Ginkgolide A enhances FoxO1 expression and reduces endoplasmic reticulum stress to mitigate osteoarthritis in mice.

This study aimed to investigate the effects of Ginkgolide A (GA) on chondrocytes under oxidative stress and to elucidate its potential molecular mechanisms. Using a destabilization of the medial meniscus (DMM) model in mice and an in vitro osteoarthritis (OA) model induced by tert-butyl hydroperoxide (TBHP) in chondrocytes, we validated the therapeutic efficacy and underlying mechanisms of GA. Potential OA targets of GA were identified through network pharmacology, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Further exploration into the effects on endoplasmic reticulum stress (ERS), apoptosis, extracellular matrix (ECM) degradation, and Forkhead Box O1 (FoxO1) related pathways was conducted using Western blotting, immunofluorescence, TUNEL staining, flow cytometry, X-ray, micro-computed tomography (Micro-CT) analysis, and histological staining. The results demonstrated that GA upregulated FoxO1 expression and inhibited ERS-related signaling pathways, thereby reducing apoptosis and ECM degradation. In conclusion, GA significantly alleviated OA symptoms both in vitro and in vivo, suggesting its potential as a therapeutic agent for OA.

A Hypoxia-Decidual Macrophage Regulatory Axis in Normal Pregnancy and Spontaneous Miscarriage.

The significance of hypoxia at the maternal-fetal interface is proven to be self-explanatory in the context of pregnancy. During the first trimester, low oxygen conditions play a crucial role in processes such as angiogenesis, trophoblast invasion and differentiation, and immune regulation. Recently, there has been increasing research on decidual macrophages, which contribute to the maintenance of immune tolerance, placental and fetal vascular development, and spiral artery remodeling, to investigate the effects of hypoxia on their biological behaviors. On these grounds, this review describes the dynamic changes in oxygen levels at the maternal-fetal interface throughout gestation, summarizing current knowledge on how the hypoxic environment sustains a successful pregnancy by regulating retention, differentiation and efferocytosis of decidual macrophages. Additionally, we explore the relationship between spontaneous miscarriages and an abnormal hypoxia-macrophage axis, shedding light on the underlying mechanisms. However, further studies are essential to elucidate these pathways in greater detail and to develop targeted interventions that could improve pregnancy outcomes.

One step toward precision dosing of caffeine in preterm infants: An external evaluation of published population pharmacokinetic models.

BACKGROUND: Several population pharmacokinetic (PopPK) models of caffeine in preterm infants have been published, but the extrapolation of these models to facilitate model-informed precision dosing (MIPD) in clinical practice is uncertain. This study aimed to comprehensively evaluate their predictive performance using an external, independent dataset. METHODS: Data used for external evaluation were based on an independent cohort of preterm infants. Currently available PopPK models for caffeine in preterm infants were identified and re-established. Prediction- and simulation-based diagnostics were used to assess model predictability. The influence of prior information was assessed using Bayesian forecasting. RESULTS: 120 plasma samples from 76 preterm infants were included in the evaluation dataset. Twelve PopPK models of caffeine in preterm infants were re-established based on our previously published study. Although two models showed superior predictive performance, none of the 12 PopPK models met all the clinical acceptance criteria of these external evaluation items. Besides, the external predictive performances of most models were unsatisfactory in prediction- and simulation-based diagnostics. Nevertheless, the application of Bayesian forecasting significantly improved the predictive performance, even with only one prior observation. CONCLUSIONS: Two models that included the most covariates had the best predictive performance across all external assessments. Inclusion of different covariates, heterogeneity of preterm infant characteristics, and different study designs influenced predictive performance. Thorough evaluation is needed before these PopPK models can be implemented in clinical practice. The implementation of MIPD for caffeine in preterm infants could benefit from the combination of PopPK models and Bayesian forecasting as a helpful tool.

Development and application of a population pharmacokinetic model repository for caffeine dose tailoring in preterm infants.

BACKGROUND: Considerable interindividual variability for the pharmacokinetics of caffeine in preterm infants has been demonstrated, emphasizing the importance of personalized dosing. This study aimed to develop and apply a repository of currently published population pharmacokinetic (PopPK) models of caffeine in preterm infants to facilitate model-informed precision dosing (MIPD). RESEARCH DESIGN AND METHODS: Literature search was conducted using PubMed, Embase, Scopus, and Web of Science databases. Relevant publications were screened, and their quality was assessed. PopPK models were reestablished to develop the model repository. Covariate effects were evaluated and the concentration-time profiles were simulated. An online simulation and calculation tool was developed as an instance. RESULTS: Twelve PopPK models were finally included in the repository. Preterm infants' age and body size, especially the postnatal age and current weight, were identified as the most clinically critical covariates. Simulated blood concentration-time profiles across these models were comparable. Caffeine citrate-dose regimen should be adjusted according to the age and body size of preterm infants. The developed online tool can be used to facilitate clinical decision-making. CONCLUSIONS: The first developed repository of PopPK models for caffeine in preterm infants has a wide range of potential applications in the MIPD of caffeine.

Molecular characterization of the SP3a gene, a negative regulator of viral infection in the orange-spotted grouper, Epinephelus coioides.

SP3 (specificity protein 3) is a transcription factor characterized by three conserved Cys2His2 zinc finger motifs that exert a transregulatory effect by binding to GC boxes, either upregulating or downregulating multiple genes or by co-regulating gene expression in coordination with other proteins. SP3 potentially regulates a series of processes, such as the cell cycle, growth, metabolic pathways, and apoptosis, and plays an important role in antiviral effect. The function of sp3 in fish is poorly understood. In this study, the Sp3a open reading frame was cloned from the orange-spotted grouper, Epinephelus coioides. The full-length open reading frame of Sp3a was 2034 bp, encoding 677 amino acids, with a predicted molecular weight of 72.34 kDa and an isoelectric point of 5.05. Phylogenetically, Sp3a in Epinephelus coioides was the most closely related to Sp3a in the Malabar grouper, Epinephelus malabaricus. RT-qPCR revealed ubiquitous expression of Sp3a in all examined grouper tissues, with no significant differences in expression levels among tissues. A eukaryotic expression vector, pEGFP-Sp3a, was constructed and transfected into grouper spleen (GS) cells. Subcellular localization of Sp3a was observed using an inverted fluorescence microscope. When Spa3 was overexpressed in GS cells, the expression of orange-spotted grouper nerve necrosis virus (RGNNV) genes (CP and RdRp) decreased significantly, indicating that Sp3a significantly inhibited RGNNV replication. siRNA inhibition of Sp3a accelerated the intracellular replication of RGNNV, implying the antiviral effect of Sp3a. Conclusively, our findings contribute to further research on the antiviral capabilities of Sp3a in grouper and other fish. Therefore, our research has potential implications on the development of the aquaculture industry.

The current clinical landscape of neonatal respiratory failure in Jiangsu Province of China: patient demographics, NICU treatment interventions, and patient outcomes.

INTRODUCTION: Neonatal respiratory failure (NRF) is a serious condition that often has high mortality and morbidity, effective interventions can be delivered in the future by identifying the risk factors associated with morbidity and mortality. However, recent advances in respiratory support have improved neonatal intensive care units (NICUs) care in China. We aimed to provide an updated review of the clinical profile and outcomes of NRF in the Jiangsu province. METHODS: Infants treated for NRF in the NICUs of 28 hospitals between March 2019 and March 2022 were retrospectively reviewed. Data collected included baseline perinatal and neonatal parameters, NICU admission- and treatment-related data, and patient outcomes in terms of mortality, major morbidity, and survival without major morbidities. RESULTS: A total of 5548 infants with NRF were included in the study. The most common primary respiratory disorder was respiratory distress syndrome (78.5%). NRF was managed with non-invasive and invasive respiratory support in 59.8% and 14.5% of patients, respectively. The application rate of surfactant therapy was 38.5%, while that of neonatal extracorporeal membrane oxygenation therapy was 0.2%. Mortality and major morbidity rates of 8.5% and 23.2% were observed, respectively. Congenital anomalies, hypoxic-ischemic encephalopathy, invasive respiratory support only and inhaled nitric oxide therapy were found to be significantly associated with the risk of death. Among surviving infants born at < 32 weeks of gestation or with a birth weight < 1500 g, caffeine therapy and repeat mechanical ventilation were demonstrated to significantly associate with increased major morbidity risk. CONCLUSION: Our study demonstrates the current clinical landscape of infants with NRF treated in the NICU, and, by proxy, highlights the ongoing advancements in the field of perinatal and neonatal intensive care in China.

Tenascin-C modulates alveolarization in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease characterized by retarded alveolarization. Tenascin-C (TN-C), an extracellular matrix glycoprotein and soluble molecule, is involved in tissue morphogenesis. In the present study, we demonstrated that the level of TN-C in lung tissues was greater in a mouse model of BPD induced by 85% oxygen. TN-C deficiency, however, impaired alveolarization in the hyperoxia-induced BPD model. In contrast, a functional TN-C blocking antibody ameliorated alveolar dysplasia in BPD-like mice. Mechanistically, hyperoxia increased the soluble TN-C (sTN-C) released from respiratory epithelial cells. On one hand, low-dose sTN-C promoted lung epithelial cell proliferation and migration, which was mediated by ICAM-1. On the other hand, high-dose sTN-C hindered the proliferation and migration of epithelial cells. Overall, this study revealed that TN-C plays a dual role in lung alveolarization and that TN-C may be a target in BPD therapy.

Effects of seasoning addition and cooking conditions on the formation of free and protein-bound heterocyclic amines and advanced glycation end products in braised lamb.

The accumulation of heterocyclic amines (HAs) and advanced glycation end products (AGEs) in thermally processed meats has been arising safety concerns. The effects of cooking conditions and seasoning addition on the formation of HAs and AGEs in Chinese traditional braised lamb were investigated by UPLC-MS/MS analysis. Soy sauce significantly increased the formation of HAs and AGEs, among which light soy sauce had the greatest promoting effect (69.45-15300.62 %). Conversely, spices inhibited HAs and AGEs formation, the inhibition rate of free HAs and AGEs reached 22.06-34.72 % when using 70 % ethanol extract. Hot blanching treatment and adding soy sauce and spices at a later stage could significantly suppress HAs and AGEs production. Flavonoids, including galangin, hesperidin, narirutin, etc., were identified as key effectors in spices. These findings help to promote awareness of the formation of HAs and AGEs in braised lamb and provide valuable insights for optimizing processing techniques to minimize their production.

Machine learning application for prediction of surgical site infection after posterior cervical surgery.

Surgical site infection (SSI) is one of the most common complications of posterior cervical surgery. It is difficult to diagnose in the early stage and may lead to severe consequences such as wound dehiscence and central nervous system infection. This retrospective study included patients who underwent posterior cervical surgery at The Second Affiliated Hospital and Yuying Childrens Hospital of Wenzhou Medical University from September 2018 to June 2022. We employed several machine learning methods, such as the gradient boosting (GB), random forests (RF), artificial neural network (ANN) and other popular machine learning models. To minimize the variability introduced by random splitting, the results underwent 10-fold cross-validation repeated 10 times. Five measurements were averaged across 10 repetitions with 10-fold cross-validation, the RF model achieved the highest AUROC (0.9916), specificity (0.9890) and precision (0.9759). The GB model achieved the highest sensitivity (0.9535) and the KNN achieved the highest sensitivity (0.9958). The application of machine learning techniques facilitated the development of a precise model for predicting SSI after posterior cervical surgery. This dynamic model can be served as a valuable tool for clinicians and patients to assess SSI risk and prevent it in clinical practice.

A nomogram for predicting the risk of Bronchopulmonary dysplasia in premature infants.

Background: Bronchopulmonary dysplasia (BPD) is a prevalent and critical complication among premature infants, with potentially long-lasting adverse effetcs. The present study aimed to establish a nomogram model to predict the risk of BPD in premature infants born at <32 weeks gestational age. Methods: A retrospective single-center study was conducted on premature infants admitted to the neonatal intensive care unit (NICU) of the Children's Hospital of Nanjing Medical University from January 2018 to December 2020. Data were collected from clinical medical records, including the perinatal data and the critical information after birth. Clinical parameters and features were analyzed using univariate and multivariate logistic regression. A nomogram based on clinical data was established and validated using bootstrapping samples. The specificity and sensitivity of the nomogram were estimated using the receiver operating characteristic (ROC) based area under the curve (AUC). Results: A total of 542 premature babies were included, and 152 infants (28.04%) were diagnosed with BPD. Birth weight, cesarean delivery, invasive/non-invasive ventilation at day 7 and 14 were identified as significant factors (p < 0.05) using univariate and the multivariate logistic regression analysis, and were entered into a nomogram. The calibration curve for BPD probability demonstrated a favorable concurrence between actual probability and predicted ability of the BPD nomogram. The nomogram showed potential differentiation, with an AUC of 0.925, 89.90% sensitivity, 76.71% specificity, and 86.35% accuracy. Conclusion: The nomogram developed in this study provides a straightforward tool to predict the probability of BPD and assist clinicians in optimizing treatment regimens for premature infants born at <32 weeks gestational age. This study highlights the importance of identifying and monitoring significant clinical factors associated with BPD in premature infants to improve clinical outcomes.

Biosynthesis of maltodextrin-derived glucan dendrimer using microbial branching enzyme.

Glucan dendrimers were developed with microbial branching enzyme (BE) treated maltodextrin. The molecular weight (Mw) of recombinant BE was 79.0 kDa, and its optimum activity was observed at pH 7.0 and 70 °C. BE converted different maltodextrins with dextrose equivalent value of 6 (MD6), 12 (MD12), or 19 (MD19) into the given glucan dendrimers, along with the marked increment of the molecular density (approximately 30-60 folds) and α-1,6 linkage percentage (up to 7.3-9.7%). Among three glucan dendrimers, the enzyme-treated MD12 showed a more homogeneous Mw distribution with the maximum Mw of 5.5 × 106 g/mol, indicating that higher substrate catalytic specificity of BE for MD12 substrate. During transglycosylation with MD12 for 24 h, the shorter chains (degree of polymerization, DP < 13) increased from 73.9% to 83.0%, accompanying by a reduction of medium chains (DP13-24) and long chains (DP > 24). Moreover, the slowly digestible and resistant nutritional fractions were increased by 6.2% and 12.5%, respectively. The results suggested that the potentiality of BE structuring glucan dendrimer with tailor-made structure and functionality for industrial application.

Emerging strategies of engineering retinal organoids and organoid-on-a-chip in modeling intraocular drug delivery: Current progress and future perspectives.

Retinal diseases are a rising concern as major causes of blindness in an aging society; therapeutic options are limited, and the precise pathogenesis of these diseases remains largely unknown. Intraocular drug delivery and nanomedicines offering targeted, sustained, and controllable delivery are the most challenging and popular topics in ocular drug development and toxicological evaluation. Retinal organoids (ROs) and organoid-on-a-chip (ROoC) are both emerging as promising in-vitro models to faithfully recapitulate human eyes for retinal research in the replacement of experimental animals and primary cells. In this study, we review the generation and application of ROs resembling the human retina in cell subtypes and laminated structures and introduce the emerging engineered ROoC as a technological opportunity to address critical issues. On-chip vascularization, perfusion, and close inter-tissue interactions recreate physiological environments in vitro, whilst integrating with biosensors facilitates real-time analysis and monitoring during organogenesis of the retina representing engineering efforts in ROoC models. We also emphasize that ROs and ROoCs hold the potential for applications in modeling intraocular drug delivery in vitro and developing next-generation retinal drug delivery strategies.

Aerobic oxidation of methane significantly reduces global diffusive methane emissions from shallow marine waters.

Methane is supersaturated in surface seawater and shallow coastal waters dominate global ocean methane emissions to the atmosphere. Aerobic methane oxidation (MOx) can reduce atmospheric evasion, but the magnitude and control of MOx remain poorly understood. Here we investigate methane sources and fates in the East China Sea and map global MOx rates in shallow waters by training machine-learning models. We show methane is produced during methylphosphonate decomposition under phosphate-limiting conditions and sedimentary release is also source of methane. High MOx rates observed in these productive coastal waters are correlated with methanotrophic activity and biomass. By merging the measured MOx rates with methane concentrations and other variables from a global database, we predict MOx rates and estimate that half of methane, amounting to 1.8 ± 2.7 Tg, is consumed annually in near-shore waters (<50 m), suggesting that aerobic methanotrophy is an important sink that significantly constrains global methane emissions.

[Pulmonary hemorrhage in very low birth weight infants: risk factors and clinical outcome]. / æžä½Žå‡ºç”Ÿä½“é‡å„¿å‘ç”Ÿè‚ºå‡ºè¡€çš„å±é™©å› ç´ åŠå ¶ä¸´åºŠè½¬å½’.

OBJECTIVES: To investigate the risk factors for pulmonary hemorrhage and its clinical outcome in very low birth weight infants (VLBWIs). METHODS: The medical data were collected from all live VLBWIs (gestational age <35 weeks) who were admitted to Jiangsu Women and Children Health Hospital and Children's Hospital of Nanjing Medical University between January 1, 2020 and December 31, 2021. Based on inclusion and exclusion criteria, 574 VLBWIs were included in the study, with 44 VLBWIs in the pulmonary hemorrhage group and 530 VLBWIs in the non-pulmonary hemorrhage group. The clinical data were compared between the two groups. A multivariate logistic regression analysis was used to identify the risk factors for pulmonary hemorrhage. RESULTS: There were significant differences between the two groups in maternal age, rate of positive-pressure ventilation for resuscitation, rate of tracheal intubation for resuscitation, and minimum body temperature within 1 hour after birth (P<0.05). The pulmonary hemorrhage group had a higher proportion of VLBWIs with grade Ⅲ-Ⅳ respiratory distress syndrome or early-onset sepsis than the non-pulmonary hemorrhage group (P<0.05). The pulmonary hemorrhage group also had a higher proportion of VLBWIs with a capillary refilling time of >3 seconds within 1 hour after birth and with the maximum positive end-expiratory pressure (PEEP) of <5 cmH2O within 24 hours after birth (P<0.05). The multivariate regression analysis showed that maternal age of 30-<35 years (OR=0.115, P<0.05) was a protective factor against pulmonary hemorrhage, while a lower temperature (<34°C) within 1 hour after birth, the maximum PEEP of <5 cm H2O within 24 hours after birth, and early-onset sepsis were risk factors for pulmonary hemorrhage (OR=11.609, 11.118, and 20.661, respectively; P<0.05). For all VLBWIs, the pulmonary hemorrhage group had a longer duration of invasive ventilation and a higher mortality rate than the non-pulmonary hemorrhage group (P<0.05); for the survival VLBWIs, the pulmonary hemorrhage group had a higher incidence rate of bronchopulmonary dysplasia than the non-pulmonary hemorrhage group (P<0.05). CONCLUSIONS: Maintaining the stability of temperature, giving appropriate PEEP, and identifying sepsis as early as possible can reduce the incidence rate of pulmonary hemorrhage, thereby helping to reduce the incidence of bronchopulmonary dysplasia and mortality in VLBWIs.

Bufogarlides A-C, three new bufadienolides with Δ14,15 double bond from the skins of Bufo bufo gargarizans.

Three new bufadienolides with a Δ14,15 double bond, named bufogarlides A-C (1-3), together with three known analogs (4-6), were isolated from the skins of Bufo bufo gargarizans. Their structures were identified by analyses of spectroscopic data (1 D and 2 D NMR, HR-ESIMS), and comparison with the literature data. All the isolates were evaluated for their cytotoxic activities against ovarian carcinoma cell lines A2780 and SKOV3. Among them, compound 5 showed the highest potential for the growth inhibition of cancerous cells A2780 and SKOV3 with the IC50 values of 21.09 and 67.08 nM, respectively.

SARS-CoV-2 Nucleocapsid Protein Has DNA-Melting and Strand-Annealing Activities With Different Properties From SARS-CoV-2 Nsp13.

Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread throughout the world and has had a devastating impact on health and economy. The biochemical characterization of SARS-CoV-2 proteins is important for drug design and development. In this study, we discovered that the SARS-CoV-2 nucleocapsid protein can melt double-stranded DNA (dsDNA) in the 5'-3' direction, similar to SARS-CoV-2 nonstructural protein 13. However, the unwinding activity of SARS-CoV-2 nucleocapsid protein was found to be more than 22 times weaker than that of SARS-CoV-2 nonstructural protein 13, and the melting process was independent of nucleoside triphosphates and Mg2+. Interestingly, at low concentrations, the SARS-CoV-2 nucleocapsid protein exhibited a stronger annealing activity than SARS-CoV-2 nonstructural protein 13; however, at high concentrations, it promoted the melting of dsDNA. These findings have deepened our understanding of the SARS-CoV-2 nucleocapsid protein and will help provide novel insights into antiviral drug development.

The biochemical and molecular investigation of flower color and scent sheds lights on further genetic modification of ornamental traits in Clivia miniata.

Clivia miniata is renowned for its evergreen and strap-like leaves, whereas its floral color and scent are lacking diversity. Here, anthocyanin, volatile terpene, and carotenoid metabolisms were integrally investigated in C. miniata flowers. The results showed that pelargonidins and lutein might cooperate to confer orange or yellow color to C. miniata flowers, but only a trace amount of (+)-limonene was detected. The expression levels of CmF3'H and CmDFR appeared to be responsible for the ratio of cyanidin and pelargonidin derivatives in C. miniata, and the low expression of CmF3'H was responsible for the lack of cyanidins in flowers. Moreover, the CmF3'H promoter could not be activated by CmMYBAs, suggesting that it was controlled by novel regulators. Only two CmTPSs were functional, with CmTPS2 responsible for (+)-limonene synthesis, contributing to the monotonous flower volatile terpenes of C. miniata. CmCCD1a and CmCCD1b were able to cleave carotenoids at the 5,6 (5',6'), and 9,10 (9',10') positions to generate volatile apocarotenoids, whereas the substrates found in low-quantities or specific subcellular localizations of CmCCD1s might constrain volatile apocarotenoid release. Consequently, activating F3'H and introducing novel F3'5'H or versatile TPS may be effective ways to modify the floral color and scent, respectively. Alternatively, modifying the carotenoid flux or CCD1 localization might affect floral color and scent simultaneously. Taking these results together, the present study provides a preliminary deciphering of the genetic constraints underlying flower color and scent development, and proposes possible schemes for further genetic modification of ornamental traits in C. miniata and other plants.

Population pharmacokinetic modeling of caffeine in preterm infants with apnea of prematurity: New findings from concomitant erythromycin and AHR genetic polymorphisms.

Current standard-dose caffeine therapy results in significant intersubject variability. The aims of this study were to develop and evaluate population pharmacokinetic (PPK) models of caffeine in preterm infants through comprehensive screening of covariates and then to propose model-informed precision dosing of caffeine for this population. A total of 129 caffeine concentrations from 96 premature neonates were incorporated into this study. Comprehensive medical record and genotype data of these neonates were collected for analysis. PPK modeling was performed by a nonlinear mixed effects modeling program (NONMEM). Final models based on the current weight (CW) or body surface area (BSA) were evaluated via multiple graphic and statistical methods. The model-informed dosing regimen was performed through Monte Carlo simulations. In addition to CW or BSA, postnatal age, coadministration with erythromycin (ERY), and aryl hydrocarbon receptor coding gene (AHR) variant (rs2158041) were incorporated into the final PPK models. Multiple evaluation results showed satisfactory prediction performance and stability of the CW- and BSA-based models. Monte Carlo simulations demonstrated that trough concentrations of caffeine in preterm infants would be affected by concomitant ERY therapy and rs2158041 under varying dose regimens. For the first time, ERY and rs2158041 were found to be associated with the clearance of caffeine in premature infants. Similar predictive performance and stability were obtained for both CW- and BSA-based PPK models. These findings provide novel insights into caffeine precision therapy for preterm infants.

[Early risk factors for death in neonates with persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide]. / ç»ä¸€æ°§åŒ–æ°®å¸å ¥æ²»ç–—çš„æ–°ç”Ÿå„¿æŒç»­è‚ºåŠ¨è„‰é«˜åŽ‹æ‚£å„¿æ­»äº¡çš„æ—©æœŸå½±å“å› ç´ åˆ†æž.

OBJECTIVES: To evaluate the early risk factors for death in neonates with persistent pulmonary hypertension of the newborn (PPHN) treated with inhaled nitric oxide (iNO). METHODS: A retrospective analysis was performed on 105 infants with PPHN (gestational age ≥34 weeks and age <7 days on admission) who received iNO treatment in the Department of Neonatology, Children's Hospital of Nanjing Medical University, from July 2017 to March 2021. Related general information and clinical data were collected. According to the clinical outcome at discharge, the infants were divided into a survival group with 79 infants and a death group with 26 infants. Univariate and multivariate Cox regression analyses were used to evaluate the risk factors for death in infants with PPHN treated with iNO. The receiver operating characteristic (ROC) curve was used to calculate the cut-off values of the factors in predicting the death risk. RESULTS: A total of 105 infants with PPHN treated with iNO were included, among whom 26 died (26/105, 24.8%). The multivariate Cox regression analysis showed that no early response to iNO (HR=8.500, 95%CI: 3.024-23.887, P<0.001), 1-minute Apgar score ≤3 points (HR=10.094, 95%CI: 2.577-39.534, P=0.001), a low value of minimum PaO2/FiO2 within 12 hours after admission (HR=0.067, 95%CI: 0.009-0.481, P=0.007), and a low value of minimum pH within 12 hours after admission (HR=0.049, 95%CI: 0.004-0.545, P=0.014) were independent risk factors for death. The ROC curve analysis showed that the lowest PaO2/FiO2 value within 12 hours after admission had an area under the ROC curve of 0.783 in predicting death risk, with a sensitivity of 84.6% and a specificity of 73.4% at the cut-off value of 50, and the lowest pH value within 12 hours after admission had an area under the ROC curve of 0.746, with a sensitivity of 76.9% and a specificity of 65.8% at the cut-off value of 7.2. CONCLUSIONS: Infants with PPHN requiring iNO treatment tend to have a high mortality rate. No early response to iNO, 1-minute Apgar score ≤3 points, the lowest PaO2/FiO2 value <50 within 12 hours after admission, and the lowest pH value <7.2 within 12 hours after admission are the early risk factors for death in such infants. Monitoring and evaluation of the above indicators will help to identify high-risk infants in the early stage.

Comparing the Nucleocapsid Proteins of Human Coronaviruses: Structure, Immunoregulation, Vaccine, and Targeted Drug.

The seven pathogenic human coronaviruses (HCoVs) include HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, which usually cause mild upper respiratory tract diseases, and SARS-CoV, MERS-CoV, and SARS-CoV-2, which cause a severe acute respiratory syndrome. The nucleocapsid (N) protein, as the dominant structural protein from coronaviruses that bind to the genomic RNA, participates in various vital activities after virus invasion and will probably become a promising target of antiviral drug design. Therefore, a comprehensive literature review of human coronavirus' pathogenic mechanism and therapeutic strategies is necessary for the control of the pandemic. Here, we give a systematic summary of the structures, immunoregulation, and potential vaccines and targeted drugs of the HCoVs N protein. First, we provide a general introduction to the fundamental structures and molecular function of N protein. Next, we outline the N protein mediated immune regulation and pathogenesis mechanism. Finally, we comprehensively summarize the development of potential N protein-targeted drugs and candidate vaccines to treat coronavirus disease 2019 (COVID-19). We believe this review provides insight into the virulence and transmission of SARS-CoV-2 as well as support for further study on epidemic control of COVID-19.