Multi-copper oxidases SKU5 and SKS1 coordinate cell wall formation using apoplastic redox-based reactions in roots.

The primary cell wall is a fundamental plant constituent that is flexible but sufficiently rigid to support the plant cell shape. Although many studies have demonstrated that reactive oxygen species (ROS) serve as important signaling messengers to modify the cell wall structure and affect cellular growth, the regulatory mechanism underlying the spatial-temporal regulation of ROS activity for cell wall maintenance remains largely unclear. Here, we demonstrate the role of the Arabidopsis (Arabidopsis thaliana) multicopper oxidase-like protein skewed 5 (SKU5) and its homolog SKU5-similar 1 (SKS1) in root cell wall formation through modulating ROS homeostasis. Loss of SKU5 and SKS1 function resulted in aberrant division planes, protruding cell walls, ectopic deposition of iron, and reduced nicotinamide adeninedinucleotide phosphate (NADPH) oxidase-dependent ROS overproduction in the root epidermis-cortex and cortex-endodermis junctions. A decrease in ROS level or inhibition of NADPH oxidase activity rescued the cell wall defects of sku5 sks1 double mutants. SKU5 and SKS1 proteins were activated by iron treatment, and iron over-accumulated in the walls between the root epidermis and cortex cell layers of sku5 sks1. The glycosylphosphatidylinositol-anchored motif was crucial for membrane association and functionality of SKU5 and SKS1. Overall, our results identified SKU5 and SKS1 as regulators of ROS at the cell surface for regulation of cell wall structure and root cell growth.

miR-29b-3p regulates cardiomyocytes pyroptosis in CVB3-induced myocarditis through targeting DNMT3A.

BACKGROUND: Viral myocarditis (VMC) is a disease resulting from viral infection, which manifests as inflammation of myocardial cells. Until now, the treatment of VMC is still a great challenge for clinicians. Increasing studies indicate the participation of miR-29b-3p in various diseases. According to the transcriptome sequencing analysis, miR-29b-3p was markedly upregulated in the viral myocarditis model. The purpose of this study was to investigate the role of miR-29b-3p in the progression of VMC. METHODS: We used CVB3 to induce primary cardiomyocytes and mice to establish a model of viral myocarditis. The purity of primary cardiomyocytes was identified by immunofluorescence. The cardiac function of mice was detected by Vevo770 imaging system. The area of inflammatory infiltration in heart tissue was shown by hematoxylin and eosin (H&E) staining. The expression of miR-29b-3p and DNMT3A was detected by quantitative real time polymerase chain reaction (qRT-PCR). The expression of a series of pyroptosis-related proteins was detected by western blot. The role of miR-29b-3p/DNMT3A in CVB3-induced pyroptosis of cardiomyocytes was studied in this research. RESULTS: Our data showed that the expression of miR-29b-3p was upregulated in CVB3-induced cardiomyocytes and heart tissues in mice. To explore the function of miR-29b-3p in CVB3-induced VMC, we conducted in vivo experiments by knocking down the expression of miR-29b-3p using antagomir. We then assessed the effects on mice body weight, histopathology changes, myocardial function, and cell pyroptosis in heart tissues. Additionally, we performed gain/loss-of-function experiments in vitro to measure the levels of pyroptosis in primary cardiomyocytes. Through bioinformatic analysis, we identified DNA methyltransferases 3A (DNMT3A) as a potential target gene of miR-29b-3p. Furthermore, we found that the expression of DNMT3A can be modulated by miR-29b-3p during CVB3 infection. CONCLUSIONS: Our results demonstrate a correlation between the expression of DNMT3A and CVB3-induced pyroptosis in cardiomyocytes. These findings unveil a previously unidentified mechanism by which CVB3 induces cardiac injury through the regulation of miR-29b-3p/DNMT3A-mediated pyroptosis.

Association between new plasma inflammatory markers and risk of colorectal neoplasms in individuals over 50 years old.

OBJECTIVE(S): The prognostic value of systemic cytokine profiles and inflammatory markers in colorectal cancer were explored by several studies. We want to know more about inflammatory biomarkers in colorectal adenoma and early cancer. METHOD: The level of 38 inflammatory markers in the plasma of 112 adenoma patients, 72 Tis-T1 staging of colorectal carcinoma patients, 34 T2-T4 staging of colorectal carcinoma patients and 53 normal subjects were detected and compared. RESULT(S): Eight inflammatory biomarkers (Eotaxin, GCSF, IL-4, IL-5, IL-17E, MCP-1, TNF-α and VEGF-A) have higher plasma concentrations in colorectal adenoma and cancer patients compared with normal participants over 50 years old. CONCLUSION(S): Inflammatory markers may have the prognostic value for colorectal adenoma and early-stage carcinoma.

Proteome-wide mendelian randomization identifies causal plasma proteins in venous thromboembolism development.

Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis. Twenty genetically regulated circulating protein abundances (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, and MSR1) were associated with VTE. Of these 13 proteins demonstrated Mendelian randomized correlations. Six proteins (F2, F11, PLEK, SERPINA1, RARRES2, and SERPINE2) had strong support in colocalization analysis. Utilizing multidimensional data, this study suggests PLEK, SERPINA1, and SERPINE2 as compelling proteins that may provide key hints for future research and possible diagnostic and therapeutic targets for VTE.

H-Bonding Room Temperature Phosphorescence Materials via Facile Preparation for Water-Stimulated Photoluminescent Ink.

Pure organic room-temperature phosphorescence (RTP) materials built upon noncovalent interactions have attracted much attention because of their high efficiency, long lifetime, and stimulus-responsive behavior. However, there are limited reports of noncovalent RTP materials because of the lack of specific design principles and clear mechanisms. Here, we report on a noncovalent material prepared via facile grinding that can emit fluorescence and RTP emission differing from their components' photoluminescent behavior. Exciplex can be formed during the preparation process to act as the minimum emission unit. We found that H-bonds in the RTP system provide restriction to nonradiative transition but also enhance energy transformation and energy level degeneracy in the system. Moreover, water-stimulated photoluminescent ink is produced from the materials to achieve double-encryption application with good resolution.

Realizing N-type SnTe Thermoelectrics with Competitive Performance through Suppressing Sn Vacancies.

Due to the intrinsically plentiful Sn vacancies, developing n-type SnTe thermoelectric materials is a big challenge. Herein, n-type SnTe thermoelectric materials with remarkable performance were successfully synthesized through suppressing Sn vacancies, followed by electron-doping. Pb alloying notably depressed the Sn vacancies via populating Sn vacancies in SnTe (supported by transmission electron microscopy), and the electrical transports were shifted from p-type to n-type through introducing electrons using I doping. In the n-type SnTe, we found that the electrical conductivity could be enhanced by increased carrier mobility through sharpening conduction bands after alloying Pb, while the lattice thermal conductivity could be reduced via strong phonon scattering after introducing defects by Pb alloying and I doping. Resulting from these enhancements, the n-type Sn0.6Pb0.4Te0.98I0.02 achieves a notably high ZTmax ∼ 0.8 at 573 K and a remarkable ZTave ∼ 0.51 at 300-823 K, which can match many excellent p-type SnTe. This work indicates that n-type SnTe could be experimentally acquired and is a promising candidate for thermoelectric generation, which will stimulate further research on n-type SnTe thermoelectric materials and even devices on the basis of both n- and p-type SnTe legs.

Insights into the Chiral Phosphoric Acid-Catalyzed Dynamic Kinetic Asymmetric Hydroamination of Racemic Allenes: An Allyl Carbocation/Phosphate Pair Mechanism.

Computational studies of chiral phosphoric acid (CPA)-catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of racemic allenes show that the reaction proceeds through a catalytic asymmetric model involving a highly reactive π-allylic carbocationic intermediate, generated from a racemic allene through an intermolecular proton transfer mediated by CPA, which also results in a high E/Z selectivity. Moreover, the distortion-interaction, atom in molecule, and electrostatic interaction analyses and space-filling models are employed on the basis of the DyKAH catalyzed by (S)-A5 (reaction 1) or (R)-A2 (reaction 2) to explain the high enantioselectivity and the controlling effects of SPINOL scaffolds on the signs of enantioselectivity. Our calculations indicate that the enantioselectivity of reactions 1 and 2 can be mainly ascribed to the favorable noncovalent interactions within the stronger chiral electrostatic environment created by the phosphoric acid in the preferential transition states. Finally, the effect of (S/R)-SPINOL-based CPAs on the signs of enantioselectivity can be explained by the different combination modes of substrates into the chiral binding pocket of the catalyst controlled by the chirality of SPINOL backbones. Overall, the new insights into the reaction rationalize the outcome and these key factors that affect the product enantioselectivity are important to guide the DyKAHs.

Auxin and cytokinin coordinate the dormancy and outgrowth of axillary bud in strawberry runner.

BACKGROUND: Axillary buds allow the production of either vegetative or reproductive shoots, which display a plastic developmental potential of the plant to suit the prevailing environmental changes. Strawberry represents one of many plant species which displays horizontal above-ground growth of shoot development for asexual reproduction. Two distinct runner growth patterns exist in different strawberry species: one is called sympodial type such as Fragaria vesca, and the other one is called monopodial type such as Fragaria pentaphylla. Despite the runner growth morphology of these strawberry species have been well known, the mechanisms that determine the distinct patterns have rarely been reported. RESULTS: In this study, we used Fragaria vesca Hawaii-4 and Fragaria pentaphylla as model species, and captured the initiated dormant bud and non-dormant bud as materials to compare their transcriptome profiles and phytohormone content. Comparisons revealed that relatively higher auxin activity is present in the dormant bud and relatively higher cytokinin activity is in the non-dormant bud. Decapitation and pharmacological experiments on dormant buds showed that the reduction of auxin accumulation triggers the regeneration of vegetative shoots in dormant buds, and exogenous cytokinin application triggers cell fate turnover and generation of reproductive shoots. CONCLUSION: Here, we uncover a mechanism by which auxin and cytokinin coordinate the dormancy and outgrowth of axillary bud in strawberry runner. Our results suggest a contrasting behavior of auxin and cytokinin in control of axillary bud development, facilitating a preliminary understanding of shoot architecture formation in strawberry.

Auxin controls circadian flower opening and closure in the waterlily.

BACKGROUND: Flowers open at sunrise and close at sunset, establishing a circadian floral movement rhythm to facilitate pollination as part of reproduction. By the coordination of endogenous factors and environmental stimuli, such as circadian clock, photoperiod, light and temperature, an appropriate floral movement rhythm has been established; however, the underlying mechanisms remain unclear. RESULTS: In our study, we use waterlily as a model which represents an early-diverging grade of flowering plants, and we aim to reveal the general mechanism of flower actions. We found that the intermediate segment of petal cells of waterlily are highly flexible, followed by a circadian cell expansion upon photoperiod stimuli. Auxin causes constitutively flower opening while auxin inhibitor suppresses opening event. Subsequent transcriptome profiles generated from waterlily's intermediate segment of petals at different day-time points showed that auxin is a crucial phytohormone required for floral movement rhythm via the coordination of YUCCA-controlled auxin synthesis, GH3-mediated auxin homeostasis, PIN and ABCB-dependent auxin efflux as well as TIR/AFB-AUX/IAA- and SAUR-triggered auxin signaling. Genes involved in cell wall organization were downstream of auxin events, resulting in the output phenotypes of rapid cell expansion during flower opening and cell shrinkage at flower closure stage. CONCLUSIONS: Collectively, our data demonstrate a central regulatory role of auxin in floral movement rhythm and provide a global understanding of flower action in waterlily, which could be a conserved feature of angiosperms.

Three-dimensional microtissues as an in vitro model for personalized radiation therapy.

This paper describes the use of 3D microtissues as an intermediate model between the 2D cell culture and the animal model to assess radiation-induced cellular and DNA damage in the context of personalized radiation therapy. An agarose microwell array was used to generate 3D microtissues with controlled size and shape. The microtissues were exposed to X-ray radiation of various doses, and the radiation damage to cells was examined using a variety of techniques with different end points. Damage to cell membranes and reduction in metabolic activity were examined with the MTT assay and dye inclusion assay. DNA damage was tested with the micronucleus assay, γ-H2AX immunostaining, and HaloChip assay. 3D microtissues exposed to X-rays are smaller compared to unexposed ones in extended cultures, indicating that X-ray radiation can retard the growth of cells in 3D microtissues, where cells at the outer shells of microtissues can prevent further damage to those inside.

Identification of loci conferring resistance to 4 foliar diseases of maize.

Foliar diseases of maize are among the most important diseases of maize worldwide. This study focused on 4 major foliar diseases of maize: Goss's wilt, gray leaf spot, northern corn leaf blight, and southern corn leaf blight. QTL mapping for resistance to Goss's wilt was conducted in 4 disease resistance introgression line populations with Oh7B as the common recurrent parent and Ki3, NC262, NC304, and NC344 as recurrent donor parents. Mapping results for Goss's wilt resistance were combined with previous studies for gray leaf spot, northern corn leaf blight, and southern corn leaf blight resistance in the same 4 populations. We conducted (1) individual linkage mapping analysis to identify QTL specific to each disease and population; (2) Mahalanobis distance analysis to identify putative multiple disease resistance regions for each population; and 3) joint linkage mapping to identify QTL across the 4 populations for each disease. We identified 3 lines that were resistant to all 4 diseases. We mapped 13 Goss's wilt QTLs in the individual populations and an additional 6 using joint linkage mapping. All Goss's wilt QTL had small effects, confirming that resistance to Goss's wilt is highly quantitative. We report several potentially important chromosomal bins associated with multiple disease resistance including 1.02, 1.03, 3.04, 4.06, 4.08, and 9.03. Together, these findings indicate that disease QTL distribution is not random and that there are locations in the genome that confer resistance to multiple diseases. Furthermore, resistance to bacterial and fungal diseases is not entirely distinct, and we identified lines resistant to both fungi and bacteria, as well as loci that confer resistance to both bacterial and fungal diseases.

Mechanisms of traditional Chinese medicine overcoming of radiotherapy resistance in breast cancer.

Breast cancer stands as the most prevalent malignancy among women, with radiotherapy serving as a primary treatment modality. Despite radiotherapy, a subset of breast cancer patients experiences local recurrence, attributed to the intrinsic resistance of tumors to radiation. Therefore, there is a compelling need to explore novel approaches that can enhance cytotoxic effects through alternative mechanisms. Traditional Chinese Medicine (TCM) and its active constituents exhibit diverse pharmacological actions, including anti-tumor effects, offering extensive possibilities to identify effective components capable of overcoming radiotherapy resistance. This review delineates the mechanisms underlying radiotherapy resistance in breast cancer, along with potential candidate Chinese herbal medicines that may sensitize breast cancer cells to radiotherapy. The exploration of such herbal interventions holds promise for improving therapeutic outcomes in the context of breast cancer radiotherapy resistance.

Insight into Carrier and Phonon Transports of PbSnS2 Crystals.

The simultaneous optimization of n-type and p-type thermoelectric materials is advantageous to the practical application of the device. As an emerging thermoelectric material, PbSnS2 exhibits highly competitive thermoelectric properties due to its unique carrier and phonon transport characteristics. To promote the utilization of this low-cost thermoelectric material, p-type PbSnS2 crystals are synthesized and optimized through Na doping and Se alloying. The resulting thermoelectric transport properties differ significantly from those reported for n-type crystals, prompting us to compare and analyze both n-type (Cl-doped) and p-type (Na-doped) PbSnS2 crystals from various perspectives. Cl doping is subject to weaker "Fermi pinning" and lower impurity ionization energy compared with Na doping, leading to higher doping efficiency. The different optimal performance directions in n-type and p-type crystals can be attributed to the distinct charge density distributions near the conduction band minimum (CBM) and the valence band maximum (VBM). Additionally, both n-type and p-type crystals exhibit ultralow lattice thermal conductivity due to the low symmetry of their twisted NaCl structure combined with the strong anharmonicity. This comprehensive analysis of PbSnS2 crystals provides a solid foundation for further performance optimization and device assembly, while also sheds light on the investigation of layered thermoelectric materials.

Multi-Omics analysis elucidates tumor microenvironment and intratumor microbes of angiogenesis subtypes in colon cancer.

BACKGROUND: Angiogenesis plays an important role in colon cancer (CC) progression. AIM: To investigate the tumor microenvironment (TME) and intratumor microbes of angiogenesis subtypes (AGSs) and explore potential targets for antiangiogenic therapy in CC. METHODS: The data were obtained from The Cancer Genome Atlas database and Gene Expression Omnibus database. K-means clustering was used to construct the AGSs. The prognostic model was constructed based on the differential genes between two subtypes. Single-cell analysis was used to analyze the expression level of SLC2A3 on different cells in CC, which was validated by immunofluorescence. Its biological functions were further explored in HUVECs. RESULTS: CC samples were grouped into two AGSs (AGS-A and AGS-B) groups and patients in the AGS-B group had poor prognosis. Further analysis revealed that the AGS-B group had high infiltration of TME immune cells, but also exhibited high immune escape. The intratumor microbes were also different between the two subtypes. A convenient 6-gene angiogenesis-related signature (ARS), was established to identify AGSs and predict the prognosis in CC patients. SLC2A3 was selected as the representative gene of ARS, which was higher expressed in endothelial cells and promoted the migration of HUVECs. CONCLUSION: Our study identified two AGSs with distinct prognoses, TME, and intratumor microbial compositions, which could provide potential explanations for the impact on the prognosis of CC. The reliable ARS model was further constructed, which could guide the personalized treatment. The SLC2A3 might be a potential target for antiangiogenic therapy.

4-vinylcyclohexene diepoxide induces apoptosis by excessive reactive oxygen species and DNA damage in human ovarian granulosa cells.

4-Vinylcyclohexene diepoxide (VCD) is a hazardous industrial material which is widely used in the production of fragrances, rubber tires, antioxidants, pesticides, flame retardants and plasticizers. Previous studies have shown that exposure to VCD damages the female reproductive system, but the effects and mechanisms of VCD exposure on human granulosa cells are not reported. In this study, we used a human granulosa cell line (SVOG) to explore the effects of VCD exposure and found that VCD exposure had toxic effects on SVOG cells in vitro. VCD exposure led to excessive accumulation of intracellular ROS, caused DNA damage in cells, altered the expression of some key genes related with apoptosis and oxidative stress, and ultimately inhibited the proliferative capacity of granulosa cells, resulting in increased apoptosis. Overall, our findings provide solid evidence showing that VCD exposure produces severe damage to human granulosa cells, which is helpful for understanding the reproductive toxicity of VCD and etiology of infertility.

Reduction of symptom after a combined behavioral intervention for reward sensitivity and rash impulsiveness in internet gaming disorder: A comparative study.

Impulsivity is both a core symptom and a key psychological mechanism in Internet Gaming Disorder (IGD), and therefore interventions for impulsivity in IGD have both theoretical and practical value. However, previous related interventions only tended to focus on a single factor of impulsivity and achieved inconsistent results. In this study, based on the theory of two-factor model of impulsivity (reward sensitivity and rash impulsiveness), four groups of IGD subjects were recruited to investigate whether there were different effects of single rash impulsiveness or reward sensitivity intervention versus a combined intervention. By comparing the different factors of impulsivity of the four groups before and after a 15-day intervention, the results showed that: (1) compared with the control group, subjects in the Go/No-go training group only had a significantly lower level of rash impulsiveness, subjects in the Stimulus-Response Compatibility (SRC) training group only had a significantly lower level of reward sensitivity, and subjects in the combined training group had significantly lower levels of both impulsivity; (2) among the three intervention groups, only the subjects in the combined training group had significantly lower IGD scores in the follow-up measure. This study indicated that the behavioral training of Go/No-go and SRC were effective in improving rash impulsiveness and reward sensitivity in IGD, respectively, but the intervention effect of the combined training was better than that of the single training.

Ferroptosis-Related Long Noncoding RNAs as Prognostic Marker for Colon Adenocarcinoma.

Background: The incidence of colon adenocarcinoma (COAD) has been increasing over time. Although ferroptosis and long noncoding RNAs (lncRNAs) have been extensively reported to participate in the tumorigenesis and development of COAD, few studies have investigated the role of ferroptosis-related lncRNAs in the prognosis of COAD. Methods: Gene-sequencing and clinical data for COAD were obtained from The Cancer Genome Atlas database. The coexpression network was constructed using known ferroptosis-related genes. Cox and least absolute shrinkage and selection operator regression were used to screen ferroptosis-related lncRNAs with prognostic value and to identify a predictive model of COAD. Patients with COAD were divided into low- and high-risk groups according to their risk score. Cases of COAD in the International Cancer Genome Consortium database were included as the testing cohort. Results: In total, nine lncRNAs (LINC02381, AC105219.1, AC009283.1, LINC01011, ELFN1-AS1, EIF3J-DT, NKILA, LINC01063, and SNHG16) were considered prognostic factors for COAD. Then, a risk score model was established. The overall survival rate of COAD patients was negatively associated with the risk score. Kaplan-Meier analyses in the original and testing cohorts showed similar results. The expression of the lncRNAs in tissue was consistent with the risk score, and the relationship with tumor mutation burden, immunity, and drug sensitivity presented a marked link between the signature and COAD. A nomogram was established for clinical applications. Conclusions: Nine ferroptosis-related lncRNAs and the established signature have a certain predictive value for prognosis of COAD patients and can be used as potential research targets for exploring treatment of COAD.

The contribution of neuropilin-1 in the stability of CD4+ CD25+ regulatory T cells through the TGF-ß1/Smads signaling pathway in the presence of lipopolysaccharides.

INTRODUCTION: This study investigates the synergistic effect of TGF-ß1 and Nrp-1 on CD4+ CD25+ Tregs ' stabilization, and the associated pathways of signal transduction, in vitro models in the presence of LPS. MATERIALS AND METHODS: Spleen CD4+ CD25+ Tregs cells of mice models in the presence of LPS, were transfected with an shRNA targeting Nrp-1, Smad2, or Smad3, may or may not be treated with recombinant TGF-ß1. Followed by subsequent determination of cellular proliferation, rate of apoptosis, observation of the Foxp3, CTLA-4, and TGF-ß1m+ expression levels, foxp3-TSDR methylation, secretion levels of the inhibitory cytokines IL-10 and TGF-ß1, and Smad2/3 of CD4+ CD25+ Tregs expression. RESULTS: A remarkable stimulation in CD4+ CD25+ Tregs ' stability is noted after administering recombinant TGF-ß1 in the presence of LPS, and promoted cellular viability, increased Foxp3, CTLA-4, and TGF-ß1m+ expression, and elevated secretion of IL-10 and TGF-ß1. This also inhibited the apoptosis and methylation of foxp3- TSDR of CD4+ CD25+ Tregs . The shRNA transfection silenced Nrp-1 and Smad3, but not Smad2, resulting in the suppression of the recombinant TGF-ß1-mediated effects in the presence of LPS. CONCLUSIONS: According to the results, Nrp-1 mediates TGF-ß1 to improve the stability of regulatory CD4+ CD25+ T cells and maybe a possible therapeutic target with the ability to improve the CD4+ CD25+ Tregs associated negative immunoregulation that is related to the TGF-ß1/Smads cell signaling during sepsis.

Quantification of uric acid concentration in tears by using PDMS inverse opal structure surface-enhanced Raman scattering substrates: Application in hyperuricemia.

Hyperuricemia is closely related to a variety of diseases and has been listed as one of the twenty most persistent diseases in the 21st century by the United Nations. Therefore, strengthening the diagnosis of hyperuricemia has become imperative. Here, ordered inverse opal array structures (PAANs) composed of PDMS and gold nanoparticles (AuNPs) have been designed using a bottom-up self-assembly method. The structures exhibit a periodic distribution of hot spots, an enhancement factor (EF) of 4.22 × 104, and a relative standard deviation (RSD) of signal intensity of less than 5%, which can provide high reproducibility of SERS signals. The PAANs substrate is used to detect uric acid in the tears of patients with hyperuricemia, and the limit of detection is 6.03 µM. The significant linear relationship between blood uric acid and tear uric acid indicates that the developed method is a rapid, effective, and non-invasive technique for the determination of uric acid in tears.

Association between CES1 rs2244613 and the pharmacokinetics and safety of dabigatran: Meta-analysis and quantitative trait loci analysis.

Objective: To date, the influence of the carboxylesterase 1 (CES1) rs2244613 genotype on the pharmacokinetics (PKs) and safety of dabigatran remains controversial. Hence, a systematic review was performed to study the association between CES1 rs2244613 genotype and the PKs and safety of dabigatran and CES1 relative expression. Methods: In addition to the three English databases (Web of Science, PubMed, and Embase), two Chinese databases (CNKI and Wanfang) were thoroughly revised. The mean differences (MD) and corresponding 95% confidence intervals (CI) were applied to evaluate the differences in PKs between the CES1 rs2244613 genotype. Odds ratio (OR) was used to study the risk for bleeding events between the CES1 rs2244613 genotypes. Subsequent expression quantitative trait loci (eQTL) analyses were performed to evaluate genotype-specific expressions in human tissues. Results: Ten studies (n = 2,777) were included. CES1 rs2244613 G allele carriers exhibited significantly lower dabigatran trough concentrations compared to T allele carriers (MD: -8.00 ng/mL; 95% CI: -15.08 to -0.92; p = 0.03). The risk for bleeding events was significantly lower in carriers of the G allele compared to T allele carriers (OR: 0.65; 95% CI: 0.44-0.96; p = 0.03). Subsequent eQTL analysis showed significant genome-wide expressions in two human tissues, whole blood (p = 5.1 × 10-10) and liver (p = 6.2 × 10-43). Conclusion: Our meta-analysis indicated a definite relation between the CES1 rs2244613 genotype and tolerability variations or pharmacokinetic fluctuations. The carriers of T allele showed higher dabigatran concentrations; therefore, they would benefit from a dose reduction. Systematic review registration: [https://inplasy.com/inplasy-2022-6-0027/], identifier [NPLASY202260027].