Two genetic variants in the HIBCH and FTCDNL1 genes are associated with susceptibility to developmental dysplasia of the hips among the Han Chinese population of Southwest China.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a common cause of childhood disability, and the incidence of DDH shows significant familial aggregation. As the genetic factors of DDH remain unknown, the correlation between five candidate single nucleotide polymorphisms (SNPs) and DDH was evaluated in the Han Chinese population of Southwest China. METHODS: A case‒control association study was conducted in 276 patients with DDH and 318 healthy controls. SNP genotyping in the case and control groups was performed by SNPshot and multiple PCR. SNPs were genotyped in the case and control groups by multiplex PCR. The relationship between DDH and candidate SNPs was evaluated using the χ2 test. RESULTS: The genotype distributions of rs291412 in HIBCH and rs769956 in FTCDNL1 were different between the case and control groups (P < 0.05). After genetic model analysis, logistic regression analysis revealed that the C allele of rs291412 had a protective effect on DDH (OR = 0.605, P = 0.010) and that the G allele of rs769956 was a risk factor (OR = 2.939, P = 0.010).s. CONCLUSION: These SNPs could be associated with susceptibility to DDH but larger population-based studies should confirm the current results.

Use of Artificial Intelligence to Improve the Calculation of Percent Adhesion for Transdermal and Topical Delivery Systems.

Adhesion is a critical quality attribute and performance characteristic for transdermal and topical delivery systems (TDS). Regulatory agencies recommend in vivo skin adhesion studies to support the approval of TDS in both new drug applications and abbreviated new drug applications. The current assessment approach in such studies is based on the visual observation of the percent adhesion, defined as the ratio of the area of TDS attached to the skin to the total area of the TDS. Visually estimated percent adhesion by trained clinicians or trial participants creates variability and bias. In addition, trial participants are typically confined to clinical centers during the entire product wear period, which may lead to challenges when translating adhesion performance to the real world setting. In this work we propose to use artificial intelligence and mobile technologies to aid and automate the collection of photographic evidence and estimation of percent adhesion. We trained state-of-art deep learning models with advanced techniques and in-house curated data. Results indicate good performance from the trained models and the potential use of such models in clinical practice is further explored.

The Impact of Dysregulated microRNA Biogenesis Machinery and microRNA Sorting on Neurodegenerative Diseases.

MicroRNAs (miRNAs) are 22-nucleotide noncoding RNAs involved in the differentiation, development, and function of cells in the body by targeting the 3'- untranslated regions (UTR) of mRNAs for degradation or translational inhibition. miRNAs not only affect gene expression inside the cells but also, when sorted into exosomes, systemically mediate the communication between different types of cells. Neurodegenerative diseases (NDs) are age-associated, chronic neurological diseases characterized by the aggregation of misfolded proteins, which results in the progressive degeneration of selected neuronal population(s). The dysregulation of biogenesis and/or sorting of miRNAs into exosomes was reported in several NDs, including Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). Many studies support the possible roles of dysregulated miRNAs in NDs as biomarkers and therapeutic treatments. Understanding the molecular mechanisms underlying the dysregulated miRNAs in NDs is therefore timely and important for the development of diagnostic and therapeutic interventions. In this review, we focus on the dysregulated miRNA machinery and the role of RNA-binding proteins (RBPs) in NDs. The tools that are available to identify the target miRNA-mRNA axes in NDs in an unbiased manner are also discussed.

Bioactive Vitamin D Attenuates MED28-Mediated Cell Growth and Epithelial-Mesenchymal Transition in Human Colorectal Cancer Cells.

Inadequate vitamin D status may increase the risk of developing multiple types of cancer. Epidemiological studies suggest an inverse association between 25-hydroxyvitamin D3 (25(OH)D3) and malignancy, including colorectal cancer. Previous studies have suggested that MED28, a Mediator subunit involved in transcriptional regulation, is associated with the growth of colorectal cancer cells; however, its role in the progression of metastasis such as epithelial-mesenchymal transition (EMT) and cell migration of colorectal cancer is unclear at present. The aim of this study was to investigate a potentially suppressive effect of calcitriol, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), a bioactive form of vitamin D, and the role of MED28 in the progression of EMT in human colorectal cancer cells. Suppression of MED28 increased the expression of E-cadherin and reduced the expression of several mesenchymal and migration biomarkers and Wnt/ß-catenin signaling molecules, whereas overexpression of MED28 enhanced the EMT features. Calcitriol suppressed the expression of MED28, and the effect of calcitriol mirrored that of MED28 silencing. Our data indicate that calcitriol attenuated MED28-mediated cell growth and EMT in human colorectal cancer cells, underlining the significance of MED28 in the progression of colorectal cancer and supporting the potential translational application of calcitriol.

TRAX Provides Neuroprotection for Huntington's Disease Via Modulating a Novel Subset of MicroRNAs.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disease caused by CAG-repeat expansions (>36) in exon 1 of HTT, which dysregulates multiple cellular machineries. Translin-associated protein X (TRAX) is a scaffold protein with diverse functions, including suppressing the microRNA (miRNA)-mediated silencing by degrading pre-miRNA. To date, the role of TRAX in neurodegenerative diseases remains unknown. OBJECTIVES: We delineated the role of TRAX upregulation during HD progression. METHODS: Expression of TRAX in the brains of humans and three mouse models with HD were analyzed by immunohistochemistry staining, western blot, and quantitative reverse transcription-polymerase chain reaction. Adeno-associated viruses harboring TRAX short hairpin RNA were intrastriatally injected into HD mice to downregulate TRAX. HD-like symptoms were analyzed by behavioral and biochemical assessments. The miRNA-sequencing and RNA-sequencing analyses were used to identify the TRAX- regulated miRNA-messenger RNA (mRNA) axis during HD progression. The identified gene targets were validated biochemically in mouse and human striatal cells. RESULTS: We discovered that TRAX was upregulated in the brains of HD patients and three HD mouse models. Downregulation of TRAX enhanced 83 miRNAs (including miR-330-3p, miR-496a-3p) and subsequently changed the corresponding mRNA networks critical for HD pathogenesis (eg, DARPP-32 and brain-derived neurotrophic factor). Disruption of the TRAX-mediated miRNA-mRNA axis accelerated the progression of HD-like symptoms, including the degeneration of motor function, accumulation of mHTT aggregates, and shortened neurite outgrowth. CONCLUSIONS: We demonstrated that TRAX upregulation is authentic and protective in HD. Our study provides a novel layer of regulation for HD pathogenesis and may lead to the development of new therapeutic strategies for HD. © 2022 International Parkinson and Movement Disorder Society.

Evasion of NK cell immune surveillance via the vimentin-mediated cytoskeleton remodeling.

Cancer immunotherapy uses the immune system to achieve therapeutic effects; however, its effect is still limited. Therefore, in addition to immune checkpoint-based treatment, the development of other strategies that can inhibit cancer cells from resisting immune cytotoxicity is important. There are currently few studies on the mechanism of tumors using cytoskeletal proteins reorganization to participate in immune escape. In this study, we identified cancer cell lines that were sensitive or resistant to natural killer cells in urothelial and lung cancer using the natural killer cell sensitivity assay. We found that immunoresistant cancer cells avoid natural killer cell-mediated cytotoxicity by upregulation of vimentin and remodeling of actin cytoskeleton. Immunofluorescence staining showed that immune cells promoted the formation of actin filaments at the immune synapse, which was not found in immunosensitive cancer cells. Pretreatment of the actin polymerization inhibitors latrunculin B increased the cytotoxicity of natural killer cells, suggesting that cytoskeleton remodeling plays a role in resisting immune cell attack. In addition, silencing of vimentin with shRNA potentiated the cytotoxicity of natural killer cells. Interestingly, the upregulation and extension of vimentin was found in tumor islands of upper tract urothelial carcinoma infiltrated by natural killer cells. Conversely, tumors without natural killer cell invasion showed less vimentin signal. The expression level of vimentin was highly correlated with natural killer cell infiltration. In summary, we found that when immune cells attack cancer cells, the cancer cells resist immune cytotoxicity through upregulated vimentin and actin reorganization. In addition, this immune resistance mechanism was also found in patient tumors, indicating the possibility that they can be applied to evaluate the immune response in clinical diagnosis.

Endoscopic transcanal transtympanic myringoplasty vs. endoscopic transcanal tympanoplasty: 1-year follow-up study.

BACKGROUND: Endoscopic transcanal transtympanic myringoplasty (ETTM) is a relatively easier technique than endoscopic transcanal tympanoplasty (ETT) for repairing tympanic membrane perforations. No studies have compared the outcomes of these two procedures with tragal perichondrium after 1-year. Furthermore, there is no evidence-based stratification according to variations in perforation size in endoscopic ear surgery. Therefore, we compared the 1-year outcomes of ETTM and ETT stratified according to perforation size. METHODS: Patients who underwent ETT and ETTM to repair eardrum perforations with a tragal perichondrium graft were identified. Pure-tone audiometric tests and otoscopic examination were performed to assess hearing outcomes and perforation sizes both preoperatively and at least 1 year postoperatively. RESULTS: In total, 158 patients (159 ears) were included. ETT was performed on 83 ears, and ETTM was performed on 76 ears. The ETTM procedure time was 10-minutes shorter than that for ETT ( p < 0.001). Perforation size was significantly correlated with graft take-rate. For large perforations, the ETT success rate was significantly higher than that of ETTM (91.7% vs. 78.9%). Success rates for small-medium perforations were comparable for both methods ( p > 0.05). However, for medium perforations, the graft take-rate of ETT reached a plateau after 6 months, while that of ETTM gradually declined during the 12-month follow-up. Both groups had a comparable mean postoperative air-bone gap gain ( p = 0.666). CONCLUSION: ETTM is suitable for repairing small perforations, whereas ETT is preferred for large perforations. Both methods, and particularly ETTM, should be employed cautiously for medium perforations.

Calcitriol Suppresses Warburg Effect and Cell Growth in Human Colorectal Cancer Cells.

Increasing lines of evidence indicate that the biologically active form of vitamin D, calcitriol (1,25-dihydroxyvitamin D3), prevents cancer progression by reducing cell proliferation, increasing cell differentiation, and inhibiting angiogenesis, among other potential roles. Cancer cells in solid tumors preferably undergo the "Warburg effect" to support cell growth by upregulating glycolysis, and the glycolytic intermediates further serve as building blocks to generate biomass. The objective of the current study is to investigate whether calcitriol affects glucose metabolism and cell growth in human colorectal cancer cells. Calcitriol reduced the expression of cyclin D1 and c-Myc. In addition, calcitriol reduced the expression of glucose transporter 1 (GLUT1) and key glycolytic enzymes and decreased extracellular acidification rate but increased oxygen consumption rate in human colorectal cancer cells. In a subcutaneous HT29 xenograft NOD/SCID mouse model, the volume and weight of the tumors were smaller in the calcitriol groups as compared with the control group, and the expression levels of GLUT1 and glycolytic enzymes, hexokinase 2 and lactate dehydrogenase A, were also lower in the calcitriol groups in a dose-responsive manner. Our data indicate that calcitriol suppresses glycolysis and cell growth in human colorectal cancer cells, suggesting an inhibitory role of the biologically active form of vitamin D in colorectal cancer progression.

Long-term inhibition of ferritin2 synthesis in trophocytes and oenocytes by ferritin2 double-stranded RNA ingestion to investigate the mechanisms of magnetoreception in honey bees (Apis mellifera).

Behavioral studies indicate that honey bees (Apis mellifera) have a capacity for magnetoreception and superparamagnetic magnetite is suggested to be a magnetoreceptor. The long-term inhibition of magnetite formation can be employed to explore the bee's magnetoreception. A recent study shows that magnetite formation, ferritin2 messenger RNA (mRNA) expression, and the protein synthesis of ferritin2 in trophocytes and oenocytes were all inhibited by a single injection of ferritin2 double-stranded RNA (dsRNA) into the hemolymph of honey bees but how to maintain this knockdown of ferritin2 for the long-term is unknown. In this study, we injected ferritin2 dsRNA into the hemolymph of worker bees three times every six days to maintain long-term inhibition; however, multi-microinjections accelerated the death of the bees. To overcome this problem, we further reared newly emerged worker bees daily with ferritin2 dsRNA throughout their lives, demonstrating no impact on their lifespans. Follow-up assays showed that the mRNA expression and protein synthesis of ferritin2 were persistently inhibited. These findings verified that daily ferritin2 dsRNA ingestion not only displays the long-term inhibition of mRNA expression and protein synthesis of ferritin2, but also did not damage the bees. This method of long-term inhibition can be used in behavioral studies of magnetoreception in honey bees.

The trophocytes and oenocytes of worker and queen honey bees (Apis mellifera) exhibit distinct age-associated transcriptome profiles.

Despite the identical genomic context, trophocytes and oenocytes in worker bees exhibit aging-related phenotypes, in contrast to the longevity phenotypes in queen bees. To explore this phenomenon at the molecular level, we evaluated the age-associated transcriptomes of trophocytes and oenocytes in worker bees and queen bees using high-throughput RNA-sequencing technology (RNA-seq). The results showed that (i) while gene expression profiles were different between worker and queen bees, they remained similar between young and old counterparts; (ii) worker bees express a high proportion of low-abundance genes, whereas queen bee transcriptomes display a high proportion of moderate-expression genes; (iii) genes were upregulated to a greater extent in queen bees vs. worker bees; and (iv) distinct aging-related and longevity-related candidate genes were found in worker and queen bees. These results provide new insights into the cellular aging and longevity of trophocytes and oenocytes in honey bees. Identification of aging-associated biomarker genes also constitutes a basis for translational research of aging in higher organisms.

Correction to: Equivalence Testing of Complex Particle Size Distribution Profiles Based on Earth Mover's Distance.

On page 5, in the second paragraph, the authors inadvertently included inaccurate information for the description of the analytical method.

Inactivation of APC Induces CD34 Upregulation to Promote Epithelial-Mesenchymal Transition and Cancer Stem Cell Traits in Pancreatic Cancer.

Pancreatic cancer (PC) is a highly lethal malignancy due to the cancer routinely being diagnosed late and having a limited response to chemotherapy. Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic malignant tumor, representing more than 85% of all pancreatic cancers. In the present study, we characterized the phenotypes of concomitant P53 and APC mutations in pancreatic neoplasms driven by the oncogene KRAS in genetically modified mice (GEMM). In this GEMM setting, APC haploinsufficiency coupled with P53 deletion and KRASG12D activation resulted in an earlier appearance of pancreatic intraepithelial neoplasia (PanIN) lesions and progressed rapidly to highly invasive and metastatic PDAC. Through a microarray analysis of murine PDAC cells derived from our APC-deficient PDAC model, we observed that APC loss leads to upregulated CD34 expression in PDAC. CD34 is a member of a family of single-pass transmembrane proteins and is selectively expressed in hematopoietic progenitor cells, vascular endothelial cells, interstitial precursor cells, and various interstitial tumor cells. However, the functional roles of CD34 in pancreatic cancer remain unclear. Thus, in this study, we explored the mechanisms regarding how CD34 promotes the deterioration of pancreatic malignancy. Our results demonstrated that the increased expression of CD34 induced by APC inactivation promotes the invasion and migration of PDAC cells, which may relate to PDAC metastasis in vivo. Collectively, our study provides first-line evidence to delineate the association between CD34 and the APC/Wnt pathway in PDAC, and reveals the potential roles of CD34 in PDAC progression.

Methods and applications of percentile estimation.

Percentile is ubiquitous in statistics and plays a significant role in the day-to-day statistical application. FDA Guidance for Industry: Assay Development for Immunogenicity Testing of Therapeutic Protein Products (2016) recommends the use of a lower confidence limit of the percentile of the negative subject population as the cut point to guarantee a pre-specified false-positive rate with high confidence. Shen proposed and compared an exact t approach with some approximated approaches. However, the exact t approach might be compromised by computational time and complexity. In this article, we proposed to use a UMOVER method as a potential alternative for percentile estimation for one application to screening and confirmatory cut point determination due to its easy implementation and similar performance to the exact t approach. The applications and performance comparison with different approaches are investigated and discussed. Furthermore, we extended the proposed method for the comparison of the percentile of the test product and percentile of the reference product followed by numerical studies.

An ultrathin ionomer interphase for high efficiency lithium anode in carbonate based electrolyte.

High coulombic efficiency and dendrite suppression in carbonate electrolytes remain challenges to the development of high-energy lithium ion batteries containing lithium metal anodes. Here we demonstrate an ultrathin (≤100 nm) lithium-ion ionomer membrane consisting of lithium-exchanged sulfonated polyether ether ketone embedded with polyhedral oligosilsesquioxane as a coating layer on copper or lithium for achieving efficient and stable lithium plating-stripping cycles in a carbonate-based electrolyte. Operando analyses and theoretical simulation reveal the remarkable ability of the ionomer coating to enable electric field homogenization over a considerably large lithium-plating surface. The membrane coating, serving as an artificial solid-electrolyte interphase filter in minimizing parasitic reactions at the electrolyte-electrode interface, enables dendrite-free lithium plating on copper with outstanding coulombic efficiencies at room and elevated (50 °C) temperatures. The membrane coated copper demonstrates itself as a promising current collector for manufacturing high-quality pre-plated lithium thin-film anode.

A modified Wald test for reference scaled assessment of analytical equivalence.

For the reference scaled equivalence hypothesis to reduce the deficiency of the current practice in analytical equivalence assessment, the Wald test with Constrained Maximum Likelihood Estimate (CMLE) of the standard error was proposed to improve the efficiency when the sample sizes of test and reference product lots are small, and variances are unequal. However, by using the Wald test with CMLE standard error, simulations show that the type I error rate is below the nominal significance level. We proposed the Modified Wald test with CMLE standard error by replacing the maximum likelihood estimate of reference standard deviation with the sample estimate (MWCMLE), resulting in further improvement of type I error rate and power over the Wald test with CMLE standard error. In this paper, we further compare the proposed MWCMLE method to the Exact-test-Based (EB) method and the Generalized Pivotal Quantity (GPQ) method with equal or unequal variances, or equal or unequal sample sizes of both product lots. The simulations show that the proposed MWCMLE method outperforms the other two methods in type I error rate control and power improvement.

Specific regions of the SulA protein recognized and degraded by the ATP-dependent ClpYQ (HslUV) protease in Escherichia coli.

In Escherichia coli, ClpYQ (HslUV) is a two-component ATP-dependent protease, in which ClpQ is the peptidase subunit and ClpY is the ATPase and unfoldase. ClpY functions to recognize protein substrates, and denature and translocate the unfolded polypeptides into the proteolytic site of ClpQ for degradation. However, it is not clear how the natural substrates are recognized by the ClpYQ protease and the mechanism by which the substrates are selected, unfolded and translocated by ClpY into the interior site of ClpQ hexamers. Both Lon and ClpYQ proteases can degrade SulA, a cell division inhibitor, in bacterial cells. In this study, using yeast two-hybrid and in vivo degradation analyses, we first demonstrated that the C-terminal internal hydrophobic region (139th∼149th aa) of SulA is necessary for binding and degradation by ClpYQ. A conserved region, GFIMRP, between 142th and 147th residues of SulA, were identified among various Gram-negative bacteria. By using MBP-SulA(F143Y) (phenylalanine substituted with tyrosine) as a substrate, our results showed that this conserved residue of SulA is necessary for recognition and degradation by ClpYQ. Supporting these data, MBP-SulA(F143Y), MBP-SulA(F143N) (phenylalanine substituted with asparagine) led to a longer half-life with ClpYQ protease in vivo. In contrast, MBP-SulA(F143D) and MBP-SulA(F143S) both have shorter half-lives. Therefore, in the E. coli ClpYQ protease complex, ClpY recognizes the C-terminal region of SulA, and F143 of SulA plays an important role for the recognition and degradation by ClpYQ protease.

The TRAX, DISC1, and GSK3 complex in mental disorders and therapeutic interventions.

Psychiatric disorders (such as bipolar disorder, depression, and schizophrenia) affect the lives of millions of individuals worldwide. Despite the tremendous efforts devoted to various types of psychiatric studies and rapidly accumulating genetic information, the molecular mechanisms underlying psychiatric disorder development remain elusive. Among the genes that have been implicated in schizophrenia and other mental disorders, disrupted in schizophrenia 1 (DISC1) and glycogen synthase kinase 3 (GSK3) have been intensively investigated. DISC1 binds directly to GSK3 and modulates many cellular functions by negatively inhibiting GSK3 activity. The human DISC1 gene is located on chromosome 1 and is highly associated with schizophrenia and other mental disorders. A recent study demonstrated that a neighboring gene of DISC1, translin-associated factor X (TRAX), binds to the DISC1/GSK3ß complex and at least partly mediates the actions of the DISC1/GSK3ß complex. Previous studies also demonstrate that TRAX and most of its interacting proteins that have been identified so far are risk genes and/or markers of mental disorders. In the present review, we will focus on the emerging roles of TRAX and its interacting proteins (including DISC1 and GSK3ß) in psychiatric disorders and the potential implications for developing therapeutic interventions.

Luteolin attenuates neutrophilic oxidative stress and inflammatory arthritis by inhibiting Raf1 activity.

Neutrophils play a significant role in inflammatory tissue injury. Activated neutrophils produce reactive oxygen species (ROS), release proteases, and form neutrophil extracellular traps (NETs), significantly affecting the pathogenesis of inflammatory arthritis. We examined the therapeutic effects of luteolin, a flavone found in many plants, in neutrophilic inflammation and on acute inflammatory arthritis. Luteolin significantly inhibited superoxide anion generation, ROS production, and NET formation in human neutrophils. The increase in elastase release, CD11b expression, and chemotaxis was also inhibited by luteolin. Luteolin significantly suppressed phosphorylation of extracellular signal-regulated kinase (Erk) and mitogen-activated protein kinase kinase-1 (MEK-1), but not c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Analysis of the molecular mechanism further revealed that luteolin acts as a Raf-1 inhibitor. In mice with complete Freund's adjuvant-induced arthritis, luteolin ameliorated neutrophil infiltration as well as the thickness of paw edema and ROS production. In conclusion, in addition to its known ROS scavenging effect, this study is the first to provide evidence that luteolin diminishes human neutrophil inflammatory responses by inhibiting Raf1-MEK-1-Erk. Our results focused on the importance of neutrophil activation in inflammatory tissue injury and offer opportunities for the development of luteolin's therapeutic potential to attenuate neutrophilic inflammatory diseases.

Equivalence Testing of Complex Particle Size Distribution Profiles Based on Earth Mover's Distance.

Particle size distribution (PSD) is an important property of particulates in drug products. In the evaluation of generic drug products formulated as suspensions, emulsions, and liposomes, the PSD comparisons between a test product and the branded product can provide useful information regarding in vitro and in vivo performance. Historically, the FDA has recommended the population bioequivalence (PBE) statistical approach to compare the PSD descriptors D50 and SPAN from test and reference products to support product equivalence. In this study, the earth mover's distance (EMD) is proposed as a new metric for comparing PSD particularly when the PSD profile exhibits complex distribution (e.g., multiple peaks) that is not accurately described by the D50 and SPAN descriptor. EMD is a statistical metric that measures the discrepancy (distance) between size distribution profiles without a prior assumption of the distribution. PBE is then adopted to perform statistical test to establish equivalence based on the calculated EMD distances. Simulations show that proposed EMD-based approach is effective in comparing test and reference profiles for equivalence testing and is superior compared to commonly used distance measures, e.g., Euclidean and Kolmogorov-Smirnov distances. The proposed approach was demonstrated by evaluating equivalence of cyclosporine ophthalmic emulsion PSDs that were manufactured under different conditions. Our results show that proposed approach can effectively pass an equivalent product (e.g., reference product against itself) and reject an inequivalent product (e.g., reference product against negative control), thus suggesting its usefulness in supporting bioequivalence determination of a test product to the reference product which both possess multimodal PSDs.

GSK3ß negatively regulates TRAX, a scaffold protein implicated in mental disorders, for NHEJ-mediated DNA repair in neurons.

Translin-associated protein X (TRAX) is a scaffold protein with various functions and has been associated with mental illnesses, including schizophrenia. We have previously demonstrated that TRAX interacts with a Gsα protein-coupled receptor, the A2A adenosine receptor (A2AR), and mediates the function of this receptor in neuritogenesis. In addition, stimulation of the A2AR markedly ameliorates DNA damage evoked by elevated oxidative stress in neurons derived from induced pluripotent stem cells (iPSCs). Here, we report that glycogen synthase kinase 3 beta (GSK3ß) and disrupted-in-schizophrenia 1 (DISC1) are two novel interacting proteins of TRAX. We present evidence to suggest that the stimulation of A2AR markedly facilitated DNA repair through the TRAX/DISC1/GSK3ß complex in a rat neuronal cell line (PC12), primary mouse neurons, and human medium spiny neurons derived from iPSCs. A2AR stimulation led to the inhibition of GSK3ß, thus dissociating the TRAX/DISC1/GSK3ß complex and facilitating the non-homologous end-joining pathway (NHEJ) by enhancing the activation of a DNA-dependent protein kinase via phosphorylation at Thr2609. Similarly, pharmacological inhibition of GSK3ß by SB216763 also facilitated the TRAX-mediated repair of oxidative DNA damage. Collectively, GSK3ß binds with TRAX and negatively affects its ability to facilitate NHEJ repair. The suppression of GSK3ß by A2AR activation or a GSK3ß inhibitor releases TRAX for the repair of oxidative DNA damage. Our findings shed new light on the molecular mechanisms underlying diseases associated with DNA damage and provides a novel target (i.e., the TRAX/DISC1/GSK3ß complex) for future therapeutic development for mental disorders.