o8G Site-Specifically Modified tRF-1-AspGTC: A Novel Therapeutic Target and Biomarker for Pulmonary Hypertension.

RATIONALE: Hypoxia and oxidative stress contribute to the development of pulmonary hypertension (PH). tRNA-derived fragments play important roles in RNA interference and cell proliferation, but their epitranscriptional roles in PH development have not been investigated. OBJECTIVE: We aimed to gain insight into the mechanistic contribution of oxidative stress-induced 8-oxoguanine in pulmonary vascular remodeling. METHODS AND RESULTS: Through small RNA modification array analysis and quantitative polymerase chain reaction, a significant upregulation of the 8-oxoguanine-modified tRF-1-AspGTC was found in the lung tissues and the serum of patients with PH. This modification occurs at the fifth 8-oxoguanine (5o8G) tRF in the seed region of the tRNA-derived fragments. Inhibition of the 5o8G tRF reversed hypoxia-induced proliferation and apoptosis resistance in pulmonary artery smooth muscle cells. Further investigation unveiled that the 5o8G tRF retargeted mRNA of WNT5A and CASP3 and inhibited their expression. Ultimately, BMPR2 (bone morphogenetic protein receptor 2)-reactive oxygen species/5o8G tRF/WNT5A signaling pathway exacerbated the progression of PH. CONCLUSIONS: Our study highlights the role of site-specific 8-oxoguanine-modified tRF in promoting the development of PH. Our findings present a promising therapeutic avenue for managing PH and propose 5o8G tRF as a potential innovative marker for diagnosing this disease.

Ethyl acetate as an acetyl source and solvent for acetylation of alcohols by KOH.

A KOH mediated mild, efficient, convenient and gram-scalable protocol for the acetylation of alcohols with EtOAc as acetyl source and solvent. Various types of alcohols were successfully transformed into according acetylated products. Good to excellent yields were offered by primary alcohols and low to moderate yields were offered by secondary alcohols.

The bacterial pathogen Pseudomonas plecoglossicida, its epidemiology, virulence factors, vaccine development, and host-pathogen interactions.

OBJECTIVE: Pseudomoans plecoglossicida has been identified as a fish pathogen since 2000 and has caused serious infections in cultured Large Yellow Croakers Larimiththys crocea in coastal eastern China during recent years. METHODS: Published literatures of this pathogen have been reviewed. RESULT: Several strains with high genomic similarity have been isolated and identified; the bacteria induce natural infection at lower water temperatures (12.0-25.5°C) and induce numerous granulomas and nodules in the visceral organs of croakers. Researchers have investigated the epidemiology of P. plecoglossicida infection, identified major virulence factors, searched for pathogenic genes, analyzed host-pathogen interactions, and endeavored to develop efficient vaccines. CONCLUSION: This paper provides an overview of these research advances to elucidate the virulence mechanisms of the pathogen and to promote vaccine development against infection.

Juvenile Hormone Involved in the Defensive Behaviors of Soldiers in Termite Reticulitermes aculabialis.

Eusocial insects have evolved specific defensive strategies to protect their colonies. In termite colonies, soldiers perform a colony-level defense by displaying mechanical biting, head-banging and mandible opening-closing behaviors. However, few studies have been reported on the factors modulating defensive behaviors in termites. Owing to JH (juvenile hormone) being involved in soldier differentiation, JH was speculated to affect defensive behaviors in termite soldiers. To determine the effect of JH on the defensive behaviors of termite soldiers, we performed a JHA-feeding and RaSsp1-silencing experiment and then tested the changes in defense-related behaviors, alarm pheromones and key JH signaling genes. The observed result was that after feeding workers with JHA, soldiers displayed the following: (1) decreased biting events and increased head-banging events; (2) a reduced expression of RaSsp1 and increased expression of Met (methoprene-tolerant, the nuclear receptor of JH) and Kr-h1 (the JH-inducible transcription factor Krüppel homolog 1); and (3) a decreased concentration of alarm pheromones, including α-pinene, ß-pinene and limonene (+, -). Further study showed that soldiers silenced for RaSsp1 also exhibited (1) decreased biting events and increased head-banging events and (2) increased expression of Met and Kr-h1. In addition, soldiers stimulated by the alarm pheromone limonene displayed an increase in the frequency of mandible opening-closing and biting behavior. All of these results show that JHA influenced the defensive behaviors of termite soldiers, possibly via downregulating RaSsp1 expression, up-regulating Met and Kr-h1 and stimulating the secretion of alarm pheromones, suggesting that the JH pathway plays important roles in modulating social behaviors in termite colonies.

ErbB3 Governs Endothelial Dysfunction in Hypoxia-Induced Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases. METHODS: Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms. RESULTS: ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH. CONCLUSIONS: Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.

Development and Validation of a Deep Learning Radiomics Model to Predict High-Risk Pathologic Pulmonary Nodules Using Preoperative Computed Tomography.

RATIONALE AND OBJECTIVES: To accurately identify the high-risk pathological factors of pulmonary nodules, our study constructed a model combined with clinical features, radiomics features, and deep transfer learning features to predict high-risk pathological pulmonary nodules. MATERIALS AND METHODS: The study cohort consisted of 469 cases of lung adenocarcinoma patients, divided into a training cohort (n = 400) and an external validation cohort (n = 69). We obtained computed tomography (CT) semantic features and clinical characteristics, as well as extracted radiomics and deep transfer learning (DTL) features from the CT images. Selected features were used for constructing prediction models using the logistic regression (LR) algorithm. The performance of the models was evaluated through metrics including the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, calibration curve, and decision curve analysis. RESULTS: The clinical model achieved an AUC of 0.774 (95% CI: 0.728-0.821) in the training cohort and 0.762 (95% confidence interval [CI]: 0.650-0.873) in the external validation cohort. The radiomics model demonstrated an AUC of 0.847 (95% CI: 0.810-0.884) in the training cohort and 0.800 (95% CI: 0.693-0.907) in the external validation cohort. The radiomics-DTL (Rad-DTL) model showed an AUC of 0.871 (95% CI: 0.838-0.905) in the training cohort and 0.806 (95% CI: 0.698-0.914) in the external validation cohort. The proposed combined model yielded AUC values of 0.872 and 0.814 in the training and external validation cohorts, respectively. The combined model demonstrated superiority over both the clinical model and the Rad-DTL model. There were no statistically significant differences observed in the comparison between the combined model incorporating clinical features and the Rad-DTL model. Decision curve analysis (DCA) indicated that the models provided a net benefit in predicting high-risk pathologic pulmonary nodules. CONCLUSION: Rad-DTL signature is a potential biomarker for predicting high-risk pathologic pulmonary nodules using preoperative CT, determining the appropriate surgical strategy, and guiding the extent of resection.

ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17.

Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

Threshold effects of population aging on carbon emissions: From the perspective of industrial structure and residential consumption.

Population aging and climate change caused by anthropogenic greenhouse gas emissions are two of the major challenges facing contemporary humanity. Based on panel data for 63 countries from 2000 to 2020, this paper empirically identifies and explores the threshold effects of population aging on carbon emissions, and tests in a causal inference framework the mediating effect mechanism of aging on carbon emissions through two pathways: industrial structure and consumption. Results show that generally when the percentage of the elderly population is higher than 14.5 %, carbon emissions related to industrial structure and residential consumption are significantly reduced although the threshold effects differ across countries. Particularly for lower-middle-income countries, the direction of the threshold effect is uncertain, which indicates the less importance of population aging for carbon emissions in these countries.

Capsaicin functions as a selective degrader of STAT3 to enhance host resistance to viral infection.

Although STAT3 has been reported as a negative regulator of type I interferon (IFN) signaling, the effects of pharmacologically inhibiting STAT3 on innate antiviral immunity are not well known. Capsaicin, approved for the treatment of postherpetic neuralgia and diabetic peripheral nerve pain, is an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), with additional recognized potencies in anticancer, anti-inflammatory, and metabolic diseases. We investigated the effects of capsaicin on viral replication and innate antiviral immune response and discovered that capsaicin dose-dependently inhibited the replication of VSV, EMCV, and H1N1. In VSV-infected mice, pretreatment with capsaicin improved the survival rate and suppressed inflammatory responses accompanied by attenuated VSV replication in the liver, lung, and spleen. The inhibition of viral replication by capsaicin was independent of TRPV1 and occurred mainly at postviral entry steps. We further revealed that capsaicin directly bound to STAT3 protein and selectively promoted its lysosomal degradation. As a result, the negative regulation of STAT3 on the type I IFN response was attenuated, and host resistance to viral infection was enhanced. Our results suggest that capsaicin is a promising small-molecule drug candidate, and offer a feasible pharmacological strategy for strengthening host resistance to viral infection.

Conversion of 5-hydroxymethylfurfural to furan-2,5-dicarboxylic acid by a simple and metal-free catalytic system.

A simple and metal-free catalytic system composed of NaOtBu/DMF and an O2 balloon efficiently converted 5-hydroxymethylfurfural (5-HMF) to furan-2,5-dicarboxylic acid with an 80.85% yield. 5-HMF analogues and various types of alcohols were also transformed to their corresponding acids in satisfactory to excellent yield by this catalytic system.

Prediction of vaginal birth after cesarean in China.

OBJECTIVE: This study aimed to develop and validate a prediction model of vaginal birth after cesarean delivery (VBAC) in China. METHODS: A nomogram for effective prediction of VBAC of singleton, cephalic and one previous low-transverse cesarean section deliveries was created by comparing the combinations of ultrasonographic and non-ultrasonographic factors from five hospitals between 2018 and 2019. RESULTS: A total of 1066 women were included. Of the women who underwent trial of labor after cesarean (TOLAC), 854 (80.1%) had a VBAC. Ultrasound factors included reached a higher area under the curve (AUC) combined with non-ultrasonographic factors. Of the three ultrasonographic factors analyzed, the best predictive factor for successful TOLAC was fetal abdominal circumference. A nomogram was generated with eight validated factors, including maternal age, gestational week, height, previous vaginal delivery, Bishop score, dilatation of the cervix at the time of admission, body mass index at delivery, and fetal abdominal circumference by ultrasound. The trained and validated AUC were 0.719 (95% confident interval 0.674-0.764) and 0.774 (95% confident interval 0.712-0.837), respectively. CONCLUSION: Our VBAC nomogram based on obstetric factors and fetal abdominal circumference obtained by ultrasound could be used to counsel women who are considering TOLAC.

Congenital radioulnar synostosis: is prenatal diagnosis possible? - A case report.

OBJECTIVES: The main objectives of this case report are to discuss prenatal ultrasound findings of congenital radioulnar synostosis and to review the literature. CASE REPORT: A patient was diagnosed with congenital radioulnar synostosis at eight months old when parents noticed limited motions in the child's left forearm. The parent denied any traumatic or family history of bony malformations. Physical examination by a pediatric orthopedics specialist and digital radiography revealed proximal radioulnar synostosis. The case report includes perinatal course, comparison between the postnatal radiography and fetal ultrasound images. CONCLUSION: Congenital radioulnar synostosis is often associated with sex chromosome abnormalities and congenital musculoskeletal disorders or syndromes affecting limbs. Isolated congenital radioulnar synostosis is hardly diagnosed before birth, in some cases even have been neglected postnatally. Knowing the developmental milestones of the forearm and specified high-risk groups might help develop a targeted screening strategy to increase the possibility of early detection and intervention.

Role of OAS gene family in COVID-19 induced heart failure.

BACKGROUND: COVID-19, the current global pandemic caused by SARS-CoV-2 infection, can damage the heart and lead to heart failure (HF) and even cardiac death. The 2',5'-oligoadenylate synthetase (OAS) gene family encode interferon (IFN)-induced antiviral proteins which is associated with the antiviral immune responses of COVID-19. While the potential association of OAS gene family with cardiac injury and failure in COVID-19 has not been determined. METHODS: The expression levels and biological functions of OAS gene family in SARS-CoV-2 infected cardiomyocytes dataset (GSE150392) and HF dataset (GSE120852) were determined by comprehensive bioinformatic analysis and experimental validation. The associated microRNAs (miRNAs) were explored from Targetscan and GSE104150. The potential OAS gene family-regulatory chemicals or ingredients were predicted using Comparative Toxicogenomics Database (CTD) and SymMap database. RESULTS: The OAS genes were highly expressed in both SARS-CoV-2 infected cardiomyocytes and failing hearts. The differentially expressed genes (DEGs) in the two datasets were enriched in both cardiovascular disease and COVID-19 related pathways. The miRNAs-target analysis indicated that 10 miRNAs could increase the expression of OAS genes. A variety of chemicals or ingredients were predicted regulating the expression of OAS gene family especially estradiol. CONCLUSION: OAS gene family is an important mediator of HF in COVID-19 and may serve as a potential therapeutic target for cardiac injury and HF in COVID-19.

ZNFX1 antisense RNA1 promotes antiviral innate immune responses via modulating ZNFX1 function.

Increasing evidence suggests that natural antisense transcriptional lncRNAs regulate their adjacent coding genes to mediate diverse aspects of biology. Bioinformatics analysis of the previously identified antiviral gene ZNFX1 revealed neighboring lncRNA ZFAS1 transcribed on the opposite strand from ZNFX1. Whether ZFAS1 exerts antiviral function via regulating the dsRNA sensor ZNFX1 is unknown. Here we found that ZFAS1 was upregulated by RNA and DNA viruses and type I IFNs (IFN-I) dependent on Jak-STAT signaling, similar to the transcription regulation of ZNFX1. Knockdown of endogenous ZFAS1 partially facilitated viral infection, while ZFAS1 overexpression showed opposite effects. In addition, mice were more resistant to VSV infection with the delivery of human ZFAS1. We further observed that ZFAS1 knockdown significantly inhibited IFNB1 expression and IFR3 dimerization, whereas ZFAS1 overexpression positively regulated antiviral innate immune pathways. Mechanistically, ZFAS1 positively regulated ZNFX1 expression and antiviral function by enhancing the protein stability of ZNFX1, thereby establishing a positive feedback loop to enhance antiviral immune activation status. In short, ZFAS1 is a positive regulator of antiviral innate immune response via regulating its neighbor gene ZNFX1, adding new mechanistic insight into lncRNA-mediated regulation of signaling in innate immunity.

Orexin-A aggravates cognitive deficits in 3xTg-AD mice by exacerbating synaptic plasticity impairment and affecting amyloid ß metabolism.

Dementia is the main clinical feature of Alzheimer's disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APP/PS1 mice. However, the effects of OXA on other types of cognitive deficits, especially in 3xTg-AD mice exhibiting both plaque and tangle pathologies, have not been reported. Furthermore, the potential electrophysiological mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid ß (Aß) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, Aß levels, tau hyperphosphorylation, BACE1 and NEP expression, and circadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased Aß and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA aggravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing Aß production and decreasing Aß clearance through disruption of the circadian rhythm and sleep-wake cycle.

Circ-calm4 regulates hypoxia-induced pulmonary artery smooth muscle autophagy by binding Purb.

Pulmonary hypertension (PH) is a serious and fatal disease characterized by pulmonary vasoconstriction and pulmonary vascular remodeling. The excessive autophagy of pulmonary artery smooth muscle cells (PASMCs) is one of the important factors of pulmonary vascular remodeling. A number of studies have shown that circular RNA (circRNA) can participate in the onset of PH. Our previous studies have shown that circRNA calmodulin 4 (circ-calm4) is involved in the progression of hypoxic PH. However, the role of circ-calm4 on regulation of hypoxic PH autophagy has not been reported. In this study, we demonstrated for the first time that hypoxia-mediated upregulated circ-calm4 expression has a key regulatory effect on autophagy in hypoxia-induced PASMCs and hypoxic PH mouse models. Knockdown of circ-calm4 both in vivo and in vitro can inhibit the autophagy in PASMCs induced by hypoxia. We also performed bioinformatics predictions and conducted experiments to verify that circ-calm4 bound to the purine-rich binding protein (Purb) to promote its expression in the nucleus, thereby initiating the transcription of autophagy-related protein Beclin1. Interestingly, we found that Beclin1 transcription initiated by Purb was accompanied by a modification of Beclin1 super-enhancer to improve transcription activity and efficiency. Overall, our results confirm that the circ-calm4/Purb/Beclin1 signal axis is involved in the occurrence of hypoxia-induced PASMCs autophagy, and the novel regulatory mechanisms and signals transduction pathways in PASMC autophagy induced by hypoxia.

Scoparone suppresses mitophagy-mediated NLRP3 inflammasome activation in inflammatory diseases.

Recent evidence shows that targeting NLRP3 inflammasome activation is an important means to treat inflammasome-driven diseases. Scoparone, a natural compound isolated from the Chinese herb Artemisia capillaris Thunb, has anti-inflammatory activity. In this study we investigated the effect of scoparone on NLRP3 inflammasome activation in inflammatory diseases. In LPS-primed, ATP or nigericin-stimulated mouse macrophage J774A.1 cells and bone marrow-derived macrophages (BMDMs), pretreatment with scoparone (50 µM) markedly restrained canonical and noncanonical NLRP3 inflammasome activation, evidenced by suppressed caspase-1 cleavage, GSDMD-mediated pyroptosis, mature IL-1ß secretion and the formation of ASC specks. We then conducted a transcriptome analysis in scoparone-pretreated BMDMs, and found that the differentially expressed genes were significantly enriched in mitochondrial reactive oxygen species (ROS) metabolic process, mitochondrial translation and assembly process, as well as in inflammatory response. We demonstrated in J774A.1 cells and BMDMs that scoparone promoted mitophagy, a well-characterized mechanism to control mitochondrial quality and reduce ROS production and subsequent NLRP3 inflammasome activation. Mitophagy blockade by 3-methyladenine (3-MA, 5 mM) reversed the protective effects of scoparone on mitochondrial damage and inflammation in the murine macrophages. Moreover, administration of scoparone (50 mg/kg) exerted significant preventive effects via inhibition of NLRP3 activation in mouse models of bacterial enteritis and septic shock. Collectively, scoparone displays potent anti-inflammatory effects via blocking NLRP3 inflammasome activation through enhancing mitophagy, highlighting a potential action mechanism in treating inflammasome-related diseases for further clinical investigation.

Advances in diagnosis,prevention and treatment of flexible flatfoot in children / 中国学校卫生

Abstract@#Flexibleis an important classification of flat foot. Flatfoot occurs due to a variety of reasons and causes the medial longitudinal arch to collapse or disappear. However, many children still do not develop a normal foot arch as the grow, and a failure to intervene in a timely manner will greatly harm a child s normal mobility development. Timely detection and intervention are the key to improve the prognosis. There is a lack of uniform quantitative criteria for the diagnosis of flexible flatfoot. Currently, the commonly used diagnostic methods include physical examination, foot printing, plantar pressure test and imaging examination. This article reviews the risk factors, diagnosis, prevention and treatment of Flexible Flatfoot.

Applications of Carbon Dots for the Treatment of Alzheimer's Disease.

There are currently approximately 50 million victims of Alzheimer's disease (AD) worldwide. The exact cause of the disease is unknown at this time, but amyloid plaques and neurofibrillary tangles in the brain are hallmarks of the disease. Current drug treatments for AD may slow the progression of the disease and improve the quality of life of patients, but they are often only minimally effective and are not cures. A major obstacle to developing and delivering more effective drug therapies is the presence of the blood-brain barrier (BBB), which prevents many compounds with therapeutic potential from reaching the central nervous system. Nanotechnology may provide a solution to this problem. Among the medical nanomaterials currently being studied, carbon dots (CDs) have attracted widespread attention because of their ability to cross the BBB, non-toxicity, and potential for drug/gene delivery.