Autophagy and circadian rhythms:interactions and clinical implications

Autophagy is a widespread biological process that controls cellular growth,survival,development,and death.Circadian rhythm is a recurring reaction of living organisms and behaviors to variations in surrounding brightness and obscurity.Most of the fundamental physiological processes in mammals,such as the sleep-wake pattern and the rhythm of nutrition and energy metabolism,are governed by circadian rhythms.Research has indicated that autophagy exhibits a specific circadian pattern in both normal and abnormal conditions.Autophagy can modulate circadian rhythms by breaking down proteins that regulate the circadian clock.The potential regulatory connection between the two has been a popular subject of clinical and fundamental research.Understanding the interaction between circadian rhythm and autophagy could potentially lead to the development of novel approaches for disease treatment in the future.The present analysis presented a summary of the molecular processes implicated in the interplay between autophagy and circadian rhythm,as well as the pathological importance of the disrupted regulatory association between these two phenomena.

Interaction between adolescent sleep rhythms and gender in an obese population

BACKGROUND The obesity rate of adolescents is gradually increasing,which seriously affects their mental health,and sleep plays an important role in adolescent obesity.AIM To investigate the relationship between sleep rhythm and obesity among adolescents and further explores the interactive effect of sleep rhythm and gender on adolescent obesity,providing a theoretical basis for developing interventions for adolescent obesity.METHODS Research data source Tianjin Mental Health Promotion Program for Students.From April to June 2022,this study selected 14201 students from 13 middle schools in a certain district of Tianjin as the research subject using the convenient cluster sampling method.Among these students,13374 accepted and completed the survey,with an effective rate of 94.2%.The demographic data and basic information of adolescents,such as height and weight,were collected through a general situation questionnaire.The sleep rhythm of adolescents was evaluated using the reduced version of the morningness-eveningness questionnaire.RESULTS A total of 13374 participants(6629 females,accounting for 49.56%;the average age is 15.21±1.433 years)were analyzed.Among them,the survey showed that 2942 adolescent were obesity,accounting for 22%and 2104 adolescent were overweight,accounting for 15.7%.Among them,1692 male adolescents are obese,with an obesity rate of 25.1%,higher than 18.9%of female adolescents.There is a statistically significant difference between the three groups(χ2=231.522,P<0.000).The obesity group has the smallest age(14.94±1.442 years),and there is a statistical difference in age among the three groups(F=69.996,P<0.000).Obesity rates are higher among individuals who are not-only-child,have residential experience within six months,have family economic poverty,and have evening-type sleep(P<0.05).Logistic regression analysis shows a correlation between sleep rhythm and adolescent obesity.Evening-type sleep rhythm can increase the risk of obesity in male adolescents[1.250(1.067-1.468)],but the effect on female obesity is not remarkable.Further logistic regression analysis in the overall population demonstrates that the interaction between evening-type sleep rhythm and the male gender poses a risk of adolescent obesity[1.122(1.043-1.208)].CONCLUSION Among adolescents,the incidence of obesity in males is higher than in females.Evening-type sleep rhythm plays an important role in male obesity but has no significant effect on female obesity.Progressive analysis suggests an interactive effect of sleep rhythm and gender on adolescent obesity,and the combination of evening-type sleep and the male gender promotes the development of adolescent obesity.In formulating precautions against adolescent obesity,obesity in male adolescents with evening-type sleep should be a critical concern.

Effects of constant light and dark conditions on the locomotor activity,body mass,and body temperature rhythms of Eurasian Tree Sparrows(Passer montanus)

Light is an essential environmental cue influencing the endogenous circadian clocks that regulate behavioral and physiological processes in animals.Despite extensive research on the circadian rhythms of avian behavior and physiology,the mechanisms by which they adapt and adjust to abnormal photoperiod conditions,such as artificial light,have yet to be fully elucidated.Here,the circadian rhythms of the body mass,activity,and core and peripheral body temperatures of the Eurasian Tree Sparrow(Passer montanus,ETS)-a diurnal passerine-were examined under three different lighting conditions:constant light(LL),constant darkness(DD),and normal light-dark cycles(LD).Our results showed that the activity,body mass,core,tarsometatarsus,and eye temperatures of the ETSs varied significantly with treatment,time,and the interaction between treatment and time;however,there was no significant change in body mass in response to the interaction between time and treatment.Under LD conditions,the ETSs exhibited significant circadian rhythms in activity and core,tarsometatarsus,and eye temperatures.Under LL conditions,only the core temperature exhibited significant rhythmicity.Under DD conditions,there were no significant circadian rhythms in activity,body mass,and eye temperature;however,the core and tarsometatarsus temperatures remained rhythmic.Our results indicate that the core body temperature rhythm of ETS is endogenous and can be maintained under abnormal photoperiods.In contrast,the activity and body surface temperature,uncoupled from the core body temperature under abnormal photoperiod conditions,strongly depend on light.These results differ from those of other diurnal avian species,suggesting a unique coping mechanism of ETS in response to an abnormal photoperiod.

Circadian Rhythms of Physiological Functions of the Pregnant Woman and the Fetus and the Biological Solemnity Thereof

The basic rhythms of nature that left their imprint on the existence of all living organism on the Earth, arose under the influence of the Earth’s rotation relative to the Sun, the Moon and other planets and stars of the Universe. This periodicity gave rise to the rhythm that has become essential for their life. Life is a continual chemical process of building up and breaking down of organic substances, which results from the substance exchange between an organism and the environment. This makes it impossible for a living organism to exist without the external environment. Since 1978-1979 we have been carrying out a task-oriented research with the aim to approximate the moment when we are able to answer all these questions. Daily fluctuations of cardiac and motor activity of the fetus have been studied (uninterrupted daily recording of fetal ECG);polysomnography of nocturnal sleep was recorded;daily fluctuations of endocrine system activity in the pregnant were studied. A correlation was made between the functional state of maternal sleep-wakefulness biological rhythm, biological clock of the human fetus and the “light-darkness” cycle of a 24-hour solar day. In the process of the study we have developed an original method of day-to-day analysis of maternal and fetal ECGs. It has been established that a healthy fetus has distinct, diurnal variations of physiological functions. The fetal biorhythms coordinate with the status of the maternal organism being, however, in an opposite phase. The curve of the dynamics of fetal physiological system functioning shows a biphasic nature (one-phase in adults). “Active” and “quiet” (sleep-like) periods have been singled out in the human fetus. No reaction is observed in “quiet” periods. However, the “zero”-type fetal reaction recorded by us within the period from 2 p.m. to 9 p.m. does not indicate unsatisfactory condition of the fetus but rather is suggestive of a definite reduction of functional levels of the fetal physiological systems, which is necessary for vital activity. Although conventionally recognized as an indicator of poor state of the fetus, this type only calls for precise attention when recorded in fetal “active” hours. The present study has been the first in the world’s medicine and biorhythmology to detect and establish the daily rhythms of cardiac and motor activity in the human fetus.

Circadian rhythms in the pathogenesis of gastrointestinal diseases

The etiology of digestive pathologies such as irritable bowel syndrome(IBS), inflammatory bowel diseases(IBD) and cancer is not yet fully understood. In recent years, several studies have evidenced circadian variations in mechanisms involved in digestive health. In situations of disturbed circadian rhythms(chronodisruption) where the central clock and the peripheral clocks receive incoherent signals, the synchronicity is lost producing implications for health. This lack of coordination could alter the tissue function and cause long term damage to the organs. Life habits such as sleep, physical exercise, social interaction, and feeding times are determinants for stability and integrity of circadian rhythms. In recent years, experimental and clinical studies have consistently evidenced that the alteration of circadian rhythms is associated with the development of digestive pathologies mainly linked to dismotility or changes in microbiota composition. Likewise, it seems reasonable to deep into the importance of chronodisruption as a factor that may participate in the development of pathologies such as IBS, IBD and digestive cancers. Moreover, life habits respecting circadian rhythms should be promoted for the prevention of these diseases. Further studies will allow us a better understanding of the mechanisms acting at molecular level, and the development of new therapeutic targets.

Bone Loss Induced by Simulated Microgravity,Ionizing Radiation and/or Ultradian Rhythms in the Hindlimbs of Rats

Objective To better understand the pathological causes of bone loss in a space environment, including microgravity, ionizing radiation, and ultradian rhythms.Methods Sprague Dawley （SD） rats were randomly divided into a baseline group, a control group, a hindlimb suspension group, a radiation group, a ultradian rhythms group and a combined-three-factor group. After four weeks of hindlimb suspension followed by X-ray exposure and/or ultradian rhythms, biomechanical properties, bone mineral density, histological analysis, microstructure parameters, and bone turnover markers were detected to evaluate bone loss in hindlimbs of rats.Results Simulated microgravity or combined-three factors treatment led to a significant decrease in the biomechanical properties of bones, reduction in bone mineral density, and deterioration of trabecular parameters. Ionizing radiation exposure also showed adverse impact while ultradian rhythms had no significant effect on these outcomes. Decrease in the concentration of the turnover markers bone alkaline phosphatase （bALP）, osteocalcin （OCN）, and tartrate-resistant acid phosphatase-5b （TRAP-Sb） in serum was in line with the changes in trabecular parameters.Conclusion Simulated microgravity is the main contributor of bone loss. Radiation also results in deleterious effects but ultradian rhythms has no significant effect. Combined-three factors treatment do not exacerbate bone loss when compared to simulated microgravity treatment alone.

Circadian rhythms of hormone secretion and obesity

The adipose tissue homeostasis is profoundly affected by circadian rhythms of corticosteroid secretion and chronic loss of hormonal oscillations is associated with obesity. How adipose tissue differentially responds to pulsatile vs continuous presence of glucocorticoids is poorly defined. To address this question, Bahrami-Nejad et al studied differentiation of pre-adipocytes, containing endogenously tagged CCAAT/enhancer binding protein and peroxisome proliferator-activated receptor(PPAR) γ(key regulators of adipocyte differentiation), in response to corticosteroids that were delivered either in an oscillatory fashion or continuously. The authors show that the bi-stable state of differentiation of pre-adipocytes and adipocytes was regulated by a combination of fast and slow positive feedback networks, that determined unique threshold of PPARγ in these cells. Evidently, pre-adipocytes used the fast feedback loop to reject differentiation cues of oscillating pulses of glucocorticoids and failed to differentiate into fat cells. In contrast, when glucocorticoids were delivered continuously, precursor cells exploited the slow feedback loop to embark on a path of maximal differentiation. This differential differentiation response of pre-adipocytes to pulsatile vs continuous exposure to glucocorticoids was corroborated in vivo. Thus, mice receiving non-oscillating doses of exogenous glucocorticoids, for 21 d, elicited excessive accumulation of visceral and subcutaneous fat. These data shed new light on the mechanisms of obesity caused by putative misalignment of circadian secretion of glucocorticoids or their persistently high levels due to chronic stress or Cushing's disease.

WNT/β-catenin pathway and circadian rhythms in obsessive-compulsive disorder

The neuropsychiatric disease named obsessive-compulsive disorder is composed by obsessions and/or compulsions.Obsessive-compulsive disorder etiologies are undefined.However,numerous mechanisms in several localizations are implicated.Some studies showed that both glutamate,inflammatory factors and oxidative stress could have main functions in obsessive-compulsive disorder.Glycogen synthase kinase-3β,the major negative controller of the WNT/β-catenin pathway is upregulated in obsessive-compulsive disorder.In obsessive-compulsive disorder,some studies presented the actions of the different circadian clock genes.WNT/β-catenin pathway and circadian clock genes appear to be intricate.Thus,this review focuses on the interaction between circadian clock genes and the WNT/β-catenin pathway in obsessive-compulsive disorder.

Nobiletin protects against metabolic syndrome by enhancing circadian rhythms

OBJECTIVE Dysregulation of circadian rhythms is associated with metabolic dysfunction,yet it is unclear whether enhancing clock function by small molecules can ameliorate metabolic disorders.METHODS We used an unbiased chemical screen in fibroblasts expressing PER2::Luc to identify the Clock amplitude-Enhancing Small Mole⁃cule.In diet-induced obese mice and DB/DB mutant mice,we evaluated the effects of the Clock amplitude-Enhancing small Molecule on metabolic syndrome and locomotor activity.RESULTS We identified Nobiletin(NOB),a natural poly⁃methoxylated flavone,as a Clock amplitude-Enhancing Small Molecule by an unbiased chemical screen.In diet-induced obese mice,NOB strongly improved metabolic syndrome and enhanced locomotor activity in a Clock gene-dependent manner.Moreover,the clock is also required for the beneficial effects of NOB on metabolic disorders in DB/DB mutant mice.Notably,NOB enhanced clock protein levels and reprogramed metabolic gene expressions in the liver.Finally,we revealed retinoid acid receptor-related orphan receptors(RORα/γ)as direct targets of NOB.CONCLUSION Altogether,our results demonstrate that a pharmacological intervention that enhances circadian rhythms by small molecule may be as a novel strategy for combating metabolic disease.

Effectiveness of patient education focusing on circadian pain rhythms:A case report and review of literature

BACKGROUND Neuropathic pain management should aim at improving quality of life and daily living activities of patients;therefore,emphasis should be placed on pain management including understanding the pain patterns during daily activity.Therefore,lifestyle guidance should be based on a detailed understanding of pain;however,previous studies commonly evaluated pain intensity at a single point in time.We report a case on patient education intervention based on the relationship between pain circadian rhythms and detailed physical activity during the day.CASE SUMMARY A man in his 60s,who suffered a brachial plexus injury in a traffic accident,presented with neuropathic pain.Early assessment of the importance of daily living activities to the patient,pain rhythmicity,and physical activity,was performed.The early assessments showed that the pain intensity was lower on days when more light-intensity physical activity(LIPA)was performed,than on days when less LIPA was performed.Consequently,patient education focused on methods to decrease the pain intensity that tended to worsen in the afternoon,and encouraged behavioral changes by suggesting the patient to take walks,which could be used to maintain LIPA in the afternoon.On reassessment,the afternoon LIPA,which had been the focus of attention,had increased and a change was noted in the circadian rhythm of pain.CONCLUSION Patient education based on a composite assessment elicited positive results in relation to the pain circadian rhythm and physical activity.

Identifying New Rhythms in Sino-US Relations

2018 marks the 40 th anniversary of China's reform and opening up,and also the 40 th anniversary of the establishment of China-US diplomatic ties.On December 16,1978,the Chinese and American governments published the Joint Communiqué of the People's Republic of China and the United States of America.Nearly at the same time,the 11th Central Committee of the Communist Party of China held its third plenary session in Beijing between December 18 and 22,1978.This was no coincidence: Sino-US relations are an issue integral to China's development.

Biomarkers of Aging: Changes in Circadian Rhythms Related to the Modulation of Metabolic Output

Twenty-four hour (circadian) rhythmicity is an important component of biological variability associated with studies relating to biomarkers of aging. Chronobiological testing techniques must be utilized because (1) many variables that are related to the modulation of metabolic output vary dramatically at different times of the day; (2) various experimental variable and treatment groups must be synchronized with environmental cues that control circadian rhythms; and (3) multiple circadian variables may interact together to modulate the rate of aging. The rhythm for physiological factors such as whole animal metabolic output, body temperature, heart rate, urine flow, potassium, etc. were found to be dissociated or altered by the senescence process; behavioral variables such as spontaneous activity, wheel running, feeding and drinking, verbal performance, as well as sleep-wakefulness rhythms, seem to be accurate predictors of biological age. Circadian rhythms for a variety of enzymes of intermediary metabolism which are directly associated with energy metabolism have been well documented. These well-defined rhythms of enzyme activity have also been shown to degenerate with aging. Rhythms tend to lose amplitude as activity falls with age and as a general loss of regulation (especially time of day where maximal activity might be found) of activity across the 24-h span occurs. As with behavioral variables, changes in enzyme rhythms appear to accurately predict aging. Generally speaking, the loss of temporal organization with age, characterized by decreased circadian amplitude, loose internal synchronization, and poor response to external environmental time queues, is associated with poor health states and decreased longevity. Temporal rhythms for whole animal parameters are highly correlated with molecular events, such as regulation of cellular metabolism. DNA repair, and gene expression. Automated data acquisition and process control systems will be required for future Chronobiological studies to develop biomarkers of aging.

Alpha Rhythms Response to 10 Hz Flicker Is Wavelength Dependent

Since Adrian and Metthew [1], light may be considered the dominant stimulus for the brain. This statement is confirmed after the discovery of the suprachiasmatic nucleus (SCN) that regulates the master biological clock [2]. In 1998 the discovery of photopigment melanopsin in the ganglion cells of the retina, give new insight in the importance of the light in the pathophysiology of the brain [3]. We have studied the effect of flashing at 10 Hz with LED light of different wavelength on the response of the alpha system. We have shown that this response, consistent with the drive of the frequency and the augmentation of the voltage of the alpha rhythms, is far more significant with the RED-LED than GREEN-LED or BLUE-LED or WHITE-LED (three-chrome) light flashing. We stem the hypothesis that the amplitude increase and phase reset of the alpha waves produced by RED-LED flashing at 10 Hz may be due either to photobiomodulation on the cytochromo c oxidase [4,5] and/or of the photopigment melanopsin, at the level of the retinal ganglion cells, that reinforce the incoming cone-LHC signal and therefore the projection to the SCN [6] or to reinforcement of postsynaptic short term responsiveness, in retinal cone-LHC synapse, due to repetitive stimulation [7,8] or both. We may speculate that the increase of amplitude and phase reset of alpha rhythms, due to flashing at 10 Hz, is primarily modulated in the retina.

Differential Puankre’s Model of Sentence Lengths Clock Rhythms in Religious Texts

The mechanism of language’s impact on people’s mind is a black box problem in psycholinguistics.In the 21st century it crossed the field of psychology and became an urgent problem in artificial intelligence and neuroscience.Religious language has a highly effective role amongst all human linguistic materials on psychological behavior.What is the mechanism of religious language impacts on the brain?This study examined the relationship between religious linguistic rhythms and brain wave rhythms.We chose 36 Koran’s sur as language material and counted the length of every sentence for definition its’rhythm.And using the same method we compared with other religious and political linguistic material.The data shows the common rhythmic structure among all those language materials.Therefore,we consider that clock rhythms display of bilateral regulation,psychotherapeutic impact of the canonic texts is based on harmonization inter-hemisphere attitudes and other rhythms.

Fascinating Rhythms Played on Fingertips

Zhao Cong, a young pipa (four-stringedChinese lute) performer with the China CentralTraditional Music Ensemble, was born into a familyof musicians. She developed an extraordinaryinterest in this ancient Chinese instrument in herchildhood. When her parents asked

Study on the Mechanism of Shimian Granules (SMG) against Depression via Regulating Circadian Rhythms

Background:According to the World Health Organization,about 350 million people worldwide are suffering from depression.It's reported that depression has been linked to several circadian rhythm perturbations,suggesting a disruption of the circadian clock system in affective disorders.The present study investigates the possible molecular mechanism of Shimian granules(SMG)in treating depression via restoring disrupted circadian rhythms.Method:Firstly,network pharmacology approach was used to identify the compounds and potential targets of SMG in TCMIP and BATMAN-TCM database.Secondly,the differential expression genes were obtained by gene expression profiling in GEO database(GSE56931,GSE98793).Further,protein-protein interactions(PPI)network was used to screen out core targets by STRING v11.Moreover,functional enrichment was carried out in DAVID database.Conclusively,the"herbs-compounds-targets-pathways"network was established to explore the mechanism of SMG in the treatment of depression.Result:It was found out that 65 compounds,18 targets and three pathways contributed to SMG in treating depression by regulating disrupted circadian rhythms,which might relate to core targets TNF,IL10,VDR in cAMP and calcium signaling pathway.Conclusion:Network pharmacology combined with gene expression profiling exhibited a powerful means to investigate the possible mechanism of formula,which contributes to theoretical basis for further study of SMG in the treatment of depression.

Devonian Sea-Level Change Rhythms in South China and Coupling Relationships Among the Earth-spheres

Twenty orthosequences and their corresponding sea-level change (SLC) cycles have been recognized in the Devonian overlying the Caledonian unconformity, of which 9, 5.5 and 5.5 occurred in the Lower, Middle and Upper Devonian respectively. They can be grouped into 4 orthosequence sets, in which the maximum flooding surfaces lie in the sulcutus Zone (D12), perbonus Zone (D13), Middle and Upper varcus Zone (D22) and gigas Zone (D21) respectively. Four instant palaeogeographical reconstructions of South China have been made in the Emsian and Givetian. Devonian sea-level change rhythms of South China can be divided into 3 categories: the autorhythmic, the worldwide and regional allorhythmic, and the coupling-rhythmic. They developed respectively in the Famennian, Pragian, Eifelian, Lochkovian, Emsian, Givetian, Frasnian and the F / F (between the Frasnian and Famennian) event. The cause of the worldwide allorhythmic SLC of the Pragian and Eifelian under comparatively dry, warm and tranquil conditions may be related to the pulsating expanding and contracting of the oceanic basin volume or the earth volume pulsation, rather than the common glaciation and plate tectonism. The coupling-rhythmic SLC related to the F/ F event is a sensitive indicator of the interaction between terrestrial and extraterrestrial factors, and coordinated action among the earth-spheres.

Sedimentation Rate Rhythms:Evidence from Filling of the Tarim Basin,Northwest China

Variations of sedimentation rate within a basin over geologic time are a time series that can be filtered into several cyclic wave curves. Based on back-stripping and the empirical mode decomposition method, the cores from 14 wells in the Tarim Basin were selected to do filtering analysis. Four cycles or quasi-cycles （33 Ma, 64.4 Ma, 103.6 Ma, and 224 Ma） were obtained. Among these, the 33 Ma period, which was related to the internal earth activity, an external force, or a combination of the two, was the most obvious. The 64.4 Ma period corresponded to the solar system crossing the galaxy plane or the periodic melting of inner-earth material. The 103.6 Ma period was related with plate collisional tectonism around the Tarim Plate. The 224 Ma period was related to one galaxy year and may also be related to the aesthenospherical convection cycle.

Circadian rhythms in the growth and reproduction of the brown alga Undaria pinnatifida and gametogenesis under different photoperiods

Circadian growth rhythm of the juvenile sporophyte of the brown alga Undaria pinnatifida was measured with the computer-aided image analysis system in constant florescent white light under constant temperature （ 10 ℃ ）. The growth rhythm persisted for 4 d in constant light with a free-running period of 25.6 h. Egg release from filamentous gametophytes pre-cultured in the light - dark regime was evaluated for six consecutive days at fixed time intervals in constant white light and 12 h light per day. Egg release rhythm persisted for 3 d in both regimes, indicating the endogenous nature. Temporal scale of egg release and gametogenesis in 18, 16, 12 and 8 h light per day were evaluated respectively using vegetatively propagated filamentous gametophytes. Egg release occurred 2 h after the onset of dark phase and peaked at midnight. Evaluation of the rates of oogonium formation, egg release or fertilization revealed no significant differences in four light-dark regimes, indicating the great plasticity of sexual reproduction. No photoperiodic effect in gametogenesis in terms of oogonium formation and egg release was found, but fertilization in short days was significantly higher than in long days. Results of this investigation further confirmed the general occurrence of circadian rhythms in intertidal seaweed species.

The role of pineal microRNA-325 in regulating circadian rhythms after neonatal hypoxic-ischemic brain damage

Circadian rhythm disorder is a common,but often neglected,consequence of neonatal hypoxic-ischemic brain damage(HIBD).However,the underlying molecular mechanisms remain largely unknown.We previously showed that,in a rat model of HIBD,up-regulation of microRNA-325(miR-325)in the pineal gland is responsible for the suppression of Aanat,a key enzyme involved in melatonin synthesis and circadian rhythm regulation.To better understand the mechanism by which miR-325 affects circadian rhythms in neonates with HIBD,we compared clinical samples from neonates with HIBD and samples from healthy neonates recruited from the First Affiliated Hospital of Soochow University(Dushuhu Branch)in 2019.We found that circulating miR-325 levels correlated positively with the severity of sleep and circadian rhythm disorders in neonates with HIBD.Furthermore,a luciferase reporter gene assay revealed that LIM homeobox 3(LHX3)is a novel downstream target of miR-325.In addition,in miR-325 knock-down mice,the transcription factor LHX3 exhibited an miR-325-dependent circadian pattern of expression in the pineal gland.We established a neonatal mouse model of HIBD by performing doublelayer ligation of the left common carotid artery and exposing the pups to a low-oxygen environment for 2 hours.Lhx3 mRNA expression was significantly down-regulated in these mice and partially rescued in miR-325 knockout mice subjected to the same conditions.Finally,we showed that improvement in circadian rhythm-related behaviors in animals with HIBD was dependent on both miR-325 and LHX3.Taken together,our findings suggest that the miR-325-LHX3 axis is responsible for regulating circadian rhythms and provide novel insights into the identification of potential therapeutic targets for circadian rhythm disorders in patients with neonatal HIBD.The clinical trial was approved by Institutional Review Board of Children’s Hospital of Soochow University(approval No.2015028)on July 20,2015.Animal experiments were approved by Animal Care and Use Committee,School of Medicine,Soochow University,China(approval No.XD-2016-1)on January 15,2016.