Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 66
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PLoS Genet ; 16(12): e1009232, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33347437

RESUMO

Motile cilia can beat with distinct patterns, but how motility variations are regulated remain obscure. Here, we have studied the role of the coiled-coil protein CFAP53 in the motility of different cilia-types in the mouse. While node (9+0) cilia of Cfap53 mutants were immotile, tracheal and ependymal (9+2) cilia retained motility, albeit with an altered beat pattern. In node cilia, CFAP53 mainly localized at the base (centriolar satellites), whereas it was also present along the entire axoneme in tracheal cilia. CFAP53 associated tightly with microtubules and interacted with axonemal dyneins and TTC25, a dynein docking complex component. TTC25 and outer dynein arms (ODAs) were lost from node cilia, but were largely maintained in tracheal cilia of Cfap53-/- mice. Thus, CFAP53 at the base of node cilia facilitates axonemal transport of TTC25 and dyneins, while axonemal CFAP53 in 9+2 cilia stabilizes dynein binding to microtubules. Our study establishes how differential localization and function of CFAP53 contributes to the unique motion patterns of two important mammalian cilia-types.

2.
Environ Sci Technol ; 54(23): 15313-15319, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33185424

RESUMO

In India, approximately 480,000 deaths occur annually from exposure to household air pollution from the use of biomass cooking fuels. Displacing biomass use with clean fuels, such as liquefied petroleum gas (LPG), can help reduce these deaths. Through government initiatives, most Indian households now own an LPG stove and one LPG cylinder. Many households, however, continue to regularly use indoor biomass-fueled mud stoves (chulhas) alongside LPG. Focusing on this population in rural Maharashtra, India, this study (N = 186) tests the effects of conditioning a sales offer for a spare LPG cylinder on a reversible commitment requiring initially disabling indoor chulhas. We find that almost all relevant households (>98%) were willing to accept this commitment. Indoor chulha use decreased by 90% (95% CI = 80% to 101%) when the sales offer included the commitment, compared to a 23% decrease (95% CI = 14% to 32%) without it. For both treatment groups, we find that 80% purchased the spare cylinder at the end of the study.

3.
Semin Cell Dev Biol ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33246807
4.
Eur J Neurol ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33124102

RESUMO

BACKGROUND AND PURPOSE: Congenital muscular dystrophies (CMDs) and congenital myopathies (CMs) are a group of genetically and clinically heterogeneous degenerative primary muscle disorders with onset at birth or during infancy. Due to vast heterogeneity, clinical examination and protein-based analyses often fail to identify the genetic causes of these diseases. The aim of this study was to genetically diagnose a cohort of 36 difficult-to-diagnose CMD and CM cases of Indian origin using next-generation sequencing methods. METHODS: Whole-exome sequencing (WES) was performed to identify pathogenic mutations in previously reported CMD and CM-related genes using variant calling and stringent variant filtration process. Subsequently, in silico homology modelling and molecular dynamics simulations (MDS) studies were undertaken for a number of novel and missense variants. RESULTS: A total of 33 and 21 rare and deleterious mutations were identified in 28 genes previously reported in CMD and CM based on OMIM, ClinVar and Orphanet, respectively. We could accurately diagnose 54% patients (n = 12/22) in the CMD group and 35% patients (n = 5/14) in the CM group. Furthermore, MDS studies for mutations located in LMNA, LAMA2 and RYR1 suggest that the wild-type proteins are more stable than their mutant counterparts, implying a potential mechanism of pathogenesis. CONCLUSION: The WES findings led us to identify reported as well as novel variants for the first time in Indian patients with CMD and CM. This allowed us to achieve an accurate genetic diagnosis, which was difficult using conventional diagnostic tools. Transferring these WES findings to clinical practice will help guide clinical care of the affected patients and inform genetic counselling.

5.
BMJ Open ; 10(10): e044127, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020110

RESUMO

INTRODUCTION: Health interventions often target pregnant women and their unborn children. Interventions in rural India targeting pregnant women, however, often do not cover the critical early windows of susceptibility during the first trimester and parts of the second trimester. This pilot seeks to determine if targeting newlyweds could protect entire pregnancies with a clean stove and fuel intervention. METHODS: We recruited 50 newlywed couples who use biomass as a cooking fuel into a clean cooking intervention that included a liquefied petroleum gas (LPG) stove, two gas cylinders, a table to place the stove on and health education. We first evaluated whether community health workers in this region could identify and recruit couples at marriage. We quantified how many additional days of pregnancy could be covered by an intervention if we recruited at marriage versus recruiting after detection of pregnancy. RESULTS: On average, we identified and visited newlywed couples within 40 (SD 21) days of marriage. Of the 50 couples recruited, 25 pregnancies and 18 deliveries were identified during this 1-year study. Due to challenges securing fuel from the LPG supply system, not all couples received their intervention prior to pregnancy. Regardless, couples recruited in the marriage arm had substantially more days with the intervention than couples recruited into a similar arm recruited at pregnancy (211 SD 46 vs 120 SD 45). At scale, a stove intervention targeting new marriages would cover about twice as many weeks of first pregnancies as an intervention recruiting after detection of pregnancy. CONCLUSIONS: We were able to recruit in early marriage using existing community health workers. Households recruited early in marriage had more days with clean fuel coverage than those recruited at pregnancy. Our findings indicate that recruitment at marriage is feasible and warrants further exploration for stove and other interventions targeting pregnancy-related outcomes.

6.
Dev Biol ; 465(2): 168-177, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32735790

RESUMO

Multiciliated cells (MCCs) differentiate hundreds of motile cilia that beat to drive fluid movement over various kinds of epithelia. In Xenopus, mice and human, the coiled-coil containing protein Mcidas (Mci) has been shown to be a key transcriptional regulator of MCC differentiation. We have examined Mci function in the zebrafish, another model organism that is widely used to study ciliary biology. We show that zebrafish mci is expressed specifically in the developing MCCs of the kidney tubules, but surprisingly, not in those of the nasal placodes. Mci proteins lack a DNA binding domain and associate with the cell-cycle transcription factors E2f4/5 for regulating MCC-specific gene expression. We found that while the zebrafish Mci protein can complex with the E2f family members, its sequence as well as the requirement and sufficiency for MCC differentiation has diverged significantly from Mci homologues of the tetrapods. We also provide evidence that compared to Gmnc, another related coiled-coil protein that has recently been shown to regulate MCC development upstream of Mci, the Mci protein originated later within the vertebrate lineage. Based on these data, we argue that in contrast to Gmnc, which has a vital role in the genetic circuitry that drives MCC formation, the requirement of Mci, at least in the zebrafish, is not obligatory.

7.
PLoS One ; 15(8): e0236355, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833993

RESUMO

INTRODUCTION: Neonatal infections are a common cause of death in India, but many families cannot access appropriate hospitals for its treatment due to various reasons. We implemented the World Health Organization PSBI management guideline when referral is not feasible within the public health system in Pune, India to evaluate feasibility, barriers and facilitators for its implementation. METHODS: A national-level consultative meeting between government officials and study partners resulted in a consensus on adaptation and implementation in four demonstration sites in selected states in India. At the state and district levels, similar meetings to plan the implementation strategy and roles were held between KEM Hospital Research Centre (KEMHRC) Pune and the public health system Pune, Maharashtra. The public health system was responsible for implementation of the intervention at eight tribal primary health centres (PHC) in Pune district, India, including delivering the intervention and ensuring supplies of all commodities while KEMHRC was responsible for technical support including training of health workers, assistance in PSBI identification and management, data collection and documentation of the implementation strategy. RESULTS: A total of 175 young infants with PSBI were identified and managed. Of these, 34 had critical illness (CI), 46 had clinical severe infection (CSI) and 10 were infants aged 0-6 days with fast breathing (FB) while 85 infants aged 7-59 days had fast breathing. Assuming a 10% incidence of PSBI among all live births, with 3071 live births recorded, the actual incidence of PSBI found in the study was 5.7%, resulting in an actual coverage was of 57%. Among the 90 infants with CI, CSI and FB in 0-6 days, who were advised referral to government tertiary care centre as per the PSBI guideline algorithm, 81 (90%) accepted referral while 9 (10%) refused and were offered treatment at primary health centres (PHC) with a seven-day course of injectable gentamicin and oral amoxicillin. All infants with FB in 7-59 days were offered treatment at PHCs as per the PSBI guideline algorithm with a seven-day course of oral amoxicillin. All except six infants who died and one with FB in 7-59 days, who was lost to follow-up, were successfully cured. Of the six who died, five had CSI and one had CI. Among the 81 infants with CI, CSI and FB in 0-6 days who accepted referral; 48(53%) were successfully referred to government tertiary facility while 33 (36.6%) preferred to visit a private tertiary health facility. The implementation strategy demonstrated a relatively high fidelity, acceptance and intervention penetration. Lack of training and confidence of the public health staff were major challenges faced, which were resolved to a large extent through supportive supervision and re-trainings. CONCLUSION: Management of PSBI is feasible to implement in out-patient facilities in the public health system, but technical support to the health system is required to jump-start the process. Fast breathing in 7-59 days old infants can be managed with oral amoxicillin without referral. A sustainable adoption of this intervention by the health system can lead to decrease in neonatal mortality and morbidity.


Assuntos
Amoxicilina/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Mortalidade Infantil , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/microbiologia , Estudos de Viabilidade , Feminino , Gentamicinas/uso terapêutico , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Masculino , Grupos Populacionais , Organização Mundial da Saúde
8.
Biol Open ; 9(5)2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409296

RESUMO

Reissner fibre (RF), discovered by the 19th-century German anatomist Ernst Reissner, is a filamentous structure present in cerebrospinal fluid (CSF). RF forms by aggregation of a glycoprotein called SCO-spondin (Sspo), but its function has remained enigmatic. Recent studies have shown that zebrafish sspo mutants develop a curved embryonic body axis. Zebrafish embryos with impaired cilia motility also develop curved bodies, which arises from failure of expression of urotensin related peptide (urp) genes in CSF-contacting neurons (CSF-cNs), impairing downstream signalling in trunk muscles. Here, we show that sspo mutants can survive into adulthood, but display severe curvatures of the vertebral column, resembling the common human spine disorder idiopathic scoliosis (IS). sspo mutants also exhibit significant reduction of urp gene expression from CSF-cNs. Consistent with epinephrine in CSF being bound by RF and required for urp expression, treating sspo mutants with this catecholamine rescued expression of the urp genes and axial defects. More strikingly, providing Urp2, specifically in the CSF-cNs, rescued body curvature of sspo homozygotes during larval stages as well as in the adult. These findings bridge existing gaps in our knowledge between cilia motility, RF, Urp signalling and spine deformities, and suggest that targeting the Urotensin pathway could provide novel therapeutic avenues for IS.

9.
Eur Respir J ; 56(3)2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32366494

RESUMO

Interpretation of spirometry involves comparing lung function parameters with predicted values to determine the presence/severity of the disease. The Global Lung Function Initiative (GLI) derived reference equations for healthy individuals aged 3-95 years from multiple populations but highlighted India as a "particular group" for whom further data are needed. We aimed to derive predictive equations for spirometry in a rural Western Indian adult population.We used spirometry data previously collected (2008-2012) from 1258 healthy adults (aged 18 years and over) by the Vadu Health and Demographic Surveillance System. We constructed sex-stratified prediction equations for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC using the Generalised Additive Model for Location, Scale and Shape (GAMLSS) method to derive the best fitting model of each outcome as a function of age and height.When compared with GLI Ethnicity Codes 1 (White Caucasian) and 5 (Other/Mixed), the Western Indian adult population appears to have lower lung volumes on average, though the FEV1/FVC ratio is comparable. Both age and height were predictive of mean FEV1 and FVC; and for females, the variability of response was also dependent on age. FEV1/FVC appears to have a very strong age effect, highlighting the limitations of using a fixed 0.7 cut-off value.The use of GLI normal values may result in overdiagnosis of lung disease in this population. We recommend that the values and equations generated from this study should be used by physicians in their routine practice for diagnosing disease and its severity in adults from the Western Indian population.

10.
Trends Cell Biol ; 30(4): 259-262, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32200804

RESUMO

Esoteric organelles called deuterosomes have been implicated in the explosive production of hundreds of basal bodies in multiciliated cells (MCCs). A new study by Meunier, Holland, and colleagues now shows that deuterosomes are dispensable, re-igniting the quest for mechanisms driving basal body biogenesis in this specialized ciliated cell type.

11.
PLoS Genet ; 16(3): e1008655, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32196499

RESUMO

E2f5 is a member of the E2f family of transcription factors that play essential roles during many cellular processes. E2f5 was initially characterized as a transcriptional repressor in cell proliferation studies through its interaction with the Retinoblastoma (Rb) protein for inhibition of target gene transcription. However, the precise roles of E2f5 during embryonic and post-embryonic development remain incompletely investigated. Here, we report that zebrafish E2f5 plays critical roles during spermatogenesis and multiciliated cell (MCC) differentiation. Zebrafish e2f5 mutants develop exclusively as infertile males. In the mutants, spermatogenesis is arrested at the zygotene stage due to homologous recombination (HR) defects, which finally leads to germ cell apoptosis. Inhibition of cell apoptosis in e2f5;tp53 double mutants rescued ovarian development, although oocytes generated from the double mutants were still abnormal, characterized by aberrant distribution of nucleoli. Using transcriptome analysis, we identified dmc1, which encodes an essential meiotic recombination protein, as the major target gene of E2f5 during spermatogenesis. E2f5 can bind to the promoter of dmc1 to promote HR, and overexpression of dmc1 significantly increased the fertilization rate of e2f5 mutant males. Besides gametogenesis defects, e2f5 mutants failed to develop MCCs in the nose and pronephric ducts during early embryonic stages, but these cells recovered later due to redundancy with E2f4. Moreover, we demonstrate that ion transporting principal cells in the pronephric ducts, which remain intercalated with the MCCs, do not contain motile cilia in wild-type embryos, while they generate single motile cilia in the absence of E2f5 activity. In line with this, we further show that E2f5 activates the Notch pathway gene jagged2b (jag2b) to inhibit the acquisition of MCC fate as well as motile cilia differentiation by the neighboring principal cells. Taken together, our data suggest that E2f5 can function as a versatile transcriptional activator and identify novel roles of the protein in spermatogenesis as well as MCC differentiation during zebrafish development.


Assuntos
Fator de Transcrição E2F5/metabolismo , Espermatogênese/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Animais , Proteínas de Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , Cílios/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fator de Transcrição E2F5/genética , Masculino , Receptores Notch/metabolismo , Transdução de Sinais , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
13.
Development ; 146(8)2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30936178

RESUMO

GEMC1 and MCIDAS are geminin family proteins that transcriptionally activate E2F4/5-target genes during multiciliogenesis, including Foxj 1 and Ccno Male mice that lacked Gemc1, Mcidas or Ccno were found to be infertile, but the origin of this defect has remained unclear. Here, we show that all three genes are necessary for the generation of functional multiciliated cells in the efferent ducts that are required for spermatozoa to enter the epididymis. In mice that are mutant for Gemc1, Mcidas or Ccno, we observed a similar spectrum of phenotypes, including thinning of the seminiferous tubule epithelia, dilation of the rete testes, sperm agglutinations in the efferent ducts and lack of spermatozoa in the epididymis (azoospermia). These data suggest that defective efferent duct development is the dominant cause of male infertility in these mouse models, and this likely extends to individuals with the ciliopathy reduced generation of multiple motile cilia with mutations in MCIDAS and CCNO.


Assuntos
Proteínas de Ciclo Celular/deficiência , DNA Glicosilases/deficiência , Ductos Ejaculatórios/metabolismo , Ductos Ejaculatórios/patologia , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Proteínas Nucleares/deficiência , Animais , Proteínas de Ciclo Celular/genética , Linhagem Celular , DNA Glicosilases/genética , Epididimo/metabolismo , Epididimo/patologia , Imunofluorescência , Humanos , Imuno-Histoquímica , Infertilidade Masculina/genética , Masculino , Camundongos , Camundongos Mutantes , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase em Tempo Real , Testículo/metabolismo , Testículo/patologia
14.
Environ Int ; 127: 540-549, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30981912

RESUMO

Household air pollution from the combustion of biomass and coal is estimated to cause approximately 780,000 premature deaths a year in India. The government has responded by promoting uptake of liquefied petroleum gas (LPG) by tens of millions of poor rural families. Many poor households with new LPG stoves, however, continue to partially use traditional smoky chulhas. Our primary objective was to evaluate three strategies to transition pregnant women in rural Maharashtra to exclusive use of LPG for cooking. We also measured reductions in kitchen concentrations of PM2.5 before and after our interventions. Our core intervention was a free stove, 2 free LPG cylinders (one on loan until delivery), and repeated health messaging. We measured stove usage of both the traditional and intervention stoves until delivery. In households that received the core intervention, an average of 66% days had no indoor cooking on a chulha. In an adjacent area, we evaluated a conditional cash transfer (CCT) based on usage of LPG in addition to the core intervention. Results were less successful, due to challenges implementing the CCT. Pregnant women in a third nearby area received the core intervention plus a maximum of one 14.2 kg cylinder per month of free fuel. In their homes, 90% of days had no indoor cooking on a chulha. On average, exclusive LPG use decreased kitchen concentrations of PM2.5 by approximately 85% (from 520 to 72 µg/m3). 85% of participating households agreed to pay the deposit on the 2nd cylinder. This high purchase rate suggests they valued how the second cylinder permitted continuous LPG supply. A program to increase access to second cylinders may, thus, be a straightforward way to encourage use of clean fuels in rural areas.


Assuntos
Culinária , Petróleo/efeitos adversos , Culinária/métodos , Utensílios de Alimentação e Culinária , Feminino , Humanos , Índia , Projetos Piloto , Gravidez , Gestantes , População Rural , Fumaça , Adulto Jovem
15.
Vaccine ; 37(17): 2331-2339, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30914221

RESUMO

OBJECTIVE: Delayed vaccination increases the susceptibility window for vaccine preventable diseases. Our analysis estimates the proportion of children between 10 and 23 months of age with delayed vaccination in India and the associated socio-demographic, maternal and child related factors. METHODS: We used individual level data from the National Family and Health Survey 4, conducted in 2015-2016. The primary outcome of the study was delayed vaccination for BCG, DPT- 1st dose and Measles. Delayed vaccination for each vaccine was defined as administration of the vaccine dose after 28 days of the minimum recommended age, as per the national immunization schedule in India. We estimated the proportion of children with delayed vaccination for each vaccine and used multivariable logistic regression to explore associated factors. FINDINGS: In the current analysis, 23.1%, 29.3% and 34.8% of children aged 10 to 23 months had delayed vaccination for BCG, DPT-1st dose and Measles respectively. Children from Muslim families (aOR 1.36 for BCG; aOR 1.45 for DPT-1; aOR 1.26 for Measles); birth weight < 2000 g (aOR 2.33 for BCG; aOR 1.53 for DPT-1; aOR 1.36 for Measles) had higher odds of delayed vaccination. Lower maternal education and belonging to a family from lower wealth quintile had higher odds of delayed vaccination. Children of mothers who had tetanus toxoid immunization during pregnancy had lower odds of delayed vaccination (aOR 0.69 for BCG; aOR 0.76 for DPT-1; aOR 0.78 for Measles). CONCLUSION: The proportion of children with delayed vaccination is high in India. Vaccine timeliness should be a core indicator of the immunization program with greater focus on groups with higher chances of delayed vaccination i.e. home birth, low birth weight new-borns, poorer households, children of mothers with lower education and children from Muslim families.


Assuntos
Programas de Imunização , Esquemas de Imunização , Tempo para o Tratamento , Vacinação , Fatores Etários , Pré-Escolar , Análise Fatorial , Saúde da Família , Feminino , Inquéritos Epidemiológicos , Humanos , Programas de Imunização/normas , Programas de Imunização/estatística & dados numéricos , Índia/epidemiologia , Lactente , Recém-Nascido , Masculino , Avaliação de Resultados em Cuidados de Saúde , Fatores Socioeconômicos , Fatores de Tempo , Vacinação/normas , Vacinação/estatística & dados numéricos
16.
Front Genet ; 10: 23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881373

RESUMO

Developmental defects in motile cilia, arising from genetic abnormalities in one or more ciliary genes, can lead to a common ciliopathy known as primary ciliary dyskinesia (PCD). Functional studies in model organisms undertaken to understand PCD or cilia biogenesis have identified 100s of genes regulated by Foxj1, the master regulator of motile ciliogenesis. However, limited systems based studies have been performed to elucidate proteins or network/s crucial to the motile ciliary interactome, although this approach holds promise for identification of multiple cilia-associated genes, which, in turn, could be utilized for screening and early diagnosis of the disease. Here, based on the assumption that FOXJ1-mediated regulatory and signaling networks are representative of the motile cilia interactome, we have constructed and analyzed the gene regulatory and protein-protein interaction network (PPIN) mediated by FOXJ1. The predicted FOXJ1 regulatory network comprises of 424 directly and 148 indirectly regulated genes. Additionally, based on gene ontology analysis, we have associated 17 directly and 6 indirectly regulated genes with possible ciliary roles. Topological and perturbation analyses of the PPIN (6927 proteins, 40,608 interactions) identified 121 proteins expressed in ciliated cells, which interact with multiple proteins encoded by FoxJ1 induced genes (FIG) as important interacting proteins (IIP). However, it is plausible that IIP transcriptionally regulated by FOXJ1 and/or differentially expressed in PCD are likely to have crucial roles in motile cilia. We have found 20 de-regulated topologically important effector proteins in the FOXJ1 regulatory network, among which some (PLSCR1, SSX2IP, ACTN2, CDC42, HSP90AA1, PIAS4) have previously reported ciliary roles. Furthermore, based on pathway enrichment of these proteins and their primary interactors, we have rationalized their possible roles in the ciliary interactome. For instance, 5 among these novel proteins that are involved in cilia associated signaling pathways (like Notch, Wnt, Hedgehog, Toll-like receptor etc.) could be 'topologically important signaling proteins.' Therefore, based on this FOXJ1 network study we have predicted important effectors in the motile cilia interactome, which are possibly associated with ciliary biology and/or function and are likely to further our understanding of the pathophysiology in ciliopathies like PCD.

17.
Development ; 146(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30877126

RESUMO

Motile cilia on multiciliated cells (MCCs) function in fluid clearance over epithelia. Studies with Xenopus embryos and individuals with the congenital respiratory disorder reduced generation of multiple motile cilia (RGMC), have implicated the nuclear protein MCIDAS (MCI), in the transcriptional regulation of MCC specification and differentiation. Recently, a paralogous protein, geminin coiled-coil domain containing (GMNC), was also shown to be required for MCC formation. Surprisingly, in contrast to the presently held view, we find that Mci mutant mice can specify MCC precursors. However, these precursors cannot produce multiple basal bodies, and mature into single ciliated cells. We identify an essential role for MCI in inducing deuterosome pathway components for the production of multiple basal bodies. Moreover, GMNC and MCI associate differentially with the cell-cycle regulators E2F4 and E2F5, which enables them to activate distinct sets of target genes (ciliary transcription factor genes versus basal body amplification genes). Our data establish a previously unrecognized two-step model for MCC development: GMNC functions in the initial step for MCC precursor specification. GMNC induces Mci expression that drives the second step of basal body production for multiciliation.


Assuntos
Proteínas de Ciclo Celular/fisiologia , Cílios/fisiologia , Camundongos Mutantes , Proteínas Nucleares/fisiologia , Animais , Corpos Basais/fisiologia , Proteínas de Transporte/fisiologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Núcleo Celular/fisiologia , Ciliopatias , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/genética , Domínios Proteicos , Peixe-Zebra
18.
Nat Genet ; 50(12): 1666-1673, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420648

RESUMO

Straightening of the body axis is a major morphogenetic event that produces the typical head-to-tail shape of the vertebrate embryo. Defects in axial straightening can lead to debilitating disorders such as idiopathic scoliosis, characterized by three-dimensional curvatures of the spine1. Although abnormal cerebrospinal fluid (CSF) flow has been implicated in the development of idiopathic scoliosis2, the molecular mechanisms operating downstream of CSF flow remain obscure. Here we show that, in zebrafish embryos, cilia-driven CSF flow transports adrenergic signals that induce urotensin neuropeptides in CSF-contacting neurons along the spinal cord. Urotensins activate their receptor on slow-twitch muscle fibers of the dorsal somite; the contraction of these fibers likely results in straightening of the body axis. Consistent with this, mutation of the urotensin receptor resulted in severe scoliosis in adult zebrafish, closely mimicking the human disorder. These findings suggest that disruption of urotensin signaling by impaired CSF flow could be a critical etiological factor underlying the pathology of idiopathic scoliosis.


Assuntos
Líquido Cefalorraquidiano/fisiologia , Cílios/fisiologia , Urotensinas/genética , Animais , Animais Geneticamente Modificados , Padronização Corporal , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento , Morfogênese/fisiologia , Neuropeptídeos/genética , Transdução de Sinais/genética , Medula Espinal/embriologia , Vertebrados/embriologia , Peixe-Zebra/embriologia , Peixe-Zebra/genética
19.
Ecohealth ; 15(4): 768-776, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315510

RESUMO

Conditional cash transfers (CCTs)-cash payments provided to households or specific household members who meet defined conditions or fulfill certain behaviors-have been extensively used in India to encourage antenatal care, institutional delivery, and vaccination. This paper describes the social design and technical development of a low-cost, meal-counting stove use monitor (the Pink Key) that enables a CCT based on liquefied petroleum gas (LPG) usage and presents pilot data from its testing and the initial deployment. The system consists of a sensing harness attached to a two-burner LPG stove and an easily removable datalogger. For each cooking event with LPG, households receive 2 rupees-less than the cost of fuel, but enough to partially defray LPG refill costs. The system could enable innovative "self-monitoring" at a large scale-participants initiate the CCT by bringing their Pink Key to antenatal clinic visits, where care providers download data and initiate payments, and participants return the sensor to their stove at home. The system aligns with existing Indian programs to improve health among poor, pregnant women, and contributes a new method to encourage the use of clean cooking technologies.


Assuntos
Técnicas de Observação do Comportamento/instrumentação , Culinária/economia , Culinária/instrumentação , Financiamento Governamental , Poluição do Ar em Ambientes Fechados/prevenção & controle , Desenho de Equipamento/instrumentação , Características da Família , Feminino , Humanos , Índia , Motivação , Gravidez , População Rural
20.
Dev Biol ; 443(2): 165-172, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30218642

RESUMO

Multiciliated cells (MCCs) differentiate arrays of motile cilia that beat to drive fluid flow over epithelia. Recent studies have established two Geminin family coiled-coil containing nuclear regulatory proteins, Gmnc and Multicilin (Mci), in the specification and differentiation of the MCCs. Both Gmnc and Mci are devoid of a DNA binding domain: they regulate transcription by associating with E2f family transcription factors, notably E2f4 and E2f5. Here, we have studied the relative contribution of these two E2f factors in MCC development using the zebrafish embryo, which differentiates MCCs within kidney tubules and the nose. We found that while E2f4 is fully dispensable, E2f5 is essential for MCCs to form in the kidney tubules. Moreover, using a variety of double mutant combinations we show that E2f5 has a more prominent role in MCC development in the zebrafish than E2f4. This contrasts with current evidence from the mouse, where E2f4 seems to be more important. Thus, distinct combinatorial activities of the E2f4 and E2f5 proteins regulate the specification and differentiation of MCCs in zebrafish and mice.


Assuntos
Fator de Transcrição E2F4/metabolismo , Fator de Transcrição E2F5/metabolismo , Peixe-Zebra/embriologia , Animais , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/genética , Cílios/metabolismo , Cílios/fisiologia , Fator de Transcrição E2F4/fisiologia , Fator de Transcrição E2F5/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Células HEK293 , Humanos , Proteínas Nucleares/metabolismo , Fatores de Transcrição , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA