Advances in fetal surgery techniques have enabled the treatment of certain congenital defects before birth.A critical area of focus is the role of perinatal imaging in optimizing prenatal interventions within the prec...Advances in fetal surgery techniques have enabled the treatment of certain congenital defects before birth.A critical area of focus is the role of perinatal imaging in optimizing prenatal interventions within the precision medicine framework.Magnetic resonance imaging(MRI)is emerging as an indispensable tool for guiding these intricate procedures with the potential to significantly enhance the standard of care and outcomes for affected fetuses.This review begins with an overview of the classification and indications for fetal surgical interventions.It then explores the detailed applications of prenatal MRI scanning and diagnostic techniques across various categories of fetal surgery.A key focus is how fetal MRI provides critical insights into specific lesion characteristics and tissue involvement,thereby aiding healthcare professionals in selecting the optimal surgical strategies for prenatal and postnatal interventions.Fetal MRI offers detailed visualizations that complement traditional ultra-sound findings,enhancing the precision of radiological planning for fetal surgery.Finally,the review highlights how integration of fetal MRI into the decision-making process enables healthcare providers to make well-informed choices,ultimately improving the prognosis and outcomes for both the mother and fetus.展开更多
Metal may affect maternal immune function,but few epidemiological studies have reported the associations between multiple-metal exposure and maternal immunoglobulin(Ig)levels.Based on the Hangzhou Birth Cohort Study,1...Metal may affect maternal immune function,but few epidemiological studies have reported the associations between multiple-metal exposure and maternal immunoglobulin(Ig)levels.Based on the Hangzhou Birth Cohort Study,1059 participants were included,and eleven metals in whole blood samples and serum IgA,IgG,IgE and IgM levels were measured.Linear regression,quantile-based g-computation(QGC),and Bayesian kernel machine regression(BKMR)models were used to evaluate the associations.Compared with the first tertile of metal levels,arsenic(As)was negatively associated with IgE(β=-0.25,95%confidence interval(CI)=-0.48 to-0.02).Moreover,significant associations of manganese(Mn)with IgA,IgG and IgM were demonstrated(β=0.10,95%CI=0.04 to 0.18;β=0.07,95%CI=0.03 to 0.12;β=0.10,95%CI=0.03 to 0.18,respectively).Cadmium(Cd)were associated with higher levels of IgM.QGC models showed the positive association of the metalmixtures with IgA and IgG,with Mn playing amajor role.Mn and Cd had positive contributions to IgM,while As had negative contributions to IgE.In the BKMR models,the latent continuous outcomes of IgA and IgG showed a significant increase when all the metals were at their 60th percentile or above compared to those at their 50th percentile.Therefore,exposure to metals was associated with maternal Igs,and mainly showed that Mn was associated with increased levels of IgA,IgG and IgM,and As was associated with low IgE levels.展开更多
Given that ovarian stimulation is vital for assisted reproductive technology(ART)and results in elevated serum estrogen levels,exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary.We ...Given that ovarian stimulation is vital for assisted reproductive technology(ART)and results in elevated serum estrogen levels,exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary.We investigated the effects of various ovarian stimulation treatments on oocyte and embryo morphology and gene expression using a mouse model and estrogen-treated mouse embryonic stem cells(m ESCs).Female C57BL/6J mice were subjected to two types of conventional ovarian stimulation and ovarian hyperstimulation;mice treated with only normal saline served as controls.Hyperstimulation resulted in high serum estrogen levels,enlarged ovaries,an increased number of aberrant oocytes,and decreased embryo formation.The messenger RNA(m RNA)-sequencing of oocytes revealed the dysregulated expression of lysine-specific demethylase 6b(Kdm6b),which may be a key factor indicating hyperstimulation-induced aberrant oocytes and embryos.In vitro,Kdm6b expression was downregulated in m ESCs treated with high-dose estrogen;treatment with an estrogen receptor antagonist could reverse this downregulated expression level.Furthermore,treatment with high-dose estrogen resulted in the upregulated expression of histone H3 lysine 27 trimethylation(H3K27me3)and phosphorylated H2A histone family member X(γ-H2AX).Notably,knockdown of Kdm6b and high estrogen levels hindered the formation of embryoid bodies,with a concomitant increase in the expression of H3K27me3 andγ-H2AX.Collectively,our findings revealed that hyperstimulation-induced high-dose estrogen could impair the demethylation of H3K27me3 by reducing Kdm6b expression.Accordingly,Kdm6b could be a promising marker for clinically predicting ART outcomes in patients with ovarian hyperstimulation syndrome.展开更多
Children conceived via assisted reproductive technologies (ART) are nowadays a substantial proportion of the population. It is important to follow up these children and evaluate whether they have elevated health risks...Children conceived via assisted reproductive technologies (ART) are nowadays a substantial proportion of the population. It is important to follow up these children and evaluate whether they have elevated health risks compared to naturally conceived (NC) children. In recent years there has been a lot of work in this field. This review will summarize what is known about the health of ART-conceived children, encompassing neonatal outcomes, birth defects, growth and gonadal developments, physical health, neurological and neurodevelopmental outcomes, psychosocial developments, risk for cancer, and epigenetic abnormalities. Most of the children conceived after ART are normal. However, there is increasing evidence that ART-conceived children are at higher risk of poor perinatal outcome, birth defects, and epigenetic disorders, and the mechanism(s) leading to these changes have not been elucidated. Continuous follow-up of children after ART is of great importance as they progress through adolescence into adulthood, and new ART techniques are constantly being introduced.展开更多
Background:Congenital heart disease(CHD)results from abnormal heart development during fetal development,leading to life-threatening complications.This study aimed to evaluate the feasibility of applying myocardial pa...Background:Congenital heart disease(CHD)results from abnormal heart development during fetal development,leading to life-threatening complications.This study aimed to evaluate the feasibility of applying myocardial parametric mapping in post-mortem magnetic resonance imaging and to examine differences in the left ventricular myocardium between fetuses with CHD and controls.Methods:This prospective case–control study was conducted on 14 deceased fetuses with CHD(CHD group)and 24 fetuses without CHD(control group).Fetuses with CHD were further stratified into the cyanotic(n=9)and non-cyanotic(n=5)CHD groups.T1,T2,and proton density relaxation times of the left ventricular myocardium were calculated and compared using multiple-dynamic multiple-echo post-mortem magnetic resonance imaging technology.Results:The myocardial T2 relaxation time was significantly different between the groups(p=0.033),with no difference in T1 or proton density relaxation times between the groups.A one-way analysis of variance with Tukey's test showed that the mean cyanotic CHD group showed a longer myocardial T2 relaxation time than the control group(98.00013.143 vs.83.5429.491 ms,p=0.003).Additionally,the correlation coefficient in the CHD group was significantly different between the myocardial T2 relaxation time and peak systolic velocity of pulmonary artery on a fetal echocardiogram(r2=0.681,p=0.010).Conclusions:These results suggest that using myocardial alterations in the T2 relaxation time may provide a accurate early warning for myocardial injury and enable noninvasive recognition of cardiac involvement in fetuses with CHD.展开更多
In recent decades,maternal–fetal medicine has undergone substantial advancements in the management of high-risk pregnancies.These include enhanced prenatal screening and diagnosis facilitated by innovations in ultras...In recent decades,maternal–fetal medicine has undergone substantial advancements in the management of high-risk pregnancies.These include enhanced prenatal screening and diagnosis facilitated by innovations in ultrasound imaging,as well as the advances in fetal medical and interventional therapies informed by the deeper understanding of pathophysiological mechanisms underlying fetal and maternal disease processes.展开更多
The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. Glucose metabolism is...The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. Glucose metabolism is an important event in spermatogenesis. Moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. Diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm DNA integrity, and ingredients of seminal plasma. Epigenetic modifications are essential during spermatogenesis. The epigenetic regulation represents chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding RNAs. If spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. Diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring.展开更多
Male Wistar 7-day-old rats were injected with 40 mg/kg ketamine intraperitoneally, followed by three additional injections of 20 mg/kg ketamine each upon restoration of the righting reflex. Neonatal rats injected with...Male Wistar 7-day-old rats were injected with 40 mg/kg ketamine intraperitoneally, followed by three additional injections of 20 mg/kg ketamine each upon restoration of the righting reflex. Neonatal rats injected with equivalent volumes of saline served as controls. Hippocampal samples were collected at 1,7 or 14 days following administration. Electron microscopy showed that neuronal structure changed noticeably following ketamine treatment. Specifically, microtubular structure became irregular and disorganized. Quantitative real time-PCR revealed that phosphorylated tau mRNA was upregulated after ketamine. Western blot analysis demonstrated that phosphorylated tau levels at serine 396 initially decreased at 1 day after ketamine injection, and then gradually returned to control values. At 14 days after injection, levels of phosphorylated tau were higher in the ketamine group than in the control group. Tau protein phosphorylated at serine 404 significantly increased after ketamine injection and then gradually decreased with time. However, the levels of tau protein at serine 404 were significantly greater in the ketamine group than in the control group until 14 days. The present results indicate that ketamine induces an increase of phosphorylated tau mRNA and excessive phosphorylation of tau protein at serine 404, causing disruption of microtubules in the neonatal rat hippocampus and potentially resulting in damage to hippocampal neurons.展开更多
Duchenne muscular dystrophy(DMD)and Becker muscular dystrophy(BMD)are caused by mutations in the DMD gene.The aim of this study is to identify pathogenic DMD variants in probands and reduce the risk of recurrence of t...Duchenne muscular dystrophy(DMD)and Becker muscular dystrophy(BMD)are caused by mutations in the DMD gene.The aim of this study is to identify pathogenic DMD variants in probands and reduce the risk of recurrence of the disease in affected families.Variations in 100 unrelated DMD/BMD patients were detected by multiplex ligation-dependent probe amplification(MLPA)and next-generation sequencing(NGS).Pathogenic variants in DMD were successfully identified in all cases,and 11 of them were novel.The most common mutations were intragenic deletions(69%),with two hotspots located in the 5'end(exons 2–19)and the central of the DMD gene(exons 45–55),while point mutations were observed in 22%patients.Further,c.1149+1G>A and c.1150?2A>G were confirmed by hybrid minigene splicing assay(HMSA).This two splice site mutations would lead to two aberrant DMD isoforms which give rise to severely truncated protein.Therefore,the clinical use of MLPA,NGS,and HMSA is an effective strategy to identify variants.Importantly,eight embryos were terminated pregnancies according to prenatal diagnosis and a healthy boy was successfully delivered by preimplantation genetic diagnosis(PGD).Early and accurate genetic diagnosis is essential for prenatal diagnosis/PGD to reduce the risk of recurrence of DMD in affected families.展开更多
Invasive genetic screening of pre-implantation embryos via biopsied trophectoderm(TE)cells has been in use for more than 20 years,while its benefits in selecting euploid embryos remain controversial.Recent advances in...Invasive genetic screening of pre-implantation embryos via biopsied trophectoderm(TE)cells has been in use for more than 20 years,while its benefits in selecting euploid embryos remain controversial.Recent advances in the ability to process embryonic cell-free DNA(cfDNA)from blastocoel fluid(BF)and spent culture media(SCM)of blastocysts in a manner similar to that of a biopsied TE sample provide a potential alternative holding great promise for obtaining cytogenetic information of the embryos without intrusive biopsy of traditional biopsy-based pre-implantation genetic testing(PGT).Several studies have reported even higher diagnostic accuracy in non-invasive PGT(ni-PGT)than conventional PGT.However,there are still several technical challenges to be overcome before ni-PGT can be accepted as a reliable genomic information source of embryo.In this review,we have summarized the emergence and current state of ni-PGT,and discussed our own perspectives on their limitations and future prospect.There is still a long way to go before truly wide clinical application of ni-PGT.展开更多
Intracytoplasmic sperm injection (ICSI) is commonly used to solve male infertility problems. Previous studies showed that early environmental exposure of an embryo may influence postnatal development. To detect whethe...Intracytoplasmic sperm injection (ICSI) is commonly used to solve male infertility problems. Previous studies showed that early environmental exposure of an embryo may influence postnatal development. To detect whether ICSI operations affect the reproductive health of a male or his offspring, we established assisted reproductive technologies (ART) conceived mouse models, and analyzed gene expression profiles in the testes of both ICSI and naturally conceived (NC) newborn F1 mice using micro-array analysis. Among the differentially expressed genes, we focused on the expression of eight male reproduction-related genes. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was used to analyze the expression of these genes in the testes of both adult and old F1 generation mice and adult F2 generation mice. Our results showed that down-regulated and somatic cell-expressed genes in newborn mice retained their differential expression patterns in adult and old F1 generation individuals, implying the persistence and fetal origin of the alteration in the expression of these genes. The intergenerational transmission of differential gene expression was observed, but most changes tended to be reduced in adult F2 generations. Controlled ovarian hyperstimulation (COH) and in vitro fertilization (IVF) mice models were added to explore the precise factors contributing to the differences in ICSI offspring. The data demonstrated that superovulation, in vitro culture, and mechanical stimulation involved in ICSI had a cumulative effect on the differential expression of these male reproductive genes.展开更多
DNA mismatch repair （MMR） is one of the biological pathways, which plays a critical role in DNA home- ostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replicati...DNA mismatch repair （MMR） is one of the biological pathways, which plays a critical role in DNA home- ostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between altera- tions of the MMR system and human fertility and related treatments, and potential effects on the next generation.展开更多
Objective:Although numerous observational studies have revealed a correlation between leukocyte telomere length(LTL)and female reproductive system diseases(RSDs),the findings of these studies have tended to be consist...Objective:Although numerous observational studies have revealed a correlation between leukocyte telomere length(LTL)and female reproductive system diseases(RSDs),the findings of these studies have tended to be consistent.In this study,we accordingly sought to clarify the causal relationships between LTL and RSDs.Methods:We performed a bidirectional two-sample Mendelian randomization(MR)analysis using pooled statistics from genome-wide association studies of LTL and nine female RSDs.The final results were analyzed using five MR methods,with the inverse variance weighted(IVW)method used as the primary outcome.We applied MR-PRESSO to exclude outliers.Sensitivity analyses were also conducted to assess heterogeneity and pleiotropy.Results:In the forward MR analysis,a genetic prediction of longer LTLs was found to be causally associated with higher risks of endometriosis(IVW:odds ratio[OR]=1.25,95%confidence interval[CI]=1.06-1.46,P=0.008),leiomyoma of the uterus(IVW:OR=1.73,95%CI=1.52-1.98,P=4.9E-16),and ovarian cysts(IVW:OR=1.31,95%CI:1.19-1.45,P=1.5E-07).In the reverse MR results,female RSDs were shown to have no significant effect on LTLs(allP values>0.05).Sensitivity analysis confirmed the robustness of these results.Conclusions:Our findings substantiate the assumption that a genetically predicted longer LTL elevates the risk of endometriosis,leiomyoma of the uterus,and ovarian cysts,with no influence of RSDs on LTL.These findings contribute to establishing a causal link between LTL and RSDs,overcoming the constraints of earlier observational studies.They also imply that LTL could potentially serve as a biomarker for the occurrence of endometriosis,leiomyoma of the uterus,and ovarian cysts.展开更多
AIM:To confirm the hypothesis that polymorphisms of the uncoupling protein 3(UCP3)gene are associated with the occurrence of nonalcoholic fatty liver disease(NAFLD).METHODS:A total of 250 NAFLD patients(147 malesand 1...AIM:To confirm the hypothesis that polymorphisms of the uncoupling protein 3(UCP3)gene are associated with the occurrence of nonalcoholic fatty liver disease(NAFLD).METHODS:A total of 250 NAFLD patients(147 malesand 103 females)and 200 healthy individuals who served as controls(control,109 males and 91 females),aged between 6 and 16 years were enrolled in this study.The four non-synonymous single nucleotide polymorphisms(SNPs)in the UCP3 gene polymorphisms of rs1726745,rs3781907,rs11235972 and rs1800849,were genotyped using MassArray.Body mass index(BMI),waist and hip circumference,blood pressure(BP),fasting blood glucose(FBG),insulin and lipid profiles were measured and B-ultrasound examination was performed in all subjects.RESULTS:NAFLD patients showed risk factors for metabolic syndrome:elevated BMI,waist-to-hip ratio,BP,FBG,homeostasis model assessment-estimated insulin resistance,total triglyceride,total cholesterol and low-density lipoprotein-cholesterol,while decreased high-density lipoprotein-cholesterol level compared with the control group.The GG genotype distributions of rs11235972 in the NAFLD group differed significantly from that in the control group.We found that waist circumference between CC(58.76±6.45 cm)and CT+TT(57.00±5.59 cm),and hip circumference between CC(71.28±7.84 cm)and CT+TT genotypes(69.06±7.75 cm)were significantly different with and without rs1800849 variation(P<0.05).CONCLUSION:A higher prevalence of rs11235972 GG genotype was observed in the NAFLD group compared with the control group.No differences were observed for the other SNPs.However,there was a significant difference in body height in addition to waist and hip circumference between the CC(mutant type group)and CT+TT group with and without rs1800849 variation.展开更多
Ectopic pregnancy is identified with the widely-applied assisted reproductive technology （ART）. Bilateral ectopic pregnancy is a rare form of ectopic pregnancy which is difficult to be diagnosed at the pre-operation...Ectopic pregnancy is identified with the widely-applied assisted reproductive technology （ART）. Bilateral ectopic pregnancy is a rare form of ectopic pregnancy which is difficult to be diagnosed at the pre-operation stage. In this paper, we presented an unusual case of heterochronic bilateral ectopic pregnancy after stimulated intrauterine insemination （IUI）, where there has been a delay of 22 d between the diagnoses of the two ectopic pregnancies. Literature was reviewed on the occurrence of bilateral ectopic pregnancy during the past four years in the MEDLINE database. We found 16 cases of bilateral ectopic pregnancy reported since 2008, and analyzed the characteristics of those cases of bilateral ectopic pregnancy. We emphasize that ovulation induction and other ARTs may increase the risk of bilateral ectopic pregnancy. Because of the difficulty in identification of bilateral ectopic pregnancy by ultraso- nography, the clinician should be aware that the treatment of one ectopic pregnancy does not preclude the occurrence of a second ectopic pregnancy in the same patient and should pay attention to the intra-operation inspection of both side fallopian tubes in any ectopic pregnancy case.展开更多
A complete hydatidiform mole coexisting with a fetus following in vitro fertilization and embryo transfer (IVF-ET) is a rare event. The diagnosis is often not easy because of the morphological similarity to a partial ...A complete hydatidiform mole coexisting with a fetus following in vitro fertilization and embryo transfer (IVF-ET) is a rare event. The diagnosis is often not easy because of the morphological similarity to a partial mole, but important to the treatment. We present a recent case in which STR polymorphism analysis clearly revealed a different genetic origin for the fetal and molar parts. STR polymorphisms on 15 variable number tandem repeat loci and a gender-determination locus, which were detected by polymerase chain reaction, indicating that the cord/placenta and molar tissue were parental and androgenous, respectively. During follow-up, the patient developed persistent gestational trophoblastic tumor (GTT) which was successfully treated with chemotherapy. In this case, STR polymorphism analysis exactly diagnosed a twin pregnancy consisting of a complete hydatidiform mole and a fetus.展开更多
Background and Objectives:Previous studies have reported there were associations between ovarian function and dietary factors,metabolic factors and gut microbiota.However,it is unclear whether causal associations exis...Background and Objectives:Previous studies have reported there were associations between ovarian function and dietary factors,metabolic factors and gut microbiota.However,it is unclear whether causal associations exist.We aimed to explore the causal relationship of these factors with risk of primary ovarian failure(POF).Methods and Study Design:Two-sample Mendelian randomization(MR)analysis was performed to genetically predict the causal effects of dietary and metabolic factors and gut microbiota on POF.The inverse variance weighted(IVW)method was used as the primary statistical method.A series of sensitivity analyses,including weighted median,MR-Egger,simple mode,weighted mode methods,and leave-one-out analysis,were conducted to assess the robustness of the MR analysis results.Results:IVW analysis revealed that cigarettes smoked per day,coffee intake and cooked vegetable intake were not causally correlated with POF at the genetic level.However,POF were associated with fresh fruit intake,BMI,Eubacterium(hallii group),Eubacterium(ventriosum group),Ad lercreutzia,Intestinibacter,Lachnospiraceae(UCG008),and Terrisporobacter.These findings were robust ac cording to extensive sensitivity analyses.Conclusions:This study identified several dietary factors,metabolic factors and gut microbiota taxa that may be causally implicated in POF,potentially offering new therapeutic tar gets.展开更多
Genetically modified pigs are valuable models of human disease and donors of xenotransplanted organs.Conventional gene targeting in pig somatic cells is extremely inefficient.Zinc-finger nuclease(ZFN)technology has be...Genetically modified pigs are valuable models of human disease and donors of xenotransplanted organs.Conventional gene targeting in pig somatic cells is extremely inefficient.Zinc-finger nuclease(ZFN)technology has been shown to be a powerful tool for efficiently inducing mutations in the genome.However,ZFN-mediated targeting in pigs has rarely been achieved.Here,we used ZFNs to knock out the porcineα-1,3-galactosyl-transferase(GGTA1)gene,which generates Gal epitopes that trigger hyperacute immune rejection in pig-to-human transplantation.Primary pig fibroblasts were transfected with ZFNs targeting the coding region of GGTA1.Eighteen mono-allelic and four biallelic knockout cell clones were obtained after drug selection with efficiencies of 23.4%and 5.2%,respectively.The biallelic cells were used to produce cloned pigs via somatic cell nuclear transfer(SCNT).Three GGTA1 null piglets were born,and one knockout primary fibroblast cell line was established from a cloned fetus.Gal epitopes on GGTA1 null pig cells were completely eliminated from the cell membrane.Functionally,GGTA1 knockout cells were protected from complement-mediated immune attacks when incubated with human serum.This study demonstrated that ZFN is an efficient tool in creating gene-modified pigs.GGTA1 null pigs and GGTA1 null fetal fibroblasts would benefit research and pig-to-human transplantation.展开更多
As shown in our previous study, two alternatively spliced androgen receptor(AR) variants, which are exclusively expressed in the granulosa cells of patients with polycystic ovary syndrome, exhibit retarded nuclear tra...As shown in our previous study, two alternatively spliced androgen receptor(AR) variants, which are exclusively expressed in the granulosa cells of patients with polycystic ovary syndrome, exhibit retarded nuclear translocation compared with wild-type AR. However, researchers have not yet determined whether these abnormalities correlate with heat shock protein 90(HSP90)and importin α(the former is a generally accepted co-chaperone of AR, and the latter is a component of classical nuclear import complexes). Here, these two variants were mainly retained in cytoplasm with HSP90 and importin α in the presence of dihydrotestosterone(DHT), and their levels in nucleus were significantly reduced, according to the immunofluorescence staining. The binding affinity of two AR variants for importin α was consistently decreased, while it was increased in WT-AR following DHT stimulation, leading to reduced nuclear import, particularly for the insertion-AR(Ins-AR). However, the binding affinities of two AR variants for HSP90 were increased in the absence of DHT compared with WT-AR, which functioned to maintain spatial structural stability, particularly for the deletion-AR(Del-AR). Therefore, the retarded nuclear translocation of two AR variants is associated with HSP90 and importin α, and the abnormal binding affinities for them play critical roles in this process.展开更多
Background Hemophagocytic lymphohistiocytosis(HLH)is a life-threatening entity which is characterized by severe hyperinflammation.Now the HLH-2004 protocol has been widely accepted and clinically used;however,many que...Background Hemophagocytic lymphohistiocytosis(HLH)is a life-threatening entity which is characterized by severe hyperinflammation.Now the HLH-2004 protocol has been widely accepted and clinically used;however,many questions still remain in clinical practice.In this review,we discuss the dilemmas in the diagnosis and treatment of HLH in children.Data sources Original research for articles and literature reviews published in PubMed was carried out using the key term“hemophagocytic lymphohistiocytosis”.Results As the gene sequencing technology progresses,the range of causal mutations and primary HLH has been redefined.The monoallelic variants may contribute to the pathogenesis of the disease.Many conditions without defective cytotoxicity of T or NK cells may lead to HLH,such as primary immunodeficiency(PID)and dysregulated immune activation or proliferation(DIAP).HLH shares overlapping clinical and laboratory characteristics with severe sepsis,but usually the single values are more pronounced in HLH than sepsis.H score is another approach to help the diagnosis of secondary HLH.Specific Th1/Th2 cytokine patterns are very helpful tools to differentiate HLH(reactivation of HLH)from sepsis.Moreover,it also has been used successfully to stratify the therapy intensity.The treatment of HLH should consider underlying diseases,triggers and severity.HLH-94 is recommended for patients who need etoposide-based therapy.Conclusions Dramatic progress has been made during the past decades in understanding the pathophysiology of HLH.However,diagnosis and treatment of HLH remain with many dilemmas because of the heterogeneous nature of the disease.Better understanding new gene defects and more effective diagnostic approaches and salvage regimens are goals for the future.展开更多
基金supported by Zhejiang Provincial Natural Science Foundation of China(Grant No.ZCLTGY24H0401)Technology Program of Jiaxing(Grant No.2024AD30125).
文摘Advances in fetal surgery techniques have enabled the treatment of certain congenital defects before birth.A critical area of focus is the role of perinatal imaging in optimizing prenatal interventions within the precision medicine framework.Magnetic resonance imaging(MRI)is emerging as an indispensable tool for guiding these intricate procedures with the potential to significantly enhance the standard of care and outcomes for affected fetuses.This review begins with an overview of the classification and indications for fetal surgical interventions.It then explores the detailed applications of prenatal MRI scanning and diagnostic techniques across various categories of fetal surgery.A key focus is how fetal MRI provides critical insights into specific lesion characteristics and tissue involvement,thereby aiding healthcare professionals in selecting the optimal surgical strategies for prenatal and postnatal interventions.Fetal MRI offers detailed visualizations that complement traditional ultra-sound findings,enhancing the precision of radiological planning for fetal surgery.Finally,the review highlights how integration of fetal MRI into the decision-making process enables healthcare providers to make well-informed choices,ultimately improving the prognosis and outcomes for both the mother and fetus.
基金supported by the National Natural Science Foundation of China(No.U22A20358)Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents(No.2020-18).
文摘Metal may affect maternal immune function,but few epidemiological studies have reported the associations between multiple-metal exposure and maternal immunoglobulin(Ig)levels.Based on the Hangzhou Birth Cohort Study,1059 participants were included,and eleven metals in whole blood samples and serum IgA,IgG,IgE and IgM levels were measured.Linear regression,quantile-based g-computation(QGC),and Bayesian kernel machine regression(BKMR)models were used to evaluate the associations.Compared with the first tertile of metal levels,arsenic(As)was negatively associated with IgE(β=-0.25,95%confidence interval(CI)=-0.48 to-0.02).Moreover,significant associations of manganese(Mn)with IgA,IgG and IgM were demonstrated(β=0.10,95%CI=0.04 to 0.18;β=0.07,95%CI=0.03 to 0.12;β=0.10,95%CI=0.03 to 0.18,respectively).Cadmium(Cd)were associated with higher levels of IgM.QGC models showed the positive association of the metalmixtures with IgA and IgG,with Mn playing amajor role.Mn and Cd had positive contributions to IgM,while As had negative contributions to IgE.In the BKMR models,the latent continuous outcomes of IgA and IgG showed a significant increase when all the metals were at their 60th percentile or above compared to those at their 50th percentile.Therefore,exposure to metals was associated with maternal Igs,and mainly showed that Mn was associated with increased levels of IgA,IgG and IgM,and As was associated with low IgE levels.
基金supported by the National Key Research and Development Program of China(No.2018YFC1004900)the National Natural Science Foundation of China(No.82101799)the Health Science and Technology Foundation of Zhejiang Province of China(No.2022KY186).
文摘Given that ovarian stimulation is vital for assisted reproductive technology(ART)and results in elevated serum estrogen levels,exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary.We investigated the effects of various ovarian stimulation treatments on oocyte and embryo morphology and gene expression using a mouse model and estrogen-treated mouse embryonic stem cells(m ESCs).Female C57BL/6J mice were subjected to two types of conventional ovarian stimulation and ovarian hyperstimulation;mice treated with only normal saline served as controls.Hyperstimulation resulted in high serum estrogen levels,enlarged ovaries,an increased number of aberrant oocytes,and decreased embryo formation.The messenger RNA(m RNA)-sequencing of oocytes revealed the dysregulated expression of lysine-specific demethylase 6b(Kdm6b),which may be a key factor indicating hyperstimulation-induced aberrant oocytes and embryos.In vitro,Kdm6b expression was downregulated in m ESCs treated with high-dose estrogen;treatment with an estrogen receptor antagonist could reverse this downregulated expression level.Furthermore,treatment with high-dose estrogen resulted in the upregulated expression of histone H3 lysine 27 trimethylation(H3K27me3)and phosphorylated H2A histone family member X(γ-H2AX).Notably,knockdown of Kdm6b and high estrogen levels hindered the formation of embryoid bodies,with a concomitant increase in the expression of H3K27me3 andγ-H2AX.Collectively,our findings revealed that hyperstimulation-induced high-dose estrogen could impair the demethylation of H3K27me3 by reducing Kdm6b expression.Accordingly,Kdm6b could be a promising marker for clinically predicting ART outcomes in patients with ovarian hyperstimulation syndrome.
基金Project supported by the National Basic Research Program (973) of China (No. 2012CB944901)the National Natural Science Foundation of China (Nos. 81070532 and 81200475)
文摘Children conceived via assisted reproductive technologies (ART) are nowadays a substantial proportion of the population. It is important to follow up these children and evaluate whether they have elevated health risks compared to naturally conceived (NC) children. In recent years there has been a lot of work in this field. This review will summarize what is known about the health of ART-conceived children, encompassing neonatal outcomes, birth defects, growth and gonadal developments, physical health, neurological and neurodevelopmental outcomes, psychosocial developments, risk for cancer, and epigenetic abnormalities. Most of the children conceived after ART are normal. However, there is increasing evidence that ART-conceived children are at higher risk of poor perinatal outcome, birth defects, and epigenetic disorders, and the mechanism(s) leading to these changes have not been elucidated. Continuous follow-up of children after ART is of great importance as they progress through adolescence into adulthood, and new ART techniques are constantly being introduced.
基金supported by Zhejiang Provincial Natural Science Foundation of China(Grant/Award number:ZCLTGY24H0401)Education Department of Zhejiang Province(Grant/Award number:Y202352970).
文摘Background:Congenital heart disease(CHD)results from abnormal heart development during fetal development,leading to life-threatening complications.This study aimed to evaluate the feasibility of applying myocardial parametric mapping in post-mortem magnetic resonance imaging and to examine differences in the left ventricular myocardium between fetuses with CHD and controls.Methods:This prospective case–control study was conducted on 14 deceased fetuses with CHD(CHD group)and 24 fetuses without CHD(control group).Fetuses with CHD were further stratified into the cyanotic(n=9)and non-cyanotic(n=5)CHD groups.T1,T2,and proton density relaxation times of the left ventricular myocardium were calculated and compared using multiple-dynamic multiple-echo post-mortem magnetic resonance imaging technology.Results:The myocardial T2 relaxation time was significantly different between the groups(p=0.033),with no difference in T1 or proton density relaxation times between the groups.A one-way analysis of variance with Tukey's test showed that the mean cyanotic CHD group showed a longer myocardial T2 relaxation time than the control group(98.00013.143 vs.83.5429.491 ms,p=0.003).Additionally,the correlation coefficient in the CHD group was significantly different between the myocardial T2 relaxation time and peak systolic velocity of pulmonary artery on a fetal echocardiogram(r2=0.681,p=0.010).Conclusions:These results suggest that using myocardial alterations in the T2 relaxation time may provide a accurate early warning for myocardial injury and enable noninvasive recognition of cardiac involvement in fetuses with CHD.
文摘In recent decades,maternal–fetal medicine has undergone substantial advancements in the management of high-risk pregnancies.These include enhanced prenatal screening and diagnosis facilitated by innovations in ultrasound imaging,as well as the advances in fetal medical and interventional therapies informed by the deeper understanding of pathophysiological mechanisms underlying fetal and maternal disease processes.
文摘The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. Glucose metabolism is an important event in spermatogenesis. Moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. Diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm DNA integrity, and ingredients of seminal plasma. Epigenetic modifications are essential during spermatogenesis. The epigenetic regulation represents chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding RNAs. If spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. Diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring.
基金supported by the project of the Ministry of Education, Zhejiang Province, China, No. Y201017446 and Y201121392the project of the Bureau of Chinese Medicine, Zhejiang Province, China, No. 2011ZA067
文摘Male Wistar 7-day-old rats were injected with 40 mg/kg ketamine intraperitoneally, followed by three additional injections of 20 mg/kg ketamine each upon restoration of the righting reflex. Neonatal rats injected with equivalent volumes of saline served as controls. Hippocampal samples were collected at 1,7 or 14 days following administration. Electron microscopy showed that neuronal structure changed noticeably following ketamine treatment. Specifically, microtubular structure became irregular and disorganized. Quantitative real time-PCR revealed that phosphorylated tau mRNA was upregulated after ketamine. Western blot analysis demonstrated that phosphorylated tau levels at serine 396 initially decreased at 1 day after ketamine injection, and then gradually returned to control values. At 14 days after injection, levels of phosphorylated tau were higher in the ketamine group than in the control group. Tau protein phosphorylated at serine 404 significantly increased after ketamine injection and then gradually decreased with time. However, the levels of tau protein at serine 404 were significantly greater in the ketamine group than in the control group until 14 days. The present results indicate that ketamine induces an increase of phosphorylated tau mRNA and excessive phosphorylation of tau protein at serine 404, causing disruption of microtubules in the neonatal rat hippocampus and potentially resulting in damage to hippocampal neurons.
基金the National Key Research and Development Program of China(No.2016YFC1000703)the Medicine and Health Science and Technology Plan Projects in Zhejiang Province(No.2014KYA246)the National Natural Science Foundation of China(Nos.81801441 and 81300532)
文摘Duchenne muscular dystrophy(DMD)and Becker muscular dystrophy(BMD)are caused by mutations in the DMD gene.The aim of this study is to identify pathogenic DMD variants in probands and reduce the risk of recurrence of the disease in affected families.Variations in 100 unrelated DMD/BMD patients were detected by multiplex ligation-dependent probe amplification(MLPA)and next-generation sequencing(NGS).Pathogenic variants in DMD were successfully identified in all cases,and 11 of them were novel.The most common mutations were intragenic deletions(69%),with two hotspots located in the 5'end(exons 2–19)and the central of the DMD gene(exons 45–55),while point mutations were observed in 22%patients.Further,c.1149+1G>A and c.1150?2A>G were confirmed by hybrid minigene splicing assay(HMSA).This two splice site mutations would lead to two aberrant DMD isoforms which give rise to severely truncated protein.Therefore,the clinical use of MLPA,NGS,and HMSA is an effective strategy to identify variants.Importantly,eight embryos were terminated pregnancies according to prenatal diagnosis and a healthy boy was successfully delivered by preimplantation genetic diagnosis(PGD).Early and accurate genetic diagnosis is essential for prenatal diagnosis/PGD to reduce the risk of recurrence of DMD in affected families.
基金We thank professors Cynthia Casson Morton and Yiping Shen from Harvard Medical School and professor Sharon YC Ruan from Hong Kong Polytechnic University for revising the manuscript.This work was supported by the National Key Research and Development Program of China(2018YFC1005003)the National Natural Science Foundation of China(81974224,81771535)+2 种基金the Natural Science Foundation of Zhejiang Province(LZ18H040001,LQ19H040007)Zhejiang Provincial Key Medical Technology Program(WKJ-ZJ-1826)Zhejiang University Education Foundation Global Partnership Fund.The authors declared no conflict of interest.
文摘Invasive genetic screening of pre-implantation embryos via biopsied trophectoderm(TE)cells has been in use for more than 20 years,while its benefits in selecting euploid embryos remain controversial.Recent advances in the ability to process embryonic cell-free DNA(cfDNA)from blastocoel fluid(BF)and spent culture media(SCM)of blastocysts in a manner similar to that of a biopsied TE sample provide a potential alternative holding great promise for obtaining cytogenetic information of the embryos without intrusive biopsy of traditional biopsy-based pre-implantation genetic testing(PGT).Several studies have reported even higher diagnostic accuracy in non-invasive PGT(ni-PGT)than conventional PGT.However,there are still several technical challenges to be overcome before ni-PGT can be accepted as a reliable genomic information source of embryo.In this review,we have summarized the emergence and current state of ni-PGT,and discussed our own perspectives on their limitations and future prospect.There is still a long way to go before truly wide clinical application of ni-PGT.
基金Project supported by the National Basic Research Program (973)of China (Nos. 2007CB948104 and 2012CB944901)the National Natural Science Foundation of China (Nos. 81070532, 81070541, and 81200475)the Zhejiang Provincial Natural Science Foundation of China (Nos. Y2090084, Y2100397, and Y2100199)
文摘Intracytoplasmic sperm injection (ICSI) is commonly used to solve male infertility problems. Previous studies showed that early environmental exposure of an embryo may influence postnatal development. To detect whether ICSI operations affect the reproductive health of a male or his offspring, we established assisted reproductive technologies (ART) conceived mouse models, and analyzed gene expression profiles in the testes of both ICSI and naturally conceived (NC) newborn F1 mice using micro-array analysis. Among the differentially expressed genes, we focused on the expression of eight male reproduction-related genes. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was used to analyze the expression of these genes in the testes of both adult and old F1 generation mice and adult F2 generation mice. Our results showed that down-regulated and somatic cell-expressed genes in newborn mice retained their differential expression patterns in adult and old F1 generation individuals, implying the persistence and fetal origin of the alteration in the expression of these genes. The intergenerational transmission of differential gene expression was observed, but most changes tended to be reduced in adult F2 generations. Controlled ovarian hyperstimulation (COH) and in vitro fertilization (IVF) mice models were added to explore the precise factors contributing to the differences in ICSI offspring. The data demonstrated that superovulation, in vitro culture, and mechanical stimulation involved in ICSI had a cumulative effect on the differential expression of these male reproductive genes.
基金Project supported by the National Basic Research Programs (973) of China(Nos.2012CB944901 and 2014CB943302)the National Natural Science Foundation of China(Nos.81200475,81370760,and 81571500)the Zhejiang Provincial Natural Science Foundation of China(No.LZ13H040001)
文摘DNA mismatch repair （MMR） is one of the biological pathways, which plays a critical role in DNA home- ostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between altera- tions of the MMR system and human fertility and related treatments, and potential effects on the next generation.
基金National Key Research and Development Program of China(2021YFC2700701,2022YFC2703803,2022YFC2703001)National Natural Science Foundation of China(82088102,82071731,82171613,8227034,81601238)+9 种基金Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2019-I2M-5-064)Science and Technology Commission of Shanghai Municipality(21Y11907600)Shanghai Municipal Commission of Health and Family Planning(20215Y0216)Collaborative Innovation Program of Shanghai Municipal Health Commission(2020CXJQ01)Clinical Research Plan of Shanghai Hospital Development Center(SHDC2020CR1008A)Shanghai Clinical Research Center for Gynecological Diseases(22MC1940200)Shanghai Urogenital System Diseases Research Center(2022ZZ01012)Shanghai Frontiers Science Research Base of Reproduction and Development,The Science and Technology Commission of Quzhou Municipality(2022K54)Open Fund Project of Key Laboratory of Reproductive Genetics,Ministry of Education,Zhejiang University(KY2022035)Open Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202202)。
文摘Objective:Although numerous observational studies have revealed a correlation between leukocyte telomere length(LTL)and female reproductive system diseases(RSDs),the findings of these studies have tended to be consistent.In this study,we accordingly sought to clarify the causal relationships between LTL and RSDs.Methods:We performed a bidirectional two-sample Mendelian randomization(MR)analysis using pooled statistics from genome-wide association studies of LTL and nine female RSDs.The final results were analyzed using five MR methods,with the inverse variance weighted(IVW)method used as the primary outcome.We applied MR-PRESSO to exclude outliers.Sensitivity analyses were also conducted to assess heterogeneity and pleiotropy.Results:In the forward MR analysis,a genetic prediction of longer LTLs was found to be causally associated with higher risks of endometriosis(IVW:odds ratio[OR]=1.25,95%confidence interval[CI]=1.06-1.46,P=0.008),leiomyoma of the uterus(IVW:OR=1.73,95%CI=1.52-1.98,P=4.9E-16),and ovarian cysts(IVW:OR=1.31,95%CI:1.19-1.45,P=1.5E-07).In the reverse MR results,female RSDs were shown to have no significant effect on LTLs(allP values>0.05).Sensitivity analysis confirmed the robustness of these results.Conclusions:Our findings substantiate the assumption that a genetically predicted longer LTL elevates the risk of endometriosis,leiomyoma of the uterus,and ovarian cysts,with no influence of RSDs on LTL.These findings contribute to establishing a causal link between LTL and RSDs,overcoming the constraints of earlier observational studies.They also imply that LTL could potentially serve as a biomarker for the occurrence of endometriosis,leiomyoma of the uterus,and ovarian cysts.
基金Supported by Zhejiang Provincial Natural Science Foundation of ChinaNo.Y2090137+8 种基金the National Key Technology R and D Program of ChinaNo.2012BAI02B03the Fundamental Research Funds for the Central UniversitiesMinistry of EducationChinaNo.2011KYJD008National Natural Science Foundation of ChinaNo.J20121252No.81200460
文摘AIM:To confirm the hypothesis that polymorphisms of the uncoupling protein 3(UCP3)gene are associated with the occurrence of nonalcoholic fatty liver disease(NAFLD).METHODS:A total of 250 NAFLD patients(147 malesand 103 females)and 200 healthy individuals who served as controls(control,109 males and 91 females),aged between 6 and 16 years were enrolled in this study.The four non-synonymous single nucleotide polymorphisms(SNPs)in the UCP3 gene polymorphisms of rs1726745,rs3781907,rs11235972 and rs1800849,were genotyped using MassArray.Body mass index(BMI),waist and hip circumference,blood pressure(BP),fasting blood glucose(FBG),insulin and lipid profiles were measured and B-ultrasound examination was performed in all subjects.RESULTS:NAFLD patients showed risk factors for metabolic syndrome:elevated BMI,waist-to-hip ratio,BP,FBG,homeostasis model assessment-estimated insulin resistance,total triglyceride,total cholesterol and low-density lipoprotein-cholesterol,while decreased high-density lipoprotein-cholesterol level compared with the control group.The GG genotype distributions of rs11235972 in the NAFLD group differed significantly from that in the control group.We found that waist circumference between CC(58.76±6.45 cm)and CT+TT(57.00±5.59 cm),and hip circumference between CC(71.28±7.84 cm)and CT+TT genotypes(69.06±7.75 cm)were significantly different with and without rs1800849 variation(P<0.05).CONCLUSION:A higher prevalence of rs11235972 GG genotype was observed in the NAFLD group compared with the control group.No differences were observed for the other SNPs.However,there was a significant difference in body height in addition to waist and hip circumference between the CC(mutant type group)and CT+TT group with and without rs1800849 variation.
基金supported by the National Basic Research Program(973)of China(No.2013CB967404)the National Natural Science Foundation of China(Nos.81170310 and 81270664)+1 种基金the Science Foundation for Distinguished Young Scholars of Zhejiang Province(No.LR14H040001)the Talent Project of Zhejiang Province(No.2011RCA028),China
文摘Ectopic pregnancy is identified with the widely-applied assisted reproductive technology （ART）. Bilateral ectopic pregnancy is a rare form of ectopic pregnancy which is difficult to be diagnosed at the pre-operation stage. In this paper, we presented an unusual case of heterochronic bilateral ectopic pregnancy after stimulated intrauterine insemination （IUI）, where there has been a delay of 22 d between the diagnoses of the two ectopic pregnancies. Literature was reviewed on the occurrence of bilateral ectopic pregnancy during the past four years in the MEDLINE database. We found 16 cases of bilateral ectopic pregnancy reported since 2008, and analyzed the characteristics of those cases of bilateral ectopic pregnancy. We emphasize that ovulation induction and other ARTs may increase the risk of bilateral ectopic pregnancy. Because of the difficulty in identification of bilateral ectopic pregnancy by ultraso- nography, the clinician should be aware that the treatment of one ectopic pregnancy does not preclude the occurrence of a second ectopic pregnancy in the same patient and should pay attention to the intra-operation inspection of both side fallopian tubes in any ectopic pregnancy case.
基金Supported by Production and Rresearch Projects of Guangdong Province (2007B090400140)
文摘A complete hydatidiform mole coexisting with a fetus following in vitro fertilization and embryo transfer (IVF-ET) is a rare event. The diagnosis is often not easy because of the morphological similarity to a partial mole, but important to the treatment. We present a recent case in which STR polymorphism analysis clearly revealed a different genetic origin for the fetal and molar parts. STR polymorphisms on 15 variable number tandem repeat loci and a gender-determination locus, which were detected by polymerase chain reaction, indicating that the cord/placenta and molar tissue were parental and androgenous, respectively. During follow-up, the patient developed persistent gestational trophoblastic tumor (GTT) which was successfully treated with chemotherapy. In this case, STR polymorphism analysis exactly diagnosed a twin pregnancy consisting of a complete hydatidiform mole and a fetus.
基金funded by National Key Research and De velopment Program of China(No.2022YFC2703803,No.2022YFC2703001,No.2021YFC2700603)National Natural Science Foundation of China(No.82088102,No.82171613,No.82171688)+5 种基金CAMS Innovation Fund for Medical Sciences(2019-I2M-5-064)Collaborative Innovation Program of Shanghai Municipal Health Commission(2020CXJQ01)Key Discipline Construction Project(2023-2025)of Three-Year Initiative Plan for Strengthening Public Health System Con struction in Shanghai(GWVI-11.1-35)Shanghai Clinical Re search Center for Gynecological Diseases(22MC1940200)Shanghai Urogenital System Diseases Research Center(2022ZZ01012)Shanghai Frontiers Science Research Center of Reproduction and Development,Zhejiang Province College Student Science and Technology Innovation Program(Xinmiao Plan)(2023R401210).
文摘Background and Objectives:Previous studies have reported there were associations between ovarian function and dietary factors,metabolic factors and gut microbiota.However,it is unclear whether causal associations exist.We aimed to explore the causal relationship of these factors with risk of primary ovarian failure(POF).Methods and Study Design:Two-sample Mendelian randomization(MR)analysis was performed to genetically predict the causal effects of dietary and metabolic factors and gut microbiota on POF.The inverse variance weighted(IVW)method was used as the primary statistical method.A series of sensitivity analyses,including weighted median,MR-Egger,simple mode,weighted mode methods,and leave-one-out analysis,were conducted to assess the robustness of the MR analysis results.Results:IVW analysis revealed that cigarettes smoked per day,coffee intake and cooked vegetable intake were not causally correlated with POF at the genetic level.However,POF were associated with fresh fruit intake,BMI,Eubacterium(hallii group),Eubacterium(ventriosum group),Ad lercreutzia,Intestinibacter,Lachnospiraceae(UCG008),and Terrisporobacter.These findings were robust ac cording to extensive sensitivity analyses.Conclusions:This study identified several dietary factors,metabolic factors and gut microbiota taxa that may be causally implicated in POF,potentially offering new therapeutic tar gets.
基金supported by grants from Ministry of Science and Technology of China(2011CBA01001,2012AA020503)the National Science Fund for Distinguished Young Scholars(31025016)+4 种基金the National Natural Science Foundation of China(31271577)Novel Agricultural Variety Breeding Project of Zhejiang Province(2012C12906-8)the Fundamental Research Funds for the Central Universitiesthe Key Construction Pro-gram of the National"985"Project(118000+193411801/006)the Research Fund for the Doctoral Program of Higher Education of China(20120101110089)
文摘Genetically modified pigs are valuable models of human disease and donors of xenotransplanted organs.Conventional gene targeting in pig somatic cells is extremely inefficient.Zinc-finger nuclease(ZFN)technology has been shown to be a powerful tool for efficiently inducing mutations in the genome.However,ZFN-mediated targeting in pigs has rarely been achieved.Here,we used ZFNs to knock out the porcineα-1,3-galactosyl-transferase(GGTA1)gene,which generates Gal epitopes that trigger hyperacute immune rejection in pig-to-human transplantation.Primary pig fibroblasts were transfected with ZFNs targeting the coding region of GGTA1.Eighteen mono-allelic and four biallelic knockout cell clones were obtained after drug selection with efficiencies of 23.4%and 5.2%,respectively.The biallelic cells were used to produce cloned pigs via somatic cell nuclear transfer(SCNT).Three GGTA1 null piglets were born,and one knockout primary fibroblast cell line was established from a cloned fetus.Gal epitopes on GGTA1 null pig cells were completely eliminated from the cell membrane.Functionally,GGTA1 knockout cells were protected from complement-mediated immune attacks when incubated with human serum.This study demonstrated that ZFN is an efficient tool in creating gene-modified pigs.GGTA1 null pigs and GGTA1 null fetal fibroblasts would benefit research and pig-to-human transplantation.
基金supported by the National Key Research and Development Program of China (2017YFC1001303)International Cooperation Project of China and Canada NSFC (81661128010)+2 种基金National Natural Science Foundation of China (31471405, 81671456, 81671412)the National Key Basic Research Program (2013CB967404) the Doctoral Innovation Fund of School of Medicine, Shanghai Jiao Tong University (BXJ201640)
文摘As shown in our previous study, two alternatively spliced androgen receptor(AR) variants, which are exclusively expressed in the granulosa cells of patients with polycystic ovary syndrome, exhibit retarded nuclear translocation compared with wild-type AR. However, researchers have not yet determined whether these abnormalities correlate with heat shock protein 90(HSP90)and importin α(the former is a generally accepted co-chaperone of AR, and the latter is a component of classical nuclear import complexes). Here, these two variants were mainly retained in cytoplasm with HSP90 and importin α in the presence of dihydrotestosterone(DHT), and their levels in nucleus were significantly reduced, according to the immunofluorescence staining. The binding affinity of two AR variants for importin α was consistently decreased, while it was increased in WT-AR following DHT stimulation, leading to reduced nuclear import, particularly for the insertion-AR(Ins-AR). However, the binding affinities of two AR variants for HSP90 were increased in the absence of DHT compared with WT-AR, which functioned to maintain spatial structural stability, particularly for the deletion-AR(Del-AR). Therefore, the retarded nuclear translocation of two AR variants is associated with HSP90 and importin α, and the abnormal binding affinities for them play critical roles in this process.
基金This study was supported in part by grants from the National Natural Science Foundation of China(No:81770202)the Natural Science Foundation of Zhejiang Province(Nos:LY19H080006,LZ12H08001).
文摘Background Hemophagocytic lymphohistiocytosis(HLH)is a life-threatening entity which is characterized by severe hyperinflammation.Now the HLH-2004 protocol has been widely accepted and clinically used;however,many questions still remain in clinical practice.In this review,we discuss the dilemmas in the diagnosis and treatment of HLH in children.Data sources Original research for articles and literature reviews published in PubMed was carried out using the key term“hemophagocytic lymphohistiocytosis”.Results As the gene sequencing technology progresses,the range of causal mutations and primary HLH has been redefined.The monoallelic variants may contribute to the pathogenesis of the disease.Many conditions without defective cytotoxicity of T or NK cells may lead to HLH,such as primary immunodeficiency(PID)and dysregulated immune activation or proliferation(DIAP).HLH shares overlapping clinical and laboratory characteristics with severe sepsis,but usually the single values are more pronounced in HLH than sepsis.H score is another approach to help the diagnosis of secondary HLH.Specific Th1/Th2 cytokine patterns are very helpful tools to differentiate HLH(reactivation of HLH)from sepsis.Moreover,it also has been used successfully to stratify the therapy intensity.The treatment of HLH should consider underlying diseases,triggers and severity.HLH-94 is recommended for patients who need etoposide-based therapy.Conclusions Dramatic progress has been made during the past decades in understanding the pathophysiology of HLH.However,diagnosis and treatment of HLH remain with many dilemmas because of the heterogeneous nature of the disease.Better understanding new gene defects and more effective diagnostic approaches and salvage regimens are goals for the future.
