Primary cilia,microtubule-based organelles protruding from the surfaces of most eukaryotic cells,have critical roles in maintaining cellular homeostasis,by sensing,transducing,and transmitting diverse extracellular an...Primary cilia,microtubule-based organelles protruding from the surfaces of most eukaryotic cells,have critical roles in maintaining cellular homeostasis,by sensing,transducing,and transmitting diverse extracellular and intracellular signals through multiple signaling pathways,including the Hedgehog,Notch,and Wnt pathways.Consequently,structural or functional abnormalities in primary cilia often lead to various human diseases,including cancer.Although primary cilia are frequently absent in most cancer types,they paradoxically facilitate tumor initiation and progression in certain malignancies.Therefore,elucidating the complex interplay between primary cilia and cancer might provide novel insights for cancer treatment.In this review,we summarize current insights into the structure and function of primary cilia,explore their roles in key tumor-associated signaling pathways,and discuss emerging evidence linking ciliary dysfunction to cancer development and progression.We also highlight recent advances in targeting cilia-associated mechanisms as potential therapeutic strategies in oncology.展开更多
Objective:Advanced gastric cancer remains highly refractory to therapy,with limited immunotherapy efficacy due to tumor microenvironment heterogeneity.Primary cilia,microtubule-based organelles involved in tumor progr...Objective:Advanced gastric cancer remains highly refractory to therapy,with limited immunotherapy efficacy due to tumor microenvironment heterogeneity.Primary cilia,microtubule-based organelles involved in tumor progression,remain insufficiently explored in gastric cancer.This study aimed to define primary cilia subtypes and establish prognostic signatures for personalized treatment strategies.Methods:Bulk transcriptomic data from over 1,500 gastric cancer samples were integrated to define distinct primary cilia subtypes.A primary ciliary phenotype-associated signature(PCS)was established using a multimachine learning survival framework incorporating ten algorithms.The prognostic predictive value and immunotherapy response prediction capability of PCS were validated across multiple independent cohorts.Singlecell RNA sequencing analysis was performed to identify cellular populations associated with high-PCS phenotype.Causal weighted gene co-expression network analysis(WGCNA)was employed to identify driving factors,followed by functional validation through cell culture experiments and xenograft models.Results:Two distinct primary cilia subtypes were identified and validated across all cohorts,with C2 patients exhibiting significantly worse overall survival compared to C1 patients.PCS demonstrated robust predictive value for both prognosis and immunotherapy response,with superior accuracy compared to existing models across multiple validation cohorts.High-PCS patients showed reduced tumor purity,increased stromal cell infiltration,and poor response to immunotherapy.Single-cell analysis revealed that fibroblasts had the highest PCS scores and identified a novel secreted modular calcium-binding protein 2(SMOC2)^(high)myofibroblastic cancer-associated fibroblast(mCAF)population as the key driver of high-PCS phenotype.Functional experiments confirmed that SMOC2 knockdown significantly suppressed gastric cancer cell proliferation,migration,and invasion,while promoting mCAF-to-inflammatory cancer-associated fibroblasts(iCAF)transition.Conclusions:PCS serves as a robust prognostic biomarker for gastric cancer patients.Additionally,targeting SMOC2^(high)mCAFs represents a potential therapeutic strategy for patients with high-PCS gastric cancer.展开更多
Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadia...Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadian rhythm control.CK1 is also essential in the nervous system,where it regulates neuronal growth,differentiation,and synaptic plasticity.Studies have shown that CK1δ phosphorylates neuron-specific proteins to regulate axonal growth and synaptogenesis.Primary cilia are non-motile microtubule structures present on the surface of most mammalian cells.Recent studies have revealed their multiple roles in cellular physiology and development,and dysfunction of cilia can impact the development and function of the nervous system.CK1 has an important role in the formation and function of primary cilia.By regulating various signaling pathways and the phosphorylation status of proteins,CK1 affects the generation,maintenance,and signaling transduction of cilia.In this review,the relationship between CK1,primary cilia,and the nervous system was explored,focusing on how CK1 influences cilia to regulate the structure and function of the nervous system.展开更多
Cilia are indispensable for organ development and function,and their dysfunction causes a range of syndromic diseases known as ciliopathies,including obesity,cystic kidney disease,situs inversus,and male infertility(R...Cilia are indispensable for organ development and function,and their dysfunction causes a range of syndromic diseases known as ciliopathies,including obesity,cystic kidney disease,situs inversus,and male infertility(Reiter and Leroux,2017;Wallmeier et al.,2020).To date,over 180 ciliopathy-associated genes have been identified(Reiter and Leroux,2017),yet the underlying mechanisms remain poorly understood.展开更多
Although the triad of bronchiectasis, sinusitis and situs inversus was first described by Kartagener in 1933, the clinical spectrum of primary ciliary dyskinesia is still under investigation. Heterotaxy defects as wel...Although the triad of bronchiectasis, sinusitis and situs inversus was first described by Kartagener in 1933, the clinical spectrum of primary ciliary dyskinesia is still under investigation. Heterotaxy defects as well as upper and lower respiratory tract symptoms are the main manifestations in childhood. It is now recognized that situs inversus is encountered in only half of patients. The first lower respiratory symptoms may be present from infancy as neonatal respiratory distress. The most common lower airway manifestations are chronic wet cough, recurrent pneumonia and therapy resistant wheezing. Patients are at risk of developing bronchiectasis which may even be the presenting finding due to delayed diagnosis. Upper respiratory tract infections such as nasal congestion, nasal drainage and recurrent sinusitis as well as otologic manifestations such as otitis media or otorrhea with conductive hearing loss are also often encountered. It seems that the type of ciliary ultrastructure defects and the involved mutated genes are associated to some extent to the clinical profile. The disease, even in nowadays, is not recognized at an early age and the primary care clinician should have knowledge of its clinical spectrum in order to select appropriately the children who need further investigation for the diagnosis of this disorder.展开更多
A review on the research of Micro Electromechanical Systems （MEMS） technology based biomimetic cilia is presented. Biomimetic cilia, enabled by the advancement of MEMS technology, have been under dynamic development...A review on the research of Micro Electromechanical Systems （MEMS） technology based biomimetic cilia is presented. Biomimetic cilia, enabled by the advancement of MEMS technology, have been under dynamic development for the past decade. After a brief description of the background of cilia and MEMS technology, different biomimetic cilia applications are reviewed. Biomimetic cilia micro-actuators, including micromachined polyimide bimorph biomimetic cilia micro-actuator, electro-statically actuated polymer biomimetic cilia micro-actuator, and magnetically actuated nanorod array biomimetic cilia micro-actuator, are presented. Subsequently micromachined underwater flow biomimetic cilia micro-sensor is studied, followed by acoustic flow micro-sensor. The fabrication of these MEMS-based biomimetic cilia devices, characterization of their physical properties, and the results of their application experiments are discussed.展开更多
Recently,cilia defects have been proposed to contribute to scoliosis.Here,we demonstrate that coiled-coil domain-containing 57(Ccdc57)plays an essential role in straightening the body axis of zebrafish by regulating c...Recently,cilia defects have been proposed to contribute to scoliosis.Here,we demonstrate that coiled-coil domain-containing 57(Ccdc57)plays an essential role in straightening the body axis of zebrafish by regulating ciliary beating in the brain ventricle(BV).Zygotic ccdc57(Zccdc57)mutant zebrafish developes scoliosis without significant changes in their bone density and calcification,and the maternal-zygotic ccdc57(MZccdc57)mutant embryos display curved bodies since the long-pec stage.The expression of ccdc57 is enriched in ciliated tissues and immunofluorescence analysis reveals colocalization of Ccdc57-HA with acetylated a-tubulin,implicating it in having a role in ciliary function.Further examination reveals that it is the coordinated cilia beating of multiple cilia bundles(MCB)in the MZccdc57 mutant embryos that is affected at 48 hours post fertilization,when the compromised cerebrospinal fluid flow and curved body axis have already occurred.Either ccdc57 m RNA injection or epinephrine treatment reverses the spinal curvature in MZccdc57 mutant larvae from ventrally curly to straight or even dorsally curly and significantly upregulates urotensin signaling.This study reveals the role of ccdc57 in maintaining coordinated cilia beating of MCB in the BV.展开更多
Laterality is a crucial physiological process intricately linked to the cilium-centrosome complex during embryo development.Defects in the process can result in severe organ mispositioning.Coiled-coil domain containin...Laterality is a crucial physiological process intricately linked to the cilium-centrosome complex during embryo development.Defects in the process can result in severe organ mispositioning.Coiled-coil domain containing 141(CCDC141)has been previously known as a centrosome-related gene,but its role in left-right(LR)asymmetry has not been characterized.In this study,we utilize the zebrafish model and human exome analysis to elucidate the function of ccdc141 in laterality defects.The knockdown of ccdc141 in zebrafish disrupts early LR signaling pathways,cilia function,and Kupffer's vesicle formation.Unlike ccdc141-knockdown embryos exhibiting aberrant LR patterns,ccdc141-null mutants show no apparent abnormality,suggesting a genetic compensation response effect.In parallel,we observe a marked reduction inα-tubulin acetylation levels in the ccdc141 crispants.The treatment with histone deacetylase(HDAC)inhibitors,particularly the HDAC6 inhibitor,rescues the ccdc141 crispant phenotypes.Furthermore,exome analysis of 70 patients with laterality defects reveals an increased burden of CCDC141 mutations,with in-vivo studies verifying the pathogenicity of the patient mutation CCDC141-R123G.Our findings highlight the critical role of ccdc141 in ciliogenesis and demonstrate that CCDC141 mutations lead to abnormal LR patterns,identifying it as a candidate gene for laterality defects.展开更多
Dear Editor,Male infertility is defined as the inability to achieve pregnancy in a fertile female partner even after 12 months of unprotected intercourse.In humans,it accounts for 40%-50%of cases of infertility,1 and ...Dear Editor,Male infertility is defined as the inability to achieve pregnancy in a fertile female partner even after 12 months of unprotected intercourse.In humans,it accounts for 40%-50%of cases of infertility,1 and it occurs most often due to problems with sperm production or sperm delivery.Male infertility is commonly due to deficiencies in semen,and semen quality is used as a surrogate measure of male fecundity.Primary ciliary dyskinesia(PCD)is a rare cause of male infertility.2,3 It is an autosomal recessive genetic condition that causes abnormal function of cilia.Cilia are microscopic finger-like projections on the surface of the cells.展开更多
A biomimetic approach is used to generate a directed transversal transportation of micron-sized particles in liquids based on the principle of cilia-type arrays in coordinated motion. Rows of flaps mimicking planar ci...A biomimetic approach is used to generate a directed transversal transportation of micron-sized particles in liquids based on the principle of cilia-type arrays in coordinated motion. Rows of flaps mimicking planar cilia are positioned off-centre along an array of cavities covered with membranes that support the flaps. These membranes are deflected from a concave to a convex shape and vice versa by pneumatic actuation applying positive and negative pressures (relative to the ambient) inside the cavities. As a result, the flap on top of the membrane tilts to the left or right within such a pressure cycle, performing a beat stroke. Since each cavity can be addressed in the device individually and in rapid succession, waves of coordinated flap motion can be run along the wall. Such metachronal waves are generated and transport of particles along the cilia surface is achieved in both symplectic and antiplectic direction. It is shown that the initial tilt of the flaps relative to the wall-normal determines the direction of transport.展开更多
This paper presents a theoretical study of a non-linear rheological fluid transport in an axisymmetric tube by cilia. An attempt has been made to explain the role of cilia motion in the transport of fluid through the ...This paper presents a theoretical study of a non-linear rheological fluid transport in an axisymmetric tube by cilia. An attempt has been made to explain the role of cilia motion in the transport of fluid through the ductus efferent of the male reproductive tract. The Ostwald-de Waele power-law viscous fluid is considered to represent the rheological fluid. We analyze pumping by means of a sequence of cilia beats from rowto-row of cilia in a given row of cells and from one row of cells to the next(metachronal wave movement). For this purpose, we consider the conditions that the corresponding Reynolds number is small enough for inertial effects to be negligible, and the wavelengthto-diameter ratio is large enough so that the pressure can be considered uniform over the cross section. Analyses and computations of the fluid motion reveal that the time-average flow rate depends on ε, a non-dimensional measure involving the mean radius a of the tube and the cilia length. Thus, the flow rate significantly varies with the cilia length.Moreover, the flow rate has been reported to be close to the estimated value 6 × 10ml/h for human efferent ducts if ε is near 0.4. The estimated value was suggested by Lardner and Shack(Lardner, T. J. and Shack, W. J. Cilia transport. Bulletin of Mathematical Biology, 34, 325–335(1972)) for human based on the experimental observations of flow rates in efferent ducts of other animals, e.g., rat, ram, and bull. In addition, the nature of the rheological fluid, i.e., the value of the fluid index n strongly influences various flow-governed characteristics. An interesting feature of this paper is that the pumping improves the thickening behavior for small values of ε or in free pumping(?P = 0) and pumping(?P > 0) regions.展开更多
Cilia play a wide range of critical roles in regulating cell motility,sensory signaling and metazoan development(Goetz and Anderson,2010;Reiter and Leroux,2017).Both motile cilia and pri-mary cilia consist of a basal ...Cilia play a wide range of critical roles in regulating cell motility,sensory signaling and metazoan development(Goetz and Anderson,2010;Reiter and Leroux,2017).Both motile cilia and pri-mary cilia consist of a basal body and a microtubule-based axoneme that is encompassed within the ciliary membrane.The formationand maintenance of ciliary structure depends on bidirectional intraflagellar transport(IFT):the kinesin-2 family motor proteins deliver ciliary precursors bound to the IFT particle protein complex from the ciliary base to the tip and the cytoplasmic dynein-2 recy-cles the anterograde IFT-protein machinery and ciliary turnover products back to the base(Scholey,2013;Reiter and Leroux,2017).Defects of ciliary structure and function lead to more than 35 types of systemic disorders in most human organ systems.which are collectively called ciliopathies(Reiter and Leroux,2017).187 established and 241 candidate ciliopathy-associated genes have been identified from the human genome(Reiter and Leroux,2017).展开更多
Cilia depend on their highly differentiated structure, a 9 ＋ 2 arrangement, to remove particles from the lung and to transport reproductive cells. Immortalized cells could potentially be of great use in cilia researc...Cilia depend on their highly differentiated structure, a 9 ＋ 2 arrangement, to remove particles from the lung and to transport reproductive cells. Immortalized cells could potentially be of great use in cilia research. Immortalization of cells with cilia structure containing the 9 ＋ 2 arrangement might be able to generate cell lines with such cilia structure. How- ever, whether immortalized cells can retain such a highly differentiated structure remains unclear. Here we demonstrate that （1） using Ela gene transfection, tracheal cells are immortalized; （2） interestingly, in a gel culture the immortalized cells form spherical aggregations within which a lumen is developed; and （3） surprisingly, inside the aggregation, cilia containing a 9 ＋ 2 arrangement grow from the cell＇s apical pole and protrude into the lumen. These results may influence future research in many areas such as understanding the mechanisms of cilia differentiation, cilia generation in other existing cell lines, cilia disorders, generation of other highly differentiated structures besides cilia using the gel culture, immortalization of other ciliated cells with the Ela gene, development of cilia motile function, and establishment of a research model to provide uniform ciliated cells.展开更多
Dear Editor,We present an exceptionally rare case about bilateral medulloepithelioma of the ciliary body.This case was approved by Ethics Committee of Capital Medical University.Written informed consent was obtained f...Dear Editor,We present an exceptionally rare case about bilateral medulloepithelioma of the ciliary body.This case was approved by Ethics Committee of Capital Medical University.Written informed consent was obtained from the patients.Discovering leukocoria in both eyes and proptosis in right eye for 2mo by parents in a 4.5-month-old boy.He had undergone no treatment elsewhere except magnetic resonance imaging examination before coming to Beijing Tongren Hospital.展开更多
Occurrence of cilia on the cell surface is usually considered evidence of a non-neoplastic process. Rarely, ciliated malignant tumors cells have been reported in pleural and ascitic fluids from ovarian and endometrial...Occurrence of cilia on the cell surface is usually considered evidence of a non-neoplastic process. Rarely, ciliated malignant tumors cells have been reported in pleural and ascitic fluids from ovarian and endometrial adenocarcinomas, though not from the cerebrospinal fluid (CSF) in association with pulmonary adenocarcinoma. We now present a case report of a patient who initially presented with neurologic symptoms. A CSF specimen revealed atypical cells with peripheral cilia and some cytoplasmic pigment. Cytologic, morphologic, and immunohistochemical analyses established this to be a metastatic adenocarcinoma of pulmonary origin with metastases to the meninges, pelvis, and the vertebrae. Cilia are generally the antithesis of malignancy as their presence is considered to be evidence of proper regulation of the cell cycle within a well-differentiated cell. This case offers the first described example of malignant ciliated cells derived from a metastatic lung adenocarcinoma. An awareness of this unusual presentation should aid in diagnosis and management when similar situations are prospectively encountered.展开更多
Dynein-decorated doublet microtubules(DMTs)are critical components of the oscillatory molecular machine of cilia,the axoneme,and have luminal surfaces patterned periodically by microtubule inner proteins(MIPs).Here we...Dynein-decorated doublet microtubules(DMTs)are critical components of the oscillatory molecular machine of cilia,the axoneme,and have luminal surfaces patterned periodically by microtubule inner proteins(MIPs).Here we present an atomic model of the 48-nm repeat of a mammalian DMT,derived from a cryoelectron microscopy(cryo-EM)map of the complex isolated from bovine respiratory cilia.展开更多
Objective:To investigate the clinical characteristics,diagnosis and treatment of male infertility associated with immotile cilia syndrome(ICS). Methods:The clinical data of six cases of male infertility associated wit...Objective:To investigate the clinical characteristics,diagnosis and treatment of male infertility associated with immotile cilia syndrome(ICS). Methods:The clinical data of six cases of male infertility associated with ICS were reviewed retrospectively. Results:The clinical features in all cases included chronic or recurrent infections of the upper and lower airways and male infertility.Sinusitis,bronchitis and bronchiectasis were found in all cases and situs inversus totalis found in two cases.Sex hormone levels,chromosome karyotype and Y chromosome microdeletion(AZF) in all cases were normal.All cases were diagnosed as severe asthenospermia by routine semen analysis.Five cases had no motile spermatozoa in semen,while there were less than 0.2%of motile sperm in one case.The total sperm count and sperm viability were normal in four cases and there were very few immotile sperm in two cases.Transmission electron microscopic examination of sperm flagellum revealed disarrangement or a partial absence of 9+2 microtubules and/or an absence of the dynein arms in six cases.The bronchial cilia in one case showed to be devoid of inner dynein arms.Five cases underwent six intracytoplasmic sperm injection(ICSI) cycles and the rates of fertilization,embryo cleavage and good quality embryos were 50.0%,69.2%and 55.6%,respectively.Two clinical pregnancies and one chemical pregnancy were achieved,with one birth of a healthy baby boy. Conclusions:The ultrastructural defect of cilia or flagellum is the most important diagnostic criteria of ICS. ICSI is an effective treatment for male infertility associated with ICS.展开更多
SPAG1(sperm-associated antigen 1)is one of over 50 genes whose pathogenic variants underlie primary ciliary dyskinesia(PCD;OMIM244400),an inherited disorder affecting the function of motile cilia,1 highly conserved or...SPAG1(sperm-associated antigen 1)is one of over 50 genes whose pathogenic variants underlie primary ciliary dyskinesia(PCD;OMIM244400),an inherited disorder affecting the function of motile cilia,1 highly conserved organelles protruding from the surface of eukaryotic cells.Pathogenic SPAG1 variants impair the assembly of dynein arms,essential elements of cilia.展开更多
Primary cilia are microtubule-based organelles involved in a variety of fundamental biological processes,including cell cycle regulation,cell polarity,and signal transduction,which are crucial for proper tissue format...Primary cilia are microtubule-based organelles involved in a variety of fundamental biological processes,including cell cycle regulation,cell polarity,and signal transduction,which are crucial for proper tissue formation and function[1,2].The characteristics of primary cilia,such as the percentage of ciliated cells,cilia type transformation,and cilia length,are dynamic and tightly regulated during development and in response to signals[3,4].展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.82203297 and 32230025)National Key R&D Program of China(Grant No.2021YFA1101001)Taishan Scholar Young Expert Program of Shandong Province(Grant No.tsqn202306154).
文摘Primary cilia,microtubule-based organelles protruding from the surfaces of most eukaryotic cells,have critical roles in maintaining cellular homeostasis,by sensing,transducing,and transmitting diverse extracellular and intracellular signals through multiple signaling pathways,including the Hedgehog,Notch,and Wnt pathways.Consequently,structural or functional abnormalities in primary cilia often lead to various human diseases,including cancer.Although primary cilia are frequently absent in most cancer types,they paradoxically facilitate tumor initiation and progression in certain malignancies.Therefore,elucidating the complex interplay between primary cilia and cancer might provide novel insights for cancer treatment.In this review,we summarize current insights into the structure and function of primary cilia,explore their roles in key tumor-associated signaling pathways,and discuss emerging evidence linking ciliary dysfunction to cancer development and progression.We also highlight recent advances in targeting cilia-associated mechanisms as potential therapeutic strategies in oncology.
基金supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project(No.2023ZD0501400)National Key Research and Development Program of China(No.2023YFA1800204)+2 种基金Beijing Natural Science Foundation(No.L234036)Beijing Tongzhou District Science and Technology Project(No.KJ2024CX066)Peking University People’s Hospital Scientific Research Development Funds(No.RDJP2024-20)。
文摘Objective:Advanced gastric cancer remains highly refractory to therapy,with limited immunotherapy efficacy due to tumor microenvironment heterogeneity.Primary cilia,microtubule-based organelles involved in tumor progression,remain insufficiently explored in gastric cancer.This study aimed to define primary cilia subtypes and establish prognostic signatures for personalized treatment strategies.Methods:Bulk transcriptomic data from over 1,500 gastric cancer samples were integrated to define distinct primary cilia subtypes.A primary ciliary phenotype-associated signature(PCS)was established using a multimachine learning survival framework incorporating ten algorithms.The prognostic predictive value and immunotherapy response prediction capability of PCS were validated across multiple independent cohorts.Singlecell RNA sequencing analysis was performed to identify cellular populations associated with high-PCS phenotype.Causal weighted gene co-expression network analysis(WGCNA)was employed to identify driving factors,followed by functional validation through cell culture experiments and xenograft models.Results:Two distinct primary cilia subtypes were identified and validated across all cohorts,with C2 patients exhibiting significantly worse overall survival compared to C1 patients.PCS demonstrated robust predictive value for both prognosis and immunotherapy response,with superior accuracy compared to existing models across multiple validation cohorts.High-PCS patients showed reduced tumor purity,increased stromal cell infiltration,and poor response to immunotherapy.Single-cell analysis revealed that fibroblasts had the highest PCS scores and identified a novel secreted modular calcium-binding protein 2(SMOC2)^(high)myofibroblastic cancer-associated fibroblast(mCAF)population as the key driver of high-PCS phenotype.Functional experiments confirmed that SMOC2 knockdown significantly suppressed gastric cancer cell proliferation,migration,and invasion,while promoting mCAF-to-inflammatory cancer-associated fibroblasts(iCAF)transition.Conclusions:PCS serves as a robust prognostic biomarker for gastric cancer patients.Additionally,targeting SMOC2^(high)mCAFs represents a potential therapeutic strategy for patients with high-PCS gastric cancer.
文摘Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadian rhythm control.CK1 is also essential in the nervous system,where it regulates neuronal growth,differentiation,and synaptic plasticity.Studies have shown that CK1δ phosphorylates neuron-specific proteins to regulate axonal growth and synaptogenesis.Primary cilia are non-motile microtubule structures present on the surface of most mammalian cells.Recent studies have revealed their multiple roles in cellular physiology and development,and dysfunction of cilia can impact the development and function of the nervous system.CK1 has an important role in the formation and function of primary cilia.By regulating various signaling pathways and the phosphorylation status of proteins,CK1 affects the generation,maintenance,and signaling transduction of cilia.In this review,the relationship between CK1,primary cilia,and the nervous system was explored,focusing on how CK1 influences cilia to regulate the structure and function of the nervous system.
基金supported by grants from the National Key Research and Development Program of China(2019YFA0802704)the National Natural Science Foundation of China(31771620)+2 种基金the Natural Science Foundation of Chongqing,China(CSTB2022NSCQMSX1424)Research Startup Fund of Southwest University(SWU117064)Open Research Fund of National Health Commission Key Laboratory of Birth Defects Prevention&Henan Key Laboratory of Population Defects Prevention(ZD202302)。
文摘Cilia are indispensable for organ development and function,and their dysfunction causes a range of syndromic diseases known as ciliopathies,including obesity,cystic kidney disease,situs inversus,and male infertility(Reiter and Leroux,2017;Wallmeier et al.,2020).To date,over 180 ciliopathy-associated genes have been identified(Reiter and Leroux,2017),yet the underlying mechanisms remain poorly understood.
文摘Although the triad of bronchiectasis, sinusitis and situs inversus was first described by Kartagener in 1933, the clinical spectrum of primary ciliary dyskinesia is still under investigation. Heterotaxy defects as well as upper and lower respiratory tract symptoms are the main manifestations in childhood. It is now recognized that situs inversus is encountered in only half of patients. The first lower respiratory symptoms may be present from infancy as neonatal respiratory distress. The most common lower airway manifestations are chronic wet cough, recurrent pneumonia and therapy resistant wheezing. Patients are at risk of developing bronchiectasis which may even be the presenting finding due to delayed diagnosis. Upper respiratory tract infections such as nasal congestion, nasal drainage and recurrent sinusitis as well as otologic manifestations such as otitis media or otorrhea with conductive hearing loss are also often encountered. It seems that the type of ciliary ultrastructure defects and the involved mutated genes are associated to some extent to the clinical profile. The disease, even in nowadays, is not recognized at an early age and the primary care clinician should have knowledge of its clinical spectrum in order to select appropriately the children who need further investigation for the diagnosis of this disorder.
基金supported by the China Scholarship Council (CSC).
文摘A review on the research of Micro Electromechanical Systems （MEMS） technology based biomimetic cilia is presented. Biomimetic cilia, enabled by the advancement of MEMS technology, have been under dynamic development for the past decade. After a brief description of the background of cilia and MEMS technology, different biomimetic cilia applications are reviewed. Biomimetic cilia micro-actuators, including micromachined polyimide bimorph biomimetic cilia micro-actuator, electro-statically actuated polymer biomimetic cilia micro-actuator, and magnetically actuated nanorod array biomimetic cilia micro-actuator, are presented. Subsequently micromachined underwater flow biomimetic cilia micro-sensor is studied, followed by acoustic flow micro-sensor. The fabrication of these MEMS-based biomimetic cilia devices, characterization of their physical properties, and the results of their application experiments are discussed.
基金supported by the National Key Research and Development Program,China(2018YFD0900406)the National Natural Science Foundation,China(31802291)the Natural Science Foundation of Hunan Province(2021JJ40342)。
文摘Recently,cilia defects have been proposed to contribute to scoliosis.Here,we demonstrate that coiled-coil domain-containing 57(Ccdc57)plays an essential role in straightening the body axis of zebrafish by regulating ciliary beating in the brain ventricle(BV).Zygotic ccdc57(Zccdc57)mutant zebrafish developes scoliosis without significant changes in their bone density and calcification,and the maternal-zygotic ccdc57(MZccdc57)mutant embryos display curved bodies since the long-pec stage.The expression of ccdc57 is enriched in ciliated tissues and immunofluorescence analysis reveals colocalization of Ccdc57-HA with acetylated a-tubulin,implicating it in having a role in ciliary function.Further examination reveals that it is the coordinated cilia beating of multiple cilia bundles(MCB)in the MZccdc57 mutant embryos that is affected at 48 hours post fertilization,when the compromised cerebrospinal fluid flow and curved body axis have already occurred.Either ccdc57 m RNA injection or epinephrine treatment reverses the spinal curvature in MZccdc57 mutant larvae from ventrally curly to straight or even dorsally curly and significantly upregulates urotensin signaling.This study reveals the role of ccdc57 in maintaining coordinated cilia beating of MCB in the BV.
基金supported by the National Natural Science Foundation of China(81970264).
文摘Laterality is a crucial physiological process intricately linked to the cilium-centrosome complex during embryo development.Defects in the process can result in severe organ mispositioning.Coiled-coil domain containing 141(CCDC141)has been previously known as a centrosome-related gene,but its role in left-right(LR)asymmetry has not been characterized.In this study,we utilize the zebrafish model and human exome analysis to elucidate the function of ccdc141 in laterality defects.The knockdown of ccdc141 in zebrafish disrupts early LR signaling pathways,cilia function,and Kupffer's vesicle formation.Unlike ccdc141-knockdown embryos exhibiting aberrant LR patterns,ccdc141-null mutants show no apparent abnormality,suggesting a genetic compensation response effect.In parallel,we observe a marked reduction inα-tubulin acetylation levels in the ccdc141 crispants.The treatment with histone deacetylase(HDAC)inhibitors,particularly the HDAC6 inhibitor,rescues the ccdc141 crispant phenotypes.Furthermore,exome analysis of 70 patients with laterality defects reveals an increased burden of CCDC141 mutations,with in-vivo studies verifying the pathogenicity of the patient mutation CCDC141-R123G.Our findings highlight the critical role of ccdc141 in ciliogenesis and demonstrate that CCDC141 mutations lead to abnormal LR patterns,identifying it as a candidate gene for laterality defects.
基金the National Key R&D Program of China(No.2017YFC1002003)the China Postdoctoral Science Foundation(No.2019M661521).
文摘Dear Editor,Male infertility is defined as the inability to achieve pregnancy in a fertile female partner even after 12 months of unprotected intercourse.In humans,it accounts for 40%-50%of cases of infertility,1 and it occurs most often due to problems with sperm production or sperm delivery.Male infertility is commonly due to deficiencies in semen,and semen quality is used as a surrogate measure of male fecundity.Primary ciliary dyskinesia(PCD)is a rare cause of male infertility.2,3 It is an autosomal recessive genetic condition that causes abnormal function of cilia.Cilia are microscopic finger-like projections on the surface of the cells.
文摘A biomimetic approach is used to generate a directed transversal transportation of micron-sized particles in liquids based on the principle of cilia-type arrays in coordinated motion. Rows of flaps mimicking planar cilia are positioned off-centre along an array of cavities covered with membranes that support the flaps. These membranes are deflected from a concave to a convex shape and vice versa by pneumatic actuation applying positive and negative pressures (relative to the ambient) inside the cavities. As a result, the flap on top of the membrane tilts to the left or right within such a pressure cycle, performing a beat stroke. Since each cavity can be addressed in the device individually and in rapid succession, waves of coordinated flap motion can be run along the wall. Such metachronal waves are generated and transport of particles along the cilia surface is achieved in both symplectic and antiplectic direction. It is shown that the initial tilt of the flaps relative to the wall-normal determines the direction of transport.
文摘This paper presents a theoretical study of a non-linear rheological fluid transport in an axisymmetric tube by cilia. An attempt has been made to explain the role of cilia motion in the transport of fluid through the ductus efferent of the male reproductive tract. The Ostwald-de Waele power-law viscous fluid is considered to represent the rheological fluid. We analyze pumping by means of a sequence of cilia beats from rowto-row of cilia in a given row of cells and from one row of cells to the next(metachronal wave movement). For this purpose, we consider the conditions that the corresponding Reynolds number is small enough for inertial effects to be negligible, and the wavelengthto-diameter ratio is large enough so that the pressure can be considered uniform over the cross section. Analyses and computations of the fluid motion reveal that the time-average flow rate depends on ε, a non-dimensional measure involving the mean radius a of the tube and the cilia length. Thus, the flow rate significantly varies with the cilia length.Moreover, the flow rate has been reported to be close to the estimated value 6 × 10ml/h for human efferent ducts if ε is near 0.4. The estimated value was suggested by Lardner and Shack(Lardner, T. J. and Shack, W. J. Cilia transport. Bulletin of Mathematical Biology, 34, 325–335(1972)) for human based on the experimental observations of flow rates in efferent ducts of other animals, e.g., rat, ram, and bull. In addition, the nature of the rheological fluid, i.e., the value of the fluid index n strongly influences various flow-governed characteristics. An interesting feature of this paper is that the pumping improves the thickening behavior for small values of ε or in free pumping(?P = 0) and pumping(?P > 0) regions.
基金supported by the National Key R&D Program of China(2017YFA0503501)the National Natural Science Foundation of China(Nos.31525015,31730052 and 31671444)
文摘Cilia play a wide range of critical roles in regulating cell motility,sensory signaling and metazoan development(Goetz and Anderson,2010;Reiter and Leroux,2017).Both motile cilia and pri-mary cilia consist of a basal body and a microtubule-based axoneme that is encompassed within the ciliary membrane.The formationand maintenance of ciliary structure depends on bidirectional intraflagellar transport(IFT):the kinesin-2 family motor proteins deliver ciliary precursors bound to the IFT particle protein complex from the ciliary base to the tip and the cytoplasmic dynein-2 recy-cles the anterograde IFT-protein machinery and ciliary turnover products back to the base(Scholey,2013;Reiter and Leroux,2017).Defects of ciliary structure and function lead to more than 35 types of systemic disorders in most human organ systems.which are collectively called ciliopathies(Reiter and Leroux,2017).187 established and 241 candidate ciliopathy-associated genes have been identified from the human genome(Reiter and Leroux,2017).
文摘Cilia depend on their highly differentiated structure, a 9 ＋ 2 arrangement, to remove particles from the lung and to transport reproductive cells. Immortalized cells could potentially be of great use in cilia research. Immortalization of cells with cilia structure containing the 9 ＋ 2 arrangement might be able to generate cell lines with such cilia structure. How- ever, whether immortalized cells can retain such a highly differentiated structure remains unclear. Here we demonstrate that （1） using Ela gene transfection, tracheal cells are immortalized; （2） interestingly, in a gel culture the immortalized cells form spherical aggregations within which a lumen is developed; and （3） surprisingly, inside the aggregation, cilia containing a 9 ＋ 2 arrangement grow from the cell＇s apical pole and protrude into the lumen. These results may influence future research in many areas such as understanding the mechanisms of cilia differentiation, cilia generation in other existing cell lines, cilia disorders, generation of other highly differentiated structures besides cilia using the gel culture, immortalization of other ciliated cells with the Ela gene, development of cilia motile function, and establishment of a research model to provide uniform ciliated cells.
文摘Dear Editor,We present an exceptionally rare case about bilateral medulloepithelioma of the ciliary body.This case was approved by Ethics Committee of Capital Medical University.Written informed consent was obtained from the patients.Discovering leukocoria in both eyes and proptosis in right eye for 2mo by parents in a 4.5-month-old boy.He had undergone no treatment elsewhere except magnetic resonance imaging examination before coming to Beijing Tongren Hospital.
文摘Occurrence of cilia on the cell surface is usually considered evidence of a non-neoplastic process. Rarely, ciliated malignant tumors cells have been reported in pleural and ascitic fluids from ovarian and endometrial adenocarcinomas, though not from the cerebrospinal fluid (CSF) in association with pulmonary adenocarcinoma. We now present a case report of a patient who initially presented with neurologic symptoms. A CSF specimen revealed atypical cells with peripheral cilia and some cytoplasmic pigment. Cytologic, morphologic, and immunohistochemical analyses established this to be a metastatic adenocarcinoma of pulmonary origin with metastases to the meninges, pelvis, and the vertebrae. Cilia are generally the antithesis of malignancy as their presence is considered to be evidence of proper regulation of the cell cycle within a well-differentiated cell. This case offers the first described example of malignant ciliated cells derived from a metastatic lung adenocarcinoma. An awareness of this unusual presentation should aid in diagnosis and management when similar situations are prospectively encountered.
文摘Dynein-decorated doublet microtubules(DMTs)are critical components of the oscillatory molecular machine of cilia,the axoneme,and have luminal surfaces patterned periodically by microtubule inner proteins(MIPs).Here we present an atomic model of the 48-nm repeat of a mammalian DMT,derived from a cryoelectron microscopy(cryo-EM)map of the complex isolated from bovine respiratory cilia.
文摘Objective:To investigate the clinical characteristics,diagnosis and treatment of male infertility associated with immotile cilia syndrome(ICS). Methods:The clinical data of six cases of male infertility associated with ICS were reviewed retrospectively. Results:The clinical features in all cases included chronic or recurrent infections of the upper and lower airways and male infertility.Sinusitis,bronchitis and bronchiectasis were found in all cases and situs inversus totalis found in two cases.Sex hormone levels,chromosome karyotype and Y chromosome microdeletion(AZF) in all cases were normal.All cases were diagnosed as severe asthenospermia by routine semen analysis.Five cases had no motile spermatozoa in semen,while there were less than 0.2%of motile sperm in one case.The total sperm count and sperm viability were normal in four cases and there were very few immotile sperm in two cases.Transmission electron microscopic examination of sperm flagellum revealed disarrangement or a partial absence of 9+2 microtubules and/or an absence of the dynein arms in six cases.The bronchial cilia in one case showed to be devoid of inner dynein arms.Five cases underwent six intracytoplasmic sperm injection(ICSI) cycles and the rates of fertilization,embryo cleavage and good quality embryos were 50.0%,69.2%and 55.6%,respectively.Two clinical pregnancies and one chemical pregnancy were achieved,with one birth of a healthy baby boy. Conclusions:The ultrastructural defect of cilia or flagellum is the most important diagnostic criteria of ICS. ICSI is an effective treatment for male infertility associated with ICS.
基金funded by the National Science Centre,Poland(No.2018/29/N/NZ5/00810 to A.R.2018/31/B/NZ2/03248 to E.Z.)by the Institute of Human Genetics PAS,Poland(Minigrant No.2021/01 to A.R.).
文摘SPAG1(sperm-associated antigen 1)is one of over 50 genes whose pathogenic variants underlie primary ciliary dyskinesia(PCD;OMIM244400),an inherited disorder affecting the function of motile cilia,1 highly conserved organelles protruding from the surface of eukaryotic cells.Pathogenic SPAG1 variants impair the assembly of dynein arms,essential elements of cilia.
基金supported by the Zhejiang University Qizhen program(226-2024-00210).
文摘Primary cilia are microtubule-based organelles involved in a variety of fundamental biological processes,including cell cycle regulation,cell polarity,and signal transduction,which are crucial for proper tissue formation and function[1,2].The characteristics of primary cilia,such as the percentage of ciliated cells,cilia type transformation,and cilia length,are dynamic and tightly regulated during development and in response to signals[3,4].
