Search Results (209)

The vital role of arbuscular mycorrhizal (AM) fungi in tea plant growth is well established; however, the mechanisms underlying how increasing cultivation chronosequence (CC) influences AM fungal distribution remain unclear. An investigation was conducted to investigate the temporal dynamics of AM fungal indices and soil properties across a 100-year tea CC (10-, 30-, 60-, and 100-year CC) in Xinyang Maojian tea (Camellia sinensis L.) plantations (Xinyang, Henan Province, China). Principal coordinate analysis was conducted to reveal the significant reorganization of AM fungal indices during early-to-mid stages (PCoA1: 89.2%, p < 0.05), with triphasic development. Mycorrhizal colonization (MC), hypha biomass (hypha), and spore density (SD) surged by 100% during 10–30 years; SD peaked at 60 years (164 spores g⁻¹) before declining, while glomalin-related soil protein (GRSP) accumulated significantly only at 100 years (p < 0.05). Concurrently, soil acidification (pH decreased from 6.37 to 4.84) and phosphorus depletion (AP from 119.6 mg kg⁻¹ to 32 mg kg⁻¹) intensified by 60 years, contrasting with the significant accumulations of soil organic organisms (SOM) (from 10.6 g kg⁻¹ to 36.4 g kg⁻¹), electrical conductivity (EC) (from 0.019 to 0.050 mS·cm⁻¹), and microaggregate accumulation (MAR) (from 25.8% to 40.3%) during the period. The linear regression model was performed to validate the significant effects (p < 0.05) of CC on the AM indices (MC, SD, hypha, and GRSP) and soil physiochemical characteristics (EC, moisture, and SOM). Variance partitioning attributed 97.4% of the total variation, while interactions among cultivation ages, nutrient characteristics (SOM and AP), and non-nutrient characteristics (pH, EC, moisture, and aggregates) accounted for 23.0%. To identify the driving factors of AM fungi indices, Pearson correlation and redundancy analysis (RDA) were performed, and EC (26.5%) and pH (20.9%) were identified as the paramount regulators of hyphal integrity and colonization efficiency. It was found that 60 years worked as a critical transition point for targeted interventions (e.g., organic amendments and pH buffering) to mitigate rhizosphere dysfunction and optimize mycorrhizal services in perennial monocultures. Full article

Background: hMPXV poses a major public health risk due to its human-to-human transmissibility, severe complications, especially in immunocompromised individuals, and global spread, necessitating effective surveillance and stringent prophylactic measures to mitigate its colossal impact. Objective: The study aimed to annotate hMPXV(IMV) proteins to propose a potential reverse vaccinology-based vaccine against hMPXV. Methods: The target MPXV(IMV) protein’s sequences, formatted in FASTA, were sourced from genome/proteome databases (BV-BRC and UniProt) (accessed on 6 November 2024), followed by CD-Hit-based redundancy removal. Epitope prediction for B-cells (lymphocytes), cytotoxic T-cells or cytotoxic T-lymphocytes (CTLs), and helper T-cells (HTLs) was executed using ABCpred, IEDB’s ANNs 4.0, and an artificial neural network-based alignment tool (NN-align 2.3)/ML-based tool (NetMHCII 2.3). Various immunoinformatics filters (antigenicity, toxicity, and allergenicity) were applied to substantiate the potency and safety of the formulated vaccine candidate. The constructed vaccine’s physiochemical and structural features (secondary and tertiary), with structural stability (confirmed by molecular docking followed by dynamic simulation with TLRs (TLR4 & TLR2) and MHCs), were determined. Additionally, cloning (using pET-28a(+) vector) was conducted to verify the vaccine’s expression potential and translation efficiency. The construct’s population coverage was also ascertained. Results: The MPXV-2-Beta vaccine constructs, of the six initially designed constructs, was identified as the most promising candidate, signifying nonallergenic profile and nontoxic features, with a predicted antigenicity score (PAS) = 0.7202, 407 residues, a molecular weight of 43,102.1 Da, pI of 9.2, and favorable stability parameters (AI: 65.65, GRAVY: −0.597, I-i: 25.92). It showed high solubility (score: 0.942). The ProSA Z-score of −9.38 confirmed the structural stability, reliability, and precision of the MPXV-2-Beta 3D model, which is comparable to experimental structures. Furthermore, 98.8% of all the residues nested within favored or allowed regions in a critical Ramachandran plot signified the model’s exceptional structural integrity and quality. Docking and dynamic simulation of MPXV-2-Beta with TLRs (TLR4 & TLR2) and MHCs demonstrated stiffer docking stability (strong polar and nonpolar interaction) and negative eigenvalue value (during dynamic simulation), suggesting its ability to enhance immune receptor activation under physiological conditions. MPXV-2-Beta was predicted to trigger a robust immune response (IR) with comprehensive world population coverage (98.55%, SD = 10.41). Conclusions: Based on the evaluated parameters, the MPXV-2-Beta designed in this study exhibited significant potential as an effective candidate against hMPXV. This study establishes a foundation for developing an efficient vaccine against hMPXV, requiring further experimental and clinical validation to confirm computational findings. Full article

Olive mill wastewater (OMW) is deemed a substantial environmental pollutant, particularly in Mediterranean regions. Lower and middle-income countries, including Jordan, suffer from water scarcity and increasing demand for water, especially for drinking and irrigation purposes. Subsequently, the management and treatment of OMW represents a major concern. This study investigates the feasibility of utilizing Jordanian kaolinite as a simple, readily available, green, and sustainable adsorbent to mitigate the environmental impact of untreated or partially treated OMW. In this work, purified kaolinite (PK) was activated with sodium ions at room temperature. The characterization of PK and sodium-activated kaolinite (PK-NaCl) was accomplished using FTIR, XRD, TGA, and BET surface area analyses. The adsorption performance of both PK and PK-NaCl for OMW treatment were evaluated through batch and column experiments. The key physiochemical parameters of OMW were systematically analyzed in all influent and effluent samples to evaluate the treatment efficiency. In all cases, sodium-activated kaolinite significantly enhances treatment efficiency. The adsorption of total phenolic compounds (TPCs) onto both PK and PK-NaCl adsorbents was studied with respect to initial concentration, adsorbent dosage, and temperature. The maximum adsorption capacity was 8.88 mg/g for PK-NaCl, which was higher than that of PK, at an adsorbent dose of 1.0 g and a temperature of 323 K. The Langmuir and Freundlich isotherm models to describe the adsorption equilibrium were implemented, and both displayed good fit with the experimental data. Additionally, the removal efficiencies of heavy metal (i.e., Zn, Fe and Mn) ions were also evaluated. The findings demonstrated that the PK-NaCl completely removed all tested heavy metal ions, regardless of their initial concentrations. Therefore, the cost-effective and easily prepared PK-NaCl significantly improved the adsorption capacity and presents a promising treatment solution for OMW. This approach could be highly beneficial for olive mills across the Mediterranean regions to mitigate the environmental impact of OM waste. Full article

Recent studies have demonstrated that machine learning-based generative models can create novel molecules with desirable properties. Among them, Conditional Variational Autoencoder (CVAE) is a powerful approach to generate molecules with desired physiochemical and pharmacological properties. However, the CVAE’s latent space is still a black-box, making it difficult to understand the relationship between the latent space and molecular properties. To address this issue, we propose the Interpretable Conditional Variational Autoencoder (ICVAE), which introduces a modified loss function that correlates the latent value with molecular properties. ICVAE established a linear mapping between latent variables and molecular properties. This linearity is not only crucial for improving interpretability, by assigning clear semantic meaning to latent dimensions, but also provides a practical advantage. It enables direct manipulation of molecular attributes through simple coordinate shifts in latent space, rather than relying on opaque, black-box optimization algorithms. Our experimental results show that the ICVAE can linearly relate one or multiple molecular properties with the latent value and generate molecules with precise properties by controlling the latent values. The ICVAE’s interpretability allows us to gain insight into the molecular generation process, making it a promising approach in drug discovery and material design. Full article

Bacterial diseases cause high mortality and considerable losses in aquaculture. The rapid expansion of intensive aquaculture has further increased the risk of large-scale outbreaks. However, the emergence of drug-resistant bacteria, food safety concerns, and environmental regulations have severely limited the availability of antimicrobial. Compared to traditional antibiotics, antimicrobial peptides (AMPs) offer broad spectrum activity, physicochemical stability, and lower resistance development. However, their low natural yield and high extraction costs along with the time-consuming and expensive nature of traditional drug discovery, pose a challenge. In this study, we applied a machine-learning macro-model to predict AMPs from three macrogenomes in the water column of South American white shrimp aquaculture ponds. The AMP content per megabase in the traditional earthen pond (TC1) was 1.8 times higher than in the biofloc pond (ZA1) and 63% higher than in the elevated pond (ZP11). A total of 1033 potential AMPs were predicted, including 6 anionic linear peptides, 616 cationic linear peptides, and 411 cationic cysteine-containing peptides. After screening based on structural, and physio-chemical properties, we selected 10 candidate peptides. Using a rapid high-throughput cell-free protein expression system, we identified nine peptides with antimicrobial activity against aquatic pathogens. Three were further validated through chemical synthesis. The three antimicrobial peptides (K-5, K-58, K-61) showed some inhibitory effects on all four pathogenic bacteria. The MIC of K-5 against Vibrio alginolyticus was 25 μM, the cell viability of the three peptides was higher than 70% at low concentrations (≤12.5 μM), and the hemolysis rate of K-5 and K-58 was lower than 5% at 200 μM. This study highlights the benefits of machine learning in AMP discovery, demonstrates the potential of cell-free protein synthesis systems for peptide screening, and provides an efficient method for high-throughput AMP identification for aquatic applications. Full article

Background: The low solubility and poor skin permeability of sulfasalazine (SLZ) present significant challenges for its effective topical delivery. The objective of the current investigation is to formulate a hydrogel-based SLZ-loaded cyclodextrin nanosponge for topical therapy in psoriasis. Methods: SLZ-loaded nanosponges were prepared by the melt polymerization method and evaluated for physiochemical characteristics, drug release, and cytocompatibility. The selected nanosponges (SLZ-NS4) were transformed to hydrogel and further evaluated for rheology, texture, safety, skin permeability, and in vivo for anti-psoriatic effect in mouse tail and imiquimod-induced psoriasis-like inflammation models in mice. Results: Physiochemical data confirms nanoscale architecture, drug inclusion in nanosponges, crystalline structure, and formulation stability. The release profile of SLZ-NS4 revealed sustained release behavior (22.98 ± 2.24% in 3 h). Cytotoxicity assays indicated negligible toxicity against THP1 cells, resulting in higher viability of cells than pure SLZ (p < 0.05). The HET-CAM assay confirmed the safety, while confocal laser scanning microscopy demonstrated deeper skin permeation of SLZ. In the mouse tail model, a remarkable decline in relative epidermal thickness, potential improvement in percent orthokeratosis, and drug activity with respect to control was observed in animals treated with SLZ-NS4 hydrogel. The efficiency of the developed SLZ-NS4-loaded hydrogel in treating psoriasis was confirmed by the decline in PASI score (81.68 ± 3.61 and 84.86 ± 5.74 with 1 and 2% w/v of SLZ-NS-HG). Histopathological analysis and assessment of oxidative stress markers revealed the profound anti-psoriatic potential of the fabricated SLZ-NS4 hydrogel. Conclusions: These findings highlight the profound potential of the developed delivery system as an effective topical therapy for psoriasis. Full article

Background/Objectives: GL-II-73 is a positive allosteric modulator that is selective for α5GABA_A receptors and has physicochemical properties that favor nanocarrier formulations when parenteral delivery to the central nervous system is desired. Our aim was to develop an optimized nanoemulsion containing GL-II-73 and subsequently test whether this would improve permeation across the blood–brain barrier (BBB) and availability in the brain. Methods: The nanoemulsions were formulated and subjected to detailed physiochemical characterization. The optimized formulation was tested in comparison to a solution of GL-II-73 in the appropriate solvent in an in vitro model of the blood–brain barrier based on human induced pluripotent stem cell-derived microvascular endothelial cells, astrocytes, and pericytes. Plasma and brain exposure to GL-II-73 and its metabolite MP-III-022 was investigated in an in vivo neuropharmacokinetic study in rats exposed to the selected nanoemulsion and the conventional solution formulation. Results: The selected biocompatible nanoemulsion exhibited satisfactory physicochemical properties for parenteral administration, with a Z-ave of 122.0 ± 1.5, PDI of 0.123 ± 0.009 and zeta potential of −40.7 ± 1.5, pH of 5.16 ± 0.04, and adequate stability after one year of storage, and allowed the localization of GL-II-73 in the stabilization layer. The permeability of GL-II-73 through the BBB was twice as high with the selected nanoemulsion as with the solution. The availability of GL-II-73 and MP-III-022 (also a positive allosteric modulator selective for α5GABA_A receptors) in the brain was 24% and 61% higher, respectively, after intraperitoneal administration of the nanoemulsion compared to the solution; the former increase was statistically significant. Conclusions: The increased permeability in vitro proved to be a good predictor for the improved availability of GL-II-73 in brain tissue in vivo from the formulation obtained by encapsulation in a nanoemulsion. The putative additive effect of the parent molecule and its metabolite MP-III-022 could lead to enhanced and/or prolonged modulation of α5GABA_A receptors in the brain. Full article

Sorghum (Sorghum bicolor) is an essential bioenergy crop. Cellulosic and non-cellulosic polysaccharides, which can be transformed into biofuels, comprise most of its biomass. Many glycosyltransferases (GT) families, including GT43, are involved in the biosynthesis of xylan in plants’ primary and secondary cells. In this study, the GT43 gene family was identified, and its secondary structure and a three-dimensional (3D) model were constructed. Additionally, subcellular localization, detection of motifs, and analyses of its phylogenetic tree, physiochemical properties, protein–protein interaction network, gene structure, functional domain, gene duplication, Cis-acting elements, sequence logos, multiple sequence alignment, and gene expression profiles were performed based on RNA-sequence analyses. As a result, eleven members of the GT43 gene family were identified, and the phylogenetic tree of the GT43 gene family showed that all GT43 genes had evolutionary relationships with sorghum. Analyses of gene structure, motifs, sequence logos, and multiple sequence alignment showed that all members of the GT43 protein family were highly conserved. Subcellular localization showed all members of the GT43 protein family were localized in different compartments of sorghum. The secondary structure of the GT43 genes comprised different percentages of α-helices, random coils, β-turns, and extended strands. The tertiary structure model showed that all GT43 proteins had similar 3D structures. The results of the current study indicated that members of the GT43 gene family (Sobic.010G238800, Sobic.003G254700, and Sobic.001G409100) were highly expressed in internodes of the sorghum plant, based on RNA-Sequencing. The framework used in this study will be valuable for advancing research aligned with modern technology requirements and for enhancing understanding of the relationships among GT43 genes in Sorghum bicolor. Full article

Background/Objectives: The novel pyrazoloquinolinone ligand CW-02-79 shows a unique profile of selective binding to σ2 receptors, but its poor solubility in both water and lipids makes its research and development a burdensome task. We aimed to develop a phospholipid-complex-based nanoemulsion formulation containing CW-02-79 suitable for intravenous administration in preclinical research. Methods: The decorated and undecorated nanoemulsions were formulated and subjected to detailed physiochemical characterization. The delivery and exposure to CW-02-79 from selected nanoemulsions were examined in the in vitro blood–brain barrier model based on human-induced pluripotent stem-cell-derived microvascular endothelial cells, astrocytes, and pericytes, and in vivo neuropharmacokinetic study in rats, respectively. Results: The developed biocompatible nanoemulsions loaded with a CW-02-79—phospholipid complex at a mass ratio of 1:10 exhibited a small droplet size and narrow size distribution, with satisfactory physicochemical stability during steam sterilization and short-term storage at 25 °C. The analysis of protein binding interactions revealed that the PEGylated nanoemulsions had fewer observable interactions compared to the undecorated nanoemulsions, especially when 0.2% DSPE-PEG2000 and 0.1% DSPE-PEG2000-mannose were combined. An in vitro BBB study demonstrated that a substantial part of CW-02-79 present in the applied nanoemulsion is able to permeate the barrier. The quantification of CW-02-79 in plasma/brain homogenate and calculated pharmacokinetic parameters confirmed good systemic and brain availability after intravenous administration. There were subtle differences in the pharmacokinetic parameters in favor of a dual surface-functionalized nanoemulson containing the glucose transporter-1-targeting ligand (mannose). Conclusions: The developed and characterized nanoemulsions enable substantial brain exposure to CW-02-79 as a prerequisite for a pharmacologically and clinically relevant selective modulation of σ2 receptors. Full article

Rosacea is a common skin condition with quite a relevance. It currently affects at least 10% of the European population at some point after the age of 30. It is a chronic disorder that mainly affects the skin on the face and is characterized by outbreaks and remissions. Under normal circumstances, the skin face presents a wide range of commensal organisms, such as Staphylococcus epidermidis or Demodex folliculorum, but dysbiosis of the skin flora plays a relevant role in inflammatory processes and the development of the disease. Metronidazole (MD) is one of the main treatments indicated to reduce redness on the cheeks, nose, chin, or forehead and also to treat flushing, erythema, pimples, and other symptoms due in part to its anti-inflammatory action. On the other hand, clindamycin (CM) is another antibiotic used for rosacea, especially for its action against anaerobic and Gram-positive bacteria. Background/Objectives: This study aimed to develop an emulgel formulation that includes MD and CM, using excipients with non-comedogenic and non-irritating properties. Methods: The formulation was characterised physiochemically, rheological measurements were made, and short-term stability studies were carried out. In vitro release, permeation studies, toxicity an in vitro inflammation model were evaluated in a HaCaT cell model. To determine the interaction between the antibiotics, the minimum inhibitory concentration was determined separately and together using the broth microdilution method. To determine the formulation’s antimicrobial activity, an agar diffusion method was used. Results: The MD-CM-gel droplet size was measured by laser diffraction and the diameter obtained was less than 2.68 ± 0.18 µm in 50% of the particles. Suitable results was observed for the short-term stability. Release and permeation data revealed sustained drug release and adequate permeation through human skin. Non-toxicity was detected and the MD showed an anti-inflammatory effect with non-interference of CM. Also, there is no antagonism between the two antibiotics and the MD-CM-gel shows better results when compared to the formulations with the antibiotics separately and to commercial formulations. Conclusions: It is suggested that, following detailed preclinical and clinical studies, MD-CM-gel could be considered as an alternative for treating rosacea. Full article

Clean water is vital for a sustainable environment, human wellness, and welfare, supporting life and contributing to a healthier environment. Fuzzy-logic-based techniques are quite effective at dealing with uncertainty about environmental issues. This study proposes two methodologies for assessing water quality based on Mamdani and Sugeno fuzzy systems, focusing on water’s physiochemical attributes, as these provide essential indicators of water’s chemical composition and potential health impacts. The goal is to evaluate water quality using a single numerical value which indicates total water quality at a specific location and time. This study utilizes data from the Acea Group and employs the Mamdani fuzzy inference system combined with various defuzzification techniques as well as the Sugeno fuzzy system with the weighted average defuzzification technique. The suggested model comprises three fuzzy middle models along with one ultimate fuzzy model. Each model has three input variables and 27 fuzzy rules, using a dataset of nine key factors to rate water quality for drinking purposes. This methodology is a suitable and alternative tool for effective water-management plans. Results show a final water quality score of 85.4% with Mamdani (centroid defuzzification) and 83.5% with Sugeno (weighted average defuzzification), indicating excellent drinking water quality in Tivoli, Italy. Water quality evaluation is vital for sustainability, ensuring clean resources, protecting biodiversity, and promoting long-term environmental health. Intermediate model evaluations for the Mamdani approach with centroid defuzzification showed amounts of 72.4%, 83.4%, and 92.5% for the first, second, and third fuzzy models, respectively. For the Sugeno method, the corresponding amounts were 76.2%, 83.5%, and 92.5%. These results show the precision of both fuzzy systems in capturing nuanced water quality variations. This study aims to develop fuzzy logic methodologies for evaluating drinking water quality using a single numerical index, ensuring a comprehensive and scalable tool for water management. Full article

Controlling the microorganisms employed in vinification is a critical factor for successful wine production. Novel methods aimed at lowering sulfites used for wine stabilization are sought. UV-C irradiation has been proposed as an alternative for reducing the viable cell count of microorganisms in wine and grape juice. Nevertheless, UV-C treatment poses the risk of altering the chemical properties of wine. Therefore, this study aimed to test and implement iron oxide–silica core–shell nanomaterial functionalized with TiO₂ in UV-C treatment of white and red wines. Material for the study consisted of the synthesized nanocomposite, Saccharomyces cerevisiae as a model yeast, and Muscaris and Cabernet Cortis wines. The viability of yeasts under treatment, the physiochemical properties of wine, and polyphenol content were tested. Studies have shown that nanomaterial can modulate the effects of UV-C treatment regarding yeast viability and polyphenol content, and the effectiveness of the treatment depends on the wine type. These results open up discussion on the possible use of the proposed hurdle technology in winemaking to control the polyphenol composition and alcohol reduction. Full article

Hydrothermal alteration provides critical information for both the exploration and scientific research of hydrothermal uranium deposits. The Xiangshan uranium ore field, the largest volcanic-hosted uranium deposit in China, is characterized by different alterations, including hematitization, illitization, sericitization, chloritization, carbonation and silicification. However, the mineralogical and geochemical characteristics of hydrothermal alterations and their relationships with uranium mineralization remain unclear. In this study, we conducted detailed petrography, TIMA mapping, μ-XRF analyses, mass balance calculations and thermodynamic modeling on the hematitized and illitized porphyritic lava from the Zoujiashan deposit in the Xiangshan ore field. During hematitization, hematite and albite are produced, while quartz, K-feldspar, chlorite, sericite and biotite are consumed, consistent with the increase in Na₂O, Al₂O₃, Fe₂O₃-T, U, As, Pb, Cu, Sc, V, Zr, Y, Hf and Th and the loss of K₂O, MgO, Li, Zn, Ni and Ba. The production of hydrothermal hematite, illite and sericite indicates that the ore fluids are acidic and oxidized. Such physiochemical conditions are favorable for uranium transport as UO₂Cl₂(aq), UO₂SO₄(aq) and UO₂OH⁺. Geological processes such as fluid–rock interactions, fluid mixing and fluid boiling could cause fO₂(g) decrease, pH increase and temperature decrease and therefore result in the decrease in uranium solubility and mineralization. Full article

In this investigation, the parent clay mineral montmorillonite (Mnt) was acid activated using sulfuric acid (H₂SO₄) at a specific mass of acid to clay mineral of 0.2 (A-Mnt) prior to the preparation of the porous clay heterostructure precursor. The derived porous acid-activated clay heterostructure (PACH) exhibited properties different from those of the conventional one (PCH). The synthesized materials were characterized using different physiochemical techniques, such as X-ray fluorescence (XRF), powder X-ray diffraction (XRD), thermogravimetric analysis (TA), ²⁹Si MAS-NMR, nitrogen adsorption–desorption, and acidity using cyclohexylamine (CHA) as a probe molecule. The PACH had a surface area of 890 m²/g and an acidity of 0.56 mmol of protons/g. An evaluation of PCH materials was conducted to assess their effectiveness in removing basic blue 41 (BB-41) from aqueous solutions. The removal process was analyzed based on the initial concentration and pH of the BB-41 solution, and the amount of solid used, employing a batch approach. The removal efficiency was found to be greater at higher pH values, specifically between six and nine. Using the Langmuir model, the maximal removal capabilities of the studied materials were determined to be between 274 and 300 mg/g. According to the results of the regeneration tests, PACH materials could still be employed after seven cycles with a 25% efficiency loss and a 50% efficiency loss for PCH materials. Utilizing the Langmuir model equations and mass balance, a single-stage batch design was suggested to estimate the required masses to remove BB-41 at different percentages from a starting concentration of 200 mg/L. Full article

Background: Morphine is a commonly prescribed opioid analgesic used to treat chronic pain. Morphine undergoes glucuronidation by UDP-glucuronosyltransferase (UGT) 2B7 to form morphine-3-glucuronide and morphine-6-glucuronide. Morphine is the gold standard for chronic pain management and has a narrow therapeutic index. Reports have shown that chronic pain patients have increasingly used other supplements to treat their chronic pain, including cannabidiol (CBD). Up to 50% of chronic pain patients report that they co-use cannabis with their prescribed opioid for pain management, including morphine. Previous work has shown that cannabidiol is a potent inhibitor of UGT2B7, including morphine-mediated metabolism. Co-use of morphine and CBD may result in unwanted drug–drug interactions (DDIs). Methods: Using available physiochemical and clinical parameters, morphine and CBD physiologically based pharmacokinetic (PBPK) models were developed and validated in both healthy and cirrhotic populations. Models for the two populations were then combined to predict the severity and clinical relevance of the potential DDIs during coadministration of both morphine and CBD in both healthy and hepatic-impaired virtual populations. Results: The predictive DDI model suggests that a ~5% increase in morphine exposure is to be expected in healthy populations. A similar increase in exposure of morphine is predicted in severe hepatic-impaired populations with an increase of ~10. Conclusions: While these predicted increases in morphine exposure are below the Food and Drug Administration’s cutoff (1.25-fold increase), morphine has a narrow therapeutic index and a 5–10% increase in exposure may be clinically relevant. Future clinical studies are needed to fully characterize the clinical relevance of morphine-related DDIs. Full article