Identification of immune- and oxidative stress-related signature genes as potential targets for mRNA vaccines for pancreatic cancer patients.

Adenocarcinoma of the pancreas (PAAD) is one of the deadliest malignant tumors, and messenger ribonucleic acid vaccines, which constitute the latest generation of vaccine technology, are expected to lead to new ideas for the treatment of pancreatic cancer. The Cancer Genome Atlas-PAAD and Genotype-Tissue Expression data were merged and analyzed. Weighted gene coexpression network analysis was used to identify gene modules associated with tumor mutational burden among the genes related to both immunity and oxidative stress. Differentially expressed immune-related oxidative stress genes were screened via univariate Cox regression analysis, and these genes were analyzed via nonnegative matrix factorization. After immune infiltration analysis, least absolute shrinkage and selection operator regression combined with Cox regression was used to construct the model, and the usefulness of the model was predicted based on the receiver operating characteristic curve and decision curve analysis curves after model construction. Finally, metabolic pathway enrichment was analyzed using gene set enrichment analysis combined with Kyoto Encyclopedia of Genes and Genomes and gene ontology biological process analyses. This model consisting of the ERAP2, mesenchymal-epithelial transition factor (MET), CXCL9, and angiotensinogen (AGT) genes can be used to help predict the prognosis of pancreatic cancer patients more accurately than existing models. ERAP2 is involved in immune activation and is important in cancer immune evasion. MET binds to hepatocyte growth factor, leading to the dimerization and phosphorylation of c-MET. This activates various signaling pathways, including MAPK and PI3K, to regulate the proliferation, invasion, and migration of cancer cells. CXCL9 overexpression is associated with a poor patient prognosis and reduces the number of CD8 + cytotoxic T lymphocytes in the PAAD tumor microenvironment. AGT is cleaved by the renin enzyme to produce angiotensin 1, and AGT-converting enzyme cleaves angiotensin 1 to produce angiotensin 2. Exposure to AGT-converting enzyme inhibitors after pancreatic cancer diagnosis is associated with improved survival. The 4 genes identified in the present study - ERAP2, MET, CXCL9, and AGT - are expected to serve as targets for messenger ribonucleic acid vaccine development and need to be further investigated in depth.

The impact of nimodipine combined with Ginkgo biloba extract on cognitive function and ADL scores in patients with Parkinson's disease: A retrospective study.

This study aims to explore the value of nimodipine combined with Ginkgo biloba extract in improving cognitive function and daily living abilities in patients with Parkinson's disease. Clinical data from 551 patients with Parkinson's disease admitted to the Neurology Department of the Affiliated Hospital of Beihua University from January 2022 to December 2022 were retrospectively collected. Cognitive function and daily living abilities were assessed in patients before treatment, and a reevaluation was conducted after 12 weeks of medication. Patients treated solely with nimodipine were categorized into the monotherapy group, while patients treated with nimodipine combined with Ginkgo biloba extract were included in the combination group. After 1:1 propensity score matching, a total of 83 pairs of patients were matched, and differences in relevant indicators between the 2 groups were compared. The total effective rate of treatment in the combination group was 90.36%, which was higher than the control group at 72.29% (P < .05). However, after treatment, the observation group showed higher Mini-Mental State Examination and activities of daily living scores compared to the control group (P < .05). The combined treatment of nimodipine and Ginkgo biloba extract in patients with Parkinson's disease has a significant effect and can effectively improve cognitive function and enhance daily living abilities.

Evaluating the Impact of an Organic Trace Mineral mix on the Redox Homeostasis, Immunity, and Performance of Sows and their Offspring.

The objective of the study was to evaluate the effects of trace mineral supplementation in sows during gestation and lactation on the performance and health status of sows and their offspring. Sows (n = 30; Landrace × Yorkshire; avg parity = 3.9) were randomly allocated into two dietary treatments. Sows received a basal diet supplemented with 12 mg/kg Cu, 30 mg/kg Fe, 90 mg/kg Zn, 70 mg/kg Mn, 0.30 mg/kg Se, and 1.5 mg/kg I from an inorganic trace mineral source (ITM) or a blend of hydroxychloride and organic trace mineral source (HOTM) from day 1 of gestation until the end of the lactation period at day 21. Compared to the ITM, the HOTM supplementation increased (P < 0.05) both litter birth weight and individual piglet birth weight. Although not statistically significant, HOTM tended to increase (P = 0.069) the level of lactose in colostrum. HOTM increased (P < 0.05) the concentration of Mn and Se in the colostrum, milk, and serum of sows and/or piglets. Notably, the Zn concentration in the serum of sows was higher in sows supplemented with ITM compared to HOTM. Moreover, HOTM increased (P < 0.05) the activities of GPX and SOD in gestating sows and piglets, as well as increased (P < 0.05) cytokines (IL-1ß, TNF-α, and IL-10) in the serum of sows. The immunoglobulins (IgA, IgG, and IgM) also increased in sows and/or piglets at certain experimental time points. In conclusion, HOTM supplementation positively affected piglet development and improved the health status of sows and piglets potentially by regulating redox homeostasis and immunity.

Mapping and analyzing the spatiotemporal dynamics of forest aboveground biomass in the ChangZhuTan urban agglomeration using a time series of Landsat images and meteorological data from 2010 to 2020.

In the context of global warming, there is a substantial demand for accurate and cost-effective assessment and comprehensive understanding of forest above-ground biomass (AGB) dynamics. The timeliness and low cost of optical remote sensing data enable the mapping of large-scale forest AGB dynamics. However, mapping forest AGB with optical remote sensing data presents challenges primarily due to data uncertainty and the complex nature of the forest environment. Previous studies have demonstrated the potential of meteorological data in enhancing forest AGB mapping. To accurately capture the dynamics of forest AGB, we initially acquired Landsat datasets, digital elevation model (DEM), and meteorological datasets (temperature, humidity, and precipitation) from 2010 to 2020 in Changsha-Zhuzhou-Xiangtan urban agglomeration (CZT) located in Hunan Province, China. Spectral variables (SVs), including spectral bands and vegetation indices, were extracted from Landsat images, while meteorological variables (MVs) were derived from the monthly meteorological data using the Savitzky-Golay (S-G) filtering algorithm. Additionally, terrain variables (TVs) were also extracted from the DEM data. Three modelling models, multiple linear regression (MLR), K nearest neighbor (KNN) and random forest (RF), were developed for mapping the dynamics of forest AGB in CZT. The result revealed that MVs have the potential to improve forest AGB mapping. Integration of MVs into the models resulted in a significant reduction in root mean square error (RMSE) ranging from 32.85 % to 19.25 % compared to utilizing only SVs. However, minimal improvement was observed with the inclusion of TVs due to negligible topographic relief within the study area. An upward trend of forest AGB in CZT was observed during this period, which can be attributed to the effective implementation of government environmental protection policies. It is confirmed that the meteorological data has significant contribution to forest AGB mapping, thereby endorsing advancements in forest resource monitoring and management programs.

Correction: Deng et al. Therapeutic Potential of a Combination of Electroacupuncture and Human iPSC-Derived Small Extracellular Vesicles for Ischemic Stroke. Cells 2022, 11, 820.

The authors wish to make the following changes to their paper [...].

[Application of LA-UNet network model in remote sensing classification of urban green space]. / LA-UNet网络模型在城市绿地遥感分类中的应用.

The accurate identification and monitoring of urban green space is of great significance in urban planning and ecological management. In view of the complex background of urban green space, the traditional remote sensing classification technology is prone to the problem of misalignment and adhesion. Taking Yuhua District of Changsha City as the research area and Gaofen-2 (GF-2) remote sensing image as the data source, we proposed a remote sensing classification method for urban green space based on the LA-UNet model, which was based on the UNet model. We introduced the DWTCA channel attention mechanism module to improve the attention of the network to green space information, and used the CARAFE module to up sample the extracted features to achieve accurate classification of trees, shrubs and other land types in the complex background of the city. The results showed that the LA-UNet model had the best classification effect of urban green space when using standard false color remote sensing images. The overall accuracy and mean intersection over union were 96.3% and 90.9%, which were 2.8% and 6.1% higher than the UNet model, respectively. In the Potsdam public dataset, the overall accuracy and mean intersection over union of the LA-UNet model were also better than those of the UNet model, which increased by 0.9% and 1.8%, respectively, indicating that the LA-UNet model had good robustness and versatility. In summary, the proposed LA-UNet model could effectively alleviate the problems of misalignment and adhesion of urban green space, with advantages in the remote sensing classification of urban green space. The improved LA-UNet model had a smaller parameter volume than the UNet model, which could effectively improve the classification accuracy of urban green space. This study would provide a methodological reference for the accurate classification and understanding the spatial distribution of urban green space.

Achieving High-Performance Na3V2(PO4)2F3 Cathode Material through a Bifunctional N-Doped Carbon Network.

Na3V2(PO4)2F3 (NVPF) is emerging as a popular cathode for sodium-ion batteries owing to its stable structure, high operating voltage, and large energy density. However, its practical application is hindered by its low conductivity. In addition, due to the loss of fluorine during synthesis, Na3V2(PO4)3 (NVP) impurity is often easily generated, resulting in a decrease in actual operating voltage. Herein, a bifunctional carbon network composed of an N-doped carbon layer and carbon bridge is constructed around NVPF particles. Through pyrolysis of polydopamine (PDA), the NVPF particles are covered in situ by an N-doped carbon layer, and the carbon bridge generated by polytetrafluoroethylene (PTFE) is also coated with N-doped carbon. Besides, PTFE also serves as a fluorine supplement to ensure that pure NVPF is obtained. As a result, the bifunctional N-doped carbon network-modified NVPF delivers a high reversible capacity (125.7 mA h g-1 at 0.2 C) and appreciable cycle stability (92.7% at 1 C over 300 cycles, and 89.8% at 10 C over 1500 cycles). When assembled into a full cell with a commercial hard carbon anode, it displays a discharge median voltage of up to 3.62 V at 0.2 C. Furthermore, it achieves a high energy density of 373.7 W h kg-1 at a power density of 461.2 W kg-1, with an excellent specific energy retention of 78.2% after 200 cycles. Therefore, this modification method is expected to be extended to other fluorine-containing materials with poor electrical conductivity.

Atramacrolodes A-D (1-4), Four Undescribed Eudesmane-type Sesquiterpenes from the Rhizome of Atractylodes macrocephala.

Four undescribed sesquiterpenes, atramacrolodes A-D (1-4), along with six known compounds 5-10 were isolated from the rhizome of Atractylodes macrocephala. Compound 3 possessed a new skeleton based on an unprecedented carton-carton connection. Their structures were determined by UV, IR, HRESIMS, NMR spectra, 13C NMR calculation with DP4+ analysis, and the comparison of experimental and calculated ECD spectra. Compounds 5 and 8 showed protective effects against paracetamol-induced liver cell injury.

Affect under need satisfaction and need thwarting: A new classification for the prediction of creative performance.

Affect plays a pivotal role in fostering creative performance, and there is increasing recognition that different levels and types of affect may exert distinct impacts on creative performance. Drawing upon self-determination theory, this study aims to explore a novel classification of affect-affect under need satisfaction and need thwarting-and examine its relationship with creative performance. Study 1 involved 75 participants to investigate the content of affect under need satisfaction and need thwarting. Study 2 explores the relationship between affect and creative performance using a sample of 115 employees from Beijing. The findings unveiled nine types of affect under need satisfaction (e.g., moderate levels of excited) and eleven types of affect under need thwarting (e.g., low levels of afraid). Positive associations were observed between affect under need satisfaction and creativity, while negative associations were found between affect under need thwarting and creativity. Empirical evidence corroborating the significant role of the new classification of affect in enhancing employee creativity within the context of Chinese academia and researchers is presented.

Preparation of near-infrared photoacoustic imaging and photothermal treatment agent for cancer using a modifiable acid-triggered molecular platform.

Ratiometric near-infrared fluorescent pH probes with various pKa values were innovatively designed and synthesized based on cyanine with a diamine moiety. The photochemical properties of these probes were thoroughly evaluated. Among the series, IR-PHA exhibited an optimal pKa value of approximately 6.40, closely matching the pH of cancerous tissues. This feature is particularly valuable for real-time pH monitoring in both living cells and living mice. Moreover, when administered intravenously to tumor-bearing mice, IR-PHA demonstrated rapid and significant enhancement of near-infrared fluorescence and photoacoustic signals within the tumor region. This outcome underscores the probe's exceptional capability for dual-modal cancer imaging utilizing near-infrared fluorescence (NIRF) and photoacoustic (PA) modalities. Concurrently, the application of a continuous-wave near-infrared laser efficiently ablated cancer cells in vivo, attributed to the photothermal effect induced by IR-PHA. The results strongly indicate that IR-PHA is well-suited for NIRF/PA dual-modality imaging and photothermal therapy of tumors. This makes it a promising candidate for theranostic applications involving small molecules.

Immunogenicity and safety of a recombinant Omicron BA.4/5-Delta COVID-19 vaccine ZF2202-A in Chinese adults.

BACKGROUND: The Recombinant Omicron BA.4/5-Delta COVID-19 Vaccine (ZF2202-A) is primarily designed for the Delta and Omicron BA.4/5 variants. Our objective was to assess the safety and immunogenicity of ZF2202-A in Chinese adults. METHODS: A total of 450 participants aged ≥ 18 years, who had completed primary or booster vaccination with a COVID-19 vaccine more than 6 months prior, were enrolled in this randomized, double-blind, active-controlled trial. Participants in the study and control groups were administered one dose of ZF2202-A and ZF2001, respectively. Immunogenicity subgroups were established in each group. RESULTS: At 14 days after vaccination, the seroconversion rates of Omicron BA.4/5, BF.7, and XBB.1 in the ZF2022-A group were 67.7 %, 58.6 %, and 62.6 %, with geometric mean titers (GMTs) of neutralizing antibodies at 350.2, 491.8, and 49.5, respectively. The main adverse reactions (ARs) were vaccination site pain, pruritus, fatigue, and asthenia in both the ZF2022-A group and ZF2001 group. CONCLUSIONS: The novel bivalent vaccine ZF2202-A demonstrated satisfactory immunogenicity and safety against Omicron variants as booster dose in adults with prior vaccination of COVID-19 vaccines.

YTHDC1 cooperates with the THO complex to prevent RNA damage-induced DNA breaks.

Certain environmental toxins are nucleic acid damaging agents, as are many chemotherapeutics used for cancer therapy. These agents induce various adducts in DNA as well as RNA. Indeed, most of the nucleic acid adducts (>90%) formed due to these chemicals, such as alkylating agents, occur in RNA 1 . However, compared to the well-studied mechanisms for DNA alkylation repair, the biological consequences of RNA damage are largely unexplored. Here, we demonstrate that RNA damage can directly result in loss of genome integrity. Specifically, we show that a human YTH domain-containing protein, YTHDC1, regulates alkylation damage responses in association with the THO complex (THOC) 2 . In addition to its established binding to N 6-methyladenosine (m6A)-containing RNAs, YTHDC1 binds to N 1-methyladenosine (m1A)-containing RNAs upon alkylation. In the absence of YTHDC1, alkylation damage results in increased alkylation damage sensitivity and DNA breaks. Such phenotypes are fully attributable to RNA damage, since an RNA-specific dealkylase can rescue these phenotypes. These R NA d amage-induced DNA b reaks (RDIBs) depend on R-loop formation, which in turn are processed by factors involved in transcription-coupled nucleotide excision repair. Strikingly, in the absence of YTHDC1 or THOC, an RNA m1A methyltransferase targeted to the nucleus is sufficient to induce DNA breaks. Our results uncover a unique role for YTHDC1-THOC in base damage responses by preventing RDIBs, providing definitive evidence for how damaged RNAs can impact genomic integrity.

GNAI3 mediated by Lin28A regulates lipopolysaccharide-induced inflammation and osteogenic differentiation in periodontal stem cells by mediating the NF-κB/NLRP3 inflammasome pathway.

OBJECTIVES: The aim of this study was to investigate the regulatory role of G protein subunit alpha i3 (GNAI3) in periodontitis. DESIGN: Following the induction of human periodontal ligament stem cells (hPDLSCs) with lipopolysaccharide (LPS), the mRNA and protein expressions of GNAI3 and Lin28A were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. The transfection efficiency of Oe-GNAI3 and sh-Lin28A was examined by virtue of RT-qPCR and western blot. With the application of ELISA and flow cytometry, the releases of inflammatory cytokines and cell apoptosis were appraised. Alkaline phosphatase (ALP) staining and alizarin red S (ARS) staining were conducted to evaluate osteogenic differentiation. Next, the binding ability of Lin28A with GNAI3 mRNA was estimated by radioimmunoprecipitation (RIP) assay while the stability of GNAI3 mRNA was assessed utilizing RT-qPCR. Western blot was employed for the measurement of inflammation-, apoptosis- and nuclear factor-kappaB (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway-related proteins and osteogenic markers. RESULTS: The expression of GNAI3 was down-regulated in LPS-induced hPDLSCs. After the transfection with Oe-GNAI3, the inflammation and apoptosis in LPS-induced hPDLSCs were inhibited while osteogenic differentiation was promoted. Moreover, Lin28A could stabilize GNAI3 mRNA and Lin28A knockdown significantly reduced GNAI3 expression. Further experiments verified that the inhibitory effects of GNAI3 overexpression on LPS-induced cellular inflammation and cell apoptosis as well as the promotive effects on osteogenic differentiation in hPDLSCs were all partially counteracted by Lin28A depletion, which may possibly be mediated via the regulation of the NF-κB/NLRP3 inflammasome pathway. CONCLUSION: GNAI3 that mediated by Lin28A regulates the inflammation and osteogenic differentiation in LPS-induced hPDLSCs by mediating the NF-κB/NLRP3 inflammasome pathway.

Effect and mechanism of gomisin D on the isoproterenol induced myocardial injury in H9C2 cells and mice.

We established myocardial injury models in vivo and in vitro to investigate the cardioprotective effect of gomisin D obtained from Schisandra chinensis. Gomisin D significantly inhibited isoproterenol-induced apoptosis and hypertrophy in H9C2 cells. Gomisin D decreased serum BNP, ANP, CK-MB, cTn-T levels and histopathological alterations, and inhibited myocardial hypertrophy in mice. In mechanisms research, gomisin D reversed ISO-induced accumulation of intracellular ROS and Ca2+. Gomisin D further improved mitochondrial energy metabolism disorders by regulating the TCA cycle. These results demonstrated that gomisin D had a significant effect on isoproterenol-induced myocardial injury by inhibiting oxidative stress, calcium overload and improving mitochondrial energy metabolism.

Hollow Layered Iron-Based Prussian Blue Cathode with Reduced Defects for High-Performance Sodium-Ion Batteries.

Fe-based Prussian blue (Fe-PB) analogues have emerged as promising cathode materials for sodium-ion batteries, owing to their cost-effectiveness, high theoretical capacity, and environmental friendliness. However, their practical application is hindered by [Fe(CN)6] defects, negatively impacting capacity and cycle stability. This work reports a hollow layered Fe-PB composite material using 1,3,5-benzenetricarboxylic acid (BTA) as a chelating and etching agent by the hydrothermal method. Compared to benzoic acid, our approach significantly reduces defects and enhances the yield of Fe-PB. Notably, the hollow layered structure shortens the diffusion path of sodium ions, enhances the activity of low-spin Fe in the Fe-PB lattice, and mitigates volume changes during Na-ion insertion/extraction into/from Fe-PB. As a sodium-ion battery cathode, this hollow layered Fe-PB exhibits an impressive initial capacity of 95.9 mAh g-1 at a high current density of 1 A g-1. Even after 500 cycles, it still maintains a considerable discharge capacity of 73.1 mAh g-1, showing a significantly lower capacity decay rate (0.048%) compared to the control sample (0.089%). Moreover, the full cell with BTA-PB-1.6 as the cathode and HC as the anode provides a considerable energy density of 312.2 Wh kg-1 at a power density of 291.0 W kg-1. This research not only enhances the Na storage performance of Fe-PB but also increases the yield of products obtained by hydrothermal methods, providing some technical reference for the production of PB materials using the low-yield hydrothermal method.

Achieving High Rate and Long Cycle Performance of Na2FePO4F Cathode Through Co-Modification of Ti Doping and Carbon Coating.

Layered Na2FePO4F (NFPF) cathode material has received widespread attention due to its green nontoxicity, abundant raw materials, and low cost. However, its poor inherent electronic conductivity and sluggish sodium ion transportation seriously impede its capacity delivery and cycling stability. In this work, NFPF by Ti doping and conformal carbon layer coating via solid-state reaction is modified. The results of experimental study and density functional theory calculations reveal that Ti doping enhances intrinsic conductivity, accelerates Na-ion transport, and generates more Na-ion storage sites, and pyrolytic carbon from polyvinylpyrrolidone (PVP) uniformly coated on the NFPF surface improves the surface/interface conductivity and suppresses the side reactions. Under the combined effect of Ti doping and carbon coating, the optimized NFPF (marked as 5T-NF@C) exhibits excellent electrochemical performance, with a high capacity of 108.4 mAh g-1 at 0.2C, a considerable capacity of 80.0 mAh g-1 even at high current density of 10C, and a high capacity retention rate of 81.8% after 2000 cycles at 10C. When assembled into a full cell with a hard carbon anode, 5T-NF@C also show good applicability. This work indicates that co-modification of Ti doping and carbon coating makes NFPF achieve high rate and long cycle performance for sodium-ion batteries.

Bibliometric and visualized analysis of hydrogels in organoids research.

Over the past decades, there has been ongoing effort to develop complex biomimetic tissue engineering strategies for in vitro cultivation and maintenance of organoids. The defined hydrogels can create organoid models for various organs by changing their properties and various active molecules. An increasing number of researches has been done on the application of hydrogels in organoids, and a large number of articles have been published on the topic. Although there have been existing reviews describing the application of hydrogels in the field of organoids, there is still a lack of comprehensive studies summarizing and analyzing the overall research trends in this field. The citation can be used as an indicator of the scientific influence of an article in its field. This study aims to evaluate the application of hydrogels in organoids through bibliometric analysis, and to predict the hotspots and developing trends in this field.

Establishment and verification of a method for analyzing nasal blackheads images.

BACKGROUND: As people pay more attention to their skin health and the demand of developing skin care products for facial blackheads grows, the value of objective and efficient image recognition methods for blackheads is becoming more evident. Inspired by this current situation, this study attempted to analyze the number of blackheads of different severity automatically on the nose using an object recognition method on photographs of the nasal blackheads of subjects. METHOD: This study collected 350 subjects' facial photos in the laboratory environment, who aged 18-60, with blackhead symptoms in the nasal region. And expert assessment was used as a reference for machine learning to verify the performance of the nasal blackhead image recognition model through consistency and correlation analysis. RESULTS: The study concluded that the algorithm accuracy reached above 0.9, the model itself was effective, and the consistency between the model and the expert assessor assessment results was good, with the number of nasal blackheads, the count of blackheads of different severity, and the intra-group correlation coefficient ICC of blackhead severity all above 0.9, indicating that the deep learning-based assessment model had high overall performance and the evaluation results were comparable to those of the expert assessor. CONCLUSION: The recognition and analyzing model of nasal blackhead images provides a scientifically objective and accurate method for identifying the number and evaluating the severity of nasal blackheads. By using this model, the efficiency of evaluating nasal blackhead images in the cosmetics clinical trial will be improved. The assessment result of nasal blackheads will be objective and stable, and not only rely on the professional knowledge and clinical experience of assessors. The model can try to be applied in cosmetics efficacy testing and continuously optimized.

A physiologically-based pharmacokinetic/pharmacodynamic modeling approach for drug-drug-gene interaction evaluation of S-warfarin with fluconazole.

Warfarin is a widely used anticoagulant, and its S-enantiomer has higher potency compared to the R-enantiomer. S-warfarin is mainly metabolized by cytochrome P450 (CYP) 2C9, and its pharmacological target is vitamin K epoxide reductase complex subunit 1 (VKORC1). Both CYP2C9 and VKORC1 have genetic polymorphisms, leading to large variations in the pharmacokinetics (PKs) and pharmacodynamics (PDs) of warfarin in the population. This makes dosage management of warfarin difficult, especially in the case of drug-drug interactions (DDIs). This study provides a whole-body physiologically-based pharmacokinetic/PD (PBPK/PD) model of S-warfarin for predicting the effects of drug-drug-gene interactions on S-warfarin PKs and PDs. The PBPK/PD model of S-warfarin was developed in PK-Sim and MoBi. Drug-dependent parameters were obtained from the literature or optimized. Of the 34 S-warfarin plasma concentration-time profiles used, 96% predicted plasma concentrations within twofold range compared to observed data. For S-warfarin plasma concentration-time profiles with CYP2C9 genotype, 364 of 386 predicted plasma concentration values (~94%) fell within the twofold of the observed values. This model was tested in DDI predictions with fluconazole as CYP2C9 perpetrators, with all predicted DDI area under the plasma concentration-time curve to the last measurable timepoint (AUClast) ratio within twofold of the observed values. The anticoagulant effect of S-warfarin was described using an indirect response model, with all predicted international normalized ratio (INR) within twofold of the observed values. This model also incorporates a dose-adjustment method that can be used for dose adjustment and predict INR when warfarin is used in combination with CYP2C9 perpetrators.