泰克地那林对四氯化碳诱导小鼠急性肾损伤的治疗作用

目的观察组蛋白去乙酰化酶抑制剂泰克地那林(CI994)对四氯化碳(CCl_4)诱导小鼠急性肾损伤的治疗作用。方法将40只8周龄雄性小鼠随机分为对照组、药物对照组、CCl_4造模组和CI994治疗组,每组10只;对照组腹腔注射生理盐水;CCl_4造模组一次性腹腔注射CCl_4;药物对照组腹腔注射生理盐水,CI994治疗组腹腔注射CCl_4,在注射CCl_4后6和24 h分别给予药物对照组和CI994治疗组腹腔注射CI994。检测各组小鼠血清尿素氮(BUN)、肌酐(Src)和胱抑素C(CysC)水平;对肾组织进行HE染色并检测丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性和细胞色素2E1(CYP2E1)mRNA表达水平。结果与CCl_4造模组比较,CI994治疗组小鼠血清BUN、Scr、CysC水平下降(P<0.05);肾组织MDA含量下降,SOD活性上升(P<0.05);HE染色显示CCl_4造模组呈现典型急性肾损伤症状,CI994治疗组肾脏损伤均较CCl_4造模组轻;肾组织CYP2E1m RNA表达水平下降(P<0.05)。结论CI994可减轻CCl_4介导的小鼠急性肾损伤,可能与I相毒物代谢蛋白CYP2E1的表达下调有关。

Formation of free-surface vortex and vortex suppression by rotating stopper-rod at end of tundish casting

A rotating stopper-rod technique was proposed to suppress the formation of free-surface vortex in the tundish.The large eddy simulation model coupled with volume of fluid model was developed to study the steel–slag–gas three-phase flow behavior.The critical slag entrapment height of the free-surface vortex and mass of residual steel were predicted at different rotating speeds(30,60,90 and 120 r/min)of the rotating stopper-rod.The numerical model was verified by water model experiment.The results showed that by rotating the stopper-rod in the opposite direction of the vortex above the submerged entry nozzle,the formation of vortex can be effectively disturbed and the critical height of the free-surface vortex can be reduced.Particularly for the 2nd strand,when the rotating speeds are 30,60,90 and 120 r/min,the critical height of the free-surface vortex above the 2nd strand is 7.3,4.7,6.3 and 7.4 cm,respectively.A reasonable rotating speed should be 60 r/min,which can reduce about 2 tons of residual steel.Other rotating speeds just can reduce about 1.6 tons of residual steel.

Risk stratification of hemodynamically significant patent ductus arteriosus by clinical and genetic factors

Background Hemodynamically significant patent ductus arteriosus(hsPDA)is associated with increased comorbidities in neonates.Early evaluation of hsPDA risk is critical to implement individualized intervention.The aim of the study was to provide a powerful reference for the early identification of high-risk hsPDA population and early treatment decisions.Methods We enrolled infants who were diagnosed with PDA and performed exome sequencing.The collapsing analyses were used to find the risk gene set(RGS)of hsPDA for model construction.The credibility of RGS was proven by RNA sequencing.Multivariate logistic regression was performed to establish models combining clinical and genetic features.The models were evaluated by area under the receiver operating curve(AUC)and decision curve analysis(DCA).Results In this retrospective cohort study of 2199 PDA patients,549(25.0%)infants were diagnosed with hsPDA.The model[all clinical characteristics selected by least absolute shrinkage and selection operator regression(all CCs)]based on six clinical variables was acquired within three days of life,including gestational age(GA),respiratory distress syndrome(RDS),the lowest platelet count,invasive mechanical ventilation,and positive inotropic and vasoactive drugs.It has an AUC of 0.790[95%confidence interval(CI)=0.749–0.832],while the simplified model(basic clinical characteristic model)including GA and RDS has an AUC of 0.753(95%CI=0.706–0.799).There was a certain consistency between RGS and differentially expressed genes of the ductus arteriosus in mice.The AUC of the models was improved by RGS,and the improvement was significant(all CCs vs.all CCs+RGS:0.790 vs.0.817,P<0.001).DCA demonstrated that all models were clinically useful.Conclusions Models based on clinical factors were developed to accurately stratify the risk of hsPDA in the first three days of life.Genetic features might further improve the model performance.

Global variation in skin injures and skincare practices in extremely preterm infants

Background Globally,are skincare practices and skin injuries in extremely preterm infants comparable?This study describes skin injuries,variation in skincare practices and investigates any association between them.Methods A web-based survey was conducted between February 2019 and August 2021.Quantifying skin injuries and describing skincare practices in extremely preterm infants were the main outcomes.The association between skin injuries and skincare practices was established using binary multivariable logistic regression adjusted for regions.Results Responses from 848 neonatal intensive care units,representing all geographic regions and income status groups were received.Diaper dermatitis(331/840,39%)and medical adhesive-related skin injuries(319/838,38%)were the most common injuries.Following a local skincare guideline reduced skin injuries[medical adhesive-related injuries:adjusted odds ratios(aOR)=0.63,95%confidence interval(CI)=0.45–0.88;perineal injuries:aOR=0.66,95%CI=0.45–0.96;local skin infections:OR=0.41,95%CI=0.26–0.65;chemical burns:OR=0.46,95%CI=0.26–0.83;thermal burns:OR=0.51,95%CI=0.27–0.96].Performing skin assessments at least every four hours reduced skin injuries(abrasion:aOR=0.48,95%CI=0.33–0.67;pressure:aOR=0.51,95%CI=0.34–0.78;diaper dermatitis:aOR=0.71,95%CI=0.51–0.99;perineal:aOR=0.52,95%CI=0.36–0.75).Regional and resource settings-based variations in skin injuries and skincare practices were observed.Conclusions Skin injuries were common in extremely preterm infants.Consistency in practice and improved surveillance appears to reduce the occurrence of these injuries.Better evidence regarding optimal practices is needed to reduce skin injuries and minimize practice variations.

Characteristics of home oxygen therapy for preterm infants with bronchopulmonary dysplasia in China:results of a multicenter cohort

Background Home oxygen therapy(HOT)is indicated upon discharge in some preterm infants with severe bronchopulmonary dysplasia(BPD).There is a lack of evidence-based consensus on the indication for HOT among these infants.Because wide variation in the institutional use of HOT exists,little is known about the role of regional social-economic level in the wide variation of HOT.Methods This was a secondary analysis of Chinese Neonatal Network(CHNN)data from January 1,2019 to December 31,2019.Infants at gestational ages<32 weeks,with a birth weight<1500 g,and with moderate or severe BPD who survived to discharge from tertiary hospitals located in 25 provinces were included in this study.Infants with major congenital anomalies and those who were discharged against medical advice were excluded.Results Of 1768 preterm infants with BPD,474 infants(26.8%)were discharged to home with oxygen.The proportion of HOT use in participating member hospitals varied from 0 to 89%,with five of 52 hospitals’observing proportions of HOT use that were significantly greater than expected,with 14 hospitals with observing proportions significantly less than expected,and with 33 hospitals with appropriate proportions.We noted a negative correlation between different performance groups of HOT and median GDP per capita(P=0.04).Conclusions The use of HOT varied across China and was negatively correlated with the levels of provincial economic levels.A local HOT guideline is needed to address the wide variation in HOT use with respect to different regional economic levels in countries like China.

Monkeypox and the perinatal period:what does maternal-fetal medicine need to know?

Background After the global elimination of smallpox,monkeypox has become the most threatening orthopoxvirus to human health.Very few studies have been reported on pregnant women and newborns.In the case of monkeypox infection,the virus can cause serious adverse pregnancy events in women,which can lead to fetal or neonatal death.Data sources We made a comprehensive review after an extensive literature search in the PubMed/Medline database and websites concerning smallpox and monkeypox.Results Two case reports reported a total of nine pregnant women,six of whom had fetal deaths.In the autopsy of a stillbirth,researchers found that the placenta was infected with monkeypox virus,but the mechanism of infection remains unclear.Smallpox vaccine should be administered to acutely exposed pregnant women and newborns.Several novel recombinant vac-cinia immunogloblin(rVIG)and human-specific monoclonal antibodies are being developed for the prevention and treatment of monkeypox virus infection.After the fetus was delivered,the newborn should take a bath as soon as possible to remove the amniotic fluid and dirt from the body.The appropriate isolation protocol for the newborn should be selected according to the infection status of the mother.It is not known whether monkeypox virus is present in breast milk,and pasteurized breast milk can be given to newborns when breastfeeding is considered.Conclusion This review presents an overview of monkeypox in the perinatal period and guides the future research direction.

Clinical experiences in the management of critically ill patients with COVID‑19 in a designated children’s hospital in China

Omicron variant has been the dominant epidemic variant of novel coronavirus in the world since 2021.Studies have shown that the incidence of severe or critical cases with coronavirus disease 2019(COVID-19)is much lower than that of the previous novel coronavirus variants[1,2];however,it is still a major challenge to treat critical pediatric patients with COVID-19,especially for those with underlying diseases.

High cholesterol intake remodels cholesterol turnover and energy homeostasis in Nile tilapia(Oreochromis niloticus)

The roles of dietary cholesterol in fish physiology are currently contradictory.The issue reflects the limited studies on the metabolic consequences of cholesterol intake in fish.The present study investigated the metabolic responses to high cholesterol intake in Nile tilapia(Oreochromis niloticus),which were fed with four cholesterol-contained diets(0.8,1.6,2.4 and 3.2%)and a control diet for eight weeks.All fish-fed cholesterol diets showed increased body weight,but accumulated cholesterol(the peak level was in the 1.6%cholesterol group).Then,we selected 1.6%cholesterol and control diets for further analysis.The high cholesterol diet impaired liver function and reduced mitochondria number in fish.Furthermore,high cholesterol intake triggered protective adaptation via(1)inhibiting endogenous cholesterol synthesis,(2)elevating the expression of genes related to cholesterol esterification and efflux,and(3)promoting chenodeoxycholic acid synthesis and efflux.Accordingly,high cholesterol intake reshaped the fish gut microbiome by increasing the abundance of Lactobacillus spp.and Mycobacterium spp.,both of which are involved in cholesterol and/or bile acids catabolism.Moreover,high cholesterol intake inhibited lipid catabolic activities through mitochondrialβ-oxidation,and lysosome-mediated lipophagy,and depressed insulin signaling sensitivity.Protein catabolism was elevated as a compulsory response to maintain energy homeostasis.Therefore,although high cholesterol intake promoted growth,it led to metabolic disorders in fish.For the first time,this study provides evidence for the systemic metabolic response to high cholesterol intake in fish.This knowledge contributes to an understanding of the metabolic syndromes caused by high cholesterol intake or deposition in fish.

Generation of a monkey with MECP2 mutations by TALEN-based gene targeting

Gene editing in model organisms has provided critical insights into brain development and diseases. Here, we report the generation of a cynomolgus monkey （Macaca fascicularis） carrying MECP2 mutations using transcription activator-like effector nucleases （TALENs）-mediated gene targeting. After injecting TALENs mRNA into monkey zygotes achieved by in vitro fertilization and embryo transplantation into surrogate monkeys, we obtained one male newborn monkey with an MECP2 deletion caused by frame- shifting mutation in various tissues. The monkey carrying the MECP2 mutation failed to survive after birth, due to either the toxicity of TALENs or the critical requirement of MECP2 for neural development. The level of MeCP2 protein was essentially depleted in the monkey＇s brain. This study demonstrates the feasibility of introducing genetic mutations in non-human primates by site-specific gene-editing methods.

Application of next generation sequencing in the screening of monogenic diseases in China,2021:a consensus among Chinese newborn screening experts

Newborn screening(NBS)refers to a maternal and newborn healthcare technology,in which special examinations of congenital and genetic diseases that could seriously impact the health of newborns,are implemented during the neonatal period to provide early diagnosis and treatment[1].With a history of more than 60 years,NBS has advanced greatly due to technological progress resulting in significant improvement in the number of diseases covered by NBS and in screening efficiency[2-7].

Chronic exposure to ethanol in male mice may be associated with hearing loss in offspring

Although paternal ethanol （EtOH） abuse has been shown to affect the growth and behavior of offspring, the exact molecular and mechanistic basis remains largely unclear. Methylation alterations in imprinted genes may be related to well-documented teratogenic effects of ethanol. Here we show that chronic paternal ethanol exposure increases the susceptibility to abnormal behavior in offspring through male game epigenetic alteration. In our study, different doses of ethanol （0, 1,1, 3.3 g kg^-1） were administered intra-gastrically to male mice and decreased sperm motility was found in the highest ethanol-exposed group compared with the controls. Data also showed a dose-dependent increase in deaf mice of the paternally ethanol-exposed groups. The methylation of H19, Peg3, Ndn and Snrpn was assessed in paternal spermatozoa and in the cerebral cortices of deaf mice. EtOH affected methylation of Peg3 （CpG 3, 7 and 9） in paternal spermatozoa and in the cerebral cortices of deaf mice, but the level of mRNA expression did not change, suggesting that other gene regulation may be involved in these processes. Overall, chronic paternal ethanol exposure could alter the methylation of imprinted genes in sire spermatozoa that could also be passed on to offspring, giving rise to developmental disorders. Our results provide possible epigenetic evidence for a paternal ethanol exposure contribution to Fetal Alcohol Syndrome （FAS）.

Variations in length of stay among survived very preterm infants admitted to Chinese neonatal intensive care units

Background This study aimed to describe length of stay(LOS)to discharge and site variations among very preterm infants(VPIs)admitted to 57 Chinese neonatal intensive care units(NICUs)and to investigate factors associated with LOS for VPIs.Methods This retrospective multicenter cohort study enrolled all infants<32 weeks’gestation and admitted to 57 NICUs which had participated in the Chinese Neonatal Network,within 7 days after birth in 2019.Exclusion criteria included major congenital anomalies,NICU deaths,discharge against medical advice,transfer to non-participating hospitals,and missing discharge date.Two multivariable linear models were used to estimate the association of infant characteristics and LOS.Results A total of 6580 infants were included in our study.The overall median LOS was 46 days[interquartile range(IQR):35-60],and the median corrected gestational age at discharge was 36 weeks(IQR:35-38).LOS and corrected gestational age at discharge increased with decreasing gestational age.The median corrected gestational age at discharge for infants at 24 weeks,25 weeks,26 weeks,27-28 weeks,and 29-31 weeks were 41 weeks,39 weeks,38 weeks,37 weeks and 36 weeks,respectively.Significant site variation of LOS was identified with observed median LOS from 33 to 71 days in different hospitals.Conclusions The study provided concurrent estimates of LOS for VPIs which survived in Chinese NICUs that could be used as references for medical staff and parents.Large variation of LOS independent of infant characteristics existed,indicating variation of care practices requiring further investigation and quality improvement.

Epigenetic clocks in the pediatric population:when and why they tick?

Recent research efforts have provided compelling evidence of genome-wide DNA methylation alterations in pediatrics.It is currently well established that epigenetic clocks,composed of DNA methylation sites,can estimate the gestational and chronological age of cells and tissues from different ages.Also,extensive research is aimed at their correlation with early life exposure and pediatric diseases.This review aimed to systematically summarize the epigenetic clocks in the pediatric population.Publications were collected from PubMed and Web of Science databases up to Apr 2021.Epigenetic clocks,DNA methylation clocks,epigenetic age acceleration or deceleration,pediatric and the pediatric population were used as search criteria.Here,we first review the currently applicative pediatric epigenetic clocks.We then highlight the interpretation for epigenetic age deviations in the pediatric population and their association with external factors,developmental trajectories,and pediatric diseases.Considering the remaining unknown of pediatric clocks,research strategies into them are also discussed.In all,pediatric epigenetic clocks may act as potent tools to understand development,growth and diseases in early life.

Decreased connexin 43 in astrocytes inhibits the neuroinflammatory reaction in an acute mouse model of neonatal sepsis

Neonatal sepsis is common in neonatal intensive care units, often complicated by injury to the immature brain. Previous studies have shown that the expression of the gap junction protein connexin 43 （Cx43） in the brain decreases when stimulated by neuro-inflammatory drugs such as lipopolysaccharide （LPS）. Here we showed that partial deletion of Cx43 in astrocytes resulted in weakened inflammatory responses. The up-regulation of pro-inflammatory cytokines was significantly reduced in mice with partial deletion of Cx43 in astrocytes compared with wild-type littermates after systemic LPS injection. Moreover, microglial activation was inhibited in mice with partial deletion of Cx43. These results showed that Cx43 in astrocytes plays a critical role in neuro-inflammatory responses. This work provides a potential therapeutic target for inhibiting neuro- inflammatory responses in neonatal sepsis.

Identification of eight novel mutations in 11 Chinese patients with maple syrup urine disease

Background Maple syrup urine disease(MSUD)is an autosomal recessive inherited disorder that affects the degradation of branched-chain amino acids and is associated with acute and chronic brain dysfunction.This study presents 11 new patients with MSUD and describes the clinical characteristics and gene mutations reported in Chinese individuals.Methods During 2011–2018,11 pedaitric patients with MSUD from 11 Chinese families were analyzed based on clinical characteristics and mass spectrometry,with confirmation via gene sequencing.Novel mutations affecting protein function were predicted with Mutation-Taster,PolyPhen-2,CADD and SIFT software.3D models of the mutated proteins were generated by using the SWISS-MODEL online server,and the models were visualized in PyMOL.The characteristics and gene mutations in patients with MSUD were analyzed retrospectively.Results Seventeen mutations in the BCKDHA,BCKDHB and DBT genes were found,8 of which are novel:c.55C>/T,c.349C>T,c.565C>T,c.808G>A,c.859C>G,and c.1270dupC in BCKDHA;c.275-2A>G in BCKDHB;and c.1291C>T in DBT.Eight patients died.Two patients had severe mental retardation and were physically handicapped.One patient with the intermediate type had relatively good prognosis,with mild psychomotor retardation and adiposity.Four mothers underwent amniocentesis for prenatal diagnosis during their second pregnancy;two fetuses were wild type,and two were carriers of one heterozygous mutation.Conclusions Eight novel mutations were associated with MSUD in Chinese patients.Prenatal diagnosis was successfully performed by genetic analysis.Mutations in the BCKDHB gene were found in the majority of Chinese patients with MSUD.

Role of the PTEN signaling pathway in autism spectrum disorder

Autism is an etiologically heterogeneous group of neurodevelopmental disorders,diagnosed mostly by the clinical behavioral phenotypes.The concept that the tumor-related gene PTEN plays a critical role in autism spectrum disorder has emerged over the last decade.In this review,we focus on the essential role of the PTEN signaling pathway in neuronal differentiation and the formation of neural circuitry,as well as genetic mouse models with Pten manipulations.Particularly,accumulated data suggest that the effect of PTEN on neural stem-cell development contributes significantly to the pathophysiology of autism spectrum disorders.

Genetic etiologies associated with infantile hydrocephalus in a Chinese infantile cohort

Background Infantile hydrocephalus(IHC)is commonly related to other central nervous system diseases,which may have adverse effects on prognosis.The causes of IHC are heterogeneous,and the genetic etiologies are not fully understood.This study aimed to analyze the genetic etiologies of an IHC cohort.Methods The data for 110 IHC patients who had received exome sequencing at the Clinical Genetic Center of the Children's Hospital of Fudan University between 2016 and 2019 were reviewed and analyzed retrospectively.An exome-wide association analysis(EWAS)was performed within this cohort using IHC as the study phenotype.Results Of the 110 IHC patients,a pathogenic or likely pathogenic variant was identified in 16(15%)patients,spanning 13 genes.The genes were mainly associated with metabolic disorders,brain abnormalities,and genetic syndromes.IHC patients who had unclear clinical etiology were more likely to possess a genetic etiology.Based on previous studies and on our EWAS results,ZEB1,SBF2,and GNAI2 were over-represented among IHC patients and might alfect the signaling pathways involved in IHC formation.Conclusions Our study showed heterogeneous genetic etiologies in an IHC cohort.It is essential to perform genetic testing on IHC patients who have unclear clinical etiology,and genes associated with metabolic disorders,brain abnormalities,and genetic syndromes should he noted.In addition,when aiming to discover IHC susceptibility genes,genes that might influence the signaling pathways involved in IHC formation should be prioritized.

Short-term developmental outcomes in neonates born to mothers with COVID-19 from Wuhan, China

Background Coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is an emerging disease.The consequences of SARS-CoV-2 exposure in infants remain unknown.Therefore,this study aims to investigate whether neonates born to mothers with COVID-19 have adverse brain development.Methods This multicenter observational study was conducted at two designated maternal and children's hospitals in Hubei Province,China's Mainland from February 1,2020 to May 15,2020.Neonates born to mothers with COVID-19 were enrolled.Brain magnetic resonance imaging(MRI)findings,and volumes of grey and white matters,and physical growth parameters were observed at 44 weeks corrected gestational age.Results Of 72 neonates born to mothers with COVID-19,8(11%)were diagnosed with COVID-19,8(11%)were critically ill,and no deaths were reported.Among the eight neonates that underwent brain MRI at corrected gestational age of 44 weeks,five neonates were diagnosed with COVID-19.Among these five neonates,three presented abnormal MRI findings including abnormal signal in white matter and delayed myelination in newborn 2,delayed myelination and brain dysplasia in newborn 3,and abnormal signal in the bilateral periventricular in newborn 5.The other three neonates without COVID-19 presented no significantly changes of brain MRI findings and the volumes of grey matter and white matter compared to those of healthy newborns at the equivalent age(P>0.05).Physical growth parameters for weight,length,and head circumference at gestational age of 44 weeks were all above the 3rd percentile for all neonates.Conclusions Some of the neonates born to mothers with COVID-19 had abnormal brain MRI findings but these neonates did not appear to have poor physical growth.These findings may provide the information on the follow-up schedule on the neonates exposed to SARS-CoV-2,but further study is required to evaluate the association between the abnormal MRI findings and the exposure to SARS-CoV-2.

Topologically protecting squeezed light on a photonic chip

Squeezed light is a critical resource in quantum sensing and information processing. Due to the inherently weak optical nonlinearity and limited interaction volume, considerable pump power is typically needed to obtain efficient interactions to generate squeezed light in bulk crystals. Integrated photonics offers an elegant way to increase the nonlinearity by confining light strictly inside the waveguide. For the construction of large-scale quantum systems performing many-photon operations, it is essential to integrate various functional modules on a chip. However, fabrication imperfections and transmission cross talk may add unwanted diffraction and coupling to other photonic elements, reducing the quality of squeezing. Here, by introducing the topological phase, we experimentally demonstrate the topologically protected nonlinear process of four-wave mixing, enabling the generation of squeezed light on a silica chip. We measure the cross-correlations at different evolution distances for various topological sites and verify the nonclassical features with high fidelity. The squeezing parameters are measured to certify the protection of cavity-free, strongly squeezed states. The demonstration of topological protection for squeezed light on a chip brings new opportunities for quantum integrated photonics,opening novel approaches for the design of advanced multi-photon circuits.

Secondary genomic findings in the 2020 China Neonatal Genomes Project participants

Background During next generation sequencing(NGS)data interpretation in critically ill newborns,there is a potential for recognizing and reporting secondary findings(SFs).Early awareness of SFs may provide clues for disease prevention.In this study,we assessed the frequency of SFs in the China Neonatal Genomes Project(CNGP)participants.Methods A total of 2020 clinical exome sequencing(CES)datasets were screened for variants from a list of 59 genes recommended by the American College of Medical Genetics and Genomics(ACMG)for secondary findings reporting v2.0(ACMG SF v2.0).Identified variants were classified according to the evidence-based guidelines reached by a joint consensus of the ACMG and the Association for Molecular Pathology(AMP).Results Among the 2020 CES datasets,we identified 23 ACMG-reportable genes in 61 individuals,resulting in an overall frequency of SFs at 3.02%.A total of 53 unique variants were identified,including 35 pathogenic and 18 likely pathogenic variants.The common disease categories of SFs associated were cardiovascular and cancer disease.The SF results affected the medical management and follow-up strategy in 49(80.3%)patients.Conclusions We presented the frequency of SFs and their impact on clinical management strategies in CNGP participants.Our study demonstrated that SFs have important practical value in disease prevention and intervention at an early stage.