Dasabuvir, a nonnucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug–drug interaction (DDI) with clopidogrel. A physiologically based ...pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl‐β‐D glucuronide metabolite of which has been reported as a strong mechanism‐based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition, the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data. Sensitivity analyses using these PBPK models suggested that CYP2C8 inhibition by clopidogrel acyl‐β‐D glucuronide may not be as potent as previously suggested. The dasabuvir and updated clopidogrel PBPK models predict a moderate increase of 1.5–1.9‐fold for Cmax and 1.9–2.8‐fold for AUC of dasabuvir when coadministered with clopidogrel. While the PBPK results suggest there is a potential for DDI between dasabuvir and clopidogrel, the magnitude is not expected to be clinically relevant.
Plant extracts have been recognized as beneficial to human health and have been evaluated as feed additive for domestic and companion animals. This study evaluated oregano and green tea extracts fed ...to Jersey cows from approximately 21 d before calving to 21 d after calving on milk production, milk composition, and blood metabolites as well as investigated immunological and antioxidant attributes. Twenty-four Jersey cows with 441 ± 27 kg of BW, 3.5 ± 0.3 of body condition score (BCS), and 2.7 ± 1.8 lactations were selected at approximately 28 d before the expected parturition date and were randomly assigned to three treatments with eight cows each: without plant extracts in diet (control – CON), addition of 10 g per day of oregano extract (OR), and addition of 5 g per day of green tea extract (GT). Feed intake, BW, BCS, blood metabolites, hemogram as well as oxidative stress biomarkers were evaluated from approximately 3 weeks prepartum to 3 weeks postpartum (transition period) while milk production and composition were evaluated during the first 3 weeks of lactation. Plant extracts did not change BW, BCS, and DM intake (DMI) throughout the transition period, but OR increased in approximately 20% total digestive nutrients and metabolizable energy intake on days 15 and 16 postpartum compared with CON. In the prepartum, OR increased in 48% platelets count compared to the CON, while GT augmented in 142% eosinophils compared with CON. Oregano extract reduced the levels of reactive species in the erythrocytes in 40% during prepartum and postpartum compared with CON, while GT reduced its levels in 24 and 29% during prepartum and postpartum, respectively, when compared with CON. In the postpartum period, OR increased in 60% the carbonylated protein content compared with CON, while GT reduced in 45% the levels of reactive species in plasma compared with CON. During the postpartum, both extracts increased in 33% the concentration of reduced glutathione when compared with CON. Moreover, GT tended to decrease feed efficiency in 11% when compared with CON; OE reduced milk pH and somatic cell count when compared with CON. In conclusion, OE and GT did not expressively affect immunological attributes in blood but reduce some oxidative stress biomarkers without compromising productive traits of Jersey cows during the transition period.
The stability of gold nanoparticles (AuNPs) stabilized electrostatically with citrate or (electro)sterically by commercially available amphiphilic block copolymers (PVP-VA or PVA-COOH) was studied ...under various physicochemical conditions. Subsequently, the mobility of the AuNPs in porous media (sand) was investigated in column studies under environmental relevant physicochemical conditions. Electrostatically stabilized AuNPs were unstable under most physicochemical conditions due to the compression of the electrical double layer. Consequently, aggregation and deposition rapidly immobilized the AuNPs. Sterically stabilized AuNPs showed significantly less sensitivity towards changes in the physicochemical conditions with high stability, high mobility with negligible retardation, and particle deposition rate coefficients ranging an order of magnitude (1.5 × 10
−3
to 1.5 × 10
−2
min
−1
) depending on the type and amount of stabilizer, and thereby the surface coverage and attachment affinity. The transport of sterically stabilized AuNPs is facilitated by reversible deposition in shallow energy minima with continuous reentrainment and blocking of available attachment sites by deposited AuNPs. The stability and mobility of NPs in the environment will thereby be highly dependent on the specific stabilizing agent and variations in the coverage on the NP. Under the given experimental conditions, transport distances of the most mobile AuNPs of up to 20 m is expected. Due to their size-specific plasmonic properties, the easily detectable AuNPs are proposed as potential model or tracer particles for studying transport of various stabilized NPs under environmental conditions.
The use of argon as a detection and shielding medium for neutrino and dark matter experiments has made the precise knowledge of the cross section for neutron capture on argon an important design and ...operational parameter. Since previous measurements were averaged over thermal spectra and have significant disagreements, a differential measurement has been performed using a time-of-flight neutron beam and a ∼4π gamma spectrometer. A fit to the differential cross section from 0.015–0.15 eV, assuming a 1/v energy dependence, yields σ2200=673±26(stat)±59(sys) mb.
In the present study, dissimilar welds of an Al-Mg-Mn alloy and a Zn-coated high-strength low-alloy steel were welded by refill friction stir spot welding. The maximum shear load recorded was ...approximately 7.8 kN, obtained from the weld produced with a 1600 rev min
−1
tool rotational speed. Microstructural analyses showed the formation of a solid-liquid structure of an Al solid solution in Mg-Al-rich Zn liquid, which gives rise to the formation of Zn-rich Al region and microfissuring in some regions during welding. Exposure of steel surface to Mg-Al-rich Zn liquid led to the formation of Fe
2
Al
5
and Fe
4
Al
13
intermetallics. The presence of defective Zn-rich Al regions and Fe-Al intermetallics at the faying surface affects the weld strength.
Plant extracts have been proposed as substitutes for chemical feed additives due to their potential as rumen fermentation modifiers and because of their antimicrobial and antioxidant activities, ...possibly reducing methane emissions. This study aimed to evaluate the use of oregano (OR), green tea extracts (GT), and their association as feed additives on the performance and methane emissions from dairy between 28 and 87 d of lactation. Thirty-two lactating dairy cows, blocked into 2 genetic groups: 16 Holstein cows and 16 crossbred Holstein-Gir, with 522.6 ± 58.3 kg of body weight, 57.2 ± 20.9 d in lactation, producing 27.5 ± 5.0 kg/cow of milk and with 3.1 ± 1.8 lactations were evaluated (means ± standard error of the means). Cows were allocated into 4 treatments: control (CON), without plant extracts in the diet; oregano extract (OR), with the addition of 0.056% of oregano extract in the dry matter (DM) of the diet; green tea (GT), with the addition of 0.028% of green tea extract in the DM of the diet; and mixture, with the addition of 0.056% oregano extract and 0.028% green tea extract in the DM of the diet. The forage-to-concentrate ratio was 60:40. Forage was composed of corn silage (94%) and Tifton hay (6%); concentrate was based on ground corn and soybean meal. Plant extracts were supplied as powder, which was previously added and homogenized into 1 kg of concentrate in natural matter, top-dressed onto the total mixed diet. No treatment by day interaction was observed for any of the evaluated variables, but some block by treatment interactions were significant. In Holstein cows, the mixture treatment decreased gross energy and tended to decrease the total-tract apparent digestibility coefficient for crude protein and total digestible nutrients when compared with OR. During the gas measurement period, GT and OR increased the digestible fraction of the ingested DM and decreased CH4 expressed in grams per kilogram of digestible DMI compared with CON. The use of extracts did not change rumen pH, total volatile fatty acid concentration, milk yield, or most milk traits. Compared with CON, oregano addition decreased fat concentration in milk. The use of plant extracts altered some milk fatty acids but did not change milk fatty acids grouped according to chain length (short or long), saturation (unsaturated or saturated), total conjugated linoleic acids, and n-3 and n-6 contents. Green tea and oregano fed separately reduced gas emission in cows during the first third of lactation and have potential to be used as feed additives for dairy cows.
The effect of temperature on sampling rates and sampler−water partition coefficients of semipermeable membrane devices (SPMDs) and low-density polyethylene (LDPE) strips was studied in an ...experimental setup under controlled flow conditions. Aqueous concentrations of chlorobenzenes, polychlorinated biphenyls (PCBs), and polyaromatic hydrocarbons (PAHs) were maintained by continuous circulation of the water over a generator column. Sampling rates for standard design SPMDs (460 cm2) were in the range of 20−200 L d-1. No significant differences were observed between sampling rates of SPMDs and LDPE strips, but the latter samplers reached equilibrium faster because of their smaller sorption capacity. Sampling rates at 30 °C were higher than at 2 °C by a factor of about 3. Sampling rate modeling indicated boundary layer-controlled uptake for compounds with log octanol−water partition coefficients smaller than 4.4 and aqueous boundary-layer controlled uptake for more hydrophobic compounds. SPMD−water partition coefficients did not significantly change with temperature, but LDPE−water partition coefficients were larger at 2 °C than at 30 °C by a factor of 2. For field application of SPMDs, the results imply that temperature is not a key factor that controls uptake rates unless large geographical and temporal scales are involved. The results confirm that water flow velocity has a profound effect on sampling rates.
Small changes make a big difference: we demonstrate how slight changes in the supersaturation have a huge impact on the formed crystal morphology and present a convenient method to monitor the level ...of local supersaturation on a flat substrate. Further we provide a non-additive based explanation for natural biomineralization processes.
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