IMP: bridging the gap for medicinal plant genomics.

Medicinal plants have garnered significant attention in ethnomedicine and traditional medicine due to their potential antitumor, anti-inflammatory and antioxidant properties. Recent advancements in genome sequencing and synthetic biology have revitalized interest in natural products. Despite the availability of sequenced genomes and transcriptomes of these plants, the absence of publicly accessible gene annotations and tabular formatted gene expression data has hindered their effective utilization. To address this pressing issue, we have developed IMP (Integrated Medicinal Plantomics), a freely accessible platform at https://www.bic.ac.cn/IMP. IMP curated a total of 8 565 672 genes for 84 high-quality genome assemblies, and 2156 transcriptome sequencing samples encompassing various organs, tissues, developmental stages and stimulations. With the integrated 10 analysis modules, users could simply examine gene annotations, sequences, functions, distributions and expressions in IMP in a one-stop mode. We firmly believe that IMP will play a vital role in enhancing the understanding of molecular metabolic pathways in medicinal plants or plants with medicinal benefits, thereby driving advancements in synthetic biology, and facilitating the exploration of natural sources for valuable chemical constituents like drug discovery and drug production.

Geometrical frustration versus Kitaev interactions in BaCo2(AsO4)2.

Recently, Co-based honeycomb magnets have been proposed as promising candidate materials to host the Kitaev spin liquid (KSL) state. One of the front-runners is BaCo2(AsO4)2 (BCAO), where it was suggested that the exchange processes between Co2+ ions via the surrounding edge-sharing oxygen octahedra could give rise to bond-dependent Kitaev interactions. In this work, we present and analyze a comprehensive inelastic neutron scattering (INS) study of BCAO with fields in the honeycomb plane. Combining the constraints from the magnon excitations in the high-field polarized state and the inelastic spin structure factor measured in zero magnetic field, we examine two leading theoretical models: the Kitaev-type [Formula: see text] model and the XXZ[Formula: see text]model. We show that the existing experimental data can be consistently accounted for by the XXZ[Formula: see text]model but not by the [Formula: see text] model, and we discuss the implications of these results for the realization of a spin liquid phase in BCAO and more generally for the realization of the Kitaev model in cobaltates.

A Prenyltransferase Participates in the Biosynthesis of Anthraquinones in Rubia cordifolia.

Anthraquinones constitute the largest group of natural quinones, which are used as safe natural dyes and have many pharmaceutical applications. In plants, anthraquinones are biosynthesized through two main routes: the polyketide pathway and the shikimate pathway. The latter primarily forms alizarin-type anthraquinones, and the prenylation of 1,4-dihydroxy-2-naphthoic acid is the first pathway-specific step. However, the prenyltransferase responsible for this key step remains uncharacterized. In this study, the cell suspension culture of Madder (Rubia cordifolia), a plant rich in alizarin-type anthraquinones, was discovered to be capable of prenylating 1,4-dihydroxy-2-naphthoic acid to form 2-carboxyl-3-prenyl-1,4-naphthoquinone and 3-prenyl-1,4-naphthoquinone. Then, a candidate gene belonging to the UbiA superfamily, R. cordifolia  dimethylallyltransferase 1 (RcDT1), was shown to account for the prenylation activity. Substrate specificity studies revealed that the recombinant RcDT1 recognized naphthoic acids primarily, followed by 4-hydroxyl benzoic acids. The prenylation activity was strongly inhibited by 1,2- and 1,4-dihydroxynaphthalene. RcDT1 RNA interference significantly reduced the anthraquinones content in R. cordifolia callus cultures, demonstrating that RcDT1 is required for alizarin-type anthraquinones biosynthesis. The plastid localization and root-specific expression further confirmed the participation of RcDT1 in anthraquinone biosynthesis. The phylogenetic analyses of RcDT1 and functional validation of its rubiaceous homologs indicated that DHNA-prenylation activity evolved convergently in Rubiaceae via recruitment from the ubiquinone biosynthetic pathway. Our results demonstrate that RcDT1 catalyzes the first pathway-specific step of alizarin-type anthraquinones biosynthesis in R. cordifolia. These findings will have profound implications for understanding the biosynthetic process of the anthraquinone ring derived from the shikimate pathway.

Identifying STRN3-RARA as a new fusion gene for acute promyelocytic leukemia.

Here we report a new fusion gene, STRN3-RARA, in acute promyelocytic leukemia (APL). It cooperates with UTX deficiency to drive full-blown APL in mice. Although STRN3-RARA leukemia quickly relapses after all-trans retinoic acid treatment, it can be restrained by cepharanthine.

CRAMdb: a comprehensive database for composition and roles of microbiome in animals.

CRAMdb (a database for composition and roles of animal microbiome) is a comprehensive resource of curated and consistently annotated metagenomes for non-human animals. It focuses on the composition and roles of the microbiome in various animal species. The main goal of the CRAMdb is to facilitate the reuse of animal metagenomic data, and enable cross-host and cross-phenotype comparisons. To this end, we consistently annotated microbiomes (including 16S, 18S, ITS and metagenomics sequencing data) of 516 animals from 475 projects spanning 43 phenotype pairs to construct the database that is equipped with 9430 bacteria, 278 archaea, 2216 fungi and 458 viruses. CRAMdb provides two main contents: microbiome composition data, illustrating the landscape of the microbiota (bacteria, archaea, fungi, and viruses) in various animal species, and microbiome association data, revealing the relationships between the microbiota and various phenotypes across different animal species. More importantly, users can quickly compare the composition of the microbiota of interest cross-host or body site and the associated taxa that differ between phenotype pairs cross-host or cross-phenotype. CRAMdb is freely available at (http://www.ehbio.com/CRAMdb).

Stress adaptation in Tibetan cashmere goats is governed by inherent metabolic differences and manifested through variable cashmere phenotypes.

Tibetan cashmere goats are not only served as a valuable model for studying adaptation to hypoxia and high-altitude conditions but also playing a pivotal role in bolstering local economies through the provision of premium quality cashmere yarn. In this study, we performed an integration and network analysis of metabolomic, transcriptomic and proteomic to elucidate the role of differentially expressed genes, important metabolites, and relevant cellular and metabolic pathways between the fine (average 12.04 ± 0.03 µm of mean fiber diameter) and coarse cashmere (average 14.88 ± 0.05 µm of mean fber diameter) producing by Tibetan cashmere goats. We identified a distinction of 56 and 71 differential metabolites (DMs) between the F and C cashmere groups under positive and negative ion modes, respectively. The KEGG pathway enrichment analysis of these DMs highlighted numerous pathways predominantly involved in amino acid and protein metabolism, as indicated by the finding that the most impactful pathway was the mammalian target of rapamycin (mTOR) signalling pathway. In the F group, we identified a distinctive metabolic profile where amino acid metabolites including serine, histidine, asparagine, glutamic acid, arginine, valine, aspartic acid, tyrosine, and methionine were upregulated, while lysine, isoleucine, glutamine, tryptophan, and threonine were downregulated. The regulatory network and gene co-expression network revealed crucial genes, metabolites, and metabolic pathways. The integrative omics analysis revealed a high enrichment of several pathways, notably encompassing protein digestion and absorption, sphingolipid signalling, and the synaptic vesicle cycle. Within the sphere of our integrative analysis, DNMT3B was identified as a paramount gene, intricately associated with significant proteins such as HMCN1, CPB2, GNG12, and LRP1. Our present study delineated the molecular underpinnings governing the variations in cashmere characteristics by conducting comprehensive analyses across metabolomic, transcriptomic, and proteomic dimensions. This research provided newly insights into the mechanisms regulating cashmere traits and facilitated the advancement of selective breeding programs aimed at cultivating high-quality superfine Tibetan cashmere goats.

Identification of an HLA-A*11:01-restricted neoepitope of mutant PIK3CA and its specific T cell receptors for cancer immunotherapy targeting hotspot driver mutations.

Hotspot driver mutations presented by human leukocyte antigens might be recognized by anti-tumor T cells. Based on their advantages of tumor-specificity and immunogenicity, neoantigens derived from hotspot mutations, such as PIK3CAH1047L, may serve as emerging targets for cancer immunotherapies. NetMHCpan V4.1 was utilized for predicting neoepitopes of PIK3CA hotspot mutation. Using in vitro stimulation, antigen-specific T cells targeting the HLA-A*11:01-restricted PIK3CA mutation were isolated from healthy donor-derived peripheral blood mononuclear cells. T cell receptors (TCRs) were cloned using single-cell PCR and sequencing. Their functionality was assessed through T cell activation markers, cytokine production and cytotoxic response to cancer cell lines pulsed with peptides or transduced genes of mutant PIK3CA. Immunogenic mutant antigens from PIK3CA and their corresponding CD8+ T cells were identified. These PIK3CA mutation-specific CD8+ T cells were subsequently enriched, and their TCRs were isolated. The TCR clones exhibited mutation-specific and HLA-restricted reactivity, demonstrating varying degrees of functional avidity. Identified TCR genes were transferred into CD8+ Jurkat cells and primary T cells deficient of endogenous TCRs. TCR-expressing cells demonstrated specific recognition and reactivity against the PIK3CAH1047L peptide presented by HLA-A*11:01-expressing K562 cells. Furthermore, mutation-specific TCR-T cells demonstrated an elevation in cytokine production and profound cytotoxic effects against HLA-A*11:01+ malignant cell lines harboring PIK3CAH1047L. Our data demonstrate the immunogenicity of an HLA-A*11:01-restricted PIK3CA hotspot mutation and its targeting therapeutic potential, together with promising candidates of TCR-T cell therapy.

Modified fructan accumulation through overexpression of wheat fructan biosynthesis pathway fusion genes Ta1SST:Ta6SFT.

BACKGROUND: Fructans are water-soluble carbohydrates that accumulate in wheat and are thought to contribute to a pool of stored carbon reserves used in grain filling and tolerance to abiotic stress. RESULTS: In this study, transgenic wheat plants were engineered to overexpress a fusion of two fructan biosynthesis pathway genes, wheat sucrose: sucrose 1-fructosyltransferase (Ta1SST) and wheat sucrose: fructan 6-fructosyltransferase (Ta6SFT), regulated by a wheat ribulose-1,5-bisphosphate carboxylase/oxygenase small subunit (TaRbcS) gene promoter. We have shown that T4 generation transgene-homozygous single-copy events accumulated more fructan polymers in leaf, stem and grain when compared in the same tissues from transgene null lines. Under water-deficit (WD) conditions, transgenic wheat plants showed an increased accumulation of fructan polymers with a high degree of polymerisation (DP) when compared to non-transgenic plants. In wheat grain of a transgenic event, increased deposition of particular fructan polymers such as, DP4 was observed. CONCLUSIONS: This study demonstrated that the tissue-regulated expression of a gene fusion between Ta1SST and Ta6SFT resulted in modified fructan accumulation in transgenic wheat plants and was influenced by water-deficit stress conditions.

METTL14 mediates nerve growth factor-stimulated testosterone synthesis in porcine theca cells.

Ovarian theca cells produce testosterone, which acts as a vital precursor substance for synthesizing estrogens during follicular development. Nerve growth factor (NGF) has been shown to participate in reproductive physiology, specifically to follicular development and ovulation. There is currently no available data on the impact of NGF on testosterone synthesis in porcine theca cells. Furthermore, m6A modification is the most common internal modification in eukaryotic mRNAs that are closely associated with female gametogenesis, follicle development, ovulation, and other related processes. It is also uncertain whether the three main enzymes associated with m6A, such as Writers, Erasers and Readers, play a role in this process. The present study, with an in vitro culture model, investigated the effect of NGF on testosterone synthesis in porcine theca cells and the role of Writers-METTL14 in this process. It was found that NGF activates the PI3K/AKT signaling pathway through METTL14, which regulates testosterone synthesis in porcine theca cells. This study will help to further elucidate the mechanisms by which NGF regulates follicular development and provide new therapeutic targets for ovary-related diseases in female animals.

Current insights into posttranscriptional regulation of fleshy fruit ripening.

Fruit ripening is a complicated process that is accompanied by the formation of fruit quality. It is not only regulated at the transcriptional level via transcription factors or DNA methylation but also fine-tuned after transcription occurs. Here, we review recent advances in our understanding of key regulatory mechanisms of fleshy fruit ripening after transcription. We mainly highlight the typical mechanisms by which fruit ripening is controlled, namely, alternative splicing, mRNA N6-methyladenosine RNA modification methylation, and noncoding RNAs at the posttranscriptional level; regulation of translation efficiency and upstream open reading frame-mediated translational repression at the translational level; and histone modifications, protein phosphorylation, and protein ubiquitination at the posttranslational level. Taken together, these posttranscriptional regulatory mechanisms, along with transcriptional regulation, constitute the molecular framework of fruit ripening. We also critically discuss the potential usage of some mechanisms to improve fruit traits.

Transcriptional landscape of pathogen-responsive lncRNAs in tomato unveils the role of hydrolase encoding genes in response to Botrytis cinerea invasion.

LncRNAs have gained increasing attention owing to their important regulatory roles on growth and stress responses of plants. However, the mechanisms underlying the functions of lncRNAs in fruit-pathogen interaction are still largely unknown. In this study, a total of 273 lncRNAs responding to Botrytis cinerea infection were identified in tomato fruit, among which a higher percentage of antisense lncRNAs were targeted to the genes enriched in hydrolase activity. To ascertain the roles of these lncRNAs, seven hydrolase-related transcripts were transiently knocked-down by virus-induced gene silencing. Silencing of lncRNACXE20 reduced the expression level of a carboxylesterase gene, further enhancing the resistance of tomato to B. cinerea. In contrast, silencing of lncRNACHI, lncRNAMMP, lncRNASBT1.9 and lncRNAPME1.9 impaired the resistance to B. cinerea, respectively. Further RT-qPCR assay and enzymatic activity detection displayed that the attenuated resistance of lncRNAMMP and lncRNASBT1.9-silenced plants was associated with the inhibition on the expression of JA-related genes, while the decreased resistance of lncRNACHI-silenced plants resulted in reduced chitinase activity. Collectively, these results may provide references for deciphering the mechanisms underlying specific lncRNAs to interfere with B. cinerea infection by regulating the expression of defence-related genes or affecting hydrolase activity.

Current challenges and therapeutic advances of CAR-T cell therapy for solid tumors.

The application of chimeric antigen receptor (CAR) T cells in the management of hematological malignancies has emerged as a noteworthy therapeutic breakthrough. Nevertheless, the utilization and effectiveness of CAR-T cell therapy in solid tumors are still limited primarily because of the absence of tumor-specific target antigen, the existence of immunosuppressive tumor microenvironment, restricted T cell invasion and proliferation, and the occurrence of severe toxicity. This review explored the history of CAR-T and its latest advancements in the management of solid tumors. According to recent studies, optimizing the design of CAR-T cells, implementing logic-gated CAR-T cells and refining the delivery methods of therapeutic agents can all enhance the efficacy of CAR-T cell therapy. Furthermore, combination therapy shows promise as a way to improve the effectiveness of CAR-T cell therapy. At present, numerous clinical trials involving CAR-T cells for solid tumors are actively in progress. In conclusion, CAR-T cell therapy has both potential and challenges when it comes to treating solid tumors. As CAR-T cell therapy continues to evolve, further innovations will be devised to surmount the challenges associated with this treatment modality, ultimately leading to enhanced therapeutic response for patients suffered solid tumors.

LncRNA CRNDE promotes hepatoma cell proliferation by regulating the metabolic reprogramming of M2 macrophages via ERK pathway.

BACKGROUND: LncRNA colorectal neoplasia differentially expressed (CRNDE) was found to be an important regulator in many cancers. This project focuses on the function of CRNDE on macrophage metabolic reprogramming and Hepatocellular carcinoma (HCC). METHOD: qRT-PCR and Immunofluorescence were used to analyze Arg-1, IL-10, CD163, CCL-18, CD206, and CRNDE expression in HCC tissues and macrophages. Western Blotting was used to analyze ERK and p-ERK expression. Edu assay, transwell assay and xenograft experiments were carried out to study cell viability, migrated and invasive capability. Immunohistochemical staining was used to evaluate Ki67 expression. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed for macrophages metabolites analysis. RESULTS: Arg-1, IL-10, CD163, CD206, and CRNDE were significantly up-regulated in HCC tissues, M2 macrophage and M0 macrophage with CRNDE overexpressed (OV-CRNDE-M0), which downregulated in M0 macrophage with CRNDE knockdown (sh-CRNDE-M0). The conditioned medium (CM) of M2 cells and OV-CRNDE-M0 cells promoted cell viability, invasion, and migration of HCC cells, the effect was reversed by sh-CRNDE-M0 cells CM. OV-CRNDE-M0 cells promoted tumor growth, Ki67 and CD206 expression in xenograft model. 61 metabolites were detected, of which 18 metabolites changed significantly in OV-CRNDE-M0 group compared to M0 group, with 9 upregulated and 9 downregulated. KEGG analysis showed the enrichment pathways were biosynthesis, glyoxylate and dicarboxylate metabolism. SMPDB analysis showed the enrichment pathways were hypoacetylaspartia, canavan disease, and aspartate metabolism. CONCLUSION: CRNDE regulated the metabolic reprogramming of M2 macrophage via ERK pathway, which thereby contributed to HCC proliferation, migration, and invasion.

Construction of Ultrafine PtIr Clusters Supported on Co3O4 Nanoflowers for Enhanced Overall Water Splitting.

Green hydrogen production through electrochemical overall water splitting has suffered from sluggish oxygen evolution reaction (OER) kinetics, inferior conversion efficiency, and high cost. Herein, ultrafine PtIr clusters are synthesized via an electrodeposition method and decorated on the Co3O4 nanoflowers assembled by nanowires (PtIr-Co3O4). The encouraging performances in electrochemical OER and hydrogen evolution reaction (HER) are achieved over the PtIr-Co3O4 catalyst, with the overpotentials as low as 410 and 237 mV at 100 mA cm-2, respectively, outperforming the commercial IrO2 and Pt/C catalysts. Due to the ultralow loading of PtIr clusters, the PtIr-Co3O4 catalyst exhibits 1270 A gIr -1 for OER at the overpotential of 400 mV. Our detailed analyses also show that the strong interactions between the ultrafine PtIr clusters and the Co3O4 nanoflowers enable the PtIr-Co3O4 catalyst to afford 10 mA cm-2 for the overall water splitting at the potential of 1.57 V, accompanied by high durability for 100 h.

Study of Allergy and Sensitization Relationship in Children and Parents in Southern China.

INTRODUCTION: The incidence of allergic diseases has increased globally, with genetics playing an essential role in these conditions' development. However, there is still a gap in understanding of how parental allergy status affects children's allergies. METHODS: An electronic questionnaire was used to assess allergy-related symptoms in kindergarten children and their parents, with a clinical diagnosis and concurrent serum allergen-specific immunoglobulin E (IgE), total IgE, and blood cell counts obtained. RESULTS: 88 family groups were enrolled, with allergy prevalence of 85.2% in children, 50% in fathers, and 42% in mothers. Allergic rhinoconjunctivitis was the most common allergic disease. When the mother had an allergy, the children's allergy diagnosis rate was 91.3%; 86.67% when the father had an allergy; and 85.71% when both parents had allergies. The child sensitization rate was 78.26% when the father had sensitization, 59.09% just as the mother had sensitization, and 84.21% when both parents had sensitization. Paternal allergies affected children's quality of life due to allergic rhinitis but not their rhinitis symptoms. Maternal allergies or sensitization did not significantly affect children's symptoms or quality-of-life scores. CONCLUSION: The study found a positive correlation between childhood and parental allergies, and further studies are needed to confirm the findings.

Mendelian randomization of circulating proteome identifies IFN-γ as a druggable target in aplastic anemia.

BACKGROUND: Aplastic anemia (AA) is a kind of bone marrow failure (BMF) characterized by pancytopenia with hypoplasia/aplasia of bone marrow. Immunosuppressive therapy and bone marrow transplantation are effective methods to treat severe aplastic anemia. However, the efficacy is limited by complications and the availability of suitable donors. This study aimed to determine whether any circulating druggable protein levels may have causal effects on AA and provide potential novel drug targets for AA. METHODS: Genetic variants strongly associated with circulating druggable protein levels to perform Mendelian randomization (MR) analyses were used. The effect of these druggable protein levels on AA risk was measured using the summary statistics from a large-scale proteomic genome-wide association study (GWAS) and FinnGen database ( https://www.finngen.fi/en/access_results ). Multivariable MR analyses were performed to statistically adjust for potential confounders, including platelet counts, reticulocyte counts, neutrophil counts, and proportions of hematopoietic stem cells. RESULTS: The data showed that higher level of circulating IFN-γ levels was causally associated with AA susceptibility. The causal effects of circulating IFN-γ levels on the AA were broadly consistent, when adjusted for platelet counts, reticulocyte counts, neutrophil counts and proportions of hematopoietic stem cells. CONCLUSIONS: High levels of circulating IFN-γ levels might increase the risk of AA and might provide a potential novel target for AA.

Transition Metal (Co, V, W, Zr) Single-Atom Decorated Biphenylene for Enhancing the Sensing Performance of SF6 Decomposition Molecules.

The highly sensitive gas sensors used to monitor the decomposition of toxic gases in the dielectric materials of electrical equipment are vital in preventing safety problems arising from corrosion of the equipment. Recently, biphenylene (BPN) has been prepared through surface interpolymer hydrofluorination (HF zipper) reaction, whereas potential gas-sensitive devices based on the BPN monolayer have lacked in-depth investigation. The stable geometries, adsorption energies, interlayer distances, and charge transfers of small molecules of toxic gases (H2S, SO2, SOF2, SO2F2) produced by SF6 chalcogenide molecules of decomposition adsorbed on the original BPN monolayer are systematically researched by using nonequilibrium Green's function methods and density functional theory. The results indicated that all small molecules adsorbed on the BPN monolayer are physisorbed, while the type of adsorption turned from physisorption to chemisorption when BPN carried out adsorption with adsorbing a transition metal atom (TMA). In addition, the characteristics of current-voltage (I-V) curves of H2S and SO2 based on the TMA-BPN gas sensors revealed that the currents in BPN-based gas sensors displayed an obvious anisotropy, and the currents in the zigzag direction are larger than that in the armchair orientation regardless of the molecular adsorption cases. Moreover, the difference of currents for TMA-decorated BPN sensors changed more remarkably before and after the adsorption of H2S and SO2 in the zigzag direction. This work offers insights into the design of gas-sensitive devices through the adsorption of small molecules on the TMA-decorated BPN monolayer.

Developmental trajectories of child and adolescent emotional problems: associations with early adult alcohol use behaviors.

BACKGROUND: Whether emotional problems during childhood and adolescence are longitudinally associated with adult alcohol use behaviors is unclear. This study examined associations between developmental trajectories of emotional problems and early adult alcohol use behaviors, while considering co-occurring conduct problems, developmental change/timing, sex differences, and potential confounds. METHODS: Participants were from the Twins Early Development Study (analytic N = 19,908 individuals). Emotional and conduct problems were measured by parent reports at child ages 4, 7, and 9 years and via self-reports at ages 9, 11, and 16 years on the Strengths and Difficulties Questionnaire. Alcohol use behaviors (alcohol consumption and alcohol-related problems) were self-reported by the twins on the Alcohol Use Disorders Identification Test at age 22 years. Piecewise latent growth curve models described nonlinear developmental trajectories of emotional and conduct problems from ages 4 to 16. At age 22, alcohol use was regressed on emotional and conduct problems' intercepts and slopes from piecewise latent growth curve model and sex differences in regression coefficients were tested. Using twin modeling, Cholesky decompositions and direct path models were compared to test whether significant phenotypic associations were best explained by direct phenotypic influences or correlated genetic and environmental influences. RESULTS: Emotional problems had different associations with alcohol-related problems versus alcohol consumption. After accounting for direct influences from conduct problems, emotional problems were not associated with alcohol-related problems, while emotional problems at age 9 were negatively associated with alcohol consumption in males. CONCLUSIONS: Overall, findings did not support emotional problems as prospective risk factors for severe alcohol use above and beyond risks associated with conduct problems. Sex- and age-specific links between emotional problems and alcohol consumption in early adulthood may be worthy of further exploration, particularly as twin analyses improved our confidence that such links may be underpinned by causal mechanisms.

Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients with Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy.

BACKGROUND: The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing. METHODS: The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR. RESULTS: The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes (P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV. CONCLUSIONS: Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy.

Retinoic acid mitigates the NSC319726-induced spermatogenesis dysfunction through cuproptosis-independent mechanisms.

Copper ionophore NSC319726 has attracted researchers' attention in treating diseases, particularly cancers. However, its potential effects on male reproduction during medication are unclear. This study aimed to determine whether NSC319726 exposure affected the male reproductive system. The reproductive toxicity of NSC319726 was evaluated in male mice following a continuous exposure period of 5 weeks. The result showed that NSC319726 exposure caused testis index reduction, spermatogenesis dysfunction, and architectural damage in the testis and epididymis. The exposure interfered with spermatogonia proliferation, meiosis initiation, sperm count, and sperm morphology. The exposure also disturbed androgen synthesis and blood testis barrier integrity. NSC319726 treatment could elevate the copper ions in the testis to induce cuproptosis in the testis. Copper chelator rescued the elevated copper ions in the testis and partly restored the spermatogenesis dysfunction caused by NSC319726. NSC319726 treatment also decreased the level of retinol dehydrogenase 10 (RDH10), thereby inhibiting the conversion of retinol to retinoic acid, causing the inability to initiate meiosis. Retinoic acid treatment could rescue the meiotic initiation and spermatogenesis while not affecting the intracellular copper ion levels. The study provided an insight into the bio-safety of NSC319726. Retinoic acid could be a potential therapy for spermatogenesis impairment in patients undergoing treatment with NSC319726.