Concentrations In Compartments Research Articles

GlutaR: AHigh-Performance Fluorescent Protein-Based Sensor for Spatiotemporal Monitoring of Glutamine Dynamics In Vivo.

Glutamine is the most abundant amino acid in human blood and muscle, and is integral to a wide variety of functions in cancer cells. However, the inability to monitor the subcellular distribution of glutamine in real-time has obscured understanding of glutamine metabolism under physiological and pathological conditions. Here, we report the development of a genetically encoded fluorescent sensor and demonstrate how this GlnBP-cpYFP fusion "GlutaR sensor" undergoes glutamine-induced conformational changes reflected in detectable fluorescence responses. Obtained after iterative screening of approximately 1,600 variants, GlutaR exhibits a ratiometric readout, fast response kinetics, and high responsivity, and we demonstrate its selectivity for monitoring glutamine fluctuations in multiple cell types. Additionally, using digitonin permeabilization of GlutaR HeLa cells, we generated a calibration curve and performedin situtitration to quantify free glutamine concentrations in subcellular compartments (cytosol, nucleus, mitochondria). Subsequently, we applied GlutaR to investigate how chemical and genetic inhibition of GS and GLS differentially alter glutamine levels in subcellular compartments. Finally, we demonstrate GlutaR's ability to monitor dynamic glutamine levels in muscle and liver tissues of diabetic micein vivo.These findings collectively demonstrate GlutaR as a versatile tool for the spatiotemporal characterization of glutamine metabolism in living cells and tissues.

A Perspective On A Promising Role For Caffeine In Modulating The Casr In Pancreatic Β-Cells

The extracellular calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that plays a crucial role in the parathyroid glands and kidneys in maintaining calcium (Ca2+) homeostasis. The extracellular CaSR is present in various cell types not implicated in controlling plasma Ca2+ levels. There is accumulating evidence that CaSR plays a significant role in regulating the function of β-cells in the pancreas. Divalent cations and insulin are released together during exocytosis, and their concentration in the restricted intercellular compartments of the pancreatic islet increases to activate CaSR in neighboring cells. Subsequently, the activated CaSR stimulates insulin vesicle release in the adjacent cells, and by repeating these steps, the signal is amplified in the whole islet. Recent work developed a photoaffinity-tagged glutathione derivative (DAZ-G) as a chemical tool. The study demonstrated that DAZ-G can identify and analyze CaSR ligands. The use of DAZ-G identified caffeine as a positive allosteric modulator of the CaSR, suggesting that the physiological effects of caffeine are partly attributed to its stimulation of the CaSR. Future work may utilize caffeine to activate the CaSR in pancreatic β-cells to improve their secretory function

Temporal variation of mercury levels in fish, soil, and sediments in an Amazon reservoir: insights from 35years of river impoundment in Pará State, Brazil.

The increase of mercury (Hg) concentrations in abiotic and biotic compartments of aquatic ecosystems following the river impoundment for building a hydroelectric reservoir is one of many environmental and social impacts that the construction of hydroelectric plants can trigger. Yet, long-term studies in Amazon reservoirs are still scarce. The present study aimed to understand the effects of dam impoundment in THg concentrations in an Amazon reservoir up to 35years of its creation. On March 2019 (35th year after filling), samples of fish, soil, and sediments were collected in the Tucuruí reservoir. Total mercury (THg) concentrations were determinate in those samples and compared with data extract from previous studies referring to the 6th, 16th and 18th years after the reservoir filling. Fish from different guilds at the 6th year after filling the Tucuruí reservoir had high THg concentrations, and those decreased in the 16th and 18th years, then the concentrations increased again in the 35th year after filling. For soils and sediments, a decline in THg concentrations was observed. These results differ from previous studies that predicted that Hg concentrations in fish would return to natural concentrations within 30years in temperate zones and no decline of THg concentrations would be observed for Amazonian reservoirs. The Tocantins river drainage basin has been subjected to multiple anthropic disturbances and land use changes over the past decades, such as the implementation of new hydroelectric plants, deforestation, and fires, which can explain our observations. This study contributes valuable long-term insights into the dynamics of Hg concentrations in an Amazonian reservoir, highlighting the complex interactions between environmental changes and Hg accumulation over decades.

Identifying biomarkers for treatment of uveal melanoma by T cell engager using a QSP model.

Uveal melanoma (UM), the primary intraocular tumor in adults, arises from eye melanocytes and poses a significant threat to vision and health. Despite its rarity, UM is concerning due to its high potential for liver metastasis, resulting in a median survival of about a year after detection. Unlike cutaneous melanoma, UM responds poorly to immune checkpoint inhibition (ICI) due to its low tumor mutational burden and PD-1/PD-L1 expression. Tebentafusp, a bispecific T cell engager (TCE) approved for metastatic UM, showed potential in clinical trials, but the objective response rate remains modest. To enhance TCE efficacy, we explored quantitative systems pharmacology (QSP) modeling in this study. By integrating a TCE module into an existing QSP model and using clinical data on UM and tebentafusp, we aimed to identify and rank potential predictive biomarkers for patient selection. We selected 30 important predictive biomarkers, including model parameters and cell concentrations in tumor and blood compartments. We investigated biomarkers using different methods, including comparison of median levels in responders and non-responders, and a cutoff-based biomarker testing algorithm. CD8+ T cell density in the tumor and blood, CD8+ T cell to regulatory T cell ratio in the tumor, and naïve CD4+ density in the blood are examples of key biomarkers identified. Quantification of predictive power suggested a limited predictive power for single pre-treatment biomarkers, which was improved by early on-treatment biomarkers and combination of predictive biomarkers. Ultimately, this QSP model could facilitate biomarker-guided patient selection, improving clinical trial efficiency and UM treatment outcomes.

Biochars from chlorine-rich feedstock are low in polychlorinated dioxins, furans and biphenyls

Chlorinated aromatic hydrocarbons like polychlorinated dibenzo-p-dioxins and -furans (PCDD/F) and polychlorinated biphenyls (PCB) are omnipresent in the environment due to historic production, use, and (unintended) release. Nowadays, their emission and maximum concentration in environmental compartments is strictly regulated. During biochar production, PCDD/F and PCB may be formed and retained on the solid pyrolysis product. Industrial biochars certified, e.g., under the European Biochar Certificate (EBC), exhibit concentrations that were always well below threshold values for soil application and even animal feed. However, this has not been sufficiently tested for chlorine (Cl) rich organic material such as marine biomass or polyvinyl chloride (PVC) contaminated feedstock. Here, we analyzed PCDD/F and PCB contamination in biochars produced at different temperatures from different biomasses with comparatively high Cl contents in the range from 0.2 % to 3.8 % (w/w, seagrass, two types of saltwater macroalgae, tobacco stalks, and PVC contaminated wood). All of the biochars produced showed PCDD/F and PCB contents well below the applicable threshold values given by the EBC (< 20 ng TEQ kg−1 for PCDD/F and < 2×105 ng kg−1 for PCB). The EBC thresholds were undershot by a minimum of factor 1.5 for PCDD/F (mostly factor 20) and by a minimum of factor 90 for PCB. Between 1 and 27 ppb of feedstock Cl were transformed to Cl bound in PCDD/F and PCB in the biochars. No consistent correlation between biomass Cl contents and contents of PCDD/F and PCB were found but higher Cl contents in the feedstock led to a more diverse PCDD/F congener pattern in the biochars. Pyrolysis of PVC-amended wood resulted in consistently higher contamination of PCDD/F and PCB in the biochars compared to pyrolysis of the other biomasses, potentially due to differences in Cl speciation in the feedstocks i.e., Cl in PVC is already covalently bound to an organic carbon backbone. A high contamination in PCDD/F and PCB in biochar was intentionally triggered by separation of pyrogas and biochar in the reactor at < 300 °C to promote condensation of contaminants on the solid product. Between 20 % and 80 % of feedstock Cl was released via the pyrogas, i.e., neutralization of HCl in burnt pyrogas might be necessary when pyrolyzing Cl-rich feedstock in industrial biochar production. Our results indicate that biochars produced from Cl-rich feedstocks with proper biochar production process control are conform with European certification guidelines for PCDD/F and PCB contamination. The results open the opportunity to exploit and valorize so far non-used marine or otherwise Cl enriched biomasses for the production of biochar and carbon sinks.

Mathematical Modeling of Vedolizumab Treatment's Effect on Microbiota and Intestinal Permeability in Inflammatory Bowel Disease Patients.

Growing evidence suggests that impaired gut permeability and gut microbiota alterations are involved in the pathogenesis of Inflammatory Bowel Diseases (IBDs), which include Ulcerative Colitis (UC) and Crohn's Disease (CD). Vedolizumab is an anti-α4β7 antibody approved for IBD treatment, used as the first treatment or second-line therapy when the first line results in inadequate effectiveness. The aim of this study is to develop a mathematical model capable of describing the pathophysiological mechanisms of Vedolizumab treatment in IBD patients. In particular, the relationship between drug concentration in the blood, colonic mucosal permeability and fecal microbiota composition was investigated and modeled to detect and predict trends in order to support and tailor Vedolizumab therapies. To pursue this aim, clinical data from a pilot study on a cluster of 11 IBD patients were analyzed. Enrolled patients underwent colonoscopy in three phases (before (t0), after 24 weeks of (t1) and after 52 weeks of (t2 ) Vedolizumab treatment) to collect mucosal biopsies for transepithelial electrical resistance (TEER) evaluation (permeability to ions), intestinal permeability measurement and histological analysis. Moreover, fecal samples were collected for the intestinal microbiota analysis at the three time points. The collected data were compared to those of 11 healthy subjects at t0, who underwent colonoscopy for screening surveillance, and used to implement a three-compartmental mathematical model (comprising central blood, peripheral blood and the intestine). The latter extends previous evidence from the literature, based on the regression of experimental data, to link drug concentration in the peripheral blood compartment with Roseburia abundance and intestinal permeability. The clinical data showed that Vedolizumab treatment leads to an increase in TEER and a reduction in intestinal permeability to a paracellular probe, improving tissue inflammation status. Microbiota analysis showed increasing values of Roseburia, albeit not statistically significant. This trend was adequately reproduced by the mathematical model, which offers a useful tool to describe the pathophysiological effects of Vedolizumab therapy on colonic mucosal permeability and fecal microbiota composition. The model's satisfactory predictive capabilities and simplicity shed light on the relationship between the drug, the microbiota and permeability and allow for its straightforward extension to diverse therapeutic conditions.

Population pharmacokinetic meta-analysis of five beta-lactams antibiotics to support dosing regimens in dogs for surgical antimicrobial prophylaxis

The Pharmacokinetic/Pharmacodynamic (PK/PD) relationship of antimicrobial drugs (AMD) for surgical prophylaxis has been poorly studied, hampering evidence-based decision making around AMD dosing and timing. Our objective is to use PK/PD principles to inform (1) the timing of administration and (2) the interval for re-administration of AMD used peri-operatively in dogs. Raw plasma concentrations of cefazolin, cefuroxime, cefalexin, amoxicillin and ampicillin were retrieved from original intravenous studies performed in dogs. E. coli and methicillin-susceptible staphylococci were identified as possible intraoperative contaminants and their epidemiological cut-offs (ECOFF) were retrieved from the EUCAST database. Individual PK data were refitted with non-linear mixed effect models (Phoenix®). We performed Monte Carlo simulation to compute i) the 95th percentile of time of peak concentration in the peripheral compartment (informing timing between administration and first incision) and ii) the duration for which at least 90% of dogs maintain a free plasma concentration above ECOFF (informing timing of re-administration: 1.5–4 h). Cefazolin (22–25 mg/kg), cefuroxime (20 mg/kg), cefalexin (15 mg/kg) and amoxicillin (16.7 mg/kg) reached peak peripheral concentrations within 30 min, but ampicillin (20 mg/kg) required 82 min, respectively. For methicillin-susceptible staphylococci, cefazolin and cefuroxime require re-administration every 2 h, whereas cefalexin and both amoxicillin and ampicillin can be readministered every 3 and 4 h, respectively. For E. coli, only cefazolin provided adequate perioperative coverage with 2-hourly administration, where cefuroxime and cefalexin failed uniformly. Alternatively, ampicillin and amoxicillin (critically ill dogs) may cover E. coli contaminations, but only if readministered every 1.5 h. These PK-derived conclusions provide a rationale for perioperative AMD administration timing.

Examining dietary supplements containing Euterpe oleracea Mart. (açaí) for potential botanical-drug interactions involving CYP3A4 inhibition

BackgroundBotanical dietary supplements (BDS) are consumed more by cancer patients than otherwise healthier patients to alleviate side effects of chemotherapy drugs or increase quality of life. The enzyme responsible for the metabolism of most anticancer drugs is CYP3A4, an enzyme predominantly located in the liver. HypothesisOur research team examined the potential risk between CYP3A4-interactive cancer drugs and Euterpe oleracea Mart. (açaí) berry and found that the compounds that passively and non-passively diffused from methanol açaí extract displayed significant inhibition of liver CYP3A4 – suggesting the potential for interactions between açaí and drugs metabolized by CYP3A4 if used synchronously. This study aims to identify the compounds responsible for the CYP3A4 inhibition using the newly automated Bioactivity – Global Natural Product Social Molecular Networking (GNPS) tool. MethodsDietary supplement capsules from two manufacturers (F1 and F2) containing aqueous extracts of açaí fruits were extracted separately by methanol (ME) and acidic methanol (AC) and standardized to cyanidin-3-O-glucoside (CG) concentration at a human-relevant dose. After solvent removal, a parallel artificial membrane permeability assay (PAMPA) was utilized to filter intestinal passive diffusion of the four extract constituents so that compounds could be tested for inhibition of hepatic CYP3A4. Passively and non-passively diffused constituents of extracts from PAMPA assays were injected into the liquid chromatography-mass spectrometry (LC–MS) and characterized for visualization and comparison of chemical entities. To elucidate the non-passively diffused compounds responsible for significant CYP3A4 inhibition, the Bioactivity – GNPS tool was used to hypothesize which compounds within the formulation extract were potentially active to accelerate their identification. ResultsThere was no significant inhibition of CYP3A4 by passively diffused constituents for any extract. There was, however, significant inhibition by non-passively diffused constituents of both F1ME and F1AC extracts with 50 % CYP3A4 inhibition at the donor compartment concentrations 5.764 and 15.58 ng/ml CG, respectively. Six compounds were predicted to be inhibitors of CYP3A4 from methanol F1 extract, including betaine and 5 unknown compounds. ConclusionThis indicates that BDS containing açaí may not inhibit CYP3A4 through passively diffused compounds. Compounds from açaí BDS that inhibit CYP3A4 may be absorbed through other mechanisms, such as transporters.

Osteochondral fluid transport in an ex vivo system

ObjectiveAlterations to fluid transport from bone-to-cartilage may contribute to the development of osteoarthritis. Larger biological molecules found in bone may transport from bone-to-cartilage (e.g., insulin, 5kDa). However, many questions remain about fluid transport between these tissues. The objectives of this study were to (1) test for diffusion of 3kDa molecular tracers from bone-to-cartilage and (2) assess potential differences in bone-to-cartilage fluid transport between different loading conditions. DesignOsteochondral cores extracted from bovine femurs (N=10 femurs, 10 cores/femur) were subjected to either no-load (i.e., pure diffusion), pre-load only, or cyclic compression (5±2% or 10±2% strain) in a two-chamber transport system. The bone was placed into the bone compartment followed by a 3kDa dextran tracer, and tracer concentrations in the cartilage compartment were measured every 5 minutes for 120 minutes. Tracer concentrations were analyzed for differences in beginning, peak and equilibrium concentrations, loading effects, and time-to-peak tracer concentration. ResultsPeak tracer concentration in the cartilage compartment was significantly higher compared to beginning and equilibrium tracer concentrations indicating fluid transport from bone-to-cartilage. Cartilage-compartment tracer concentration, and maximum fluorescent intensity was influenced by strain magnitude. No time-to-peak relationship was found when comparing strain magnitudes impact on cartilage-compartment tracer concentration. ConclusionThis study shows that osteochondral fluid transport occurs from bone-to-cartilage with 3kDa dextran molecules. These are much larger molecules to move between bone and cartilage than previously reported. Further, these results demonstrate the potential for cyclic compression to impact osteochondral fluid transport. Determining the baseline osteochondral fluid transport in healthy tissues is crucial to elucidating the potential mechanisms of progression and onset of osteoarthritis.

In silico modeling for ex vivo placenta perfusion of nicotine.

Nicotine readily crosses the placenta to reach fetuses. However, membrane transporters, e.g., organic cation transporters (OCTs) play a role in the clearance of nicotine from the fetal to the maternal side, and this is rarely investigated clinically. In this work, we use an in silico model to simulate an ex vivo placenta perfusion experiment, which is the gold standard for measuring the transplacental permeability of compounds, including nicotine. The model consists of a system of seven ordinary differential equations (ODEs), where each equation represents the nicotine concentration in compartments that emulate the ex vivo experiment setup. The transport role of OCTs is simulated bi-directionally at the placenta's basal membrane (the fetal side). We show that the model can not only reproduce the actual ex vivo experiment results, but also predict the likely maternal and fetal nicotine concentrations when the OCT transporters are inhibited, which leads to a ∼12% increase in fetal nicotine concentration after 2hours of OCT modulated nicotine perfusion. In conclusion, a first in silico model is proposed in this paper that can be used to simulate some subtle features of trans-placental properties of nicotine.

Model-based comparison of subcutaneous versus sublingual apomorphine administration in the treatment of motor fluctuations in Parkinson’s disease

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson’s disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting “on demand” therapy for patients with Parkinson’s disease experiencing motor fluctuations.

Sources, Occurrences, and Risks of Polycyclic Aromatic Hydro-Carbons (PAHs) in Bangladesh: A Review of Current Status

Polycyclic aromatic hydrocarbons (PAHs) pollution has emerged as a significant environmental issue in Bangladesh in the recent years, driven by both economic and population growth. This review aims to investigate the current trends in PAHs pollution research, covering sediments, water, aquatic organisms, air particles, and associated health risks in Bangladesh. A comparative analysis with PAHs research in other countries is conducted, and potential future research directions are explored. This review suggests that the research on PAHs pollution in Bangladesh is less well studied and has fewer research publications compared to other countries. Dominant sources of PAHs in Bangladesh are fossil fuel combustion, petroleum hydrocarbons, urban discharges, industrial emissions, shipbreaking, and shipping activities. The concentrations of PAHs in sediments, water, air particles, and aquatic organisms in Bangladesh were found to be higher than those in most of the other countries around the world. Therefore, coastal sediments showed higher PAHs pollution than urban areas. Health risk assessments reveal both carcinogenic and non-carcinogenic risks to residents in Bangladesh due to the consumption of aquatic organisms. According to this investigation, it can be concluded that there are considerably higher PAHs concentrations in different environmental compartments in Bangladesh, which have received less research attention compared with other countries of the world. Considering these circumstances, this review recommends that future PAHs pollution research directions should focus on aquatic ecosystems, shipbreaking areas, air particles, and direct exposure to human health risks. Therefore, this study recommends addressing the identification of PAH sources, bioaccumulation, biomagnification in the food web, and biomarker responses of benthic organisms in future PAHs pollution research.

Influence of Bile Acids on Clindamycin Hydrochloride Skin Permeability: InVitro and InSilico Preliminary Study.

Topical clindamycin formulations are widely used in clinical practice, but poor bioavailability and restricted skin penetration considerably limit their therapeutic efficacy. Penetration enhancement represents a promising and rational strategy to overcome the drawbacks of conventional topical pharmaceutical formulations. We aim to assess the influence of cholic acid (CA) and deoxycholic acid (DCA) on the permeability of clindamycin hydrochloride by performing the in vitro skin parallel artificial membrane permeability assay (skin-PAMPA) at two relevant pH values (5.5 and 6.5) and the interactions of tested substances with skin ATP-binding cassette (ABC) transporters in silico. After the incubation period, the clindamycin hydrochloride concentrations in both compartments were determined spectrophotometrically, and the apparent permeability coefficients (Papp) were calculated. Vienna LiverTox web service was used to predict the interactions of clindamycin and bile acids with potential drug transporters located in human skin. Both CA and DCA at the highest studied concentration of 100μM in the tested solutions increased the skin-PAMPA membrane permeability of clindamycin hydrochloride. This effect was more pronounced for CA and at a higher studied pH value of 6.5, which is characteristic of most dermatological indications treated with topical clindamycin preparations. Clindamycin transport may also be mediated by ABC transporters located in skin and facilitated in the presence of bile acids. The results of this study provide a solid foundation for further research directed at the improvement of topical formulations using bile acids as penetration-enhancing excipients, as well as the therapeutic efficacy of clindamycin hydrochloride.

Long-term changes in 90Sr pools of Scots pine biomass in the Chornobyl Red Forest

The trenches of the waste burial site in the Chornobyl Red Forest represent a big reservoir of radionuclides for the artificial plantation of Scots pine established in that area, but the long term dynamics of tree biomass contamination, especially with 90Sr, remains unclear. The present study was conducted between 2005 and 2018 on two groups of trees of the same age. The IN group is represented by trees growing on the trench containing highly radioactive contaminated fertile soil and organic matter, while the OUT group is located outside the trench. Within a little more than one decade, the total aboveground biomass doubled in the trees of the group OUT and increased more than four times in the group IN. In the group OUT, the concentrations of 90Sr have decreased in all biomass compartments compared to 2005, while in the group IN, the concentrations demonstrated a trend to increase. Regression analysis shows that both decrease in the compartment concentrations in the group OUT (slope coefficient 0.55) and increase in the group IN (1.58) were significant. As a result of the changes in the biomass inventories and 90Sr concentrations, in absence of changes in plantation density, the contamination of total aboveground biomass by 90Sr in the group OUT would have increased slightly in 2018 (from approximately 18 GBq ha−1 to 23 GBq ha−1) compared to 2005, while in the group IN it would have increased almost 6-fold, reaching approximately 560 GBq ha−1, or about (19 ± 9) % of the total 90Sr inventory in the trench area. Trenches of the Red Forest were shown to act as long-lasting hot spots of 90Sr bioavailability for forest trees.

Distribution and Homogenization of Multiple Mercury Species Inputs to Freshwater Wetland Mesocosms.

Mercury (Hg)-impaired aquatic ecosystems often receive multiple inputs of different Hg species with varying potentials for transformation and bioaccumulation. Over time, these distinct input pools of Hg homogenize in their relative distributions and bioaccumulation potentials as a result of biogeochemical processes and other aging processes within the ecosystem. This study sought to evaluate the relative time scale for homogenization of multiple Hg inputs to wetlands, information that is relevant for ecosystem management strategies that consider Hg source apportionment. We performed experiments in simulated freshwater wetland mesocosms that were dosed with four isotopically labeled mercury forms: two dissolved forms (Hg2+ and Hg-humic acid) and two particulate forms (nano-HgS and Hg adsorbed to FeS). Over the course of one year, we monitored the four Hg isotope endmembers for their relative distribution between surface water, sediment, and fish in the mesocosms, partitioning between soluble and particulate forms, and conversion to methylated mercury (MeHg). We also evaluated the reactivity and mobility of Hg through sequential selective extractions of sediment and the uptake flux of aqueous Hg in a diffusive gradient in thin-film (DGT) passive samplers. We observed that the four isotope spikes were relatively similar in surface water concentration (ca. 3000 ng/L) immediately after spike addition. At 1-3 months after dosing, Hg concentrations were 1-50 ng/L and were greater for the initially dissolved isotope endmembers than the initially particulate endmembers. In contrast, the Hg isotope endmembers in surface sediments were similar in relative concentration within 2 months after spike addition. However, the uptake fluxes of Hg in DGT samplers, deployed in both the water column and surface sediment, were generally greater for initially dissolved Hg endmembers and lower for initially particulate endmembers. At one year postdosing, the DGT-uptake fluxes were converging toward similar values between the Hg isotope endmembers. However, the relative distribution of isotope endmembers was still significantly different in both the water column and sediment (p < 0.01 according to one-way ANOVA analysis). In contrast, selective sequential extractions resulted in a homogeneous distribution, with >90% of each endmember extracted in the KOH fraction, suggesting that Hg species were associated with sediment organic matter. For MeHg concentrations in surface sediment and fish, the relative contributions from each endmember were significantly different at all sampling time points. Altogether, these results provide insights into the time scales of distribution for different Hg species that enter a wetland ecosystem. While these inputs attain homogeneity in concentration in primary storage compartments (i.e., sediments) within weeks after addition, these input pools remain differentiated for more than one year in terms of reactivity for passive samplers, MeHg concentration, and bioaccumulation.

Developing mathematical models to compare and analyse the pharmacokinetics of morphine and fentanyl.

The two-compartment model is generally used in pharmacokinetics to illustrate the distribution and excretion of drugs. In this study, we evaluated the distribution patterns of morphine and fentanyl by using a two-compartment model. Using numeric analysis techniques, non-linear ordinary differential equations were used to mathematically analyse drug distribution, transition, and concentration in the body compartments. Math Works, Inc., MATLAB, version 2023a, a programming tool, was used to characterise the impact of initial concentration and rate constants on the kinetics of the drug. For a definite therapeutic concentration of morphine and fentanyl in blood, pharmacokinetic characteristics were plotted. The study results showed the time taken by morphine and fentanyl to reach a target concentration in the blood that is sufficient to generate the preferred therapeutic effects. The mathematical models comparing morphine and fentanyl pharmacokinetics showed that fentanyl reached the target therapeutic concentration 125 minutes earlier than morphine and was metabolised and removed from the body more rapidly (44 minutes earlier than morphine). These comparative mathematical models on morphine and fentanyl enable the determination of drug dosages and understanding of drug efficacy that facilitates optimising dosing regimens. The right choice between them can be made based on the time to reach the target therapeutic concentration in the blood, elimination time, severity of pain, and patient characteristics.

Predicting environmental concentrations of nanomaterials for exposure assessment - a review

There have been major advances in the science to predict the likely environmental concentrations of nanomaterials, which is a key component of exposure and subsequent risk assessment. Considerable progress has been since the first Material Flow Analyses (MFAs) in 2008, which were based on very limited information, to more refined current tools that take into account engineered nanoparticle (ENP) size distribution, form, dynamic release, and better-informed release factors. These MFAs provide input for all environmental fate models (EFMs), that generate estimates of particle flows and concentrations in various environmental compartments. While MFA models provide valuable information on the magnitude of ENP release, they do not account for fate processes, such as homo- and heteroaggregation, transformations, dissolution, or corona formation. EFMs account for these processes in differing degrees. EFMs can be divided into multimedia compartment models (e.g., atmosphere, waterbodies and their sediments, soils in various landuses), of which there are currently a handful with varying degrees of complexity and process representation, and spatially-resolved watershed models which focus on the water and sediment compartments. Multimedia models have particular applications for considering predicted environmental concentrations (PECs) in particular regions, or for developing generic “fate factors” (i.e., overall persistence in a given compartment) for life-cycle assessment. Watershed models can track transport and eventual fate of emissions into a flowing river, from multiple sources along the waterway course, providing spatially and temporally resolved PECs. Both types of EFMs can be run with either continuous sources of emissions and environmental conditions, or with dynamic emissions (e.g., temporally varying for example as a new nanomaterial is introduced to the market, or with seasonal applications), to better understand the situations that may lead to peak PECs that are more likely to result in exceedance of a toxicological threshold. In addition, bioaccumulation models have been developed to predict the internal concentrations that may accumulate in exposed organisms, based on the PECs from EFMs. The main challenge for MFA and EFMs is a full validation against observed data. To date there have been no field studies that can provide the kind of dataset(s) needed for a true validation of the PECs. While EFMs have been evaluated against a few observations in a small number of locations, with results that indicate they are in the right order of magnitude, there is a great need for field data. Another major challenge is the input data for the MFAs, which depend on market data to estimate the production of ENPs. The current information has major gaps and large uncertainties. There is also a lack of robust analytical techniques for quantifying ENP properties in complex matrices; machine learning may be able to fill this gap. Nevertheless, there has been major progress in the tools for generating PECs. With the emergence of nano- and microplastics as a leading environmental concern, some EFMs have been adapted to these materials. However, caution is needed, since most nano- and microplastics are not engineered, therefore their characteristics are difficult to generalize, and there are new fate and transport processes to consider.

Enhancing transmucosal delivery of CBD through nanoemulsion: in vitro and in vivo studies.

Cannabidiol (CBD) has gained significant attention as a complementary and alternative medicine due to its promising therapeutic properties. However, CBD faces obstacles when administered orally due to its poor solubility in water, leading to limited absorption into the bloodstream and low and variable bioavailability. Therefore, the development of innovative delivery approaches that can enhance CBD's bioavailability, facilitate administration, and promote patient adherence is crucial. We propose a new approach for buccal delivery of CBD based on a self-assembling nanoemulsion (NE) made of a mixture of surfactants (Tween 80 and Labrasol) and medium chain triglycerides (MCTs). The NE formulation showed properties suitable for buccal administration, including appropriate size, CBD content, and surface properties, and, if compared to a CBD-MCT solution, it exhibited better control of administered doses, faster dissolution in buccal medium, and enhanced stability. The CBD-NE effectively released its active load within 5h, remained stable even when diluted in simulated buccal fluids, and could be easily administered through a commercially available spray, providing consistent and reproducible doses of NE with optimized properties. In vitro permeation studies demonstrated that the CBD-NE facilitated swift and consistent permeation through the buccal mucosa, resulting in a higher concentration in the acceptor compartment compared to CBD-MCT. Furthermore, the in vivo study in mice showed that a single buccal administration of CBD-NE led to a quicker onset of action than a CBD solution in MCT, while maintaining the same plasma levels over time and leading to typically higher plasma concentrations compared to those usually achieved through oral administration. In conclusion, our CBD-NE represents a promising alternative formulation strategy for buccal CBD administration, overcoming the challenges associated with conventional formulations such as variable bioavailability and low control of administered doses.

Research of aerosol removal by passive containment cooling system

Passive containment cooling system (PCCS) can effectively remove the heat from the containment and maintain the pressure and temperature in case of accident, thus ensuring the containment integrity. PCCS introduces thermophoresis and diffusiophoresis aerosol deposition and changes the distribution of fission products in the containment, thus affecting containment dose evaluation and off-site source term assessment. In this paper, a Generation III PWR nuclear power plant model with PCCS is established by using ASTEC (Accident Source Term Evaluation Code), and the removal effect of PCCS on fission product aerosol is studied under the large break loss of coolant accident. The results show that one train of PCCS can increase the aerosol removal factor for approximately 0.05/h. Taking five trains of PCCS in this study as an example, aerosol deposition effect introduced by PCCS reduces suspended aerosol in containment by 10 %–20 %, and the effect is more significant in the PCCS-locating compartment. Meanwhile, the gas flow among compartments changes the aerosol mass in the adjacency of the PCCS-locating compartment. This phenomenon weakens the removal effect in the PCCS-locating compartment and make the aerosol concentration in adjacent compartments tend to be consistent.

Mathematical Modelling of the Oral Administration of Drugs into the Stomach and the Treatment Effect with the Influence of Temperature

This research deals with the mathematical formulation that mimics the oral administration of drug intake into the stomach and the therapeutic effect of temperature increases. We solved the formulated ordinary differential equations (ODEs) using the Laplace method, and the numerical simulation was carried out using Wolfram Mathematica by varying the thermal conductivity and the treatment terms and studying the significant role they play in eliminating the drug from the human body. The study showed that the pertinent parameters influence the drug concentration in the stomach compartment under the influence of temperature. In conclusion, with the help of this simple model, researchers should be able to better understand oral drug administration and provide reliable and appropriate care to patients.