Maximum Concentration Research Articles

Maternal ozone exposure lowers infant’s birthweight: A nationwide cohort of over 4 million livebirths in Iran

BackgroundNationwide evidence linking maternal ozone exposure with fetal growth restriction (FGR) was extensively scarce, especially in the Middle East with dry climate and distinct religious culture. MethodsWe carried out a national retrospective birth cohort study using registry-based records from 749 hospitals across 31 provinces in Iran from 2013 to 2018. Monthly concentrations of maximum daily average 8-hour (MDA8) ozone at 0.125° × 0.125° resolution were extracted from well-validated spatiotemporal grid dataset. Linear and logistic regression models were employed to evaluate associations of maternal MDA8 ozone exposure with birthweight outcomes. Assuming causality, the comparative risk assessment framework was utilized to estimate the burden of low birthweight (LBW), small for gestational age (SGA), and birthweight loss per livebirth (BLL) attributable to ambient ozone pollution. ResultsOf 4030383 livebirths included in the study, 264304 (6.6%) were LBW and 484405 (12.0%) were SGA. Each 10-ppb increase in MDA8 ozone exposure was associated with an odds ratio of 1.123 (95% confidence interval [CI]: 1.104 to 1.142) for LBW and 1.210 (95% CI: 1.197 to 1.223) for SGA, and a 30.5-g (95% CI: 29.0 to 32.0) reduction in birthweight. We observed approximately linear exposure-response relationships of maternal MDA8 ozone exposure with LBW (Pnonlinear= 0.786), SGA (Pnonlinear= 0.156), and birthweight reduction (Pnonlinear= 0.104). Under the premise of causal association, we estimated 6.6% (95% CI: 5.7 to 7.5) of LBW, 10.1% (95% CI: 9.6 to 10.6) of SGA, and 18.8 g (95% CI: 17.9 to 19.7) of BLL could be attributable to maternal ozone exposure in Iran. Considerably greater risk and burden of ozone-related FGR were observed among younger, less-educated, and rural-dwelling mothers. ConclusionsOur study provided compelling evidence that maternal ozone exposure was associated with heightened FGR risk and burden, particularly among socioeconomically disadvantaged mothers. These findings underscored the urgent need for government to incorporate socioeconomic factors into future ozone-related health policies, not only to mitigate pollution, but also minimize inequality.

DETERMINATION OF GREENHOUSE GAS CONCENTRATION IN THE ATMOSPHERE BY EARTH REMOTE SENSING MEANS. CARTOGRAPHIC AND ANALYTICAL ASSESSMENT OF THE GEOSPATIAL DISTRIBUTION OF ITS VALUES

This article covers the issue of improving the methodology of remote determination of the concentration of greenhouse gases in the atmosphere using the Copernicus Program — Sentinel-5P and MOD11A2.061 Terra satellite systems, as well as the cartographic-analytical assessment of its geospatial distribution. The specified methodology provided for remote determination of the concentration of greenhouse gases CH4, CO, and NO2, development of maps of the distribution of the determined concentration on the territory of Ukraine, localization of areas of formation of the intensity of emission and sequestration of greenhouse gases taking into account data on the soil cover, abiotic conditions of the territory and anthropogenic influences, in particular, military activities. A set of maps of the geospatial distribution of CH4, CO, and NO2, greenhouse gas concentrations, the temperature of the Earth’s surface within the warm period (01.05—30.10) during 2019—2022, as well as a map of the geospatial localization of the maximum concentrations of greenhouse gases within the warm period of the research time interval developed according to the results of emissions from soils, landscapes, production facilities, and combat zones. It was determined that for the warm period of the year, on average for 2019—2022, the optimal temperature range within which the intensity of nitrogen dioxide emission on the territory of Ukraine reaches maximum values is from 13 to 19 °C. If the temperature of the Earth’s surface exceeds the value of 20 °C, the volume of emission emissions is significantly reduced. It is shown that soils with different emission and assessment status are widespread in Ukraine during the warm period. In the South and Southwest of the state, soils with the highest emission capacity of methane to the atmosphere prevail, in particular Jc49-1/3a — Calcaric Fluvisols, Lg54-1a — Gleyic Luvisols, Kh31-2a — Haplic Kastanozems, Gh23-3a — Humic Gleysols. In large cities, as well as in the territories of the South-East of Ukraine, where normal chernozems (Ch22-2a) / (normal chernozems) are common, the maximum concentration of NO2 in the atmosphere is formed, which is caused by the influence of the high temperature of the earth’s surface and the localized consequences of Russia’s military aggression. It was revealed that over the past 4 years, there has been a trend of decreasing CO concentration, which indirectly indicates the negative impact of Russia’s military aggression, a decrease in industrial production, and the relocation of production facilities to the west of the country.

Effect of chloroquine pre-treatment on the metoclopramide’s pharmacokinetics after their co-administration

ABSTRACT Background This study evaluated the pharmacokinetic interactions of orally administered chloroquine and metoclopramide. Methods The study employed a randomized and two-phase cross-over design with 4-week washout plan. Twelve healthy male volunteers were shortlisted according to the set criteria and were administered with metoclopramide 10 mg PO and chloroquine (a total of 1500 mg) at different intervals which were (500 mg at 0, 6, and 24 h). The concentration of chloroquine and metoclopramide in the blood samples was estimated using a validated HPLC-UV technique to affirm the maximum concentration (Cmax), time to reach Cmax (Tmax), and area under the curve (AUC). Results Cmax, T1/2, and AUC of metoclopramide were increased up to 20, 10, and 47.8%, respectively, by the concomitantly administering Chloroquine. Chloroquine-treated phase showed increased values of Cmax (ng/ml), AUC (ng.h/ml), and T½ (h), i.e. 41.35 ± 1.61, 504.12 ± 66.25, and 5.72 ± 2.63, as compared to that reference phase i.e. 34.52 ± 4.92, 341.14 ± 112.8, and 5.19 ± 1.14, respectively. Conclusions Chloroquine was found to attenuate CYP2D6 activity in healthy Pakistani male volunteers. Hence, patients that are prescribed with metoclopramide or other CYP2D6-substrate drugs require a dose adjustment when administered with chloroquine.

Benzotriazoles and bisphenols in wastewater from the food processing industry and the quantitative changes during mechanical/biochemical treatment processes

Benzotriazoles (BTRs) and bisphenols (BPs), categorized as contaminants of emerging concern (CECs), pose significant risks to human health and ecosystems due to their endocrine-disrupting properties and environmental persistence. This study investigates the occurrence and behavior of nine BTRs and ten BPs in wastewater generated in a large-scale meat processing plant, evaluating the effectiveness of a modern mechanical-biological industrial on-site treatment plant in removing these contaminants, and based on the concentration levels from eleven sampling points at different stages of the treatment process. The method used to determine these micropollutants' concentration was ultrasound-assisted emulsification-microextraction for analytes isolation and gas chromatography–mass spectrometry for detection (USAEME-GC/MS). The results indicate that the rigorous quality control processes in the meat processing facility effectively limit the presence of these micropollutants, especially concerning BPs, which are absent or below detection limits in raw wastewater. While the concentrations of some of these micropollutants increased at different points in the treatment process, these values were relatively low, typically below one microgram per liter. Among the compounds analyzed, the only one present after completing the treatment was 5Cl-BTR (maximum concentration: 3007 ng/L), and these contamination levels are around seven times lower than the reference value associated with non-cancer health risk for drinking water. This study contributes to understanding these CECs in industrial wastewater and highlights the importance of effective treatment systems for environmental protection.

A study of the pharmacokinetics of clozapine and its metabolites by the dynamics of its distribution in the oral fluid of healthy volunteers.

Clozapine (CLZ) -related accidents or crimes are common in the world. Oral fluid drug detection is a convenient measure of dealing with things like that. There has not been any literature reported detailedly the representation rule of clozapine and its metabolites in oral fluid so far. The study aimed to describe the pharmacokinetics of CLZ and its metabolites N-desmethylclozapine and clozapine-N-oxide in human oral fluid after a single 12.5mg oral dose of CLZ. Twenty-nine volunteers, including 20 males and 9 females, were recruited, and 2mL oral fluid was collected from each participant at post-consumption time-points of prior (zero), 0.5, 1.5, 3, 5, 8, 12, 24, 36, 51, 82, and 130h, respectively. Analytes of interest were extracted with solid-phase extraction and analyzed with liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated using the pharmacokinetic software DAS according to the non-compartment model. The maximum concentration, the time of maximum concentration, oral clearance, and the elimination half-life of clozapine were 16.57 ± 9.63ng/mL, 4.53 ± 3.61h, 57.65 ± 23.77 L/h and 53.58 ± 52.28h, respectively. The maximum concentration, the time of maximum concentration, and the elimination half-life of the metabolite N-desmethylclozapine were 3.08 ± 1.19ng/mL, 9.38 ± 9.33h and 62.67 ± 82.57h, respectively; of clozapine-N-oxide were 1.15 ± 0.36ng/mL, 4.53 ± 2.19h and 19.15 ± 23.11h, respectively. It was the first study on the pharmacokinetics of CLZ and its metabolites in the oral fluid of Chinese healthy volunteers, and it provided a basis for the therapeutic drug monitoring and toxicological interpretation in clozapine-related cases.

The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Ritlecitinib, a Janus Kinase 3 and Tyrosine-Protein Kinase Family Inhibitor, in Humans.

Ritlecitinib is an oral once-daily irreversible inhibitor of Janus kinase 3 and tyrosine-protein kinase family being developed for the treatment of moderate-to-severe alopecia areata. This study examined the disposition of ritlecitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite profiles. The results indicated ritlecitinib had a systemic clearance of 43.7 L/h, a steady state volume of distribution of 73.8 L, extent of absorption of 89%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 64%. An observed long terminal half-life of total radioactivity was primarily attributed to ritlecitinib binding to plasma albumin. Ritlecitinib was the main circulating drug species in plasma (∼30%), with one major pharmacologically inactive cysteine conjugated metabolite (M2) at >10%. Oxidative metabolism (fractional clearance 0.47) and glutathione-related conjugation (fractional clearance 0.24) were the primary routes of elimination for ritlecitinib with the greatest disposition of radioactivity shown in the urine (∼71%). In vitro phenotyping indicated ritlecitinib cytochrome P450 (CYP) fraction of metabolism assignments of 0.29 for CYP3A, 0.09 for CYP2C8, 0.07 for CYP1A2, and 0.02 for CYP2C9. In vitro phenotyping in recombinant human glutathione S-transferases indicated ritlecitinib was turned over by a number of cytosolic and microsomal enzyme isoforms. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of ritlecitinib, a JAK3 and TEC family kinase inhibitor for alopecia areata in humans, as well as characterization of clearance pathways and pharmacokinetics of ritlecitinib and its metabolites. As an AMS-based ADME study design, we have expanded on reporting the standard ADME endpoints, providing key pharmacokinetic parameters, such as clearance, volume of distribution, and bioavailability, allowing for a more comprehensive understanding of drug disposition.

A comparative evaluation of bioequivalence of Gan & Lee glargine U300 and Toujeo® in Chinese healthy male participants.

To assess the bioequivalence between Gan & Lee (GL) glargine U300 and Toujeo® regarding pharmacokinetics (PK), pharmacodynamics (PD), and safety in Chinese healthy male participants. A single-center, randomized, double-blind, single-dose, two-preparation, two-sequence, four-cycle repeated crossover design study was performed to compare GL glargine U300 and Toujeo® in 40 healthy participants. The primary PK endpoints were the area under the curve of glargine metabolites, M1 concentration from 0 to 24 hours (AUC0-24h), and the maximum glargine concentration within 24 hours post-dose (Cmax). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 hours (AUCGIR.0-24h) and the maximum GIR within 24 hours post-dose (GIRmax). GL Glargine U300 demonstrated comparable PK parameters (AUC0-24h, Cmax, AUC0-12h, and AUC12-24h of M1) and PD responses [AUCGIR.0-24h, GIRmax, AUCGIR.0-12h, and AUCGIR.12-24h] to those of Toujeo®, as indicated by 90% confidence intervals ranging from 80% to 125%. No significant disparities in safety profiles were observed between the two treatment groups, and there were no reported instances of serious adverse events. The PK, PD, and safety of GL glargine U300 were bioequivalent to that of Toujeo®. https://www.chinadrugtrials.org.cn/, identifier CTR20212419.

Simultaneous Production of MK-7 and Iturin A by Bacillus velezensis ND.

Bacillus velezensis can produce various secondary metabolites, such as the antibacterial compound iturin A and the coagulation-promoting menaquinone-7 (MK-7). To enhance the economic feasibility of the fermentation process, a co-production strategy, involving the simultaneous production of MK-7 and iturin A by Bacillus velezensis ND, was investigated in this study. Firstly, the effects of cultivation temperature and initial pH on the synthesis of MK-7 and iturin A were investigated. Considering the co-production of iturin A and MK-7, the optimal temperature and pH were determined as 32°C and 7, respectively. Subsequently, important nutrients for the co-production process were investigated. It was observed that glycerol, soybean meal, yeast extract, and L-glutamate had a significant effect on the co-produce process. An optimal medium composed of glycerol (72.19mL L-1), L-glutamate (1.4g L-1), yeast extract (16.88g L-1), and soybean meal (130.95g L-1) was obtained by response surface methodology (RSM). This co-produce process was further scaled up in a biofilm reactor, and the maximum concentration of MK-7 and iturin A reached 46.88mg L-1 and 5.58g L-1, respectively. Finally, we established an effective method for separately extracting the two metabolites from the fermentation broth. The superiority of this co-production fermentation strategy demonstrates its significant potential for industrial production.

Bed Roughness Incorporated Lift Force Formulation for Sediment Concentration Solutions

Within the field of sediment transport dynamics, there is an emphasis on the need for providing and improving simplified analytical solutions from which the findings can be extended upon. Typically, solutions have been developed from the understanding and incorporation of vertical velocity components/distribution; however, there remains opportunity for analytical enhancement. Under uniform open channel dilute sediment laden flow conditions, the type II concentration profile reflects the maximum concentration at a distance from the bed. To analytically depict the type II profile, it is essential to describe the vertical velocity components acting within the flow hydrodynamics. Yet, the impact of bed roughness on the vertical velocity distribution influencing a sediment particle has not been articulated. Hence, in this research, the impact of bed roughness is incorporated into the vertical velocity distribution to formulate the lift force acting upon a particle, to provide a sediment concentration solution. The proposed analytical vertical velocity distribution solution is validated against existing formulations, followed by the proposed sediment concentration being validated against existing solutions. Here, the results indicate that analytically incorporating the bed roughness alongside the secondary current induced vortices provides a lift force solution that can depict the type II concentration profile. Under relatively low shear velocity, increasing the sediment diameter allows for a clearer depiction of the near surface region and profile curvature. Furthermore, the proposed sediment concentration solution can accurately depict the near surface region, curvature of concentration, and maximum concentration under relatively large shear velocity data. Importantly, under conditions where both the shear velocity and sediment diameter are relatively large, the maximum concentration is captured with greater accuracy; however, the curvature of the profile and the near surface region accuracy are hindered. It is to be noted, that due to the formulation of the proposed velocity distribution the accuracy of the solution towards the bed decreases due to instability caused as the characteristic depth decreases to zero.

Changes in biogenic amines during fermentation of Chinese rice wine (Huangjiu) and the underlying mechanisms

ABSTRACT Chinese rice wine (Huangjiu) is a traditional fermented wine in China. The biogenic amines are the important index during its fermentation. This study investigated the changes in biogenic amine content and its formation during fermentation of Chinese rice wine, and analyzed the correlation between the physicochemical and biological factors of Chinese rice wine and the production of biogenic amines. Results showed that, during the pre-fermentation stage (stage I), the content of biogenic amine was significantly negatively correlated with sugar level and acidity, and was significantly positively correlated with amino acid concentration. The maximum biogenic amine concentration in Chinese rice wine was 36.79 mg/L. During the post-fermentation stage (stage II), a significant increase in the content of lactic acid bacteria was positively correlated with biogenic amine content. The maximum biogenic amine concentration in Chinese rice wine was 22.50 mg/L. The high amino acid concentration and lactic acid bacteria concentration in the fermentation process enhance the biogenic amine formation. These results have provided a theoretical support for control of biogenic amine content in fermentation of Chinese rice wine.

French nuclear glass synthesis: Focus on liquid waste dissolution kinetics

In France, high-level nuclear wastes are confined in glass using a calcination-vitrification process. The waste can also be vitrified by liquid feeding, which imply to add directly the liquid waste. In this study, we focus on nuclear waste vitrification process by direct liquid feeding in order to decipher the dissolution kinetics of the waste in the molten glass. We propose an experimental and analytical protocol to study the dissolution in the solid glass frit of the liquid waste dried beforehand during the glass melting process. This methodology allows to: i) identify the intermediate reaction phases which formed and dissolved during the process; ii) characterizes the evolution of waste element concentrations in the dried waste as a function of time and temperature on glass obtained after cooling; iii) define kinetic parameters relative to the process of intermediate reaction phases dissolution in the molten glass. The three main intermediate reaction phases formed and dissolved in function of temperature are Ca-REE (Rare Earth Elements)- silicate, Ce- oxide and Zr- oxide. At each temperature step (800 to 1200 °C) the evolution of REE (La, Ce, Nd and Pr) and Zr concentrations in the glass samples obtained after cooling shows a fast increase followed by a stabilization in time, which reflects the fast dissolution of the dried waste in the molten glass, i.e. the fast dissolution of intermediate reaction phases. The molten glass is completely homogeneous at classical synthesis temperature (1200 °C). A parameterization methodology of element concentration evolution as a function of time and temperature is proposed here in order to define the kinetic parameters corresponding to the dried waste dissolution (i.e. concentration at a given time t, maximal concentration at a given temperature, characteristic time and activation energy). The results show that the activation related to the formation and dissolution processes of the intermediate reaction phases, i.e. whether they constitute intermediate compounds formed in temperature by the interaction between the dried waste and the glass frit, and the phases formed without reacting with the glass frit, directly in the dried waste during heat treatment.

Optimization design of support structure based on 3D printing technology

Parts are often warped and deformed when they are molded using selective laser melting (SLM) technology. Thus, it is necessary to study the addition support modes of parts molded using SLM. Consequently, we designed dendritic, E-stage and conical supports, having different structural parameters and different partitions using Magics, and then, we analyzed their performances using the finite element software Abaqus. The structural parameters of the supports were optimized and finally tested using SLM molding technology. The maximum stress concentration was found for dendritic supports, followed by E-stage supports, and then conical supports. The stress concentration and deformation level of Scheme 2 were less than those of Scheme 1. The stress intensity and deformation levels for two partitions were less than those for three partitions. For parts molded by SLM, the deformation was maximum for conical supports, followed by dendritic supports, and then E-stage supports. When gradient supports of similar volumes were added, additional partitions did not effectively improve the molding quality. When supports of similar volumes were added, adding gradient supports did not effectively improve the molding quality. The results provide a basis for the application of SLM in molding high-precision parts.

Intracellular islatravir-triphosphate half-life supports extended dosing intervals.

Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t½) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t½ of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 study was performed to evaluate the pharmacokinetics and safety of islatravir in plasma and the pharmacokinetics of islatravir-TP in peripheral blood mononuclear cells after administration of a single oral dose of islatravir 30 mg. Eligible participants were healthy adult males without HIV infection between the ages of 18 and 65 years. Fourteen participants were enrolled. The median time to maximum plasma islatravir concentration was 1 hour. Plasma islatravir concentrations decreased in a biphasic manner, with a t½ of 73 hours. The t½ (percentage geometric coefficient of variation) of islatravir-TP in peripheral blood mononuclear cells through 6 weeks (~1008 hours) after dosing was 8.1 days or 195 hours (25.6%). Islatravir was generally well tolerated with no drug-related adverse events observed. Islatravir-TP has a long intracellular t½, supporting further clinical investigation of islatravir administered at an extended dosing interval.

The toxic legacy of artisanal and informal mining: XRF and gis analysis of soil contamination by Hg, Pb and As in the Secocha annex, Camaná, Peru

Hg, used as the main input in the gold amalgamation process in artisanal mining, along with lead Pb and As present in the toxic waste resulting from mining activity, cause serious effects on the environment and human health, as it occurs in the Secocha annex (Camaná, Peru). The objectives of the present study were to determine the concentrations of Hg, Pb, and As in the soil of the Secocha annex, evaluate the level of contamination of the site, determine the spatial distribution of contamination and the concentrations of the evaluated elements, and determine the origin of these contaminants. To achieve these objectives, satellite imagery, field sampling, X-ray fluorescence techniques, soil quality environmental regulations, geo-accumulation indices (Igeo), and geographic information system techniques were used. The results revealed maximum concentrations of 350 and 176.6 mg/kg for Hg and Pb, respectively. Of the 72 soil samples collected, the concentrations of Hg located within the urban/industrial area, where gold recovery activities are carried out, exceeded environmental regulations to a greater extent. In turn, the calculated Igeo revealed extreme soil contamination (5 < Igeo) due to the presence of Hg in most of the study area (95%), followed by moderate to heavy contamination (2 < Igeo < 3) due to the presence of Pb and As (0.5 and 5%, respectively). To reduce contamination and the concentrations of the evaluated elements, it is recommended to carry out studies to reuse inputs, change gold processing methodologies, and/or relocate the generated waste.

Clinical Effects and Pharmacokinetic Profile of Intramuscular Dexmedetomidine (10 μg/kg) in Cats.

This study investigated the pharmacokinetic profile of and pharmacodynamic response to dexmedetomidine administered intramuscularly (IM) at a dose of 10 μg/kg in healthy cats. Nine adult cats were evaluated before and after administration of the drug, with serial collections of plasma samples. Dexmedetomidine induced deep sedation, with a rapid onset of action and a duration of one hour, reaching a peak between 20 and 30 min after administration. The half-life (T½) was 70.2 ± 48 min, with a maximum concentration (Cmax) of 2.2 ± 1.9 ng/mL and time to reach maximum concentration (Tmax) of 26.4 ± 19.8 min. The area under the curve (AUC) was 167.1 ± 149.1 ng/mL*min, with a volume of distribution (Vd) of 2159.9 ± 3237.8 mL/kg and clearance (Cl) of 25.8 ± 33.0 mL/min/kg. There was a reduction in heart rate (HR) and respiratory rate (RR) in relation to the baseline, with a slight decrease in systolic (SBP), diastolic (DBP), and mean (MAP) blood pressure in the first hour. Blood glucose increased after 60 min. Dexmedetomidine proved to be effective and safe, with rapid absorption, metabolization, and elimination, promoting good sedation with minimal adverse effects after IM administration in healthy cats.

The Effect of Thickened Water on Ciprofloxacin Pharmacokinetics: A Comparative Study in Adult Males.

Background/Objectives: The use of food thickeners with ciprofloxacin tablets may result in a gelatinous appearance and experience delayed dissolution, which presents a challenge for the drug's efficacy, creating a healthcare economic issue. However, the pharmacokinetic impact of this compound in humans remains uncertain. Therefore, a comparative pharmacokinetic study of ciprofloxacin was conducted on healthy adult Japanese males. Methods: We compared the effects of administering tablets with water or thickened water and crushed tablets mixed with thickened water. The maximum blood concentration (Cmax) of ciprofloxacin determines the drug's efficacy. Results: There were variations in drug absorption across different administration methods. The group who took the tablets immersed in thickened water exhibited different results in the area under the blood drug concentration-time curve (AUC) and Cmax compared to the group who took the tablets in regular water. Notably, the group that consumed the crushed tablets mixed with thickened water demonstrated equivalent results for both AUC and Cmax. Conclusions: Administering crushed tablets in thickened water may yield pharmacokinetics comparable to those of tablets taken with water. However, the process of crushing tablets may result in the loss of active ingredients and compromise the formulation, necessitating a comprehensive assessment before administration.

Tissue distribution of renadirsen sodium, a dystrophin exon-skipping antisense oligonucleotide, in heart and diaphragm after subcutaneous administration to cynomolgus monkeys

The pharmacokinetics and tissue distribution of renadirsen sodium, a dystrophin exon-skipping phosphorothioate-modified antisense oligonucleotide with 2’-O,4’-C-ethylene-bridged nucleic acid (ENA), after subcutaneous or intravenous administration to cynomolgus monkeys were investigated. The plasma concentration of renadirsen after subcutaneous administration at 1, 3, and 10 mg/kg increased with the dose. The absolute bioavailability at 3 mg/kg after subcutaneous administration was calculated as 88.6%, and the time to reach maximum plasma concentration of renadirsen was within 4 h, indicating the efficient and rapid absorption following subcutaneous administration. The exposure of muscle tissues to renadirsen was found to increase with repeated dosing at 6 mg/kg, and higher exposure was observed in the diaphragm and heart than in the quadriceps femoris and anterior tibialis muscles. Renadirsen achieved more exon 45-skipped dystrophin mRNA in the diaphragm and heart than in the quadriceps femoris and anterior tibialis muscles. Renadirsen also showed a cumulative skipping effect in a repeated-dose study. The findings on exon 45-skipped dystrophin mRNA in these muscle tissues were consistent with the concentration of renadirsen in these tissues. Because it is not feasible to directly evaluate drug concentration and exon skipping in the heart and diaphragm in humans, the pharmacokinetics and pharmacodynamics of renadirsen in these tissues in monkeys are crucial for the design and interpretation of clinical settings.

Geophysical and geoenvironmental engineering assessment of contaminated workstation soils in a metamorphic environment

This study aims to employ the electrical method, multi-pollution indices, and statistical optimization to establish a common ground for the utilization of contaminated soil as construction material and for agricultural purposes. Two samples each were taken at a depth of 0.5 m and 1.0 m from the eatery, auto-mechanic, car wash, and transformer workstations and at a control site in Akungba-Akoko, southwestern Nigeria. The concentrations of the following geochemical parameters were analyzed: Cr, Pb, Zn, Cd, Mn, and Cu. The resistivity distribution of the workstations’ subsurface layers was determined using Schlumberger vertical electrical sounding (VES). The generated geoelectrical sections revealed four geoelectric layers (topsoil, weathered layer, partially weathered/fracture bedrock, and bedrock) with two curve types: HA (50%) and AA (50%) across the workstations. The topsoil resistivity values (65–184 Ωm) from the VES results suggest moderately rich organic matter and averagely very fine-grained sand. The concentrations of the heavy metals in all the soil samples are within the maximum allowable concentration as stipulated by the National Environmental Standards and Regulations Enforcement Agency in the soil and are suitable for farm activities. Similarly, the geotechnical tests of the Atterberg limit, grain size analysis, compaction, and CBR revealed that all the soil samples met the criteria of a good pavement design but with poor landfill material. Pearson's correlation coefficient revealed that a strong relationship between Igeo\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${I}_{geo}$$\\end{document}-PLI, Igeo\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${I}_{geo}$$\\end{document}-RI, PLI-RI, TSR-Fines, MDD-CBR, LL-MDD, and LL-CBR exists among the multi-pollution indices, the geotechnical properties of soil, and the resistivity distribution of the topsoil. This suggests similar levels of heavy metal pollution and a common source of anthropogenic activities throughout the four workshops and provides the link between geotechnical properties and resistivity distribution for future soil management strategies. The exposure of children and adults to multiple heavy metals through inhalation at the four workstations shows no significant non-cancer or cancer risks.

Secondary metabolites in Cordyceps javanica with insecticidal potential

Cordyceps javanica has been registered as a fungal insecticide in several countries. However, little is known about whether metabolic toxins are involved in the insecticidal process. In this research, we assessed the insecticidal activity of the fermentation broth of C. javanica. Myzus persicae mortality differed when exposed to the metabolized C. javanica broths at 3 days post fermentation (DPF) and 5 DPF. Comparison of the metabolic fluid at 3 DPF and 5 DPF revealed a key alkaloid, heteratisine, which was found to have insecticidal activity and acetylcholinesterase (AChE) inhibitory activity. Heteratisine has high insecticidal activity against adult M. persicae, the absolute 50% lethal concentration (LC50) was only 0.2272 mg/L. Heteratisine showed high inhibitory activity on AChE with the 50% maximal inhibitory concentration (IC50) of 76.69 μM. Molecular docking and dynamic simulations showed that heteratisine conjugation occurs at the peripheral anionic site (PAS) of the AChE of M. persicae, leading to suppression of enzyme activity. Heteratisine was rarely found in fungal metabolites, which helps us to understand the complex and elaborate insecticidal mechanism of C. javanica.

Coronavirus spike protein fragment-containing chimeric virus-like particles stimulate human dendritic cell maturation

Introduction. Viral capsid proteins can assemble into virus-like particles lacking infectivity and bearing parental virus antigens or artificially introduced antigens from other pathogens. At least some of such particles are highly immunogenic and could serve as a platform for promising vaccines. In this work, we assessed an effect of virus-like particles decorated with a SARS-CoV-2 spike protein fragment on human dendritic cell phenotype and functional properties. Materials and methods. The virus-like particles were assembled using chimeric molecules obtained by fusing genetic sequences encoding a norovirus major capsid protein VP1 fragment and a coronavirus spike protein fragment, including the receptor-binding domain. Dendritic cells were obtained from monocytes in vitro. Results. Incubation of immature dendritic cells with virus-like particles induced their phenotypic and functional maturation. The former was revealed by significantly increased expression of HLA-DR, CD80, CD86 and CD83. Dendritic cell phenotype after incubation with virus-like particles at the maximum concentration of 10 μg/ml did not differ significantly from that of mature dendritic cells in positive control. Along with phenotypic maturation, virus-like particles caused a manifold increase in the production of pro-inflammatory tumor necrosis factor-α, anti-inflammatory interleukin-10, as well as interleukin-6, which can stimulate both antibody synthesis and cellular pro-inflammatory reactions. The pronounced stimulation of dendritic cells by virus-like particles coated with coronavirus antigens evidence about successful particle recognition. Finally, we discuss plausible mechanisms for recognition of such virus-like particles by dendritic cell receptors. Conclusion. It has been shown that chimeric virus-like particles induced phenotypic and functional dendritic cell maturation, which is manifested by markedly elevated expression of functionally important membrane molecules, as well as a manifold rise in production of cytokines with a wide functional range. In our opinion, the data obtained indicate a promise of using virus-like particles based on norovirus proteins to display SARS-CoV-2 antigens.