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Abstract Sickle cell anemia (SCA) negatively impacts the ability to achieve educational and occupational goals increasing vulnerability to socioeconomic challenges. In a cross‐sectional analysis of 332 SCA adults, we investigated whether the distressed community index (DCI) was associated with SCA‐related complications and nutritional status. More patients with higher DCI had Medicaid insurance. A higher DCI was independently associated with tobacco use and lower body mass index, serum albumin, and vitamin D 25‐OH levels after adjusting for insurance status but was not associated with SCA‐related complications. Future studies investigating access to healthy foods may help improve health equity in patients with SCA.

Objectives Measuring the quality of care is paramount to inform policies for healthcare services. Nevertheless, little is known about the quality of primary care and acute care provided in Korea. This study investigated trends in the quality of primary care and acute care. Methods Case-fatality rates and avoidable hospitalization rates were used as performance indicators to assess the quality of primary care and acute care. Admission data for the period 2008 to 2020 were extracted from the National Health Insurance Claims Database. Case-fatality rates and avoidable hospitalization rates were standardized by age and sex to adjust for patients’ characteristics over time, and significant changes in the rates were identified by joinpoint regression. Results The average annual percent change in age-/sex-standardized case-fatality rates for acute myocardial infarction was -2.3% (95% confidence interval, -4.6 to 0.0). For hemorrhagic and ischemic stroke, the age-/sex-standardized case-fatality rates were 21.8% and 5.9%, respectively in 2020; these rates decreased since 2008 (27.1 and 8.7%, respectively). The average annual percent change in age-/sex-standardized avoidable hospitalization rates ranged from -9.4% to -3.0%, with statistically significant changes between 2008 and 2020. In 2020, the avoidable hospitalization rates decreased considerably compared with the 2019 rate because of the coronavirus disease 2019 pandemic. Conclusions The avoidable hospitalization rates and case-fatality rates decreased overall during the past decade, but they were relatively high compared with other countries. Strengthening primary care is an essential requirement to improve patient health outcomes in the rapidly aging Korean population.

Abstract The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread around the world. Mutant strains of SARS-CoV-2 are constantly emerging. At present, Omicron variants have become mainstream. In this work, we carried out a systematic and comprehensive analysis of the reported spike protein antibodies, counting the epitopes and genotypes of these antibodies. We further comprehensively analyzed the impact of Omicron mutations on antibody epitopes and classified these antibodies according to their binding patterns. We found that the epitopes of the H-RBD class antibodies were significantly less affected by Omicron mutations than other classes. Binding and virus neutralization experiments showed that such antibodies could effectively inhibit the immune escape of Omicron. Cryo-EM results showed that this class of antibodies utilized a conserved mechanism to neutralize SARS-CoV-2. Our results greatly help us deeply understand the impact of Omicron mutations. Meanwhile, it also provides guidance and insights for developing Omicron antibodies and vaccines.

ObjectivesThe aim of the current study was to explore the impact of plaque calcification in terms of absolute calcified plaque volume (CPV) and in the context of its percentage of the total plaque volume at a lesion and patient level on the progression of coronary artery disease.BackgroundCoronary artery calcification is an established marker of risk of future cardiovascular events. Despite this, plaque calcification is also considered a marker of plaque stability, and it increases in response to medical therapy.MethodsThis analysis included 925 patients with 2,568 lesions from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) registry, in which patients underwent clinically indicated serial coronary computed tomography angiography. Plaque calcification was examined by using CPV and percent CPV (PCPV), calculated as (CPV/plaque volume) × 100 at a per-plaque and per-patient level (summation of all individual plaques).ResultsCPV was strongly correlated with plaque volume (r = 0.780; p

Flexible and wearable devices are attracting more and more attention. Herein, we propose a self-powered triboelectric nanogenerator based on the triboelectric effect of fish scales. As the pressure on the nanogenerator increases, the output voltage of the triboelectric nanogenerator increases. The nanogenerator can output a voltage of 7.4 V and a short-circuit current of 0.18 μA under a pressure of 50 N. The triboelectric effect of fish scales was argued to be related to the lamellar structure composed of collagen fiber bundles. The nanogenerator prepared by fish scales can sensitively perceive human activities such as walking, finger tapping, and elbow bending. Moreover, fish scales are a biomass material with good biocompatibility with the body. The fish-scale nanogenerator is a kind of flexible, wearable, and self-powered triboelectric nanogenerator showing great prospects in healthcare and body information monitoring.

ObjectivesThe prevalence of unruptured intracranial aneurysms (UIAs) in the acute ischemic stroke (AIS) cohort is probably higher than in the general population. This study investigated the prevalence of UIAs in AIS patients and the management risk and prognosis when treating AIS.MethodsFrom January 2020 to January 2023, we conducted a single-center retrospective study at Tianjin Huanhu Hospital. Each patient underwent both brain MRI and MRA/CTA to diagnose AIS and UIAs. Clinical, radiologic, and therapeutic data during hospitalization and prognosis were analyzed. Propensity-score matching (PSM) was performed to evaluate the risk of in-hospital adverse events, unfavorable outcomes at discharge when receiving post-stroke treatment and stroke recurrence.ResultsIn all, 2,181 AIS patients were included, of whom 270 had UIAs (12.4%; 95%CI 11.0–13.8%). From the unmatched and matched cohort, the incidence of in-hospital adverse events and unfavorable outcomes at discharge in patients with UIAs were not significantly different; the risk of stroke recurrence was significantly higher in patients with UIAs than in those without (unmatched: aHR, 1.71 [1.08–2.70]; matched: aHR, 2.55 [1.16–5.58]). Multivariable Cox regression models showed that aneurysm size and the presence of homoregional infarction associated with higher risk of recurrence (unmatched: aHR, 1.31 [1.21–1.41] and aHR, 3.50 [1.52–8.10]; matched: aHR, 1.28 [1.18–1.40]; p

Abstract BackgroundDigital therapeutics (DTx) are therapeutic interventions driven by software and directly provided to patients, allowing them to manage their health with ease in any setting. A growing interest in DTx has spurred a discussion concerning their reimbursement pathways. However, DTx are still at a premature stage, with insufficient evidence on effectiveness, efficiency, and safety. Currently, although industries desire to quickly enter the market, especially by getting their products reimbursed by the National Health Insurance (NHI) fund, the NHI is cautious about DTx due to their uncertainties. Thus, public discussion and social consensus are crucial in deciding whether to reimburse DTx by the NHI fund. ObjectiveThis study examined multiple stakeholders’ awareness and attitudes toward DTx and perceptions of regulatory pathways for adopting DTx. MethodsIn-depth interviews were conducted with 11 stakeholders in South Korea (industry: n=4, health care: n=3, academia: n=2, and consumer: n=2) using semistructured guidelines. They were purposively sampled to identify individuals with expertise in DTx and NHI policies. The interviews were conducted either in person or via a videoconference for 45-70 minutes. Qualitative data were analyzed using directed content analysis, which uses interview guidelines as an analytical framework. ResultsFindings were divided into three categories: (1) awareness and attitude toward DTx, (2) perception of whether DTx are worth entering the market and being reimbursed by the NHI fund, and (3) perception of how to enter the market and how to reimburse DTx by the NHI fund if they are worth it. Although consumer stakeholders were not familiar with the basic concept of DTx, the other stakeholders understood it thoroughly. However, all participants showed positive attitudes and acceptance of DTx. Most of them responded that DTx are worth entering the market, but they could not reach an agreement on the pathways for DTx to enter the market. Although participants were in favor of the reimbursement of DTx in principle, they responded that a conservative approach is required due to insufficient clinical evidence for DTx. ConclusionsWe found that stakeholders in South Korea had positive attitudes toward DTx, perceived them as worth using, and agreed to allow them to enter the market. The main issue was not the problem of the technology itself but the difference in opinion as to the pathways for reimbursement. Therefore, this study concluded that the NHI fund, which is operated very conservatively, is insufficient to quickly adopt and implement DTx. Various reimbursement methods, including tax-based financing, raising innovation funds for new technologies, and pilot studies using the NHI fund, should be used to rapidly generate clinical evidence and reduce the uncertainties of DTx to secure a stable market.

The present study investigated the anti-inflammatory potential of phlorofucofuroeckol-A (PFF-A) from Ecklonia cava in TNF-α/IFN-γ-stimulated HaCaT keratinocytes and an acute ear edema mice model. Upon investigation, PFF-A had no cytotoxicity up to 62.5 μg/mL and indicated a dose-dependent-cytoprotective effect with a reduction of intracellular ROS in TNF-α/IFN-γ-stimulated HaCaT keratinocytes. PFF-A downregulated the mRNA expression of inflammatory cytokines (IL-25, IL-33, TSLP, IL-1β, IL-6, IL-8, IL-13, IFN-γ, and TNF-α) and chemokines (Eotaxin, MDC, RANTES, and TARC) in TNF-α/IFN-γ-stimulated HaCaT keratinocytes. Furthermore, PFF-A inhibited the activation of the NFκB/MAPK signaling whereas activated the Nrf2/HO-1 signaling. As an extended evaluation, PFF-A treatment significantly decreased the ear thickness and the expression of inflammatory mediators including iNOS and COX-2 in the TPA-induced ear edema mice model. This study suggests the anti-inflammatory potential of PFF-A in the skin and the potential of E. cava consisting of PFF-A to develop functional foods that have effects on abnormal immune responses.

Objective: This retrospective study aims to evaluate the utility of exome sequencing (ES) in identifying genetic causes of congenital orofacial clefts (OFCs) in fetuses with or without other structural abnormalities, and to further explore congenital OFCs genetic causes.Methods: The study enrolled 107 singleton pregnancies diagnosed with fetal OFCs between January 2016 and May 2022, and categorized them into two groups: isolated cleft lip and/or palate (CL/CP) and syndromic CL/CP. Cases with positive karyotyping and chromosomal microarray analysis results were excluded. Whole-exome sequencing was performed on eligible fetuses and their parents. Monogenic variants identified by ES and perinatal outcomes were recorded and evaluated during postnatal follow-up.Results: Clinically significant variants were identified in 11.2% (12/107) of fetuses, with no significant difference in detection rate between the isolated CL/CP group and the syndromic CL/CP group (8/83, 9.6% vs. 4/24, 16.7%, p = 0.553). Additionally, sixteen (16/107, 15.0%) fetuses had variants of uncertain significance. We identified 12 clinically significant variations that correlated with clinical phenotypes in 11 genes from 12 fetuses, with CHD7 being the most frequently implicated gene (n = 2). Furthermore, we observed a significant difference in termination rates and survival rates between the isolated CL/CP and syndromic CL/CP groups (41.0% vs. 70.8% and 56.6% vs. 20.8%, p < 0.05 for both).Conclusion: Based on our findings, it is clear that ES provides a significant increase in diagnostic yield for the molecular diagnosis of congenital OFCs, thereby substantially improving the existing prenatal diagnostic capabilities. This study also sheds light on seven novel pathogenic variants, broadening our understanding of the genetic underpinnings of OFCs and expanding the disease spectrums of relevant genes.

Summary: The dissection of a gene regulatory network (GRN) that complements the genome-wide association study (GWAS) locus and the crosstalk underlying multiple agronomical traits remains a major challenge. In this study, we generate 558 transcriptional profiles of lint-bearing ovules at one day post-anthesis from a selective core cotton germplasm, from which 12,207 expression quantitative trait loci (eQTLs) are identified. Sixty-six known phenotypic GWAS loci are colocalized with 1,090 eQTLs, forming 38 functional GRNs associated predominantly with seed yield. Of the eGenes, 34 exhibit pleiotropic effects. Combining the eQTLs within the seed yield GRNs significantly increases the portion of narrow-sense heritability. The extreme gradient boosting (XGBoost) machine learning approach is applied to predict seed cotton yield phenotypes on the basis of gene expression. Top-ranking eGenes (NF-YB3, FLA2, and GRDP1) derived with pleiotropic effects on yield traits are validated, along with their potential roles by correlation analysis, domestication selection analysis, and transgenic plants.

Doxorubicin, a member of the anthracycline family, is a widely prescribed anticancer chemotherapy drug. Unfortunately, cumulative doses of doxorubicin can cause mitochondrial dysfunction, leading to acute or chronic cardiotoxicity. This study demonstrated that Neopetroside-B (NPS-B) protects cardiomyocytes in the presence of doxorubicin. NPS-B improved mitochondrial function in cardiomyocytes by increasing ATP production and oxygen consumption rates. On the other hand, NPS-B negatively influenced cancer cell lines by increasing reactive oxygen species. We analyzed NPS-B-influenced metabolites (VIP > 1.0; AUC>0.7; p 2.0) and constructed metabolite-protein enrichment, which showed that NPS-B affected uracil metabolism and NAD-binding proteins (e.g., aldehyde dehydrogenase and glutathione reductase) in cardiomyocytes. However, for the cancer cells, NPS-B decreased the NAD+/NADH balance, impairing cell viability. In a xenograft mouse model treated with doxorubicin, NPS-B reduced cardiac fibrosis and improved cardiac function. NPS-B may be a beneficial intervention to reducing doxorubicin-induced cardiotoxicity with anticancer effects.

Congenital heart disease (CHD) is a serious condition with unknown etiology. In a recent study, a compound heterozygous mutation (c.3526C > T [p.Arg1176Trp] and c.4643A > G [p.Asp1548Gly]) in the ASXL3 gene was identified, which is associated with CHD. This mutation was overexpressed in HL-1 mouse cardiomyocyte cells, leading to increased cell apoptosis and decreased cell proliferation. However, whether this effect is mediated by long noncoding RNAs (lncRNAs) is yet to be determined. We identified the differences among lncRNA and mRNA profiles in mouse heart tissues using sequencing to explore this issue. We detected HL-1 cell proliferation and apoptosis through CCK8 and flow cytometry. Fgfr2, lncRNA, and Ras/ERK signaling pathway expressions were evaluated using quantitative real time polymerase chain reaction (qRT-PCR) and western blot (WB) assays. We also conducted functional investigations by silencing lncRNA NONMMUT063967.2. The sequencing revealed significant changes in lncRNA and mRNA profiles, with the expression of lncRNA NONMMUT063967.2 being significantly promoted in the ASXL3 gene mutations group (MT) while the expression of Fgfr2 being downregulated. The in vitro experiments showed that ASXL3 gene mutations inhibited the proliferation of cardiomyocytes and accelerated cell apoptosis by promoting the expression of lncRNAs (NONMMUT063967.2, NONMMUT063918.2, and NONMMUT063891.2), suppressing the formation of FGFR2 transcripts, and inhibiting the Ras/ERK signaling pathway. The decrease in FGFR2 had the same effect on the Ras/ERK signaling pathway, proliferation, and apoptosis in mouse cardiomyocytes as ASXL3 mutations. Further mechanistic studies revealed that suppression of lncRNA NONMMUT063967.2 and overexpression of FGFR2 reversed the effects of the ASXL3 mutations on the Ras/ERK signaling pathway, proliferation, and apoptosis in mouse cardiomyocytes. Therefore, ASXL3 mutation decreases FGFR2 expression by upregulating lncRNA NONMMUT063967.2, inhibiting cell proliferation and promoting cell apoptosis in mouse cardiomyocytes.

Background Post-transplant diabetes mellitus (PTDM) is a risk factor for poor outcomes after kidney transplantation (KT). However, the outcomes of KT have improved recently. Therefore, we investigated whether PTDM is still a risk factor for mortality, major atherosclerotic cardiovascular events (MACEs), and graft failure in KT recipients. Methods We studied a retrospective cohort of KT recipients (between 1994 and 2017) at a single tertiary center, and compared the rates of death, MACEs, overall graft failure, and death-censored graft failure after KT between patients with and without PTDM using Kaplan-Meier analysis and a Cox proportional hazard model. Results Of 571 KT recipients, 153 (26.8%) were diagnosed with PTDM. The mean follow-up duration was 9.6 years. In the Kaplan- Meier analysis, the PTDM group did not have a significantly increased risk of death or four-point MACE compared with the non-diabetes mellitus group (log-rank test, P=0.957 and P=0.079, respectively). Multivariate Cox proportional hazard models showed that PTDM did not have a negative impact on death or four-point MACE (P=0.137 and P=0.181, respectively). In addition, PTDM was not significantly associated with overall or death-censored graft failure. However, patients with a long duration of PTDM had a higher incidence of four-point MACE. Conclusion Patient survival and MACEs were comparable between groups with and without PTDM. However, PTDM patients with long duration diabetes were at higher risk of cardiovascular disease.

The picture hesitant fuzzy sets (PHFSs), which consider neutral membership degree as well as positive and negative membership degrees, provide decision makers (DMs) a flexible attitude to evaluate criteria values in complex multi-criteria decision-making (MCDM) situations. However, existing MCDM approaches based on PHFSs still have some drawbacks in both evaluation information expression and criteria values fusion. In this paper, our aim is to overcome these shortcomings by proposing new decision-making methods. To achieve this purpose, a new fuzzy information representation tool, called probabilistic picture hesitant fuzzy sets (P-PHFSs), is first introduced by capturing the probability of each element in PHFSs. The characteristic of P-PHFSs is that they provide more freedom to DMs so that criterion values of each alternative can be adequately described. To facilitate the use of P-PHFSs, we define the basic operational rules and comparison method of P-PHFSs. Then we also propose some aggregation operators for P-PHFSs and provide information fusion process. Furthermore, some desirable properties of these operators is discussed, and the relationship between the developed operators and the existing ones is investigated. Based on the proposed operators, two MCDM methods are developed under probabilistic picture hesitant fuzzy environment. Finally, two numerical examples are given to show the application of the developed methods, and a comparison analysis is conducted to demonstrate the effectiveness of the proposed approaches.

Abstract Background There are a few studies on the chromosomal aberration of Ultrasound soft markers (USMs). The aim of this study was to determine the detection rate of clinically significant chromosomal abnormalities (CSCA) in fetuses with different USMs. Methods This study included fetuses with USMs who underwent invasive prenatal diagnosis for karyotype and/or chromosomal microarray (CMA) by categorizing into two groups: a single USM (SUSM) and multiple USMs (MUSMs). Results Of the 358 cases with USMs, CSCA occurred in 3.09% (8/259) and 8.08% (8/99) of the SUSM and MUSM groups, respectively (P

Patients with lung cancer may experience various symptoms as the disease progresses, which may reduce the benefits of cancer treatment, reduce treatment compliance, delay cancer treatment, reduce the quality of life (QoL), and impact survival. This review discusses comprehensive symptom assessment and management, which are crucial for high-quality lung cancer treatment. Traditional Chinese medicine (TCM) is important in relieving cancer-related symptoms in patients with lung cancer. Including patient-reported outcomes (PROs) in clinical trials and practice can provide a better assessment of symptom burden and the effectiveness of symptom management. Patient-centered care with TCM in lung cancer patients may include six steps: Symptom screening, etiology investigation, comprehensive assessment, integrative management, reassessment, and regular symptom follow-up monitoring. PRO measures can be used to evaluate symptom intensity, the degree to which symptoms interfere with activities of daily living, and the QoL. Clearly defined and reliable PRO measures can enhance patient satisfaction and improve symptom control. Quantitative PRO measures developed from the TCM perspective should be considered one of the important outcome measurements in TCM care. A multidisciplinary collaborative symptom management model, including TCM and conventional therapy, will be the future goal for treating patients with lung cancer.

The accurate, quantitative, and objective prediction of the brain age for premature infants will contribute to the exploration of brain maturity and catch-up growth. Traditional approaches rely heavily on a pediatrician’s clinical experience, which makes the whole process time-consuming and labor-intensive. To solve this problem, we propose a deep learning-based brain age prediction model for preterm infants via neonatal MRI for this purpose, and it is called as BAPNET for short. First of all, we collected a specific dataset including MR images of 281 preterm infants. Then, a pretraining model (DeepBrainNet) is applied as the main backbone, and transfer learning is utilized to enhance the baseline model by making knowledge transfer from the ImageNet dataset. The proposal can be viewed as a specific prediction model by absorbing knowledge enhancement from peripheral visual features. On a test set of 70 preterm infants held out from the original dataset, 2D-BPANET achieved results with an mean square error (MAE) of 1.15 and the 95% - 95% content tolerance interval for a difference (prediction and ground truth) of [−3.82, 3.39], whereas 3D-BPANET achieved better results with an MAE of 1.8 and a difference of [0.51, 3.09]. Meanwhile, we leverage heatmaps to verify the consistency between hindbrain regions and cortical fold regions outputted by our model and the latest studies of brain development in preterm infants. In conclusion, BPANET demonstrates that deep learning can estimate brain maturity in preterm infants and provides a reference standard for preterm infant brain development, which could be applied as a promising tool.

Abstract Background (R)-mandelic acid (R-MA) is a highly valuable hydroxyl acid in the pharmaceutical industry. However, biosynthesis of optically pure R-MA remains significant challenges, including the lack of suitable catalysts and high toxicity to host strains. Adaptive laboratory evolution (ALE) was a promising and powerful strategy to obtain specially evolved strains. Results Herein, we report a new cell factory of the Gluconobacter oxydans to biocatalytic styrene oxide into R-MA by utilizing the G. oxydans endogenous efficiently incomplete oxidization and the epoxide hydrolase (SpEH) heterologous expressed in G. oxydans. With a new screened strong endogenous promoter P 12780 , the production of R-MA was improved to 10.26 g/L compared to 7.36 g/L of using P lac . As R-MA showed great inhibition for the reaction and toxicity to cell growth, adaptive laboratory evolution (ALE) strategy was introduced to improve the cellular R-MA tolerance. The adapted strain that can tolerate 6 g/L R-MA was isolated (named G. oxydans STA), while the wild-type strain cannot grow under this stress. The conversion rate was increased from 0.366 g/L/h of wild type to 0.703 g/L/h by the recombinant STA, and the final R-MA titer reached 14.06 g/L. Whole-genome sequencing revealed multiple gene-mutations in STA, in combination with transcriptome analysis under R-MA stress condition, we identified five critical genes that were associated with R-MA tolerance, among which AcrA overexpression could further improve R-MA titer to 15.70 g/L, the highest titer reported from bulk styrene oxide substrate. Conclusions The microbial engineering with systematic combination of static regulation, ALE, and transcriptome analysis strategy provides valuable solutions for high-efficient chemical biosynthesis, and our evolved G. oxydans would be better to serve as a chassis cell for hydroxyl acid production.

This article examines discourses that shaped different outcomes for Yemeni refugees in 2018 and Afghan special contributors in 2021 in South Korea. Following the country’s mission to evacuate its Afghan interlocutors in 2021, Afghans are fast‐tracked for social integration through the creation of emergency enforcement ordinances, with South Korean society broadly welcoming them as national heroes and recognizing them as “special contributors” rather than refugees. In contrast, Yemeni refugees arriving in 2018 were subjected to Islamophobic and legal abuse, constructed as potential sex offenders and terrorists, and accused of being fake refugees. In both cases, refugee protections according to South Korea’s 2013 Refugee Law were withheld as Yemenis and Afghans were processed through alternative systems. This article concludes that Muslim refugee issues in South Korea are masculinized and delves into the multi‐faceted complex factors at play when analyzing the differences between the reception of Afghan evacuees and Yemeni refugees in the South Korean context.

Background Thiazolidinediones (TZDs) have been associated with various safety concerns including weight gain, bladder cancer, and congestive heart failure (CHF). This study evaluated the efficacy and safety of lobeglitazone, a novel TZD in patients with type 2 diabetes mellitus (T2DM) in real practice. Methods In this non-interventional, multi-center, retrospective, and observational study conducted at 15 tertiary or secondary referral hospitals in Korea, a total of 2,228 patients with T2DM who received lobeglitazone 0.5 mg for more than 1 year were enrolled. Results Overall adverse events (AEs) occurred in 381 patients (17.10%) including edema in 1.97% (n=44). Cerebrovascular and cardiovascular diseases were identified in 0.81% (n=18) and 0.81% (n=18), respectively. One case of CHF was reported as an AE. Edema occurred in 1.97% (n=44) of patients. Hypoglycemia occurred in 2.47% (n=55) of patients. Fracture occurred in 1.17% (n=26) of all patients. Lobeglitazone significantly decreased HbA1c level, resulting in a mean treatment difference of −1.05%± 1.35% (P

Summary: Recent trends suggest novel natural compounds as promising treatments for cardiovascular disease. The authors examined how neopetroside A, a natural pyridine nucleoside containing an α-glycoside bond, regulates mitochondrial metabolism and heart function and investigated its cardioprotective role against ischemia/reperfusion injury. Neopetroside A treatment maintained cardiac hemodynamic status and mitochondrial respiration capacity and significantly prevented cardiac fibrosis in murine models. These effects can be attributed to preserved cellular and mitochondrial function caused by the inhibition of glycogen synthase kinase-3 beta, which regulates the ratio of nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide, reduced, through activation of the nuclear factor erythroid 2–related factor 2/NAD(P)H quinone oxidoreductase 1 axis in a phosphorylation-independent manner.