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Dabigatran acylglucuronide, an active metabolite of dabigatran, exhibits higher plasma concentrations and distinct anticoagulant effects compared to dabigatran, suggesting that it may play a more significant role in overall anticoagulant activity than previously assumed. Idarucizumab, a monoclonal antibody fragment, binds to both free and thrombin-bound dabigatran, neutralizing its anticoagulant effects. However, its efficacy in reversing anticoagulation induced by dabigatran acylglucuronide remains unclear. This study aimed to evaluate whether idarucizumab differentially reverses the anticoagulant effects of dabigatran and dabigatran acylglucuronide. In vitro experiments were conducted using blood from healthy, drug-free donors. Plasma samples were spiked with either dabigatran or dabigatran acylglucuronide, followed by idarucizumab. Standard coagulation assays, including prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), as well as thrombin generation assays (TGA), were performed. At a concentration of 1 µM, idarucizumab demonstrated significantly greater reversal of dabigatran acylglucuronide-induced anticoagulation than that of dabigatran in PT, aPTT, and TT assays. Consistently, TGA showed stronger neutralization of dabigatran acylglucuronide, with IC 50 values for C max , endogenous thrombin potential, and lag time at least 2.0-fold higher than those of dabigatran. These findings indicate that idarucizumab exerts a more potent reversal effect on dabigatran acylglucuronide compared to dabigatran.

Dabigatran etexilate (DABE), a prodrug of dabigatran (DAB), is a direct thrombin inhibitor used to prevent ischemic stroke and thromboembolism during atrial fibrillation. The effect of genetic polymorphisms on its metabolism, particularly , has not been extensively explored in humans. This study aimed to investigate the effects of , , and polymorphisms on the pharmacokinetics of DAB and its acylglucuronide metabolites in healthy subjects. A total of 124 healthy males were genotyped for , , and polymorphisms. After a single 150 mg dose of DABE, plasma concentrations of total and free DAB, as well as dabigatran acylglucuronide (DABG) were measured using LC-MS/MS. Pharmacokinetic parameters were analyzed using non-compartmental methods, and statistical comparisons were conducted between the genotype groups. c.253G>T significantly affected free DAB pharmacokinetics, with a lower T and oral clearance in TT genotype (n = 28, < 0.05). For DABG, C was significantly higher in GG genotypes (n = 32, 42.3 ± 16.3 ng/mL) compared to that in GT (n = 64, 32.4 ± 20.5 ng/mL) and TT (29.7 ± 17.1 ng/mL) genotypes. Similarly, the AUC of DABG was highest in GG genotypes (327 ± 148.3 ng h·mL ), followed by GT (238.7 ± 166.5 ng h·mL ) and TT (223.3 ± 165.4 ng h·mL ) genotypes ( < 0.05). The metabolite-to-parent ratios (m/p ratios) for C and AUC were significantly higher in GG and GT genotypes than that in TT genotype. and polymorphisms had no significant impact on the pharmacokinetics of DAB or DABG. polymorphisms were associated with difference in DAB glucuronidation and pharmacokinetics in healthy male participants.

The toxicokinetics of β-amanitin, a toxic bicyclic octapeptide present abundantly in Amanitaceae mushrooms, was evaluated in mice after intravenous (iv) and oral administration. The area under plasma concentration curves (AUC) following iv injection increased in proportion to doses of 0.2, 0.4, and 0.8 mg/kg. β-amanitin disappeared rapidly from plasma with a half-life of 18.3–33.6 min, and 52.3% of the iv dose was recovered as a parent form. After oral administration, the AUC again increased in proportion with doses of 2, 5, and 10 mg/kg. Absolute bioavailability was 7.3–9.4%, which resulted in 72.4% of fecal recovery from orally administered β-amanitin. Tissue-to-plasma AUC ratios of orally administered β-amanitin were the highest in the intestine and stomach. It also readily distributed to kidney > spleen > lung > liver ≈ heart. Distribution to intestines, kidneys, and the liver is in agreement with previously reported target organs after acute amatoxin poisoning. In addition, β-amanitin weakly or negligibly inhibited major cytochrome P450 and 5′-diphospho-glucuronosyltransferase activities in human liver microsomes and suppressed drug transport functions in mammalian cells that overexpress transporters, suggesting the remote drug interaction potentials caused by β-amanitin exposure.

ObjectiveGenome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case–control population.MethodsWe newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations.ResultsWe identified six new RA-risk loci (SLAMF6, CXCL13, SWAP70, NFKBIA, ZFP36L1 and LINC00158) with pmeta<5×10−8 and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases.ConclusionThis study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.

Considering the high morbidity and mortality of Coronavirus disease 2019 (COVID-19) in patients with malignancy, they are regarded as a priority for COVID-19 vaccination. However, general vaccine uptake rates among cancer patients are known to be lower than in their healthy counterparts. Thus, we aimed to investigate the attitude and acceptance rates for the COVID-19 vaccine in cancer patients and identify predictive factors for vaccination that could be modified to increase vaccine uptake rates, via a paper-based survey (58 items over six domains). A total of 1001 cancer patients participated in this nationwide, multicenter survey between February and April 2021. We observed that 61.8% of respondents were willing to receive the COVID-19 vaccine. Positive predictive factors found to be independently associated with vaccination were male gender, older age, obesity, previous influenza vaccination history, absence of cancer recurrence, time since cancer diagnosis over 5 years, and higher EuroQol Visual Analogue Scale scores. Along with the well-known factors that are positively correlated with vaccination, here, we report that patients’ disease status and current health status were also associated with their acceptance of the COVID-19 vaccination. Moreover, 91.2% of cancer patients were willing to be vaccinated if their attending physicians recommend it, indicating that almost 30% could change their decision upon physicians’ recommendation. Unlike other factors, which are unmodifiable, physicians’ recommendation is the single modifiable factor that could change patients’ behavior. In conclusion, we firstly report that Korean cancer patients’ acceptance rate of the COVID-19 vaccination was 61.8% and associated with disease status and current health status. Physicians should play a major role in aiding cancer patients’ decision-making concerning COVID-19 vaccines.

The connection between marine biogenic dimethyl sulfide (DMS) and the formation of aerosol particles in the Arctic atmosphere was evaluated by analyzing atmospheric DMS mixing ratio, aerosol particle size distribution and aerosol chemical composition data that were concurrently collected at Ny-Ålesund, Svalbard (78.5° N, 11.8° E), during April and May 2015. Measurements of aerosol sulfur (S) compounds showed distinct patterns during periods of Arctic haze (April) and phytoplankton blooms (May). Specifically, during the phytoplankton bloom period the contribution of DMS-derived SO42− to the total aerosol SO42− increased by 7-fold compared with that during the proceeding Arctic haze period, and accounted for up to 70 % of fine SO42− particles (<  2.5 µm in diameter). The results also showed that the formation of submicron SO42− aerosols was significantly associated with an increase in the atmospheric DMS mixing ratio. More importantly, two independent estimates of the formation of DMS-derived SO42− aerosols, calculated using the stable S-isotope ratio and the non-sea-salt SO42− ∕ methanesulfonic acid ratio, respectively, were in close agreement, providing compelling evidence that the contribution of biogenic DMS to the formation of aerosol particles was substantial during the Arctic phytoplankton bloom period.

Neuropeptide Y (NPY) is highly abundant in the brain and involved in various physiological processes related to food intake and anxiety, as well as human diseases such as obesity and cancer. However, the molecular details of the interactions between NPY and its receptors are poorly understood. Here, we report a cryo-electron microscopy structure of the NPY-bound neuropeptide Y1 receptor (Y 1 R) in complex with G i1 protein. The NPY C-terminal segment forming the extended conformation binds deep into the Y 1 R transmembrane core, where the amidated C-terminal residue Y36 of NPY is located at the base of the ligand-binding pocket. Furthermore, the helical region and two N-terminal residues of NPY interact with Y 1 R extracellular loops, contributing to the high affinity of NPY for Y 1 R. The structural analysis of NPY-bound Y 1 R and mutagenesis studies provide molecular insights into the activation mechanism of Y 1 R upon NPY binding. The human neuropeptide Y (NPY) acts through G-protein coupled receptors and is involved in food intake, stress response, anxiety, and memory retention. Here, the authors show that, unlike in other neuropeptides, both the N-terminal and the C-terminal regions of NPY interact with the NPY receptor 1.

A free-standing catalyst electrode for the urea oxidation reaction (UOR) and hydrogen evolution reaction (HER) in a urea electrolysis cell was synthesized by electroplating a Ni–Fe alloy onto carbon felt, followed by phosphidation (P-NiFe@CF). The prepared P-NiFe@CF catalyst consisted of Ni 5 P 4 , NiP 2 , and FeP with 3D flower-like P-NiFe architecture on CF. P-NiFe@CF exhibited excellent electrocatalytic activity for the UOR (demanding only 1.39 V ( vs. RHE) to achieve 200 mA cm −2 ), and for the HER with a low overpotential of 0.023 V ( vs. RHE) at 10 mA cm −2 , indicating its feasibility as a bifunctional catalyst electrode for urea electrolysis. A urea electrolysis cell with P-NiFe@CF as both the free-standing anode and cathode generated a current density of 10 mA cm −2 at a cell potential of 1.37 V ( vs. RHE), which is considerably lower than that of water electrolysis, and also lower than previously reported values. The results indicate that the P-NiFe@CF catalyst electrodes can be used as free-standing bifunctional electrodes for urea electrolyzers.

PurposeObstructive sleep apnea (OSA) is highly prevalent and causes serious cardiovascular complications. Several screening questionnaires for OSA have been introduced, but only few validation studies have been conducted in general population. The aim of the present study was to assess the diagnostic value of three OSA screening questionnaires (Berlin Questionnaire, BQ; STOP-Bang Questionnaire, STOP-B; Four-Variable Screening Tool, Four-V) in a Korean community sample.MethodsA total of 1148 community-dwelling participants completed the BQ, STOP-B, and Four-V. An overnight in-laboratory polysomnography (PSG) was conducted in randomly selected 116 participants. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, and area under the curve (AUC) were calculated.ResultsThe Four-V with cutoff ≥ 8 showed high sensitivity for overall OSA (69.4%), and the Four-V with cutoff ≥ 9 showed high specificity for both overall OSA (81.5%) and moderate to severe OSA (69.0%). On the other hand, the STOP-B showed acceptable sensitivity and specificity for both overall OSA (61.3 and 79.6%, respectively) and moderate to severe OSA (72.4 and 67.8%, respectively). The STOP-Bang also showed the largest area under the receiver-operator characteristic curve for both overall OSA (0.752) and moderate to severe OSA (0.750). The BQ showed the lowest performance in predicting OSA.ConclusionsAmong the three questionnaires, the STOP-B was revealed as the most useful screening tool for OSA in terms of sensitivity, specificity, and area under the receiver-operator characteristic curve in the population of South Korea.

We conducted continuous measurements of nanoparticles down to 3 nm size in the Arctic at Mount Zeppelin, Ny Ålesund, Svalbard, from October 2016 to December 2018, providing a size distribution of nanoparticles (3–60 nm). A significant number of nanoparticles as small as 3 nm were often observed during new particle formation (NPF), particularly in summer, suggesting that these were likely produced near the site rather than being transported from other regions after growth. The average NPF frequency per year was 23 %, having the highest percentage in August (63 %). The average formation rate (J) and growth rate (GR) for 3–7 nm particles were 0.04 cm−3 s−1 and 2.07 nm h−1, respectively. Although NPF frequency in the Arctic was comparable to that in continental areas, the J and GR were much lower. The number of nanoparticles increased more frequently when air mass originated over the south and southwest ocean regions; this pattern overlapped with regions having strong chlorophyll a concentration and dimethyl sulfide (DMS) production capacity (southwest ocean) and was also associated with increased NH3 and H2SO4 concentration, suggesting that marine biogenic sources were responsible for gaseous precursors to NPF. Our results show that previously developed NPF occurrence criteria (low loss rate and high cluster growth rate favor NPF) are also applicable to NPF in the Arctic.