Dear Editor,Type1diabetes(T1D)isa lifelong(chronic)disease and a major health problem throughout the world.This disease can be treatedby either insulin injection or islet transplantation.Islet transplantation is consi...Dear Editor,Type1diabetes(T1D)isa lifelong(chronic)disease and a major health problem throughout the world.This disease can be treatedby either insulin injection or islet transplantation.Islet transplantation is considered as a better treatment for T1D patients,because islets can produce and release insulin at the appropriate time,resulting in tight blood glucose control.展开更多
The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases(NDs)such as Alzheimer’s disease,Parkinson's disease,or Amyotrophic Lateral Sclerosis.In a process known as‘seedin...The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases(NDs)such as Alzheimer’s disease,Parkinson's disease,or Amyotrophic Lateral Sclerosis.In a process known as‘seeding’,prion-like proteins such as amyloid beta,microtubule-associated protein tau,α-synuclein,silence superoxide dismutase 1,or transactive response DNA-binding protein 43 kDa,propagate their misfolded conformations by transforming their respective soluble monomers into fibrils.Cellular and molecular evidence of prion-like propagation in NDs,the clinical relevance of their‘seeding’capacities,and their levels of contribution towards disease progression have been intensively studied over recent years.This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization,endo-lysosomal leaking,aggregate degradation,and secretion.Debates on the importance of the role of prion-like protein aggregates in NDs,whether causal or consequent,are also discussed.Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.展开更多
Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the pr...Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.展开更多
The structural integrity of the sperm flagellum is essential for proper sperm function.Flagellar defects can result in male infertility,yet the precise mechanisms underlying this relationship are not fully understood....The structural integrity of the sperm flagellum is essential for proper sperm function.Flagellar defects can result in male infertility,yet the precise mechanisms underlying this relationship are not fully understood.CCDC181,a coiled-coil domain-containing protein,is known to localize on sperm flagella and at the basal regions of motile cilia.Despite this knowledge,the specific functions of CCDC181 in flagellum biogenesis remain unclear.In this study,Ccdc181 knockout mice were generated.The absence of CCDC181 led to defective sperm head shaping and flagellum formation.Furthermore,the Ccdc181 knockout mice exhibited extremely low sperm counts,grossly aberrant sperm morphologies,markedly diminished sperm motility,and typical multiple morphological abnormalities of the flagella(MMAF).Additionally,an interaction between CCDC181 and the MMAF-related protein LRRC46 was identified,with CCDC181 regulating the localization of LRRC46 within sperm flagella.These findings suggest that CCDC181 plays a crucial role in both manchette formation and sperm flagellum biogenesis.展开更多
Infertility represents a significant health concern,with sperm quantity and quality being crucial determinants of male fertility.Oligoasthenoteratozoospermia(OAT)is characterized by reduced sperm motility,lower sperm ...Infertility represents a significant health concern,with sperm quantity and quality being crucial determinants of male fertility.Oligoasthenoteratozoospermia(OAT)is characterized by reduced sperm motility,lower sperm concentration,and morphological abnormalities in sperm heads and flagella.Although variants in several genes have been implicated in OAT,its genetic etiologies and pathogenetic mechanisms remain inadequately understood.In this study,we identified a homozygous nonsense mutation(c.916C>T,p.Arg306*)in the coiled-coil domain containing 146(CCDC146)gene in an infertile male patient with OAT.This mutation resulted in the production of a truncated CCDC146 protein(amino acids 1-305),retaining only two out of five coiled-coil domains.To validate the pathogenicity of the CCDC146 mutation,we generated a mouse model(Ccdc146^(mut/mut))with a similar mutation to that of the patient.Consistently,the Ccdc146mut/mut mice exhibited infertility,characterized by significantly reduced sperm counts,diminished motility,and multiple defects in sperm heads and flagella.Furthermore,the levels of axonemal proteins,including DNAH17,DNAH1,and SPAG6,were significantly reduced in the sperm of Ccdc146^(mut/mut) mice.Additionally,both human and mouse CCDC146 interacted with intraflagellar transport protein 20(IFT20),but this interaction was lost in the mutated versions,leading to the degradation of IFT20.This study identified a novel deleterious homozygous nonsense mutation in CCDC146 that causes male infertility,potentially by disrupting axonemal protein transportation.These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.展开更多
Genetic risk factors have been shown to contribute to the development of sexual dysfunction.However,the role of methylenetetrahydrofolate reductase(MTHFR)gene variants in the risk of erectile dysfunction(ED)remains un...Genetic risk factors have been shown to contribute to the development of sexual dysfunction.However,the role of methylenetetrahydrofolate reductase(MTHFR)gene variants in the risk of erectile dysfunction(ED)remains unclear.In this study,we recruited 1254 participants who underwent ED assessed by the International Index of Erectile Function-5.The MTHFR c.677C>T variant was also measured by fluorescence polymerase chain reaction(PCR).No significant difference in the genotypic frequency of the MTHFR C677T polymorphism(CC,CT,and TT)was observed between men from the ED and non-ED groups.In addition,on binary logistic regression analysis,both crude and adjusted models showed that the risk of ED was not significantly associated with the C677T polymorphism.Interestingly,a significantly higher frequency of the 677TT polymorphism was found in severe and moderate ED(P=O.02).The positive correlation between the MTHFR 677TT polymorphism and severe ED was confirmed by logistic regression analysis,even after adjusting for potential confounders(odds ratio[OR]=2.46,95%confidence interval[CI]:1.15-5.50,P=0.02).These findings suggest a positive correlation between the MTHFR 677TT polymorphism and the risk of severe ED.Identification of MTHFR gene polymorphisms may provide complementary information for ED patients during routineclinicaldiagnosis.展开更多
Male infertility is a worldwide health issue,affecting 8%–12%of the global population.Oligoasthenoteratozoospermia(OAT)represents a severe type of male infertility,characterized by reduced sperm count and motility an...Male infertility is a worldwide health issue,affecting 8%–12%of the global population.Oligoasthenoteratozoospermia(OAT)represents a severe type of male infertility,characterized by reduced sperm count and motility and an increased frequency of sperm with aberrant morphology.Using whole-exome sequencing,this study identified a novel missense mutation(c.848C>A,p.A283E)in the coiled-coil domain-containing 34 gene(CCDC34)in a consanguineous Pakistani family.This rare mutation was predicted to be deleterious and to affect the protein stability.Hematoxylin and eosin staining of spermatozoa from the patient with OAT revealed multiple morphological abnormalities of the flagella and transmission electron microscopy indicated axonemal ultrastructural defects with a lack of outer dynein arms.These findings indicated that CCDC34 plays a role in maintaining the axonemal ultrastructure and the assembly or stability of the outer dynein arms,thus expanding the phenotypic spectrum of CCDC34 missense mutations.展开更多
Infertility is a major health issue,affecting approximately 15%of couples of child-bearing age.Although nearly half of idiopathic infertility cases are assumed to have a genetic basis,the underlying causes remain larg...Infertility is a major health issue,affecting approximately 15%of couples of child-bearing age.Although nearly half of idiopathic infertility cases are assumed to have a genetic basis,the underlying causes remain largely unknown in most infertile men.展开更多
Meiosis is an essential step in gametogenesis which is the key process in sexually reproducing organisms as meiotic aberrations may result in infertility. In meiosis, programmed DNA double-strand break (DSB) formation...Meiosis is an essential step in gametogenesis which is the key process in sexually reproducing organisms as meiotic aberrations may result in infertility. In meiosis, programmed DNA double-strand break (DSB) formation is one of the fundamental processes that are essential for maintaining homolog interactions and correcting segregation of chromosomes. Although the number and distribution of meiotic DSBs are tightly regulated, still abnormalities in DSB formation are known to cause meiotic arrest and infertility. This review is a detailed account of molecular bases of meiotic DSB formation, its evolutionary conservation, and variations in different species. We further reviewed the mutations of DSB formation genes in association with human infertility and also proposed the future directions and strategies about the study of meiotic DSB formation.展开更多
Multiple morphological abnormalities of the sperm flagella(MMAF)is a severe form of asthenozoospermia categorized by immotile spermatozoa with abnormal flagella in ejaculate.Whole-exome sequencing(WES)is used to detec...Multiple morphological abnormalities of the sperm flagella(MMAF)is a severe form of asthenozoospermia categorized by immotile spermatozoa with abnormal flagella in ejaculate.Whole-exome sequencing(WES)is used to detect pathogenic variants in patients with MMAF.In this study,a novel homozygous frameshift variant(c.6158_6159insT)in dynein axonemal heavy chain 8(DNAH8)from two infertile brothers with MMAF in a consanguineous Pakistani family was identified by WES.Reverse transcription-polymerase chain reaction(RT-PCR)confirmed DNAH8 mRNA decay in these patients with the DNAH8 mutation.Hematoxylin–eosin staining and transmission electron microscopy revealed highly divergent morphology and ultrastructure of sperm flagella in these patients.Furthermore,an immunofluorescence assay showed the absence of DNAH8 and a reduction in its associated protein DNAH17 in the patients'spermatozoa.Collectively,our study expands the phenotypic spectrum of patients with DNAH8-related MMAF worldwide.展开更多
Mutations or dysregulated expression of NF-kappaB-activating protein(NKAP)family genes have been found in human cancers.How NKAP family gene mutations promote tumor initiation and progression remains to be determined....Mutations or dysregulated expression of NF-kappaB-activating protein(NKAP)family genes have been found in human cancers.How NKAP family gene mutations promote tumor initiation and progression remains to be determined.Here,we characterized dNKAP,the Drosophila homolog of NKAP,and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model.dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics,including tissue overgrowth,cell-invasive behavior,abnormal cell polarity,and cell adhesion defects.dNKAP knockdown causes both R-loop accumulation and DNA damage,indicating the disruption of genome integrity.Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase(JNK)-dependent apoptosis and causes aberrant cell proliferation in distinct cell populations.Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues.Furthermore,JNK signaling is essential for dNKAP depletion-mediated cell invasion.Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways.dNKAP knockdown and oncogenic Ras,Notch,or Yki mutations show synergies in driving tumorigenesis,further supporting the tumor-suppressive role of dNKAP.In summary,this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.展开更多
In the Drosophila larval brain, type I and type Ⅱ neuroblasts（NBs） undergo a series of asymmetric divisions which give rise to distinct progeny lineages. The intermediate neural progenitors（INPs） exist only in ty...In the Drosophila larval brain, type I and type Ⅱ neuroblasts（NBs） undergo a series of asymmetric divisions which give rise to distinct progeny lineages. The intermediate neural progenitors（INPs） exist only in type Ⅱ NB lineages. In this study, we reveal a novel function of Inscuteable（Insc） that acts to maintain type I NB lineage identity. In insc type I NB clones of mosaic analyses with a repressible cell marker（MARCM）, the formation of extra Deadpan（Dpn）tNB-like and GMC-like cells is observed. The lack of Insc leads to the defective localization and segregation of Numb during asymmetric cell division. By the end of cytokinesis, this results in insufficient Numb in ganglion mother cells（GMCs）. The formation of extra Deadpan（Dpn）tcells in insc clones is prevented by the attenuation of Notch activity. This suggests that Insc functions through the Numb/Notch signaling pathway. We also show that in the absence of Insc in type I NB lineages, the cellular identity of GMCs is altered where they adopt an INP-like cell fate as indicated by the initiation of Dpn expression accompanied by a transient presence of Earmuff（Erm）.These INP-like cells have the capacity to divide multiple times. We conclude that Insc is necessary for the maintenance of type I NB lineage identity. Genetic manipulations to eliminate most type I NBs with overproliferating type Ⅱ NBs in the larval brain lead to altered circadian rhythms and defective phototaxis in adult flies. This indicates that the homeogenesis of NB lineages is important for the adult＇s brain function.展开更多
Flow cytometry is now a recognized methodology within animal spermatology, and has moved from being a research tool to become routine in the assessment of animal semen destined to breeding. The availability of ＇bench...Flow cytometry is now a recognized methodology within animal spermatology, and has moved from being a research tool to become routine in the assessment of animal semen destined to breeding. The availability of ＇bench-top＇ flow cytometers and of newer and versatile markers for cell structure and function had allowed the instrumentation to measure more sperm parameters, from viability to reactiveness when exposed to exogenous stimuli, and to increase our capabilities to sort spermatozoa for potential fertilizing capacity, or chromosomal sex. The present review summarizes the state of the art regarding flow cytometry applied to animal andrology, albeit keeping an open comparative intent. It critically evaluates the present and future capabilities of flow cytometry for the diagnostics of potential fertility and for the development of current reproductive technologies such as sperm freezing, sperm selection and sperm sorting. The flow cytometry methods will probably further revolutionize our understanding of the sperm physiology and their functionality, and will undoubtedly extend its application in isolating many uncharacterized features of spermatozoa. However, continuous follow-up of the methods is a necessity owing to technical developments and the complexity of mapping spermatozoa.展开更多
Here,a new species of bent-toed gecko,Cyrtodactylus phukhaensis sp.nov.,is described from Doi Phu Kha,Nan province,Thailand based on molecular and morphological evidence.A phylogeny based on NADH dehydrogenase subunit...Here,a new species of bent-toed gecko,Cyrtodactylus phukhaensis sp.nov.,is described from Doi Phu Kha,Nan province,Thailand based on molecular and morphological evidence.A phylogeny based on NADH dehydrogenase subunit 2(ND2)and its flanking tRNAs places the new species in the chauquangensis group as a sister taxon to Cyrtodact ylus wayakonei.The new species can be differentiated from other members of the chauquangensis group by having a unique combina tion of 7 or 8 suprala bials,23-28 longitudinal rows of dorsal tubercles,8-10 infrala bials,9 femoral pores,7 precloacal pores,40-47 ventral scales,and a lack of bands crossingthe temporal area.In addition,results from a chromosome study of C.phukhaensis sp.nov.showed that the new species has a diploid chromosome number of 40 with a fundamental number of 46.The formula of the karyotype was as follows:2n(40)=2m+4sm+34t.Our findings suggest that further studies of Cyrtodactylus biodiversity in northern Thailand are needed.展开更多
基金supported by grants from the National Basic Research Program of China (973 programs) (2011CB944203,2011CB944204)the National High-Tech R&D Program of China (863 Programs) (2014AA021602)+3 种基金the National Natural Science Foundation of China (31401271)the Key Deployment Project of the Chinese Academy of Sciences (KSZD-EW-Z-005-003-002)the Science and Technology Planning Project of Guangdong Province,China (2014B030301058,2015A030310119)Bureau of Science and Technology of GuangzhouMunicipality (201505011111498).
文摘Dear Editor,Type1diabetes(T1D)isa lifelong(chronic)disease and a major health problem throughout the world.This disease can be treatedby either insulin injection or islet transplantation.Islet transplantation is considered as a better treatment for T1D patients,because islets can produce and release insulin at the appropriate time,resulting in tight blood glucose control.
基金supported by the National Natural Science Foundation of China(82071424)the Zhejiang University Education Foundation Global Partnership Fund(188170+194452115/011).
文摘The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases(NDs)such as Alzheimer’s disease,Parkinson's disease,or Amyotrophic Lateral Sclerosis.In a process known as‘seeding’,prion-like proteins such as amyloid beta,microtubule-associated protein tau,α-synuclein,silence superoxide dismutase 1,or transactive response DNA-binding protein 43 kDa,propagate their misfolded conformations by transforming their respective soluble monomers into fibrils.Cellular and molecular evidence of prion-like propagation in NDs,the clinical relevance of their‘seeding’capacities,and their levels of contribution towards disease progression have been intensively studied over recent years.This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization,endo-lysosomal leaking,aggregate degradation,and secretion.Debates on the importance of the role of prion-like protein aggregates in NDs,whether causal or consequent,are also discussed.Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.
基金supported by the GRF RGC&CRF,Hong Kong(Grant Nos.:475012 and C5045-20 EF)HMRF,Hong Kong(Grant No.:03141386)+3 种基金ITF,Hong Kong(Grant No.:ITS/209/12)UGC Direct Grant 2011,2012,2021.032HKOG Trust Fund 2011,2014,2019the National Natural Science Foundation of China(Grant Nos.:81974225 and 82201823)。
文摘Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.
基金supported by the National Natural Science Foundation of China(82071709,81971446,82171599,82374212)Global Select Project(DJK-LX-2022010)of the Institute of Health and Medicine,Hefei Comprehensive National Science CenterJoint Fund for New Medicine of USTC(YD9100002034)。
文摘The structural integrity of the sperm flagellum is essential for proper sperm function.Flagellar defects can result in male infertility,yet the precise mechanisms underlying this relationship are not fully understood.CCDC181,a coiled-coil domain-containing protein,is known to localize on sperm flagella and at the basal regions of motile cilia.Despite this knowledge,the specific functions of CCDC181 in flagellum biogenesis remain unclear.In this study,Ccdc181 knockout mice were generated.The absence of CCDC181 led to defective sperm head shaping and flagellum formation.Furthermore,the Ccdc181 knockout mice exhibited extremely low sperm counts,grossly aberrant sperm morphologies,markedly diminished sperm motility,and typical multiple morphological abnormalities of the flagella(MMAF).Additionally,an interaction between CCDC181 and the MMAF-related protein LRRC46 was identified,with CCDC181 regulating the localization of LRRC46 within sperm flagella.These findings suggest that CCDC181 plays a crucial role in both manchette formation and sperm flagellum biogenesis.
基金supported by the National Key Research and Developmental Program of China(2021YFC2700202,2022YFC2702601,2019YFA0802600,2022YFA0806303)National Natural Science Foundation of China(32470915,32000587,32270901,82171601)+1 种基金Global Select Project(DJK-LX-2022010)of the Institute of Health and Medicine,Hefei Comprehensive National Science Center,Joint Fund for New Medicine of USTC(YD9100002034)Scientific Research Foundation for Scholars of the First Affiliated Hospital of USTC(RC2023054)。
文摘Infertility represents a significant health concern,with sperm quantity and quality being crucial determinants of male fertility.Oligoasthenoteratozoospermia(OAT)is characterized by reduced sperm motility,lower sperm concentration,and morphological abnormalities in sperm heads and flagella.Although variants in several genes have been implicated in OAT,its genetic etiologies and pathogenetic mechanisms remain inadequately understood.In this study,we identified a homozygous nonsense mutation(c.916C>T,p.Arg306*)in the coiled-coil domain containing 146(CCDC146)gene in an infertile male patient with OAT.This mutation resulted in the production of a truncated CCDC146 protein(amino acids 1-305),retaining only two out of five coiled-coil domains.To validate the pathogenicity of the CCDC146 mutation,we generated a mouse model(Ccdc146^(mut/mut))with a similar mutation to that of the patient.Consistently,the Ccdc146mut/mut mice exhibited infertility,characterized by significantly reduced sperm counts,diminished motility,and multiple defects in sperm heads and flagella.Furthermore,the levels of axonemal proteins,including DNAH17,DNAH1,and SPAG6,were significantly reduced in the sperm of Ccdc146^(mut/mut) mice.Additionally,both human and mouse CCDC146 interacted with intraflagellar transport protein 20(IFT20),but this interaction was lost in the mutated versions,leading to the degradation of IFT20.This study identified a novel deleterious homozygous nonsense mutation in CCDC146 that causes male infertility,potentially by disrupting axonemal protein transportation.These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.
基金This work was supported by the National Natural Science Foundation of China(No.81901543,No.82071709,No.81901545,No.81971333,and No.82171599)the Key Research and Development Project of Anhui Province(2022e07020014)+2 种基金the Key Laboratory of Male Reproduction and Genetics of NHC(KF202003)the Joint Fund for Medical Artificial Intelligence(MAI2022Q010)the Joint Research Center for Genomic Resources(2017B01012-2021K001).
文摘Genetic risk factors have been shown to contribute to the development of sexual dysfunction.However,the role of methylenetetrahydrofolate reductase(MTHFR)gene variants in the risk of erectile dysfunction(ED)remains unclear.In this study,we recruited 1254 participants who underwent ED assessed by the International Index of Erectile Function-5.The MTHFR c.677C>T variant was also measured by fluorescence polymerase chain reaction(PCR).No significant difference in the genotypic frequency of the MTHFR C677T polymorphism(CC,CT,and TT)was observed between men from the ED and non-ED groups.In addition,on binary logistic regression analysis,both crude and adjusted models showed that the risk of ED was not significantly associated with the C677T polymorphism.Interestingly,a significantly higher frequency of the 677TT polymorphism was found in severe and moderate ED(P=O.02).The positive correlation between the MTHFR 677TT polymorphism and severe ED was confirmed by logistic regression analysis,even after adjusting for potential confounders(odds ratio[OR]=2.46,95%confidence interval[CI]:1.15-5.50,P=0.02).These findings suggest a positive correlation between the MTHFR 677TT polymorphism and the risk of severe ED.Identification of MTHFR gene polymorphisms may provide complementary information for ED patients during routineclinicaldiagnosis.
基金supported by the National Natural Science Foundation of China(No.82071709,No.32070850,and No.82171601)the National Key Research and Developmental Program of China(2022YFC2702601 and 2022YFA0806303)the Joint Fund for New Medicine of USTC(YD9100002034).
文摘Male infertility is a worldwide health issue,affecting 8%–12%of the global population.Oligoasthenoteratozoospermia(OAT)represents a severe type of male infertility,characterized by reduced sperm count and motility and an increased frequency of sperm with aberrant morphology.Using whole-exome sequencing,this study identified a novel missense mutation(c.848C>A,p.A283E)in the coiled-coil domain-containing 34 gene(CCDC34)in a consanguineous Pakistani family.This rare mutation was predicted to be deleterious and to affect the protein stability.Hematoxylin and eosin staining of spermatozoa from the patient with OAT revealed multiple morphological abnormalities of the flagella and transmission electron microscopy indicated axonemal ultrastructural defects with a lack of outer dynein arms.These findings indicated that CCDC34 plays a role in maintaining the axonemal ultrastructure and the assembly or stability of the outer dynein arms,thus expanding the phenotypic spectrum of CCDC34 missense mutations.
基金supported by the Fundamental Research Funds for the Central Universities(WK2070080005)。
文摘Infertility is a major health issue,affecting approximately 15%of couples of child-bearing age.Although nearly half of idiopathic infertility cases are assumed to have a genetic basis,the underlying causes remain largely unknown in most infertile men.
基金This work was supported by the National Key Research and Developmental Program of China(2018YFC1003700,2018YFC1003400,and 2016YFC1000600)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19000000)+1 种基金the National Natural Science Foundation of China(31890780,31630050,32061143006,82071709,and 31871514)the Fundamental Research Funds for the Central Universities(YD2070002006).
文摘Meiosis is an essential step in gametogenesis which is the key process in sexually reproducing organisms as meiotic aberrations may result in infertility. In meiosis, programmed DNA double-strand break (DSB) formation is one of the fundamental processes that are essential for maintaining homolog interactions and correcting segregation of chromosomes. Although the number and distribution of meiotic DSBs are tightly regulated, still abnormalities in DSB formation are known to cause meiotic arrest and infertility. This review is a detailed account of molecular bases of meiotic DSB formation, its evolutionary conservation, and variations in different species. We further reviewed the mutations of DSB formation genes in association with human infertility and also proposed the future directions and strategies about the study of meiotic DSB formation.
基金This work was supported by the National Natural Science Foundation of China(No.31871514,No.81971333,and No.82071709)the National Key Research and Development Program of China(2019YFA0802600 and 2021YFC2700202)。
文摘Multiple morphological abnormalities of the sperm flagella(MMAF)is a severe form of asthenozoospermia categorized by immotile spermatozoa with abnormal flagella in ejaculate.Whole-exome sequencing(WES)is used to detect pathogenic variants in patients with MMAF.In this study,a novel homozygous frameshift variant(c.6158_6159insT)in dynein axonemal heavy chain 8(DNAH8)from two infertile brothers with MMAF in a consanguineous Pakistani family was identified by WES.Reverse transcription-polymerase chain reaction(RT-PCR)confirmed DNAH8 mRNA decay in these patients with the DNAH8 mutation.Hematoxylin–eosin staining and transmission electron microscopy revealed highly divergent morphology and ultrastructure of sperm flagella in these patients.Furthermore,an immunofluorescence assay showed the absence of DNAH8 and a reduction in its associated protein DNAH17 in the patients'spermatozoa.Collectively,our study expands the phenotypic spectrum of patients with DNAH8-related MMAF worldwide.
基金supported by the National Natural Science Foundation of China(31970668).
文摘Mutations or dysregulated expression of NF-kappaB-activating protein(NKAP)family genes have been found in human cancers.How NKAP family gene mutations promote tumor initiation and progression remains to be determined.Here,we characterized dNKAP,the Drosophila homolog of NKAP,and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model.dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics,including tissue overgrowth,cell-invasive behavior,abnormal cell polarity,and cell adhesion defects.dNKAP knockdown causes both R-loop accumulation and DNA damage,indicating the disruption of genome integrity.Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase(JNK)-dependent apoptosis and causes aberrant cell proliferation in distinct cell populations.Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues.Furthermore,JNK signaling is essential for dNKAP depletion-mediated cell invasion.Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways.dNKAP knockdown and oncogenic Ras,Notch,or Yki mutations show synergies in driving tumorigenesis,further supporting the tumor-suppressive role of dNKAP.In summary,this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.
基金supported by the National Basic Research Program of China (No.2013CB945600)the National Natural Science Foundation of China (No.31371381)
文摘In the Drosophila larval brain, type I and type Ⅱ neuroblasts（NBs） undergo a series of asymmetric divisions which give rise to distinct progeny lineages. The intermediate neural progenitors（INPs） exist only in type Ⅱ NB lineages. In this study, we reveal a novel function of Inscuteable（Insc） that acts to maintain type I NB lineage identity. In insc type I NB clones of mosaic analyses with a repressible cell marker（MARCM）, the formation of extra Deadpan（Dpn）tNB-like and GMC-like cells is observed. The lack of Insc leads to the defective localization and segregation of Numb during asymmetric cell division. By the end of cytokinesis, this results in insufficient Numb in ganglion mother cells（GMCs）. The formation of extra Deadpan（Dpn）tcells in insc clones is prevented by the attenuation of Notch activity. This suggests that Insc functions through the Numb/Notch signaling pathway. We also show that in the absence of Insc in type I NB lineages, the cellular identity of GMCs is altered where they adopt an INP-like cell fate as indicated by the initiation of Dpn expression accompanied by a transient presence of Earmuff（Erm）.These INP-like cells have the capacity to divide multiple times. We conclude that Insc is necessary for the maintenance of type I NB lineage identity. Genetic manipulations to eliminate most type I NBs with overproliferating type Ⅱ NBs in the larval brain lead to altered circadian rhythms and defective phototaxis in adult flies. This indicates that the homeogenesis of NB lineages is important for the adult＇s brain function.
文摘Flow cytometry is now a recognized methodology within animal spermatology, and has moved from being a research tool to become routine in the assessment of animal semen destined to breeding. The availability of ＇bench-top＇ flow cytometers and of newer and versatile markers for cell structure and function had allowed the instrumentation to measure more sperm parameters, from viability to reactiveness when exposed to exogenous stimuli, and to increase our capabilities to sort spermatozoa for potential fertilizing capacity, or chromosomal sex. The present review summarizes the state of the art regarding flow cytometry applied to animal andrology, albeit keeping an open comparative intent. It critically evaluates the present and future capabilities of flow cytometry for the diagnostics of potential fertility and for the development of current reproductive technologies such as sperm freezing, sperm selection and sperm sorting. The flow cytometry methods will probably further revolutionize our understanding of the sperm physiology and their functionality, and will undoubtedly extend its application in isolating many uncharacterized features of spermatozoa. However, continuous follow-up of the methods is a necessity owing to technical developments and the complexity of mapping spermatozoa.
基金financially supported by the National Research Council of Thailand (167951)the Thailand Science Research and Innovation (TSRI) (DBG6180025)+4 种基金Chiang Mai University to Siriwadee CHOMDEJpartially supported by the Thailand Science Research and Innovation fund and the University of Phayao (FF65-UoE003) to Chatmongkon SUWANNAPOOMthe International Partnership Program of Chinese Academy of Sciences (CAS) (152453KYSB20170033)Southeast Asia Biodiversity Research Institute,CAS (Y4ZK111B01: 2017CASSEABRIQG002) to Jing CHEExcellence Center in Veterinary Bioscience to Korakot NGANVONGPANIT.
文摘Here,a new species of bent-toed gecko,Cyrtodactylus phukhaensis sp.nov.,is described from Doi Phu Kha,Nan province,Thailand based on molecular and morphological evidence.A phylogeny based on NADH dehydrogenase subunit 2(ND2)and its flanking tRNAs places the new species in the chauquangensis group as a sister taxon to Cyrtodact ylus wayakonei.The new species can be differentiated from other members of the chauquangensis group by having a unique combina tion of 7 or 8 suprala bials,23-28 longitudinal rows of dorsal tubercles,8-10 infrala bials,9 femoral pores,7 precloacal pores,40-47 ventral scales,and a lack of bands crossingthe temporal area.In addition,results from a chromosome study of C.phukhaensis sp.nov.showed that the new species has a diploid chromosome number of 40 with a fundamental number of 46.The formula of the karyotype was as follows:2n(40)=2m+4sm+34t.Our findings suggest that further studies of Cyrtodactylus biodiversity in northern Thailand are needed.
