HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m5 C Methylation of Atf7 mRNA.

PIWI-interacting RNAs (piRNAs) are highly expressed in various cardiovascular diseases. However, their role in cardiomyocyte death caused by ischemia/reperfusion (I/R) injury, especially necroptosis, remains elusive. In this study, a heart necroptosis-associated piRNA (HNEAP) is found that regulates cardiomyocyte necroptosis by targeting DNA methyltransferase 1 (DNMT1)-mediated 5-methylcytosine (m5 C) methylation of the activating transcription factor 7 (Atf7) mRNA transcript. HNEAP expression level is significantly elevated in hypoxia/reoxygenation (H/R)-exposed cardiomyocytes and I/R-injured mouse hearts. Loss of HNEAP inhibited cardiomyocyte necroptosis and ameliorated cardiac function in mice. Mechanistically, HNEAP directly interacts with DNMT1 and attenuates m5 C methylation of the Atf7 mRNA transcript, which increases Atf7 expression level. ATF7 can further downregulate the transcription of Chmp2a, an inhibitor of necroptosis, resulting in the reduction of Chmp2a level and the progression of cardiomyocyte necroptosis. The findings reveal that piRNA-mediated m5 C methylation is involved in the regulation of cardiomyocyte necroptosis. Thus, the HNEAP-DNMT1-ATF7-CHMP2A axis may be a potential target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.

[Diagnosis and treatment of a child with alveolar capillary dysplasia with misalignment of pulmonary veins due to variant of FOXF1 gene].

OBJECTIVE: To explore the diagnosis, treatment and genetic characteristics of a neonate with severe pulmonary hypertension and respiratory failure. METHODS: Perinatal history, clinical manifestations, laboratory finding and diagnosis and treatment data of the child were collected. Whole exome sequencing was carried out for the child, and Sanger sequencing was used to verify the candidate variants. RESULTS: The female neonate has developed progressive respiratory failure and refractory pulmonary hypertension shortly after birth. Conventional treatment such as mechanical ventilation, vasoactive drugs, and inhaled nitric oxide were ineffective. She has developed sustained pulmonary hypertension after weaning from extracorporeal membrane oxygenation therapy, and had died after the treatment had ceased. Whole exome sequencing revealed that she has harbored a heterozygous de novo variant of c.682_683insGCGGCGGC (p.G234Rfs*148) of the FOXF1 gene, which was predicted as pathogenic based on guidelines from the American College of Medical Genetics and Genomics (ACMG), with evidence items of PVS1_Strong+PM2_Supporting+PS2. Based on her clinical manifestations and result of genetic testing, the child was diagnosed with alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV). CONCLUSION: Discovery of the c.682_683insGCGGCGGC (p.G234 Rfs*148) variant of the FOXF1 gene has expanded the mutational spectrum of the FOXF1 gene, which has facilitated implementation of specific treatment and provided a basis for clinical diagnosis and genetic counseling.

Molecular therapy of cardiac ischemia-reperfusion injury based on mitochondria and ferroptosis.

Excessive death of myocardial cells can lead to various cardiovascular diseases and even develop into heart failure, so developing ideal treatment plans based on pathogenesis is of great significance for cardiopathy. After the heart undergoes ischemia‒reperfusion (I/R), myocardial cells accumulate a large amount of peroxides, leading to mitochondrial dysfunction and inducing ferroptosis. Ferroptosis is a form of iron-dependent regulatory cell death (RCD) caused by imbalanced redox and iron metabolism that leads to severe cell damage through the accumulation of peroxides. The mechanism of ferroptosis is highly correlated with mitochondrial metabolism. Myocardial cells are rich in a large number of mitochondria, which serve as energy supply centers and are prone to producing reactive oxygen species (ROS), providing opportunities for oxidative stress caused by ferroptosis. Ferroptosis is related to various cardiovascular diseases, and potential treatment methods designed around ferroptosis may alter the pathological progression of cardiovascular diseases. Therefore, this review investigates the regulatory mechanisms of ferroptosis, exploring the close pathological and physiological connections between ferroptosis and mitochondrial and cardiac I/R injury. Targeting ferroptosis and mitochondria for intervention may be an effective plan for preventing and treating cardiac I/R injury.

Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome.

Schinzel-Giedion syndrome (SGS) is a multiple malformation syndrome characterized by typical facial features, severe neurodevelopmental delay, and multiple congenital abnormalities. SGS is associated with de novo pathogenic variants in the SETBP1 gene. In specific, SETBP1 variants in over 50 patients with classical or non-classical SGS were clustered within exon 4. A male Chinese neonate with dysmorphic facial features, nervous system disorders, and organ malformations at birth was examined in this study and long-term followed-up. Whole-exome sequencing was performed to identify any underlying pathogenic variants in the proband. Additionally, we reviewed the literature that documents the main clinical features and underlying variants of all patients genetically diagnosed with SGS. The neonate had a characteristic midface retraction, abnormal electroencephalogram waveforms, and genital abnormalities. The patient did not initially develop hydronephrosis or undergo a comprehensive skeletal assessment. Six months after birth, the patient had an epileptic seizure and experienced persistent neurodevelopmental delay with auditory and visual abnormalities. Color Doppler ultrasonography at 18 months revealed hydronephrosis and bilateral widening of the lateral ventricles. The patient died suddenly 20.5 months after birth. Whole-exome sequencing revealed a heterozygous de novo variant (c.2605A > G:p.S869G) in exon 4 degradation sequence in SETBP1. The reported de novo heterozygous variant in SETBP1 (c.2605A > G:p.S869G) broadens the knowledge of the scientific community's on the possible SGS genetic alterations. To the best of our knowledge, this is the first report of SETBP1 variant (c.2605A > G:p.S869G) in SGS. The clinical manifestations of neonatal SGS are atypical, and genetic testing is crucial for diagnosis. Long-term follow-up should be conducted after diagnosis to optimize the therapeutic interventions.

Reinforcement Learning-Based Reactive Obstacle Avoidance Method for Redundant Manipulators.

Redundant manipulators are widely used in fields such as human-robot collaboration due to their good flexibility. To ensure efficiency and safety, the manipulator is required to avoid obstacles while tracking a desired trajectory in many tasks. Conventional methods for obstacle avoidance of redundant manipulators may encounter joint singularity or exceed joint position limits while tracking the desired trajectory. By integrating deep reinforcement learning into the gradient projection method, a reactive obstacle avoidance method for redundant manipulators is proposed. We establish a general DRL framework for obstacle avoidance, and then a reinforcement learning agent is applied to learn motion in the null space of the redundant manipulator Jacobian matrix. The reward function of reinforcement learning is redesigned to handle multiple constraints automatically. Specifically, the manipulability index is introduced into the reward function, and thus the manipulator can maintain high manipulability to avoid joint singularity while executing tasks. To show the effectiveness of the proposed method, the simulation of 4 degrees of planar manipulator freedom is given. Compared with the gradient projection method, the proposed method outperforms in a success rate of obstacles avoidance, average manipulability, and time efficiency.

Incidence of retinopathy of prematurity treatment in extremely preterm infants in China.

BACKGROUND: Retinopathy of prematurity (ROP) continues to be a major cause of visual impairment and blindness in premature infants and children. OBJECTIVES: To investigate the incidence of severe ROP receiving treatment in extremely preterm (EP) infants in China over time. The risk factors for ROP treatment were also assessed. METHODS: This was a multicentre retrospective study and a subanalysis of baseline data from the "Outcomes of EP infants in China 2010-2019" study. This study was conducted in 68 tertiary neonatal care centres from 31 provinces of China. Infants with a gestational age of 230 -276  weeks and admitted to a neonatal unit within the first 72 h of life between 2010 and 2019 were enrolled. Incidence of ROP was analysed in infants who survived to 32 weeks postmenstrual age and screened for ROP. Multivariable modified Poisson regression models were used to identify risk factors for ROP treatment. RESULTS: Among 7295 eligible infants, 4701 (64.5%) survived to 32 weeks postmenstrual age and met ROP screening criteria. Of the 3756 infants who screened and with ROP data, 2320 (61.8%) developed ROP of any stage. The overall incidence of ROP treatment was 12.6%, decreasing from 45.5% at 23 weeks to 8.3% at 27 weeks. During the 10-year period, the incidence of ROP treatment did not change, although the incidence of any ROP increased over time. Independent risk factors associated with ROP treatment included lower gestational age, small for gestational age, multiple birth, severe intraventricular haemorrhage, patent ductus arteriosus and supplemental oxygen duration. CONCLUSIONS: The incidence of EP infants receiving ROP treatment showed no change during this 10-year period in China. Prevention of prematurity and foetal growth restriction, judicious use of oxygen and reducing comorbidities are promising factors that may reduce the incidence of ROP needing treatment in these high-risk infants.

Case Report: Transient antenatal bartter syndrome in an extremely preterm infant with a novel MAGED2 variant.

Variants in the MAGED2 may cause antenatal transient Bartter syndrome, which is characterised by polyhydramnios, preterm labour, postnatal polyuria, hypokalaemia and metabolic alkalosis. Transient gross hematuria and acute kidney injury in such cases have not been reported previously. The patient, a boy, was born at a gestational age of 27 + 5 weeks. Polyhydramnios has been detected at 24 weeks of gestation. Polyuria, hyponatraemia, hypokalaemia, weight loss, transient hematuria and acute kidney injury occur after birth. The urinary ultrasonography showed no abnormality, and after a month of treatment with liquid electrolytes and nutritional management, the clinical symptoms improved. Whole-exome sequencing revealed a variant in MAGED2: c.1426C > T, p.Arg476X, inherited from the mother, who was healthy. During the 1-year follow-up, the child grew and developed with normal renal function and electrolyte levels. This is the first report of transient antenatal Bartter syndrome caused by a MAGED2 variant in China in an extremely preterm infant who exhibited previously unreported symptoms: transient hematuria and acute kidney injury. This newly found variant expands the spectrum of genetic variants associated with antenatal Bartter syndrome; it can be detected by early genetic testing and overmedication, thereby avoided.

A novel synonymous ABCA3 variant identified in a Chinese family with lethal neonatal respiratory failure.

BACKGROUND: Lethal respiratory failure is primarily caused by a deficiency of pulmonary surfactant, and is the main cause of neonatal death among preterm infants. Pulmonary surfactant metabolism dysfunction caused by variants in the ABCA3 gene is a rare disease with very poor prognosis. Currently, the mechanisms associated with some ABCA3 variants have been determined, including protein mistrafficking and impaired phospholipid transport. However, some novel variants and their underlying pathogenesis has not been fully elucidated yet. In this study we aimed to identify the genetic features in a family with lethal respiratory failure. METHODS: We studied members of two generations of a Chinese family, including a female proband, her parents, her monozygotic twin sister, and her older sister. Trio whole exome sequencing (WES) were used on the proband and her parents to identify the ABCA3 variants. Sanger sequencing and real-time quantitative polymerase chain reaction (PCR) were used on the monozygotic twin sister of proband to validate the ABCA3 synonymous variant and exon deletion, respectively. The potential pathogenicity of the identified synonymous variant was predicted using the splice site algorithms dbscSNV11_AdaBoost, dbscSNV11_RandomForest, and Human Splicing Finder (HSF). RESULTS: All patients showed severe respiratory distress, which could not be relieved by mechanical ventilation, supplementation of surfactant, or steroid therapy, and died at an early age. WES analysis revealed that the proband had compound heterozygous ABCA3 variants, including a novel synonymous variant c.G873A (p.Lys291Lys) in exon 8 inherited from the mother, and a heterozygous deletion of exons 4-7 inherited from the father. The synonymous variant was consistently predicted to be a cryptic splice donor site that may lead to aberrant splicing of the pre-mRNA by three different splice site algorithms. The deletion of exons 4-7 of the ABCA3 gene was determined to be a likely pathogenic variant. The variants were confirmed in the monozygotic twin sister of proband by Sanger sequencing and qPCR respectively. The older sister of proband was not available to determine if she also carried both ABCA3 variants, but it is highly likely based on her clinical course. CONCLUSIONS: We identified a novel synonymous variant and a deletion in the ABCA3 gene that may be responsible for the pathogenesis in patients in this family. These results add to the known mutational spectrum of the ABCA3 gene. The study of ABCA3 variants may be helpful for the implementation of patient-specific therapies.

Is preterm donor milk better than preterm formula for very-low-birth-weight infants?

BACKGROUND: Preterm human milk has advantages over preterm formula (PF), but it may compromise some functions after pasteurization. OBJECTIVE: To explore the effects of preterm donor milk (DM) on growth, feeding tolerance, and severe morbidity in very-low-birth-weight infants. METHOD: This was a single-center, prospective cohort study that included 304 preterm infants weighing <1,500 g or of gestational age <32 weeks. If the mother's own milk was insufficient, the parents decided to use PF (n = 155) or DM (n = 149). The two groups were uniformly managed according to the standard NICU protocol. Growth parameters, feeding tolerance, and severe morbidity such as necrotizing enterocolitis, were compared between the two groups. RESULTS: The daily weight gain and weekly head growth in the DM group were not different from those in the PF group (P > 0.05). Feeding intolerance in the DM group was significantly lower than that in PF group (P < 0.05), and parenteral nutrition time and hospitalization time were also shorter than that in the PF group (P < 0.05). Moreover, the incidence of necrotizing enterocolitis and sepsis was also significantly lower in the DM group (P < 0.05). CONCLUSION: The study indicated that preterm DM does not affect the growth of very-low-birth-weight infants. Further, it significantly reduces feeding intolerance, helps achieve full enteral feeding early, and has protective effects against necrotizing enterocolitis and sepsis. Thus, compared with formula, preterm DM can lower the rate of infection in preterm infants and is worthy of promotion.

Downregulation of lncRNA GAS5 Alleviates Hippocampal Neuronal Damage in Mice with Depression-Like Behaviors Via Modulation of MicroRNA-26a/EGR1 Axis.

BACKGROUND: Accumulating evidences have demonstrated the roles of several long non-coding RNAs (lncRNAs) in depression. We aim to examine the capabilities of lncRNA growth arrest-specific transcript 5 (GAS5) on mice with depression-like behaviors and the mechanism of action. METHODS: Fifty-six healthy mice were selected for model establishment. Morris water maze test and trapeze test were performed for evaluating learning and memory ability. The binding relationship between lncRNA GAS5 and microRNA-26a (miR-26a) and the target relationship between miR-26a and EGR1 were verified by dual-luciferase reporter gene assay. The apoptosis of neurons in the hippocampal CA1 region of mice was detected by TUNEL staining. The expression of inflammatory factors, lncRNA GAS5, miR-26a, early growth response gene 1 (EGR1), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway- and apoptosis-related factors in hippocampal tissues was tested by RT-qPCR and western blot analysis. RESULTS: miR-26a expression was down-regulated while EGR1 and lncRNA GAS5 expression were up-regulated in hippocampal tissues of mice with depression-like behaviors. LncRNA GAS5 specifically bound to miR-26a and miR-26a targeted EGR1. Silencing of lncRNA GAS5 curtailed the release of inflammatory factors and the apoptosis of hippocampal neuron of mice with depression-like behaviors. EGR1 suppressed PI3K/AKT pathway activation to promote the release of inflammatory factors and the apoptosis of hippocampal neurons in mice with depression-like behaviors. CONCLUSION: Our study provides evidence that silencing of lncRNA GAS5 could activate PI3K/AKT pathway to protect hippocampal neurons against damage in mice with depression-like behaviors by regulating the miR-26a/EGR1 axis.

[Clinical effect of continuous blood purification in treatment of multiple organ dysfunction syndrome in neonates].

OBJECTIVE: To study the clinical effect and complications of continuous blood purification (CBP) in the treatment of multiple organ dysfunction syndrome (MODS) in neonates. METHODS: A retrospective analysis was performed for the clinical data of 21 neonates with MODS who were admitted to the neonatal intensive care unit from November 2015 to April 2019 and were treated with CBP. Clinical indices were observed before treatment, at 6, 12, 24, and 36 hours of CBP treatment, and at the end of treatment to evaluate the clinical effect and safety of CBP treatment. RESULTS: Among the 21 neonates with MODS undergoing CBP, 17 (81%) had response to treatment. The neonates with response to CBP treatment had a significant improvement in oxygenation index at 6 hours of treatment, a significant increase in urine volume at 24 hours of treatment, a stable blood pressure within the normal range at 24 hours of treatment, and significant reductions in the doses of the vasoactive agents epinephrine and dopamine at 6 hours of treatment (P<0.05), as well as a significant reduction in serum K+ level at 6 hours of treatment, a significant improvement in blood pH at 12 hours of treatment, and significant reductions in blood lactic acid, blood creatinine, and blood urea nitrogen at 12 hours of treatment (P<0.05). Among the 21 neonates during CBP treatment, 6 experienced thrombocytopenia, 1 had membrane occlusion, and 1 experienced bleeding, and no hypothermia, hypotension, or infection was observed. CONCLUSIONS: CBP is a safe, feasible, and effective method for the treatment of MODS in neonates, with few complications.

Efficiency of high-frequency oscillatory ventilation combined with pulmonary surfactant in the treatment of neonatal meconium aspiration syndrome.

The aim of this study was to investigate the clinical efficiency of the use high-frequency oscillatory ventilation (HFOV) combined with pulmonary surfactant (PS) for the treatment of neonatal meconium aspiration syndrome (MAS). Clinical data of 53 MAS patients admitted to neonatal intensive care unit (NICU) was collected and the patients were divided into 3 groups according to the different treatment approach: group 1 conventional mechanical ventilation (CMV); group 2 HFOV; group 3 HFOV + PS. By monitoring the changes in oxygenation function indicators such as inhaled oxygen concentration (FiO2), oxygenation index (OI) and arterial oxygen tension/alveolar arterial oxygen tension (a/ApO2) of three groups after 2, 12, 24, 48 h of treatment, the usage of the ventilator, duration of hospitalization, changes in clinical manifestations and outcomes of three groups were analyzed. As compared to group 1, the difference in all the oxygenation function indicators after treatment in group 2 and group 3 was statistically significant at different points in time (P < 0.05). However, the timing and extent of the change in the indicators in group 3 were more significant than in group 2; as compared to group 1, the ventilation time, duration of the oxygen therapy and hospitalization time of group 2 and group 3 were significantly shorter and the difference was statistically significant (P < 0.05). Early use of HFOV combined with PS to treat MAS has significant therapeutic effect, especially for the treatment of severe MAS where it can be used as a safer and more effective rescue measure.

[Comparison of caffeine citrate and aminophylline for treating primary apnea in premature infants].

OBJECTIVE: To investigate the clinical efficacy and safety of caffeine citrate and aminophylline in the treatment of primary apnea in premature infants. METHODS: The clinical data of 125 premature infants with primary apnea from March 2013 to March 2014 were retrospectively analyzed. According to the therapeutic strategy, the patients were divided into caffeine citrate group (n=65) and aminophylline group (n=60). The overall response rates and adverse reaction rates in the two groups were compared. RESULTS: The overall response rate in the caffeine citrate group was 86% (56 cases), which was significantly higher than that in the aminophylline group (72%, 43 cases) (P<0.05). The adverse reactions in the caffeine citrate group included tachycardia (1 case), restlessness (5 cases), feeding intolerance (7 cases), electrolyte disturbance (2 cases), and high blood glucose (5 cases), the incidence of which was significantly lower than that in the aminophylline group (P<0.05). CONCLUSIONS: Caffeine citrate is more effective and causes fewer adverse reactions than aminophylline in the treatment of primary apnea in premature infants.

The effect of vascular endothelial growth factor C expression in tumor-associated macrophages on lymphangiogenesis and lymphatic metastasis in breast cancer.

The aim of this study was to investigate the effect of vascular endothelial growth factor-C (VEGF-C) expression in tumor-associated macrophages (TAMs) on lymphatic microvessel density (LMVD) and lymphatic endothelial cell proliferation (LECP) and to determine the role of VEGF-C expression in lymphangiogenesis in patients with breast cancer. Breast cancer tissue specimens confirmed by pathological analysis were obtained from 75 patients. Samples were observed by microscopy analysis after immunohistochemical double­staining. The total number of TAMs and the number of VEGF-C-positive TAMs were determined. LMVD and LECP were calculated for the intratumoral and peritumoral areas. Correlation analysis was performed among these indexes, lymph vessel invasion (LVI) and lymph node metastasis in the peritumoral regions. Immunohistochemical double-staining demonstrated that VEGF-C was markedly expressed in TAMs. The number of TAMs, LMVD and LECP in the peritumoral areas was significantly higher than that in the intratumoral areas (P<0.001). We observed positive correlations between the following parameters: the number of TAMs and the peritumoral LMVD (P<0.001), the percentage of TAMs expressing VEGF-C and the peritumoral LMVD (P<0.001), the number of TAMs and the peritumoral LECP (P<0.001), and the percentage of TAMs expressing VEGF-C and the peritumoral LECP (P<0.001). Furthermore, the total number of TAMs and VEGF-C-positive TAMs, LMVD and LECP in cases with lymph node metastasis or LVI were significantly higher compared to those in cases without lymph node metastasis or LVI (P<0.01 or P<0.05). Our findings suggest that TAMs play a critical role in tumor-induced lymphangiogenesis through upregulating VEGF-C, which may contribute to lymphatic invasion in breast cancer.