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A bstract In this paper, we calculate the matrix element and form factors of vector-to- vector ( V I → V II ) transition within the standard light-front (SLF) and covariant light- front (CLF) quark models (QMs), and investigate the self-consistency and Lorentz covari- ance of the CLF QM within two types of correspondences between the manifest covariant Bethe-Salpeter approach and the LF approach. The zero-mode and valence contributions to the form factors of V I → V II transition in the CLF QM and their relation to the SLF results are analyzed, and the main conclusions obtained via the decay constants of vector and axial-vector mesons and the form factors of P → V transition in the previous works are confirmed again. Furthermore, we present our numerical predictions for the form factors of c → ( q, s ) ( q = u, d ) induced D * → ( K * , ρ ), D ∗ → ( ϕ, K * ), J/ Ψ → D s ∗ D ∗ , B c ∗ → B s ∗ B ∗ transitions and b → ( c, s, q ) induced B ∗  → ( D ∗ ,  K ∗ ,  ρ ), B s ∗ → D s ∗ ϕ K ∗ , B c ∗ → J / Ψ D s ∗ D ∗ , ϒ 1 S → B c ∗ B s ∗ B ∗ the relevant phenomenological studies of meson decays.

Metabolic reprogramming is associated with NLRP3 inflammasome activation in activated macrophages, contributing to inflammatory responses. Tanshinone IIA (Tan-IIA) is a major constituent from Salvia miltiorrhiza Bunge, which exhibits anti-inflammatory activity. In this study, we investigated the effects of Tan-IIA on inflammation in macrophages in focus on its regulation of metabolism and redox state. In lipopolysaccharides (LPS)-stimulated mouse bone marrow-derived macrophages (BMDMs), Tan-IIA (10 μM) significantly decreased succinate-boosted IL-1β and IL-6 production, accompanied by upregulation of IL-1RA and IL-10 release via inhibiting succinate dehydrogenase (SDH). Tan-IIA concentration dependently inhibited SDH activity with an estimated IC 50 of 4.47 μM in LPS-activated BMDMs. Tan-IIA decreased succinate accumulation, suppressed mitochondrial reactive oxygen species production, thus preventing hypoxia-inducible factor-1α (HIF-1α) induction. Consequently, Tan-IIA reduced glycolysis and protected the activity of Sirtuin2 (Sirt2), an NAD + -dependent protein deacetylase, by raising the ratio of NAD + /NADH in activated macrophages. The acetylation of α-tubulin was required for the assembly of NLRP3 inflammasome; Tan-IIA increased the binding of Sirt2 to α-tubulin, and thus reduced the acetylation of α-tubulin, thus impairing this process. Sirt2 knockdown or application of Sirt2 inhibitor AGK-2 (10 μM) neutralized the effects of Tan-IIA, suggesting that Tan-IIA inactivated NLRP3 inflammasome in a manner dependent on Sirt2 regulation. The anti-inflammatory effects of Tan-IIA were observed in mice subjected to LPS challenge: pre-administration of Tan-IIA (20 mg/kg, ip) significantly attenuated LPS-induced acute inflammatory responses, characterized by elevated IL-1β but reduced IL-10 levels in serum. The peritoneal macrophages isolated from the mice displayed similar metabolic regulation. In conclusion, Tan-IIA reduces HIF-1α induction via SDH inactivation, and preserves Sirt2 activity via downregulation of glycolysis, contributing to suppression of NLRP3 inflammasome activation. This study provides a new insight into the anti-inflammatory action of Tan-IIA from the respect of metabolic and redox regulation. Upon LPS stimulation, macrophages undergo metabolic reprogramming to enhance glycolysis with suppressed oxidative metabolism, which further increased succinate accumulation and SDH activity to boost inflammatory response. Tan-IIA remarkably inhibited mitochondrial ROS generation through interrupting SDH hyperactivation to further reduce HIF-1α stabilization and transcription. And for that, attenuated glycolysis and preserved Sirt2 activity contributed to suppression of NLRP3 inflammatory activation to further reduce the maturation of IL-1β.

Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory synaptic transmission in glutamatergic neurons. The number and subunit composition of AMPARs are fundamental to synaptic plasticity and the formation of entire neural networks. Accordingly, the insertion and functionalization of AMPARs at the postsynaptic membrane have become a core issue related to neural circuit formation and information processing in the central nervous system. In this review, we summarize current knowledge regarding the related mechanisms of AMPAR expression and trafficking. The proteins related to AMPAR trafficking are discussed in detail, including vesicle-related proteins, cytoskeletal proteins, synaptic proteins, and protein kinases. Furthermore, significant emphasis was placed on the pivotal role of the actin cytoskeleton, which spans throughout the entire transport process in AMPAR transport, indicating that the actin cytoskeleton may serve as a fundamental basis for AMPAR trafficking. Additionally, we summarize the proteases involved in AMPAR post-translational modifications. Moreover, we provide an overview of AMPAR transport and localization to the postsynaptic membrane. Understanding the assembly, trafficking, and dynamic synaptic expression mechanisms of AMPAR may provide valuable insights into the cognitive decline associated with neurodegenerative diseases.

Supratentorial ependymoma (ST-EPN) is a type of malignant brain tumor mainly seen in children. Since 2014, it has been known that an intrachromosomal fusion C11orf95-RELA is an oncogenic driver in ST-EPN [Parker et al. Nature 506:451–455 (2014); Pietsch et al. Acta Neuropathol 127:609–611 (2014)] but the molecular mechanisms of oncogenesis are unclear. Here we show that the C11orf95 component of the fusion protein dictates DNA binding activity while the RELA component is required for driving the expression of ependymoma-associated genes. Epigenomic characterizations using ChIP-seq and HiChIP approaches reveal that C11orf95-RELA modulates chromatin states and mediates chromatin interactions, leading to transcriptional reprogramming in ependymoma cells. Our findings provide important characterization of the molecular underpinning of C11orf95-RELA fusion and shed light on potential therapeutic targets for C11orf95-RELA subtype ependymoma.

Background This study aimed to analyze and study the clinical effect of suture anchors in the treatment of radial head fractures (RHFs). Methods A total of 11 patients (five male and six female) with RHFs who were treated from March 2016 to June 2021 were included in this study. They were 17–61 (average 38.5) years old. In terms of the Johnston–Mason classification, two cases were type II, seven cases were type III, and two cases were type IV. All patients were treated with open reduction and anchor internal fixation. Results All 11 patients were followed up, all incisions healed by first intention, and the duration of follow-up was 14–20 months. The average operation time was 40 ± 15 min. The clinical healing time was 4–6 (average 5) weeks. No patients had any complications, such as traumatic arthritis, malunion, nerve injury, joint stiffness, or incision infection. The clinical effects were evaluated according to the Mayo Elbow Performance Score. The scores of all 11 cases were 90–95, all excellent. Conclusion The application of suture anchor internal fixation in the treatment of RHFs has the advantages of accurate reduction, no need for a secondary operation to remove the fixation materials, less trauma, fewer complications, good fracture healing, and good recovery of elbow extension, flexion, and rotation functions.

Brain tumors are the leading cause of cancer-related death in children. Tazemetostat is an FDA-approved enhancer of zeste homolog (EZH2) inhibitor. To determine its role in difficult-to-treat pediatric brain tumors, we examined EZH2 levels in a panel of 22 PDOX models and confirmed EZH2 mRNA over-expression in 9 GBM (34.6 ± 12.7-fold) and 11 medulloblastoma models (6.2 ± 1.7 in group 3, 6.0 ± 2.4 in group 4) accompanied by elevated H3K27me3 expression. Therapeutic efficacy was evaluated in 4 models (1 GBM, 2 medulloblastomas and 1 ATRT) via systematically administered tazemetostat (250 and 400 mg/kg, gavaged, twice daily) alone and in combination with cisplatin (5 mg/kg, i.p., twice) and/or radiation (2 Gy/day × 5 days). Compared with the untreated controls, tazemetostat significantly (Pcorrected < 0.05) prolonged survival times in IC-L1115ATRT (101% at 400 mg/kg) and IC-2305GBM (32% at 250 mg/kg, 45% at 400 mg/kg) in a dose-dependent manner. The addition of tazemetostat with radiation was evaluated in 3 models, with only one [IC-1078MB (group 4)] showing a substantial, though not statistically significant, prolongation in survival compared to radiation treatment alone. Combining tazemetostat (250 mg/kg) with cisplatin was not superior to cisplatin alone in any model. Analysis of in vivo drug resistance detected predominance of EZH2-negative cells in the remnant PDOX tumors accompanied by decreased H3K27me2 and H3K27me3 expressions. These data supported the use of tazemetostat in a subset of pediatric brain tumors and suggests that EZH2-negative tumor cells may have caused therapy resistance and should be prioritized for the search of new therapeutic targets. This study confirms the preservation of EZH2 overexpression in 22 patient-derived orthotopic xenograft models of pediatric brain tumors. The authors demonstrate the activity of an FDA-approved EZH2 inhibitor, tazemetostat, alone and in combination with radiation in a subset of the models, and identifies EZH2-negative cells as potential cause of therapy resistance.

Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin Xiao-Nan Li 1 , 2 , 3 , Jun Song 1 , 2 , 3 , Lin Zhang 1 , 2 , Scott A. LeMaire 1 , 2 , Xiaoyang Hou 1 , 2 , 3 , Cheng Zhang 1 , 2 , 3 , Joseph S. Coselli 1 , 2 , Li Chen 3 , Xing Li Wang 1 , 2 , Yun Zhang 3 and Ying H. Shen 1 , 2 1 Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas; 2 Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas; 3 Qilu Hospital, Shandong University, Jinan, Shandong, China. Corresponding authors: Yun Zhang, zhangyun{at}sdu.edu.cn , and Ying H. Shen, hyshen{at}bcm.edu . X.-N.L. and J.S. contributed equally to this study. Abstract OBJECTIVE Oxidative stress induced by free fatty acids contributes to the development of cardiovascular diseases in patients with metabolic syndrome. Reducing oxidative stress may attenuate these pathogenic processes. Activation of AMP-activated protein kinase (AMPK) has been reported to reduce intracellular reactive oxygen species (ROS) levels. The thioredoxin (Trx) system is a major antioxidant system. In this study, we investigated the mechanisms involved in the AMPK-mediated regulation of Trx expression and the reduction of intracellular ROS levels. RESEARCH DESIGN AND METHODS We observed that activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) significantly reduced ROS levels induced by palmitic acid in human aortic endothelial cells. Activation of AMPK increased expression of the antioxidant Trx, which mediated the ROS reduction. RT-PCR showed that AMPK regulated Trx at the transcriptional level. RESULTS Forkhead transcription factor 3 (FOXO3) was identified as the target transcription factor involved in the upregulation of Trx expression. FOXO3 bound to the Trx promoter, recruited the histone acetylase p300 to the Trx promoter, and formed a transcription activator complex, which was enhanced by AICAR treatment. AMPK activated FOXO3 by promoting its nuclear translocation. We further showed that AICAR injection increased the expression of Trx and decreased ROS production in the aortic wall of ApoE−/− mice fed a high-fat diet. CONCLUSIONS These results suggest that activation of the AMPK-FOXO3 pathway reduces ROS levels by inducing Trx expression. Thus, the AMPK-FOXO3-Trx axis may be an important defense mechanism against excessive ROS production induced by metabolic stress and could be a therapeutic target in treating cardiovascular diseases in metabolic syndrome. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received October 31, 2008. Accepted June 28, 2009. © 2009 by the American Diabetes Association.

The poor clinical outcomes of pediatric high-grade glioma (pHGG) highlight the urgent need for new therapies. Oligodendrocyte lineage transcription factor 2 (OLIG2) is a pro-mitotic transcription factor highly expressed in glioma stem cells and may represent a novel therapeutic target. To evaluate the therapeutic efficacy of an OLIG2 inhibitor CT-179 in pHGG, we determined the OLIG2 mRNA expression in 10 patient-derived orthotopic xenograft (PDOX) models. In vitro activities of CT-179 were analyzed in monolayer and neurosphere cells (0–10 µM) with and without radiation (XRT) (0–8 Gy), brain penetration was evaluated in tumor-bearing PDOX mice, and in vivo efficacy was determined at 15–240 mg/kg (oral) alone or combined with XRT (2 Gy/day × 5 days). Changes in animal survival times were analyzed using the Kaplan–Meier method, followed by pair-wise comparisons. Increased OLIG2 mRNA expression was detected in seven out of ten PDOX models. CT-179 inhibited cell viability in a time- and dose-dependent manner in all eight pGBM xenograft tumors (IC50 0.03–10 µM) and was potentiated by XRT (0.03–1 µM). Oral gavage (24 mg/kg) of CT-179 for 5 days led to effective penetration in mouse cerebrum (3232.7 ± 569.2 ng/g), cerebellum (1563.3 ± 269.6 ng/g), brain stem (1685.3 ± 309 ng/g), and PDOX tumors (1814 ± 110.3 ng/g) vs. 361.3 ± 1.5 ng/mL in serum. CT-179 alone was not active at 200 mg/kg in four models, although it was moderately effective at 240 mg/kg in one model. When combined with XRT, a significant extension of animal survival times was observed in two out of four models. Doses needed to eliminate OLIG2 expression in vitro varied from 0.3 to >1 µM in pGBM cells. In summary, our data showed that orally administered CT-179 penetrated the blood–brain barrier (BBB) and exhibited potential for inhibiting pGBM growth when combined with XRT.

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal childhood cancer of the brain. Despite the introduction of conventional chemotherapy and radiotherapy, improvements in survival have been marginal and long-term survivorship is uncommon. Thus, new targets for therapeutics are critically needed. Early phase clinical trials exploring molecularly-targeted therapies against the epidermal growth factor receptor (EGFR) and novel immunotherapies targeting interleukin receptor-13α2 (IL-13Rα2) have demonstrated activity in this disease. To identify additional therapeutic markers for cell surface receptors, we performed exome sequencing (16 new samples, 22 previously published samples, total 38 with 26 matched normal DNA samples), RNA deep sequencing (17 new samples, 11 previously published samples, total 28 with 18 matched normal RNA samples), and immunohistochemistry (17 DIPG tissue samples) to examine the expression of the interleukin-4 (IL-4) signaling axis components (IL-4, interleukin 13 (IL-13), and their respective receptors IL-4Rα, IL-13Rα1, and IL-13Rα2). In addition, we correlated cytokine and receptor expression with expression of the oncogenes EGFR and c-MET. In DIPG tissues, transcript-level analysis found significant expression of IL-4, IL-13, and IL-13Rα1/2, with strong differential expression of IL-13Rα1/2 in tumor versus normal brain. At the protein level, immunohistochemical studies revealed high content of IL-4 and IL-13Rα1/2 but notably low expression of IL-13. Additionally, a strong positive correlation was observed between c-Met and IL-4Rα. The genomic and transcriptional landscape across all samples was also summarized. These data create a foundation for the design of potential new immunotherapies targeting IL-13 cell surface receptors in DIPG.

Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 ± 3.8) reveals stable molecular subtypes (RELA and PFA) and convergent DNA methylation reprogramming during serial relapses accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation in the late recurrences. A set of differentially methylated CpGs (DMCs) and DNA methylation regions (DMRs) are found to persist in primary and relapse tumors (potential driver DMCs) and are acquired exclusively in the relapses (potential booster DMCs). Integrating with RNAseq reveals differentially expressed genes regulated by potential driver DMRs ( CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and potential booster DMRs ( PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). DMCs predicators of relapse are also identified in the primary tumors. This study provides a high-resolution epigenetic roadmap of serial EPN relapses and 13 orthotopic PDX models to facilitate biological and preclinical studies. While recurrence is frequent in ependymoma, the underlying molecular mechanisms remain to be explored. Here, the authors investigate epigenetic, genetic and tumorigenic changes in 30 patient-matched repeated relapses over 13 years and identify distinct patterns of DNA methylation.