Role of NADPH Oxidase 4 on Dry Eye Syndrome in Mice.

Objective: This study aims to investigate the effect of NADPH oxidase 4 (NOX4)-mediated inflammation on concanavalin A (ConA)-induced dry eye syndrome (DES) in mice. Methods: Thirty-six mice were randomly divided into Control, Model, no-load Control, and NOX4 interference group. Adenovirus was injected (10 µL) into the lacrimal glands of both eyes of mice in no-load Control group and NOX4 interference group. Four days after adenovirus injection, the Control group was injected with phosphate-buffered saline, and the other groups were injected with ConA (200 µg) in the lacrimal glands of mice to establish DES models. The tear secretion rate was estimated by phenol red thread test. Lissamine green eye staining was used to evaluate conjunctival damage. The corneal surface was observed by hematoxylin-eosin (HE) staining and scanning electron microscopy (SEM). The morphology and quantity of conjunctival epithelial cells and goblet cells were observed by Periodic acid-Schiff staining. The expression of NOX4, NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), interleukin-1ß (IL-1ß), and mucin 5 subtype AC (MUC5AC) was detected by immunohistochemistry. Results: Compared with the Control group, the Model group showed a significant decrease in tear secretion and an upregulation in microscopic image score. The HE staining and SEM showed corneal and conjunctiva damage in the Model group. The protein expression of NOX4, NLRP3, and IL-1ß was upregulated, but MUC5AC was downregulated in the Model group. After interfering with NOX4, all these indicators were reversed. Conclusion: The pathological process of concanavalin A-induced DES appears to be related to NOX4.

Enhanced Reactivities of Iron(IV)-Oxo Porphyrin Species in Oxidation Reactions Promoted by Intramolecular Hydrogen-Bonding.

High-valent iron-oxo species are one of the common intermediates in both biological and biomimetic catalytic oxidation reactions. Recently, hydrogen-bonding (H-bonding) has been proved to be critical in determining the selectivity and reactivity. However, few examples have been established for mechanistic insights into the H-bonding effect. Moreover, intramolecular H-bonding effect on both C-H activation and oxygen atom transfer (OAT) reactions in synthetic porphyrin model system has not been investigated yet. In this study, a series of heme-containing iron(IV)-oxo porphyrin species with or without intramolecular H-bonding are synthesized and characterized. Kinetic studies revealed that intramolecular H-bonding can significantly enhance the reactivity of iron(IV)-oxo species in OAT, C-H activation, and electron-transfer reactions. This unprecedented unified H-bonding effect is elucidated by theoretical calculations, which showed that intramolecular H-bonding interactions lower the energy of the anti-bonding orbital of iron(IV)-oxo porphyrin species, resulting in the enhanced reactivities in oxidation reactions irrespective of the reaction type. To the best of the knowledge, this is the first extensive investigation on the intramolecular H-bonding effect in heme system. The results show that H-bonding interactions have a unified effect with iron(IV)-oxo porphyrin species in all three investigated reactions.

Wearable Sensor-Based Residual Multifeature Fusion Shrinkage Networks for Human Activity Recognition.

Human activity recognition (HAR) based on wearable sensors has emerged as a low-cost key-enabling technology for applications such as human-computer interaction and healthcare. In wearable sensor-based HAR, deep learning is desired for extracting human active features. Due to the spatiotemporal dynamic of human activity, a special deep learning network for recognizing the temporal continuous activities of humans is required to improve the recognition accuracy for supporting advanced HAR applications. To this end, a residual multifeature fusion shrinkage network (RMFSN) is proposed. The RMFSN is an improved residual network which consists of a multi-branch framework, a channel attention shrinkage block (CASB), and a classifier network. The special multi-branch framework utilizes a 1D-CNN, a lightweight temporal attention mechanism, and a multi-scale feature extraction method to capture diverse activity features via multiple branches. The CASB is proposed to automatically select key features from the diverse features for each activity, and the classifier network outputs the final recognition results. Experimental results have shown that the accuracy of the proposed RMFSN for the public datasets UCI-HAR, WISDM, and OPPORTUNITY are 98.13%, 98.35%, and 93.89%, respectively. In comparison with existing advanced methods, the proposed RMFSN could achieve higher accuracy while requiring fewer model parameters.

Expression of TXLNA in brain gliomas and its clinical significance: a bioinformatics analysis.

BACKGROUND: To analyze the expression of TXLNA in brain gliomas and its clinical significance. METHODS: Gene Expression Profiling Interactive Analysis（GEPIA）and Chinese Glioma Genome Atlas（CGGA）databases were retrieved as the methods. To assess the disparity between TXLNA expression in glioma and normal brain tissue. The Kaplan-Meier survival curve was employed to preliminarily evaluate the survival curves of the high and low expression groups, this was done for investigate the correlation between TXLNA expression level and the survival and prognosis of glioma. A Cox proportional regression risk model of multivariate nature was employed to evaluate the elements impacting the survival and prognosis of glioma. Gene pool enrichment analysis（GSEA）was used to investigate the related function of TXLNA in glioma. A Pearson correlation test and co-expression analysis were employed to identify the genes most associated with TXLNA expression. RESULT: The enrichment analysis results were observably enriched in signal pathways for instance the cell cycle and completion and coordination cascade pathways, and it is evident that high expression of TXLNA in gliomas is related to a poor survival and a bad patient prognosis, thus making it an independent prognostic factor for gliomas. Genes such as STK40 and R1MS1 are significantly correlated with TXLNA, playing a synergistic or antagonistic role. CONCLUSIONS: The prognosis of GBM patients is strongly linked to the high expression of TXLNA, which may be a viable therapeutic target for curbing cancer progression and creating new immunotherapies for GBM.

Proteomic analysis of anti-aging effects of Dendrobium nobile Lindl. alkaloids in aging-accelerated SAMP8 mice.

Senescence-accelerated mouse prone 8 (SAMP8) mice exhibit cognitive defects and neuron loss with aging, and were used to study anti-aging effects of Dendrobium nobile alkaloids (DNLA). DNLA (20 and 40 mg/kg) were orally administered to SAMP8 mice from 6 to 10 months of age. At 10-month of age, behavioral tests via Y-maze and Open-field and neuron damage via Nissl staining were evaluated. Protein was extracted and subjected to phosphorylated proteomic analysis followed by bioinformatic analysis. The cognitive deficits and neuron loss in hippocampus and cortex of aged SAMP8 mice were improved by DNLA. Hippocampal proteomic analysis revealed 196 differentially expressed protein/genes in SAMP8 compared to age-matched senescence-accelerated resistant SAMR1 mice. Gene Oncology enriched the tubulin binding, microtubule binding, and other activities. Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed endocytosis, mRNA surveillance, tight junction, protein processing in endoplasmic reticulum, aldosterone synthesis and secretion, and glucagon signaling pathway changes. Upregulated protein/genes in the hippocampus of SAMP8 mice, such as Lmtk3, Usp10, Dzip1, Csnk2b, and Rtn1, were attenuated by DNLA; whereas downregulated protein/genes, such as Kctd16, Psd3, Bsn, Atxn2l, and Kif1a, were rescued by DNLA. The aberrant protein/gene expressions of SAMP8 mice were correlated with transcriptome changes of Alzheimer's disease in the Gene Expression Omnibus (GEO) database, and the scores were attenuated by DNLA. Thus, DNLA improved cognitive dysfunction and ameliorated neuronal injury in aged SAMP8 mice, and attenuated aberrant protein/gene expressions.

Prediction of drug-target interactions via neural tangent kernel extraction feature matrix factorization model.

Drug discovery is a complex and lengthy process that often requires years of research and development. Therefore, drug research and development require a lot of investment and resource support, as well as professional knowledge, technology, skills, and other elements. Predicting of drug-target interactions (DTIs) is an important part of drug development. If machine learning is used to predict DTIs, the cost and time of drug development can be significantly reduced. Currently, machine learning methods are widely used to predict DTIs. In this study neighborhood regularized logistic matrix factorization method based on extracted features from a neural tangent kernel (NTK) to predict DTIs. First, the potential feature matrix of drugs and targets is extracted from the NTK model, then the corresponding Laplacian matrix is constructed according to the feature matrix. Next, the Laplacian matrix of the drugs and targets is used as the condition for matrix factorization to obtain two low-dimensional matrices. Finally, the matrix of the predicted DTIs was obtained by multiplying these two low-dimensional matrices. For the four gold standard datasets, the present method is significantly better than the other methods that is compared to, indicating that the automatic feature extraction method using the deep learning model is competitive compared with the manual feature selection method.

Photo/Ni dual-catalyzed radical defluorinative sulfonylation to synthesize gem-difluoro allylsulfones.

Radical defluorinative functionalization of α-trifluoromethyl styrenes represents an effective way toward gem-difluoroalkenes. There are general interests in developing novel synthetic protocols for defluorinative functionalization with various types of radicals. However, reports on the preparation of gem-difluoro allylsulfones via an S-centered radical pathway are limited. Herein, we developed a photo/nickel dual-catalyzed defluorinative sulfonylation that rapidly and reliably synthesizes gem-difluoro allylsulfones. The merit of this protocol is exhibited by its mild conditions and wide scope, thus providing a novel strategy for the sulfonyl radical participating in radical defluorinative coupling.

Prophylactic IVC filter placement in patients with severe intracranial, spinal cord, and orthopedic injuries at high thromboembolic event risk: A utilization and outcomes analysis of the National Trauma Data Bank.

PURPOSE: To determine relationships between prophylactic inferior vena cava filter (IVCF) insertion and pulmonary embolism (PE), deep venous thrombosis (DVT), and in-hospital mortality outcomes in patients with severe traumatic pelvic/lower extremity, intracranial, and spinal cord injuries. METHODS: Adult patients with severe traumatic pelvic/lower extremity, intracranial, and spinal cord injuries admitted to level I-IV trauma centers were selected from the National Trauma Data Bank (NTDB). IVCFs that were inserted both ≤48 h after admission and before a lower extremity venous ultrasound were defined as prophylactic. Associations between prophylactic IVCF insertion and PE, DVT, and overall mortality outcomes during admission were estimated using logistic regression models after propensity score matching. Additionally, factors predictive of prophylactic IVCF insertion were estimated using multivariate logistic regression. RESULTS: Of 462,838 patients, 11,938 (2.6%) underwent prophylactic IVCF insertion. Prophylactic IVCF utilization decreased over time (6.3% in 2008 to 1.8% in 2015). Factors associated with prophylactic IVCF placement were injury pattern, trauma center level/region, Injury Severity Score, and race. Prophylactic IVCF placement was positively associated with PE (Odds Ratio (OR): 5.25, p < 0.01) and DVT (OR: 5.55, p < 0.01), but negatively associated with in-hospital mortality compared to the propensity score-matched control group (OR: 0.46, p < 0.01). CONCLUSION: Prophylactic IVCF insertion in adult patients with severe pelvic/lower extremity fractures, intracranial injuries, and spinal cord injuries was negatively associated with in-hospital mortality, but positively associated with VTE. Further research evaluating the use of prophylactic IVCF placement in trauma patients with these specific severe injury types may be warranted.

Comprehensive analysis: Necroptosis-related lncRNAs can effectively predict the prognosis of glioma patients.

Glioma is the most common and fatal primary brain tumor in humans. A significant role for long non-coding RNA (lncRNA) in glioma is the regulation of gene expression and chromatin recombination, and immunotherapy is a promising cancer treatment. Therefore, it is necessary to identify necroptosis-related lncRNAs in glioma. In this study, we collected and evaluated the RNA-sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA, https://www.ncbi.nlm.nih.gov/, Data Release 32.0, March 29, 2022) glioma patients, and necroptosis-related lncRNAs were screened. Cox regression and least absolute shrinkage and selection operator (LASSO) analysis were performed to construct a risk score formula to explore the different overall survival between high- and low-risk groups in TCGA. Gene Ontology (GO) and pathway enrichment analysis (Kyoto Encyclopedia of Genes and Genomes (KEGG)) were performed to identify the function of screened genes. The immune correlation analysis showed that various immune cells and pathways positively associated with a patient's risk score. Furthermore, the analysis of the tumor microenvironment indicated many immune cells and stromal cells in the tumor microenvironment of glioma patients. Six necroptosis-related lncRNAs were concerned to be involved in survival and adopted to construct the risk score formula. The results showed that patients with high-risk scores held poor survival in TCGA. Compared with current clinical data, the area under the curve (AUC) of different years suggested that the formula had better predictive power. We verified that necroptosis-related lncRNAs play a significant role in the occurrence and development of glioma, and the constructed risk model can reasonably predict the prognosis of glioma. The results of these studies added some valuable guidance to understanding glioma pathogenesis and treatment, and these necroptosis-related lncRNAs may be used as biomarkers and therapeutic targets for glioma prevention.

New biomarker: the gene HLA-DRA associated with low-grade glioma prognosis.

BACKGROUND: Low-grade gliomas (LGG) are WHO grade II tumors presenting as the most common primary malignant brain tumors in adults. Currently, LGG treatment involves either or a combination of surgery, radiation therapy, and chemotherapy. Despite the knowledge of constitutive genetic risk factors contributing to gliomas, the role of single genes as diagnostic and prognostic biomarkers is limited. The aim of the current study is to discover the predictive and prognostic genetic markers for LGG. METHODS: Transcriptome data and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We first performed the tumor microenvironment (TME) survival analysis using the Kaplan-Meier method. An analysis was undertaken to screen for differentially expressed genes. The function of these genes was studied by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Following which a protein-protein interaction network (PPI) was constructed and visualized. Univariate and multivariate COX analyses were performed to obtain the probable prognostic genes. The key genes were selected by an intersection of core and prognostic genes. A clinical correlation analysis of single-gene expression was undertaken. GSEA enrichment analysis was performed to identify the function of key genes. Finally, a single gene-related correlation analysis was performed to identify the core immune cells involved in the development of LGG. RESULTS: A total of 529 transcriptome data and 515 clinical samples were obtained from the TCGA. Immune cells and stromal cells were found to be significantly increased in the LGG microenvironment. The top five core genes intersected with the top 38 prognostically relevant genes and two key genes were identified. Our analysis revealed that a high expression of HLA-DRA was associated with a poor prognosis of LGG. Correlation analysis of immune cells showed that HLA-DRA expression level was related to immune infiltration, positively related to macrophage M1 phenotype, and negatively related to activation of NK cells. CONCLUSIONS: HLA-DRA may be an independent prognostic indicator and an important biomarker for diagnosing and predicting survival in LGG patients. It may also be associated with the immune infiltration phenotype in LGG.

Utilization and Comparative Effectiveness of Uterine Artery Embolization versus Hysterectomy for Severe Postpartum Hemorrhage: A National Inpatient Sample Study.

PURPOSE: To identify differences in mortality or length of hospital stay for mothers treated with uterine artery embolization (UAE) or hysterectomy for severe postpartum hemorrhage (PPH), as well as to analyze whether geographic or clinical determinants affected the type of therapy received. MATERIALS AND METHODS: This National Inpatient Sample study from 2005 to 2017 included all patients with live-birth deliveries. Severe PPH was defined as PPH that required transfusion, hysterectomy, or UAE. Propensity score weighting-adjusted demographic, maternal, and delivery risk factors were used to assess mortality and prolonged hospital stay. RESULTS: Of 9.8 million identified live births, PPH occurred in 31.0 per 1,000 cases. The most common intervention for PPH was transfusion (116.4 per 1,000 cases of PPH). Hysterectomy was used more frequently than UAE (20.4 vs 12.9 per 1,000 cases). The following factors predicted that hysterectomy would be used more commonly than UAE: previous cesarean delivery, breech fetal position, placenta previa, transient hypertension during pregnancy without pre-eclampsia, pre-existing hypertension without pre-eclampsia, pre-existing hypertension with pre-eclampsia, unspecified maternal hypertension, and gestational diabetes (all P < .001). Delivery risk factors associated with greater utilization of hysterectomy over UAE included postterm pregnancy, premature rupture of membranes, cervical laceration, forceps vaginal delivery, and shock (all P < .001). There was no difference in mortality between hysterectomy and UAE. After balancing demographic, maternal, and delivery risk factors, the odds of prolonged hospital stay were 0.38 times lower with UAE than hysterectomy (P < .001). CONCLUSIONS: Despite similar mortality and shorter hospital stays, UAE is used far less than hysterectomy in the management of severe PPH.

Enthalpy-Entropy Compensation Effect in Oxidation Reactions by Manganese(IV)-Oxo Porphyrins and Nonheme Iron(IV)-Oxo Models.

"Enthalpy-Entropy Compensation Effect" (EECE) is ubiquitous in chemical reactions; however, such an EECE has been rarely explored in biomimetic oxidation reactions. In this study, six manganese(IV)-oxo complexes bearing electron-rich and -deficient porphyrins are synthesized and investigated in various oxidation reactions, such as hydrogen atom transfer (HAT), oxygen atom transfer (OAT), and electron-transfer (ET) reactions. First, all of the six Mn(IV)-oxo porphyrins are highly reactive in the HAT, OAT, and ET reactions. Interestingly, we have observed a reversed reactivity in the HAT and OAT reactions by the electron-rich and -deficient Mn(IV)-oxo porphyrins, depending on reaction temperatures, but not in the ET reactions; the electron-rich Mn(IV)-oxo porphyrins are more reactive than the electron-deficient Mn(IV)-oxo porphyrins at high temperature (e.g., 0 °C), whereas at low temperature (e.g., -60 °C), the electron-deficient Mn(IV)-oxo porphyrins are more reactive than the electron-rich Mn(IV)-oxo porphyrins. Such a reversed reactivity between the electron-rich and -deficient Mn(IV)-oxo porphyrins depending on reaction temperatures is rationalized with EECE; that is, the lower is the activation enthalpy, the more negative is the activation entropy, and vice versa. Interestingly, a unified linear correlation between the activation enthalpies and the activation entropies is observed in the HAT and OAT reactions of the Mn(IV)-oxo porphyrins. Moreover, from the previously reported HAT reactions of nonheme Fe(IV)-oxo complexes, a linear correlation between the activation enthalpies and the activation entropies is also observed. To the best of our knowledge, we report the first detailed mechanistic study of EECE in the oxidation reactions by synthetic high-valent metal-oxo complexes.

Identifying Intermediates in Electrocatalytic Water Oxidation with a Manganese Corrole Complex.

Water nucleophilic attack (WNA) on high-valent terminal Mn-oxo species is proposed for O-O bond formation in natural and artificial water oxidation. Herein, we report an electrocatalytic water oxidation reaction with MnIII tris(pentafluorophenyl)corrole (1) in propylene carbonate (PC). O2 was generated at the MnV/IV potential with hydroxide, but a more anodic potential was required to evolve O2 with only water. With a synthetic MnV(O) complex of 1, a second-order rate constant, k2(OH-), of 7.4 × 103 M-1 s-1 was determined in the reaction of the MnV(O) complex of 1 with hydroxide, whereas its reaction with water occurred much more slowly with a k2(H2O) value of 4.4 × 10-3 M-1 s-1. This large reactivity difference of MnV(O) with hydroxide and water is consistent with different electrocatalytic behaviors of 1 with these two substrates. Significantly, during the electrolysis of 1 with water, a MnIV-peroxo species was identified with various spectroscopic methods, including UV-vis, electron paramagnetic resonance, and infrared spectroscopy. Isotope-labeling experiments confirmed that both O atoms of this peroxo species are derived from water, suggesting the involvement of the WNA mechanism in water oxidation by a Mn complex. Density functional theory calculations suggested that the nucleophilic attack of hydroxide on MnV(O) and also WNA to 1e--oxidized MnV(O) are feasibly involved in the catalytic cycles but that direct WNA to MnV(O) is not likely to be the main O-O bond formation pathway in the electrocatalytic water oxidation by 1.

Predictors of Successful Yttrium-90 Radioembolization Bridging or Downstaging in Patients with Hepatocellular Carcinoma.

Purpose: This study aims to identify clinical and imaging prognosticators associated with the successful bridging or downstaging to liver transplantation (LT) in patients undergoing Yttrium-90 radioembolization (Y90-RE) for hepatocellular carcinoma (HCC). Methods: Retrospectively, patients with Y90-RE naïve HCC who were candidates or potential candidates for LT and underwent Y90-RE were included. Patients were then divided into favorable (maintained or achieved Milan criteria (MC) eligibility) or unfavorable (lost eligibility or unchanged MC ineligibility) cohorts based on changes to their MC eligibility after Y90-RE. Penalized logistic regression analysis was performed to identify the significant baseline prognosticators. Results: Between 2013 and 2018, 135 patients underwent Y90-RE treatment. Among the 59 (42%) patients within MC, LT eligibility was maintained in 49 (83%) and lost in 10 (17%) patients. Within the 76 (56%) patients outside MC, eligibility was achieved in 32 (42%) and unchanged in 44 (58%). Among the 81 (60%) patients with a favorable response, 16 (20%) went on to receive LT. Analysis of the baseline characteristics revealed that lower Albumin-Bilirubin score, lower Child-Pugh class, lower Barcelona Clinic Liver Cancer stage, HCC diagnosis using dynamic contrast-enhanced imaging on CT or MRI, normal/higher albumin levels, decreased severity of tumor burden, left lobe HCC disease, and absence of HBV-associated cirrhosis, baseline abdominal pain, or fatigue were all associated with a higher likelihood of bridging or downstaging to LT eligibility (p's < 0.05). Conclusion: Certain baseline clinical and tumor characteristics are associated with the successful bridging or downstaging of potential LT candidates with HCC undergoing Y90-RE.

SLC15A4 Serves as a Novel Prognostic Biomarker and Target for Lung Adenocarcinoma.

BACKGROUND: SLC15A family members are known as electrogenic transporters that take up peptides into cells through the proton-motive force. Accumulating evidence indicates that aberrant expression of SLC15A family members may play crucial roles in tumorigenesis and tumor progression in various cancers, as they participate in tumor metabolism. However, the exact prognostic role of each member of the SLC15A family in human lung cancer has not yet been elucidated. MATERIALS AND METHODS: We investigated the SLC15A family members in lung cancer through accumulated data from TCGA and other available online databases by integrated bioinformatics analysis to reveal the prognostic value, potential clinical application and underlying molecular mechanisms of SLC15A family members in lung cancer. RESULTS: Although all family members exhibited an association with the clinical outcomes of patients with NSCLC, we found that none of them could be used for squamous cell carcinoma of the lung and that SLC15A2 and SLC15A4 could serve as biomarkers for lung adenocarcinoma. In addition, we further investigated SLC15A4-related genes and regulatory networks, revealing its core molecular pathways in lung adenocarcinoma. Moreover, the IHC staining pattern of SLC15A4 in lung adenocarcinoma may help clinicians predict clinical outcomes. CONCLUSION: SLC15A4 could be used as a survival prediction biomarker for lung adenocarcinoma due to its potential role in cell division regulation. However, more studies including large patient cohorts are required to validate the clinical utility of SLC15A4 in lung adenocarcinoma.

Recent Advances in Predicting Protein S-Nitrosylation Sites.

Protein S-nitrosylation (SNO) is a process of covalent modification of nitric oxide (NO) and its derivatives and cysteine residues. SNO plays an essential role in reversible posttranslational modifications of proteins. The accurate prediction of SNO sites is crucial in revealing a certain biological mechanism of NO regulation and related drug development. Identification of the sites of SNO in proteins is currently a very hot topic. In this review, we briefly summarize recent advances in computationally identifying SNO sites. The challenges and future perspectives for identifying SNO sites are also discussed. We anticipate that this review will provide insights into research on SNO site prediction.

Trb3 controls mesenchymal stem cell lineage fate and enhances bone regeneration by scaffold-mediated local gene delivery.

Aberrant lineage commitment of mesenchymal stem cells (MSCs) in marrow contributes to abnormal bone formation due to reduced osteogenic and increased adipogenic potency. While several major transcriptional factors associated with lineage differentiation have been found during the last few decades, the molecular switch for MSC fate determination and its role in skeletal regeneration remains largely unknown, limiting creation of effective therapeutic approaches. Tribbles homolog 3 (Trb3), a member of tribbles family pseudokinases, is known to exert diverse roles in cellular differentiation. Here, we investigated the reciprocal role of Trb3 in the regulation of osteogenic and adipogenic differentiation of MSCs in the context of bone formation, and examined the mechanisms by which Trb3 controls the adipo-osteogenic balance. Trb3 promoted osteoblastic commitment of MSCs at the expense of adipocyte differentiation. Mechanistically, Trb3 regulated cell-fate choice of MSCs through BMP/Smad and Wnt/ß-catenin signals. Importantly, in vivo local delivery of Trb3 using a novel gelatin-conjugated caffeic acid-coated apatite/PLGA (GelCA-PLGA) scaffold stimulated robust bone regeneration and inhibited fat-filled cyst formation in rodent non-healing mandibular defect models. These findings demonstrate Trb3-based therapeutic strategies that favor osteoblastogenesis over adipogenesis for improved skeletal regeneration and future treatment of bone-loss disease. The distinctive approach implementing a scaffold-mediated local gene transfer may further broaden the translational use of targeting specific therapeutic gene related to lineage commitment for clinical bone treatment.

Diagnostic and prognostic role of NR3C4 in breast cancer through a genomic network understanding.

The androgen receptor (AR, NR3C4) is believed to participate in the development of breast cancer, but its molecular mechanism and role in prognosis is still controversial and opaque. This study aimed to explore the expression, associations with clinicopathologic features and underlying molecular mechanisms of AR in breast cancer. The present study investigated invasive breast carcinoma through comprehensive bioinformatics. The expression and mutation rate of AR in breast cancer was obtained from the TCGA database. Training survival prediction analysis was applied to the data extracted from the KM plotter database. The prediction of the survival cohort was validated using the bcGenExMiner database in breast cancer molecular subgroups. Represented immunohistochemical images of AR and its related expression with the molecular subtype status were generated. The underlying molecular mechanism for AR in breast cancer was analyzed with the GEO dataset and Gene Ontology. A protein-to-protein interaction network and core pathways were constructed to show the protein functions with AR. Our results show that AR expression was significantly higher in cancerous tissue than in normal breast tissue and differentially expressed in the clinical stages. AR would also generally be considered as a favorable prognostic biomarker when including the major molecular subtypes of breast cancer. AR IHC staining could be easily used in clinical applications. The major molecular functions for AR were regulating the cell cycle checkpoints and chromatin remodeling. Our investigation showed that AR expression level could be used as a favorable and independent prognostic prediction factor for the disease-free survival time in breast cancer, especially for the ER-positive subgroup. However, AR was not a sensitive prognostic biomarker for the prediction of overall survival time or for the PR and TBC subgroups. In terms of the underlying molecular mechanism, AR may mainly participate in the cell cycle checkpoints related to the G1/S transition of the mitotic cell cycle to control the subdivision of the epithelial terminal unit and chromatin remodeling in breast cancer.

Unprecedented Reactivities of Highly Reactive Manganese(III)-Iodosylarene Porphyrins in Oxidation Reactions.

We report that Mn(III)-iodosylarene porphyrins, [MnIII(Porp)(sArIO)]+, are capable of activating the C-H bonds of hydrocarbons, including unactivated alkanes such as cyclohexane, with unprecedented reactivities, such as a low kinetic isotope effect, a saturation behavior of reaction rates, and no electronic effect of porphyrin ligands on the reactivities of [MnIII(Porp)(sArIO)]+. In oxygen atom transfer (OAT) reactions, the sulfoxidation of para-X-substituted thioanisoles by [MnIII(Porp)(sArIO)]+ affords a very unusual behavior in the Hammett plot with the saturation behavior of reaction rates and no electronic effect of porphyrin ligands on reactivities. The reactivities and mechanisms of [MnIII(Porp)(sArIO)]+ are then compared with those of the corresponding MnIV(Porp)(O) complex. The present study reports the first example of highly reactive Mn(III)-iodosylarene porphyrins with unprecedented reactivities in C-H bond activation and OAT reactions.

CircHivep2 contributes to microglia activation and inflammation via miR-181a-5p/SOCS2 signalling in mice with kainic acid-induced epileptic seizures.

Epilepsy is a chronic brain disease characterized by recurrent seizures. Circular RNA (circRNA) is a novel family of endogenous non-coding RNAs that have been proposed to regulate gene expression. However, there is a lack of data on the role of circRNA in epilepsy. In this study, the circRNA profiles were evaluated by microarray analysis. In total, 627 circRNAs were up-regulated, whereas 892 were down-regulated in the hippocampus in mice with kainic acid (KA)-induced epileptic seizures compared with control. The expression of circHivep2 was significantly down-regulated in hippocampus tissues of mice with KA-induced epileptic seizures and BV-2 microglia cells upon KA treatment. Bioinformatics analysis predicted that circHivep2 interacts with miR-181a-5p to regulate SOCS2 expression, which was validated using a dual-luciferase reporter assay. Moreover, overexpression of circHivep2 significantly inhibited KA-induced microglial activation and the expression of inflammatory factors in vitro, which was blocked by miR-181a-5p, whereas circHivep2 knockdown further induced microglia cell activation and the release of pro-inflammatory proteins in BV-2 microglia cells after KA treatment. The application of circHivep2+ exosomes derived from adipose-derived stem cells (ADSCs) exerted significant beneficial effects on the behavioural seizure scores of mice with KA-induced epilepsy compared to control exosomes. The circHivep2+ exosomes also inhibited microglial activation, the expression of inflammatory factors, and the miR-181a-5p/SOCS2 axis in vivo. Our results suggest that circHivep2 regulates microglia activation in the progression of epilepsy by interfering with miR-181a-5p to promote SOCS2 expression, indicating that circHivep2 may serve as a therapeutic tool to prevent the development of epilepsy.