Ovarian aging is characterized by a progressive decline in oocyte quality and quantity with age.Icariin(ICA),a flavonoid compound derived from Epimedium species,has demonstrated potential as an agent for ovarian resto...Ovarian aging is characterized by a progressive decline in oocyte quality and quantity with age.Icariin(ICA),a flavonoid compound derived from Epimedium species,has demonstrated potential as an agent for ovarian restoration.In this study,a subcutaneous implantation system using gelatin methacryloyl(GelMA)hydrogel embedded with ICA was developed to restore ovarian function in aged female mice.Mice were assigned to receive subcutaneous implantation of GelMA alone(GelMA group),GelMA containing ICA(GelMA/ICA group),or a sham operation.Ovarian morphology,serum hormone levels,follicle counts across developmental stages,and reproductive outcomes were evaluated.In vitro fertilization(IVF)and embryo culture assays were performed to assess oocyte developmental potential,while a 10 day natural mating trial was conducted to determine fertility restoration.RNA sequencing(RNA-seq)and RT-qPCR were performed to elucidate the underlying molecular mechanisms.Results showed that GelMA/ICA treatment significantly increased ovarian index(0.19±0.01 vs.0.13±0.01,P<0.0001)and follicle numbers at all developmental stages,including primordial(383.33±151.65 vs.107.14±32.26,P<0.0001),primary(203.33±83.22 vs.91.43±27.04,P=0.003),and secondary follicles(154.17±52.00 vs.59.28±20.50,P=0.029)compared to the sham controls.Hormonal analyses revealed a significant reduction in serum follicle-stimulating hormone(FSH,11.97±3.53 vs.53.10±17.89 ng/mL,P=0.0008),accompanied by elevated anti-Müllerian hormone(AMH,22.97±2.26 vs.5.54±1.56 ng/mL,P<0.0001)and estradiol(E2,315.30±37.62 vs.168.5±14.78 pg/mL,P<0.0001).Oocyte yield and developmental potential improved significantly,as reflected by the increased number of superovulated MII oocytes(17.83±5.15 vs.4.83±4.79,P=0.0002),and higher proportions of two-cell(85.90%±6.16%vs.50.00%±10.00%,P=0.0009),four-cell(81.67%±9.76%vs.50.00%±10.00%,P=0.0061),and blastocyst stage embryos(64.25%±10.55%vs.23.33%±15.28%,P=0.0067).Live birth numbers were significantly increased following GelMA/ICA treatment(6.90±3.21 vs.1.72±2.05,P=0.0001).Transcriptomic analysis revealed up-regulation of genes associated with cytoskeletal organization(Vil1,Tubb3),lipid storage(Soat2,Plin4),oocyte maturation(Oosp2),and cytokine secretion(Cxcl12).Collectively,these findings suggest that GelMA/ICA hydrogels effectively reverse key hallmarks of ovarian aging and restore reproductive function in aged mice,offering a promising platform for fertility preservation and a novel therapeutic for future investigations into ovarian aging.展开更多
V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating ene...V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.展开更多
Objective:To test the diagnostic performance of percent free prostate-specific antigen(%fPSA)in predicting any prostate cancer(PCa)and high-grade prostate cancer(HGPCa)in a retrospective multi-center biopsy cohort wit...Objective:To test the diagnostic performance of percent free prostate-specific antigen(%fPSA)in predicting any prostate cancer(PCa)and high-grade prostate cancer(HGPCa)in a retrospective multi-center biopsy cohort with a PSA level of 4.0e10.0 ng/mL in China.Methods:Consecutive patients with a PSA of 4.0-10.0 ng/mL who underwent transrectal ultrasound-guided biopsy were enrolled at 16 Chinese medical centers from January 1st,2010 to December 31st,2013.Total and free serum PSA determinations were performed using three types of electro-chemiluminescence immunoassays recalibrated to the World Health Organization(WHO)standard.The diagnostic accuracy of PSA,%fPSA,and %fPSA in combination with PSA(%fPSA t PSA)was determined using the area under the receiver operating characteristic(ROC)curve(AUC).Results:A total of 2310 consecutive men with PSA levels between 4.0 and 10.0 ng/mL were included,and the detection rate of PCa was 25.1%.The AUC of%fPSA and %fPSA t PSA in predicting any PCa was superior to PSA alone in men aged≥60 years(0.623 vs.0.534,p<0.0001)but not in men aged 40e59 years(0.517 vs.0.518,p=0.939).Similar result was yield in predicting HGPCa.Conclusion:In a clinical setting of Chinese men with 4.0e10.0 ng/mL PSA undergoing initial prostate biopsy,adding %fPSA to PSA can moderately improve the diagnostic accuracy for any PCa and HGPCa compared with PSA alone in patients≥60 but not in patients aged 40-59 years.展开更多
Primary ciliary dyskinesia(PCD)is a clinically rare,genetically and phenotypically heterogeneous condition characterized by chronic respiratory tract infections,male infertility,tympanitis,and laterality abnormalities...Primary ciliary dyskinesia(PCD)is a clinically rare,genetically and phenotypically heterogeneous condition characterized by chronic respiratory tract infections,male infertility,tympanitis,and laterality abnormalities.PCD is typically resulted from variants in genes encoding assembly or structural proteins that are indispensable for the movement of motile cilia.Here,we identified a novel nonsense mutation,c.466G>T,in cilia-and flagella-associated protein 300(CFAP300)resulting in a stop codon(p.Glu156*)through whole-exome sequencing(WES).The proband had a PCD phenotype with laterality defects and immotile sperm flagella displaying a combined loss of the inner dynein arm(IDA)and outer dynein arm(ODA).Bioinformatic programs predicted that the mutation is deleterious.Successful pregnancy was achieved through intracytoplasmic sperm injection(ICSI).Our results expand the spectrum of CFAP300 variants in PCD and provide reproductive guidance for infertile couples suffering from PCD caused by them.展开更多
Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.How...Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.However,relatively few studies have explored the impact of post-translational modifications(PTM)on OC progression,which is essential for uncovering new therapeutic targets.This study aimed to systematically identify the key PTM types involved in OCprogression,and to explore and evaluate their translational potential as therapeutic targets.Methods:First,we utilized multiple general PTM antibodies to compare gross PTM levels between normal ovarian and OC tissues from clinical females.After identifying lactylation as the PTM with the most significant differences,we selected representative samples for label-free mass spectrometry to identify specific lactylation sites.Next,we transfected A2780(OC)cells with either wild-type(WT)or mutant(K192A[Q])poly(ADP-ribose)polymerase 1(PARP1)conjugated to enhanced green fluorescent protein(EGFP)with a StrepⅡpeptide tag and assessed various cellular indexes related to cell proliferation(clonogenicity assay),migration(scratch wound healing assay),and reactive oxygen species levels.Results:Pan-lactylation was significantly upregulated in clinical OC samples,with PARP1 lactylation at K192 being one of the most common modifications.The growth and migration of A2780 cells were markedly suppressed by overexpressing PARP1-WT but not mutant PARP1.Overexpressing PARP1 significantly downregulated the phosphorylation of extracellular signal-regulated kinases 1/2(ERK1/2).Conclusion:This study uncovered a novel PTM of PARP1 in OC,lactylation,and demonstrated that lactylation at K192 is crucial in regulating OC cell growth and migration via the ERK1/2 pathway.Further investigations are required to elucidate the broader functional implications of PARP1 lactylation and its therapeutic potential.展开更多
Premature ovarian insufficiency(POI)is characterized by irreversible loss of ovarian function before 40 years of age and affects 3.7%of women worldwide(Golezar et al.,2019;Huang et al.,2021).Raised serum follicle-stim...Premature ovarian insufficiency(POI)is characterized by irreversible loss of ovarian function before 40 years of age and affects 3.7%of women worldwide(Golezar et al.,2019;Huang et al.,2021).Raised serum follicle-stimulating hormone(FSH)levels,menstrual disturbance,and estrogen deficiency are the main symptoms of POl(European Society for Human Reproduction et al.,2016).Besides infertility,patients have an increased risk of long-term complications due to the early deficiency of ovarian steroids,such as osteoporosis,cardiovascular disease,and metabolic disorders(lshizuka,2021).Due to the lack of biomarkers for prediction or early diagnosis,most patients are not diagnosed until the failure stage(serum levels of FSH above 25 IU/L and amenorrhea),missing opportunities for intervention.Therefore,developing sensitive biomarkers for diminished ovarian reserves is paramount for timely treatment to improve reproductive outcomes and prevent long-term complications.展开更多
Dear Editor,Inguinal hernia repair(IHR)performed during childhood is a prevalent etiological factor for obstructive azoospermia(OA)attributed to vasal injury.OA couples can achieve pregnancy through intracytoplasmic s...Dear Editor,Inguinal hernia repair(IHR)performed during childhood is a prevalent etiological factor for obstructive azoospermia(OA)attributed to vasal injury.OA couples can achieve pregnancy through intracytoplasmic sperm injection or natural pregnancy after microsurgical anastomosis.Recent advancements have highlighted the potential utility of laparoscopy-assisted vasovasostomy for treating OA caused by childhood herniorrhaphy.展开更多
Circular RNAs(circRNAs)are key regulators of reproductive biology.However,limited information is available regarding circRNA expression profiles in seminal plasma samples from individuals with male infertility.The pre...Circular RNAs(circRNAs)are key regulators of reproductive biology.However,limited information is available regarding circRNA expression profiles in seminal plasma samples from individuals with male infertility.The present study aimed to identify circRNAs associated with infertility in seminal plasma samples and to clarify their potential as biomarkers,as well as the possible molecular mechanisms underlying their functions.Nextgeneration RNA sequencing was conducted to analyze circRNA profiles in seminal plasma from healthy controls,oligoasthenospermia(OAZ)patients,and non-obstructive azoospermia(NOA)patients.Bioinformatics analysis revealed that 637 circRNAs were differentially expressed between OAZ and control subjects,and 272 circRNAs were differentially expressed between NOA and control subjects.The expression of key circRNAs(hsa-SAP130_0002,hsa-TRPC1_0001,hsa-FBRS_0001,hsa-ACACA_0025,hsa-UTRN_0042,and hsa-ZNF532_0023)was then validated by qPCR,and their diagnostic accuracy for infertility was confirmed through receiver operating characteristic curve analysis.Additionally,a possible circRNA-miRNA-mRNA regulatory network was constructed for these candidate biomarkers.Collectively,this study identifies a novel set of circRNAs with potential as diagnostic biomarkers for male infertility and provides molecular insights that may facilitate both diagnostic and therapeutic efforts.展开更多
Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal ves...Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal vesicle oocytes.In the current study,we found that nuclear speckles(NSs),a subnuclear structure mainly composed of serine-arginine(SR)proteins,changed from a diffuse spotted distribution in mouse NSN oocytes to an aggregated pattern in SN oocytes.We also found that the SR protein-specific kinase 1(SRPK1),an enzyme that phosphorylates SR proteins,co-localized with NSs at the SN stage,and that NSN oocytes failed to transition to SN oocytes after the inhibition of SRPK1 activity.Furthermore,the typical structure of the chromatin ring around the nucleolus in SN oocytes collapsed after treatment with an SRPK1 inhibitor.Mechanistically,phosphorylated SR proteins were found to be related to chromatin as shown by a salt extraction experiment,and in situ DNaseⅠassay showed that the accessibility of chromatin was enhanced in SN oocytes when SRPK1 was inhibited,accompanied by a decreased repressive modification on histone and the abnormal recurrence of a transcriptional signal.In conclusion,our results indicated that SRPK1-regulated phosphorylation of SR proteins was involved in the NSN-SN transition and played an important role in maintaining the condensed nucleus of SN oocytes via interacting with chromatin.展开更多
Primordial germ cells(PGCs),the precursors of oocytes and spermatozoa,are highly pluripotent.In recent years,the in vitro induction of human primordial germ cell-like cells(h PGCLCs)has advanced significantly.However,...Primordial germ cells(PGCs),the precursors of oocytes and spermatozoa,are highly pluripotent.In recent years,the in vitro induction of human primordial germ cell-like cells(h PGCLCs)has advanced significantly.However,the stability and efficacy of obtaining h PGCLCs in vitro still require improvement.In the current study,we identified a novel induction system using Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12(DMEM/F-12)as the basal medium,supplemented with B27 and N2(referred to as N2B27)in combination with four cytokines:bone morphogenetic protein 4,stem cell factor,epidermal growth factor,and leukemia inhibitory factor.The h PGCLCs induced under these conditions closely resembled PGCs from 4-to 5-week-old embryos at the transcriptomic level.Compared with traditional GK15(GMEM supplemented with 15%Knockout?Serum Replacement)-based induction conditions,the N2B27 system significantly increased the speed and efficacy of h PGCLC induction.RNA sequencing analysis revealed that this improvement was due to an increased cellular capacity to cope with hypoxic stress and avoid apoptosis.The N2B27 medium promoted enhanced mitochondrial activity,enabling cells to better manage hypoxic stress while reducing the production of reactive oxygen species.Moreover,through gradient concentration experiments,we demonstrated that the addition of the common antioxidant N-acetyl-L-cysteine at an optimized concentration further enhanced the efficiency of PGCLC induction under GK15 conditions.In summary,we have established an optimized induction system that enhances the efficiency of h PGCLC differentiation by improving cellular resilience to hypoxic stress and apoptosis.展开更多
Autism spectrum disorder(ASD)is a neurodevelopmental disorder where de novo mutations play a significant role.Although coding mutations in ASD have been extensively characterized,the impact of non-coding de novo mutat...Autism spectrum disorder(ASD)is a neurodevelopmental disorder where de novo mutations play a significant role.Although coding mutations in ASD have been extensively characterized,the impact of non-coding de novo mutations(ncDNMs)remains less understood.Here,we integrate cortex cell-specific cis-regulatory element annotations,a deep learning-based variant prediction model,and massively parallel reporter assays to systematically evaluate the functional impact of 227,878 ncDNMs from Simons Simplex Collection(SSC)and Autism Speaks MSSNG resource(MSSNG)cohorts.Our analysis identifies 238 ncDNMs with confirmed functional regulatory effects,including 137 down-regulated regulatory mutations(DrMuts)and 101 up-regulated regulatory mutations(UrMuts).Subsequent association analyses reveal that only DrMuts regulating loss-of-function(LoF)intolerant genes rather than other ncDNMs are significantly associated with the risk of ASD(Odds ratio=4.34;P=0.001).A total of 42 potential ASD-risk DrMuts across 41 candidate ASD-susceptibility genes are identified,including 12 recognized and 29 unreported genes.Interestingly,these noncoding disruptive mutations tend to be observed in genes extremely intolerant to LoF mutations.Our study introduces an optimized approach for elucidating the functional roles of ncDNMs,thereby expanding the spectrum of pathogenic variants and deepening our understanding of the complex molecular mechanisms underlying ASD.展开更多
The effect of prenatal exposure to ambient particulate matter(PM)on birth weight varies considerably across studies,and the findings remain inconclusive.In this study,we conducted a meta-analysis to assess the associa...The effect of prenatal exposure to ambient particulate matter(PM)on birth weight varies considerably across studies,and the findings remain inconclusive.In this study,we conducted a meta-analysis to assess the associations between exposure to PM_(2.5) and PM10 and birth weight.A total of 74 studies were identified through searches in Web of Science,PubMed,Embase,and Ovid Medline,as well as manual searches,up to October 2024.We found that for each 10μg/m^(3) increase in PM_(2.5),the risk of low birth weight(LBW)increased significantly during the entire pregnancy(odds ratio[OR]=2.41,95%confidence interval[CI]:1.99–2.91)and in all trimesters.Similarly,for every 10μg/m^(3) increase in PM10 concentration,the risk of LBW increased significantly during the entire pregnancy(OR=1.46,95%CI:1.16–1.84).Subgroup analysis by maternal age for PM_(2.5) showed that mothers aged 30 and above had a significantly higher risk of LBW(OR=3.69,95%CI:2.81–4.84),compared with those under 30.In conclusion,maternal exposure to PM_(2.5) and PM_(10) is associated with an increased risk of LBW across all trimesters.Additionally,mothers aged 30 and above are at a higher risk of LBW,compared with younger mothers.Further research is needed to clarify the biological mechanisms by which PM pollution may contribute to LBW.展开更多
Background:The life-course management of children with tetralogy of Fallot(TOF)has focused on demonstrating brain structural alterations,developmental trajectories,and cognition-related changes that unfold over time.M...Background:The life-course management of children with tetralogy of Fallot(TOF)has focused on demonstrating brain structural alterations,developmental trajectories,and cognition-related changes that unfold over time.Methods:We introduce an magnetic resonance imaging(MRI)dataset comprising TOF children who underwent brain MRI scanning and cross-sectional neurocognitive follow-up.The dataset includes brain three-dimensional T1-weighted imaging(3D-T1WI),three-dimensional T2-weighted imaging(3D-T2WI),and neurodevelopmental evaluations using the Wechsler Preschool and Primary Scale of Intelligence–Fourth Edition(WPPSI-IV).Results:Thirty-one children with TOF(age range:4–33 months;18 males)were recruited and completed corrective surgery at the Children’s Hospital of Nanjing Medical University,Nanjing,China.Aiming to promote the neurodevelopmental outcomes in children with TOF,we have meticulously curated a comprehensive dataset designed to dissect the complex interplay among risk factors,neuroimaging findings,and adverse neurodevelopmental outcomes.Conclusion:This article aims to introduce our open-source dataset on neurodevelopment in children with TOF,which covers the data types,data acquisition and processing methods,the procedure for accessing the data,and related publications.展开更多
Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with ...Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with chronic comorbidities.Diabetes mellitus is one of high-risk factors for severe outcome of coronavirus disease 2019(COVID-19).Establishment of animal models that parallel the clinical and pathological features of COVID-19 complicated with diabetes is thus highly essential.Here,in this study,we constructed leptin receptor gene knockout hamsters with the phenotype of diabetes mellitus(db/db),and revealed that the diabetic hamsters were more susceptible to SARS-CoV-2 and its variants than wild-type hamsters.SARS-CoV-2 and its variants induced a stronger immune cytokine response in the lungs of diabetic hamsters than in wild-type hamsters.Comparative histopathology analyses also showed that infection of SARS-CoV-2 and the variants caused more severe lung tissue injury in diabetic hamsters,and may induce serious complications such as diabetic kidney disease and cardiac lesions.Our findings demonstrated that despite the decreased respiratory pathogenicity,the SARS-CoV-2 variants were still capable of impairing other organs such as kidney and heart in diabetic hamsters,suggesting that the risk of evolving SARS-CoV-2 variants to diabetic patients should never be neglected.This hamster model may help better understand the pathogenesis mechanism of severe COVID-19 in patients with diabetes.It will also aid in development and testing of effective therapeutics and prophylactic treatments against SARS-CoV-2 variants among these high-risk populations.展开更多
Prenatal maternal psychological distress,particularly depression,has been increasingly recognized as a factor that influences fetal growth;however,its impact on early childhood development remains less well understood...Prenatal maternal psychological distress,particularly depression,has been increasingly recognized as a factor that influences fetal growth;however,its impact on early childhood development remains less well understood.The present study investigated the association between prenatal depression and children's growth trajectories,as well as the odds of overweight and obesity from 1 to 36 months,while also accounting for maternal anxiety and stress.We analyzed data from 4710 mother-child dyads in the Jiangsu Birth Cohort,assessing maternal psychological distress across trimesters and categorizing participants into groups with mild,moderate,and severe depressive symptomatology.Children's weight-for-length z-scores(WLZ)were used to assess overweight/obesity prevalence,and growth patterns were identified through trajectory models.The results from the generalized estimating equations analysis showed that greater depressive symptomatology during pregnancy was associated with a 28%to 41%increase in the odds of childhood overweight/obesity across all three trimesters,compared with mild depressive symptomatology.We identified five distinct WLZ growth trajectory patterns,and found that mothers with greater depressive symptomatology were 39%–47%more likely to have children who followed a very-high-stable growth trajectory,compared with mothers with mild depressive symptomatology.These findings highlight the significant impact of prenatal depression on adverse growth patterns and childhood overweight/obesity,underscoring the need for early intervention.展开更多
Generating B cell-deficient mutant is the first step to produce human antibody repertoires in large animal models. In this study, we applied the clustered regularly interspaced short palindromic repeat （CRISPR）/CRIS...Generating B cell-deficient mutant is the first step to produce human antibody repertoires in large animal models. In this study, we applied the clustered regularly interspaced short palindromic repeat （CRISPR）/CRISPR-associated （Cas） system to target the JH region of the pig IgM heavy chain gene which is crucial for B cell development and differentiation. Transfection of IgM-targeting Cas9 plasmid in primary porcine fetal fibroblasts （PFFs） enabled inducing gene knock out （KO） in up to 53.3% of colonies analyzed, a quarter of which harbored biallelic modification, which was much higher than that of the traditional homologous recombination （HR）. With the aid of somatic cell nuclear transfer （SCNT） technology, three piglets with the biallelic lgM heavy chain gene mutation were produced. The piglets showed no antibody-producing B cells which indicated that the biallelic mutation of the lgM heavy chain gene effectively knocked out the function of the IgM and resulted in a B cell-deficient phenotype. Our study suggests that the CRISPR/Cas9 system combined with SCNT technology is an efficient genome-editing approach in pigs.展开更多
Oxysterol binding protein like 2(OSBPL2), an important regulator in cellular lipid metabolism and transport, was identified as a novel deafness-causal gene in our previous work. To resemble the phenotypic features of ...Oxysterol binding protein like 2(OSBPL2), an important regulator in cellular lipid metabolism and transport, was identified as a novel deafness-causal gene in our previous work. To resemble the phenotypic features of OSBPL2 mutation in animal models and elucidate the potential genotypephenotype associations, the OSBPL2-disrupted Bama miniature(BM) pig model was constructed using CRISPR/Cas9-mediated gene editing, somatic cell nuclear transfer(SCNT) and embryo transplantation approaches, and then subjected to phenotypic characterization of auditory function and serum lipid profiles. The OSBPL2-disrupted pigs displayed progressive hearing loss(HL) with degeneration/apoptosis of cochlea hair cells(HCs) and morphological abnormalities in HC stereocilia, as well as hypercholesterolaemia. High-fat diet(HFD) feeding aggravated the development of HL and led to more severe hypercholesterolaemia. The dual phenotypes of progressive HL and hypercholesterolaemia resembled in OSBPL2-disrupted pigs confirmed the implication of OSBPL2 mutation in nonsydromic hearing loss(NSHL) and contributed to the potential linkage between auditory dysfunction and dyslipidaemia/hypercholesterolaemia.展开更多
Biochemical or clinical changes of hyperandrogenism are important elements of polycystic ovary syndrome （PCOS）. There is currently no consensus on the definition and diagnostic criteria of hyperandrogenism in PCOS. ...Biochemical or clinical changes of hyperandrogenism are important elements of polycystic ovary syndrome （PCOS）. There is currently no consensus on the definition and diagnostic criteria of hyperandrogenism in PCOS. The aim of this study was to investigate the complex symptoms of hyperandrogenic disorders and the correlations between metabolism and hyperandrogenism in patients with PCOS from an outpatient reproductive medicine clinic in China. We conducted a case control study of 125 PCOS patients and 130 controls to evaluate differences in body mass index （BMI）, total testosterone （TT）, modified Ferriman-Gallwey hirsutism score, sex hormone binding globulin （SHBG）, homeostasis model assessment-estimated insulin resistance （HOMA-IR） and free androgen index （FAI） between PCOS patients and controls and subgroups of PCOS. The prevalence of acne and hirsutism did not differ significantly between the hyperandrogenic and non-hyperandrogenic subgroup. Patients with signs of hyper- androgenism had significantly higher BMI （P 〈 0.05）, but differences in TT, SHBG, FAI and waist/hip ratio were insignificant. The odds ratio of overweight was calculated for all PCOS patients. Our results suggest that PCOS patients with high BMI tend to have functional disorders of androgen excess; therefore, BMI may be a strong pre-dictor of hyperandrogenism in PCOS.展开更多
The International Agency for Research on Cancer and the World Health Organization have designated airborne particulates, including particulates of median aerodynamic diameter 〈 2.5 gm （PM2.5）, as Group 1 carcinogen...The International Agency for Research on Cancer and the World Health Organization have designated airborne particulates, including particulates of median aerodynamic diameter 〈 2.5 gm （PM2.5）, as Group 1 carcinogens. It has not been determined, however, whether exposure to ambient PM2.5 is associated with an increase in respiratory related diseases. This meta-analysis assessed the association between exposure to ambient fine particulate matter （PM2.5） and the risk of respiratory tract diseases, using relevant articles extracted from PubMed, Web of Science, and Embase. In results, of the 1,126 articles originally identified, 35 （3.1%） were included in this meta-analysis. PM2.5 was found to be associated with respiratory tract diseases. After subdivision by age group, respiratory tract disease, and continent, PM2.5 was strongly associated with respiratory tract diseases in children, in persons with cough, lower respiratory illness, and wheezing, and in individuals from North America, Europe, and Asia. The risk of respiratory tract diseases was greater for exposure to traffic-related than non-traffic-related air pollution. In children, the pooled relative risk （RR） represented significant increases in wheezing （8.2%）, cough （7.5%）, and lower respiratory illness （15.3%）. The pooled RRs in children were 1.091 （95%CI： 1.049, 1.135） for exposure to 〈 25 gg/m3 PM2.5, and 1.126 （95%CI： 1.067, l. 190） for exposure to 〉 25 gg/m3 PM2.5. In conclusion, exposure to ambient PM2.5 was significantly associated with the development of respiratory tract diseases, especially in children exposed to high concentrations of PM2.5.展开更多
Di-n-butyl phthalate （DBP） is an endocrine-disrupting chemical that has the potential to affect male reproduction. However, the reproductive effects of low-dose DBP are still not well known, especially at the molecu...Di-n-butyl phthalate （DBP） is an endocrine-disrupting chemical that has the potential to affect male reproduction. However, the reproductive effects of low-dose DBP are still not well known, especially at the molecular level. In the present study, pubertal male Sprague-Dawley rats were orally administered DBP at a wide range of doses （0.1, 1.0, 10, 100 and 500 mg kg^-1 day^-1） for 30 days. The selected end points included reproductive organ weights, testicular histopathology and serum hormonal levels. Additionally, proteomic analysis was performed to identify proteins that are differentially expressed as a result of exposure to DBP at low doses （0.1, 1.0 and 10 mg kg^-1 day^-1）. Toxic effects were observed in the high-dose groups, including anomalous development of testes and epididymides, severe atrophy of seminiferous tubules, loss of spermatogenesis and abnormal levels of serum hormones. Treatment with low doses of DBP seemed to exert a ＇stimulative effect＇ on the serum hormones. Proteomics analysis of rat testes showed 20 differentially expressed proteins. Among these proteins, alterations in the expression of HnRNPA2/B1, vimentin and superoxide dismutase 1 （SOD1） were further confirmed by Western blot and immunohistochemistry. Taken together, we conclude that high doses of DBP led to testicular toxicity, and low doses of DBP led to changes in the expression of proteins involved in spermatogenesis as well as changes in the number and function of Sertoli and Leydig cells, although no obvious morphological changes appeared. The identification of these differentially expressed proteins provides important information about the mechanisms underlying the effects of DBP on male rat reproduction.展开更多
基金supported by the National Natural Science Foundation of China(82271671)Nanjing Drum Tower Hospital Academic Innovation Peak Fund(2024-DF-02)+4 种基金Clinical Trials from Nanjing Drum Tower Hospital(2023-LCYJ-MS-05)Nanjing International Science and Technology Cooperation Program(202201027)to L.D.Research Project of State Key Laboratory of Reproductive Medicine and Offspring Health(SKLRM-2022D2)Changzhou Medical Center of Nanjing Medical University(CMCM202203)Clinical Trials from Nanjing Drum Tower Hospital(2022-LCYJ-ZD-02)to H.S.
文摘Ovarian aging is characterized by a progressive decline in oocyte quality and quantity with age.Icariin(ICA),a flavonoid compound derived from Epimedium species,has demonstrated potential as an agent for ovarian restoration.In this study,a subcutaneous implantation system using gelatin methacryloyl(GelMA)hydrogel embedded with ICA was developed to restore ovarian function in aged female mice.Mice were assigned to receive subcutaneous implantation of GelMA alone(GelMA group),GelMA containing ICA(GelMA/ICA group),or a sham operation.Ovarian morphology,serum hormone levels,follicle counts across developmental stages,and reproductive outcomes were evaluated.In vitro fertilization(IVF)and embryo culture assays were performed to assess oocyte developmental potential,while a 10 day natural mating trial was conducted to determine fertility restoration.RNA sequencing(RNA-seq)and RT-qPCR were performed to elucidate the underlying molecular mechanisms.Results showed that GelMA/ICA treatment significantly increased ovarian index(0.19±0.01 vs.0.13±0.01,P<0.0001)and follicle numbers at all developmental stages,including primordial(383.33±151.65 vs.107.14±32.26,P<0.0001),primary(203.33±83.22 vs.91.43±27.04,P=0.003),and secondary follicles(154.17±52.00 vs.59.28±20.50,P=0.029)compared to the sham controls.Hormonal analyses revealed a significant reduction in serum follicle-stimulating hormone(FSH,11.97±3.53 vs.53.10±17.89 ng/mL,P=0.0008),accompanied by elevated anti-Müllerian hormone(AMH,22.97±2.26 vs.5.54±1.56 ng/mL,P<0.0001)and estradiol(E2,315.30±37.62 vs.168.5±14.78 pg/mL,P<0.0001).Oocyte yield and developmental potential improved significantly,as reflected by the increased number of superovulated MII oocytes(17.83±5.15 vs.4.83±4.79,P=0.0002),and higher proportions of two-cell(85.90%±6.16%vs.50.00%±10.00%,P=0.0009),four-cell(81.67%±9.76%vs.50.00%±10.00%,P=0.0061),and blastocyst stage embryos(64.25%±10.55%vs.23.33%±15.28%,P=0.0067).Live birth numbers were significantly increased following GelMA/ICA treatment(6.90±3.21 vs.1.72±2.05,P=0.0001).Transcriptomic analysis revealed up-regulation of genes associated with cytoskeletal organization(Vil1,Tubb3),lipid storage(Soat2,Plin4),oocyte maturation(Oosp2),and cytokine secretion(Cxcl12).Collectively,these findings suggest that GelMA/ICA hydrogels effectively reverse key hallmarks of ovarian aging and restore reproductive function in aged mice,offering a promising platform for fertility preservation and a novel therapeutic for future investigations into ovarian aging.
基金support from various sources,including the National Natural Science Foundation of China(Grant Nos.81570774,82070872,92049118,and 82370854)the Junior Thousand Talents Program of China,and the Nanjing Medical University Startup Fund(All awarded to J.L.)support provided by Jiangsu Province's Innovation Personal as well as Innovative and Entrepreneurial Team of Jiangsu Province(Grant No.JSSCTD2021)(All awarded to J.L.).
文摘V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.
文摘Objective:To test the diagnostic performance of percent free prostate-specific antigen(%fPSA)in predicting any prostate cancer(PCa)and high-grade prostate cancer(HGPCa)in a retrospective multi-center biopsy cohort with a PSA level of 4.0e10.0 ng/mL in China.Methods:Consecutive patients with a PSA of 4.0-10.0 ng/mL who underwent transrectal ultrasound-guided biopsy were enrolled at 16 Chinese medical centers from January 1st,2010 to December 31st,2013.Total and free serum PSA determinations were performed using three types of electro-chemiluminescence immunoassays recalibrated to the World Health Organization(WHO)standard.The diagnostic accuracy of PSA,%fPSA,and %fPSA in combination with PSA(%fPSA t PSA)was determined using the area under the receiver operating characteristic(ROC)curve(AUC).Results:A total of 2310 consecutive men with PSA levels between 4.0 and 10.0 ng/mL were included,and the detection rate of PCa was 25.1%.The AUC of%fPSA and %fPSA t PSA in predicting any PCa was superior to PSA alone in men aged≥60 years(0.623 vs.0.534,p<0.0001)but not in men aged 40e59 years(0.517 vs.0.518,p=0.939).Similar result was yield in predicting HGPCa.Conclusion:In a clinical setting of Chinese men with 4.0e10.0 ng/mL PSA undergoing initial prostate biopsy,adding %fPSA to PSA can moderately improve the diagnostic accuracy for any PCa and HGPCa compared with PSA alone in patients≥60 but not in patients aged 40-59 years.
基金supported by the China Postdoctoral Science Foundation Grant(2023M734294)Jiangsu Provincial Medical Key Discipline Cultivation Unit(JSDW202215)the National Natural Science Foundation of China(No.82001618).
文摘Primary ciliary dyskinesia(PCD)is a clinically rare,genetically and phenotypically heterogeneous condition characterized by chronic respiratory tract infections,male infertility,tympanitis,and laterality abnormalities.PCD is typically resulted from variants in genes encoding assembly or structural proteins that are indispensable for the movement of motile cilia.Here,we identified a novel nonsense mutation,c.466G>T,in cilia-and flagella-associated protein 300(CFAP300)resulting in a stop codon(p.Glu156*)through whole-exome sequencing(WES).The proband had a PCD phenotype with laterality defects and immotile sperm flagella displaying a combined loss of the inner dynein arm(IDA)and outer dynein arm(ODA).Bioinformatic programs predicted that the mutation is deleterious.Successful pregnancy was achieved through intracytoplasmic sperm injection(ICSI).Our results expand the spectrum of CFAP300 variants in PCD and provide reproductive guidance for infertile couples suffering from PCD caused by them.
文摘Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.However,relatively few studies have explored the impact of post-translational modifications(PTM)on OC progression,which is essential for uncovering new therapeutic targets.This study aimed to systematically identify the key PTM types involved in OCprogression,and to explore and evaluate their translational potential as therapeutic targets.Methods:First,we utilized multiple general PTM antibodies to compare gross PTM levels between normal ovarian and OC tissues from clinical females.After identifying lactylation as the PTM with the most significant differences,we selected representative samples for label-free mass spectrometry to identify specific lactylation sites.Next,we transfected A2780(OC)cells with either wild-type(WT)or mutant(K192A[Q])poly(ADP-ribose)polymerase 1(PARP1)conjugated to enhanced green fluorescent protein(EGFP)with a StrepⅡpeptide tag and assessed various cellular indexes related to cell proliferation(clonogenicity assay),migration(scratch wound healing assay),and reactive oxygen species levels.Results:Pan-lactylation was significantly upregulated in clinical OC samples,with PARP1 lactylation at K192 being one of the most common modifications.The growth and migration of A2780 cells were markedly suppressed by overexpressing PARP1-WT but not mutant PARP1.Overexpressing PARP1 significantly downregulated the phosphorylation of extracellular signal-regulated kinases 1/2(ERK1/2).Conclusion:This study uncovered a novel PTM of PARP1 in OC,lactylation,and demonstrated that lactylation at K192 is crucial in regulating OC cell growth and migration via the ERK1/2 pathway.Further investigations are required to elucidate the broader functional implications of PARP1 lactylation and its therapeutic potential.
基金supported by the National Key Research&Developmental Program of China(2022YFC2703800,2022YFC2703000)the National Natural Science Foundation of China(82125014,82371646,32070847)+1 种基金Basic Science Center Program of NSFC(31988101)the Natural Science Foundation of Shandong Province(ZR202105250005,ZR2022YQ69,tsqn202211371).
文摘Premature ovarian insufficiency(POI)is characterized by irreversible loss of ovarian function before 40 years of age and affects 3.7%of women worldwide(Golezar et al.,2019;Huang et al.,2021).Raised serum follicle-stimulating hormone(FSH)levels,menstrual disturbance,and estrogen deficiency are the main symptoms of POl(European Society for Human Reproduction et al.,2016).Besides infertility,patients have an increased risk of long-term complications due to the early deficiency of ovarian steroids,such as osteoporosis,cardiovascular disease,and metabolic disorders(lshizuka,2021).Due to the lack of biomarkers for prediction or early diagnosis,most patients are not diagnosed until the failure stage(serum levels of FSH above 25 IU/L and amenorrhea),missing opportunities for intervention.Therefore,developing sensitive biomarkers for diminished ovarian reserves is paramount for timely treatment to improve reproductive outcomes and prevent long-term complications.
基金supported by the National Key R&D Program of China(No.2022YFC2702701)Shanghai Scientific and Technological Project(No.20Y11907600)Clinical Research Innovation Plan of Shanghai General Hospital(No.CTCCR-2021C17).
文摘Dear Editor,Inguinal hernia repair(IHR)performed during childhood is a prevalent etiological factor for obstructive azoospermia(OA)attributed to vasal injury.OA couples can achieve pregnancy through intracytoplasmic sperm injection or natural pregnancy after microsurgical anastomosis.Recent advancements have highlighted the potential utility of laparoscopy-assisted vasovasostomy for treating OA caused by childhood herniorrhaphy.
基金funded by the National Key R&D Program of China(Grant No.2022YFC2702800 to Y.C.)the National Natural Science Foundation of China(Grant No.82122025 to Y.Y.)the National Key R&D Program of China(Grant No.2021YFC2700200 to Y.C.).
文摘Circular RNAs(circRNAs)are key regulators of reproductive biology.However,limited information is available regarding circRNA expression profiles in seminal plasma samples from individuals with male infertility.The present study aimed to identify circRNAs associated with infertility in seminal plasma samples and to clarify their potential as biomarkers,as well as the possible molecular mechanisms underlying their functions.Nextgeneration RNA sequencing was conducted to analyze circRNA profiles in seminal plasma from healthy controls,oligoasthenospermia(OAZ)patients,and non-obstructive azoospermia(NOA)patients.Bioinformatics analysis revealed that 637 circRNAs were differentially expressed between OAZ and control subjects,and 272 circRNAs were differentially expressed between NOA and control subjects.The expression of key circRNAs(hsa-SAP130_0002,hsa-TRPC1_0001,hsa-FBRS_0001,hsa-ACACA_0025,hsa-UTRN_0042,and hsa-ZNF532_0023)was then validated by qPCR,and their diagnostic accuracy for infertility was confirmed through receiver operating characteristic curve analysis.Additionally,a possible circRNA-miRNA-mRNA regulatory network was constructed for these candidate biomarkers.Collectively,this study identifies a novel set of circRNAs with potential as diagnostic biomarkers for male infertility and provides molecular insights that may facilitate both diagnostic and therapeutic efforts.
基金National Natural Science Foundation of China(Grant Nos.32070838 and 82301874)Open Fund of State Key Laboratory of Reproductive Medicine,Nanjing Medical University(Grant No.SKLRM K202102)。
文摘Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal vesicle oocytes.In the current study,we found that nuclear speckles(NSs),a subnuclear structure mainly composed of serine-arginine(SR)proteins,changed from a diffuse spotted distribution in mouse NSN oocytes to an aggregated pattern in SN oocytes.We also found that the SR protein-specific kinase 1(SRPK1),an enzyme that phosphorylates SR proteins,co-localized with NSs at the SN stage,and that NSN oocytes failed to transition to SN oocytes after the inhibition of SRPK1 activity.Furthermore,the typical structure of the chromatin ring around the nucleolus in SN oocytes collapsed after treatment with an SRPK1 inhibitor.Mechanistically,phosphorylated SR proteins were found to be related to chromatin as shown by a salt extraction experiment,and in situ DNaseⅠassay showed that the accessibility of chromatin was enhanced in SN oocytes when SRPK1 was inhibited,accompanied by a decreased repressive modification on histone and the abnormal recurrence of a transcriptional signal.In conclusion,our results indicated that SRPK1-regulated phosphorylation of SR proteins was involved in the NSN-SN transition and played an important role in maintaining the condensed nucleus of SN oocytes via interacting with chromatin.
基金funded by the National Key R&D Program(Grant Nos.2022YFC2702800 and 2021YFC2700302 to Y.Y.)the National Natural Science Foundation of China(Grant Nos.82122025 to Y.Y.,82221005 to J.S.,and 82201763 to L.L.)。
文摘Primordial germ cells(PGCs),the precursors of oocytes and spermatozoa,are highly pluripotent.In recent years,the in vitro induction of human primordial germ cell-like cells(h PGCLCs)has advanced significantly.However,the stability and efficacy of obtaining h PGCLCs in vitro still require improvement.In the current study,we identified a novel induction system using Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12(DMEM/F-12)as the basal medium,supplemented with B27 and N2(referred to as N2B27)in combination with four cytokines:bone morphogenetic protein 4,stem cell factor,epidermal growth factor,and leukemia inhibitory factor.The h PGCLCs induced under these conditions closely resembled PGCs from 4-to 5-week-old embryos at the transcriptomic level.Compared with traditional GK15(GMEM supplemented with 15%Knockout?Serum Replacement)-based induction conditions,the N2B27 system significantly increased the speed and efficacy of h PGCLC induction.RNA sequencing analysis revealed that this improvement was due to an increased cellular capacity to cope with hypoxic stress and avoid apoptosis.The N2B27 medium promoted enhanced mitochondrial activity,enabling cells to better manage hypoxic stress while reducing the production of reactive oxygen species.Moreover,through gradient concentration experiments,we demonstrated that the addition of the common antioxidant N-acetyl-L-cysteine at an optimized concentration further enhanced the efficiency of PGCLC induction under GK15 conditions.In summary,we have established an optimized induction system that enhances the efficiency of h PGCLC differentiation by improving cellular resilience to hypoxic stress and apoptosis.
基金supported by the National Natural Science of China(82322032 and 82221005)the Outstanding Youth Foundation of Jiangsu Province(BK20220050)+4 种基金the National Key Research&Development(R&D)Program of China(2024YFC2706800 and 2021YFC2700600)the Major Project of Changzhou Medical Center(CZKY1040101)the Major Project of Taizhou Clinical Medical College(TZKY20240003)the Major Program of Gusu School(GSKY20210102)the China Postdoctoral Science Foundation(2024M760296).
文摘Autism spectrum disorder(ASD)is a neurodevelopmental disorder where de novo mutations play a significant role.Although coding mutations in ASD have been extensively characterized,the impact of non-coding de novo mutations(ncDNMs)remains less understood.Here,we integrate cortex cell-specific cis-regulatory element annotations,a deep learning-based variant prediction model,and massively parallel reporter assays to systematically evaluate the functional impact of 227,878 ncDNMs from Simons Simplex Collection(SSC)and Autism Speaks MSSNG resource(MSSNG)cohorts.Our analysis identifies 238 ncDNMs with confirmed functional regulatory effects,including 137 down-regulated regulatory mutations(DrMuts)and 101 up-regulated regulatory mutations(UrMuts).Subsequent association analyses reveal that only DrMuts regulating loss-of-function(LoF)intolerant genes rather than other ncDNMs are significantly associated with the risk of ASD(Odds ratio=4.34;P=0.001).A total of 42 potential ASD-risk DrMuts across 41 candidate ASD-susceptibility genes are identified,including 12 recognized and 29 unreported genes.Interestingly,these noncoding disruptive mutations tend to be observed in genes extremely intolerant to LoF mutations.Our study introduces an optimized approach for elucidating the functional roles of ncDNMs,thereby expanding the spectrum of pathogenic variants and deepening our understanding of the complex molecular mechanisms underlying ASD.
文摘The effect of prenatal exposure to ambient particulate matter(PM)on birth weight varies considerably across studies,and the findings remain inconclusive.In this study,we conducted a meta-analysis to assess the associations between exposure to PM_(2.5) and PM10 and birth weight.A total of 74 studies were identified through searches in Web of Science,PubMed,Embase,and Ovid Medline,as well as manual searches,up to October 2024.We found that for each 10μg/m^(3) increase in PM_(2.5),the risk of low birth weight(LBW)increased significantly during the entire pregnancy(odds ratio[OR]=2.41,95%confidence interval[CI]:1.99–2.91)and in all trimesters.Similarly,for every 10μg/m^(3) increase in PM10 concentration,the risk of LBW increased significantly during the entire pregnancy(OR=1.46,95%CI:1.16–1.84).Subgroup analysis by maternal age for PM_(2.5) showed that mothers aged 30 and above had a significantly higher risk of LBW(OR=3.69,95%CI:2.81–4.84),compared with those under 30.In conclusion,maternal exposure to PM_(2.5) and PM_(10) is associated with an increased risk of LBW across all trimesters.Additionally,mothers aged 30 and above are at a higher risk of LBW,compared with younger mothers.Further research is needed to clarify the biological mechanisms by which PM pollution may contribute to LBW.
基金supported by the National Natural Science Foundation of China(82270310)Noncommunicable Chronic Diseases-National Science and Technology Major Project(No.2024ZD0527000 and No.2024ZD0527005)+2 种基金Jiangsu Provincial key research and development program(BE2023662)General project of Nanjing Health Commission(YKK22166).
文摘Background:The life-course management of children with tetralogy of Fallot(TOF)has focused on demonstrating brain structural alterations,developmental trajectories,and cognition-related changes that unfold over time.Methods:We introduce an magnetic resonance imaging(MRI)dataset comprising TOF children who underwent brain MRI scanning and cross-sectional neurocognitive follow-up.The dataset includes brain three-dimensional T1-weighted imaging(3D-T1WI),three-dimensional T2-weighted imaging(3D-T2WI),and neurodevelopmental evaluations using the Wechsler Preschool and Primary Scale of Intelligence–Fourth Edition(WPPSI-IV).Results:Thirty-one children with TOF(age range:4–33 months;18 males)were recruited and completed corrective surgery at the Children’s Hospital of Nanjing Medical University,Nanjing,China.Aiming to promote the neurodevelopmental outcomes in children with TOF,we have meticulously curated a comprehensive dataset designed to dissect the complex interplay among risk factors,neuroimaging findings,and adverse neurodevelopmental outcomes.Conclusion:This article aims to introduce our open-source dataset on neurodevelopment in children with TOF,which covers the data types,data acquisition and processing methods,the procedure for accessing the data,and related publications.
基金supported by the National Natural Science Foundation of Jiangsu Province(BE20197310 to J-M.L.)the National Key R&D Program of China(2021YFF0702500 to J-M.L.and A-M.S.,and the Start-up Funding of Scientific Researches for Postdoc in Guangzhou,Guangdong Province to H-F.L.).
文摘Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with chronic comorbidities.Diabetes mellitus is one of high-risk factors for severe outcome of coronavirus disease 2019(COVID-19).Establishment of animal models that parallel the clinical and pathological features of COVID-19 complicated with diabetes is thus highly essential.Here,in this study,we constructed leptin receptor gene knockout hamsters with the phenotype of diabetes mellitus(db/db),and revealed that the diabetic hamsters were more susceptible to SARS-CoV-2 and its variants than wild-type hamsters.SARS-CoV-2 and its variants induced a stronger immune cytokine response in the lungs of diabetic hamsters than in wild-type hamsters.Comparative histopathology analyses also showed that infection of SARS-CoV-2 and the variants caused more severe lung tissue injury in diabetic hamsters,and may induce serious complications such as diabetic kidney disease and cardiac lesions.Our findings demonstrated that despite the decreased respiratory pathogenicity,the SARS-CoV-2 variants were still capable of impairing other organs such as kidney and heart in diabetic hamsters,suggesting that the risk of evolving SARS-CoV-2 variants to diabetic patients should never be neglected.This hamster model may help better understand the pathogenesis mechanism of severe COVID-19 in patients with diabetes.It will also aid in development and testing of effective therapeutics and prophylactic treatments against SARS-CoV-2 variants among these high-risk populations.
基金supported by the National Natural Science Foundation of China(Grant No.82373581 to Yuan Lin).
文摘Prenatal maternal psychological distress,particularly depression,has been increasingly recognized as a factor that influences fetal growth;however,its impact on early childhood development remains less well understood.The present study investigated the association between prenatal depression and children's growth trajectories,as well as the odds of overweight and obesity from 1 to 36 months,while also accounting for maternal anxiety and stress.We analyzed data from 4710 mother-child dyads in the Jiangsu Birth Cohort,assessing maternal psychological distress across trimesters and categorizing participants into groups with mild,moderate,and severe depressive symptomatology.Children's weight-for-length z-scores(WLZ)were used to assess overweight/obesity prevalence,and growth patterns were identified through trajectory models.The results from the generalized estimating equations analysis showed that greater depressive symptomatology during pregnancy was associated with a 28%to 41%increase in the odds of childhood overweight/obesity across all three trimesters,compared with mild depressive symptomatology.We identified five distinct WLZ growth trajectory patterns,and found that mothers with greater depressive symptomatology were 39%–47%more likely to have children who followed a very-high-stable growth trajectory,compared with mothers with mild depressive symptomatology.These findings highlight the significant impact of prenatal depression on adverse growth patterns and childhood overweight/obesity,underscoring the need for early intervention.
基金supported by a grant from the Jiangsu Key Laboratory of Xenotransplantation (BM2012116)
文摘Generating B cell-deficient mutant is the first step to produce human antibody repertoires in large animal models. In this study, we applied the clustered regularly interspaced short palindromic repeat （CRISPR）/CRISPR-associated （Cas） system to target the JH region of the pig IgM heavy chain gene which is crucial for B cell development and differentiation. Transfection of IgM-targeting Cas9 plasmid in primary porcine fetal fibroblasts （PFFs） enabled inducing gene knock out （KO） in up to 53.3% of colonies analyzed, a quarter of which harbored biallelic modification, which was much higher than that of the traditional homologous recombination （HR）. With the aid of somatic cell nuclear transfer （SCNT） technology, three piglets with the biallelic lgM heavy chain gene mutation were produced. The piglets showed no antibody-producing B cells which indicated that the biallelic mutation of the lgM heavy chain gene effectively knocked out the function of the IgM and resulted in a B cell-deficient phenotype. Our study suggests that the CRISPR/Cas9 system combined with SCNT technology is an efficient genome-editing approach in pigs.
基金supported by grants from the National Natural Science Foundation of China (81771000 and 31571302)the Key Research and Development Program of Jiangsu Province (Social Development: BE2016762)+2 种基金the Key Project of Science and Technology Innovation of Nanjing Medical University (2017NJMUCX001)grants from the China Postdoctoral Science Foundation (2016M600431)the Jiangsu Planned Projects for Postdoctoral Research Funds (1601071B)
文摘Oxysterol binding protein like 2(OSBPL2), an important regulator in cellular lipid metabolism and transport, was identified as a novel deafness-causal gene in our previous work. To resemble the phenotypic features of OSBPL2 mutation in animal models and elucidate the potential genotypephenotype associations, the OSBPL2-disrupted Bama miniature(BM) pig model was constructed using CRISPR/Cas9-mediated gene editing, somatic cell nuclear transfer(SCNT) and embryo transplantation approaches, and then subjected to phenotypic characterization of auditory function and serum lipid profiles. The OSBPL2-disrupted pigs displayed progressive hearing loss(HL) with degeneration/apoptosis of cochlea hair cells(HCs) and morphological abnormalities in HC stereocilia, as well as hypercholesterolaemia. High-fat diet(HFD) feeding aggravated the development of HL and led to more severe hypercholesterolaemia. The dual phenotypes of progressive HL and hypercholesterolaemia resembled in OSBPL2-disrupted pigs confirmed the implication of OSBPL2 mutation in nonsydromic hearing loss(NSHL) and contributed to the potential linkage between auditory dysfunction and dyslipidaemia/hypercholesterolaemia.
基金supported by grants from the Major State Basic Research Development Program of China(973 Program:No.2012CB944902 and No.2012CB944703)the National Natural Science Foundation of China(No.30801236)the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘Biochemical or clinical changes of hyperandrogenism are important elements of polycystic ovary syndrome （PCOS）. There is currently no consensus on the definition and diagnostic criteria of hyperandrogenism in PCOS. The aim of this study was to investigate the complex symptoms of hyperandrogenic disorders and the correlations between metabolism and hyperandrogenism in patients with PCOS from an outpatient reproductive medicine clinic in China. We conducted a case control study of 125 PCOS patients and 130 controls to evaluate differences in body mass index （BMI）, total testosterone （TT）, modified Ferriman-Gallwey hirsutism score, sex hormone binding globulin （SHBG）, homeostasis model assessment-estimated insulin resistance （HOMA-IR） and free androgen index （FAI） between PCOS patients and controls and subgroups of PCOS. The prevalence of acne and hirsutism did not differ significantly between the hyperandrogenic and non-hyperandrogenic subgroup. Patients with signs of hyper- androgenism had significantly higher BMI （P 〈 0.05）, but differences in TT, SHBG, FAI and waist/hip ratio were insignificant. The odds ratio of overweight was calculated for all PCOS patients. Our results suggest that PCOS patients with high BMI tend to have functional disorders of androgen excess; therefore, BMI may be a strong pre-dictor of hyperandrogenism in PCOS.
基金supported by the National Natural Science Foundation of China(Grant No.81473013 and No.81673210)Jiangsu Province Blue Project of UniversityInnovation of Graduate Student Training Project in Jiangsu Province(KYLX15_0976)
文摘The International Agency for Research on Cancer and the World Health Organization have designated airborne particulates, including particulates of median aerodynamic diameter 〈 2.5 gm （PM2.5）, as Group 1 carcinogens. It has not been determined, however, whether exposure to ambient PM2.5 is associated with an increase in respiratory related diseases. This meta-analysis assessed the association between exposure to ambient fine particulate matter （PM2.5） and the risk of respiratory tract diseases, using relevant articles extracted from PubMed, Web of Science, and Embase. In results, of the 1,126 articles originally identified, 35 （3.1%） were included in this meta-analysis. PM2.5 was found to be associated with respiratory tract diseases. After subdivision by age group, respiratory tract disease, and continent, PM2.5 was strongly associated with respiratory tract diseases in children, in persons with cough, lower respiratory illness, and wheezing, and in individuals from North America, Europe, and Asia. The risk of respiratory tract diseases was greater for exposure to traffic-related than non-traffic-related air pollution. In children, the pooled relative risk （RR） represented significant increases in wheezing （8.2%）, cough （7.5%）, and lower respiratory illness （15.3%）. The pooled RRs in children were 1.091 （95%CI： 1.049, 1.135） for exposure to 〈 25 gg/m3 PM2.5, and 1.126 （95%CI： 1.067, l. 190） for exposure to 〉 25 gg/m3 PM2.5. In conclusion, exposure to ambient PM2.5 was significantly associated with the development of respiratory tract diseases, especially in children exposed to high concentrations of PM2.5.
基金ACKNOWLEDGMENTS We gratefully acknowledge the assistance of Feng Chen with the statistical analysis. The study was supported by grants from the National Basic Research Program of China （973 Program） （No. 2009CB941703）, Jiangsu Provincial Natural Science Funds （No. BK2007235） and the National Natural Science Foundation of China （No. 30901222）.
文摘Di-n-butyl phthalate （DBP） is an endocrine-disrupting chemical that has the potential to affect male reproduction. However, the reproductive effects of low-dose DBP are still not well known, especially at the molecular level. In the present study, pubertal male Sprague-Dawley rats were orally administered DBP at a wide range of doses （0.1, 1.0, 10, 100 and 500 mg kg^-1 day^-1） for 30 days. The selected end points included reproductive organ weights, testicular histopathology and serum hormonal levels. Additionally, proteomic analysis was performed to identify proteins that are differentially expressed as a result of exposure to DBP at low doses （0.1, 1.0 and 10 mg kg^-1 day^-1）. Toxic effects were observed in the high-dose groups, including anomalous development of testes and epididymides, severe atrophy of seminiferous tubules, loss of spermatogenesis and abnormal levels of serum hormones. Treatment with low doses of DBP seemed to exert a ＇stimulative effect＇ on the serum hormones. Proteomics analysis of rat testes showed 20 differentially expressed proteins. Among these proteins, alterations in the expression of HnRNPA2/B1, vimentin and superoxide dismutase 1 （SOD1） were further confirmed by Western blot and immunohistochemistry. Taken together, we conclude that high doses of DBP led to testicular toxicity, and low doses of DBP led to changes in the expression of proteins involved in spermatogenesis as well as changes in the number and function of Sertoli and Leydig cells, although no obvious morphological changes appeared. The identification of these differentially expressed proteins provides important information about the mechanisms underlying the effects of DBP on male rat reproduction.
