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  • Frontiers Media SA  (17)
  • 1
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    Tacrolimus pharmacokinetics in pediatric nephrotic syndrome: A combination of population pharmacokinetic modelling and machine learning approaches to improve individual prediction
    Frontiers Media SA ; 2022
    In:  Frontiers in Pharmacology Vol. 13 ( 2022-11-15)
    Details
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 13 ( 2022-11-15)
    Abstract: Background and Aim: Tacrolimus (TAC) is a first-line immunosuppressant for the treatment of refractory nephrotic syndrome (RNS), but the pharmacokinetics of TAC varies widely among individuals, and there is still no accurate model to predict the pharmacokinetics of TAC in RNS. Therefore, this study aimed to combine population pharmacokinetic (PPK) model and machine learning algorithms to develop a simple and accurate prediction model for TAC. Methods: 139 children with RNS from August 2013 to December 2018 were included, and blood samples of TAC trough and partial peak concentrations were collected. The blood concentration of TAC was determined by enzyme immunoassay; CYP3A5 was genotyped by polymerase chain reaction-restriction fragment length polymorphism method; MYH9 , LAMB2 , ACTN4 and other genotypes were determined by MALDI-TOF MS method; PPK model was established by nonlinear mixed-effects method. Based on this, six machine learning algorithms, including eXtreme Gradient Boosting (XGBoost), Random Forest (RF), Extra-Trees, Gradient Boosting Decision Tree (GBDT), Adaptive boosting (AdaBoost) and Lasso, were used to establish the machine learning model of TAC clearance. Results: A one-compartment model of first-order absorption and elimination adequately described the pharmacokinetics of TAC. Age, co-administration of Wuzhi capsules, CYP3A5 *3/*3 genotype and CTLA4 rs4553808 genotype were significantly affecting the clearance of TAC. Among the six machine learning models, the Lasso algorithm model performed the best (R 2 = 0.42). Conclusion: For the first time, a clearance prediction model of TAC in pediatric patients with RNS was established using PPK combined with machine learning, by which the individual clearance of TAC can be predicted more accurately, and the initial dose of administration can be optimized to achieve the goal of individualized treatment.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    DOI: 10.3389/fphar.2022.942129
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2587355-6
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  • 2
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    Data_Sheet_1.PDF
    Frontiers Media SA ; 2022
    In:  Frontiers in Veterinary Science Vol. 9 ( 2022-8-25)
    Details
    In: Frontiers in Veterinary Science, Frontiers Media SA, Vol. 9 ( 2022-8-25)
    Abstract: Excessive fat deposition in the tail of sheep will affect its feed efficiency, which will increase the feeding cost. The purpose of this study was to identify the single nucleotide polymorphisms (SNPs) of RAP1GAP and rBAT genes by PCR amplification and Sanger sequencing, the SNPs were genotyped by KASP genotyping assays to evaluate their association with tail fat deposition traits. The results showed that two intronic mutations of g.13561 G & gt; A and g.1460 T & gt; C were found in RAP1GAP and rBAT , respectively. There were three genotypes of GG, AG, AA and CC, CT and TT at these two loci, respectively. Association analysis showed that g.13561 G & gt; A of RAP1GAP was associated with tail width, tail fat weight and relative tail fat weight ( P & lt; 0.05). The g.1460 T & gt; C of rBAT was associated with tail width and tail fat weight ( P & lt; 0.05). Different combinations of genotypes also differed significantly with tail fat deposition traits. In the tail fat tissue, the expression levels of RAP1GAP gene was significantly higher in small-tailed sheep than in big-tailed sheep, and the expression levels of rBAT gene was significantly higher in big-tailed sheep than in small-tailed sheep. In the liver, the expression levels of RAP1GAP and rBAT gene was significantly higher at 6 months than at 0 and 3 months. In conclusion, RAP1GAP and rBAT polymorphisms can be used as a candidate molecular marker to reduce tail fat deposition in sheep.
    Type of Medium: Online Resource
    ISSN: 2297-1769
    URL: Article
    URL: Article
    DOI: 10.3389/fvets.2022.974513
    DOI: 10.3389/fvets.2022.974513.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2834243-4
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  • 3
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    Table_1.xls
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-11-9)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-11-9)
    Abstract: Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) are critical for immune suppression by restricting immune cell infiltration in the tumor stromal zones from penetrating tumor islands and changing their function status, particularly for CD8 + T cells. However, assessing and quantifying the impact of CAFs on immune cells and investigating how this impact is related to clinical outcomes, especially the efficacy of immunotherapy, remain unclear. Materials and methods The TME was characterized using immunohistochemical (IHC) analysis using a large-scale sample size of gene expression profiles. The CD8 + T cell/CAF ratio (CFR) association with survival was investigated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) lung cancer cohorts. The correlation between CFR and immunotherapeutic efficacy was computed in five independent cohorts. The correlation between CFR and objective response rates (ORRs) following pembrolizumab monotherapy was investigated in 20 solid tumor types. To facilitate clinical translation, the IHC-detected CD8/α-SMA ratio was applied as an immunotherapeutic predictive biomarker in a real-world lung cancer cohort. Results Compared with normal tissue, CAFs were enriched in cancer tissue, and the amount of CAFs was overwhelmingly higher than that in other immune cells. CAFs are positively correlated with the extent of immune infiltration. A higher CFR was strongly associated with improved survival in lung cancer, melanoma, and urothelial cancer immunotherapy cohorts. Within most cohorts, there was no clear evidence for an association between CFR and programmed death-ligand 1 (PD-L1) or tumor mutational burden (TMB). Compared with TMB and PD-L1, a higher correlation coefficient was observed between CFR and the ORR following pembrolizumab monotherapy in 20 solid tumor types (Spearman’s r = 0.69 vs. 0.44 and 0.21). In a real-world cohort, patients with a high CFR detected by IHC benefited considerably from immunotherapy as compared with those with a low CFR (hazard ratio, 0.37; 95% confidence interval, 0.19–0.75; p & lt; 0.001). Conclusions CFR is a newly found and simple parameter that can be used for identifying patients unlikely to benefit from immunotherapy. Future studies are needed to confirm this finding.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2022.974265
    DOI: 10.3389/fimmu.2022.974265.s001
    DOI: 10.3389/fimmu.2022.974265.s002
    DOI: 10.3389/fimmu.2022.974265.s003
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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  • 4
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    Data_Sheet_4.XLSX
    Frontiers Media SA ; 2022
    In:  Frontiers in Microbiology Vol. 13 ( 2022-11-23)
    Details
    In: Frontiers in Microbiology, Frontiers Media SA, Vol. 13 ( 2022-11-23)
    Abstract: Klebsiella pneumoniae is a primary culprit of antibiotic-resistant nosocomial infections worldwide, and infections caused by NDM-producing strains are a major threat due to limited therapeutic options. The majority of bla NDM cases occur on plasmids; therefore, we explored the relationships between plasmids and bla NDM genes in K. pneumoniae by analyzing the variants of bla NDM , replicon types, conjugative transfer regions of 171 bla NDM -harboring plasmids from 4,451 K. pneumoniae plasmids. Of the nine identified bla NDM variants, bla NDM-1 (73.68%) and bla NDM-5 (16.37%) were the most dominant. Over half of the bla NDM -harboring plasmids of K. pneumoniae were classified into IncF plasmids. IncX3 single-replicon plasmids (46–57 kb) carried genes encoding relaxases of the MOB P family, T4CP genes of the VirD4/TraG subfamily, and VirB-like T4SS gene clusters, which were mainly geographically distributed in China. We found 10 bla NDM -harboring IncN plasmids (38.38–63.05 kb) carrying the NW-type origin of transfer ( oriT ) regions, genes coding for relaxases of MOB F family, genes encoding T4CPs of the TrwB/TraD subfamily, and Trw-like T4SS gene clusters, which were also mainly geographically distributed in China. Moreover, we identified 21 IncC plasmids carrying bla NDM-1 (140.1–329.2 kb), containing the A/C-type oriT s, genes encoding relaxases of MOB H family, genes encoding T4CPs belonging to TrwB/TraD subfamily, and Tra_F-like T4SS gene clusters. The bla NDM -harboring IncC plasmids were widely geographically distributed all over the world, mainly in the United States, China and Viet Nam. These findings enhance our understanding of the diversity of bla NDM -harboring plasmids in K. pneumoniae .
    Type of Medium: Online Resource
    ISSN: 1664-302X
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fmicb.2022.1008905
    DOI: 10.3389/fmicb.2022.1008905.s001
    DOI: 10.3389/fmicb.2022.1008905.s002
    DOI: 10.3389/fmicb.2022.1008905.s003
    DOI: 10.3389/fmicb.2022.1008905.s004
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2587354-4
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  • 5
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    Data_Sheet_1.PDF
    Frontiers Media SA ; 2022
    In:  Frontiers in Microbiology Vol. 13 ( 2022-9-21)
    Details
    In: Frontiers in Microbiology, Frontiers Media SA, Vol. 13 ( 2022-9-21)
    Abstract: The marbling fat regulates the flavor of mutton and measures the fat density in the loin eye and is the most important parameter of carcass grading. The objective of this study was to explore the relationship of rumen microbiota and mutton marbling grade. One hundred and eighty-seven feedlot-finished Hu male lambs (Age: 180 day; Final BW: 46.32 ± 6.03 kg) were slaughtered, and ruminal contents and marbling grade were collected. Ruminal microbial DNA extraction and 16S rRNA gene sequencing was performed to investigate microbial composition and to predict microbial metabolic pathways. The animal cohort was then grouped based on marbling grades [low marbling (LM), marbling grade ≤ 1; Medium marbling (MM), 1 & lt; marbling grade ≤ 3; High Marbling (HM), 3 & lt; marbling grade ≤ 5] and intramuscular fat-associated microorganisms were pinpointed using LEfSe and random forest classification model. Intramuscular fat content had significantly differences among the three groups ( P & lt; 0.05), and was significantly correlated with VFAs profiling. HM sheep showed a higher abundance of one bacterial taxon ( Kandleria ), and two taxa were overrepresented in the MM sheep ( Pseudobutyrivibrio and Monoglobus ), respectively. In addition, the main intramuscular fat deposition pathway was found to involve peroxisome proliferator-activated receptor (PPAR) fatty acid synthesis. By studying the effect of the ruminal microbiome on the marbling of sheep, the present study provides insights into the production of high-quality mutton.
    Type of Medium: Online Resource
    ISSN: 1664-302X
    URL: Article
    URL: Article
    DOI: 10.3389/fmicb.2022.978263
    DOI: 10.3389/fmicb.2022.978263.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2587354-4
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  • 6
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    A Novel Bifunctional Fusion Protein, Vunakizumab-IL22, for Protection Against Pulmonary Immune Injury Caused by Influenza Virus
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-8-24)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-8-24)
    Abstract: Influenza A virus infection is usually associated with acute lung injury, which is typically characterized by tracheal mucosal barrier damage and an interleukin 17A (IL-17A)-mediated inflammatory response in lung tissues. Although targeting IL-17A has been proven to be beneficial for attenuating inflammation around lung cells, it still has a limited effect on pulmonary tissue recovery after influenza A virus infection. In this research, interleukin 22 (IL-22), a cytokine involved in the repair of the pulmonary mucosal barrier, was fused to the C-terminus of the anti-IL-17A antibody vunakizumab to endow the antibody with a tissue recovery function. The vunakizumab-IL22 (vmab-IL-22) fusion protein exhibits favorable stability and retains the biological activities of both the anti-IL-17A antibody and IL-22 in vitro . Mice infected with lethal H1N1 influenza A virus and treated with vmab-mIL22 showed attenuation of lung index scores and edema when compared to those of mice treated with saline or vmab or mIL22 alone. Our results also illustrate that vmab-mIL22 triggers the upregulation of MUC2 and ZO1, as well as the modulation of cytokines such as IL-1β, HMGB1 and IL-10, indicating the recovery of pulmonary goblet cells and the suppression of excessive inflammation in mice after influenza A virus infection. Moreover, transcriptome profiling analysis suggest the downregulation of fibrosis-related genes and signaling pathways, including genes related to focal adhesion, the inflammatory response pathway, the TGF-β signaling pathway and lung fibrosis upon vmab-mIL22 treatment, which indicates that the probable mechanism of vmab-mIL22 in ameliorating H1N1 influenza A-induced lung injury. Our results reveal that the bifunctional fusion protein vmab-mIL22 can trigger potent therapeutic effects in H1N1-infected mice by enhancing lung tissue recovery and inhibiting pulmonary inflammation, which highlights a potential approach for treating influenza A virus infection by targeting IL-17A and IL-22 simultaneously.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2021.727941
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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  • 7
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    Table_1.csv
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-9-14)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-9-14)
    Abstract: Dysregulation of immune cell infiltration in the tumor microenvironment contributes to the progression of osteosarcoma (OS). In the present study, we explored genes related to immune cell infiltration and constructed a risk model to predict the prognosis of and guide therapeutic strategies for OS. The gene expression profile of OS was obtained from TARGET and Gene Expression Omnibus, which were set as the discovery and verification cohorts. CIBERSORT and Kaplan survival analyses were used to analyze the effects of immune cells on the overall survival rates of OS in the discovery cohort. Differentially expressed gene (DEG) analysis and protein–protein interaction (PPI) networks were used to analyze genes associated with immune cell infiltration. Cox regression analysis was used to select key genes to construct a risk model that classified OS tissues into high- and low-risk groups. The prognostic value of the risk model for survival and metastasis was analyzed by Kaplan–Meier survival analyses, receiver operating characteristic curves, and immunohistochemical experiments. Immunological characteristics and response effects of immune checkpoint blockade (ICB) therapy in OS tissues were analyzed using the ESTIMATE and Tumor Immune Dysfunction and Exclusion algorithms, while sensitivity for both targeted and chemotherapy drugs was analyzed using the OncoPredict algorithm. It was demonstrated that the high infiltration of resting dendritic cells in OS tissues was associated with poor prognosis. A total of 225 DEGs were found between the high- and low-infiltration groups of OS tissues, while 94 genes interacted with others. Through COX analyses, among these 94 genes, four genes (including AOC3, CDK6, COL22A1, and RNASE6) were used to construct a risk model. This risk model showed a remarkable prognostic value for survival rates and metastasis in both the discovery and verification cohorts. Even though a high microsatellite instability score was observed in the high-risk group, the ICB response in the high-risk group was poor. Furthermore, using OncoPredict, we found that the high-risk group OS tissues were resistant to seven drugs and sensitive to 25 drugs. Therefore, our study indicates that the resting dendritic cell signature constructed by AOC3, CDK6, COL22A1, and RNASE6 may contribute to predicting osteosarcoma prognosis and thus therapy guidance.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2022.1017120
    DOI: 10.3389/fimmu.2022.1017120.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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  • 8
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    DataSheet2.docx
    Frontiers Media SA ; 2022
    In:  Frontiers in Genetics Vol. 13 ( 2022-3-14)
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    In: Frontiers in Genetics, Frontiers Media SA, Vol. 13 ( 2022-3-14)
    Abstract: In sheep meat production, the rib eye area is an important index to evaluate carcass traits. However, conventional breeding programs have led to slow genetic progression in rib eye muscle area. Operationalizing molecular marker assisted breeding is an optimized breeding method that might improve this situation. Therefore, the present study used whole genome sequencing data to excavate candidate genes associated with the rib eye muscle. Male Hu lambs ( n = 776) with pedigrees and 274 lambs with no pedigree were included. The genetic parameters of the rib eye area were estimated using a mixed linear mixed model. The rib eye area showed medium heritability (0.32 ± 0.13). Whole-genome sequencing of 40 large rib eye sheep [17.97 ± 1.14, (cm 2 )] and 40 small rib eye sheep [7.89 ± 0.79, (cm 2 )] was performed. Case-control genome-wide association studies and the fixation index identified candidate rib eye-associated genes. Seven single nucleotide polymorphisms (SNPs) in six genes ( ALS2 , ST6GAL2 , LOC105611989 , PLXNA4 , DPP6 , and COL12A1 ) were identified as candidates. The study population was expanded to 1050 lambs to perform KASPar genotyping on five SNPs, which demonstrated that SNPs in LOC105611989 , DPP6 , and COL12A1 correlated significantly with the rib eye area, which could be used as genetic markers for molecular breeding of the rib eye area. The results provided genetic parameters estimated on the rib eye area and information for breeding based on carcass traits in Hu sheep.
    Type of Medium: Online Resource
    ISSN: 1664-8021
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fgene.2022.824742
    DOI: 10.3389/fgene.2022.824742.s001
    DOI: 10.3389/fgene.2022.824742.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606823-0
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  • 9
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    Table_5.XLSX
    Frontiers Media SA ; 2022
    In:  Frontiers in Veterinary Science Vol. 9 ( 2022-7-5)
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    In: Frontiers in Veterinary Science, Frontiers Media SA, Vol. 9 ( 2022-7-5)
    Abstract: Fat deposition is an important economic trait that is closely related to feed efficiency and carcass performance in livestock. In this study, the fat deposition-related traits of 1,293 Hu sheep were measured and descriptive statistical analysis was conducted. The results showed that the coefficient of variation of all fat deposition-related traits was higher than 24%. In addition, single nucleotide polymorphisms and the expression characteristics of TRAPPC9 (encoding trafficking protein particle complex subunit 9) and BAIAP2 (encoding brain-specific Angiogenesis inhibitor 1-associated protein 2) genes in Hu sheep were detected using PCR amplification, Sanger sequencing, KASPar genotyping, and quantitative real-time reverse transcription PCR (qRT-PCR). The associations between SNPs and fat deposition-related traits were also analyzed. Two intronic mutations, TRAPPC9 g.57654 A & gt; G and BAIAP2 g.46061 C & gt; T, were identified in Hu sheep. The result of association analysis showed that TRAPPC9 g.57654 A & gt; G and BAIAP2 g.46061 C & gt; T were both significantly associated with the weight of tail fat, tail fat relative weight (body weight), and tail fat relative weight (carcass) ( P & lt; 0.05). Comprehensive effects analysis showed that there were significant differences between the combined genotypes and tail fat and perirenal fat deposition. Moreover, qRT-PCR analysis showed that TRAPPC9 and BAIAP2 are widely expressed, and their expression levels were significantly higher in the small-tail group compared with those in the big-tail group ( P & lt; 0.01). These results provided important candidate molecular markers that could be used in strategies to reduce tail fat deposition in Hu sheep.
    Type of Medium: Online Resource
    ISSN: 2297-1769
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fvets.2022.928375
    DOI: 10.3389/fvets.2022.928375.s001
    DOI: 10.3389/fvets.2022.928375.s002
    DOI: 10.3389/fvets.2022.928375.s003
    DOI: 10.3389/fvets.2022.928375.s004
    DOI: 10.3389/fvets.2022.928375.s005
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2834243-4
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  • 10
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    Editorial: Medicinal plants as a source of novel autoimmune-modulating and anti-inflammatory drug products
    Frontiers Media SA ; 2022
    In:  Frontiers in Pharmacology Vol. 13 ( 2022-9-6)
    Details
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 13 ( 2022-9-6)
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    DOI: 10.3389/fphar.2022.978581
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2587355-6
    SSG: 15,3
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