Association between dichotomized VASARI feature and overall survival in glioblastoma patients: a single-institution propensity score matching analysis.

OBJECTIVES: This study aimed to investigate the intra- and inter-observer consistency of the Visually Accessible Rembrandt Images (VASARI) feature set before and after dichotomization, and the association between dichotomous VASARI features and the overall survival (OS) in glioblastoma (GBM) patients. METHODS: This retrospective study included 351 patients with pathologically confirmed IDH1 wild-type GBM between January 2016 and June 2022. Firstly, VASARI features were assessed by four radiologists with varying levels of experience before and after dichotomization. Cohen's kappa coefficient (κ) was calculated to measure the intra- and inter-observer consistency. Then, after adjustment for confounders using propensity score matching, Kaplan-Meier curves were used to compare OS differences for each dichotomous VASARI feature. Next, patients were randomly stratified into a training set (n = 211) and a test set (n = 140) in a 3:2 ratio. Based on the training set, Cox proportional hazards regression analysis was adopted to develop combined and clinical models to predict OS, and the performance of the models was evaluated with the test set. RESULTS: Eleven VASARI features with κ value of 0.61-0.8 demonstrated almost perfect agreement after dichotomization, with the range of κ values across all readers being 0.874-1.000. Seven VASARI features were correlated with GBM patient OS. For OS prediction, the combined model outperformed the clinical model in both training set (C-index, 0.762 vs. 0.723) and test set (C-index, 0.812 vs. 0.702). CONCLUSION: The dichotomous VASARI features exhibited excellent inter- and intra-observer consistency. The combined model outperformed the clinical model for OS prediction.

Comprehensive analysis of disulfidptosis-related lncRNAs for predicting prognosis and response of immunotherapy in pancreatic adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is a common and deadly tumor. Currently, there is a severe lack of therapeutic options. As a novel mode of cell death, increasing evidence reveals the important role of the disulfidptosis in cancer. However, few studies have utilized disulfidptosis-related long-stranded non-coding RNAs (DRlncRNAs) to investigate the prognosis of PAAD. Methods: We comprehensively analyzed the expression and prognostic value of 958 DRlncRNAs in PAAD using data from The Cancer Genome Atlas (TCGA). We established and validated a new DRlncRNAs-related prognostic index by least absolute shrinkage and selection operator (LASSO) and COX regression analysis. In addition, we built a nomogram consisting of risk score, age, gender, tumor grade and stage to validate the clinical feasibility of the index. We further evaluated the value of the index in terms of PAAD functional pathways, tumor microenvironment (TME) and tumor mutations. Results: We designed a risk model for five DRlncRNAs and demonstrated its accuracy using receiver operating characteristic (ROC) curves. COX regression suggested that the model may be an independent predictor of cancer prognosis. Tumor immune infiltration analysis revealed that low-risk subgroups had higher extent of immune infiltration, higher sensitivity to immunotherapy and a higher TME score. This is helpful for us to discover more precise immunotherapy for PAAD patients. Conclusions: In conclusion, we established a DRlncRNA index comprising of five DRlncRNAs, which may provide new insights for clinical diagnosis and precision therapy.

The causal relationship between autoimmune thyroid disorders and telomere length: A Mendelian randomization and colocalization study.

This study aimed to evaluate whether there is a causal relationship between autoimmune thyroid disorders (AITDs) and telomere length (TL) in the European population and whether there is reverse causality. In this study, Mendelian randomization (MR) and colocalization analysis were conducted to assess the potential causal relationship between AITDs and TL using summary statistics from large-scale genome-wide association studies, followed by analysis of the relationship between TL and thyroid stimulating hormone and free thyroxine (FT4) to help interpret the findings. The inverse variance weighted (IVW) method was used to estimate the causal estimates. The weighted median, MR-Egger and leave-one-out methods were used as sensitivity analyses. The IVW method results showed a significant causal relationship between autoimmune hyperthyroidism and TL (ß = -1.93 × 10-2 ; p = 4.54 × 10-5 ). There was no causal relationship between autoimmune hypothyroidism and TL (ß = -3.99 × 10-3 ; p = 0.324). The results of the reverse MR analysis showed that genetically TL had a significant causal relationship on autoimmune hyperthyroidism (IVW: odds ratio (OR) = 0.49; p = 2.83 × 10-4 ) and autoimmune hypothyroidism (IVW: OR = 0.86; p = 7.46 × 10-3 ). Both horizontal pleiotropy and heterogeneity tests indicated the validity of our bidirectional MR study. Finally, colocalization analysis suggested that there were shared causal variants between autoimmune hyperthyroidism and TL, further highlighting the robustness of the results. In conclusion, autoimmune hyperthyroidism may accelerate telomere attrition, and telomere attrition is a causal factor for AITDs.

Noninvasive Isocitrate Dehydrogenase 1 Status Prediction in Grade II/III Glioma Based on Magnetic Resonance Images: A Transfer Learning Strategy.

OBJECTIVE: The aim of this study was to evaluate transfer learning combined with various convolutional neural networks (TL-CNNs) in predicting isocitrate dehydrogenase 1 ( IDH1 ) status of grade II/III gliomas. METHODS: Grade II/III glioma patients diagnosed at the Tangdu Hospital (August 2009 to May 2017) were retrospectively enrolled, including 54 patients with IDH1 mutant and 56 patients with wild-type IDH1 . Convolutional neural networks, AlexNet, GoogLeNet, ResNet, and VGGNet were fine-tuned with T2-weighted imaging (T2WI), fluid attenuation inversion recovery (FLAIR), and contrast-enhanced T1-weighted imaging (T1CE) images. The single-modal networks were integrated with averaged sigmoid probabilities, logistic regression, and support vector machine. FLAIR-T1CE-fusion (FC-fusion), T2WI-T1CE-fusion (TC-fusion), and FLAIR-T2WI-T1CE-fusion (FTC-fusion) were used for fine-tuning TL-CNNs. RESULTS: IDH1 -mutant prediction accuracies using AlexNet, GoogLeNet, ResNet, and VGGNet achieved 70.0% (AUC = 0.660), 65.0% (AUC = 0.600), 70.0% (AUC = 0.700), and 80.0% (AUC = 0.730) for T2WI images, 70.0% (AUC = 0.660), 70.0% (AUC = 0.620), 70.0% (AUC = 0.710), and 80.0% (AUC = 0.720) for FLAIR images, and 73.7% (AUC = 0.744), 73.7% (AUC = 0.656), 73.7% (AUC = 0.633), and 73.7% (AUC = 0.700) for T1CE images, respectively. The highest AUC (0.800) was achieved using VGGNet and FC-fusion images. CONCLUSIONS: TL-CNNs (especially VGGNet) had a potential predictive value for IDH1 -mutant status of grade II/III gliomas.

Intraocular Lens Power Calculation in Eyes After Myopic Laser Refractive Surgery and Radial Keratotomy: Bayesian Network Meta-analysis.

PURPOSE: To compare the accuracy of formulas for calculating intraocular lens power in eyes after myopic laser refractive surgery or radial keratotomy. DESIGN: Bayesian network meta-analysis. METHODS: PubMed, Embase, the Cochrane Data Base of Systematic Reviews, and the Cochrane Central Register of Controlled Trials databases were searched for retrospective and prospective clinical studies published from January 1, 2012, to August 24, 2022. The outcome measurement was the percentage of eyes with a predicted error within the target refractive range (±0.50 diopter [D] or ±1.00 D). RESULTS: Our meta-analysis includes 24 studies of 1172 eyes after myopic refractive surgery that use 12 formulas for intraocular lens power calculation. (1) A network meta-analysis showed that Barrett true-K no history, the optical coherence tomography (OCT) formula, and the Masket formula had a significantly higher percent of eyes within ±0.50 D of the goal than the Haigis-L formula, whereas the Wang-Koch-Maloney formula showed the poor predictability. Using an error criterion of within ±1.00 D, the same 3 formulas performed slightly better than the Haigis-L formula. Based on performance using both prediction error criteria, the Barrett true-K no history formula, OCT formula, and Masket formula showed the highest probability of ranking as the top 3 among the 12 methods. (2) A direct meta-analysis with a subset of 4 studies and 5 formulas indicated that formulas did not differ in percent success for either the ±0.5 D or ±1.0 D error range in eyes that had undergone radial keratotomy. CONCLUSIONS: The OCT, Masket, and Barrett true-K no history formulas are more accurate for eyes with previous myopic laser refractive surgery, whereas no significant difference was found among the formulas for eyes that had undergone radial keratotomy.

Artificial Intelligence and Machine (Deep) Learning in Otorhinolaryngology: A Bibliometric Analysis Based on VOSviewer and CiteSpace.

BACKGROUND: Otorhinolaryngology diseases are well suited for artificial intelligence (AI)-based interpretation. The use of AI, particularly AI based on deep learning (DL), in the treatment of human diseases is becoming more and more popular. However, there are few bibliometric analyses that have systematically studied this field. OBJECTIVE: The objective of this study was to visualize the research hot spots and trends of AI and DL in ENT diseases through bibliometric analysis to help researchers understand the future development of basic and clinical research. METHODS: In all, 232 articles and reviews were retrieved from The Web of Science Core Collection. Using CiteSpace and VOSviewer software, countries, institutions, authors, references, and keywords in the field were visualized and examined. RESULTS: The majority of these papers came from 44 nations and 498 institutions, with China and the United States leading the way. Common diseases used by AI in ENT include otosclerosis, otitis media, nasal polyps, sinusitis, and so on. In the early years, research focused on the analysis of hearing and articulation disorders, and in recent years mainly on the diagnosis, localization, and grading of diseases. CONCLUSIONS: The analysis shows the periodical hot spots and development direction of AI and DL application in ENT diseases from the time dimension. The diagnosis and prognosis of otolaryngology diseases and the analysis of otolaryngology endoscopic images have been the focus of current research and the development trend of future.

Association Between Educational Attainment and Thyroid Function: Results From Mendelian Randomization and the NHANES Study.

CONTEXT: Many observational studies have reported on the association between educational attainment (EA) and thyroid function, but the causal relationship remains unclear. OBJECTIVE: We aimed to obtain causal effects of EA on thyroid function and to quantify the mediating effects of modifiable risk factors. METHODS: Two-sample mendelian randomization (MR) was performed by using summary statistics from large genome-wide association studies (GWAS) to assess the effect of EA on thyroid function, including hypothyroidism, hyperthyroidism, thyrotropin (TSH), and free thyroxine (FT4). A multivariable analysis was conducted to assess the mediating role of smoking and help to explain the association between EA and thyroid function. Similar analysis was further performed using data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2002. RESULTS: In MR analysis, EA was causally associated with TSH (ß = .046; 95% CI, 0.015-0.077; P = 4.00 × 10-3), rather than hypothyroidism, hyperthyroidism, and FT4. Importantly, smoking could serve as a mediator in the association between EA and TSH, in which the mediating proportion was estimated to be 10.38%. After adjusting for smoking in the multivariable MR analysis, the ß value of EA on TSH was attenuated to 0.030 (95% CI, 0.016-0.045; P = 9.32 × 10-3). Multivariable logistic regression model in NHANES suggested a dose-response relationship between TSH (quartile [Q]4 vs Q1: odds ratio = 1.33; 95% CI, 1.05-1.68; P for trend = .023) and EA. Smoking, systolic blood pressure, and body mass index partially mediated the association between EA and TSH, with the proportion of the mediation effects being 43.82%, 12.28%, and 6.81%, respectively. CONCLUSION: There is a potentially causal association between EA and TSH, which could be mediated by several risk factors, such as smoking.

Serine-arginine splicing factor 2 promotes oesophageal cancer progression by regulating alternative splicing of interferon regulatory factor 3.

OBJECTIVE: Often, alternative splicing is used by cancer cells to produce or increase proteins that promote growth and survival through alternative splicing. Although RNA-binding proteins are known to regulate alternative splicing events associated with tumorigenesis, their role in oesophageal cancer (EC) has rarely been explored. METHODS: We analysed the expression pattern of several relatively well characterized splicing regulators on 183 samples from TCGA cohort of oesophageal cancer; the effectiveness of the knockdown of SRSF2 was subsequently verified by immunoblotting; we measured the ability of cells treated with lenti-sh-SRSF2/lenti-sh2-SRSF2 to invade through an extracellular matrix coating by transwell invasion assay; using RNA-seq data to identify its potential target genes; we performed qRT-PCR to detect the changes of exon 2 usage in lenti-sh-SRSF2 transduced KYSE30 cells to determine the possible effect of SRSF2 on splicing regulation of IRF3; RNA Electrophoretic mobility shift assay (RNA-EMSA) was performed by the incubation of purified SRSF2 protein and biotinylated RNA probes; we performed luciferase assay to confirm the effect of SRSF2 on IFN1 promoter activity. RESULTS: We found upregulation of SRSF2 is correlated with the development of EC; Knock-down of SRSF2 inhibits EC cell proliferation, migration, and invasion; SRSF2 regulates the splicing pattern of IRF3 in EC cells; SRSF2 interacts with exon 2 of IRF3 to regulate its exclusion; SRSF2 inhibits the transcription of IFN1 in EC cells. CONCLUSION: This study identified a novel regulatory axis involved in EC from the various aspects of splicing regulation.

Nodular Fasciitis of the Nose and External Auditory Canal: Two Rare Case Reports.

Nodular fasciitis(NF) is a proliferative disease of fibroblasts and myofibroblasts that generally affects subcutaneous tissue, muscle tissue, and fascia. NF usually occurs in young adults aged 20-40 and is more common in the upper extremities and relatively rare in the region of the head and neck. Here, we report on two patients with NF in the ear and nose. Under general anesthesia, the masses of NF were completely resected along the safety margin. The patients recovered well after surgery and there was no recurrence after more than half a year of follow-up.

GPX4-independent ferroptosis-a new strategy in disease's therapy.

Ferroptosis is a form of programmed cell death characterized by intracellular iron accumulation and lipid peroxidation, and earlier studies identified glutathione peroxidase 4 (GPX4) as an essential regulator of this process. Ferroptosis plays an essential role in tumors, degenerative diseases, and ischemia-reperfusion injury. However, researchers have found that inhibition of GPX4 does not entirely suppress ferroptosis in certain diseases, or cells express resistance to ferroptosis agonists that inhibit GPX4. As research progresses, it has been discovered that there are multiple regulatory pathways for ferroptosis that are independent of GPX4. The study of GPX4-independent ferroptosis pathways can better target ferroptosis to prevent and treat various diseases. Here, the currently inhibited pulmonary GPX4-dependent ferroptosis pathways will be reviewed.

Systemic Lupus Erythematosus Patients With Related Organic Damage Are at High Risk of Hypothyroidism.

Purpose: The aim of this study included determining the prevalence of hypothyroidism in patients with systemic lupus erythematosus (SLE), clarifying the clinical characteristics of SLE patients with hypothyroidism, and identifying the relationship between hypothyroidism and SLE-related organic damage. Another purpose was to analyze the relationship between SLE and thyroid autoantibody. We also intended to discuss the pathogenesis of hypothyroidism in SLE patients, which would provide clues for further investigation. Methods: This study recruited 856 SLE patients and 856 age- and sex-matched healthy population and compared the prevalence of hypothyroidism between the cases and controls. Univariate and multivariate logistic analyses were applied to identify risk factors for hypothyroidism in SLE patients. Results: SLE patients had higher prevalence of clinical hypothyroidism (9.10%) and TgAb+TPOAb- (10.40%) than controls. The prevalence of hypothyroidism was the highest in SLE patients aged 16-26 years (18.9%) and decreased with age. The prevalence of autoimmune hypothyroidism in SLE group was higher than that in the control group (64.4% vs. 51.5%, P=0.042), which was mainly due to TgAb; the prevalence of non-autoimmune hypothyroidism in SLE group was also significantly higher than that in the control group (67.3% vs. 47.8%, P<0.001). Based on multivariate analysis, the use of glucocorticoids/immunosuppressants, liver abnormality, lupus nephritis (LN), and cardiac insufficiency were independently associated with hypothyroidism in SLE patients. Conclusion: The prevalence of hypothyroidism in SLE patients was higher than that in controls and decreased with age. The results suggested that young SLE patients combined with LN, liver abnormality and cardiac insufficiency were at higher risk of hypothyroidism. According to the results of this study, we speculated that SLE might have impact on thyroid, and SLE might be one of the causes of hypothyroidism.

A single-cell atlas of diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is one of the most common yet aggressive types of B cell lymphoma and remains incurable in 40% of patients. Herein, we profile the transcriptomes of 94,324 cells from 17 DLBCLs and 3 control samples using single-cell RNA sequencing. Altogether, 73 gene expression programs are identified in malignant cells, demonstrating high intra- and intertumor heterogeneity. Furthermore, 2,754 pairs of suggestive cell-cell interactions are predicted, indicating a complex and highly dynamic tumor microenvironment. Especially for B cell lymphomas, a strong costimulatory CD70-CD27 interaction is predicted between malignant and T cells. Furthermore, coinhibitory signals mediated by TIM3 or TIGIT seem to be the main driving force for T cell exhaustion. Finally, we find that chronic hepatitis B virus infection may have a significant impact on tumor cell survival and immune evasion in DLBCL. Our results provide insights into B cell lymphomagenesis and may facilitate the design of targeted immunotherapy strategies.

Polysaccharide from dandelion enriched nutritional composition, antioxidant capacity, and inhibited bioaccumulation and inflammation in Channa asiatica under hexavalent chromium exposure.

Taraxacum mongolicum polysaccharide (TMP) exhibits anti-inflammatory and antioxidant activity, making it an attractive candidate for aquatic-product-safety applications. Here, this study was aimed to investigate the effects of dietary TMP on the growth, nutritional composition, antioxidant capacity, bioaccumulation and inflammation in Channa asiatica under hexavalent chromium stress. The C. asiatica was randomly distributed into five groups: The first group served as the blank control group (CK), the subsequent groups were fed TMP-supplemented feed (0, 0.5, 1.0 and 2.0 g/kg), respectively, and exposed to waterborne Cr6+ for 28 days. Our results indicated that the TMP effectively increased (P < 0.05) C. asiatica muscle flavour amino acid, total free amino acids, monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), and EPA + DHA contents, enhanced positively antioxidant enzyme activity (GPX, SOD, CAT, T-AOC), reduced oxidative stress parameters (MDA, PC), and up-regulated antioxidant-related genes mRNA expression. Meanwhile, the appropriate amount of TMP supplementation also inhibited the bioaccumulation of Cr6+ in tissues and alleviated the inflammatory response (P < 0.05). Furthermore, sensory evaluation implied that the overall score of sashimi and cooked fillet in the 2.0 g/kg TMP group was the highest in the experimental group, second only to CK. In brief, these results elucidate that TMP-supplemented diets excellently ameliorated the growth, enriched nutritional composition and antioxidant capacity, and inhibited bioaccumulation and inflammation in C. asiatica exposed to waterborne Cr6+.

Life-threatening hemoptysis accompanied by internal thoracic artery aneurysms in a 28-year-old perinatal woman: a case report.

BACKGROUND: Life-threatening hemoptysis presents an immediate diagnostic and therapeutic challenge, especially during the perinatal period. CASE PRESENTATION: A 28-year-old perinatal woman with no significant past medical or surgical history presented with repeating hemoptysis and respiratory failure. Computed tomography revealed a 2.1 × 3.2  cm2 inhomogeneous tumorous lesion in the right superior mediastinum and a right main bronchus obstruction along with atelectasis of the right lung. Bronchoscopy showed a tumorous protrusion blocking the right main bronchus with active hemorrhage, and malignancy was suspected. Bronchial artery embolization (BAE) was performed to control the bleeding. The arteriogram revealed tortuosity, dilation and hypertrophy of the right bronchial arteries and aneurysms of the internal thoracic artery (ITA). The bleeding completely stopped after BAE. Bronchoscopy was performed again to remove residual blood clots. The patient recovered soon after the procedure and was discharged. CONCLUSIONS: Life-threatening hemoptysis concomitant with ITA aneurysms, which may have a misleading clinical diagnosis and treatment options, has not been reported previously in perinatal women. BAE could be used as a first-line treatment irrespective of the underlying causes.

Folic acid and deoxycholic acid derivative modified Fe3O4 nanoparticles for efficient pH-dependent drug release and multi-targeting against liver cancer cells.

The novel nano-drug carrier (FDCA-FA-MNPs) was constructed by grafting formyl deoxycholic acid (FDCA) and folic acid (FA) on the surface of Fe3O4 magnetic nanoparticles (MNPs), possessing the advantages of superparamagnetism, good stability, low cytotoxicity and good blood compatibility. The hydrophobic anti-cancer drug doxorubicin hydrochloride (DOX) was successfully loaded onto FDCA-FA-MNPs through supramolecular interactions (hydrogen bond between FDCA and drug and hydrophobic interaction and π-π stacking between drug and drug). The drug loading amount and drug loading capacity were 509.1 mg g-1 and 33.73 wt%, respectively. In addition, drug release had a pH responsive and controllable release performance, the release rate at pH 5.3 (45.6%) was four times that at pH 7.4 (11.5%), and the tumor microenvironment was favorable for drug release. More importantly, the novel nano-drug carrier combined the hepatocellular targeting of FDCA, the cancer cell targeting of FA, and the magnetic targeting of Fe3O4, showing excellent cancer-killing efficiency (78%) in vitro. Therefore, the nano-drug carrier synthesized in this paper has potential practical application value in the targeted therapy of liver cancer.

CircRNA-vgll3 promotes osteogenic differentiation of adipose-derived mesenchymal stem cells via modulating miRNA-dependent integrin α5 expression.

Adipose-derived mesenchymal stem cells (ADSCs) are promising candidate for regenerative medicine to repair non-healing bone defects due to their high and easy availability. However, the limited osteogenic differentiation potential greatly hinders the clinical application of ADSCs in bone repair. Accumulating evidences demonstrate that circular RNAs (circRNAs) are involved in stem/progenitor cell fate determination, but their specific role in stem/progenitor cell osteogenesis, remains mostly undescribed. Here, we show that circRNA-vgll3 originating from the vgll3 locus markedly enhances osteogenic differentiation of ADSCs; nevertheless, silencing of circRNA-vgll3 dramatically attenuates ADSC osteogenesis. Furthermore, we validate that circRNA-vgll3 functions in ADSC osteogenesis through a circRNA-vgll3/miR-326-5p/integrin α5 (Itga5) pathway. Itga5 promotes ADSC osteogenic differentiation and miR-326-5p suppresses Itga5 translation. CircRNA-vgll3 directly sequesters miR-326-5p in the cytoplasm and inhibits its activity to promote osteogenic differentiation. Moreover, the therapeutic potential of circRNA-vgll3-modified ADSCs with calcium phosphate cement (CPC) scaffolds was systematically evaluated in a critical-sized defect model in rats. Our results demonstrate that circRNA-vgll3 markedly enhances new bone formation with upregulated bone mineral density, bone volume/tissue volume, trabeculae number, and increased new bone generation. This study reveals the important role of circRNA-vgll3 during new bone biogenesis. Thus, circRNA-vgll3 engineered ADSCs may be effective potential therapeutic targets for bone regenerative medicine.

Mydgf promotes Cardiomyocyte proliferation and Neonatal Heart regeneration.

Myeloid-derived growth factor (Mydgf), a paracrine protein secreted by bone marrow-derived monocytes and macrophages, was found to protect against cardiac injury following myocardial infarction (MI) in adult mice. We speculated that Mydgf might improve heart function via myocardial regeneration, which is essential for discovering the target to reverse heart failure. Methods: Two genetic mouse lines were used: global Mydgf knockout (Mydgf-KO) and Mydgf-EGFP mice. Two models of cardiac injury, apical resection was performed in neonatal and MI was performed in adult mice. Quantitative reverse transcription-polymerase chain reaction, western blot and flow cytometry were performed to study the protein expression. Immunofluorescence was performed to detect the proliferation of cardiomyocytes. Heart regeneration and cardiac function were evaluated by Masson's staining and echocardiography, respectively. RNA sequencing was employed to identify the key involved in Mydgf-induced cardiomyocyte proliferation. Mydgf recombinant protein injection was performed as a therapy for cardiac repair post MI in adult mice. Results: Mydgf expression could be significantly induced in neonatal mouse hearts after cardiac injury. Unexpectedly, we found that Mydgf was predominantly expressed by endothelial cells rather than macrophages in injured neonatal hearts. Mydgf deficiency impeded neonatal heart regeneration and injury-induced cardiomyocyte proliferation. Mydgf recombinant protein promoted primary mouse cardiomyocyte proliferation. Employing RNA sequencing and functional verification, we demonstrated that c-Myc/FoxM1 pathway mediated Mydgf-induced cardiomyocyte expansion. Mydgf recombinant protein improved cardiac function in adult mice after MI injury with inducing cardiomyocyte proliferation. Conclusion: Mydgf promotes cardiomyocyte proliferation by activating c-Myc/FoxM1 pathway and improves heart regeneration both in neonatal and adult mice after cardiac injury, providing a potential target to reverse cardiac remodeling and heart failure.

The Biosynthetic Pathway of Ergothioneine in Culinary-Medicinal Winter Mushroom, Flammulina velutipes (Agaricomycetes).

Ergothioneine is a natural 2-thiol-amidazole amino acid that plays an important role in inflammation, depression, and cardiovascular disease. Flammulina velutipes is a common basidiomycete mushroom rich in ergothioneine (EGT). However, the biosynthetic pathway of EGT in F. velutipes is still unclear. In this study, the F. velutipes ergothioneine biosynthetic gene 1 (Fvegtl), F. velutipes ergothioneine biosynthetic gene 2 (Fvegt2), and F. velutipes ergothioneine biosynthetic gene 3 (Fvegt3) were cloned and expressed, and the activities of the proteins encoded by these three genes (FvEgt1, F. velutipes ergothioneine biosynthase 1; FvEgt2, F. velutipes ergothioneine biosynthase 2; and FvEgt3, F. velutipes ergothioneine biosynthase 3) were identified. The results showed that FvEgtl not only has the function of methyltransferase, but also has the function of hercynlcysteineteine sulfoxide (Hersul) synthase, which can catalyze the production of Hersul from histidine and cysteine in F. velutipes. FvEgt2 and FvEgt3 are two functionally different cysteine desulfurase enzymes. Among them, FvEgt2 is a cysteine-cysteine desulfurase-which catalyzes the activation of the S-H bond on cysteine, while FvEgt3 is a pyridoxal phosphate (PLP)-dependent cysteine desulfurase responsible for catalyzing the production of ketimine complex. Our results show that FvEgt1/FvEgt2/FvEgt3 can simultaneously catalyze the production of EGT by histidine, cysteine, and pyridoxal phosphate. Collectively, the in vitro synthesis of EGT in the edible fungus F. velutipes was first achieved, which laid the foundation for the biological production of EGT.

miR-762 regulates the proliferation and differentiation of retinal progenitor cells by targeting NPDC1.

Retinal degenerations, which lead to irreversible decline in visual function, are still no effective recovery treatments. Currently, retinal progenitor cell (RPC) transplantation therapy is expected to provide a new approach to treat these diseases; however, the limited proliferation capacity and differentiation potential toward specific retinal neurons of RPCs hinder their potential clinical applications. microRNAs have been reported to serve as important regulators in the cell fate determination of stem/progenitor cells. In this study, our data demonstrated that miR-762 inhibited NPDC1 expression to positively regulate RPC proliferation and suppress RPC neuronal differentiation. Furthermore, the knockdown of miR-762 upregulated NPDC1 expression in RPCs, leading to the inhibition of RPC proliferation and the increase in neuronal differentiation. Moreover, NPDC1 could rescue anti-miR-762-induced RPC proliferation deficiency and the inhibitory effect of miR-762 on RPC differentiation. In conclusion, our study demonstrated that miR-762 plays a crucial role in regulating RPC proliferation and differentiation by directly targeting NPDC1, which is firstly reported that microRNAs positively regulate RPC proliferation and negatively regulate RPC differentiation, which provides a comprehensive understanding of the molecular mechanisms that dominate RPC proliferation and differentiation in vitro.

Targeting Local Osteogenic and Ancillary Cells by Mechanobiologically Optimized Magnesium Scaffolds for Orbital Bone Reconstruction in Canines.

Large-sized orbital bone defects have serious consequences that destroy orbital integrity and result in maxillofacial deformities and vision loss. The treatment of orbital bone defects is currently palliative and not reparative, suggesting an urgent demand for biomaterials that regenerate orbital bones. In this study, via alloying, extrusion and surface modification, we developed mechanobiologically optimized magnesium (Mg) scaffolds (Ca-P-coated Mg-Zn-Gd scaffolds, referred to as Ca-P-Mg) for the orthotopic reconstruction of large-sized orbital bone defects. At 6 months after transplanting the scaffolds to a clinically relevant canine large animal model, large-sized defects were successfully bridged by an abundance of new bone with normal mechanical properties that corresponded to gradual degradation of the implants. The osteogenic and ancillary cells, including vascular endothelial cells and trigeminal neurons, played important roles in this process. The scaffolds robustly enhanced bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation. In addition, the increased angiogenesis including increased ratio of the specific endothelial subtype CD31hi endomucinhi (CD31hiEmcnhi) endothelial cells can facilitate osteogenesis. Furthermore, the scaffolds trigger trigeminal neurons via transient receptor potential vanilloid subtype 1 (Trpv1) to produce the neuropeptide calcitonin gene-related peptide (CGRP), which promotes angiogenesis and osteogenesis. Overall, our investigations revealed the efficacy of Ca-P-Mg scaffolds in healing orbital bone defects and warrant further exploration of these scaffolds for clinical applications.