stat measurements in presence of a pancreatic lipase inhibitor proved to be an efficient way to widen the scope of the proposed experimental approach to foods that are intrinsically made of both proteins and lipids.
Aims
Rupture-prone atherosclerotic plaques are characterized by inflammation and a large necrotic core. Inflammation is linked to high metabolic activity. Advanced glycation endproducts (AGEs) and ...their major precursor methylglyoxal are formed during high metabolic activity and can have detrimental effects on cellular function and may induce cell death. Therefore, we investigated whether plaque AGEs are increased in human carotid rupture-prone plaques and are associated with plaque inflammation and necrotic core formation.
Methods and results
The protein-bound major methylglyoxal-derived AGE 5-hydro-5-methylimidazolone (MG-H1) and N
ɛ-(carboxymethyl)lysine (CML) were measured in human carotid endarterectomy specimens (n = 75) with tandem mass spectrometry. MG-H1 and CML levels were associated with rupture-prone plaques, increased protein levels of the inflammatory mediators IL-8 and MCP-1 and with higher MMP-9 activity. Immunohistochemistry showed that AGEs accumulated predominantly in macrophages surrounding the necrotic core and co-localized with cleaved caspase-3. Intra-plaque comparison revealed that glyoxalase-1 (GLO-1), the major methylglyoxal-detoxifying enzyme, mRNA was decreased (−13%, P < 0.05) in ruptured compared with stable plaque segments. In line, in U937 monoctyes, we found reduced (GLO-1) activity (−38%, P < 0.05) and increased MGO (346%, P < 0.05) production after stimulation with the inflammatory mediator TNF. Direct incubation with methylglyoxal increased apoptosis up to two-fold.
Conclusion
This is the first study showing that AGEs are associated with human rupture-prone plaques. Furthermore, this study suggests a cascade linking inflammation, reduced GLO-1, methylglyoxal- and AGE-accumulation, and subsequent apoptosis. Thereby, AGEs may act as mediators of the progression of stable to rupture-prone plaques, opening a window towards novel treatments and biomarkers to treat cardiovascular diseases.
Satellite-based retrievals of tropospheric NO2 columns are widely used to infer NOx (≡ NO + NO2) emissions. These retrievals rely on model information for the vertical distribution of NO2. The free ...tropospheric background above 2 km is particularly important because the sensitivity of the retrievals increases with altitude. Free tropospheric NOx also has a strong effect on tropospheric OH and ozone concentrations. Here we use observations from three aircraft campaigns (SEAC4RS, DC3, and ATom) and four atmospheric chemistry models (GEOS-Chem, GMI, TM5, and CAMS) to evaluate the model capabilities for simulating NOx in the free troposphere and attribute it to sources. NO2 measurements during the Studies of Emissions and Atmospheric Composition, Clouds, and Climate Coupling by Regional Surveys (SEAC4RS) and Deep Convective Clouds and Chemistry (DC3) campaigns over the southeastern U.S. in summer show increasing concentrations in the upper troposphere above 10 km, which are not replicated by the GEOS-Chem, although the model is consistent with the NO measurements. Using concurrent NO, NO2, and ozone observations from a DC3 flight in a thunderstorm outflow, we show that the NO2 measurements in the upper troposphere are biased high, plausibly due to interference from thermally labile NO2 reservoirs such as peroxynitric acid (HNO4) and methyl peroxy nitrate (MPN). We find that NO2 concentrations calculated from the NO measurements and NO–NO2 photochemical steady state (PSS) are more reliable to evaluate the vertical profiles of NO2 in models. GEOS-Chem reproduces the shape of the PSS-inferred NO2 profiles throughout the troposphere for SEAC4RS and DC3 but overestimates NO2 concentrations by about a factor of 2. The model underestimates MPN and alkyl nitrate concentrations, suggesting missing organic NOx chemistry. On the other hand, the standard GEOS-Chem model underestimates NO observations from the Atmospheric Tomography Mission (ATom) campaigns over the Pacific and Atlantic oceans, indicating a missing NOx source over the oceans. We find that we can account for this missing source by including in the model the photolysis of particulate nitrate on sea salt aerosols at rates inferred from laboratory studies and field observations of nitrous acid (HONO) over the Atlantic. The median PSS-inferred tropospheric NO2 column density for the ATom campaign is 1.7 ± 0.44 × 1014 molec. cm-2, and the NO2 column density simulated by the four models is in the range of 1.4–2.4 × 1014 molec. cm-2, implying that the uncertainty from using modeled NO2 tropospheric columns over clean areas in the retrievals for stratosphere–troposphere separation is about 1 × 1014 molec. cm-2. We find from GEOS-Chem that lightning is the main primary NOx source in the free troposphere over the tropics and southern midlatitudes, but aircraft emissions dominate at northern midlatitudes in winter and in summer over the oceans. Particulate nitrate photolysis increases ozone concentrations by up to 5 ppbv (parts per billion by volume) in the free troposphere in the northern extratropics in the model, which would largely correct the low model bias relative to ozonesonde observations. Global tropospheric OH concentrations increase by 19 %. The contribution of the free tropospheric background to the tropospheric NO2 columns observed by satellites over the contiguous U.S. increases from 25 ± 11 % in winter to 65 ± 9 % in summer, according to the GEOS-Chem vertical profiles. This needs to be accounted for when deriving NOx emissions from satellite NO2 column measurements.
We present a simulation of the global present-day composition of the troposphere which includes the chemistry of halogens (Cl, Br, I). Building on previous work within the GEOS-Chem model we include ...emissions of inorganic iodine from the oceans, anthropogenic and biogenic sources of halogenated gases, gas phase chemistry, and a parameterised approach to heterogeneous halogen chemistry. Consistent with Schmidt et al. (2016) we do not include sea-salt debromination. Observations of halogen radicals (BrO, IO) are sparse but the model has some skill in reproducing these. Modelled IO shows both high and low biases when compared to different datasets, but BrO concentrations appear to be modelled low. Comparisons to the very sparse observations dataset of reactive Cl species suggest the model represents a lower limit of the impacts of these species, likely due to underestimates in emissions and therefore burdens. Inclusion of Cl, Br, and I results in a general improvement in simulation of ozone (O3) concentrations, except in polar regions where the model now underestimates O3 concentrations. Halogen chemistry reduces the global tropospheric O3 burden by 18.6 %, with the O3 lifetime reducing from 26 to 22 days. Global mean OH concentrations of 1.28 × 106 molecules cm−3 are 8.2 % lower than in a simulation without halogens, leading to an increase in the CH4 lifetime (10.8 %) due to OH oxidation from 7.47 to 8.28 years. Oxidation of CH4 by Cl is small (∼ 2 %) but Cl oxidation of other VOCs (ethane, acetone, and propane) can be significant (∼ 15–27 %). Oxidation of VOCs by Br is smaller, representing 3.9 % of the loss of acetaldehyde and 0.9 % of the loss of formaldehyde.
An mRNA Vaccine against SARS-CoV-2 — Preliminary Report Jackson, Lisa A; Anderson, Evan J; Rouphael, Nadine G ...
New England journal of medicine/The New England journal of medicine,
11/2020, Letnik:
383, Številka:
20
Journal Article
Recenzirano
Odprti dostop
Two inoculations with a new SARS-CoV-2 mRNA-based vaccine that encodes a protein in the coronavirus spike elicited high titers of virus-neutralizing antibody in healthy adult volunteers. ...Virus-specific T-cell responses were also elicited. Interim findings indicated that a dose of 100 μg per injection maximized immune response and minimized the reactogenicity of the vaccine.
The Moderna mRNA-1273 vaccine, which elicited antibodies and T cells specific for the Covid-19 virus in adults 55 years of age or younger, elicited similarly high levels of neutralizing-antibody and ...CD4 T-cell responses in a small group of older adults, including those 71 years of age or older.
Using the data taken at the Pierre Auger Observatory between December 2004 and December 2012, we have examined the implications of the distributions of depths of atmospheric shower maximum (X ...sub(max)), using a hybrid technique, for composition and hadronic interaction models. We do this by fitting the distributions with predictions from a variety of hadronic interaction models for variations in the composition of the primary cosmic rays and examining the quality of the fit. Regardless of what interaction model is assumed, we find that our data are not well described by a mix of protons and iron nuclei over most of the energy range. Acceptable fits can be obtained when intermediate masses are included, and when this is done consistent results for the proton and iron-nuclei contributions can be found using the available models. We observe a strong energy dependence of the resulting proton fractions, and find no support from any of the models for a significant contribution from iron nuclei. However, we also observe a significant disagreement between the models with respect to the relative contributions of the intermediate components.
Ultrahigh energy cosmic ray air showers probe particle physics at energies beyond the reach of accelerators. Here we introduce a new method to test hadronic interaction models without relying on the ...absolute energy calibration, and apply it to events with primary energy 6-16 EeV (E_{CM}=110-170 TeV), whose longitudinal development and lateral distribution were simultaneously measured by the Pierre Auger Observatory. The average hadronic shower is 1.33±0.16 (1.61±0.21) times larger than predicted using the leading LHC-tuned models EPOS-LHC (QGSJetII-04), with a corresponding excess of muons.
Postoperative radiotherapy for International Federation of Gynaecology and Obstetrics (FIGO) stage-1 endometrial carcinoma is a subject of controversy due to the low relapse rate and the lack of data ...from randomised trials. We did a multicentre prospective randomised trial to find whether postoperative pelvic radiotherapy improves locoregional control and survival for patients with stage-1 endometrial carcinoma
Patients with stage-1 endometrial carcinoma (grade 1 with deep ≥50% myometrial invasion, grade 2 with any invasion, or grade 3 with superficial <50% invasion) were enrolled. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, without lymphadenectomy, 715 patients from 19 radiation oncology centres were randomised to pelvic radiotherapy (46 Gy) or no further treatment. The primary study endpoints were locoregional recurrence and death, with treatment-related morbidity and survival after relapse as secondary endpoints.
Analysis was done according to the intention-to-treat principle. Of the 715 patients, 714 could be evaluated. The median duration of follow-up was 52 months. 5-year actuarial locoregional recurrence rates were 4% in the radiotherapy group and 14% in the control group (p<0·001). Actuarial 5-year overall survival rates were similar in the two groups: 81% (radiotherapy) and 85% (controls), p=0·31. Endometrial-cancer-related death rates were 9% in the radiotherapy group and 6% in the control group (p=0·37). Treatment-related complications occurred in 25% of radiotherapy patients, and in 6% of the controls (p<0·0001). Two-thirds of the complications were grade 1. Grade 3–4 complications were seen in eight patients, of which seven were in the radiotherapy group (2%). 2-year survival after vaginal recurrence was 79%, in contrast to 21% after pelvic recurrence or distant metastases. Survival after relapse was significantly (p=0·02) better for patients in the control group. Multivariate analysis showed that for locoregional recurrence, radiotherapy and age below 60 years were significant favourable prognostic factors.
Postoperative radiotherapy in stage-1 endometrial carcinoma reduces locoregional recurrence but has no impact on overall survival. Radiotherapy increases treatment-related morbidity. Postoperative radiotherapy is not indicated in patients with stage-1 endometrial carcinoma below 60 years and patients with grade-2 tumours with superficial invasion.
The deposition of ozone to seawater is an important ozone sink. Despite constituting as much as a third of the total ozone deposition, it receives significantly less attention than the deposition to ...terrestrial ecosystems. Models have typically calculated the deposition rate based on a resistance-in-series model with a uniform waterside resistance. This leads to models having an essentially uniform deposition velocity of approximately 0.05 cm s−1 to seawater, which is significantly higher than the limited observational dataset. Following from Luhar et al. (2018) we include a representation of the oceanic deposition of ozone in the GEOS-Chem model of atmospheric chemistry and transport based on its reaction with sea-surface iodide. The updated scheme halves the calculated annual area-weighted mean deposition velocity to water from 0.0464 cm s−1 (25th and 75th percentiles of 0.0461 cm s−1 and 0.0471 cm s−1 respectively) to 0.0231 cm s−1 (25th and 75th percentiles of 0.0121 cm s−1 and 0.0303 cm s−1 respectively). The calculated ozone deposition velocity varies from 0.009 cm s−1 in polar waters to 0.040 cm s−1 at the tropics. This improves comparisons to observations. The variability is driven mainly by the temperature-dependent rate constant for the reaction between iodide and ozone, the temperature dependence of the solubility, and variations in the ocean iodide concentration. The calculated annual deposition flux of ozone to the ocean is reduced from 222 to 122 Tg yr−1, and overall deposition of ozone to all surface types reduces from 862 to 758 Tg yr−1. Tropospheric ozone burdens and global mean OH increase from 324 to 328 Tg, and from 1.17×106 to 1.18×106 molec.cm-3, respectively. A total of 34 % of surface grid boxes experience a 10 % or greater increase in ozone concentration. Comparisons between observations of surface ozone and the model are improved with the new parameterization notably around the Southern Ocean. Process-level representation of oceanic deposition of ozone thus appears essential for representing the concentration of surface ozone over the planet.
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