Sample records for abnormal spindle-like microcephaly

  1. Primary microcephaly caused by novel compound heterozygous mutations in ASPM

    PubMed Central

    Okamoto, Nobuhiko; Kohmoto, Tomohiro; Naruto, Takuya; Masuda, Kiyoshi; Imoto, Issei

    2018-01-01

    Autosomal recessive primary microcephaly (microcephaly primary hereditary, MCPH) is a genetically heterogeneous rare developmental disorder that is characterized by prenatal onset of abnormal brain growth, which leads to intellectual disability of variable severity. We report a 5-year-old male who presented with a severe form of primary microcephaly. Targeted panel sequencing revealed compound heterozygous truncating mutations of the abnormal spindle-like microcephaly-associated (ASPM) gene, which confirmed the MCPH5 diagnosis. A novel NM_018136.4: c.9742_9745del (p.Lys3248Serfs*13) deletion mutation was identified. PMID:29644084

  2. Primary microcephaly caused by novel compound heterozygous mutations in ASPM.

    PubMed

    Okamoto, Nobuhiko; Kohmoto, Tomohiro; Naruto, Takuya; Masuda, Kiyoshi; Imoto, Issei

    2018-01-01

    Autosomal recessive primary microcephaly (microcephaly primary hereditary, MCPH) is a genetically heterogeneous rare developmental disorder that is characterized by prenatal onset of abnormal brain growth, which leads to intellectual disability of variable severity. We report a 5-year-old male who presented with a severe form of primary microcephaly. Targeted panel sequencing revealed compound heterozygous truncating mutations of the abnormal spindle-like microcephaly-associated ( ASPM ) gene, which confirmed the MCPH5 diagnosis. A novel NM_018136.4: c.9742_9745del (p.Lys3248Serfs*13) deletion mutation was identified.

  3. Congenital microcephaly: A diagnostic challenge during Zika epidemics.

    PubMed

    Alvarado-Socarras, Jorge L; Idrovo, Álvaro J; Contreras-García, Gustavo A; Rodriguez-Morales, Alfonso J; Audcent, Tobey A; Mogollon-Mendoza, Adriana C; Paniz-Mondolfi, Alberto

    2018-02-19

    The multiple, wide and diverse etiologies of congenital microcephaly are complex and multifactorial. Recent advances in genetic testing have improved understanding of novel genetic causes of congenital microcephaly. The recent Zika virus (ZIKV) epidemic in Latin America has highlighted the need for a better understanding of the underlying pathological mechanisms of microcephaly including both infectious and non-infectious causes. The diagnostic approach to microcephaly needs to include potential infectious and genetic etiologies, as well as environmental in-utero exposures such as alcohol, toxins, and medications. Emerging genetic alterations linked to microcephaly include abnormal mitotic microtubule spindle structure and abnormal function of centrosomes. We discuss the diagnostic challenge of congenital microcephaly in the context of understanding the links with ZIKV emergence as a new etiological factor involved in this birth defect. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease.

    PubMed

    Li, Rui; Sun, Le; Fang, Ai; Li, Peng; Wu, Qian; Wang, Xiaoqun

    2017-11-01

    The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial (RG) and outer radial glial (oRG) cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in culture dishes successfully, however we demonstrate a new paradigm that recapitulates neocortical development process with VZ, OSVZ formation and the lamination organization of cortical layer structure. In addition, using patient-specific induced pluripotent stem cells (iPSCs) with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.

  5. Genetic Causes of Microcephaly and Lessons for Neuronal Development

    PubMed Central

    Gilmore, Edward C.; Walsh, Christopher A.

    2012-01-01

    The study of human developmental microcephaly is providing important insights into brain development. It has become clear that developmental microcephalies are associated with abnormalities in cellular production, and that the pathophysiology of microcephaly provides remarkable insights into how the brain generates the proper number of neurons that determine brain size. Most of the genetic causes of ‘primary’ developmental microcephaly (i.e., not associated with other syndromic features) are associated with centrosomal abnormalities. In addition to other functions, centrosomal proteins control the mitotic spindle, which is essential for normal cell proliferation during mitosis. However, the brain is often uniquely affected when microcephaly genes are mutated implying special centrosomal related functions in neuronal production. Although models explaining how this could occur have some compelling data, they are not without controversy. Interestingly, some of the microcephaly genes show evidence that they were targets of evolutionary selection in primates and human ancestors, suggesting potential evolutionary roles in controlling neuronal number and brain volume across species. Mutations in DNA repair pathway genes also lead to microcephaly. Double stranded DNA breaks appear to be a prominent type of damage that needs to be repaired during brain development, yet why defects in DNA repair affect the brain preferentially and if DNA repair relates to centrosome function, are not clearly understood. PMID:24014418

  6. Microcephaly: general considerations and aids to nosology.

    PubMed

    Opitz, J M; Holt, M C

    1990-01-01

    Microcephaly is defined as an occipito-frontal head circumference (OFC) 2 or more standard deviations below the mean for age and sex using the new Roche et al. [Pediatrics 1987;79:706-712] charts, and corrected for parental OFC by the method of Weaver and Christian [J Pediatr 1980;96:990-994]. "Relative" microcephaly, i.e., a small head on a small child, may be associated with a much better intellectual prognosis than absolute microcephaly, although the average IQ of children with absolute microcephaly ascertained in a normal school system is normal when compared with that of appropriate control children. "Primary" microcephaly means an abnormal OFC at birth (corrected for gestational age and length), and "secondary" microcephaly a normal birth OFC with later, acquired microcephaly due to deceleration of brain growth reflecting infection, trauma, intoxication, metabolic disease, the Rett syndrome, or a true CNS degenerative disease. Some cases of syndromal microcephaly may be associated with normal intelligence including some "primordial dwarfs," children with Dubowitz syndrome, FAS, mild SC-Roberts syndrome, and an occasional Brachmann-de Lange individual. The nosology of (syndromal) microcephaly is extraordinarily complex and requires the assistance of special library resources and information retrieval expertise. At a minimum, it requires McKusick's Catalog of Mendelian Inheritance in Man (MIM); however, we find that our work is greatly enhanced by recently developed electronic databases such as MIM-online (OMIM), POSSUM, SYNDROME, and MEDLINE, as well. Three groups of syndromal and non-syndromal microcephaly are discussed selectively in order to illustrate the marvels of pleiotropy in human development and its abnormalities and the difficulties encountered in splitting and lumping entities with overlapping manifestations.

  7. Practice Parameter: Evaluation of the child with microcephaly (an evidence-based review)

    PubMed Central

    Ashwal, Stephen; Michelson, David; Plawner, Lauren; Dobyns, William B.

    2009-01-01

    Objective: To make evidence-based recommendations concerning the evaluation of the child with microcephaly. Methods: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a 4-tiered scheme of evidence classification. Results: Microcephaly is an important neurologic sign but there is nonuniformity in its definition and evaluation. Microcephaly may result from any insult that disturbs early brain growth and can be seen in association with hundreds of genetic syndromes. Annually, approximately 25,000 infants in the United States will be diagnosed with microcephaly (head circumference <−2 SD). Few data are available to inform evidence-based recommendations regarding diagnostic testing. The yield of neuroimaging ranges from 43% to 80%. Genetic etiologies have been reported in 15.5% to 53.3%. The prevalence of metabolic disorders is unknown but is estimated to be 1%. Children with severe microcephaly (head circumference <−3 SD) are more likely (∼80%) to have imaging abnormalities and more severe developmental impairments than those with milder microcephaly (−2 to −3 SD; ∼40%). Coexistent conditions include epilepsy (∼40%), cerebral palsy (∼20%), mental retardation (∼50%), and ophthalmologic disorders (∼20% to ∼50%). Recommendations: Neuroimaging may be considered useful in identifying structural causes in the evaluation of the child with microcephaly (Level C). Targeted and specific genetic testing may be considered in the evaluation of the child with microcephaly who has clinical or imaging abnormalities that suggest a specific diagnosis or who shows no evidence of an acquired or environmental etiology (Level C). Screening for coexistent conditions such as cerebral palsy, epilepsy, and sensory deficits may also be considered (Level C). Further study is needed regarding the yield of diagnostic testing in children with microcephaly. GLOSSARY CP = cerebral palsy; GDD = global developmental delay; HC = head

  8. Molecular genetics of human primary microcephaly: an overview

    PubMed Central

    2015-01-01

    Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder that is characterised by microcephaly present at birth and non-progressive mental retardation. Microcephaly is the outcome of a smaller but architecturally normal brain; the cerebral cortex exhibits a significant decrease in size. MCPH is a neurogenic mitotic disorder, though affected patients demonstrate normal neuronal migration, neuronal apoptosis and neural function. Twelve MCPH loci (MCPH1-MCPH12) have been mapped to date from various populations around the world and contain the following genes: Microcephalin, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1 and CDK6. It is predicted that MCPH gene mutations may lead to the disease phenotype due to a disturbed mitotic spindle orientation, premature chromosomal condensation, signalling response as a result of damaged DNA, microtubule dynamics, transcriptional control or a few other hidden centrosomal mechanisms that can regulate the number of neurons produced by neuronal precursor cells. Additional findings have further elucidated the microcephaly aetiology and pathophysiology, which has informed the clinical management of families suffering from MCPH. The provision of molecular diagnosis and genetic counselling may help to decrease the frequency of this disorder. PMID:25951892

  9. Dominantly inherited syndrome of microcephaly and cleft palate.

    PubMed

    Halal, F

    1983-05-01

    Two sisters and their mother had a syndrome of microcephaly, cleft palate, and variable anomalies such as unusual facial appearance, hypotelorism, abnormal retinal pigmentation, maxillary hypoplasia, goiter, camptodactyly, mild mental retardation, and abnormal dermatoglyphics. This is an evidently dominantly inherited trait, either autosomal or X-linked.

  10. Prevalence of Antibodies to Zika Virus in Mothers from Hawaii Who Delivered Babies with and without Microcephaly between 2009-2012.

    PubMed

    Kumar, Mukesh; Ching, Lauren; Astern, Joshua; Lim, Eunjung; Stokes, Alexander J; Melish, Marian; Nerurkar, Vivek R

    2016-12-01

    Zika virus (ZIKV) is an emerging mosquito-borne pathogen. ZIKV infection is linked to the development of severe fetal abnormalities that include spontaneous abortion, stillbirth, hydranencephaly, and microcephaly. ZIKV outbreaks have been recorded in the United States. We recently demonstrated the first congenital ZIKV infection in the United States. In this study, we investigated archived blood samples from six mothers who gave birth to babies with microcephaly and 12 mothers who gave birth to healthy babies in Hawaii between 2009 and 2012. We tested maternal blood for the presence of ZIKV IgM and IgG antibodies using commercially available human ZIKV IgM and IgG ELISA kits. Blood from one mother who delivered babies with microcephaly tested positive for ZIKV IgM antibody (16.6%) and blood from three mothers tested positive for ZIKV IgG antibody (50%). ZIKV showed a trend toward significance with microcephaly. ZIKV IgG antibody positive mothers were more likely to deliver babies with microcephaly than mothers who were negative for ZIKV IgG antibodies (Odds ratio [OR] = 11.0, 95% confidence interval [CI] = 0.8-147.9, p = 0.083). Similarly, ZIKV IgM antibody positive mothers were also more likely to deliver babies with microcephaly than mothers who were negative for ZIKV IgM antibody (OR = 6.8, 95% CI = 0.2-195.1). These data provide further evidence of a link between ZIKV infection and microcephaly and suggests presence of ZIKV positive cases and associated microcephaly in the United States as early as 2009.

  11. Possible Association Between Zika Virus Infection and Microcephaly - Brazil, 2015.

    PubMed

    Schuler-Faccini, Lavinia; Ribeiro, Erlane M; Feitosa, Ian M L; Horovitz, Dafne D G; Cavalcanti, Denise P; Pessoa, André; Doriqui, Maria Juliana R; Neri, Joao Ivanildo; Neto, Joao Monteiro de Pina; Wanderley, Hector Y C; Cernach, Mirlene; El-Husny, Antonette S; Pone, Marcos V S; Serao, Cassio L C; Sanseverino, Maria Teresa V

    2016-01-29

    In early 2015, an outbreak of Zika virus, a flavivirus transmitted by Aedes mosquitoes, was identified in northeast Brazil, an area where dengue virus was also circulating. By September, reports of an increase in the number of infants born with microcephaly in Zika virus-affected areas began to emerge, and Zika virus RNA was identified in the amniotic fluid of two women whose fetuses had been found to have microcephaly by prenatal ultrasound. The Brazil Ministry of Health (MoH) established a task force to investigate the possible association of microcephaly with Zika virus infection during pregnancy and a registry for incident microcephaly cases (head circumference ≥2 standard deviations [SD] below the mean for sex and gestational age at birth) and pregnancy outcomes among women suspected to have had Zika virus infection during pregnancy. Among a cohort of 35 infants with microcephaly born during August-October 2015 in eight of Brazil's 26 states and reported to the registry, the mothers of all 35 had lived in or visited Zika virus-affected areas during pregnancy, 25 (71%) infants had severe microcephaly (head circumference >3 SD below the mean for sex and gestational age), 17 (49%) had at least one neurologic abnormality, and among 27 infants who had neuroimaging studies, all had abnormalities. Tests for other congenital infections were negative. All infants had a lumbar puncture as part of the evaluation and cerebrospinal fluid (CSF) samples were sent to a reference laboratory in Brazil for Zika virus testing; results are not yet available. Further studies are needed to confirm the association of microcephaly with Zika virus infection during pregnancy and to understand any other adverse pregnancy outcomes associated with Zika virus infection. Pregnant women in Zika virus-affected areas should protect themselves from mosquito bites by using air conditioning, screens, or nets when indoors, wearing long sleeves and pants, using permethrin-treated clothing and gear

  12. Mucinous breast carcinoma with myoepithelial-like spindle cells.

    PubMed

    Miyake, Yasuyuki; Hirokawa, Mitsuyoshi; Norimatsu, Yoshiaki; Kanahara, Takuo; Monobe, Yasumasa; Ohno, Setsuyo; Miyamoto, Tomoyuki; Yakushiji, Hiromasa; Sakaguchi, Takuya; Aratake, Yatsuki; Ohno, Eiji

    2009-06-01

    Appearance of spindle cells has been believed as a benign index of breast cytology. But, we have frequently observed the spindle cells in smears from mucinous carcinoma of the breast. Here, we characterized the biochemical nature of the spindle cells, so as to clarify their identity in cytology. Nineteen cases of breast mucinous carcinoma were used for cytological examination. The spindle cells were located at edges of tumor cell nests and in the backgrounds of cytological specimens. Immunohistological examination revealed that the spindle cells exhibited both immunoreactivity against carcinoembryonic antigen (CEA) and epithelial membrane antigen (EMA). Immunoreactivity against vimentin, cytokeratin, or alpha-smooth muscle actin was, however, not observed. The mode of distribution of biochemical markers suggests that the positive cells for anti-CEA antibody and anti-EMA antibody are tumor cells compressed by mucin, while the vimentin-positive cells are fibroblasts. We assert that the presence of spindle cells can be a characteristic feature of mucinous carcinoma of the breast. Discrimination of the spindle cells in mucinous carcinoma from myoepithelial cells and naked bipolar nuclei in benign lesions was established here. It should facilitate precise diagnosis of breast cancer. (c) 2009 Wiley-Liss, Inc.

  13. Microcephaly

    MedlinePlus

    ... possibly even below the first percentile for your baby's age and sex. A child with more severe microcephaly may also have a backward-sloping forehead. When to see a doctor Chances are your doctor will detect microcephaly at the baby's birth or at a regular well-baby checkup. ...

  14. Computational and Organotypic Modeling of Microcephaly ...

    EPA Pesticide Factsheets

    Microcephaly is associated with reduced cortical surface area and ventricular dilations. Many genetic and environmental factors precipitate this malformation, including prenatal alcohol exposure and maternal Zika infection. This complexity motivates the engineering of computational and experimental models to probe the underlying molecular targets, cellular consequences, and biological processes. We describe an Adverse Outcome Pathway (AOP) framework for microcephaly derived from literature on all gene-, chemical-, or viral- effects and brain development. Overlap with NTDs is likely, although the AOP connections identified here focused on microcephaly as the adverse outcome. A query of the Mammalian Phenotype Browser database for ‘microcephaly’ (MP:0000433) returned 85 gene associations; several function in microtubule assembly and centrosome cycle regulated by (microcephalin, MCPH1), a gene for primary microcephaly in humans. The developing ventricular zone is the likely target. In this zone, neuroprogenitor cells (NPCs) self-replicate during the 1st trimester setting brain size, followed by neural differentiation of the neocortex. Recent studies with human NPCs confirmed infectivity with Zika virions invoking critical cell loss (apoptosis) of precursor NPCs; similar findings have been shown with fetal alcohol or methylmercury exposure in rodent studies, leading to mathematical models of NPC dynamics in size determination of the ventricular zone. A key event

  15. Monodisperse spindle-like FeWO{sub 4} nanoparticles: Controlled hydrothermal synthesis and enhanced optical properties

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Guo, Jinxue; Zhou, Xiaoyu; Lu, Yibin

    2012-12-15

    Monodisperse FeWO{sub 4} nanoparticles with specific spindle-like morphology have been synthesized in the presence of citric acid through hydrothermal process. In the synthesis route, citric acid played four roles such as the reducing agent, chelating regents, structure-directing agent and stabilizing agents. In addition, the morphology of FeWO{sub 4} was dramatically tuned by the pH value of the precursor medium. The optical properties of FeWO{sub 4} were investigated with UV-Vis spectra and photoluminescence spectroscopy. The photocatalytic experiments demonstrated that the decomposition efficiency of the monodisperse spindle-like FeWO{sub 4} nanoparticles is 74% after 30 min of UV irradiation, which displayed remarkable enhancedmore » photodegradation activity compared with ordinary FeWO{sub 4} sample (57%) and normal TiO{sub 2} photocatalysts P-25 (56%). - Monodisperse spindle-like FeWO{sub 4} nanoparticles with enhanced photocatalytic activities. Highlights: Black-Right-Pointing-Pointer Monodisperse spindle-like FeWO{sub 4} were synthesized with hydrothermal method. Black-Right-Pointing-Pointer Citric acid plays key roles in the hydrothermal synthesis. Black-Right-Pointing-Pointer Their morphology can be tuned with pH value of the precursor medium. Black-Right-Pointing-Pointer They show enhanced photocatalytic activities with irradiation of UV light.« less

  16. Mutations in the kinesin-like protein Eg5 disrupting localization to the mitotic spindle.

    PubMed Central

    Sawin, K E; Mitchison, T J

    1995-01-01

    Eg5, a member of the bimC subfamily of kinesin-like microtubule motor proteins, localizes to spindle microtubules in mitosis but not to interphase microtubules. We investigated the molecular basis for spindle localization by transient transfection of Xenopus A6 cells with myc-tagged derivatives of Eg5. Expressed at constitutively high levels from a cytomegalovirus promoter, mycEg5 protein is cytoplasmic throughout interphase, begins to bind microtubules in early prophase, and remains localized to spindle and/or midbody microtubules through mitosis to the end of telophase. Both N- and C-terminal regions of Eg5 are required for this cell-cycle-regulated targeting. Eg5 also contains within its C-terminal domain a sequence conserved among bimC subfamily proteins that includes a potential p34cdc2 phosphorylation site. We show that mutation of a single threonine (T937) within this site to nonphosphorylatable alanine abolishes localization of the mutant protein to the spindle, whereas mutation of T937 to serine preserves spindle localization. We hypothesize that phosphorylation of Eg5 may regulate its localization to the spindle in the cell cycle. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:7753799

  17. Profound microcephaly, primordial dwarfism with developmental brain malformations: a new syndrome.

    PubMed

    Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; Saleem, Sahar N; Ahmed, Mahmoud K H; Issa, Mahmoud; Effat, Laila K; Kayed, Hisham F; Zaki, Maha S; Gaber, Khaled R

    2012-08-01

    We describe two sibs with a lethal form of profound congenital microcephaly, intrauterine and postnatal growth retardation, subtle skeletal changes, and poorly developed brain. The sibs had striking absent cranial vault with sloping of the forehead, large beaked nose, relatively large ears, and mandibular micro-retrognathia. Brain magnetic resonance imaging (MRI) revealed extremely simplified gyral pattern, large interhemispheric cyst and agenesis of corpus callosum, abnormally shaped hippocampus, and proportionately affected cerebellum and brainstem. In addition, fundus examination showed foveal hypoplasia with optic nerve atrophy. No abnormalities of the internal organs were found. This profound form of microcephaly was identified at 17 weeks gestation by ultrasound and fetal brain MRI helped in characterizing the developmental brain malformations in the second sib. Molecular analysis excluded mutations in potentially related genes such as RNU4ATAC, SLC25A19, and ASPM. These clinical and imaging findings are unlike that of any recognized severe forms of microcephaly which is believed to be a new microcephalic primordial dwarfism (MPD) with developmental brain malformations with most probably autosomal recessive inheritance based on consanguinity and similarly affected male and female sibs. Copyright © 2012 Wiley Periodicals, Inc.

  18. Congenital Zika Virus Infection: Beyond Neonatal Microcephaly.

    PubMed

    Melo, Adriana Suely de Oliveira; Aguiar, Renato Santana; Amorim, Melania Maria Ramos; Arruda, Monica B; Melo, Fabiana de Oliveira; Ribeiro, Suelem Taís Clementino; Batista, Alba Gean Medeiros; Ferreira, Thales; Dos Santos, Mayra Pereira; Sampaio, Virgínia Vilar; Moura, Sarah Rogéria Martins; Rabello, Luciana Portela; Gonzaga, Clarissa Emanuelle; Malinger, Gustavo; Ximenes, Renato; de Oliveira-Szejnfeld, Patricia Soares; Tovar-Moll, Fernanda; Chimelli, Leila; Silveira, Paola Paz; Delvechio, Rodrigo; Higa, Luiza; Campanati, Loraine; Nogueira, Rita M R; Filippis, Ana Maria Bispo; Szejnfeld, Jacob; Voloch, Carolina Moreira; Ferreira, Orlando C; Brindeiro, Rodrigo M; Tanuri, Amilcar

    2016-12-01

    Recent studies have reported an increase in the number of fetuses and neonates with microcephaly whose mothers were infected with the Zika virus (ZIKV) during pregnancy. To our knowledge, most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects. To describe the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurological damage associated with ZIKV infection in Brazil. We observed 11 infants with congenital ZIKV infection from gestation to 6 months in the state of Paraíba, Brazil. Ten of 11 women included in this study presented with symptoms of ZIKV infection during the first half of pregnancy, and all 11 had laboratory evidence of the infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by magnetic resonance imaging. Histopathological analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis. Description of the major lesions caused by ZIKV congenital infection. Of the 11 infants, 7 (63.6%) were female, and the median (SD) maternal age at delivery was 25 (6) years. Three of 11 neonates died, giving a perinatal mortality rate of 27.3%. The median (SD) cephalic perimeter at birth was 31 (3) cm, a value lower than the limit to consider a microcephaly case. In all patients, neurological impairments were identified, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence (ie, arthrogryposis). Results of limited testing for other causes of microcephaly, such as genetic disorders and viral and bacterial infections, were negative, and the ZIKV genome was found in both maternal and neonatal tissues (eg, amniotic fluid, cord blood, placenta, and

  19. Description of 13 Infants Born During October 2015-January 2016 With Congenital Zika Virus Infection Without Microcephaly at Birth - Brazil.

    PubMed

    van der Linden, Vanessa; Pessoa, André; Dobyns, William; Barkovich, A James; Júnior, Hélio van der Linden; Filho, Epitacio Leite Rolim; Ribeiro, Erlane Marques; Leal, Mariana de Carvalho; Coimbra, Pablo Picasso de Araújo; Aragão, Maria de Fátima Viana Vasco; Verçosa, Islane; Ventura, Camila; Ramos, Regina Coeli; Cruz, Danielle Di Cavalcanti Sousa; Cordeiro, Marli Tenório; Mota, Vivian Maria Ribeiro; Dott, Mary; Hillard, Christina; Moore, Cynthia A

    2016-12-02

    Congenital Zika virus infection can cause microcephaly and severe brain abnormalities (1). Congenital Zika syndrome comprises a spectrum of clinical features (2); however, as is the case with most newly recognized teratogens, the earliest documented clinical presentation is expected to be the most severe. Initial descriptions of the effects of in utero Zika virus infection centered prominently on the finding of congenital microcephaly (3). To assess the possibility of clinical presentations that do not include congenital microcephaly, a retrospective assessment of 13 infants from the Brazilian states of Pernambuco and Ceará with normal head size at birth and laboratory evidence of congenital Zika virus infection was conducted. All infants had brain abnormalities on neuroimaging consistent with congenital Zika syndrome, including decreased brain volume, ventriculomegaly, subcortical calcifications, and cortical malformations. The earliest evaluation occurred on the second day of life. Among all infants, head growth was documented to have decelerated as early as 5 months of age, and 11 infants had microcephaly. These findings provide evidence that among infants with prenatal exposure to Zika virus, the absence of microcephaly at birth does not exclude congenital Zika virus infection or the presence of Zika-related brain and other abnormalities. These findings support the recommendation for comprehensive medical and developmental follow-up of infants exposed to Zika virus prenatally. Early neuroimaging might identify brain abnormalities related to congenital Zika infection even among infants with a normal head circumference (4).

  20. Differential Diagnosis of Benign Spindle Cell Lesions.

    PubMed

    Magro, Gaetano

    2018-03-01

    Spindle cell lesions of the breast cover a wide spectrum of diseases ranging from reactive tumor-like lesions to high-grade malignant tumors. The recognition of the benign spindle cell tumor-like lesions (nodular fasciitis; reactive spindle cell nodule after biopsy, inflammatory pseudotumor/inflammatory myofibroblastic tumor; fascicular variant of pseudoangiomatous stromal hyperplasia) and tumors (myofibroblastoma, benign fibroblastic spindle cell tumor, leiomyoma, schwannoma, spindle cell lipoma, solitary fibrous tumor, myxoma) is crucial to avoid confusion with morphologically similar but more aggressive bland-appearing spindle cell tumors, such as desmoid-type fibromatosis, low-grade (fibromatosis-like) spindle cell carcinoma, low-grade fibrosarcoma/myofibroblastic sarcoma and dermatofibrosarcoma protuberans. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Zika Virus Associated with Microcephaly.

    PubMed

    Mlakar, Jernej; Korva, Misa; Tul, Nataša; Popović, Mara; Poljšak-Prijatelj, Mateja; Mraz, Jerica; Kolenc, Marko; Resman Rus, Katarina; Vesnaver Vipotnik, Tina; Fabjan Vodušek, Vesna; Vizjak, Alenka; Pižem, Jože; Petrovec, Miroslav; Avšič Županc, Tatjana

    2016-03-10

    A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and placenta. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inflammation. ZIKV was found in the fetal brain tissue on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain.

  2. MULTIPOLAR SPINDLE 1 (MPS1), a novel coiled-coil protein of Arabidopsis thaliana, is required for meiotic spindle organization.

    PubMed

    Jiang, Hua; Wang, Fen-Fei; Wu, Yu-Ting; Zhou, Xi; Huang, Xue-Yong; Zhu, Jun; Gao, Ju-Fang; Dong, Rui-Bin; Cao, Kai-Ming; Yang, Zhong-Nan

    2009-09-01

    The spindle is essential for chromosome segregation during meiosis, but the molecular mechanism of meiotic spindle organization in higher plants is still not well understood. Here, we report on the identification and characterization of a plant-specific protein, MULTIPOLAR SPINDLE 1 (MPS1), which is involved in spindle organization in meiocytes of Arabidopsis thaliana. The homozygous mps1 mutant exhibits male and female sterility. Light microscopy showed that mps1 mutants produced multiple uneven spores during anther development, most of which aborted in later stages. Cytological analysis showed that chromosome segregation was abnormal in mps1 meiocytes. Immunolocalization showed unequal bipolar or multipolar spindles in mps1 meiocytes, which indicated that aberrant spindles resulted in disordered chromosome segregation. MPS1 encodes a 377-amino-acid protein with putative coiled-coil motifs. In situ hybridization analysis showed that MPS1 is strongly expressed in meiocytes.

  3. Mutations in the murine homologue of TUBB5 cause microcephaly by perturbing cell cycle progression and inducing p53-associated apoptosis.

    PubMed

    Breuss, Martin; Fritz, Tanja; Gstrein, Thomas; Chan, Kelvin; Ushakova, Lyubov; Yu, Nuo; Vonberg, Frederick W; Werner, Barbara; Elling, Ulrich; Keays, David A

    2016-04-01

    Microtubules play a crucial role in the generation, migration and differentiation of nascent neurons in the developing vertebrate brain. Mutations in the constituents of microtubules, the tubulins, are known to cause an array of neurological disorders, including lissencephaly, polymicrogyria and microcephaly. In this study we explore the genetic and cellular mechanisms that cause TUBB5-associated microcephaly by exploiting two new mouse models: a conditional E401K knock-in, and a conditional knockout animal. These mice present with profound microcephaly due to a loss of upper-layer neurons that correlates with massive apoptosis and upregulation of p53. This phenotype is associated with a delay in cell cycle progression and ectopic DNA elements in progenitors, which is dependent on the dosage of functional Tubb5. Strikingly, we report ectopic Sox2-positive progenitors and defects in spindle orientation in our knock-in mouse line, which are absent in knockout animals. This work sheds light on the functional repertoire of Tubb5, reveals that the E401K mutation acts by a complex mechanism, and demonstrates that the cellular pathology driving TUBB5-associated microcephaly is cell death. © 2016. Published by The Company of Biologists Ltd.

  4. Microcephaly Information Page

    MedlinePlus

    ... You are here Home » Disorders » All Disorders Microcephaly Information Page Microcephaly Information Page What research is being done? The National ... the U.S. and Worldwide NINDS Clinical Trials Related Information Patient Organizations Birth Defect Research for Children, Inc. ...

  5. Growth and characterization of spindle-like Ga2O3 nanocrystals by electrochemical reaction in hydrofluoric solution

    NASA Astrophysics Data System (ADS)

    Feng, Lungang; Li, Yufeng; Su, Xilin; Wang, Shuai; Liu, Hao; Wang, Jiangteng; Gong, Zhina; Ding, Wen; Zhang, Ye; Yun, Feng

    2016-12-01

    We report a novel fabrication method of spindle-like gallium oxide (Ga2O3) nanocrystals via two steps processed by electrochemical reaction of the MOVPE-grown GaN epitaxial layer in HF/ethanol (1:6) electrolyte and subsequent heat treatment. Depending on the electrolyte concentration, reaction time and applied voltage, micrometer- to nanometer-size spindle-like gallium fluoride tri-hydrate (GaF3·3H2O) of different densities and geometrical dimensions were formed on the surface of GaN. EDS, XPS and XRD were used to characterize the properties of the material before and after heat treatment. It is found that due to heat treatment at above 600 °C, nanocrystalline Ga2O3 were transformed from the GaF3·3H2O via pyrohydrolysis reaction mechanism. The band gap of ∼5.1 eV of the spindle-like Ga2O3 was measured by the optical absorption spectroscopy.

  6. Case report: microcephaly associated with Zika virus infection, Colombia.

    PubMed

    Mattar, Salim; Ojeda, Carolina; Arboleda, Janna; Arrieta, German; Bosch, Irene; Botia, Ingrid; Alvis-Guzman, Nelson; Perez-Yepes, Carlos; Gerhke, Lee; Montero, German

    2017-06-13

    Recently there has been a large outbreak of Zika virus infections in Colombia, South America. The epidemic began in September 2015 and continued to April 2017, for the total number of Zika cases reported of 107,870. For those confirmed Zika cases, there were nearly 20,000 (18.5%) suspected to be pregnant women, resulting in 157 confirmed cases of microcephaly in newborns reported by their health government agency. There is a clear under-estimation of the total number of cases and in addition no prior publications have been published to demonstrate the clinical aspects of the Zika infection in Colombia. We characterized one Zika presentation to be able to compare and contrast with other cases of Zika infection already reported in the literature. In this case report, we demonstrate congenital microcephaly at week 19 of gestation in a 34-year-old mother who showed symptoms compatible with Zika virus infection from Sincelejo, State of Sucre, in the Colombian Caribbean. Zika virus RNA was detected in the placenta using real-time reverse transcriptase polymerase chain reaction (RT-PCR). At week 25, the fetus weigh estimate was 770 g, had a cephalic perimeter of 20.2 cm (5th percentile), ventriculomegaly on the right side and dilatation of the fourth ventricle. At week 32, the microcephaly was confirmed with a cephalic perimeter of 22 cm, dilatation of the posterior atrium to 13 mm, an abnormally small cerebellum (29 mm), and an augmented cisterna magna. At birth (39 weeks by cesarean section), the head circumference was 27.5 cm, and computerized axial tomography (Siemens Corp, 32-slides) confirmed microcephaly with calcifications. We report a first case of maternal Zika virus infection associated with fetal microcephaly in Colombia and confirmed similar presentation to those observed previous in Brazil, 2015-2016.

  7. Cytoskeletal mechanisms in positioning of the second-division spindles and meiotic restitution in tobacco (Nicotiana tabacum L.) microsporogenesis.

    PubMed

    Sidorchuk, Yuriy Vladimirovich; Deineko, Elena Victorovna

    2017-06-01

    Microsporogenesis patterns of the polyploid (2n = 4x = 96) and diploid (2n = 2x = 48) Nicotiana tabacum L. (cv. Havana Petit line SR1) plants have been analyzed and compared. Four types of abnormal positions of the second-division spindles-tripolar, parallel, proximal, and fused-have been observed. Of these abnormalities, only tripolar (2.4%) and parallel (1.4%) spindles are observable in diploid plants. As for polyploids, the increased ploidy is accompanied by an increase in the incidence of tripolar (22.8%) and parallel (8.1%) spindle orientations and emergence of two remaining abnormalities (proximal and fused spindles, 3.3%). As has been shown, the spindle position abnormalities in diploid plants have no effect on the meiotic products, whereas both dyads and triads are detectable among the tetrads in polyploid plants. Analysis of cytoskeletal remodeling has allowed for the insight into the role of interzonal radial microtubule system in spindle positioning during the second division. The reason underlying the change in spindle positioning is disturbed polymerization-depolymerization processes and interdigitation of microtubule plus ends within the interzonal cytoskeleton system in late telophase I-interkinesis and prophase II. As has been demonstrated, fused second-division spindles are formed as a result of fused cytoskeletal structures in prophase-prometaphase II in the case when the nuclei are drawn abnormally close to one another. © 2017 International Federation for Cell Biology.

  8. Prenatal diagnosis and molecular cytogenetic characterization of de novo pure partial trisomy 6p associated with microcephaly, craniosynostosis and abnormal maternal serum biochemistry.

    PubMed

    Chen, Chih-Ping; Chen, Ming; Chen, Chen-Yu; Chern, Schu-Rern; Wu, Peih-Shan; Chang, Shun-Ping; Kuo, Yu-Ling; Chen, Wen-Lin; Pan, Chen-Wen; Wang, Wayseen

    2014-02-25

    We present prenatal diagnosis and molecular cytogenetic characterization of de novo pure trisomy 6p22.3 → p25.3 encompassing BMP6 in a fetus associated with microcephaly and craniosynostosis on prenatal ultrasound, abnormal maternal serum biochemistry of a low PAPP-A level in the first-trimester combined test, and a karyotype of 46,XX,der(22)t(6;22)(p22.3;p13)dn. The present case demonstrates the usefulness of rapid prenatal identification of the origin of the extra chromosome material on the short arm of an acrocentric chromosome by spectral karyotyping, fluorescence in situ hybridization and array comparative genomic hybridization. We review the phenotypic abnormality of craniosynostosis in previously reported patients with partial trisomy 6p. We discuss the genotype-phenotype correlation of the involved gene of BMP6 in this case. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. A syndrome of microcephaly, short stature, polysyndactyly, and dental anomalies caused by a homozygous KATNB1 mutation.

    PubMed

    Yigit, Gökhan; Wieczorek, Dagmar; Bögershausen, Nina; Beleggia, Filippo; Möller-Hartmann, Claudia; Altmüller, Janine; Thiele, Holger; Nürnberg, Peter; Wollnik, Bernd

    2016-03-01

    Using whole-exome sequencing, we identified a homozygous acceptor splice-site mutation in intron 6 of the KATNB1 gene in a patient from a consanguineous Turkish family who presented with congenital microcephaly, lissencephaly, short stature, polysyndactyly, and dental abnormalities. cDNA analysis revealed complete loss of the natural acceptor splice-site resulting either in the usage of an alternative, exonic acceptor splice-site inducing a frame-shift and premature protein truncation or, to a minor extent, in complete skipping of exon 7. Both effects most likely lead to complete loss of KATNB1 function. Homozygous and compound heterozygous mutations in KATNB1 have very recently been described as a cause of microcephaly with brain malformations and seizures. We extend the KATNB1 associated phenotype by describing a syndrome characterized by primordial dwarfism, lissencephaly, polysyndactyly, and dental anomalies, which is caused by a homozygous truncating KATNB1 mutation. © 2015 Wiley Periodicals, Inc.

  10. Mammalian neurogenesis requires Treacle-Plk1 for precise control of spindle orientation, mitotic progression, and maintenance of neural progenitor cells.

    PubMed

    Sakai, Daisuke; Dixon, Jill; Dixon, Michael J; Trainor, Paul A

    2012-01-01

    The cerebral cortex is a specialized region of the brain that processes cognitive, motor, somatosensory, auditory, and visual functions. Its characteristic architecture and size is dependent upon the number of neurons generated during embryogenesis and has been postulated to be governed by symmetric versus asymmetric cell divisions, which mediate the balance between progenitor cell maintenance and neuron differentiation, respectively. The mechanistic importance of spindle orientation remains controversial, hence there is considerable interest in understanding how neural progenitor cell mitosis is controlled during neurogenesis. We discovered that Treacle, which is encoded by the Tcof1 gene, is a novel centrosome- and kinetochore-associated protein that is critical for spindle fidelity and mitotic progression. Tcof1/Treacle loss-of-function disrupts spindle orientation and cell cycle progression, which perturbs the maintenance, proliferation, and localization of neural progenitors during cortical neurogenesis. Consistent with this, Tcof1(+/-) mice exhibit reduced brain size as a consequence of defects in neural progenitor maintenance. We determined that Treacle elicits its effect via a direct interaction with Polo-like kinase1 (Plk1), and furthermore we discovered novel in vivo roles for Plk1 in governing mitotic progression and spindle orientation in the developing mammalian cortex. Increased asymmetric cell division, however, did not promote increased neuronal differentiation. Collectively our research has therefore identified Treacle and Plk1 as novel in vivo regulators of spindle fidelity, mitotic progression, and proliferation in the maintenance and localization of neural progenitor cells. Together, Treacle and Plk1 are critically required for proper cortical neurogenesis, which has important implications in the regulation of mammalian brain size and the pathogenesis of congenital neurodevelopmental disorders such as microcephaly.

  11. Mammalian Neurogenesis Requires Treacle-Plk1 for Precise Control of Spindle Orientation, Mitotic Progression, and Maintenance of Neural Progenitor Cells

    PubMed Central

    Sakai, Daisuke; Dixon, Jill; Dixon, Michael J.; Trainor, Paul A.

    2012-01-01

    The cerebral cortex is a specialized region of the brain that processes cognitive, motor, somatosensory, auditory, and visual functions. Its characteristic architecture and size is dependent upon the number of neurons generated during embryogenesis and has been postulated to be governed by symmetric versus asymmetric cell divisions, which mediate the balance between progenitor cell maintenance and neuron differentiation, respectively. The mechanistic importance of spindle orientation remains controversial, hence there is considerable interest in understanding how neural progenitor cell mitosis is controlled during neurogenesis. We discovered that Treacle, which is encoded by the Tcof1 gene, is a novel centrosome- and kinetochore-associated protein that is critical for spindle fidelity and mitotic progression. Tcof1/Treacle loss-of-function disrupts spindle orientation and cell cycle progression, which perturbs the maintenance, proliferation, and localization of neural progenitors during cortical neurogenesis. Consistent with this, Tcof1 +/− mice exhibit reduced brain size as a consequence of defects in neural progenitor maintenance. We determined that Treacle elicits its effect via a direct interaction with Polo-like kinase1 (Plk1), and furthermore we discovered novel in vivo roles for Plk1 in governing mitotic progression and spindle orientation in the developing mammalian cortex. Increased asymmetric cell division, however, did not promote increased neuronal differentiation. Collectively our research has therefore identified Treacle and Plk1 as novel in vivo regulators of spindle fidelity, mitotic progression, and proliferation in the maintenance and localization of neural progenitor cells. Together, Treacle and Plk1 are critically required for proper cortical neurogenesis, which has important implications in the regulation of mammalian brain size and the pathogenesis of congenital neurodevelopmental disorders such as microcephaly. PMID:22479190

  12. Structures of actin-like ParM filaments show architecture of plasmid-segregating spindles.

    PubMed

    Bharat, Tanmay A M; Murshudov, Garib N; Sachse, Carsten; Löwe, Jan

    2015-07-02

    Active segregation of Escherichia coli low-copy-number plasmid R1 involves formation of a bipolar spindle made of left-handed double-helical actin-like ParM filaments. ParR links the filaments with centromeric parC plasmid DNA, while facilitating the addition of subunits to ParM filaments. Growing ParMRC spindles push sister plasmids to the cell poles. Here, using modern electron cryomicroscopy methods, we investigate the structures and arrangements of ParM filaments in vitro and in cells, revealing at near-atomic resolution how subunits and filaments come together to produce the simplest known mitotic machinery. To understand the mechanism of dynamic instability, we determine structures of ParM filaments in different nucleotide states. The structure of filaments bound to the ATP analogue AMPPNP is determined at 4.3 Å resolution and refined. The ParM filament structure shows strong longitudinal interfaces and weaker lateral interactions. Also using electron cryomicroscopy, we reconstruct ParM doublets forming antiparallel spindles. Finally, with whole-cell electron cryotomography, we show that doublets are abundant in bacterial cells containing low-copy-number plasmids with the ParMRC locus, leading to an asynchronous model of R1 plasmid segregation.

  13. Asparagine synthetase deficiency detected by whole exome sequencing causes congenital microcephaly, epileptic encephalopathy and psychomotor delay.

    PubMed

    Ben-Salem, Salma; Gleeson, Joseph G; Al-Shamsi, Aisha M; Islam, Barira; Hertecant, Jozef; Ali, Bassam R; Al-Gazali, Lihadh

    2015-06-01

    Deficiency of Asparagine Synthetase (ASNSD, MIM 615574) is a very rare autosomal recessive disorder presenting with some brain abnormalities. Affected individuals have congenital microcephaly and progressive encephalopathy associated with severe intellectual disability and intractable seizures. The loss of function of the asparagine synthetase (ASNS, EC 6.3.5.4), particularly in the brain, is the major cause of this particular congenital microcephaly. In this study, we clinically evaluated an affected child from a consanguineous Emirati family presenting with congenital microcephaly and epileptic encephalopathy. In addition, whole-exome sequencing revealed a novel homozygous substitution mutation (c.1193A > C) in the ASNS gene. This mutation resulted in the substitution of highly conserved tyrosine residue by cysteine (p.Y398C). Molecular modeling analysis predicts hypomorphic and damaging effects of this mutation on the protein structure and altering its enzymatic activity. Therefore, we conclude that the loss of ASNS function is most likely the cause of this condition in the studied family. This report brings the number of reported families with this very rare disorder to five and the number of pathogenic mutations in the ASNS gene to four. This finding extends the ASNS pathogenic mutations spectrum and highlights the utility of whole-exome sequencing in elucidation the causes of rare recessive disorders that are heterogeneous and/or overlap with other conditions.

  14. Lack of Diaph3 relaxes the spindle checkpoint causing the loss of neural progenitors

    PubMed Central

    Damiani, Devid; Goffinet, André M.; Alberts, Arthur; Tissir, Fadel

    2016-01-01

    The diaphanous homologue Diaph3 (aka mDia2) is a major regulator of actin cytoskeleton. Loss of Diaph3 has been constantly associated with cytokinesis failure ascribed to impaired accumulation of actin in the cleavage furrow. Here we report that Diaph3 is required before cell fission, to ensure the accurate segregation of chromosomes. Inactivation of the Diaph3 gene causes a massive loss of cortical progenitor cells, with subsequent depletion of intermediate progenitors and neurons, and results in microcephaly. In embryonic brain extracts, Diaph3 co-immunoprecipitates with BubR1, a key regulator of the spindle assembly checkpoint (SAC). Diaph3-deficient cortical progenitors have decreased levels of BubR1 and fail to properly activate the SAC. Hence, they bypass mitotic arrest and embark on anaphase in spite of incorrect chromosome segregation, generating aneuploidy. Our data identify Diaph3 as a major guard of cortical progenitors, unravel novel functions of Diaphanous formins and add insights into the pathobiology of microcephaly. PMID:27848932

  15. Microcephaly and Macrocephaly in Autism.

    ERIC Educational Resources Information Center

    Fombonne, Eric; Roge, Bernadette; Claverie, Jacques; Courty, Stephanie; Fremolle, Jeanne

    1999-01-01

    Analysis of data from 126 children with autism found macrocephaly (head circumstance microcephaly (head circumference <3rd centile) was found in 15.1%. Microcephaly was significantly associated with the presence of medical disorders. (Author/DB)

  16. Improved lithium-ion battery anode capacity with a network of easily fabricated spindle-like carbon nanofibers.

    PubMed

    Liu, Mengting; Xie, Wenhe; Gu, Lili; Qin, Tianfeng; Hou, Xiaoyi; He, Deyan

    2016-01-01

    A novel network of spindle-like carbon nanofibers was fabricated via a simplified synthesis involving electrospinning followed by preoxidation in air and postcarbonization in Ar. Not only was the as-obtained carbon network comprised of beads of spindle-like nanofibers but the cubic MnO phase and N elements were successfully anchored into the amorphous carbon matrix. When directly used as a binder-free anode for lithium-ion batteries, the network showed excellent electrochemical performance with high capacity, good rate capacity and reliable cycling stability. Under a current density of 0.2 A g -1 , it delivered a high reversible capacity of 875.5 mAh g -1 after 200 cycles and 1005.5 mAh g -1 after 250 cycles with a significant coulombic efficiency of 99.5%.

  17. Akap350 Recruits Eb1 to The Spindle Poles, Ensuring Proper Spindle Orientation and Lumen Formation in 3d Epithelial Cell Cultures.

    PubMed

    Almada, Evangelina; Tonucci, Facundo M; Hidalgo, Florencia; Ferretti, Anabela; Ibarra, Solange; Pariani, Alejandro; Vena, Rodrigo; Favre, Cristián; Girardini, Javier; Kierbel, Arlinet; Larocca, M Cecilia

    2017-11-02

    The organization of epithelial cells to form hollow organs with a single lumen requires the accurate three-dimensional arrangement of cell divisions. Mitotic spindle orientation is defined by signaling pathways that provide molecular links between specific spots at the cell cortex and astral microtubules, which have not been fully elucidated. AKAP350 is a centrosomal/Golgi scaffold protein, implicated in the regulation of microtubule dynamics. Using 3D epithelial cell cultures, we found that cells with decreased AKAP350 expression (AKAP350KD) formed polarized cysts with abnormal lumen morphology. Analysis of mitotic cells in AKAP350KD cysts indicated defective spindle alignment. We established that AKAP350 interacts with EB1, a microtubule associated protein that regulates spindle orientation, at the spindle poles. Decrease of AKAP350 expression lead to a significant reduction of EB1 levels at spindle poles and astral microtubules. Conversely, overexpression of EB1 rescued the defective spindle orientation induced by deficient AKAP350 expression. The specific delocalization of the AKAP350/EB1complex from the centrosome decreased EB1 levels at astral microtubules and lead to the formation of 3D-organotypic structures which resembled AKAP350KD cysts. We conclude that AKAP350 recruits EB1 to the spindle poles, ensuring EB1 presence at astral microtubules and proper spindle orientation during epithelial morphogenesis.

  18. Reduced sleep spindle activity point to a TRN-MD thalamus-PFC circuit dysfunction in schizophrenia.

    PubMed

    Ferrarelli, Fabio; Tononi, Giulio

    2017-02-01

    Sleep disturbances have been reliably reported in patients with schizophrenia, thus suggesting that abnormal sleep may represent a core feature of this disorder. Traditional electroencephalographic studies investigating sleep architecture have found reduced deep non-rapid eye movement (NREM) sleep, or slow wave sleep (SWS), and increased REM density. However, these findings have been inconsistently observed, and have not survived meta-analysis. By contrast, several recent EEG studies exploring brain activity during sleep have established marked deficits in sleep spindles in schizophrenia, including first-episode and early-onset patients, compared to both healthy and psychiatric comparison subjects. Spindles are waxing and waning, 12-16Hz NREM sleep oscillations that are generated within the thalamus by the thalamic reticular nucleus (TRN), and are then synchronized and sustained in the cortex. While the functional role of sleep spindles still needs to be fully established, increasing evidence has shown that sleep spindles are implicated in learning and memory, including sleep dependent memory consolidation, and spindle parameters have been associated to general cognitive ability and IQ. In this article we will review the EEG studies demonstrating sleep spindle deficits in patients with schizophrenia, and show that spindle deficits can predict their reduced cognitive performance. We will then present data indicating that spindle impairments point to a TRN-MD thalamus-prefrontal cortex circuit deficit, and discuss about the possible molecular mechanisms underlying thalamo-cortical sleep spindle abnormalities in schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Synthesis and luminescent properties of spindle-like CaWO{sub 4}:Sm{sup 3+} phosphors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tian, Yue; Department of Physics, Dalian Maritime University, Dalian, Liaoning 116026; Liu, Yu

    2012-01-15

    Graphical abstract: In this paper, spindle-like CaWO{sub 4}:Sm{sup 3+} phosphors were prepared via a polyvinylpyrrolidone (PVP)-assisted sonochemical process. Dependence of emission intensity on Sm{sup 3+} ions concentration in the CaWO{sub 4}:Sm{sup 3+} phosphor were also calculated via a nonlinear fitting by using the formula y = ax/(1 + bx{sup c}). Highlights: Black-Right-Pointing-Pointer The samples were prepared via a PVP assisted sonochemical process. Black-Right-Pointing-Pointer The color coordinates for 1 mol% Sm{sup 3+} doped CaWO{sub 4} phosphor were calculated. Black-Right-Pointing-Pointer The D-D interaction is responsible for concentration quenching between Sm{sup 3+} ions. Black-Right-Pointing-Pointer The critical energy transfer distances (R{sub c}) were obtained.more » -- Abstract: Spindle-like CaWO{sub 4}:Sm{sup 3+} phosphors were prepared via a Polyvinylpyrrolidone (PVP)-assisted sonochemical process, and characterized by using X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM) and photoluminescence spectroscopy (PL). The XRD results suggested that the prepared samples are single-phase. The FE-SEM images indicated that the prepared CaWO{sub 4}:Sm{sup 3+} phosphors are composed of many spindles with maximum average diameter of 150 nm and maximum average length of 500 nm. Under 404 nm excitation, the characteristic emissions corresponding to {sup 4}G{sub 5/2} {yields} {sup 6}H{sub J} (J = 5/2, 7/2, 9/2 and 11/2) transitions of Sm{sup 3+} in CaWO{sub 4} phosphors were observed. The color coordinates for 1 mol% Sm{sup 3+} doped CaWO{sub 4} phosphor were calculated to be (0.595, 0.404). The fluorescent concentration quenching of Sm{sup 3+} doped spindle-like phosphors was studied based on the Van Uitert's model, and it was found that the electric dipole-dipole (D-D) interaction is the dominant energy transfer mechanism between Sm{sup 3+} ions in the CaWO{sub 4}:Sm{sup 3+} phosphors. The critical energy transfer distance was

  20. Microcephaly and Other Birth Defects: Zika

    MedlinePlus

    ... Español (Spanish) Recommend on Facebook Tweet Share Compartir Zika and Microcephaly Microcephaly is a birth defect in ... pregnancy or has stopped growing after birth. Congenital Zika Syndrome Congenital Zika syndrome is a unique pattern ...

  1. Characteristics of Dysphagia in Infants with Microcephaly Caused by Congenital Zika Virus Infection, Brazil, 2015.

    PubMed

    Leal, Mariana C; van der Linden, Vanessa; Bezerra, Thiago P; de Valois, Luciana; Borges, Adriana C G; Antunes, Margarida M C; Brandt, Kátia G; Moura, Catharina X; Rodrigues, Laura C; Ximenes, Coeli R

    2017-08-01

    We summarize the characteristics of dysphagia in 9 infants in Brazil with microcephaly caused by congenital Zika virus infection. The Schedule for Oral Motor Assessment, fiberoptic endoscopic evaluation of swallowing, and the videofluoroscopic swallowing study were used as noninstrumental and instrumental assessments. All infants had a degree of neurologic damage and showed abnormalities in the oral phase. Of the 9 infants, 8 lacked oral and upper respiratory tract sensitivity, leading to delays in initiation of the pharyngeal phase of swallowing. Those delays, combined with marked oral dysfunction, increased the risk for aspiration of food, particularly liquid foods. Dysphagia resulting from congenital Zika virus syndrome microcephaly can develop in infants >3 months of age and is severe.

  2. Characteristics of Dysphagia in Infants with Microcephaly Caused by Congenital Zika Virus Infection, Brazil, 2015

    PubMed Central

    van der Linden, Vanessa; Bezerra, Thiago P.; de Valois, Luciana; Borges, Adriana C.G.; Antunes, Margarida M.C.; Brandt, Kátia G.; Moura, Catharina X.; Rodrigues, Laura C.; Ximenes, Coeli R.

    2017-01-01

    We summarize the characteristics of dysphagia in 9 infants in Brazil with microcephaly caused by congenital Zika virus infection. The Schedule for Oral Motor Assessment, fiberoptic endoscopic evaluation of swallowing, and the videofluoroscopic swallowing study were used as noninstrumental and instrumental assessments. All infants had a degree of neurologic damage and showed abnormalities in the oral phase. Of the 9 infants, 8 lacked oral and upper respiratory tract sensitivity, leading to delays in initiation of the pharyngeal phase of swallowing. Those delays, combined with marked oral dysfunction, increased the risk for aspiration of food, particularly liquid foods. Dysphagia resulting from congenital Zika virus syndrome microcephaly can develop in infants >3 months of age and is severe. PMID:28604336

  3. Targeting Alp7/TACC to the spindle pole body is essential for mitotic spindle assembly in fission yeast

    PubMed Central

    Tang, Ngang Heok; Okada, Naoyuki; Fong, Chii Shyang; Arai, Kunio; Sato, Masamitsu; Toda, Takashi

    2014-01-01

    The conserved TACC protein family localises to the centrosome (the spindle pole body, SPB in fungi) and mitotic spindles, thereby playing a crucial role in bipolar spindle assembly. However, it remains elusive how TACC proteins are recruited to the centrosome/SPB. Here, using fission yeast Alp7/TACC, we have determined clustered five amino acid residues within the TACC domain required for SPB localisation. Critically, these sequences are essential for the functions of Alp7, including proper spindle formation and mitotic progression. Moreover, we have identified pericentrin-like Pcp1 as a loading factor to the mitotic SPB, although Pcp1 is not a sole platform. PMID:24937146

  4. Spindle epithelial tumor with thymus-like differentiation: a case report and review of literature.

    PubMed

    Misra, R K; Mitra, Shaila; Yadav, Rajesh; Bundela, Alpana

    2013-01-01

    Spindle epithelial tumor with thymus-like differentiation (SETTLE) is an extremely rare type of thyroid tumor with fewer than 35 reported cases available in the literature so far, most of them having been diagnosed histologically after resection. The tumor is believed to be derived from branchial-pouch or thymic remnants, occurring in young adults, predominantly in males, with a male:female ratio 1.8:1. A 14-year-old girl presented with a nodular mass in her right thyroid that had been present for 1 year. Ultrasonological study revealed a heterogeneous solid mass (2.5 × 1.5 × 1.5 cm) in the right lobe of the thyroid. Fine-needle aspiration (FNA) smears were highly cellular and comprised of predominantly dissociated uniform spindle cells with naked oval nuclei along with some aggregates and groups. Occasional islands of epithelial cells were also present. Cytologically, the spindle cells had bland nuclear chromatin, with very scanty mitotic figures. Upon examination of the FNA smears, a provisional diagnosis of SETTLE was suggested along with a request for an incisional biopsy to rule out another differential diagnosis of medullary carcinoma thyroid. On the resected tissue specimen, diagnosis was histologically confirmed to be SETTLE. Immunohistochemical study revealed a strong and diffuse positivity for high-molecular-weight keratin and vimentin, and negativity for thyroglobulin, calcitonin, S-100 protein, desmin, chromogranin and synaptophysin. Cytologically, SETTLE can safely be considered, especially if spindle elements are observed along with the occasional group of epithelial cells in FNA smears from the thyroid of young adults. It can help in the preoperative recognition of lesions based on distinctive cytomorphological features and immunohistochemical characteristics, allowing a more sound therapeutic approach because these patients can present with delayed metastasis. Copyright © 2013 S. Karger AG, Basel.

  5. Automated mitotic spindle tracking suggests a link between spindle dynamics, spindle orientation, and anaphase onset in epithelial cells

    PubMed Central

    Larson, Matthew E.; Bement, William M.

    2017-01-01

    Proper spindle positioning at anaphase onset is essential for normal tissue organization and function. Here we develop automated spindle-tracking software and apply it to characterize mitotic spindle dynamics in the Xenopus laevis embryonic epithelium. We find that metaphase spindles first undergo a sustained rotation that brings them on-axis with their final orientation. This sustained rotation is followed by a set of striking stereotyped rotational oscillations that bring the spindle into near contact with the cortex and then move it rapidly away from the cortex. These oscillations begin to subside soon before anaphase onset. Metrics extracted from the automatically tracked spindles indicate that final spindle position is determined largely by cell morphology and that spindles consistently center themselves in the XY-plane before anaphase onset. Finally, analysis of the relationship between spindle oscillations and spindle position relative to the cortex reveals an association between cortical contact and anaphase onset. We conclude that metaphase spindles in epithelia engage in a stereotyped “dance,” that this dance culminates in proper spindle positioning and orientation, and that completion of the dance is linked to anaphase onset. PMID:28100633

  6. Microcephaly and Zika virus: Neuroradiological aspects, clinical findings and a proposed framework for early evaluation of child development.

    PubMed

    Cicuto Ferreira Rocha, Nelci Adriana; de Campos, Ana Carolina; Cicuto Ferreira Rocha, Fellipe; Pereira Dos Santos Silva, Fernanda

    2017-11-01

    As the recent outbreak of microcephaly cases caused by Zika virus has been declared a global health emergency, providing assessment guidelines for multidisciplinary teams providing early developmental screening and stimulation to infants with microcephaly is much needed. Thus, the aim of this manuscript is to provide an overview on what is known about neuroradiological aspects and clinical findings in infants with microcephaly caused by Zika virus and to propose a framework for early evaluation of child development. The keywords "Zika virus" and "microcephaly" were searched in PubMed database for articles published from incept to May 2017. These texts were reviewed, and the ones addressing neuroradiological and clinical findings in infants were selected. Recommendations for early assessment were made based on the International Classification of Functionality Disability and Health (ICF) model. The database search yielded 599 publications and 36 were selected. The studies detected microcephaly with diffuse brain malformations and calcifications, ventriculomegaly, optic nerve hypoplasia, macular atrophy, cataracts, impaired visual and hearing function, arthrogryposis, spasticity, hyperreflexia, irritability, tremors, and seizures, but very little is known about early development. Early assessments were described based on the ICF domains (Body Function and Structures, Activities and Participation and Contextual factors). Studies published showed abnormal brain, optic, neurologic and orthopedic findings, but very little is known about other aspects of functioning in infants with microcephaly caused by Zika virus. The biopsychosocial model based on the ICF paradigm provides an adequate framework to describe the condition of the infant with microcephaly receiving rehabilitative efforts to minimize disability. Efforts towards early identification of developmental delays should be taken within the first six months of life. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Characterization of Topographically Specific Sleep Spindles in Mice

    PubMed Central

    Kim, Dongwook; Hwang, Eunjin; Lee, Mina; Sung, Hokun; Choi, Jee Hyun

    2015-01-01

    Study Objective: Sleep spindles in humans have been classified as slow anterior and fast posterior spindles; recent findings indicate that their profiles differ according to pharmacology, pathology, and function. However, little is known about the generation mechanisms within the thalamocortical system for different types of spindles. In this study, we aim to investigate the electrophysiological behaviors of the topographically distinctive spindles within the thalamocortical system by applying high-density EEG and simultaneous thalamic LFP recordings in mice. Design: 32-channel extracranial EEG and 2-channel thalamic LFP were recorded simultaneously in freely behaving mice to acquire spindles during spontaneous sleep. Subjects: Hybrid F1 male mice of C57BL/6J and 129S4/svJae. Measurements and Results: Spindle events in each channel were detected by spindle detection algorithm, and then a cluster analysis was applied to classify the topographically distinctive spindles. All sleep spindles were successfully classified into 3 groups: anterior, posterior, and global spindles. Each spindle type showed distinct thalamocortical activity patterns regarding the extent of similarity, phase synchrony, and time lags between cortical and thalamic areas during spindle oscillation. We also found that sleep slow waves were likely to associate with all types of sleep spindles, but also that the ongoing cortical decruitment/recruitment dynamics before the onset of spindles and their relationship with spindle generation were also variable, depending on the spindle types. Conclusion: Topographically specific sleep spindles show distinctive thalamocortical network behaviors. Citation: Kim D, Hwang E, Lee M, Sung H, Choi JH. Characterization of topographically specific sleep spindles in mice. SLEEP 2015;38(1):85–96. PMID:25325451

  8. Further evidences for sleep instability and impaired spindle-delta dynamics in schizophrenia: a whole-night polysomnography study with neuroloop-gain and sleep-cycle analysis.

    PubMed

    Sasidharan, Arun; Kumar, Sunil; Nair, Ajay Kumar; Lukose, Ammu; Marigowda, Vrinda; John, John P; Kutty, Bindu M

    2017-10-01

    Sleep offers a unique window into the brain dysfunctions in schizophrenia. Many past sleep studies have reported abnormalities in both macro-sleep architecture (like increased awakenings) as well as micro-sleep-architecture (like spindle deficits) in patients with schizophrenia (PSZ). The present study attempts to replicate previous reports of macro- and micro-sleep-architectural abnormalities in schizophrenia. In addition, the study also examined sleep-stage changes and spindle-delta dynamics across sleep-cycles to provide further evidence in support of the dysfunctional thalamocortical mechanisms causing sleep instability and poor sleep maintenance associated with schizophrenia pathophysiology. Whole-night polysomnography was carried out among 45 PSZ and 39 age- and gender-matched healthy control subjects. Sleep-stage dynamics were assessed across sleep-cycles using a customized software algorithm. Spindle-delta dynamics across sleep-cycles were determined using neuroloop-gain analysis. PSZ showed macro-sleep architecture abnormalities such as prolonged sleeplessness, increased intermittent-awakenings, long sleep-onset latency, reduced non-rapid eye movement (NREM) stage 2 sleep, increased stage transitions, and poor sleep efficiency. They also showed reduced spindle density (sigma neuroloop-gain) but comparable slow wave density (delta neuroloop-gain) throughout the sleep. Sleep-cycle-wise analysis revealed transient features of sleep instability due to significantly increased intermittent awakenings especially in the first and third sleep-cycles, and unstable and recurrent stage transitions in both NREM (first sleep-cycle) and rapid eye movement (REM) sleep-periods (second sleep-cycle). Spindle deficits were persistent across the first three cycles and were positively correlated with sleep disruption during the subsequent REM sleep. In addition to replicating previously reported sleep deficits in PSZ, the current study showed subtle deficits in NREM

  9. CENP-W Plays a Role in Maintaining Bipolar Spindle Structure

    PubMed Central

    Kaczmarczyk, Agnieszka; Sullivan, Kevin F.

    2014-01-01

    The CENP-W/T complex was previously reported to be required for mitosis. HeLa cells depleted of CENP-W displayed profound mitotic defects, with mitotic timing delay, disorganized prometaphases and multipolar spindles as major phenotypic consequences. In this study, we examined the process of multipolar spindle formation induced by CENP-W depletion. Depletion of CENP-W in HeLa cells labeled with histone H2B and tubulin fluorescent proteins induced rapid fragmentation of originally bipolar spindles in a high proportion of cells. CENP-W depletion was associated with depletion of Hec1 at kinetochores. The possibility of promiscuous centrosomal duplication was ruled out by immunofluorescent examination of centrioles. However, centrioles were frequently observed to be abnormally split. In addition, a large proportion of the supernumerary poles lacked centrioles, but were positively stained with different centrosomal markers. These observations suggested that perturbation in spindle force distribution caused by defective kinetochores could contribute to a mechanical mechanism for spindle pole disruption. ‘Spindle free’ nocodazole arrested cells did not exhibit pole fragmentation after CENP-W depletion, showing that pole fragmentation is microtubule dependent. Inhibition of centrosome separation by monastrol reduced the incidence of spindle pole fragmentation, indicating that Eg5 plays a role in spindle pole disruption. Surprisingly, CENP-W depletion rescued the monopolar spindle phenotype of monastrol treatment, with an increased frequency of bipolar spindles observed after CENP-W RNAi. We overexpressed the microtubule cross-linking protein TPX2 to create spindle poles stabilized by the microtubule cross-linking activity of TPX2. Spindle pole fragmentation was suppressed in a TPX2-dependent fashion. We propose that CENP-W, by influencing proper kinetochore assembly, particularly microtubule docking sites, can confer spindle pole resistance to traction forces exerted

  10. Muscle spindles exhibit core lesions and extensive degeneration of intrafusal fibers in the Ryr1{sup I4895T/wt} mouse model of core myopathy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zvaritch, Elena; MacLennan, David H., E-mail: david.maclennan@utoronto.ca

    Muscle spindles from the hind limb muscles of adult Ryr1{sup I4895T/wt} (IT/+) mice exhibit severe structural abnormalities. Up to 85% of the spindles are separated from skeletal muscle fascicles by a thick layer of connective tissue. Many intrafusal fibers exhibit degeneration, with Z-line streaming, compaction and collapse of myofibrillar bundles, mitochondrial clumping, nuclear shrinkage and pyknosis. The lesions resemble cores observed in the extrafusal myofibers of this animal model and of core myopathy patients. Spindle abnormalities precede those in extrafusal fibers, indicating that they are a primary pathological feature in this murine Ryr1-related core myopathy. Muscle spindle involvement, if confirmedmore » for human core myopathy patients, would provide an explanation for an array of devastating clinical features characteristic of these diseases and provide novel insights into the pathology of RYR1-related myopathies. - Highlights: • Muscle spindles exhibit structural abnormalities in a mouse model of core myopathy. • Myofibrillar collapse and mitochondrial clumping is observed in intrafusal fibers. • Myofibrillar degeneration follows a pattern similar to core formation in extrafusal myofibers. • Muscle spindle abnormalities are a part of the pathological phenotype in the mouse model of core myopathy. • Direct involvement of muscle spindles in the pathology of human RYR1-related myopathies is proposed.« less

  11. p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex.

    PubMed

    Belzil, Camille; Asada, Naoyuki; Ishiguro, Kei-Ichiro; Nakaya, Takeo; Parsons, Kari; Pendolino, Valentina; Neumayer, Gernot; Mapelli, Marina; Nakatani, Yoshihiro; Sanada, Kamon; Nguyen, Minh Dang

    2014-05-08

    Apical neural progenitors (aNPs) drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600) in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis. © 2014. Published by The Company of Biologists Ltd.

  12. Sleep EEG of Microcephaly in Zika Outbreak.

    PubMed

    Kanda, Paulo Afonso Medeiros; Aguiar, Aline de Almeida Xavier; Miranda, Jose Lucivan; Falcao, Alexandre Loverde; Andrade, Claudia Suenia; Reis, Luigi Neves Dos Santos; Almeida, Ellen White R Bacelar; Bello, Yanes Brum; Monfredinho, Arthur; Kanda, Rafael Guimaraes

    2018-01-01

    Microcephaly (MC), previously considered rare, is now a health emergency of international concern because of the devastating Zika virus pandemic outbreak of 2015. The authors describe the electroencephalogram (EEG) findings in sleep EEG of epileptic children who were born with microcephaly in areas of Brazil with active Zika virus transmission between 2014 and 2017. The authors reviewed EEGs from 23 children. Nine were females (39.2%), and the age distribution varied from 4 to 48 months. MC was associated with mother positive serology to toxoplasmosis (toxo), rubella (rub), herpes, and dengue (1 case); toxo (1 case); chikungunya virus (CHIKV) (1 case); syphilis (1 case); and Zika virus (ZIKV) (10 cases). In addition, 1 case was associated with perinatal hypoxia and causes of 9 cases remain unknown. The main background EEG abnormality was diffuse slowing (10 cases), followed by classic (3 cases) and modified (5 cases) hypsarrhythmia. A distinct EEG pattern was seen in ZIKV (5 cases), toxo (2 cases), and undetermined cause (1 case). It was characterized by runs of frontocentrotemporal 4.5-13 Hz activity (7 cases) or diffuse and bilateral runs of 18-24 Hz (1 case). In ZIKV, this rhythmic activity was associated with hypsarrhythmia or slow background. Further studies are necessary to determine if this association is suggestive of ZIKV infection. The authors believe that EEG should be included in the investigation of all newly diagnosed congenital MC, especially those occurring in areas of autochthonous transmission of ZIKV.

  13. Reducing Unintended Pregnancies as a Strategy to Avert Zika-Related Microcephaly Births in the United States: A Simulation Study.

    PubMed

    Ahrens, Katherine A; Hutcheon, Jennifer A; Gavin, Loretta; Moskosky, Susan

    2017-05-01

    Introduction There is increasing evidence that infection with the Zika virus (ZIKV) during pregnancy can lead to severe brain abnormalities in infants exposed in utero. The objective of our analysis was to estimate the contribution of enhanced contraception access to averting ZIKV-related microcephaly births in the United States, alone and in combination with another possible strategy, anti-ZIKV vaccination. Methods We used Monte Carlo sampling techniques (n = 100,000 simulations) to estimate the number of microcephaly births expected under strategies of enhanced contraception only, vaccination only, both enhanced contraception and vaccination, and status quo (no intervention). Enhanced contraceptive access was assumed to reduce unintended pregnancy rates by 46% and anti-ZIKV vaccination was assumed to be 90% effective. Plausible values for effectiveness of enhanced contraceptive access, ZIKV cumulative incidence, ZIKV-related microcephaly risk, and anti-ZIKV vaccination parameters were derived from the literature or best available knowledge. Results Enhanced contraceptive access alone reduced the median number of ZIKV-related microcephaly births by 16% (95% simulation interval: 5, 23), while the anti-ZIKV vaccine alone reduced these births by 9% (95% SI: 0, 18), 45% (95% SI: 36, 54), and 81% (95% SI: 71, 91), under conservative (10% vaccine uptake), moderate (50% vaccine uptake), and optimistic (90% vaccine uptake) scenarios, respectively. The reduction in ZIKV-related microcephaly births was always greater if both interventions were employed. Discussion Enhanced contraceptive access alone has the ability to produce a meaningful reduction in microcephaly births, and could provide an important adjuvant prevention strategy even following the development of a highly-effective anti-ZIKV vaccine.

  14. Facts about Microcephaly

    MedlinePlus

    ... input class="button submit" name="commit" type="submit" value="Submit" /> Information For… Media Policy ... and Severe Microcephaly Comparison The images are in the public domain and thus free of any copyright restrictions. As a matter of ...

  15. SAP-like domain in nucleolar spindle associated protein mediates mitotic chromosome loading as well as interphase chromatin interaction

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Verbakel, Werner, E-mail: werner.verbakel@chem.kuleuven.be; Carmeliet, Geert, E-mail: geert.carmeliet@med.kuleuven.be; Engelborghs, Yves, E-mail: yves.engelborghs@fys.kuleuven.be

    2011-08-12

    Highlights: {yields} The SAP-like domain in NuSAP is a functional DNA-binding domain with preference for dsDNA. {yields} This SAP-like domain is essential for chromosome loading during early mitosis. {yields} NuSAP is highly dynamic on mitotic chromatin, as evident from photobleaching experiments. {yields} The SAP-like domain also mediates NuSAP-chromatin interaction in interphase nucleoplasm. -- Abstract: Nucleolar spindle associated protein (NuSAP) is a microtubule-stabilizing protein that localizes to chromosome arms and chromosome-proximal microtubules during mitosis and to the nucleus, with enrichment in the nucleoli, during interphase. The critical function of NuSAP is underscored by the finding that its depletion in HeLa cellsmore » results in various mitotic defects. Moreover, NuSAP is found overexpressed in multiple cancers and its expression levels often correlate with the aggressiveness of cancer. Due to its localization on chromosome arms and combination of microtubule-stabilizing and DNA-binding properties, NuSAP takes a special place within the extensive group of spindle assembly factors. In this study, we identify a SAP-like domain that shows DNA binding in vitro with a preference for dsDNA. Deletion of the SAP-like domain abolishes chromosome arm binding of NuSAP during mitosis, but is not sufficient to abrogate its chromosome-proximal localization after anaphase onset. Fluorescence recovery after photobleaching experiments revealed the highly dynamic nature of this NuSAP-chromatin interaction during mitosis. In interphase cells, NuSAP also interacts with chromatin through its SAP-like domain, as evident from its enrichment on dense chromatin regions and intranuclear mobility, measured by fluorescence correlation spectroscopy. The obtained results are in agreement with a model where NuSAP dynamically stabilizes newly formed microtubules on mitotic chromosomes to enhance chromosome positioning without immobilizing these microtubules. Interphase Nu

  16. Sodium citrate (Na{sub 3}Cit)-assisted hydrothermal synthesis of uniform spindle-like SrMoO{sub 4}:Eu{sup 3+} phosphors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ren, Xiaolei; Zhang, Yu; Li, Qiuyu

    2014-11-15

    Graphical abstract: A facile hydrothermal method for the synthesis of uniform spindle-like SrMoO{sub 4}:Eu{sup 3+} phosphors with the assistance of sodium citrate (Na{sub 3}Cit). - Highlights: • Well-crystallized spindle-like SrMoO{sub 4}:Eu{sup 3+} phosphors have been synthesized. • The influence of the reaction temperature and reaction time were clearly shown. • The dosage of Na{sub 3}Cit has a strong effect on the spindle-like SrMoO{sub 4}:Eu{sup 3+} phosphors. • The growth mechanism for the formation of final samples was proposed. - Abstract: Highly uniform spindle-like SrMoO{sub 4}:Eu{sup 3+} phosphors have been prepared by a facile hydrothermal method using sodium citrate (Na{sub 3}Cit)more » as the chelating reagent. X-ray powder diffraction (XRD), field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectrum (EDS), transmission electron microscopy (TEM), X-ray photoelectron spectra (XPS), Fourier transform-infrared spectroscopy (FT-IR) and photoluminescence spectra (PL) were used to characterize the resulting samples. The dosage of sodium citrate, reaction temperature and reaction time play key roles in the formation of the final samples. The possible formation mechanism for SrMoO{sub 4}:Eu{sup 3+} phosphors has been proposed. Upon excitation by ultraviolet radiation, the as-synthesized SrMoO{sub 4}:Eu{sup 3+} phosphors show the characteristic {sup 5}D{sub 0}–{sup 7}F{sub J} (J = 1, 2, 3, 4) emission lines with red emission {sup 5}D{sub 0}–{sup 7}F{sub 2} (613 nm) as the most prominent group.« less

  17. The Multidimensional Aspects of Sleep Spindles and Their Relationship to Word-Pair Memory Consolidation

    PubMed Central

    Lustenberger, Caroline; Wehrle, Flavia; Tüshaus, Laura; Achermann, Peter; Huber, Reto

    2015-01-01

    Study Objectives: Several studies proposed a link between sleep spindles and sleep dependent memory consolidation in declarative learning tasks. In addition to these state-like aspects of sleep spindles, they have also trait-like characteristics, i.e., were related to general cognitive performance, an important distinction that has often been neglected in correlative studies. Furthermore, from the multitude of different sleep spindle measures, often just one specific aspect was analyzed. Thus, we aimed at taking multidimensional aspects of sleep spindles into account when exploring their relationship to word-pair memory consolidation. Design: Each subject underwent 2 study nights with all-night high-density electroencephalographic (EEG) recordings. Sleep spindles were automatically detected in all EEG channels. Subjects were trained and tested on a word-pair learning task in the evening, and retested in the morning to assess sleep related memory consolidation (overnight retention). Trait-like aspects refer to the mean of both nights and state-like aspects were calculated as the difference between night 1 and night 2. Setting: Sleep laboratory. Participants: Twenty healthy male subjects (age: 23.3 ± 2.1 y) Measurements and Results: Overnight retention was negatively correlated with trait-like aspects of fast sleep spindle density and positively with slow spindle density on a global level. In contrast, state-like aspects were observed for integrated slow spindle activity, which was positively related to the differences in overnight retention in specific regions. Conclusion: Our results demonstrate the importance of a multidimensional approach when investigating the relationship between sleep spindles and memory consolidation and thereby provide a more complete picture explaining divergent findings in the literature. Citation: Lustenberger C, Wehrle F, Tüshaus L, Achermann P, Huber R. The multidimensional aspects of sleep spindles and their relationship to word

  18. Prevalence and Clinical Attributes of Congenital Microcephaly - New York, 2013-2015.

    PubMed

    Graham, Krishika A; Fox, Deborah J; Talati, Achala; Pantea, Cristian; Brady, Laura; Carter, Sondra L; Friedenberg, Eric; Vora, Neil M; Browne, Marilyn L; Lee, Christopher T

    2017-02-10

    Congenital Zika virus infection can cause microcephaly and other severe fetal neurological anomalies (1). To inform microcephaly surveillance efforts and assess ascertainment sources, the New York State Department of Health and the New York City Department of Health and Mental Hygiene sought to determine the prevalence of microcephaly in New York during 2013-2015, before known importation of Zika virus infections. Suspected newborn microcephaly diagnoses were identified from 1) reports submitted by birth hospitals in response to a request and 2) queries of a hospital administrative discharge database for newborn microcephaly diagnoses. Anthropometric measurements, maternal demographics, and pregnancy characteristics were abstracted from newborn records from both sources. Diagnoses were classified using microcephaly case definitions developed by CDC and the National Birth Defects Prevention Network (NBDPN) (2). During 2013-2015, 284 newborns in New York met the case definition for severe congenital microcephaly (prevalence = 4.2 per 10,000 live births). Most newborns with severe congenital microcephaly were identified by both sources; 263 (93%) were identified through hospital requests and 256 (90%) were identified through administrative discharge data. The proportions of newborns with severe congenital microcephaly who were black (30%) or Hispanic (31%) were higher than the observed proportions of black (15%) or Hispanic (23%) infants among New York live births. Fifty-eight percent of newborns with severe congenital microcephaly were born to mothers with pregnancy complications or who had in utero or perinatal infections or teratogenic exposures, genetic disorders, or family histories of birth defects.

  19. A newly recognized syndrome of severe growth deficiency, microcephaly, intellectual disability, and characteristic facial features.

    PubMed

    Vinkler, Chana; Leshinsky-Silver, Esther; Michelson, Marina; Haas, Dorothea; Lerman-Sagie, Tally; Lev, Dorit

    2014-01-01

    Genetic syndromes with proportionate severe short stature are rare. We describe two sisters born to nonconsanguineous parents with severe linear growth retardation, poor weight gain, microcephaly, characteristic facial features, cutaneous syndactyly of the toes, high myopia, and severe intellectual disability. During infancy and early childhood, the girls had transient hepatosplenomegaly and low blood cholesterol levels that normalized later. A thorough evaluation including metabolic studies, radiological, and genetic investigations were all normal. Cholesterol metabolism and transport were studied and no definitive abnormality was found. No clinical deterioration was observed and no metabolic crises were reported. After due consideration of other known hereditary causes of post-natal severe linear growth retardation, microcephaly, and intellectual disability, we propose that this condition represents a newly recognized autosomal recessive multiple congenital anomaly-intellectual disability syndrome. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  20. Zika virus infection and microcephaly: Evidence regarding geospatial associations.

    PubMed

    Vissoci, João Ricardo Nickenig; Rocha, Thiago Augusto Hernandes; Silva, Núbia Cristina da; de Sousa Queiroz, Rejane Christine; Thomaz, Erika Bárbara Abreu Fonseca; Amaral, Pedro Vasconcelos Maia; Lein, Adriana; Branco, Maria Dos Remédios Freitas Carvalho; Aquino, José; Rodrigues, Zulimar Márita Ribeiro; da Silva, Antônio Augusto Moura; Staton, Catherine

    2018-04-01

    Although the Zika virus (ZIKV) epidemic ceased to be a public health emergency by the end of 2016, studies to improve knowledge about this emerging disease are still needed, especially those investigating a causal relationship between ZIKV in pregnant women and microcephaly in neonates. However, there are still many challenges in describing the relationship between ZIKV and microcephaly. The few studies focusing on the epidemiological profile of ZIKV and its changes over time are largely limited to systematic reviews of case reports and dispersal mapping of ZIKV spread over time without quantitative methods to analyze patterns and their covariates. Since Brazil has been at the epicenter of the ZIKV epidemic, this study examines the geospatial association between ZIKV and microcephaly in Brazil. Our study is categorized as a retrospective, ecological study based on secondary databases. Data were obtained from January to December 2016, from the following data sources: Brazilian System for Epidemiological Surveillance, Disease Notification System, System for Specialized Management Support, and Brazilian Institute of Geography and Statistics. Data were aggregated by municipality. Incidence rates were estimated per 100,000 inhabitants. Analyses consisted of mapping the aggregated incidence rates of ZIKV and microcephaly, followed by a Getis-Ord-Gi spatial cluster analysis and a Bivariate Local Moran's I analysis. The incidence of ZIKV cases is changing the virus's spatial pattern, shifting from Brazil's Northeast region to the Midwest and North regions. The number of municipalities in clusters of microcephaly incidence is also shifting from the Northeast region to the Midwest and North, after a time lag is considered. Our findings suggest an increase in microcephaly incidence in the Midwest and North regions, associated with high levels of ZIKV infection months before. The greatest burden of microcephaly shifted from the Northeast to other Brazilian regions at the

  1. The Multidimensional Aspects of Sleep Spindles and Their Relationship to Word-Pair Memory Consolidation.

    PubMed

    Lustenberger, Caroline; Wehrle, Flavia; Tüshaus, Laura; Achermann, Peter; Huber, Reto

    2015-07-01

    Several studies proposed a link between sleep spindles and sleep dependent memory consolidation in declarative learning tasks. In addition to these state-like aspects of sleep spindles, they have also trait-like characteristics, i.e., were related to general cognitive performance, an important distinction that has often been neglected in correlative studies. Furthermore, from the multitude of different sleep spindle measures, often just one specific aspect was analyzed. Thus, we aimed at taking multidimensional aspects of sleep spindles into account when exploring their relationship to word-pair memory consolidation. Each subject underwent 2 study nights with all-night high-density electroencephalographic (EEG) recordings. Sleep spindles were automatically detected in all EEG channels. Subjects were trained and tested on a word-pair learning task in the evening, and retested in the morning to assess sleep related memory consolidation (overnight retention). Trait-like aspects refer to the mean of both nights and state-like aspects were calculated as the difference between night 1 and night 2. Sleep laboratory. Twenty healthy male subjects (age: 23.3 ± 2.1 y). Overnight retention was negatively correlated with trait-like aspects of fast sleep spindle density and positively with slow spindle density on a global level. In contrast, state-like aspects were observed for integrated slow spindle activity, which was positively related to the differences in overnight retention in specific regions. Our results demonstrate the importance of a multidimensional approach when investigating the relationship between sleep spindles and memory consolidation and thereby provide a more complete picture explaining divergent findings in the literature. © 2015 Associated Professional Sleep Societies, LLC.

  2. Lanthanide co-doped paramagnetic spindle-like mesocrystals for imaging and autophagy induction

    NASA Astrophysics Data System (ADS)

    Xu, Yun-Jun; Lin, Jun; Lu, Yang; Zhong, Sheng-Liang; Wang, Lei; Dong, Liang; Wu, Ya-Dong; Peng, Jun; Zhang, Li; Pan, Xiao-Feng; Zhou, Wei; Zhao, Yang; Wen, Long-Ping; Yu, Shu-Hong

    2016-07-01

    We synthesized two novel lanthanide doped spindle-like mesocrystals, YF3:Ce,Eu,Gd and YF3:Ce,Tb,Gd (abbreviated as YEG and YTG mesospindles, respectively). Both of them possess paramagnetic and fluorescent properties, and their excellent cyto-compatibility and low haemolysis are further confirmed. Therefore, they could act as dual mode contrast agents for magnetic resonance imaging (MRI) and fluorescence imaging. Furthermore, YEG and YTG mesospindles induce dose and time dependent autophagy by activating the PI3K signaling pathway. The autophagy induced by YEG and YTG mesocrystals is confirmed by enhanced autophagosome formation, normal cargo degradation, and no disruption of lysosomal function. This work is important to illustrate how rare-earth mesocrystals affect the autophagic pathway, indicating the potential of the YEG and YTG mesospindles in diagnosis and therapy.We synthesized two novel lanthanide doped spindle-like mesocrystals, YF3:Ce,Eu,Gd and YF3:Ce,Tb,Gd (abbreviated as YEG and YTG mesospindles, respectively). Both of them possess paramagnetic and fluorescent properties, and their excellent cyto-compatibility and low haemolysis are further confirmed. Therefore, they could act as dual mode contrast agents for magnetic resonance imaging (MRI) and fluorescence imaging. Furthermore, YEG and YTG mesospindles induce dose and time dependent autophagy by activating the PI3K signaling pathway. The autophagy induced by YEG and YTG mesocrystals is confirmed by enhanced autophagosome formation, normal cargo degradation, and no disruption of lysosomal function. This work is important to illustrate how rare-earth mesocrystals affect the autophagic pathway, indicating the potential of the YEG and YTG mesospindles in diagnosis and therapy. Electronic supplementary information (ESI) available: Size distribution, HRTEM image and additional cellular data. See DOI: 10.1039/c6nr03171d

  3. A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?: Brain tumors and microcephaly arise from opposing derangements regulating progenitor growth. Drivers of microcephaly could be attractive brain tumor targets.

    PubMed

    Lang, Patrick Y; Gershon, Timothy R

    2018-05-01

    New targets for brain tumor therapies may be identified by mutations that cause hereditary microcephaly. Brain growth depends on the repeated proliferation of stem and progenitor cells. Microcephaly syndromes result from mutations that specifically impair the ability of brain progenitor or stem cells to proliferate, by inducing either premature differentiation or apoptosis. Brain tumors that derive from brain progenitor or stem cells may share many of the specific requirements of their cells of origin. These tumors may therefore be susceptible to disruptions of the protein products of genes that are mutated in microcephaly. The potential for the products of microcephaly genes to be therapeutic targets in brain tumors are highlighted hereby reviewing research on EG5, KIF14, ASPM, CDK6, and ATR. Treatments that disrupt these proteins may open new avenues for brain tumor therapy that have increased efficacy and decreased toxicity. © 2018 WILEY Periodicals, Inc.

  4. Microcephaly: computational and organotypic modeling of a ...

    EPA Pesticide Factsheets

    lecture discusses computational and organotypic models of microcephaly in an AOP Framework and ToxCast assays. Lecture slide presentation at UNC Chapel Hill for Advanced Toxicology course lecture on Computational Approaches to Developmental and Reproductive Toxicology with presentation on computational and organotypic modeling of a complex human birth defect microcephaly with is associated with the recent Zika virus outbreak.

  5. Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells

    PubMed Central

    Boorgu, Devi Sai Sri Kavya; Levin, Michael; Kaplan, David L.

    2018-01-01

    ABSTRACT Zika virus (ZIKV) is a mosquito-transmitted flavivirus with a causative link to microcephaly, a condition resulting in reduced cranial size and brain abnormalities. Despite recent progress, there is a current lack of in vivo models that permit the study of systemic virus on human neurons in a developing organism that replicates the pathophysiology of human disease. Furthermore, no treatment to date has been reported to reduce ZIKV-induced microcephaly. We tested the effects of ZIKV on human induced neural stem cells (hiNSCs) in vitro and found that infected hiNSCs secrete inflammatory cytokines, display altered differentiation, and become apoptotic. We also utilized this in vitro system to assess the therapeutic effects of niclosamide, an FDA-approved anthelminthic, and found that it decreases ZIKV production, partially restores differentiation, and prevents apoptosis in hiNSCs. We intracranially injected hiNSCs into developing chicks, subjected them to systemic ZIKV infection via the chorioallantoic membrane (CAM), a tissue similar in structure and function to the mammalian placenta, and found that humanized ZIKV-infected embryos developed severe microcephaly including smaller crania, decreased forebrain volume and enlarged ventricles. Lastly, we utilized this humanized model to show that CAM-delivery of niclosamide can partially rescue ZIKV-induced microcephaly and attenuate infection of hiNSCs in vivo. This article has an associated First Person interview with the first author of the paper. PMID:29378701

  6. Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: preliminary report of a case-control study.

    PubMed

    de Araújo, Thalia Velho Barreto; Rodrigues, Laura Cunha; de Alencar Ximenes, Ricardo Arraes; de Barros Miranda-Filho, Demócrito; Montarroyos, Ulisses Ramos; de Melo, Ana Paula Lopes; Valongueiro, Sandra; de Albuquerque, Maria de Fátima Pessoa Militão; Souza, Wayner Vieira; Braga, Cynthia; Filho, Sinval Pinto Brandão; Cordeiro, Marli Tenório; Vazquez, Enrique; Di Cavalcanti Souza Cruz, Danielle; Henriques, Cláudio Maierovitch Pessanha; Bezerra, Luciana Caroline Albuquerque; da Silva Castanha, Priscila Mayrelle; Dhalia, Rafael; Marques-Júnior, Ernesto Torres Azevedo; Martelli, Celina Maria Turchi

    2016-12-01

    The microcephaly epidemic, which started in Brazil in 2015, was declared a Public Health Emergency of International Concern by WHO in 2016. We report the preliminary results of a case-control study investigating the association between microcephaly and Zika virus infection during pregnancy. We did this case-control study in eight public hospitals in Recife, Brazil. Cases were neonates with microcephaly. Two controls (neonates without microcephaly), matched by expected date of delivery and area of residence, were selected for each case. Serum samples of cases and controls and cerebrospinal fluid samples of cases were tested for Zika virus-specific IgM and by quantitative RT-PCR. Laboratory-confirmed Zika virus infection during pregnancy was defined as detection of Zika virus-specific IgM or a positive RT-PCR result in neonates. Maternal serum samples were tested by plaque reduction neutralisation assay for Zika virus and dengue virus. We estimated crude odds ratios (ORs) and 95% CIs using a median unbiased estimator for binary data in an unconditional logistic regression model. We estimated ORs separately for cases with and without radiological evidence of brain abnormalities. Between Jan 15, 2016, and May 2, 2016, we prospectively recruited 32 cases and 62 controls. 24 (80%) of 30 mothers of cases had Zika virus infection compared with 39 (64%) of 61 mothers of controls (p=0·12). 13 (41%) of 32 cases and none of 62 controls had laboratory-confirmed Zika virus infection; crude overall OR 55·5 (95% CI 8·6-∞); OR 113·3 (95% CI 14·5-∞) for seven cases with brain abnormalities; and OR 24·7 (95% CI 2·9-∞) for four cases without brain abnormalities. Our data suggest that the microcephaly epidemic is a result of congenital Zika virus infection. We await further data from this ongoing study to assess other potential risk factors and to confirm the strength of association in a larger sample size. Brazilian Ministry of Health, Pan American Health Organization

  7. Sleep Spindle Characteristics in Children with Neurodevelopmental Disorders and Their Relation to Cognition

    PubMed Central

    Wise, Merrill S.

    2016-01-01

    Empirical evidence indicates that sleep spindles facilitate neuroplasticity and “off-line” processing during sleep, which supports learning, memory consolidation, and intellectual performance. Children with neurodevelopmental disorders (NDDs) exhibit characteristics that may increase both the risk for and vulnerability to abnormal spindle generation. Despite the high prevalence of sleep problems and cognitive deficits in children with NDD, only a few studies have examined the putative association between spindle characteristics and cognitive function. This paper reviews the literature regarding sleep spindle characteristics in children with NDD and their relation to cognition in light of what is known in typically developing children and based on the available evidence regarding children with NDD. We integrate available data, identify gaps in understanding, and recommend future research directions. Collectively, studies are limited by small sample sizes, heterogeneous populations with multiple comorbidities, and nonstandardized methods for collecting and analyzing findings. These limitations notwithstanding, the evidence suggests that future studies should examine associations between sleep spindle characteristics and cognitive function in children with and without NDD, and preliminary findings raise the intriguing question of whether enhancement or manipulation of sleep spindles could improve sleep-dependent memory and other aspects of cognitive function in this population. PMID:27478646

  8. Zika Virus Infection as a Cause of Congenital Brain Abnormalities and Guillain-Barré Syndrome: Systematic Review.

    PubMed

    Krauer, Fabienne; Riesen, Maurane; Reveiz, Ludovic; Oladapo, Olufemi T; Martínez-Vega, Ruth; Porgo, Teegwendé V; Haefliger, Anina; Broutet, Nathalie J; Low, Nicola

    2017-01-01

    association with Zika virus infection. For GBS, we included 36 items, of which more than half the relevant studies supported a causal association in seven of ten dimensions (all except dose-response relationship, specificity, and animal experimental evidence). Articles identified nonsystematically from May 30 to July 29, 2016 strengthened the review findings. The expert panel concluded that (a) the most likely explanation of available evidence from outbreaks of Zika virus infection and clusters of microcephaly is that Zika virus infection during pregnancy is a cause of congenital brain abnormalities including microcephaly, and (b) the most likely explanation of available evidence from outbreaks of Zika virus infection and GBS is that Zika virus infection is a trigger of GBS. The expert panel recognised that Zika virus alone may not be sufficient to cause either congenital brain abnormalities or GBS but agreed that the evidence was sufficient to recommend increased public health measures. Weaknesses are the limited assessment of the role of dengue virus and other possible cofactors, the small number of comparative epidemiological studies, and the difficulty in keeping the review up to date with the pace of publication of new research. Rapid and systematic reviews with frequent updating and open dissemination are now needed both for appraisal of the evidence about Zika virus infection and for the next public health threats that will emerge. This systematic review found sufficient evidence to say that Zika virus is a cause of congenital abnormalities and is a trigger of GBS.

  9. Zika Virus Infection as a Cause of Congenital Brain Abnormalities and Guillain–Barré Syndrome: Systematic Review

    PubMed Central

    Reveiz, Ludovic; Oladapo, Olufemi T.; Martínez-Vega, Ruth; Haefliger, Anina

    2017-01-01

    relevant studies supported a causal association with Zika virus infection. For GBS, we included 36 items, of which more than half the relevant studies supported a causal association in seven of ten dimensions (all except dose–response relationship, specificity, and animal experimental evidence). Articles identified nonsystematically from May 30 to July 29, 2016 strengthened the review findings. The expert panel concluded that (a) the most likely explanation of available evidence from outbreaks of Zika virus infection and clusters of microcephaly is that Zika virus infection during pregnancy is a cause of congenital brain abnormalities including microcephaly, and (b) the most likely explanation of available evidence from outbreaks of Zika virus infection and GBS is that Zika virus infection is a trigger of GBS. The expert panel recognised that Zika virus alone may not be sufficient to cause either congenital brain abnormalities or GBS but agreed that the evidence was sufficient to recommend increased public health measures. Weaknesses are the limited assessment of the role of dengue virus and other possible cofactors, the small number of comparative epidemiological studies, and the difficulty in keeping the review up to date with the pace of publication of new research. Conclusions Rapid and systematic reviews with frequent updating and open dissemination are now needed both for appraisal of the evidence about Zika virus infection and for the next public health threats that will emerge. This systematic review found sufficient evidence to say that Zika virus is a cause of congenital abnormalities and is a trigger of GBS. PMID:28045901

  10. Hearing Loss in Infants with Microcephaly and Evidence of Congenital Zika Virus Infection - Brazil, November 2015-May 2016.

    PubMed

    Leal, Mariana C; Muniz, Lilian F; Ferreira, Tamires S A; Santos, Cristiane M; Almeida, Luciana C; Van Der Linden, Vanessa; Ramos, Regina C F; Rodrigues, Laura C; Neto, Silvio S Caldas

    2016-09-02

    Congenital infection with Zika virus causes microcephaly and other brain abnormalities (1). Hearing loss associated with other congenital viral infections is well described; however, little is known about hearing loss in infants with congenital Zika virus infection. A retrospective assessment of a series of 70 infants aged 0-10 months with microcephaly and laboratory evidence of Zika virus infection was conducted by the Hospital Agamenon Magalhães in Brazil and partners. The infants were enrolled during November 2015-May 2016 and had screening and diagnostic hearing tests. Five (7%) infants had sensorineural hearing loss, all of whom had severe microcephaly; however, one child was tested after receiving treatment with an ototoxic antibiotic. If this child is excluded, the prevalence of sensorineural hearing loss was 5.8% (four of 69), which is similar to that seen in association with other congenital viral infections. Additional information is needed to understand the prevalence and spectrum of hearing loss in children with congenital Zika virus infection; all infants born to women with evidence of Zika virus infection during pregnancy should have their hearing tested, including infants who appear normal at birth.

  11. The Clathrin-dependent Spindle Proteome*

    PubMed Central

    Rao, Sushma R.; Flores-Rodriguez, Neftali; Page, Scott L.; Wong, Chin; Robinson, Phillip J.; Chircop, Megan

    2016-01-01

    The mitotic spindle is required for chromosome congression and subsequent equal segregation of sister chromatids. These processes involve a complex network of signaling molecules located at the spindle. The endocytic protein, clathrin, has a “moonlighting” role during mitosis, whereby it stabilizes the mitotic spindle. The signaling pathways that clathrin participates in to achieve mitotic spindle stability are unknown. Here, we assessed the mitotic spindle proteome and phosphoproteome in clathrin-depleted cells using quantitative MS/MS (data are available via ProteomeXchange with identifier PXD001603). We report a spindle proteome that consists of 3046 proteins and a spindle phosphoproteome consisting of 5157 phosphosites in 1641 phosphoproteins. Of these, 2908 (95.4%) proteins and 1636 (99.7%) phosphoproteins are known or predicted spindle-associated proteins. Clathrin-depletion from spindles resulted in dysregulation of 121 proteins and perturbed signaling to 47 phosphosites. The majority of these proteins increased in mitotic spindle abundance and six of these were validated by immunofluorescence microscopy. Functional pathway analysis confirmed the reported role of clathrin in mitotic spindle stabilization for chromosome alignment and highlighted possible new mechanisms of clathrin action. The data also revealed a novel second mitotic role for clathrin in bipolar spindle formation. PMID:27174698

  12. The Clathrin-dependent Spindle Proteome.

    PubMed

    Rao, Sushma R; Flores-Rodriguez, Neftali; Page, Scott L; Wong, Chin; Robinson, Phillip J; Chircop, Megan

    2016-08-01

    The mitotic spindle is required for chromosome congression and subsequent equal segregation of sister chromatids. These processes involve a complex network of signaling molecules located at the spindle. The endocytic protein, clathrin, has a "moonlighting" role during mitosis, whereby it stabilizes the mitotic spindle. The signaling pathways that clathrin participates in to achieve mitotic spindle stability are unknown. Here, we assessed the mitotic spindle proteome and phosphoproteome in clathrin-depleted cells using quantitative MS/MS (data are available via ProteomeXchange with identifier PXD001603). We report a spindle proteome that consists of 3046 proteins and a spindle phosphoproteome consisting of 5157 phosphosites in 1641 phosphoproteins. Of these, 2908 (95.4%) proteins and 1636 (99.7%) phosphoproteins are known or predicted spindle-associated proteins. Clathrin-depletion from spindles resulted in dysregulation of 121 proteins and perturbed signaling to 47 phosphosites. The majority of these proteins increased in mitotic spindle abundance and six of these were validated by immunofluorescence microscopy. Functional pathway analysis confirmed the reported role of clathrin in mitotic spindle stabilization for chromosome alignment and highlighted possible new mechanisms of clathrin action. The data also revealed a novel second mitotic role for clathrin in bipolar spindle formation. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Available Evidence of Association between Zika Virus and Microcephaly

    PubMed Central

    Wu, Jing; Huang, Da-Yong; Ma, Jun-Tao; Ma, Ying-Hua; Hu, Yi-Fei

    2016-01-01

    Objective: To clarify the possible association between the Zika virus (ZIKV) and microcephaly and understand where we are in terms of research and the debate on the causation between mild maternal clinical features and severe fetal microcephaly. Data Sources: We did a comprehensive literature review with the keywords “zika” and/or “microcephaly” from inception to May 27, 2016, with PubMed. Study Selection: Studies were included and analyzed if they met all of the following criteria: “probable or confirmed infant microcephaly” and “probable or confirmed ZIKV infection among mothers or infants”. Results: We emphasize the diagnosis of ZIKV infection, including maternal clinical manifestations, maternal and fetal laboratory confirmation, and possible autopsy if need. Other confounders that may lead to microcephaly should be excluded from the study. We presented the results from clinical manifestations of ZIKV infection, testing methods evolving but the mechanism of microcephaly uncertain, flexible definition challenging the diagnosis of microcephaly, and limited causal reference on pregnant women. We made analog comparison of severe acute respiratory syndrome and chikungunya virus in terms of DNA mutation and global movement to provide further research recommendation. The chance of catch-up growth may decrease the number of pervious “diagnosed” microcephaly. Conclusions: There are some evidence available through mice models and direct isolation of ZIKV in affected pregnancies on kindly causal relationship but not convincible enough. We analyzed and presented the weakness or limitation of published reports with the desire to shed light to further study directions. PMID:27647195

  14. A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells

    PubMed Central

    Hehnly, Heidi; Canton, David; Bucko, Paula; Langeberg, Lorene K; Ogier, Leah; Gelman, Irwin; Santana, L Fernando; Wordeman, Linda; Scott, John D

    2015-01-01

    Correct orientation of the mitotic spindle in stem cells underlies organogenesis. Spindle abnormalities correlate with cancer progression in germ line-derived tumors. We discover a macromolecular complex between the scaffolding protein Gravin/AKAP12 and the mitotic kinases, Aurora A and Plk1, that is down regulated in human seminoma. Depletion of Gravin correlates with an increased mitotic index and disorganization of seminiferous tubules. Biochemical, super-resolution imaging, and enzymology approaches establish that this Gravin scaffold accumulates at the mother spindle pole during metaphase. Manipulating elements of the Gravin-Aurora A-Plk1 axis prompts mitotic delay and prevents appropriate assembly of astral microtubules to promote spindle misorientation. These pathological responses are conserved in seminiferous tubules from Gravin−/− mice where an overabundance of Oct3/4 positive germ line stem cells displays randomized orientation of mitotic spindles. Thus, we propose that Gravin-mediated recruitment of Aurora A and Plk1 to the mother (oldest) spindle pole contributes to the fidelity of symmetric cell division. DOI: http://dx.doi.org/10.7554/eLife.09384.001 PMID:26406118

  15. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

    PubMed Central

    Ji, Jianling; Lee, Hane; Argiropoulos, Bob; Dorrani, Naghmeh; Mann, John; Martinez-Agosto, Julian A; Gomez-Ospina, Natalia; Gallant, Natalie; Bernstein, Jonathan A; Hudgins, Louanne; Slattery, Leah; Isidor, Bertrand; Le Caignec, Cédric; David, Albert; Obersztyn, Ewa; Wiśniowiecka-Kowalnik, Barbara; Fox, Michelle; Deignan, Joshua L; Vilain, Eric; Hendricks, Emily; Horton Harr, Margaret; Noon, Sarah E; Jackson, Jessi R; Wilkens, Alisha; Mirzaa, Ghayda; Salamon, Noriko; Abramson, Jeff; Zackai, Elaine H; Krantz, Ian; Innes, A Micheil; Nelson, Stanley F; Grody, Wayne W; Quintero-Rivera, Fabiola

    2015-01-01

    Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from −2 SD to −5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype–phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs. PMID:25944381

  16. Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep.

    PubMed

    Huupponen, E; Maksimow, A; Lapinlampi, P; Särkelä, M; Saastamoinen, A; Snapir, A; Scheinin, H; Scheinin, M; Meriläinen, P; Himanen, S-L; Jääskeläinen, S

    2008-02-01

    Dexmedetomidine, a selective alpha(2)-adrenoceptor agonist, induces a unique, sleep-like state of sedation. The objective of the present work was to study human electroencephalogram (EEG) sleep spindles during dexmedetomidine sedation and compare them with spindles during normal physiological sleep, to test the hypothesis that dexmedetomidine exerts its effects via normal sleep-promoting pathways. EEG was continuously recorded from a bipolar frontopolar-laterofrontal derivation with Entropy Module (GE Healthcare) during light and deep dexmedetomidine sedation (target-controlled infusions set at 0.5 and 3.2 ng/ml) in 11 healthy subjects, and during physiological sleep in 10 healthy control subjects. Sleep spindles were visually scored and quantitatively analyzed for density, duration, amplitude (band-pass filtering) and frequency content (matching pursuit approach), and compared between the two groups. In visual analysis, EEG activity during dexmedetomidine sedation was similar to physiological stage 2 (S2) sleep with slight to moderate amount of slow-wave activity and abundant sleep spindle activity. In quantitative EEG analyses, sleep spindles were similar during dexmedetomidine sedation and normal sleep. No statistically significant differences were found in spindle density, amplitude or frequency content, but the spindles during dexmedetomidine sedation had longer duration (mean 1.11 s, SD 0.14 s) than spindles in normal sleep (mean 0.88 s, SD 0.14 s; P=0.0014). Analysis of sleep spindles shows that dexmedetomidine produces a state closely resembling physiological S2 sleep in humans, which gives further support to earlier experimental evidence for activation of normal non-rapid eye movement sleep-promoting pathways by this sedative agent.

  17. Spindle

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    2013-04-04

    Spindle is software infrastructure that solves file system scalabiltiy problems associated with starting dynamically linked applications in HPC environments. When an HPC applications starts up thousands of pricesses at once, and those processes simultaneously access a shared file system to look for shared libraries, it can cause significant performance problems for both the application and other users. Spindle scalably coordinates the distribution of shared libraries to an application to avoid hammering the shared file system.

  18. Reduced Sleep Spindle Activity in Early-Onset and Elevated Risk for Depression

    ERIC Educational Resources Information Center

    Lopez, Jorge; Hoffmann, Robert; Armitage, Roseanne

    2010-01-01

    Objective: Sleep disturbances are common in major depressive disorder (MDD), although polysomnographic (PSG) abnormalities are more prevalent in adults than in children and adolescents with MDD. Sleep spindle activity (SPA) is associated with neuroplasticity mechanisms during brain maturation and is more abundant in childhood and adolescence than…

  19. Cytological characteristics and classification of spindle inhibitors according to their effects on segmentation mitoses.

    PubMed

    Sentein, P; Ates, Y

    1978-01-01

    The effects of spindle inhibitors and of protein synthesis inhibitors on segmentation mitoses allow us to classify them into six groups : 1. Colchicine type : destruction of the whole achromatic apparatus and centrospheres without storing of dense bodies; 2. Quinoline type : same effect on the achromatic apparatus, but blocked centrospheres with accumulation of dense bodies; 3. Chloralhydrate type : Incomplete destruction of achromatic apparatus, spindle residue which maintains the chromosomes in a star shape, inactive centrospheres sequestered by the reticulum, but without accumulation of dense bodies; 4. Phenylurethane type : Incomplete and reversible action, which leads to easy production of pluripolar mitoses; 5. Carboxylic acid type : dissociation of the spindle, sometimes with blocking of the centrosphere, together with profound chromosome changes without primitive breaks; the intensity and quality of their action is related to the number of carbon atoms in the acid considered; 6. Protein synthesis inhibitor type : (cycloheximide, pederin) characterized by a stop of the nuclear cycle at telo-prophase when the action is sufficient, chromosome abnormalities, sometimes, reduced to strings of beads, and freeing of asters; at weaker concentrations mitosis is possible, but the congression of chromosomes at the equator is abnormal because of functional disturbance of the kinetochores. The nature and grading of these effects, their association (or non - association) to chromosome damage, the soundness of the spindle when only the chromosomes are affected (nitrogen mustard) make this one of the tests which gives the most specific data about the action of antimitotic substances.

  20. Pygmoid Australomelanesian Homo sapiens skeletal remains from Liang Bua, Flores: Population affinities and pathological abnormalities

    PubMed Central

    Jacob, T.; Indriati, E.; Soejono, R. P.; Hsü, K.; Frayer, D. W.; Eckhardt, R. B.; Kuperavage, A. J.; Thorne, A.; Henneberg, M.

    2006-01-01

    Liang Bua 1 (LB1) exhibits marked craniofacial and postcranial asymmetries and other indicators of abnormal growth and development. Anomalies aside, 140 cranial features place LB1 within modern human ranges of variation, resembling Australomelanesian populations. Mandibular and dental features of LB1 and LB6/1 either show no substantial deviation from modern Homo sapiens or share features (receding chins and rotated premolars) with Rampasasa pygmies now living near Liang Bua Cave. We propose that LB1 is drawn from an earlier pygmy H. sapiens population but individually shows signs of a developmental abnormality, including microcephaly. Additional mandibular and postcranial remains from the site share small body size but not microcephaly. PMID:16938848

  1. Pygmoid Australomelanesian Homo sapiens skeletal remains from Liang Bua, Flores: population affinities and pathological abnormalities.

    PubMed

    Jacob, T; Indriati, E; Soejono, R P; Hsü, K; Frayer, D W; Eckhardt, R B; Kuperavage, A J; Thorne, A; Henneberg, M

    2006-09-05

    Liang Bua 1 (LB1) exhibits marked craniofacial and postcranial asymmetries and other indicators of abnormal growth and development. Anomalies aside, 140 cranial features place LB1 within modern human ranges of variation, resembling Australomelanesian populations. Mandibular and dental features of LB1 and LB6/1 either show no substantial deviation from modern Homo sapiens or share features (receding chins and rotated premolars) with Rampasasa pygmies now living near Liang Bua Cave. We propose that LB1 is drawn from an earlier pygmy H. sapiens population but individually shows signs of a developmental abnormality, including microcephaly. Additional mandibular and postcranial remains from the site share small body size but not microcephaly.

  2. Zika Virus Infection and Microcephaly: Evidence for a Causal Link.

    PubMed

    Wang, Jin-Na; Ling, Feng

    2016-10-20

    Zika virus (ZIKV) is a flavivirus related to the Dengue, yellow fever and West Nile viruses. Since the explosive outbreaks of ZIKV in Latin America in 2015, a sudden increase in the number of microcephaly cases has been observed in infants of women who were pregnant when they contracted the virus. The severity of this condition raises grave concerns, and extensive studies on the possible link between ZIKV infection and microcephaly have been conducted. There is substantial evidence suggesting that there is a causal link between ZIKV and microcephaly, however, future studies are warranted to solidify this association. To summarize the most recent evidence on this issue and provide perspectives for future studies, we reviewed the literature to identify existing evidence of the causal link between ZIKV infection and microcephaly within research related to the epidemics, laboratory diagnosis, and possible mechanisms.

  3. Autopsy and Postmortem Studies Are Concordant: Pathology of Zika Virus Infection Is Neurotropic in Fetuses and Infants With Microcephaly Following Transplacental Transmission.

    PubMed

    Schwartz, David A

    2017-01-01

    -Pathology studies have been important in concluding that Zika virus infection occurring in pregnant women can result in vertical transmission of the agent from mother to fetus. Fetal and infant autopsies have provided crucial direct evidence that Zika virus can infect an unborn child, resulting in microcephaly, other malformations, and, in some cases, death. -To better understand the etiologic role and mechanism(s) of Zika virus in causing birth defects such as microcephaly, this communication analyzes the spectrum of clinical and autopsy studies reported from fetuses and infants who developed intrauterine Zika virus infection, and compares these findings with experimental data related to Zika virus infection. -Retrospective analysis of reported clinical, autopsy, pathology, and related postmortem studies from 9 fetuses and infants with intrauterine Zika virus infection and microcephaly. -All fetuses and infants examined demonstrated an overlapping spectrum of gross and microscopic neuropathologic abnormalities. Direct cytopathic effects of infection by the Zika virus were confined to the brain; in cases where other organs were evaluated, no direct viral effects were identified. -There is concordance of the spectrum of brain damage, reinforcing previous data indicating that the Zika virus has a strong predilection for cells of the fetal central nervous system following vertical transmission. The occurrence of additional congenital abnormalities suggests that intrauterine brain damage from Zika virus interferes with normal fetal development, resulting in fetal akinesia. Experimental in vitro and in vivo studies of Zika virus infection corroborate the human autopsy findings of neural specificity.

  4. Dynactin-dependent cortical dynein and spherical spindle shape correlate temporally with meiotic spindle rotation in Caenorhabditis elegans

    PubMed Central

    Crowder, Marina E.; Flynn, Jonathan R.; McNally, Karen P.; Cortes, Daniel B.; Price, Kari L.; Kuehnert, Paul A.; Panzica, Michelle T.; Andaya, Armann; Leary, Julie A.; McNally, Francis J.

    2015-01-01

    Oocyte meiotic spindles orient with one pole juxtaposed to the cortex to facilitate extrusion of chromosomes into polar bodies. In Caenorhabditis elegans, these acentriolar spindles initially orient parallel to the cortex and then rotate to the perpendicular orientation. To understand the mechanism of spindle rotation, we characterized events that correlated temporally with rotation, including shortening of the spindle in the pole-to pole axis, which resulted in a nearly spherical spindle at rotation. By analyzing large spindles of polyploid C. elegans and a related nematode species, we found that spindle rotation initiated at a defined spherical shape rather than at a defined spindle length. In addition, dynein accumulated on the cortex just before rotation, and microtubules grew from the spindle with plus ends outward during rotation. Dynactin depletion prevented accumulation of dynein on the cortex and prevented spindle rotation independently of effects on spindle shape. These results support a cortical pulling model in which spindle shape might facilitate rotation because a sphere can rotate without deforming the adjacent elastic cytoplasm. We also present evidence that activation of spindle rotation is promoted by dephosphorylation of the basic domain of p150 dynactin. PMID:26133383

  5. Three-dimensional morphological and textural complexity of Archean putative microfossils from the Northeastern Pilbara Craton: indications of biogenicity of large (>15 microm) spheroidal and spindle-like structures.

    PubMed

    Sugitani, Kenichiro; Grey, Kathleen; Nagaoka, Tsutomu; Mimura, Koichi

    2009-09-01

    We recently reported a diverse assemblage of carbonaceous structures (thread-like, film-like, spheroidal, and spindle-like) from chert in the ca. 3.0 Ga Farrel Quartzite of the Gorge Creek Group in the Pilbara Craton, Western Australia. Results from a rigorous examination of occurrence, composition, morphological complexity, size distributions, and taphonomy provided presumptive evidence for biogenicity. In this study, we present new data of morphological and textural complexity of large (>15 microm) spheroidal and spindle-like structures, using an in-focus, 3-D image reconstruction system, which further raises the scale of credibility that these structures are microfossils. While many of the large spheroids are single-walled, and the wall is irregularly folded, a few specimens are partially blistered, double walled, or have a dimpled wall. The wall-surface texture varies from smooth and homogeneous (hyaline) to patchy, granular or reticulate. Such variation is best explained as resulting from taphonomic processes. Additionally, an inner solitary body, present in some large spheroids, is hollow and partially broken, which indicates a primary origin for this substructure. Spindle-like structures have two types of flange-like appendage; one is attached at the equatorial plane of the body, whereas the other appears to be attached peripherally. In both cases, the appendage tends to have a flat geometry, a tapering thickness, and constancy in shape, proportions, and dimensions. Spindle-wall surfaces are variously textured and heterogeneous. These morphological and textural complexities and heterogeneity refute potential abiogenic formation models for these structures, such as crystals coated with organic matter, fenestrae, and the diagenetic redistribution of carbonaceous matter. When coupled with other data from Raman spectroscopy, NanoSIMS analysis, and palynology, the evidence that these large carbonaceous structures are biogenic appears compelling, though it is

  6. Nap sleep spindle correlates of intelligence.

    PubMed

    Ujma, Péter P; Bódizs, Róbert; Gombos, Ferenc; Stintzing, Johannes; Konrad, Boris N; Genzel, Lisa; Steiger, Axel; Dresler, Martin

    2015-11-26

    Sleep spindles are thalamocortical oscillations in non-rapid eye movement (NREM) sleep, that play an important role in sleep-related neuroplasticity and offline information processing. Several studies with full-night sleep recordings have reported a positive association between sleep spindles and fluid intelligence scores, however more recently it has been shown that only few sleep spindle measures correlate with intelligence in females, and none in males. Sleep spindle regulation underlies a circadian rhythm, however the association between spindles and intelligence has not been investigated in daytime nap sleep so far. In a sample of 86 healthy male human subjects, we investigated the correlation between fluid intelligence and sleep spindle parameters in an afternoon nap of 100 minutes. Mean sleep spindle length, amplitude and density were computed for each subject and for each derivation for both slow and fast spindles. A positive association was found between intelligence and slow spindle duration, but not any other sleep spindle parameter. As a positive correlation between intelligence and slow sleep spindle duration in full-night polysomnography has only been reported in females but not males, our results suggest that the association between intelligence and sleep spindles is more complex than previously assumed.

  7. Abnormal laughter-like vocalisations replacing speech in primary progressive aphasia.

    PubMed

    Rohrer, Jonathan D; Warren, Jason D; Rossor, Martin N

    2009-09-15

    We describe ten patients with a clinical diagnosis of primary progressive aphasia (PPA) (pathologically confirmed in three cases) who developed abnormal laughter-like vocalisations in the context of progressive speech output impairment leading to mutism. Failure of speech output was accompanied by increasing frequency of the abnormal vocalisations until ultimately they constituted the patient's only extended utterance. The laughter-like vocalisations did not show contextual sensitivity but occurred as an automatic vocal output that replaced speech. Acoustic analysis of the vocalisations in two patients revealed abnormal motor features including variable note duration and inter-note interval, loss of temporal symmetry of laugh notes and loss of the normal decrescendo. Abnormal laughter-like vocalisations may be a hallmark of a subgroup in the PPA spectrum with impaired control and production of nonverbal vocal behaviour due to disruption of fronto-temporal networks mediating vocalisation.

  8. Surveillance of microcephaly and selected brain anomalies in Argentina: Relationship with Zika virus and other congenital infections.

    PubMed

    Tellechea, Ana Laura; Luppo, Victoria; Morales, María Alejandra; Groisman, Boris; Baricalla, Agustin; Fabbri, Cintia; Sinchi, Anabel; Alonso, Alicia; Gonzalez, Cecilia; Ledesma, Bibiana; Masi, Patricia; Silva, María; Israilev, Adriana; Rocha, Marcela; Quaglia, Marcela; Bidondo, María Paz; Liascovich, Rosa; Barbero, Pablo

    2018-06-19

    Zika virus (ZIKV) vertical transmission may lead to microcephaly and other congenital anomalies. In March and April 2016, the first outbreak of ZIKV occurred in Argentina. The objective was to describe the surveillance of newborns with microcephaly and other selected brain anomalies in Argentina, and evaluation different etiologies. Participants were enrolled between April 2016 and March 2017. newborns from the National Network of Congenital Abnormalities of Argentina (RENAC) with head circumference lower than the 3rd percentile according to gestational age and sex, or selected brain anomalies. Blood and urine samples from cases and their mothers were tested for ZIKV by real-time polymerase chain reaction (RT-PCR), antigen-specific Immunoglobulin M (MAC-ELISA) and plaque-reduction neutralization test (PRNT 90 ). Toxoplasmosis, rubella, herpes simplex, syphilis, and cytomegalovirus (CMV) infection were also tested. A total of 104 cases were reported, with a prevalence of 6.9 per 10,000 [95% confidence interval (CI): 5.7-8.4], a significant increase when compared with the data prior to 2016, Prevalence Rate Ratio 1.7 (95% CI 1.2-2.3). In five cases positive serology for ZIKV (IgM and IgG by PRNT) was detected. The five cases presented microcephaly with craniofacial disproportion. We detected four cases of CMV infection, three cases of congenital toxoplasmosis, two cases of herpes simplex infection, and one case of congenital syphilis. The prevalence of microcephaly was significantly higher when compared with the previous period. The system had the capacity to detect five cases with congenital ZIKV syndrome in a country with limited viral circulation. © 2018 Wiley Periodicals, Inc.

  9. Abnormal laughter-like vocalisations replacing speech in primary progressive aphasia

    PubMed Central

    Rohrer, Jonathan D.; Warren, Jason D.; Rossor, Martin N.

    2009-01-01

    We describe ten patients with a clinical diagnosis of primary progressive aphasia (PPA) (pathologically confirmed in three cases) who developed abnormal laughter-like vocalisations in the context of progressive speech output impairment leading to mutism. Failure of speech output was accompanied by increasing frequency of the abnormal vocalisations until ultimately they constituted the patient's only extended utterance. The laughter-like vocalisations did not show contextual sensitivity but occurred as an automatic vocal output that replaced speech. Acoustic analysis of the vocalisations in two patients revealed abnormal motor features including variable note duration and inter-note interval, loss of temporal symmetry of laugh notes and loss of the normal decrescendo. Abnormal laughter-like vocalisations may be a hallmark of a subgroup in the PPA spectrum with impaired control and production of nonverbal vocal behaviour due to disruption of fronto-temporal networks mediating vocalisation. PMID:19435636

  10. Microcephaly epidemic related to the Zika virus and living conditions in Recife, Northeast Brazil.

    PubMed

    Souza, Wayner Vieira de; Albuquerque, Maria de Fátima Pessoa Militão de; Vazquez, Enrique; Bezerra, Luciana Caroline Albuquerque; Mendes, Antonio da Cruz Gouveia; Lyra, Tereza Maciel; Araujo, Thalia Velho Barreto de; Oliveira, André Luiz Sá de; Braga, Maria Cynthia; Ximenes, Ricardo Arraes de Alencar; Miranda-Filho, Demócrito de Barros; Cabral Silva, Amanda Priscila de Santana; Rodrigues, Laura; Martelli, Celina Maria Turchi

    2018-01-12

    Starting in August 2015, there was an increase in the number of cases of neonatal microcephaly in Northeast Brazil. These findings were identified as being an epidemic of microcephaly related to Zika virus (ZIKV) infection. The present study aims to analyse the spatial distribution of microcephaly cases in Recife (2015-2016), which is in Northeast Brazil, and its association with the living conditions in this city. This was an ecological study that used data from reported cases of microcephaly from the State Health Department of Pernambuco (August 2015 to July 2016). The basic spatial unit of analysis was the 94 districts of Recife. The case definition of microcephaly was: neonates with a head circumference of less than the cut-off point of -2 standard deviations below the mean value from the established Fenton growth curve. As an indicator of the living conditions of the 94 districts, the percentage of heads of households with an income of less than twice the minimum wage was calculated. The districts were classified into four homogeneous strata using the K-means clustering algorithm. We plotted the locations of each microcephaly case over a layer of living conditions. During the study period, 347 microcephaly cases were reported, of which 142 (40.9%) fulfilled the definition of a microcephaly case. Stratification of the 94 districts resulted in the identification of four strata. The highest stratum in relation to the living conditions presented the lowest prevalence rate of microcephaly, and the overall difference between this rate and the rates of the other strata was statistically significant. The results of the Kruskal-Wallis test demonstrated that there was a strong association between a higher prevalence of microcephaly and poor living conditions. After the first 6 months of the study period, there were no microcephaly cases recorded within the population living in the richest socio-economic strata. This study showed that those residing in areas with

  11. The spindle protein CHICA mediates localization of the chromokinesin Kid to the mitotic spindle.

    PubMed

    Santamaria, Anna; Nagel, Susanna; Sillje, Herman H W; Nigg, Erich A

    2008-05-20

    Microtubule-based motor proteins provide essential forces for bipolar organization of spindle microtubules and chromosome movement, prerequisites of chromosome segregation during the cell cycle. Here, we describe the functional characterization of a novel spindle protein, termed "CHICA," that was originally identified in a proteomic survey of the human spindle apparatus [1]. We show that CHICA localizes to the mitotic spindle and is both upregulated and phosphorylated during mitosis. CHICA-depleted cells form shorter spindles and fail to organize a proper metaphase plate, highly reminiscent of the phenotype observed upon depletion of the chromokinesin Kid, a key mediator of polar ejection forces [2-6]. We further show that CHICA coimmunoprecipitates with Kid and is required for the spindle localization of Kid without affecting its chromosome association. Moreover, upon depletion of either CHICA or Kid (or both proteins simultaneously), chromosomes collapse onto the poles of monastrol-induced monopolar spindles. We conclude that CHICA represents a novel interaction partner of the chromokinesin Kid that is required for the generation of polar ejection forces and chromosome congression.

  12. Localization of the Kinesin-like Protein Xklp2 to Spindle Poles Requires a Leucine Zipper, a Microtubule-associated Protein, and Dynein

    PubMed Central

    Wittmann, Torsten; Boleti, Haralabia; Antony, Claude; Karsenti, Eric; Vernos, Isabelle

    1998-01-01

    Xklp2 is a plus end–directed Xenopus kinesin-like protein localized at spindle poles and required for centrosome separation during spindle assembly in Xenopus egg extracts. A glutathione-S-transferase fusion protein containing the COOH-terminal domain of Xklp2 (GST-Xklp2-Tail) was previously found to localize to spindle poles (Boleti, H., E. Karsenti, and I. Vernos. 1996. Cell. 84:49–59). Now, we have examined the mechanism of localization of GST-Xklp2-Tail. Immunofluorescence and electron microscopy showed that Xklp2 and GST-Xklp2-Tail localize specifically to the minus ends of spindle pole and aster microtubules in mitotic, but not in interphase, Xenopus egg extracts. We found that dimerization and a COOH-terminal leucine zipper are required for this localization: a single point mutation in the leucine zipper prevented targeting. The mechanism of localization is complex and two additional factors in mitotic egg extracts are required for the targeting of GST-Xklp2-Tail to microtubule minus ends: (a) a novel 100-kD microtubule-associated protein that we named TPX2 (Targeting protein for Xklp2) that mediates the binding of GST-Xklp2-Tail to microtubules and (b) the dynein–dynactin complex that is required for the accumulation of GST-Xklp2-Tail at microtubule minus ends. We propose two molecular mechanisms that could account for the localization of Xklp2 to microtubule minus ends. PMID:9813089

  13. RBBP8 syndrome with microcephaly, intellectual disability, short stature and brachydactyly.

    PubMed

    Mumtaz, Sara; Yıldız, Esra; Jabeen, Saliha; Khan, Amjad; Tolun, Aslıhan; Malik, Sajid

    2015-12-01

    Primary microcephaly is clinically variable and genetically heterogeneous. Four phenotypically distinct types of autosomal recessive microcephaly syndromes are due to different RBBP8 mutations. We report on a consanguineous Pakistani family with homozygous RBBP8 mutation c.1808_1809delTA (p.Ile603Lysfs*7) manifesting microcephaly and a distinct combination of skeletal, limb and ectodermal defects, mild intellectual disability, minor facial anomalies, anonychia, disproportionate short stature and brachydactyly, and additionally talipes in one patient. © 2015 Wiley Periodicals, Inc.

  14. Arsenite inhibits mitotic division and perturbs spindle dynamics in HeLa S3 cells.

    PubMed

    Huang, S C; Lee, T C

    1998-05-01

    Arsenical compounds, known to be human carcinogens, were shown to disturb cell cycle progression and induce cytogenetic alterations in a variety of cell systems. We report here that a 24 h treatment of arsenite induced mitotic accumulation in human cell lines. HeLa S3 and KB cells were most susceptible: 35% of the total cell population was arrested at the mitotic stage after treatment with 5 microM sodium arsenite in HeLa S3 cells and after 10 microM in KB cells. Under a microscope, we observed abnormal mitotic figures in arsenite-arrested mitotic cells, including deranged chromosome congression, elongated polar distance of mitotic spindle, and enhanced microtubule immunofluorescence. The spindle microtubules of arsenite-arrested mitotic cells were more resistant to nocodazole-induced dissolution than those of control mitotic cells. According to turbidity assay, arsenite at concentrations below 100 microM significantly enhanced polymerization of tubulins. Since spindle dynamics play a crucial role in mitotic progression, our results suggest that arsenite-induced mitotic arrest may be due to arsenite's effects on attenuation of spindle dynamics.

  15. Chornobyl, radiation, neural tube defects, and microcephaly.

    PubMed

    Wertelecki, Wladimir; Yevtushok, Lyubov; Kuznietsov, Illia; Komov, Oleksandr; Lapchenko, Serhii; Akhmedzanova, Diana; Ostapchuk, Lyubov

    2018-06-13

    Pregnant women residing in areas impacted by the Chornobyl ionizing radiation of the Rivne Province in Ukraine have persistent higher levels of incorporated cesium-137. In these areas the neural tube defects and microcephaly rates are significantly higher than in areas with lower maternal cesium-137 incorporated levels. In two Rivne counties with populations proximal to nuclear power plants the rates of neural tube defects and microcephaly are the highest in the province. The neural tube defects rates in Rivne are persistently among the highest in Europe. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  16. Sleep spindles and intelligence in early childhood-developmental and trait-dependent aspects.

    PubMed

    Ujma, Péter P; Sándor, Piroska; Szakadát, Sára; Gombos, Ferenc; Bódizs, Róbert

    2016-12-01

    Sleep spindles act as a powerful marker of individual differences in cognitive ability. Sleep spindle parameters correlate with both age-related changes in cognitive abilities and with the age-independent concept of IQ. While some studies have specifically demonstrated the relationship between sleep spindles and intelligence in young children, our previous work in older subjects revealed sex differences in the sleep spindle correlates of IQ, which was never investigated in small children before. We investigated the relationship between age, Raven Colored Progressive Matrices (CPM) scores and sleep spindles in 28 young children (age 4-8 years, 15 girls). We specifically investigated sex differences in the psychometric correlates of sleep spindles. We also aimed to separate the correlates of sleep spindles that are because of age-related maturation from other effects that reflect an age-independent relationship between sleep spindles and general intelligence. Our results revealed a modest positive correlation between fast spindle amplitude and age. Raven CPM scores positively correlated with both slow and fast spindle amplitude, but this effect remained a tendency in males and vanished after correcting for the effects of age. Age-corrected correlations between Raven CPM scores and both slow and fast spindle amplitude were only significant in females. Overall, our results show that in male children sleep spindles are a maturational marker, but in female children they indicate trait-like intelligence, in line with previous studies in adolescent and adult subjects. Thalamocortical white matter connectivity may be the underlying mechanism behind both higher spindle amplitude and higher intelligence in female, but not male subjects. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  17. Is cohesin required for spindle-pole-body/centrosome cohesion?

    PubMed Central

    Jin, Hui; Avey, Martin

    2012-01-01

    Centrosomes are microtubule-organizing centers that nucleate spindle microtubules during cell division. In budding yeast, the centrosome, often referred to as the spindle pole body, shares structural components with the centriole, the central core of the animal centrosome. The parental centrosome is duplicated when DNA replication takes place. Like sister chromatids tethered together by cohesin, duplicated centrosomes are linked and then separate to form the bipolar spindle necessary for chromosome segregation. Recent studies have shown that cohesin is also localized to the animal centrosome and is perhaps directly involved in engaging paired centrioles. Here we discuss the potential role of cohesin in mediating spindle-pole-body cohesion in the context of yeast meiosis. We propose that the coordination of chromosome segregation with centrosome cohesion and duplication is mediated by the antagonistic interaction between the Aurora kinase and the Polo kinase and that the role of cohesin in centrosome regulation appears to be indirect in budding yeast. PMID:22482005

  18. The Challenge of Assessing Microcephaly in the Context of the Zika Virus Epidemic.

    PubMed

    Quintó, Llorenç; García-Basteiro, Alberto L; Bardají, Azucena; González, Raquel; Padilla, Norma; Martinez-Espinosa, Flor E; Arévalo-Herrera, Myriam; Macete, Eusébio; Menéndez, Clara

    2017-03-10

    The present article examines the impact of the current limitations of the microcephaly definition in the context of the Zika virus outbreak. It highlights its dependence on the method used for determining gestational age and other anthropometric parameters, and includes original results of prevalence of microcephaly in four countries from two different continents (Mozambique, Brazil, Guatemala and Colombia). Alternative definitions of microcephaly are proposed to allow the identification of true cases of microcephaly in a more accurate manner. © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. A Possible Link Between Pyriproxyfen and Microcephaly

    PubMed Central

    Parens, Raphael; Nijhout, H. Frederik; Morales, Alfredo; Xavier Costa, Felipe; Bar-Yam, Yaneer

    2017-01-01

    The Zika virus has been the primary suspect in the large increase in incidence of microcephaly in 2015-6 in Brazil. While evidence for Zika being the cause of some of the cases is strong, its role as the primary cause of the large number of cases in Brazil has not been confirmed. Recently, the disparity between the incidences in different geographic locations has led to questions about the virus's role. Here we consider the alternative possibility that the use of the insecticide pyriproxyfen for control of mosquito populations in Brazilian drinking water is the primary cause. Pyriproxifen is a juvenile hormone analog which has been shown to correspond in mammals to a number of fat soluble regulatory molecules including retinoic acid, a metabolite of vitamin A, with which it has cross-reactivity and whose application during development has been shown to cause microcephaly. Methoprene, another juvenile hormone analog that was approved as an insecticide based upon tests performed in the 1970s, has metabolites that bind to the mammalian retinoid X receptor, and has been shown to cause developmental disorders in mammals. Isotretinoin is another example of a retinoid causing microcephaly in human babies via maternal exposure and activation of the retinoid X receptor in developing fetuses. Moreover, tests of pyriproxyfen by the manufacturer, Sumitomo, widely quoted as giving no evidence for developmental toxicity, actually found some evidence for such an effect, including low brain mass and arhinencephaly—incomplete formation of the anterior cerebral hemispheres—in exposed rat pups. Finally, the pyriproxyfen use in Brazil is unprecedented—it has never before been applied to a water supply on such a scale. Claims that it is not being used in Recife, the epicenter of microcephaly cases, do not distinguish the metropolitan area of Recife, where it is widely used, and the municipality, and have not been adequately confirmed. Given this combination of information about

  20. Modulation of jaw muscle spindle afferent activity following intramuscular injections with hypertonic saline.

    PubMed

    Ro, J Y; Capra, N F

    2001-05-01

    Transient noxious chemical stimulation of small diameter muscle afferents modulates jaw movement-related responses of caudal brainstem neurons. While it is likely that the effect is mediated from the spindle afferents in the mesencephalic nucleus (Vmes) via the caudally projecting Probst's tract, the mechanisms of pain induced modulations of jaw muscle spindle afferents is not known. In the present study, we tested the hypothesis that jaw muscle nociceptors gain access to muscle spindle afferents in the same muscle via central mechanisms and alter their sensitivity. Thirty-five neurons recorded from the Vmes were characterized as muscle spindle afferents based on their responses to passive jaw movements, muscle palpation, and electrical stimulation of the masseter nerve. Each cell was tested by injecting a small volume (250 microl) of either 5% hypertonic and/or isotonic saline into the receptor-bearing muscle. Twenty-nine units were tested with 5% hypertonic saline, of which 79% (23/29) showed significant modulation of mean firing rates (MFRs) during one or more phases of ramp-and-hold movements. Among the muscle spindle primary-like units (n = 12), MFRs of 4 units were facilitated, five reduced, two showed mixed responses and one unchanged. In secondary-like units (n = 17), MFRs of 9 were facilitated, three reduced and five unchanged. Thirteen units were tested with isotonic saline, of which 77% showed no significant changes of MFRs. Further analysis revealed that the hypertonic saline not only affected the overall output of muscle spindle afferents, but also increased the variability of firing and altered the relationship between afferent signal and muscle length. These results demonstrated that activation of muscle nociceptors significantly affects proprioceptive properties of jaw muscle spindles via central neural mechanisms. The changes can have deleterious effects on oral motor function as well as kinesthetic sensibility.

  1. Does Zika Virus Cause Microcephaly - Applying the Bradford Hill Viewpoints

    PubMed Central

    Awadh, Asma; Chughtai, Abrar Ahmad; Dyda, Amalie; Sheikh, Mohamud; Heslop, David J.; MacIntyre, Chandini Raina

    2017-01-01

    Introduction: Zika virus has been documented since 1952, but been associated with mild, self-limiting disease. Zika virus is classified as an arbovirus from a family of Flaviviridae and primarily spread by Aedes Aegypti mosquitos. However, in a large outbreak in Brazil in 2015, Zika virus has been associated with microcephaly. Methods: In this review we applied the Bradford-Hill viewpoints  to investigate the association between Zika virus and microcephaly. We examined historical studies, available data and also compared historical rates of microcephaly prior to the Zika virus outbreak. The available evidence was reviewed against the Bradford Hill viewpoints. Results: All  the nine criteria were met to varying degrees: strength of association, consistency of the association, specificity, temporality, plausibility, coherence, experimental evidence, biological gradient and analogy. Conclusion: Using the Bradford Hill Viewpoints as an evaluation framework for causation is highly suggestive that the association between Zika virus and microcephaly is causal. Further studies using animal models on the viewpoints which were not as strongly fulfilled would be helpful. PMID:28357156

  2. Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update

    PubMed Central

    Huang, Lijia; Vanstone, Megan R.; Hartley, Taila; Osmond, Matthew; Barrowman, Nick; Allanson, Judith; Baker, Laura; Dabir, Tabib A.; Dipple, Katrina M.; Dobyns, William B.; Estrella, Jane; Faghfoury, Hanna; Favaro, Francine P.; Goel, Himanshu; Gregersen, Pernille A.; Gripp, Karen W.; Grix, Art; Guion-Almeida, Maria-Leine; Harr, Margaret H.; Hudson, Cindy; Hunter, Alasdair G.W.; Johnson, John; Joss, Shelagh K.; Kimball, Amy; Kini, Usha; Kline, Antonie D.; Lauzon, Julie; Lildballe, Dorte L.; López-González, Vanesa; Martinezmoles, Johanna; Meldrum, Cliff; Mirzaa, Ghayda M.; Morel, Chantal F.; Morton, Jenny E.V.; Pyle, Louise C.; Quintero-Rivera, Fabiola; Richer, Julie; Scheuerle, Angela E.; Schönewolf-Greulich, Bitten; Shears, Deborah J.; Silver, Josh; Smith, Amanda C.; Temple, I. Karen; van de Kamp, Jiddeke M.; van Dijk, Fleur S.; Vandersteen, Anthony M.; White, Sue M.; Zackai, Elaine H.; Zou, Ruobing; Bulman, Dennis E.; Boycott, Kym M.; Lines, Matthew A.

    2017-01-01

    Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5–116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ~27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late “catch-up” growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2). PMID:26507355

  3. Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.

    PubMed

    Huang, Lijia; Vanstone, Megan R; Hartley, Taila; Osmond, Matthew; Barrowman, Nick; Allanson, Judith; Baker, Laura; Dabir, Tabib A; Dipple, Katrina M; Dobyns, William B; Estrella, Jane; Faghfoury, Hanna; Favaro, Francine P; Goel, Himanshu; Gregersen, Pernille A; Gripp, Karen W; Grix, Art; Guion-Almeida, Maria-Leine; Harr, Margaret H; Hudson, Cindy; Hunter, Alasdair G W; Johnson, John; Joss, Shelagh K; Kimball, Amy; Kini, Usha; Kline, Antonie D; Lauzon, Julie; Lildballe, Dorte L; López-González, Vanesa; Martinezmoles, Johanna; Meldrum, Cliff; Mirzaa, Ghayda M; Morel, Chantal F; Morton, Jenny E V; Pyle, Louise C; Quintero-Rivera, Fabiola; Richer, Julie; Scheuerle, Angela E; Schönewolf-Greulich, Bitten; Shears, Deborah J; Silver, Josh; Smith, Amanda C; Temple, I Karen; van de Kamp, Jiddeke M; van Dijk, Fleur S; Vandersteen, Anthony M; White, Sue M; Zackai, Elaine H; Zou, Ruobing; Bulman, Dennis E; Boycott, Kym M; Lines, Matthew A

    2016-02-01

    Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2). © 2015 WILEY PERIODICALS, INC.

  4. Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome.

    PubMed

    McIntyre, Rebecca E; Lakshminarasimhan Chavali, Pavithra; Ismail, Ozama; Carragher, Damian M; Sanchez-Andrade, Gabriela; Forment, Josep V; Fu, Beiyuan; Del Castillo Velasco-Herrera, Martin; Edwards, Andrew; van der Weyden, Louise; Yang, Fengtang; Ramirez-Solis, Ramiro; Estabel, Jeanne; Gallagher, Ferdia A; Logan, Darren W; Arends, Mark J; Tsang, Stephen H; Mahajan, Vinit B; Scudamore, Cheryl L; White, Jacqueline K; Jackson, Stephen P; Gergely, Fanni; Adams, David J

    2012-01-01

    Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome. The mechanism by which disruption of CENPJ causes the proportionate, primordial growth failure that is characteristic of Seckel syndrome is unknown. By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpj(tm/tm)) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome. Immunohistochemistry revealed increased levels of DNA damage and apoptosis throughout Cenpj(tm/tm) embryos and adult mice showed an elevated frequency of micronucleus induction, suggesting that Cenpj-deficiency results in genomic instability. Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome. Instead, Cenpj(tm/tm) embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells. Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome.

  5. Disruption of Mouse Cenpj, a Regulator of Centriole Biogenesis, Phenocopies Seckel Syndrome

    PubMed Central

    McIntyre, Rebecca E.; Lakshminarasimhan Chavali, Pavithra; Forment, Josep V.; Fu, Beiyuan; Del Castillo Velasco-Herrera, Martin; Edwards, Andrew; van der Weyden, Louise; Yang, Fengtang; Ramirez-Solis, Ramiro; Estabel, Jeanne; Gallagher, Ferdia A.; Logan, Darren W.; Arends, Mark J.; Tsang, Stephen H.; Mahajan, Vinit B.; Scudamore, Cheryl L.; White, Jacqueline K.; Jackson, Stephen P.; Gergely, Fanni; Adams, David J.

    2012-01-01

    Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome. The mechanism by which disruption of CENPJ causes the proportionate, primordial growth failure that is characteristic of Seckel syndrome is unknown. By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpjtm/tm) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome. Immunohistochemistry revealed increased levels of DNA damage and apoptosis throughout Cenpjtm/tm embryos and adult mice showed an elevated frequency of micronucleus induction, suggesting that Cenpj-deficiency results in genomic instability. Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome. Instead, Cenpjtm/tm embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells. Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome. PMID:23166506

  6. An astral simulacrum of the central spindle accounts for normal, spindle-less, and anucleate cytokinesis in echinoderm embryos

    PubMed Central

    Su, Kuan-Chung; Bement, William M.; Petronczki, Mark; von Dassow, George

    2014-01-01

    Cytokinesis in animal cells depends on spindle-derived spatial cues that culminate in Rho activation, and thereby actomyosin assembly, in a narrow equatorial band. Although the nature, origin, and variety of such cues have long been obscure, one component is certainly the Rho activator Ect2. Here we describe the behavior and function of Ect2 in echinoderm embryos, showing that Ect2 migrates from spindle midzone to astral microtubules in anaphase and that Ect2 shapes the pattern of Rho activation in incipient furrows. Our key finding is that Ect2 and its binding partner Cyk4 accumulate not only at normal furrows, but also at furrows that form in the absence of associated spindle, midzone, or chromosomes. In all these cases, the cell assembles essentially the same cytokinetic signaling ensemble—opposed astral microtubules decorated with Ect2 and Cyk4. We conclude that if multiple signals contribute to furrow induction in echinoderm embryos, they likely converge on the same signaling ensemble on an analogous cytoskeletal scaffold. PMID:25298401

  7. Mechanisms of plant spindle formation.

    PubMed

    Zhang, Han; Dawe, R Kelly

    2011-04-01

    In eukaryotes, the formation of a bipolar spindle is necessary for the equal segregation of chromosomes to daughter cells. Chromosomes, microtubules and kinetochores all contribute to spindle morphogenesis and have important roles during mitosis. A unique property of flowering plant cells is that they entirely lack centrosomes, which in animals have a major role in spindle formation. The absence of these important structures suggests that plants have evolved novel mechanisms to assure chromosome segregation. In this review, we highlight some of the recent studies on plant mitosis and argue that plants utilize a variation of "spindle self-organization" that takes advantage of the early polarity of plant cells and accentuates the role of kinetochores in stabilizing the spindle midzone in prometaphase.

  8. Drosophila parthenogenesis: A tool to decipher centrosomal vs acentrosomal spindle assembly pathways

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Riparbelli, Maria Giovanna; Callaini, Giuliano

    2008-04-15

    Development of unfertilized eggs in the parthenogenetic strain K23-O-im of Drosophila mercatorum requires the stochastic interactions of self-assembled centrosomes with the female chromatin. In a portion of the unfertilized eggs that do not assemble centrosomes, microtubules organize a bipolar anastral mitotic spindle around the chromatin like the one formed during the first female meiosis, suggesting that similar pathways may be operative. In the cytoplasm of eggs in which centrosomes do form, monastral and biastral spindles are found. Analysis by laser scanning confocal microscopy suggests that these spindles are derived from the stochastic interaction of astral microtubules directly with kinetochore regionsmore » or indirectly with kinetochore microtubules. Our findings are consistent with the idea that mitotic spindle assembly requires both acentrosomal and centrosomal pathways, strengthening the hypothesis that astral microtubules can dictate the organization of the spindle by capturing kinetochore microtubules.« less

  9. Dynein-mediated pulling forces drive rapid mitotic spindle elongation in Ustilago maydis

    PubMed Central

    Fink, Gero; Schuchardt, Isabel; Colombelli, Julien; Stelzer, Ernst; Steinberg, Gero

    2006-01-01

    Spindle elongation segregates chromosomes and occurs in anaphase, an essential step in mitosis. Dynein-mediated pulling forces position the spindle, but their role in anaphase is a matter of debate. Here, we demonstrate that dynein is responsible for rapid spindle elongation in the model fungus Ustilago maydis. We show that initial slow elongation is supported by kinesin-5, which is located in the spindle mid-zone. When the spindle reaches ∼2 μm in length, the elongation rate increases four-fold. This coincides with the appearance of long and less-dynamic microtubules (MTs) at each pole that accumulate dynein at their tips. Laser-mediated nanosurgery revealed that these MTs exert pulling forces in control cells, but not in dynein mutants. In addition, dynein mutants undergo initial slow anaphase, but fail to establish less-dynamic MTs and do not perform rapid spindle elongation, suggesting that dynein drives anaphase B. This is most likely mediated by cortical sliding of astral MTs along stationary dynein, which is off-loaded from the MT plus-end to the cortex. PMID:17024185

  10. SLK-dependent activation of ERMs controls LGN–NuMA localization and spindle orientation

    PubMed Central

    Machicoane, Mickael; de Frutos, Cristina A.; Fink, Jenny; Rocancourt, Murielle; Lombardi, Yannis; Garel, Sonia; Piel, Matthieu

    2014-01-01

    Mitotic spindle orientation relies on a complex dialog between the spindle microtubules and the cell cortex, in which F-actin has been recently implicated. Here, we report that the membrane–actin linkers ezrin/radixin/moesin (ERMs) are strongly and directly activated by the Ste20-like kinase at mitotic entry in mammalian cells. Using microfabricated adhesive substrates to control the axis of cell division, we found that the activation of ERMs plays a key role in guiding the orientation of the mitotic spindle. Accordingly, impairing ERM activation in apical progenitors of the mouse embryonic neocortex severely disturbed spindle orientation in vivo. At the molecular level, ERM activation promotes the polarized association at the mitotic cortex of leucine-glycine-asparagine repeat protein (LGN) and nuclear mitotic apparatus (NuMA) protein, two essential factors for spindle orientation. We propose that activated ERMs, together with Gαi, are critical for the correct localization of LGN–NuMA force generator complexes and hence for proper spindle orientation. PMID:24958772

  11. Synchronization and Propagation of Global Sleep Spindles

    PubMed Central

    de Souza, Rafael Toledo Fernandes; Gerhardt, Günther Johannes Lewczuk; Schönwald, Suzana Veiga; Rybarczyk-Filho, José Luiz; Lemke, Ney

    2016-01-01

    Sleep spindles occur thousands of times during normal sleep and can be easily detected by visual inspection of EEG signals. These characteristics make spindles one of the most studied EEG structures in mammalian sleep. In this work we considered global spindles, which are spindles that are observed simultaneously in all EEG channels. We propose a methodology that investigates both the signal envelope and phase/frequency of each global spindle. By analysing the global spindle phase we showed that 90% of spindles synchronize with an average latency time of 0.1 s. We also measured the frequency modulation (chirp) of global spindles and found that global spindle chirp and synchronization are not correlated. By investigating the signal envelopes and implementing a homogeneous and isotropic propagation model, we could estimate both the signal origin and velocity in global spindles. Our results indicate that this simple and non-invasive approach could determine with reasonable precision the spindle origin, and allowed us to estimate a signal speed of 0.12 m/s. Finally, we consider whether synchronization might be useful as a non-invasive diagnostic tool. PMID:26963102

  12. Ophthalmologic abnormalities in Mowat-Wilson syndrome and a mutation in ZEB2.

    PubMed

    Ariss, Michelle; Natan, Kristina; Friedman, Neil; Traboulsi, Elias I

    2012-09-01

    Mowat-Wilson syndrome is a genetic disorder characterized by a distinct facial appearance, moderate-to-severe mental retardation, microcephaly, agenesis of the corpus callosum, Hirschsprung disease, congenital heart disease, and genital anomalies. Ophthalmological abnormalities have been rarely described in patients with this condition which is caused by mutations in the ZEB2 gene. We report a 9-year-old female with this syndrome who has severe ocular abnormalities including bilateral microphthalmia, cataract, and retinal aplasia.

  13. Microcephaly/lymphedema and terminal deletion of the long arm of chromosome 13

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Fryns, J.P.

    1995-07-03

    Recently, we examined a 2-year-old boy with the association of microcephaly and significant pedal edema that extended to the distal parts of the legs. Prometaphase chromosome studies showed a small terminal deletion in the long arm of chromosome 13 of band 13q34, karyotype 46,XY,del(13)(q34{yields}qter). The present finding of a small terminal 13q34 deletion in this young boy with microcephaly/lymphedema is a first indication that the lymphedema/microcephaly association can be due to a small terminal 13q deletion. 2 refs.

  14. Temporal and SUMO-specific SUMOylation contribute to the dynamics of Polo-like kinase 1 (PLK1) and spindle integrity during mouse oocyte meiosis.

    PubMed

    Feitosa, Weber Beringui; Hwang, KeumSil; Morris, Patricia L

    2018-02-15

    During mammalian meiosis, Polo-like kinase 1 (PLK1) is essential during cell cycle progression. In oocyte maturation, PLK1 expression is well characterized but timing of posttranslational modifications regulating its activity and subcellular localization are less clear. Small ubiquitin-related modifier (SUMO) posttranslational modifier proteins have been detected in mammalian gametes but their precise function during gametogenesis is largely unknown. In the present paper we report for mouse oocytes that both PLK1 and phosphorylated PLK1 undergo SUMOylation in meiosis II (MII) oocytes using immunocytochemistry, immunoprecipitation and in vitro SUMOylation assays. At MII, PLK1 is phosphorylated at threonine-210 and serine-137. MII oocyte PLK1 and phosphorylated PLK1 undergo SUMOylation by SUMO-1, -2 and -3 as shown by individual in vitro assays. Using these assays, forms of phosphorylated PLK1 normalized to PLK1 increased significantly and correlated with SUMOylated PLK1 levels. During meiotic progression and maturation, SUMO-1-SUMOylation of PLK1 is involved in spindle formation whereas SUMO-2/3-SUMOylation may regulate PLK1 activity at kinetochore-spindle attachment sites. Microtubule integrity is required for PLK1 localization with SUMO-1 but not with SUMO-2/3. Inhibition of SUMOylation disrupts proper meiotic bipolar spindle organization and spindle-kinetochore attachment. The data show that both temporal and SUMO-specific-SUMOylation play important roles in orchestrating functional dynamics of PLK1 during mouse oocyte meiosis, including subcellular compartmentalization. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Health and Development at Age 19-24 Months of 19 Children Who Were Born with Microcephaly and Laboratory Evidence of Congenital Zika Virus Infection During the 2015 Zika Virus Outbreak - Brazil, 2017.

    PubMed

    Satterfield-Nash, Ashley; Kotzky, Kim; Allen, Jacob; Bertolli, Jeanne; Moore, Cynthia A; Pereira, Isabela Ornelas; Pessoa, André; Melo, Flavio; Santelli, Ana Carolina Faria E Silva; Boyle, Coleen A; Peacock, Georgina

    2017-12-15

    In November 2015, the Brazilian Ministry of Health (MOH) declared the Zika virus outbreak a public health emergency after an increase in microcephaly cases was reported in the northeast region of the country (1). During 2015-2016, 15 states in Brazil with laboratory-confirmed Zika virus transmission reported an increase in birth prevalence of microcephaly (2.8 cases per 10,000 live births), significantly exceeding prevalence in four states without confirmed transmission (0.6 per 10,000) (2). Although children with microcephaly and laboratory evidence of Zika virus infection have been described in early infancy (3), their subsequent health and development have not been well characterized, constraining planning for the care and support of these children and their families. The Brazilian MOH, the State Health Secretariat of Paraíba, and CDC collaborated on a follow-up investigation of the health and development of children in northeastern Brazil who were reported to national surveillance with microcephaly at birth. Nineteen children with microcephaly at birth and laboratory evidence of Zika virus infection were assessed through clinical evaluations, caregiver interviews, and review of medical records. At follow-up (ages 19-24 months), most of these children had severe motor impairment, seizure disorders, hearing and vision abnormalities, and sleep difficulties. Children with microcephaly and laboratory evidence of Zika virus infection have severe functional limitations and will require specialized care from clinicians and caregivers as they age.

  16. Acro-spondylo-pubic dysostosis associated with cataracts, microcephaly, and normal intelligence.

    PubMed

    Chacon-Camacho, Oscar F; Villegas-Ruiz, Vanessa; Buentello-Volante, Beatriz; Piña-Aguilar, Raul E; Peláez-González, Hugo; Ramírez, Magdalena; González-Rodríguez, Johanna; Zenteno, Juan Carlos

    2015-02-01

    We report on an adult male with normal intelligence who exhibited an unusual combination of microcephaly, dysostoses of limbs, vertebrae, patellae, and pubic bone, camptodactyly of all fingers, and syndactyly of toes, absent nails on thumbs and some fingers, bilateral cataract, cryptorchidism, polythelia, and nipple-like skin pigmentations of shoulders and upper back. We have been unable to find a description of a similar combination of manifestations in literature. The cause of the anomalies remains unknown. © 2014 Wiley Periodicals, Inc.

  17. Interdependency of fission yeast Alp14/TOG and coiled coil protein Alp7 in microtubule localization and bipolar spindle formation.

    PubMed

    Sato, Masamitsu; Vardy, Leah; Angel Garcia, Miguel; Koonrugsa, Nirada; Toda, Takashi

    2004-04-01

    The Dis1/TOG family plays a pivotal role in microtubule organization. In fission yeast, Alp14 and Dis1 share an essential function in bipolar spindle formation. Here, we characterize Alp7, a novel coiled-coil protein that is required for organization of bipolar spindles. Both Alp7 and Alp14 colocalize to the spindle pole body (SPB) and mitotic spindles. Alp14 localization to these sites is fully dependent upon Alp7. Conversely, in the absence of Alp14, Alp7 localizes to the SPBs, but not mitotic spindles. Alp7 forms a complex with Alp14, where the C-terminal region of Alp14 interacts with the coiled-coil domain of Alp7. Intriguingly, this Alp14 C terminus is necessary and sufficient for mitotic spindle localization. Overproduction of either full-length or coiled-coil region of Alp7 results in abnormal V-shaped spindles and stabilization of interphase microtubules, which is induced independent of Alp14. Alp7 may be a functional homologue of animal TACC. Our results shed light on an interdependent relationship between Alp14/TOG and Alp7. We propose a two-step model that accounts for the recruitment of Alp7 and Alp14 to the SPB and microtubules.

  18. In situ immune response and mechanisms of cell damage in central nervous system of fatal cases microcephaly by Zika virus.

    PubMed

    Azevedo, Raimunda S S; de Sousa, Jorge R; Araujo, Marialva T F; Martins Filho, Arnaldo J; de Alcantara, Bianca N; Araujo, Fernanda M C; Queiroz, Maria G L; Cruz, Ana C R; Vasconcelos, Beatriz H Baldez; Chiang, Jannifer O; Martins, Lívia C; Casseb, Livia M N; da Silva, Eliana V; Carvalho, Valéria L; Vasconcelos, Barbara C Baldez; Rodrigues, Sueli G; Oliveira, Consuelo S; Quaresma, Juarez A S; Vasconcelos, Pedro F C

    2018-01-08

    Zika virus (ZIKV) has recently caused a pandemic disease, and many cases of ZIKV infection in pregnant women resulted in abortion, stillbirth, deaths and congenital defects including microcephaly, which now has been proposed as ZIKV congenital syndrome. This study aimed to investigate the in situ immune response profile and mechanisms of neuronal cell damage in fatal Zika microcephaly cases. Brain tissue samples were collected from 15 cases, including 10 microcephalic ZIKV-positive neonates with fatal outcome and five neonatal control flavivirus-negative neonates that died due to other causes, but with preserved central nervous system (CNS) architecture. In microcephaly cases, the histopathological features of the tissue samples were characterized in three CNS areas (meninges, perivascular space, and parenchyma). The changes found were mainly calcification, necrosis, neuronophagy, gliosis, microglial nodules, and inflammatory infiltration of mononuclear cells. The in situ immune response against ZIKV in the CNS of newborns is complex. Despite the predominant expression of Th2 cytokines, other cytokines such as Th1, Th17, Treg, Th9, and Th22 are involved to a lesser extent, but are still likely to participate in the immunopathogenic mechanisms of neural disease in fatal cases of microcephaly caused by ZIKV.

  19. Sleep spindles and cognitive performance across adolescence: A meta-analytic review.

    PubMed

    Reynolds, C M; Short, M A; Gradisar, M

    2018-07-01

    Higher sleep spindle activity generally relates to better cognitive performance in adults, while studies in children often show the opposite. As children become young adults, there is rapid brain maturation and development of higher-order cognitive functions, and therefore investigations within this age group may elucidate the relationship between spindles and cognition in this developmental period. Twelve studies published between 2009 and 2016 were identified. Meta-analyses revealed a positive relationship between spindles and cognition overall (r = 0.27), however effects varied depending on cognitive domain. Moderate positive relationships were seen for fluid IQ (r = 0.44), working memory/executive function (r = 0.40) and speed/accuracy (r = 0.33), while full IQ/verbal IQ was not significantly associated (r = -0.05). Meta-regressions indicated cognitive domain and spindle characteristic had a small influence over effect sizes, while age and gender did not have a significant influence. The relationship between spindles and cognition in adolescents is likely influenced by individual neural makeup and brain maturation. Copyright © 2018 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

  20. Mechanical design principles of a mitotic spindle.

    PubMed

    Ward, Jonathan J; Roque, Hélio; Antony, Claude; Nédélec, François

    2014-12-18

    An organised spindle is crucial to the fidelity of chromosome segregation, but the relationship between spindle structure and function is not well understood in any cell type. The anaphase B spindle in fission yeast has a slender morphology and must elongate against compressive forces. This 'pushing' mode of chromosome transport renders the spindle susceptible to breakage, as observed in cells with a variety of defects. Here we perform electron tomographic analyses of the spindle, which suggest that it organises a limited supply of structural components to increase its compressive strength. Structural integrity is maintained throughout the spindle's fourfold elongation by organising microtubules into a rigid transverse array, preserving correct microtubule number and dynamically rescaling microtubule length.

  1. Genetics Home Reference: autosomal recessive primary microcephaly

    MedlinePlus

    ... microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet. 2005 May;76( ... genome editing and CRISPR-Cas9? What is precision medicine? What is newborn screening? New Pages Alopecia areata ...

  2. TALEN-based generation of a cynomolgus monkey disease model for human microcephaly

    PubMed Central

    Ke, Qiong; Li, Weiqiang; Lai, Xingqiang; Chen, Hong; Huang, Lihua; Kang, Zhuang; Li, Kai; Ren, Jie; Lin, Xiaofeng; Zheng, Haiqing; Huang, Weijun; Ma, Yunhan; Xu, Dongdong; Chen, Zheng; Song, Xinming; Lin, Xinyi; Zhuang, Min; Wang, Tao; Zhuang, Fengfeng; Xi, Jianzhong; Mao, Frank Fuxiang; Xia, Huimin; Lahn, Bruce T; Zhou, Qi; Yang, Shihua; Xiang, Andy Peng

    2016-01-01

    Gene editing in non-human primates may lead to valuable models for exploring the etiologies and therapeutic strategies of genetically based neurological disorders in humans. However, a monkey model of neurological disorders that closely mimics pathological and behavioral deficits in humans has not yet been successfully generated. Microcephalin 1 (MCPH1) is implicated in the evolution of the human brain, and MCPH1 mutation causes microcephaly accompanied by mental retardation. Here we generated a cynomolgus monkey (Macaca fascicularis) carrying biallelic MCPH1 mutations using transcription activator-like effector nucleases. The monkey recapitulated most of the important clinical features observed in patients, including marked reductions in head circumference, premature chromosome condensation (PCC), hypoplasia of the corpus callosum and upper limb spasticity. Moreover, overexpression of MCPH1 in mutated dermal fibroblasts rescued the PCC syndrome. This monkey model may help us elucidate the role of MCPH1 in the pathogenesis of human microcephaly and better understand the function of this protein in the evolution of primate brain size. PMID:27502025

  3. Interdependency of Fission Yeast Alp14/TOG and Coiled Coil Protein Alp7 in Microtubule Localization and Bipolar Spindle FormationD⃞

    PubMed Central

    Sato, Masamitsu; Vardy, Leah; Angel Garcia, Miguel; Koonrugsa, Nirada; Toda, Takashi

    2004-01-01

    The Dis1/TOG family plays a pivotal role in microtubule organization. In fission yeast, Alp14 and Dis1 share an essential function in bipolar spindle formation. Here, we characterize Alp7, a novel coiled-coil protein that is required for organization of bipolar spindles. Both Alp7 and Alp14 colocalize to the spindle pole body (SPB) and mitotic spindles. Alp14 localization to these sites is fully dependent upon Alp7. Conversely, in the absence of Alp14, Alp7 localizes to the SPBs, but not mitotic spindles. Alp7 forms a complex with Alp14, where the C-terminal region of Alp14 interacts with the coiled-coil domain of Alp7. Intriguingly, this Alp14 C terminus is necessary and sufficient for mitotic spindle localization. Overproduction of either full-length or coiled-coil region of Alp7 results in abnormal V-shaped spindles and stabilization of interphase microtubules, which is induced independent of Alp14. Alp7 may be a functional homologue of animal TACC. Our results shed light on an interdependent relationship between Alp14/TOG and Alp7. We propose a two-step model that accounts for the recruitment of Alp7 and Alp14 to the SPB and microtubules. PMID:14742702

  4. Automated frequency analysis of synchronous and diffuse sleep spindles.

    PubMed

    Huupponen, Eero; Saastamoinen, Antti; Niemi, Jukka; Virkkala, Jussi; Hasan, Joel; Värri, Alpo; Himanen, Sari-Leena

    2005-01-01

    Sleep spindles have different properties in different localizations in the cortex. First main objective was to develop an amplitude-independent multi-channel spindle detection method. Secondly the method was applied to study the anteroposterior frequency differences of pure synchronous (visible bilaterally, either frontopolarly or centrally) and diffuse (visible bilaterally both frontopolarly and centrally) sleep spindles. A previously presented spindle detector based on the fuzzy reasoning principle and a level detector were combined to form a multi-channel spindle detector. The spindle detector had a 76.17% true positive rate and 0.93% false-positive rate. Pure central spindles were faster and pure frontal spindles were slower than diffuse spindles measured simultaneously from both locations. The study of frequency relations of spindles might give new information about thalamocortical sleep spindle generating mechanisms. Copyright (c) 2005 S. Karger AG, Basel.

  5. The Spindle Cell Neoplasms of the Oral Cavity.

    PubMed

    Shamim, Thorakkal

    2015-01-01

    Spindle cell neoplasms are defined as neoplasms that consist of spindle-shaped cells in the histopathology. Spindle cell neoplasms can affect the oral cavity. In the oral cavity, the origin of the spindle cell neoplasms may be traced to epithelial, mesenchymal and odontogenic components. This article aims to review the spindle cell neoplasms of the oral cavity with emphasis on histopathology.

  6. The Spindle Cell Neoplasms of the Oral Cavity

    PubMed Central

    Shamim, Thorakkal

    2015-01-01

    Spindle cell neoplasms are defined as neoplasms that consist of spindle-shaped cells in the histopathology. Spindle cell neoplasms can affect the oral cavity. In the oral cavity, the origin of the spindle cell neoplasms may be traced to epithelial, mesenchymal and odontogenic components. This article aims to review the spindle cell neoplasms of the oral cavity with emphasis on histopathology. PMID:26351482

  7. Genetics Home Reference: Amish lethal microcephaly

    MedlinePlus

    ... occurs in approximately 1 in 500 newborns in the Old Order Amish population of Pennsylvania. It has not been found outside this population. Related Information What information about a genetic condition can statistics provide? Why ... in the SLC25A19 gene cause Amish lethal microcephaly . The SLC25A19 ...

  8. Mechanical design principles of a mitotic spindle

    PubMed Central

    Ward, Jonathan J; Roque, Hélio; Antony, Claude; Nédélec, François

    2014-01-01

    An organised spindle is crucial to the fidelity of chromosome segregation, but the relationship between spindle structure and function is not well understood in any cell type. The anaphase B spindle in fission yeast has a slender morphology and must elongate against compressive forces. This ‘pushing’ mode of chromosome transport renders the spindle susceptible to breakage, as observed in cells with a variety of defects. Here we perform electron tomographic analyses of the spindle, which suggest that it organises a limited supply of structural components to increase its compressive strength. Structural integrity is maintained throughout the spindle's fourfold elongation by organising microtubules into a rigid transverse array, preserving correct microtubule number and dynamically rescaling microtubule length. DOI: http://dx.doi.org/10.7554/eLife.03398.001 PMID:25521247

  9. Thalamocortical and intracortical laminar connectivity determines sleep spindle properties.

    PubMed

    Krishnan, Giri P; Rosen, Burke Q; Chen, Jen-Yung; Muller, Lyle; Sejnowski, Terrence J; Cash, Sydney S; Halgren, Eric; Bazhenov, Maxim

    2018-06-27

    Sleep spindles are brief oscillatory events during non-rapid eye movement (NREM) sleep. Spindle density and synchronization properties are different in MEG versus EEG recordings in humans and also vary with learning performance, suggesting spindle involvement in memory consolidation. Here, using computational models, we identified network mechanisms that may explain differences in spindle properties across cortical structures. First, we report that differences in spindle occurrence between MEG and EEG data may arise from the contrasting properties of the core and matrix thalamocortical systems. The matrix system, projecting superficially, has wider thalamocortical fanout compared to the core system, which projects to middle layers, and requires the recruitment of a larger population of neurons to initiate a spindle. This property was sufficient to explain lower spindle density and higher spatial synchrony of spindles in the superficial cortical layers, as observed in the EEG signal. In contrast, spindles in the core system occurred more frequently but less synchronously, as observed in the MEG recordings. Furthermore, consistent with human recordings, in the model, spindles occurred independently in the core system but the matrix system spindles commonly co-occurred with core spindles. We also found that the intracortical excitatory connections from layer III/IV to layer V promote spindle propagation from the core to the matrix system, leading to widespread spindle activity. Our study predicts that plasticity of intra- and inter-cortical connectivity can potentially be a mechanism for increased spindle density as has been observed during learning.

  10. Zika virus infection, associated microcephaly, and low yellow fever vaccination coverage in Brazil: is there any causal link?

    PubMed

    De Góes Cavalcanti, Luciano Pamplona; Tauil, Pedro Luiz; Alencar, Carlos Henrique; Oliveira, Wanderson; Teixeira, Mauro Martins; Heukelbach, Jorg

    2016-06-30

    Since the end of 2014, Zika virus (ZIKV) infection has been rapidly spreading in Brazil. To analyze the possible association of yellow fever vaccine with a protective effect against ZIKV-related microcephaly, the following spatial analyses were performed, using Brazilian municipalities as units: i) yellow fever vaccination coverage in Brazilian municipalities in individuals aged 15-49; ii) reported cases of microcephaly by municipality; and iii) confirmed cases of microcephaly related to ZIKV, by municipality. SaTScan software was used to identify clusters of municipalities for high risk of microcephaly. There were seven significant high risk clusters of confirmed microcephaly cases, with four of them located in the Northeast where yellow fever vaccination rates were the lowest. The clusters harbored only 2.9% of the total population of Brazil, but 15.2% of confirmed cases of microcephaly. We hypothesize that pregnant women in regions with high yellow fever vaccination coverage may pose their offspring to lower risk for development of microcephaly. There is an urgent need for systematic studies to confirm the possible link between low yellow fever vaccination coverage, Zika virus infection and microcephaly.

  11. Spindle Epithelial Tumor with Thymus-Like Differentiation (SETTLE): A Next-Generation Sequencing Study.

    PubMed

    Stevens, Todd M; Morlote, Diana; Swensen, Jeff; Ellis, Michelle; Harada, Shuko; Spencer, Sharon; Prieto-Granada, Carlos N; Folpe, Andrew L; Gatalica, Zoran

    2018-05-07

    Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a malignant biphasic neoplasm of the thyroid or neck with propensity for late metastasis. Unlike synovial sarcoma, its main morphologic mimic, SETTLE lacks synovial sarcoma-associated translocations. A single case of SETTLE has shown a KRAS mutation but to date no comprehensive next generation sequencing studies of this rare neoplasm have been undertaken. Herein, we subjected 5 well defined cases of SETTLE to direct sequence analysis of 592 genes and fusion gene analysis of 52 genes frequently rearranged in human cancers. We identified one case with two pathogenic variants in the KMT2D gene, one being in an intron splice site (c.674-1A>G) and the other being a frameshift variant (p.M2829fs). This same case also had a pathogenic nonsense variant in the KMT2C gene (p.R1237*). A second case of SETTLE carried a pathogenic NRAS missense variant, Q61R. No other molecular alterations, microsatellite instability, gene fusions or amplifications were identified.

  12. Retention of Pax3 expression in satellite cells of muscle spindles.

    PubMed

    Kirkpatrick, Lisa J; Yablonka-Reuveni, Zipora; Rosser, Benjamin W C

    2010-04-01

    Intrafusal fibers within muscle spindles retain features characteristic of immaturity, unlike the larger and more numerous extrafusal fibers constituting the bulk of skeletal muscle. Satellite cells (SCs), myogenic progenitors, are detected on the surfaces of both intrafusal and extrafusal fibers, but little is known of spindle SCs. We have recently demonstrated that, like their extrafusal counterparts, SCs in muscle spindles of posthatch chickens express paired box transcription factor 7 (Pax7) protein. During vertebrate embryogenesis, myogenic progenitors express both Pax7 and Pax3 proteins. In postnatal mice, Pax3 appears in rare SC subsets, whereas Pax7 is expressed by all SCs within extrafusal fibers. Here we test the hypothesis that Pax3 protein maintains localized expression within SCs of muscle spindles. Immunohistochemical techniques were used to identify SCs by their Pax7 expression within anterior latissimus dorsi muscle excised from posthatch chickens of various ages. A greater percentage of SCs express Pax3 within intrafusal than extrafusal fibers at each age, and the proportion of SCs expressing Pax3 declines with aging. This is the first study to localize Pax3 expression in posthatch avian muscle and within SCs of muscle spindles. We suggest that Pax3-positive SCs are involved in fiber maintenance.

  13. The structure of the mitotic spindle and nucleolus during mitosis in the amebo-flagellate Naegleria.

    PubMed

    Walsh, Charles J

    2012-01-01

    Mitosis in the amebo-flagellate Naegleria pringsheimi is acentrosomal and closed (the nuclear membrane does not break down). The large central nucleolus, which occupies about 20% of the nuclear volume, persists throughout the cell cycle. At mitosis, the nucleolus divides and moves to the poles in association with the chromosomes. The structure of the mitotic spindle and its relationship to the nucleolus are unknown. To identify the origin and structure of the mitotic spindle, its relationship to the nucleolus and to further understand the influence of persistent nucleoli on cellular division in acentriolar organisms like Naegleria, three-dimensional reconstructions of the mitotic spindle and nucleolus were carried out using confocal microscopy. Monoclonal antibodies against three different nucleolar regions and α-tubulin were used to image the nucleolus and mitotic spindle. Microtubules were restricted to the nucleolus beginning with the earliest prophase spindle microtubules. Early spindle microtubules were seen as short rods on the surface of the nucleolus. Elongation of the spindle microtubules resulted in a rough cage of microtubules surrounding the nucleolus. At metaphase, the mitotic spindle formed a broad band completely embedded within the nucleolus. The nucleolus separated into two discreet masses connected by a dense band of microtubules as the spindle elongated. At telophase, the distal ends of the mitotic spindle were still completely embedded within the daughter nucleoli. Pixel by pixel comparison of tubulin and nucleolar protein fluorescence showed 70% or more of tubulin co-localized with nucleolar proteins by early prophase. These observations suggest a model in which specific nucleolar binding sites for microtubules allow mitotic spindle formation and attachment. The fact that a significant mass of nucleolar material precedes the chromosomes as the mitotic spindle elongates suggests that spindle elongation drives nucleolar division.

  14. P21-activated kinase 4 (PAK4) is required for metaphase spindle positioning and anchoring.

    PubMed

    Bompard, G; Rabeharivelo, G; Cau, J; Abrieu, A; Delsert, C; Morin, N

    2013-02-14

    The oncogenic kinase PAK4 was recently found to be involved in the regulation of the G1 phase and the G2/M transition of the cell cycle. We have also identified that PAK4 regulates Ran GTPase activity during mitosis. Here, we show that after entering mitosis, PAK4-depleted cells maintain a prolonged metaphase-like state. In these cells, chromosome congression to the metaphase plate occurs with normal kinetics but is followed by an extended period during which membrane blebbing and spindle rotation are observed. These bipolar PAK4-depleted metaphase-like spindles have a defective astral microtubule (MT) network and are not centered in the cell but are in close contact with the cell cortex. As the metaphase-like state persists, centrosome fragmentation occurs, chromosomes scatter from the metaphase plate and move toward the spindle poles with an active spindle assembly checkpoint, a phenotype that is reminiscent of cohesion fatigue. PAK4 also regulates the acto-myosin cytoskeleton and we report that PAK4 depletion results in the induction of cortical membrane blebbing during prometaphase arrest. However, we show that membrane blebs, which are strongly enriched in phospho-cofilin, are not responsible for the poor anchoring of the spindle. As PAK4 depletion interferes with the localization of components of the dynein/dynactin complexes at the kinetochores and on the astral MTs, we propose that loss of PAK4 could induce a change in the activities of motor proteins.

  15. AIRE is a critical spindle-associated protein in embryonic stem cells

    PubMed Central

    Gu, Bin; Lambert, Jean-Philippe; Cockburn, Katie; Gingras, Anne-Claude; Rossant, Janet

    2017-01-01

    Embryonic stem (ES) cells go though embryo-like cell cycles regulated by specialized molecular mechanisms. However, it is not known whether there are ES cell-specific mechanisms regulating mitotic fidelity. Here we showed that Autoimmune Regulator (Aire), a transcription coordinator involved in immune tolerance processes, is a critical spindle-associated protein in mouse ES(mES) cells. BioID analysis showed that AIRE associates with spindle-associated proteins in mES cells. Loss of function analysis revealed that Aire was important for centrosome number regulation and spindle pole integrity specifically in mES cells. We also identified the c-terminal LESLL motif as a critical motif for AIRE’s mitotic function. Combined maternal and zygotic knockout further revealed Aire’s critical functions for spindle assembly in preimplantation embryos. These results uncovered a previously unappreciated function for Aire and provide new insights into the biology of stem cell proliferation and potential new angles to understand fertility defects in humans carrying Aire mutations. DOI: http://dx.doi.org/10.7554/eLife.28131.001 PMID:28742026

  16. Human microcephaly protein RTTN interacts with STIL and is required to build full-length centrioles.

    PubMed

    Chen, Hsin-Yi; Wu, Chien-Ting; Tang, Chieh-Ju C; Lin, Yi-Nan; Wang, Won-Jing; Tang, Tang K

    2017-08-15

    Mutations in many centriolar protein-encoding genes cause primary microcephaly. Using super-resolution and electron microscopy, we find that the human microcephaly protein, RTTN, is recruited to the proximal end of the procentriole at early S phase, and is located at the inner luminal walls of centrioles. Further studies demonstrate that RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly. CRISPR/Cas9-mediated RTTN gene knockout in p53-deficient cells induce amplification of primitive procentriole bodies that lack the distal-half centriolar proteins, POC5 and POC1B. Additional analyses show that RTTN serves as an upstream effector of CEP295, which mediates the loading of POC1B and POC5 to the distal-half centrioles. Interestingly, the naturally occurring microcephaly-associated mutant, RTTN (A578P), shows a low affinity for STIL binding and blocks centriole assembly. These findings reveal that RTTN contributes to building full-length centrioles and illuminate the molecular mechanism through which the RTTN (A578P) mutation causes primary microcephaly.Mutations in many centriolar protein-encoding genes cause primary microcephaly. Here the authors show that human microcephaly protein RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly, contributing to building full-length centrioles.

  17. Biophysical Aspects of Spindle Evolution

    NASA Astrophysics Data System (ADS)

    Farhadifar, Reza; Baer, Charlie; Needleman, Daniel

    2011-03-01

    The continual propagation of genetic material from one generation to the next is one of the most basic characteristics of all organisms. In eukaryotes, DNA is segregated into the two daughter cells by a highly dynamic, self-organizing structure called the mitotic spindle. Mitotic spindles can show remarkable variability between tissues and organisms, but there is currently little understanding of the biophysical and evolutionary basis of this diversity. We are studying how spontaneous mutations modify cell division during nematode development. By comparing the mutational variation - the raw material of evolution - with the variation present in nature, we are investigating how the mitotic spindle is shaped over the course of evolution. This combination of quantitative genetics and cellular biophysics gives insight into how the structure and dynamics of the spindle is formed through selection, drift, and biophysical constraints.

  18. v-Src-induced nuclear localization of YAP is involved in multipolar spindle formation in tetraploid cells.

    PubMed

    Kakae, Keiko; Ikeuchi, Masayoshi; Kuga, Takahisa; Saito, Youhei; Yamaguchi, Naoto; Nakayama, Yuji

    2017-01-01

    The protein-tyrosine kinase, c-Src, is involved in a variety of signaling events, including cell division. We have reported that v-Src, which is a mutant variant of the cellular proto-oncogene, c-Src, causes delocalization of Aurora B kinase, resulting in a furrow regression in cytokinesis and the generation of multinucleated cells. However, the effect of v-Src on mitotic spindle formation is unknown. Here we show that v-Src-expressing HCT116 and NIH3T3 cells undergo abnormal cell division, in which cells separate into more than two cells. Upon v-Src expression, the proportion of multinucleated cells is increased in a time-dependent manner. Flow cytometry analysis revealed that v-Src increases the number of cells having a ≥4N DNA content. Microscopic analysis showed that v-Src induces the formation of multipolar spindles with excess centrosomes. These results suggest that v-Src induces multipolar spindle formation by generating multinucleated cells. Tetraploidy activates the tetraploidy checkpoint, leading to a cell cycle arrest of tetraploid cells at the G1 phase, in which the nuclear exclusion of the transcription co-activator YAP plays a critical role. In multinucleated cells that are induced by cytochalasin B and the Plk1 inhibitor, YAP is excluded from the nucleus. However, v-Src prevents this nuclear exclusion of YAP through a decrease in the phosphorylation of YAP at Ser127 in multinucleated cells. Furthermore, v-Src decreases the expression level of p53, which also plays a critical role in the cell cycle arrest of tetraploid cells. These results suggest that v-Src promotes abnormal spindle formation in at least two ways: generation of multinucleated cells and a weakening of the tetraploidy checkpoint. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Mutations in CDK5RAP2 cause Seckel syndrome.

    PubMed

    Yigit, Gökhan; Brown, Karen E; Kayserili, Hülya; Pohl, Esther; Caliebe, Almuth; Zahnleiter, Diana; Rosser, Elisabeth; Bögershausen, Nina; Uyguner, Zehra Oya; Altunoglu, Umut; Nürnberg, Gudrun; Nürnberg, Peter; Rauch, Anita; Li, Yun; Thiel, Christian Thomas; Wollnik, Bernd

    2015-09-01

    Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.

  20. Mutations in CDK5RAP2 cause Seckel syndrome

    PubMed Central

    Yigit, Gökhan; Brown, Karen E; Kayserili, Hülya; Pohl, Esther; Caliebe, Almuth; Zahnleiter, Diana; Rosser, Elisabeth; Bögershausen, Nina; Uyguner, Zehra Oya; Altunoglu, Umut; Nürnberg, Gudrun; Nürnberg, Peter; Rauch, Anita; Li, Yun; Thiel, Christian Thomas; Wollnik, Bernd

    2015-01-01

    Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152. PMID:26436113

  1. The spindle kinesin-like protein HsEg5 is an autoantigen in systemic lupus erythematosus.

    PubMed

    Whitehead, C M; Winkfein, R J; Fritzler, M J; Rattner, J B

    1996-10-01

    Autoantibodies directed against the mitotic spindle apparatus (MSA) have been shown to target an antigen referred to as NuMA (nuclear mitotic apparatus). In this study, we identified a second MSA antigen as the spindle kinesin-like protein HsEg5. We studied the frequency of antibodies to HsEg5 in human sera that demonstrate the MSA pattern of staining, the frequency of autoantibodies to HsEg5 in patients with systemic lupus erythematosus (SLE), and the clinical features of patients with antibodies to HsEg5. A prototype serum from an SLE patient was used to isolate a 4.8-kilobase complementary DNA (cDNA) from a HeLa cDNA library. Western blot, immunoprecipitation, and sequence analysis revealed that the antigen was an approximately 130-kd protein, HsEg5. The frequency of autoantibodies to recombinant HsEg5 in 51 sera that demonstrated an MSA pattern of staining on HEp-2 and HeLa cells was detected by immunoblotting 2 constructs of the cDNA. The clinical features of patients with antibodies directed against HsEg5 was obtained by retrospective chart review. The antigen responsible for the MSA-35 pattern was identified as the human kinesin-like protein HsEg5. Seven of 51 sera (14%) that demonstrated an MSA pattern of staining reacted with recombinant HsEg5. Six of 7 of the HsEg5-positive patients (86%) had SLE, and 1 had Sjögren's syndrome. The indirect immunofluorescent staining pattern of sera that reacted with HsEg5 could be distinguished from the other sera that reacted with NuMA. In an unselected cohort of 52 SLE patients, 3 (6%) had autoantibodies reactive with the recombinant HsEg5. Autoantibodies to MSA fall into 2 major classes: those reactive with NuMA and those reactive with HsEg5. Autoantibodies to HsEg5 are found in a lower frequency than NuMA in sera that demonstrate the MSA pattern of staining and appear to be specifically associated with SLE. HsEg5 can be distinguished from NuMA by indirect immunofluorescence and Western blotting.

  2. Computational and Organotypic Modeling of Microcephaly (Teratology Society)

    EPA Science Inventory

    Microcephaly is associated with reduced cortical surface area and ventricular dilations. Many genetic and environmental factors precipitate this malformation, including prenatal alcohol exposure and maternal Zika infection. This complexity motivates the engineering of computation...

  3. Unknown syndrome: abnormal facies, hypothyroidism, postaxial polydactyly, and severe retardation: a third patient.

    PubMed Central

    Cavalcanti, D P

    1989-01-01

    Young and Simpson in 1987 and Fryns and Moerman in 1988 each reported a case of a new unknown syndrome with hypothyroidism, severe global retardation, and abnormal facies, including microcephaly, blepharophimosis, bulbous nose, thin upper lip, low set ears, and micrognathia. A male infant with a similar pattern of malformations and postaxial polydactyly is reported here. Images PMID:2614801

  4. Radiological Characterization of Cerebral Phenotype in Newborn Microcephaly Cases from 2015 Outbreak in Brazil

    PubMed Central

    Ramalho Rocha, Yuri Raoni; Cavalcanti Costa, José Ricardo; Almeida Costa, Pericles; Maia, Gessica; Vasconcelos, Rafael de Medeiros; Ramos Tejo, Cynthia; Martins Batista, Rafaella; Lima Neto, Manoel; Martins de Lima, Gustavo Graco; Negromonte, Francisco; Borba, Marcelle; Bezerra Jeronimo, Selma Maria; Sequerra, Eduardo Bouth; Moreira Neto, Manuel

    2016-01-01

    Introduction: Brazil is facing, since October of 2015, an outbreak of microcephalic fetuses. This outbreak is correlated with the beginning of circulation of Zika virus (ZIKV) in the country. Although it is clear that the size of the head is diminished in these fetuses, the brain phenotype associated with these malformations is unknown. Methods: We collected computed tomography images of the microcephaly cases from the region of Natal, Rio Grande do Norte, from September 2015 to February 2016. Findings: The microcephalies derived from the current outbreak are associated with intracerebral calcifications, malformation of the ventricular system, migratory disorders in the telencephalon and, in a lower frequency, malformation of the cerebellum and brainstem. Discussion: The characteristics described herein are not usually found in other types of microcephaly. We suggest that this work can be used as a guideline to identify microcephaly cases associated to the current outbreak. PMID:27617166

  5. Measuring mitotic spindle dynamics in budding yeast

    NASA Astrophysics Data System (ADS)

    Plumb, Kemp

    In order to carry out its life cycle and produce viable progeny through cell division, a cell must successfully coordinate and execute a number of complex processes with high fidelity, in an environment dominated by thermal noise. One important example of such a process is the assembly and positioning of the mitotic spindle prior to chromosome segregation. The mitotic spindle is a modular structure composed of two spindle pole bodies, separated in space and spanned by filamentous proteins called microtubules, along which the genetic material of the cell is held. The spindle is responsible for alignment and subsequent segregation of chromosomes into two equal parts; proper spindle positioning and timing ensure that genetic material is appropriately divided amongst mother and daughter cells. In this thesis, I describe fluorescence confocal microscopy and automated image analysis algorithms, which I have used to observe and analyze the real space dynamics of the mitotic spindle in budding yeast. The software can locate structures in three spatial dimensions and track their movement in time. By selecting fluorescent proteins which specifically label the spindle poles and cell periphery, mitotic spindle dynamics have been measured in a coordinate system relevant to the cell division. I describe how I have characterised the accuracy and precision of the algorithms by simulating fluorescence data for both spindle poles and the budding yeast cell surface. In this thesis I also describe the construction of a microfluidic apparatus that allows for the measurement of long time-scale dynamics of individual cells and the development of a cell population. The tools developed in this thesis work will facilitate in-depth quantitative analysis of the non-equilibrium processes in living cells.

  6. Microcephaly genes evolved adaptively throughout the evolution of eutherian mammals

    PubMed Central

    2014-01-01

    Background Genes associated with the neurodevelopmental disorder microcephaly display a strong signature of adaptive evolution in primates. Comparative data suggest a link between selection on some of these loci and the evolution of primate brain size. Whether or not either positive selection or this phenotypic association are unique to primates is unclear, but recent studies in cetaceans suggest at least two microcephaly genes evolved adaptively in other large brained mammalian clades. Results Here we analyse the evolution of seven microcephaly loci, including three recently identified loci, across 33 eutherian mammals. We find extensive evidence for positive selection having acted on the majority of these loci not just in primates but also across non-primate mammals. Furthermore, the patterns of selection in major mammalian clades are not significantly different. Using phylogenetically corrected comparative analyses, we find that the evolution of two microcephaly loci, ASPM and CDK5RAP2, are correlated with neonatal brain size in Glires and Euungulata, the two most densely sampled non-primate clades. Conclusions Together with previous results, this suggests that ASPM and CDK5RAP2 may have had a consistent role in the evolution of brain size in mammals. Nevertheless, several limitations of currently available data and gene-phenotype tests are discussed, including sparse sampling across large evolutionary distances, averaging gene-wide rates of evolution, potential phenotypic variation and evolutionary reversals. We discuss the implications of our results for studies of the genetic basis of brain evolution, and explicit tests of gene-phenotype hypotheses. PMID:24898820

  7. A defect-driven diagnostic method for machine tool spindles

    PubMed Central

    Vogl, Gregory W.; Donmez, M. Alkan

    2016-01-01

    Simple vibration-based metrics are, in many cases, insufficient to diagnose machine tool spindle condition. These metrics couple defect-based motion with spindle dynamics; diagnostics should be defect-driven. A new method and spindle condition estimation device (SCED) were developed to acquire data and to separate system dynamics from defect geometry. Based on this method, a spindle condition metric relying only on defect geometry is proposed. Application of the SCED on various milling and turning spindles shows that the new approach is robust for diagnosing the machine tool spindle condition. PMID:28065985

  8. Sleep Spindles Are Related to Schizotypal Personality Traits and Thalamic Glutamine/Glutamate in Healthy Subjects

    PubMed Central

    Lustenberger, Caroline; O’Gorman, Ruth L.; Pugin, Fiona; Tüshaus, Laura; Wehrle, Flavia; Achermann, Peter; Huber, Reto

    2015-01-01

    Background: Schizophrenia is a severe mental disorder affecting approximately 1% of the worldwide population. Yet, schizophrenia-like experiences (schizotypy) are very common in the healthy population, indicating a continuum between normal mental functioning and the psychosis found in schizophrenic patients. A continuum between schizotypy and schizophrenia would be supported if they share the same neurobiological origin. Two such neurobiological markers of schizophrenia are: (1) a reduction of sleep spindles (12–15 Hz oscillations during nonrapid eye movement sleep), likely reflecting deficits in thalamo-cortical circuits and (2) increased glutamine and glutamate (Glx) levels in the thalamus. Thus, this study aimed to investigate whether sleep spindles and Glx levels are related to schizotypal personality traits in healthy subjects. Methods: Twenty young male subjects underwent 2 all-night sleep electroencephalography recordings (128 electrodes). Sleep spindles were detected automatically. After those 2 nights, thalamic Glx levels were measured by magnetic resonance spectroscopy. Subjects completed a magical ideation scale to assess schizotypy. Results: Sleep spindle density was negatively correlated with magical ideation (r = −.64, P < .01) and thalamic Glx levels (r = −.70, P < .005). No correlation was found between Glx levels in the thalamus and magical ideation (r = .12, P > .1). Conclusions: The common relationship of sleep spindle density with schizotypy and thalamic Glx levels indicates a neurobiological overlap between nonclinical schizotypy and schizophrenia. Thus, sleep spindle density and magical ideation may reflect the anatomy and efficiency of the thalamo-cortical system that shows pronounced impairment in patients with schizophrenia. PMID:25074975

  9. Mutations in CENPE define a novel kinetochore-centromeric mechanism for Microcephalic Primordial Dwarfism

    PubMed Central

    Mirzaa, Ghayda M.; Vitre, Benjamin; Carpenter, Gillian; Abramowicz, Iga; Gleeson, Joseph G.; Paciorkowski, Alex R.; Cleveland, Don W.; Dobyns, William B.; O’Driscoll, Mark

    2015-01-01

    Defects in centrosome, centrosomal-associated and spindle-associated proteins are the most frequent cause of Primary Microcephaly (PM) and Microcephalic Primordial Dwarfism (MPD) syndromes in humans. Mitotic progression and segregation defects, microtubule spindle abnormalities and impaired DNA damage-induced G2-M cell cycle checkpoint proficiency have been documented in cell lines from these patients. This suggests that impaired mitotic entry, progression and exit strongly contribute to PM and MPD. Considering the vast protein networks involved in coordinating this cell cycle stage, the list of potential target genes that could underlie novel developmental disorders is large. One such complex network, with a direct microtubule-mediated physical connection to the centrosome, is the kinetochore. This centromeric-associated structure nucleates microtubule attachments onto mitotic chromosomes. Here, we described novel compound heterozygous variants in CENPE in two siblings who exhibit a profound MPD associated with developmental delay, simplified gyri and other isolated abnormalities. CENPE encodes centromere-associated protein E (CENP-E), a core kinetochore component functioning to mediate chromosome congression initially of misaligned chromosomes and in subsequent spindle microtubule capture during mitosis. Firstly, we present a comprehensive clinical description of these patients. Then, using patient cells we document abnormalities in spindle microtubule organisation, mitotic progression and segregation, before modeling the cellular pathogenicity of these variants in an independent cell system. Our cellular analysis shows that a pathogenic defect in CENP-E, a kinetochore-core protein, largely phenocopies PCNT-mutated Microcephalic Osteodysplastic Primordial Dwarfism type II patient cells. PCNT encodes a centrosome-associated protein. These results highlight a common underlying pathomechanism. Our findings provide the first evidence for a kinetochore-based route to

  10. Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism.

    PubMed

    Mirzaa, Ghayda M; Vitre, Benjamin; Carpenter, Gillian; Abramowicz, Iga; Gleeson, Joseph G; Paciorkowski, Alex R; Cleveland, Don W; Dobyns, William B; O'Driscoll, Mark

    2014-08-01

    Defects in centrosome, centrosomal-associated and spindle-associated proteins are the most frequent cause of primary microcephaly (PM) and microcephalic primordial dwarfism (MPD) syndromes in humans. Mitotic progression and segregation defects, microtubule spindle abnormalities and impaired DNA damage-induced G2-M cell cycle checkpoint proficiency have been documented in cell lines from these patients. This suggests that impaired mitotic entry, progression and exit strongly contribute to PM and MPD. Considering the vast protein networks involved in coordinating this cell cycle stage, the list of potential target genes that could underlie novel developmental disorders is large. One such complex network, with a direct microtubule-mediated physical connection to the centrosome, is the kinetochore. This centromeric-associated structure nucleates microtubule attachments onto mitotic chromosomes. Here, we described novel compound heterozygous variants in CENPE in two siblings who exhibit a profound MPD associated with developmental delay, simplified gyri and other isolated abnormalities. CENPE encodes centromere-associated protein E (CENP-E), a core kinetochore component functioning to mediate chromosome congression initially of misaligned chromosomes and in subsequent spindle microtubule capture during mitosis. Firstly, we present a comprehensive clinical description of these patients. Then, using patient cells we document abnormalities in spindle microtubule organization, mitotic progression and segregation, before modeling the cellular pathogenicity of these variants in an independent cell system. Our cellular analysis shows that a pathogenic defect in CENP-E, a kinetochore-core protein, largely phenocopies PCNT-mutated microcephalic osteodysplastic primordial dwarfism-type II patient cells. PCNT encodes a centrosome-associated protein. These results highlight a common underlying pathomechanism. Our findings provide the first evidence for a kinetochore-based route to

  11. Zika virus infection during pregnancy and microcephaly occurrence: a review of literature and Brazilian data.

    PubMed

    De Carvalho, Newton Sérgio; De Carvalho, Beatriz Freitas; Fugaça, Cyllian Arias; Dóris, Bruna; Biscaia, Evellyn Silverio

    2016-01-01

    In November of 2015, the Ministry of Health of Brazil published an announcement confirming the relationship between Zika virus and the microcephaly outbreak in the Northeast, suggesting that infected pregnant women might have transmitted the virus to their fetuses. The objectives of this study were to conduct a literature review about Zika virus infection and microcephaly, evaluate national and international epidemiological data, as well as the current recommendations for the health teams. Zika virus is an arbovirus, whose main vector is the Aedes sp. The main symptoms of the infection are maculopapular rash, fever, non-purulent conjunctivitis, and arthralgia. Transmission of this pathogen occurs mainly by mosquito bite, but there are also reports via the placenta. Microcephaly is defined as a measure of occipto-frontal circumference being more than two standard deviations below the mean for age and gender. The presence of microcephaly demands evaluation of the patient, in order to diagnose the etiology. Health authorities issued protocols, reports and notes concerning the management of microcephaly caused by Zika virus, but there is still controversy about managing the cases. The Ministry of Health advises notifying any suspected or confirmed cases of children with microcephaly related to the pathogen, which is confirmed by a positive specific laboratory test for the virus. The first choice for imaging exam in children with this malformation is transfontanellar ultrasound. The most effective way to control this outbreak of microcephaly probably caused by this virus is to combat the vector. Since there is still uncertainty about the period of vulnerability of transmission via placenta, the use of repellents is crucial throughout pregnancy. More investigations studying the consequences of this viral infection on the body of newborns and in their development are required. Copyright © 2016 Elsevier Editora Ltda. All rights reserved.

  12. Spindle epithelial tumor with thymus-like differentiation of the thyroid in a 70-year-old man.

    PubMed

    Lee, Sunhye; Kim, Yon Seon; Lee, Jeong Hyeon; Hwang, Sung Ho; Oh, Yu-Hwan; Ko, Byung Kyun; Ham, Soo-Youn

    2018-06-01

    Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare tumor of the thyroid gland mostly occurring in young patients. The imaging findings of SETTLE tumors are yet to be defined. However, they are usually described as well-defined heterogeneously enhanced masses on CT scan. The current case has the potential growth as compared with a 2009 chest radiography. We took into account the possibility of SETTLE in the case of a bulky mass in patients over 70 years old, particularly in the lower neck. Herein, we report a case of the oldest patient so far. The patient underwent a right lobectomy of the thyroid and mass excision. Follow-up CT scans after 6 months revealed no local recurrence. Surgery is the gold standard treatment for SETTLE. Chemotherapy and radiotherapy could be another possible option for patients with advanced stage SETTLE.

  13. Measuring and modeling polymer concentration profiles near spindle boundaries argues that spindle microtubules regulate their own nucleation

    NASA Astrophysics Data System (ADS)

    Kaye, Bryan; Stiehl, Olivia; Foster, Peter J.; Shelley, Michael J.; Needleman, Daniel J.; Fürthauer, Sebastian

    2018-05-01

    Spindles are self-organized microtubule-based structures that segregate chromosomes during cell division. The mass of the spindle is controlled by the balance between microtubule turnover and nucleation. The mechanisms that control the spatial regulation of microtubule nucleation remain poorly understood. While previous work found that microtubule nucleators bind to pre-existing microtubules in the spindle, it is still unclear whether this binding regulates the activity of those nucleators. Here we use a combination of experiments and mathematical modeling to investigate this issue. We measured the concentration of microtubules and soluble tubulin in and around the spindle. We found a very sharp decay in the concentration of microtubules at the spindle interface. This is inconsistent with a model in which the activity of nucleators is independent of their association with microtubules but consistent with a model in which microtubule nucleators are only active when bound to pre-existing microtubules. This argues that the activity of microtubule nucleators is greatly enhanced when bound to pre-existing microtubules. Thus, microtubule nucleators are both localized and activated by the microtubules they generate.

  14. Inscuteable Regulates the Pins-Mud Spindle Orientation Pathway

    PubMed Central

    Mauser, Jonathon F.; Prehoda, Kenneth E.

    2012-01-01

    During asymmetric cell division, alignment of the mitotic spindle with the cell polarity axis ensures that the cleavage furrow separates fate determinants into distinct daughter cells. The protein Inscuteable (Insc) is thought to link cell polarity and spindle positioning in diverse systems by binding the polarity protein Bazooka (Baz; aka Par-3) and the spindle orienting protein Partner of Inscuteable (Pins; mPins or LGN in mammals). Here we investigate the mechanism of spindle orientation by the Insc-Pins complex. Previously, we defined two Pins spindle orientation pathways: a complex with Mushroom body defect (Mud; NuMA in mammals) is required for full activity, whereas binding to Discs large (Dlg) is sufficient for partial activity. In the current study, we have examined the role of Inscuteable in mediating downstream Pins-mediated spindle orientation pathways. We find that the Insc-Pins complex requires Gαi for partial activity and that the complex specifically recruits Dlg but not Mud. In vitro competition experiments revealed that Insc and Mud compete for binding to the Pins TPR motifs, while Dlg can form a ternary complex with Insc-Pins. Our results suggest that Insc does not passively couple polarity and spindle orientation but preferentially inhibits the Mud pathway, while allowing the Dlg pathway to remain active. Insc-regulated complex assembly may ensure that the spindle is attached to the cortex (via Dlg) before activation of spindle pulling forces by Dynein/Dynactin (via Mud). PMID:22253744

  15. Self-Organization and Forces in the Mitotic Spindle.

    PubMed

    Pavin, Nenad; Tolić, Iva M

    2016-07-05

    At the onset of division, the cell forms a spindle, a precise self-constructed micromachine composed of microtubules and the associated proteins, which divides the chromosomes between the two nascent daughter cells. The spindle arises from self-organization of microtubules and chromosomes, whose different types of motion help them explore the space and eventually approach and interact with each other. Once the interactions between the chromosomes and the microtubules have been established, the chromosomes are moved to the equatorial plane of the spindle and ultimately toward the opposite spindle poles. These transport processes rely on directed forces that are precisely regulated in space and time. In this review, we discuss how microtubule dynamics and their rotational movement drive spindle self-organization, as well as how the forces acting in the spindle are generated, balanced, and regulated.

  16. The Physics of the Metaphase Spindle.

    PubMed

    Oriola, David; Needleman, Daniel J; Brugués, Jan

    2018-05-20

    The assembly of the mitotic spindle and the subsequent segregation of sister chromatids are based on the self-organized action of microtubule filaments, motor proteins, and other microtubule-associated proteins, which constitute the fundamental force-generating elements in the system. Many of the components in the spindle have been identified, but until recently it remained unclear how their collective behaviors resulted in such a robust bipolar structure. Here, we review the current understanding of the physics of the metaphase spindle that is only now starting to emerge.

  17. Theory of meiotic spindle assembly

    NASA Astrophysics Data System (ADS)

    Furthauer, Sebastian; Foster, Peter; Needleman, Daniel; Shelley, Michael

    2016-11-01

    The meiotic spindle is a biological structure that self assembles from the intracellular medium to separate chromosomes during meiosis. It consists of filamentous microtubule (MT) proteins that interact through the fluid in which they are suspended and via the associated molecules that orchestrate their behavior. We aim to understand how the interplay between fluid medium, MTs, and regulatory proteins allows this material to self-organize into the spindle's highly stereotyped shape. To this end we develop a continuum model that treats the spindle as an active liquid crystal with MT turnover. In this active material, molecular motors, such as dyneins which collect MT minus ends and kinesins which slide MTs past each other, generate active fluid and material stresses. Moreover nucleator proteins that are advected with and transported along MTs control the nucleation and depolymerization of MTs. This theory captures the growth process of meiotic spindles, their shapes, and the essential features of many perturbation experiments. It thus provides a framework to think about the physics of this complex biological suspension.

  18. NUCLEOPORINS NPP-1, NPP-3, NPP-4, NPP-11 and NPP-13 ARE REQUIRED FOR PROPER SPINDLE ORIENTATION IN C. ELEGANS

    PubMed Central

    Schetter, Aaron; Askjaer, Peter; Piano, Fabio; Mattaj, Iain; Kemphues, Kenneth

    2006-01-01

    Nucleoporins are components of the nuclear pore, which is required for nucleo-cytoplasmic transport. We report a role for a subclass of nucleoporins in orienting the mitotic spindle in C. elegans embryos. RNAi-mediated depletion of any of five putative nucleoporins npp-1, npp-3, npp-4, npp-11, and npp-13 leads to indistinguishable spindle orientation defects. Transgenic worms expressing NPP-1::GFP or NPP-11::GFP show GFP localization at the nuclear envelope, consistent with their predicted function. NPP-1 interacts with the other nucleoporins in yeast two-hybrid assays suggesting that the proteins affect spindle orientation by a common process. The failed orientation phenotype of npp-1(RNAi) is at least partially epistatic to the ectopic spindle rotation in the AB blastomere of par-3 mutant embryos. This suggests that NPP-1 contributes to the mechanics of spindle orientation. However, NPP-1 is also required for PAR-6 asymmetry at the two-cell stage, indicating that nucleoporins may be required to define cortical domains in the germ line blasotmere P1. Nuclear envelope structure is abnormal in npp-1(RNAi) embryos but the envelope maintains its integrity and most nuclear proteins we assayed accumulate normally. These findings raise the possibility that these nucleoporins may have direct roles in orienting the mitotic spindle and the maintenance of cell polarity. PMID:16325795

  19. Biotin-deficient diet induces chromosome misalignment and spindle defects in mouse oocytes.

    PubMed

    Tsuji, Ai; Nakamura, Toshinobu; Shibata, Katsumi

    2015-01-01

    Increased abnormal oocytes due to meiotic chromosome misalignment and spindle defects lead to elevated rates of infertility, miscarriage, and trisomic conceptions. Here, we investigated the effect of biotin deficiency on oocyte quality. Three-week-old female ICR mice were fed a biotin-deficient or control diet (0, 0.004 g biotin/kg diet) for 21 days. On day 22, these mouse oocytes were analyzed by immunofluorescence. Due to biotin, undernutrition increased the frequency of abnormal oocytes (the biotin deficient vs. control: 40 vs. 16%). Next, the remaining mice in the biotin-deficient group were fed a control or biotin-deficient diet from day 22 to 42. Although biotin nutritional status in the recovery group was restored, the frequency of abnormal oocytes in the recovery group was still higher than that in the control group (48 vs. 18%). Our results indicate that steady, sufficient biotin intake is required for the production of high-quality oocytes in mice.

  20. Regulation of spindle integrity and mitotic fidelity by BCCIP

    PubMed Central

    Huhn, S C; Liu, J; Ye, C; Lu, H; Jiang, X; Feng, X; Ganesan, S; White, E; Shen, Z

    2017-01-01

    Centrosomes together with the mitotic spindle ensure the faithful distribution of chromosomes between daughter cells, and spindle orientation is a major determinant of cell fate during tissue regeneration. Spindle defects are not only an impetus of chromosome instability but are also a cause of developmental disorders involving defective asymmetric cell division. In this work, we demonstrate BCCIP, especially BCCIPα, as a previously unidentified component of the mitotic spindle pole and the centrosome. We demonstrate that BCCIP localizes proximal to the mother centriole and participates in microtubule organization and then redistributes to the spindle pole to ensure faithful spindle architecture. We find that BCCIP depletion leads to morphological defects, disoriented mitotic spindles, chromosome congression defects and delayed mitotic progression. Our study identifies BCCIP as a novel factor critical for microtubule regulation and explicates a mechanism utilized by BCCIP in tumor suppression. PMID:28394342

  1. Intramedullary spindle cell hemangioma: case report.

    PubMed

    Nasser, Rani; Ashayeri, Kimberly; Legatt, Alan D; Houten, John K

    2016-09-01

    The authors describe the case of a 48-year-old man found to have the first reported intramedullary spinal cord spindle cell hemangioma. Previous research indicates that spindle cell hemangiomas are rarely found in the spine. Only 3 previous cases exist, all in the intradural, extramedullary space. In the present case, gross-total resection of the tumor was possible with no loss of function from baseline. This report presents the successful resection of the first reported intramedullary spindle cell hemangioma and reports 4-month follow-up, demonstrating the biological behavior of this rare tumor.

  2. Microcephaly and Zika virus: a clinical and epidemiological analysis of the current outbreak in Brazil.

    PubMed

    Nunes, Magda Lahorgue; Carlini, Celia Regina; Marinowic, Daniel; Neto, Felipe Kalil; Fiori, Humberto Holmer; Scotta, Marcelo Comerlato; Zanella, Pedro Luis Ávila; Soder, Ricardo Bernardi; da Costa, Jaderson Costa

    2016-01-01

    This study aimed to critically review the literature available regarding the Zika virus outbreak in Brazil and its possible association with microcephaly cases. Experts from Instituto do Cérebro do Rio Grande do Sul performed a critical (nonsystematic) literature review regarding different aspects of the Zika virus outbreak in Brazil, such as transmission, epidemiology, diagnostic criteria, and its possible association with the increase of microcephaly reports. The PubMed search using the key word "Zika virus" in February 2016 yielded 151 articles. The manuscripts were reviewed, as well as all publications/guidelines from the Brazilian Ministry of Health, World Health Organization and Centers for Disease Control and Prevention (CDC - United States). Epidemiological data suggest a temporal association between the increased number of microcephaly notifications in Brazil and outbreak of Zika virus, primarily in the Brazil's Northeast. It has been previously documented that many different viruses might cause congenital acquired microcephaly. Still there is no consensus on the best curve to measure cephalic circumference, specifically in preterm neonates. Conflicting opinions regarding the diagnosis of microcephaly (below 2 or 3 standard deviations) that should be used for the notifications were also found in the literature. The development of diagnostic techniques that confirm a cause-effect association and studies regarding the physiopathology of the central nervous system impairment should be prioritized. It is also necessary to strictly define the criteria for the diagnosis of microcephaly to identify cases that should undergo an etiological investigation. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  3. RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans

    PubMed Central

    Shamseldin, Hanan; Alazami, Anas M.; Manning, Melanie; Hashem, Amal; Caluseiu, Oana; Tabarki, Brahim; Esplin, Edward; Schelley, Susan; Innes, A. Micheil; Parboosingh, Jillian S.; Lamont, Ryan; Majewski, Jacek; Bernier, Francois P.; Alkuraya, Fowzan S.

    2015-01-01

    Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963∗] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration. PMID:26608784

  4. Curcumin-induced mitotic arrest is characterized by spindle abnormalities, defects in chromosomal congression and DNA damage

    PubMed Central

    Manson, Margaret M.

    2013-01-01

    The chemopreventive agent curcumin has anti-proliferative effects in many tumour types, but characterization of cell cycle arrest, particularly with physiologically relevant concentrations, is still incomplete. Following oral ingestion, the highest concentrations of curcumin are achievable in the gut. Although it has been established that curcumin induces arrest at the G2/M stage of the cell cycle in colorectal cancer lines, it is not clear whether arrest occurs at the G2/M transition or in mitosis. To elucidate the precise stage of arrest, we performed a direct comparison of the levels of curcumin-induced G2/M boundary and mitotic arrest in eight colorectal cancer lines (Caco-2, DLD-1, HCA-7, HCT116p53+/+, HCT116p53–/–, HCT116p21–/–, HT-29 and SW480). Flow cytometry confirmed that these lines underwent G2/M arrest following treatment for 12h with clinically relevant concentrations of curcumin (5–10 μM). In all eight lines, the majority of this arrest occurred at the G2/M transition, with a proportion of cells arresting in mitosis. Examination of the mitotic index using fluorescence microscopy showed that the HCT116 and Caco-2 lines exhibited the highest levels of curcumin-induced mitotic arrest. Image analysis revealed impaired mitotic progression in all lines, exemplified by mitotic spindle abnormalities and defects in chromosomal congression. Pre-treatment with inhibitors of the DNA damage signalling pathway abrogated curcumin-induced mitotic arrest, but had little effect at the G2/M boundary. Moreover, pH2A.X staining seen in mitotic, but not interphase, cells suggests that this aberrant mitosis results in DNA damage. PMID:23125222

  5. Sleep spindles and intelligence: evidence for a sexual dimorphism.

    PubMed

    Ujma, Péter P; Konrad, Boris Nikolai; Genzel, Lisa; Bleifuss, Annabell; Simor, Péter; Pótári, Adrián; Körmendi, János; Gombos, Ferenc; Steiger, Axel; Bódizs, Róbert; Dresler, Martin

    2014-12-03

    Sleep spindles are thalamocortical oscillations in nonrapid eye movement sleep, which play an important role in sleep-related neuroplasticity and offline information processing. Sleep spindle features are stable within and vary between individuals, with, for example, females having a higher number of spindles and higher spindle density than males. Sleep spindles have been associated with learning potential and intelligence; however, the details of this relationship have not been fully clarified yet. In a sample of 160 adult human subjects with a broad IQ range, we investigated the relationship between sleep spindle parameters and intelligence. In females, we found a positive age-corrected association between intelligence and fast sleep spindle amplitude in central and frontal derivations and a positive association between intelligence and slow sleep spindle duration in all except one derivation. In males, a negative association between intelligence and fast spindle density in posterior regions was found. Effects were continuous over the entire IQ range. Our results demonstrate that, although there is an association between sleep spindle parameters and intellectual performance, these effects are more modest than previously reported and mainly present in females. This supports the view that intelligence does not rely on a single neural framework, and stronger neural connectivity manifesting in increased thalamocortical oscillations in sleep is one particular mechanism typical for females but not males. Copyright © 2014 the authors 0270-6474/14/3416358-11$15.00/0.

  6. Sleep spindles in humans: insights from intracranial EEG and unit recordings

    PubMed Central

    Andrillon, Thomas; Nir, Yuval; Staba, Richard J.; Ferrarelli, Fabio; Cirelli, Chiara; Tononi, Giulio; Fried, Itzhak

    2012-01-01

    Sleep spindles are an electroencephalographic (EEG) hallmark of non-rapid eye movement (NREM) sleep and are believed to mediate many sleep-related functions, from memory consolidation to cortical development. Spindles differ in location, frequency, and association with slow waves, but whether this heterogeneity may reflect different physiological processes and potentially serve different functional roles remains unclear. Here we utilized a unique opportunity to record intracranial depth EEG and single-unit activity in multiple brain regions of neurosurgical patients to better characterize spindle activity in human sleep. We find that spindles occur across multiple neocortical regions, and less frequently also in the parahippocampal gyrus and hippocampus. Most spindles are spatially restricted to specific brain regions. In addition, spindle frequency is topographically organized with a sharp transition around the supplementary motor area between fast (13-15Hz) centroparietal spindles often occurring with slow wave up-states, and slow (9-12Hz) frontal spindles occurring 200ms later on average. Spindle variability across regions may reflect the underlying thalamocortical projections. We also find that during individual spindles, frequency decreases within and between regions. In addition, deeper sleep is associated with a reduction in spindle occurrence and spindle frequency. Frequency changes between regions, during individual spindles, and across sleep may reflect the same phenomenon, the underlying level of thalamocortical hyperpolarization. Finally, during spindles neuronal firing rates are not consistently modulated, although some neurons exhibit phase-locked discharges. Overall, anatomical considerations can account well for regional spindle characteristics, while variable hyperpolarization levels can explain differences in spindle frequency. PMID:22159098

  7. Heterogeneous Origins of Human Sleep Spindles in Different Cortical Layers.

    PubMed

    Hagler, Donald J; Ulbert, István; Wittner, Lucia; Erőss, Loránd; Madsen, Joseph R; Devinsky, Orrin; Doyle, Werner; Fabó, Dániel; Cash, Sydney S; Halgren, Eric

    2018-03-21

    Sleep spindles are a cardinal feature in human NREM sleep and may be important for memory consolidation. We studied the intracortical organization of spindles in men and women by recording spontaneous sleep spindles from different cortical layers using linear microelectrode arrays. Two patterns of spindle generation were identified using visual inspection, and confirmed with factor analysis. Spindles (10-16 Hz) were largest and most common in upper and middle channels, with limited involvement of deep channels. Many spindles were observed in only upper or only middle channels, but approximately half occurred in both. In spindles involving both middle and upper channels, the spindle envelope onset in middle channels led upper by ∼25-50 ms on average. The phase relationship between spindle waves in upper and middle channels varied dynamically within spindle epochs, and across individuals. Current source density analysis demonstrated that upper and middle channel spindles were both generated by an excitatory supragranular current sink while an additional deep source was present for middle channel spindles only. Only middle channel spindles were accompanied by deep low (25-50 Hz) and high (70-170 Hz) gamma activity. These results suggest that upper channel spindles are generated by supragranular pyramids, and middle channel by infragranular. Possibly, middle channel spindles are generated by core thalamocortical afferents, and upper channel by matrix. The concurrence of these patterns could reflect engagement of cortical circuits in the integration of more focal (core) and distributed (matrix) aspects of memory. These results demonstrate that at least two distinct intracortical systems generate human sleep spindles. SIGNIFICANCE STATEMENT Bursts of ∼14 Hz oscillations, lasting ∼1 s, have been recognized for over 80 years as cardinal features of mammalian sleep. Recent findings suggest that they play a key role in organizing cortical activity during memory

  8. Brownian dynamics simulation of fission yeast mitotic spindle formation

    NASA Astrophysics Data System (ADS)

    Edelmaier, Christopher

    2014-03-01

    The mitotic spindle segregates chromosomes during mitosis. The dynamics that establish bipolar spindle formation are not well understood. We have developed a computational model of fission-yeast mitotic spindle formation using Brownian dynamics and kinetic Monte Carlo methods. Our model includes rigid, dynamic microtubules, a spherical nuclear envelope, spindle pole bodies anchored in the nuclear envelope, and crosslinkers and crosslinking motor proteins. Crosslinkers and crosslinking motor proteins attach and detach in a grand canonical ensemble, and exert forces and torques on the attached microtubules. We have modeled increased affinity for crosslinking motor attachment to antiparallel microtubule pairs, and stabilization of microtubules in the interpolar bundle. We study parameters controlling the stability of the interpolar bundle and assembly of a bipolar spindle from initially adjacent spindle-pole bodies.

  9. A Mutation in γ-Tubulin Alters Microtubule Dynamics and Organization and Is Synthetically Lethal with the Kinesin-like Protein Pkl1pV⃞

    PubMed Central

    Paluh, Janet L.; Nogales, Eva; Oakley, Berl R.; McDonald, Kent; Pidoux, Alison L.; Cande, W. Z.

    2000-01-01

    Mitotic segregation of chromosomes requires spindle pole functions for microtubule nucleation, minus end organization, and regulation of dynamics. γ-Tubulin is essential for nucleation, and we now extend its role to these latter processes. We have characterized a mutation in γ-tubulin that results in cold-sensitive mitotic arrest with an elongated bipolar spindle but impaired anaphase A. At 30°C cytoplasmic microtubule arrays are abnormal and bundle into single larger arrays. Three-dimensional time-lapse video microscopy reveals that microtubule dynamics are altered. Localization of the mutant γ-tubulin is like the wild-type protein. Prediction of γ-tubulin structure indicates that non-α/β-tubulin protein–protein interactions could be affected. The kinesin-like protein (klp) Pkl1p localizes to the spindle poles and spindle and is essential for viability of the γ-tubulin mutant and in multicopy for normal cell morphology at 30°C. Localization and function of Pkl1p in the mutant appear unaltered, consistent with a redundant function for this protein in wild type. Our data indicate a broader role for γ-tubulin at spindle poles in regulating aspects of microtubule dynamics and organization. We propose that Pkl1p rescues an impaired function of γ-tubulin that involves non-tubulin protein–protein interactions, presumably with a second motor, MAP, or MTOC component. PMID:10749926

  10. Novel loss-of-function variants in DIAPH1 associated with syndromic microcephaly, blindness, and early onset seizures.

    PubMed

    Al-Maawali, Almundher; Barry, Brenda J; Rajab, Anna; El-Quessny, Malak; Seman, Ann; Coury, Stephanie Newton; Barkovich, A James; Yang, Edward; Walsh, Christopher A; Mochida, Ganeshwaran H; Stoler, Joan M

    2016-02-01

    Exome sequencing identified homozygous loss-of-function variants in DIAPH1 (c.2769delT; p.F923fs and c.3145C>T; p.R1049X) in four affected individuals from two unrelated consanguineous families. The affected individuals in our report were diagnosed with postnatal microcephaly, early-onset epilepsy, severe vision impairment, and pulmonary symptoms including bronchiectasis and recurrent respiratory infections. A heterozygous DIAPH1 mutation was originally reported in one family with autosomal dominant deafness. Recently, however, a homozygous nonsense DIAPH1 mutation (c.2332C4T; p.Q778X) was reported in five siblings in a single family affected by microcephaly, blindness, early onset seizures, developmental delay, and bronchiectasis. The role of DIAPH1 was supported using parametric linkage analysis, RNA and protein studies in their patients' cell lines and further studies in human neural progenitors cells and a diap1 knockout mouse. In this report, the proband was initially brought to medical attention for profound metopic synostosis. Additional concerns arose when his head circumference did not increase after surgical release at 5 months of age and he was diagnosed with microcephaly and epilepsy at 6 months of age. Clinical exome analysis identified a homozygous DIAPH1 mutation. Another homozygous DIAPH1 mutation was identified in the research exome analysis of a second family with three siblings presenting with a similar phenotype. Importantly, no hearing impairment is reported in the homozygous affected individuals or in the heterozygous carrier parents in any of the families demonstrating the autosomal recessive microcephaly phenotype. These additional families provide further evidence of the likely causal relationship between DIAPH1 mutations and a neurodevelopmental disorder. © 2016 Wiley Periodicals, Inc.

  11. Spatiotemporal characteristics of sleep spindles depend on cortical location.

    PubMed

    Piantoni, Giovanni; Halgren, Eric; Cash, Sydney S

    2017-02-01

    Since their discovery almost one century ago, sleep spindles, 0.5-2s long bursts of oscillatory activity at 9-16Hz during NREM sleep, have been thought to be global and relatively uniform throughout the cortex. Recent work, however, has brought this concept into question but it remains unclear to what degree spindles are global or local and if their properties are uniform or location-dependent. We addressed this question by recording sleep in eight patients undergoing evaluation for epilepsy with intracranial electrocorticography, which combines high spatial resolution with extensive cortical coverage. We find that spindle characteristics are not uniform but are strongly influenced by the underlying cortical regions, particularly for spindle density and fundamental frequency. We observe both highly isolated and spatially distributed spindles, but in highly skewed proportions: while most spindles are restricted to one or very few recording channels at any given time, there are spindles that occur over widespread areas, often involving lateral prefrontal cortices and superior temporal gyri. Their co-occurrence is affected by a subtle but significant propagation of spindles from the superior prefrontal regions and the temporal cortices towards the orbitofrontal cortex. This work provides a brain-wide characterization of sleep spindles as mostly local graphoelements with heterogeneous characteristics that depend on the underlying cortical area. We propose that the combination of local characteristics and global organization reflects the dual properties of the thalamo-cortical generators and provides a flexible framework to support the many functions ascribed to sleep in general and spindles specifically. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Spindle cell oncocytoma of the pituitary gland with follicle-like component: organotypic differentiation to support its origin from folliculo-stellate cells.

    PubMed

    Vajtai, Istvan; Beck, Jürgen; Kappeler, Andreas; Hewer, Ekkehard

    2011-08-01

    Spindle cell oncocytoma (SCO) is a rare, non-adenomatous tumor originating from the anterior pituitary gland. Composed of fusiform, mitochondrion-rich cells sharing several immunophenotypic and ultrastructural properties with folliculo-stellate cells (FSC), SCO has been proposed to represent a neoplastic counterpart of the latter. To date, however, SCO has failed to meet one criterion commonly used in histological-based taxonomy and diagnostics; that of recapitulating any of FSCs' morphologically defined developmental or physiological states. We describe a unique example of SCO wherein a conventional fascicular texture was seen coexisting with and organically merging into follicle-like arrangements. The sellar tumor of 2.7 × 2.6 × 2.5 cm was transphenoidally resected from a 55-year old female. Preoperative magnetic resonance imaging indicated an isointense, contrast enhancing mass with suprasellar extension. Histology showed multiple rudimentary to well-formed, follicle-like cavities on a classical spindle cell background; while all the participating cells exhibited an SCO immunophenotype, including positivity for S100 protein, vimentin, EMA, Bcl-2, and TTF-1, as well as staining with the antimitochondrial antibody 113-1. Conversely no expression of GFAP, follicular-epithelial cytokeratin, carcinoembryonic antigen, or anterior pituitary hormones was detected. Ultrastructurally, tumor cells facing follicular lumina displayed organelles of epithelial specialization, in particular surface microvilli and apical tight junctions. This constellation is felt to be reminiscent of FSCs' metaplastic transition to follicular epithelium, as observed during embryonic development and physiological renewal of the hormone-secreting parenchyma. Such finding is apt to being read as a supporting argument for SCO's descent from the FSC lineage.

  13. Analysis and topology optimization design of high-speed driving spindle

    NASA Astrophysics Data System (ADS)

    Wang, Zhilin; Yang, Hai

    2018-04-01

    The three-dimensional model of high-speed driving spindle is established by using SOLIDWORKS. The model is imported through the interface of ABAQUS, A finite element analysis model of high-speed driving spindle was established by using spring element to simulate bearing boundary condition. High-speed driving spindle for the static analysis, the spindle of the stress, strain and displacement nephogram, and on the basis of the results of the analysis on spindle for topology optimization, completed the lightweight design of high-speed driving spindle. The design scheme provides guidance for the design of axial parts of similar structures.

  14. Early Presence of Sleep Spindles on Electroencephalography Is Associated With Good Outcome After Pediatric Cardiac Arrest.

    PubMed

    Ducharme-Crevier, Laurence; Press, Craig A; Kurz, Jonathan E; Mills, Michele G; Goldstein, Joshua L; Wainwright, Mark S

    2017-05-01

    The role of sleep architecture as a biomarker for prognostication after resuscitation from cardiac arrest in children hospitalized in an ICU remains poorly defined. We sought to investigate the association between features of normal sleep architecture in children after cardiac arrest and a favorable neurologic outcome at 6 months. Retrospective review of medical records and continuous electroencephalography monitoring. Cardiac and PICU of a tertiary children's hospital. All patients from 6 months to 18 years old resuscitated from cardiac arrest who underwent continuous electroencephalography monitoring in the first 24 hours after in- or out-of-hospital cardiac arrest from January 2010 to June 2015. None. Thirty-four patients underwent continuous electroencephalography monitoring after cardiac arrest. The median age was 6.1 years (interquartile range, 1.5-12.5 yr), 20 patients were male (59%). Most cases (n = 23, 68%) suffered from in-hospital cardiac arrest. Electroencephalography monitoring was initiated a median of 9.3 hours (5.8-14.9 hr) after return of spontaneous circulation, for a median duration of 14.3 hours (6.0-16.0 hr) within the first 24-hour period after the cardiac arrest. Five patients had normal spindles, five had abnormal spindles, and 24 patients did not have any sleep architecture. The presence of spindles was associated with a favorable neurologic outcome at 6-month postcardiac arrest (p = 0.001). Continuous electroencephalography monitoring can be used in children to assess spindles in the ICU. The presence of spindles on continuous electroencephalography monitoring in the first 24 hours after resuscitation from cardiac arrest is associated with a favorable neurologic outcome. Assessment of sleep architecture on continuous electroencephalography after cardiac arrest could improve outcome prediction.

  15. Phosphorylation of CPAP by Aurora-A Maintains Spindle Pole Integrity during Mitosis.

    PubMed

    Chou, En-Ju; Hung, Liang-Yi; Tang, Chieh-Ju C; Hsu, Wen-Bin; Wu, Hsin-Yi; Liao, Pao-Chi; Tang, Tang K

    2016-03-29

    CPAP is required for centriole elongation during S/G2 phase, but the role of CPAP in mitosis is incompletely understood. Here, we show that CPAP maintains spindle pole integrity through its phosphorylation by Aurora-A during mitosis. Depletion of CPAP induced a prolonged delay in mitosis, pericentriolar material (PCM) dispersion, and multiple mitotic abnormalities. Further studies demonstrated that CPAP directly interacts with and is phosphorylated by Aurora-A at serine 467 during mitosis. Interestingly, the dispersal of the PCM was effectively rescued by ectopic expression of wild-type CPAP or a phospho-mimic CPAP-S467D mutant, but not a non-phosphorylated CPAP-S467A mutant. Finally, we found that CPAP-S467D has a low affinity for microtubule binding but a high affinity for PCM proteins. Together, our results support a model wherein CPAP is required for proper mitotic progression, and phosphorylation of CPAP by Aurora-A is essential for maintaining spindle pole integrity. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Combination spindle-drive system for high precision machining

    DOEpatents

    Gerth, Howard L.

    1977-07-26

    A combination spindle-drive is provided for fabrication of optical quality surface finishes. Both the spindle-and-drive utilize the spindle bearings for support, thereby removing the conventional drive-means bearings as a source of vibration. An airbearing spindle is modified to carry at the drive end a highly conductive cup-shaped rotor which is aligned with a stationary stator to produce torque in the cup-shaped rotor through the reaction of eddy currents induced in the rotor. This arrangement eliminates magnetic attraction forces and all force is in the form of torque on the cup-shaped rotor.

  17. Sleep spindle density in narcolepsy.

    PubMed

    Christensen, Julie Anja Engelhard; Nikolic, Miki; Hvidtfelt, Mathias; Kornum, Birgitte Rahbek; Jennum, Poul

    2017-06-01

    Patients with narcolepsy type 1 (NT1) show alterations in sleep stage transitions, rapid-eye-movement (REM) and non-REM sleep due to the loss of hypocretinergic signaling. However, the sleep microstructure has not yet been evaluated in these patients. We aimed to evaluate whether the sleep spindle (SS) density is altered in patients with NT1 compared to controls and patients with narcolepsy type 2 (NT2). All-night polysomnographic recordings from 28 NT1 patients, 19 NT2 patients, 20 controls (C) with narcolepsy-like symptoms, but with normal cerebrospinal fluid hypocretin levels and multiple sleep latency tests, and 18 healthy controls (HC) were included. Unspecified, slow, and fast SS were automatically detected, and SS densities were defined as number per minute and were computed across sleep stages and sleep cycles. The between-cycle trends of SS densities in N2 and NREM sleep were evaluated within and between groups. Between-group comparisons in sleep stages revealed no significant differences in any type of SS. Within-group analyses of the SS trends revealed significant decreasing trends for NT1, HC, and C between first and last sleep cycle. Between-group analyses of SS trends between first and last sleep cycle revealed that NT2 differ from NT1 patients in the unspecified SS density in NREM sleep, and from HC in the slow SS density in N2 sleep. SS activity is preserved in NT1, suggesting that the ascending neurons to thalamic activation of SS are not significantly affected by the hypocretinergic system. NT2 patients show an abnormal pattern of SS distribution. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans.

    PubMed

    Shamseldin, Hanan; Alazami, Anas M; Manning, Melanie; Hashem, Amal; Caluseiu, Oana; Tabarki, Brahim; Esplin, Edward; Schelley, Susan; Innes, A Micheil; Parboosingh, Jillian S; Lamont, Ryan; Majewski, Jacek; Bernier, Francois P; Alkuraya, Fowzan S

    2015-12-03

    Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963(∗)] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  19. Monitoring Method of Cutting Force by Using Additional Spindle Sensors

    NASA Astrophysics Data System (ADS)

    Sarhan, Ahmed Aly Diaa; Matsubara, Atsushi; Sugihara, Motoyuki; Saraie, Hidenori; Ibaraki, Soichi; Kakino, Yoshiaki

    This paper describes a monitoring method of cutting forces for end milling process by using displacement sensors. Four eddy-current displacement sensors are installed on the spindle housing of a machining center so that they can detect the radial motion of the rotating spindle. Thermocouples are also attached to the spindle structure in order to examine the thermal effect in the displacement sensing. The change in the spindle stiffness due to the spindle temperature and the speed is investigated as well. Finally, the estimation performance of cutting forces using the spindle displacement sensors is experimentally investigated by machining tests on carbon steel in end milling operations under different cutting conditions. It is found that the monitoring errors are attributable to the thermal displacement of the spindle, the time lag of the sensing system, and the modeling error of the spindle stiffness. It is also shown that the root mean square errors between estimated and measured amplitudes of cutting forces are reduced to be less than 20N with proper selection of the linear stiffness.

  20. Loss-of-function mutation in RUSC2 causes intellectual disability and secondary microcephaly.

    PubMed

    Alwadei, Ali H; Benini, Ruba; Mahmoud, Adel; Alasmari, Ali; Kamsteeg, Erik-Jan; Alfadhel, Majid

    2016-12-01

    Inherited aberrancies in intracellular vesicular transport are associated with a variety of neurological and non-neurological diseases. RUSC2 is a gene found on chromosome 9p13.3 that codes for iporin, a ubiquitous protein with high expression in the brain that interacts with Rab proteins (GTPases implicated in intracellular protein trafficking). Although mutations in Rab proteins have been described as causing brain abnormalities and intellectual disability, until now no disease-causing mutations in RUSC2 have ever been reported in humans. We describe, to our knowledge for the first time, three patients with inherited homozygous nonsense mutations identified in RUSC2 on whole-exome sequencing. All three patients had central hypotonia, microcephaly, and moderate to severe intellectual disability. Two patients had additional features of early-onset epilepsy and absence of the splenium. This report adds to the ever-expanding landscape of genetic causes of intellectual disability and increases our understanding of the cellular processes underlying this important neurological entity. © 2016 Mac Keith Press.

  1. Optimal design of high-speed loading spindle based on ABAQUS

    NASA Astrophysics Data System (ADS)

    Yang, Xudong; Dong, Yu; Ge, Qingkuan; Yang, Hai

    2017-12-01

    The three-dimensional model of high-speed loading spindle is established by using ABAQUS’s modeling module. A finite element analysis model of high-speed loading spindle was established by using spring element to simulate bearing boundary condition. The static and dynamic performance of the spindle structure with different specifications of the rectangular spline and the different diameter neck of axle are studied in depth, and the influence of different spindle span on the static and dynamic performance of the high-speed loading spindle is studied. Finally, the optimal structure of the high-speed loading spindle is obtained. The results provide a theoretical basis for improving the overall performance of the test-bed

  2. Modal identification of spindle-tool unit in high-speed machining

    NASA Astrophysics Data System (ADS)

    Gagnol, Vincent; Le, Thien-Phu; Ray, Pascal

    2011-10-01

    The accurate knowledge of high-speed motorised spindle dynamic behaviour during machining is important in order to ensure the reliability of machine tools in service and the quality of machined parts. More specifically, the prediction of stable cutting regions, which is a critical requirement for high-speed milling operations, requires the accurate estimation of tool/holder/spindle set dynamic modal parameters. These estimations are generally obtained through Frequency Response Function (FRF) measurements of the non-rotating spindle. However, significant changes in modal parameters are expected to occur during operation, due to high-speed spindle rotation. The spindle's modal variations are highlighted through an integrated finite element model of the dynamic high-speed spindle-bearing system, taking into account rotor dynamics effects. The dependency of dynamic behaviour on speed range is then investigated and determined with accuracy. The objective of the proposed paper is to validate these numerical results through an experiment-based approach. Hence, an experimental setup is elaborated to measure rotating tool vibration during the machining operation in order to determine the spindle's modal frequency variation with respect to spindle speed in an industrial environment. The identification of natural frequencies of the spindle under rotating conditions is challenging, due to the low number of sensors and the presence of many harmonics in the measured signals. In order to overcome these issues and to extract the characteristics of the system, the spindle modes are determined through a 3-step procedure. First, spindle modes are highlighted using the Frequency Domain Decomposition (FDD) technique, with a new formulation at the considered rotating speed. These extracted modes are then analysed through the value of their respective damping ratios in order to separate the harmonics component from structural spindle natural frequencies. Finally, the stochastic

  3. Physiological and ultrastructural analysis of elongating mitotic spindles reactivated in vitro

    PubMed Central

    1986-01-01

    We have developed a simple procedure for isolating mitotic spindles from the diatom Stephanopyxis turris and have shown that they undergo anaphase spindle elongation in vitro upon addition of ATP. The isolated central spindle is a barrel-shaped structure with a prominent zone of microtubule overlap. After ATP addition greater than 75% of the spindle population undergoes distinct structural rearrangements: the spindles on average are longer and the two half-spindles are separated by a distinct gap traversed by only a small number of microtubules, the phase-dense material in the overlap zone is gone, and the peripheral microtubule arrays have depolymerized. At the ultrastructural level, we examined serial cross-sections of spindles after 1-, 5-, and 10-min incubations in reactivation medium. Microtubule depolymerization distal to the poles is confirmed by the increased number of incomplete, i.e., c-microtubule profiles specifically located in the region of overlap. After 10 min we see areas of reduced microtubule number which correspond to the gaps seen in the light microscope and an overall reduction in the number of half-spindle microtubules to about one-third the original number. The changes in spindle structure are highly specific for ATP, are dose-dependent, and do not occur with nonhydrolyzable nucleotide analogues. Spindle elongation and gap formation are blocked by 10 microM vanadate, equimolar mixtures of ATP and AMPPNP, and by sulfhydryl reagents. This process is not affected by nocodazole, erythro-9-[3-(2-hydroxynonyl)]adenine, cytochalasin D, and phalloidin. In the presence of taxol, the extent of spindle elongation is increased; however, distinct gaps still form between the two half- spindles. These results show that the response of isolated spindles to ATP is a complex process consisting of several discrete steps including initiation events, spindle elongation mechanochemistry, controlled central spindle microtubule plus-end depolymerization, and loss

  4. Do All Dinoflagellates have an Extranuclear Spindle?

    PubMed

    Moon, Eunyoung; Nam, Seung Won; Shin, Woongghi; Park, Myung Gil; Coats, D Wayne

    2015-11-01

    The syndinean dinoflagellates are a diverse assemblage of alveolate endoparasites that branch basal to the core dinoflagellates. Because of their phylogenetic position, the syndineans are considered key model microorganisms in understanding early evolution in the dinoflagellates. Closed mitosis with an extranuclear spindle that traverses the nucleus in cytoplasmic grooves or tunnels is viewed as one of the morphological features shared by syndinean and core dinoflagellates. Here we describe nuclear morphology and mitosis in the syndinean dinoflagellate Amoebophrya sp. from Akashiwo sanguinea, a member of the A. ceratii complex, as revealed by protargol silver impregnation, DNA specific fluorochromes, and transmission electron microscopy. Our observations show that not all species classified as dinoflagellates have an extranuclear spindle. In Amoebophrya sp. from A. sanguinea, an extranuclear microtubule cylinder located in a depression in the nuclear surface during interphase moves into the nucleoplasm via sequential membrane fusion events and develops into an entirely intranuclear spindle. Results suggest that the intranuclear spindle of Amoebophrya spp. may have evolved from an ancestral extranuclear spindle and indicate the need for taxonomic revision of the Amoebophryidae. Copyright © 2015 Elsevier GmbH. All rights reserved.

  5. Spatial signals link exit from mitosis to spindle position.

    PubMed

    Falk, Jill Elaine; Tsuchiya, Dai; Verdaasdonk, Jolien; Lacefield, Soni; Bloom, Kerry; Amon, Angelika

    2016-05-11

    In budding yeast, if the spindle becomes mispositioned, cells prevent exit from mitosis by inhibiting the mitotic exit network (MEN). The MEN is a signaling cascade that localizes to spindle pole bodies (SPBs) and activates the phosphatase Cdc14. There are two competing models that explain MEN regulation by spindle position. In the 'zone model', exit from mitosis occurs when a MEN-bearing SPB enters the bud. The 'cMT-bud neck model' posits that cytoplasmic microtubule (cMT)-bud neck interactions prevent MEN activity. Here we find that 1) eliminating cMT- bud neck interactions does not trigger exit from mitosis and 2) loss of these interactions does not precede Cdc14 activation. Furthermore, using binucleate cells, we show that exit from mitosis occurs when one SPB enters the bud despite the presence of a mispositioned spindle. We conclude that exit from mitosis is triggered by a correctly positioned spindle rather than inhibited by improper spindle position.

  6. O-Linked N-Acetylglucosamine Cycling Regulates Mitotic Spindle Organization*

    PubMed Central

    Tan, Ee Phie; Caro, Sarah; Potnis, Anish; Lanza, Christopher; Slawson, Chad

    2013-01-01

    Any defects in the correct formation of the mitotic spindle will lead to chromosomal segregation errors, mitotic arrest, or aneuploidy. We demonstrate that O-linked N-acetylglucosamine (O-GlcNAc), a post-translational modification of serine and threonine residues in nuclear and cytoplasmic proteins, regulates spindle function. In O-GlcNAc transferase or O-GlcNAcase gain of function cells, the mitotic spindle is incorrectly assembled. Chromosome condensation and centrosome assembly is impaired in these cells. The disruption in spindle architecture is due to a reduction in histone H3 phosphorylation by Aurora kinase B. However, gain of function cells treated with the O-GlcNAcase inhibitor Thiamet-G restored the assembly of the spindle and partially rescued histone phosphorylation. Together, these data suggest that the coordinated addition and removal of O-GlcNAc, termed O-GlcNAc cycling, regulates mitotic spindle organization and provides a potential new perspective on how O-GlcNAc regulates cellular events. PMID:23946484

  7. Human Nek7-interactor RGS2 is required for mitotic spindle organization

    PubMed Central

    de Souza, Edmarcia Elisa; Hehnly, Heidi; Perez, Arina Marina; Meirelles, Gabriela Vaz; Smetana, Juliana Helena Costa; Doxsey, Stephen; Kobarg, Jörg

    2015-01-01

    The mitotic spindle apparatus is composed of microtubule (MT) networks attached to kinetochores organized from 2 centrosomes (a.k.a. spindle poles). In addition to this central spindle apparatus, astral MTs assemble at the mitotic spindle pole and attach to the cell cortex to ensure appropriate spindle orientation. We propose that cell cycle-related kinase, Nek7, and its novel interacting protein RGS2, are involved in mitosis regulation and spindle formation. We found that RGS2 localizes to the mitotic spindle in a Nek7-dependent manner, and along with Nek7 contributes to spindle morphology and mitotic spindle pole integrity. RGS2-depletion leads to a mitotic-delay and severe defects in the chromosomes alignment and congression. Importantly, RGS2 or Nek7 depletion or even overexpression of wild-type or kinase-dead Nek7, reduced γ-tubulin from the mitotic spindle poles. In addition to causing a mitotic delay, RGS2 depletion induced mitotic spindle misorientation coinciding with astral MT-reduction. We propose that these phenotypes directly contribute to a failure in mitotic spindle alignment to the substratum. In conclusion, we suggest a molecular mechanism whereupon Nek7 and RGS2 may act cooperatively to ensure proper mitotic spindle organization. PMID:25664600

  8. Human Nek7-interactor RGS2 is required for mitotic spindle organization.

    PubMed

    de Souza, Edmarcia Elisa; Hehnly, Heidi; Perez, Arina Marina; Meirelles, Gabriela Vaz; Smetana, Juliana Helena Costa; Doxsey, Stephen; Kobarg, Jörg

    2015-01-01

    The mitotic spindle apparatus is composed of microtubule (MT) networks attached to kinetochores organized from 2 centrosomes (a.k.a. spindle poles). In addition to this central spindle apparatus, astral MTs assemble at the mitotic spindle pole and attach to the cell cortex to ensure appropriate spindle orientation. We propose that cell cycle-related kinase, Nek7, and its novel interacting protein RGS2, are involved in mitosis regulation and spindle formation. We found that RGS2 localizes to the mitotic spindle in a Nek7-dependent manner, and along with Nek7 contributes to spindle morphology and mitotic spindle pole integrity. RGS2-depletion leads to a mitotic-delay and severe defects in the chromosomes alignment and congression. Importantly, RGS2 or Nek7 depletion or even overexpression of wild-type or kinase-dead Nek7, reduced γ-tubulin from the mitotic spindle poles. In addition to causing a mitotic delay, RGS2 depletion induced mitotic spindle misorientation coinciding with astral MT-reduction. We propose that these phenotypes directly contribute to a failure in mitotic spindle alignment to the substratum. In conclusion, we suggest a molecular mechanism whereupon Nek7 and RGS2 may act cooperatively to ensure proper mitotic spindle organization.

  9. Infant leukemia and congenital abnormalities: A Children’s Oncology Group study

    PubMed Central

    Johnson, Kimberly J.; Roesler, Michelle A.; Linabery, Amy M.; Hilden, Joanne M.; Davies, Stella M.; Ross, Julie A.

    2010-01-01

    Background Leukemia in infants is rare and has not been well-studied apart from leukemia in older children. Differences in survival and the molecular characteristics of leukemia in infants vs. older children suggest a distinct etiology, likely involving prenatal factors. Procedure We examined the association between eight categories of maternally-reported congenital abnormalities (CAs) (cleft lip or palate, spina bifida or other spinal defect, large or multiple birthmarks, other chromosomal abnormalities, small head or microcephaly, rib abnormalities, urogenital abnormalities, and other) and infant leukemia in a case-control study. The study included 443 cases diagnosed at <1 year of age at a Children’s Oncology Group institution in the United States or Canada from 1996-2006 and 324 controls. Controls were recruited from the cases’ geographic area either by random digit dialing (1999-2002) or through birth certificates (2003-2008) and were frequency-matched to cases on birth year. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression after adjustment for birth year and a measure of follow-up time to account for differences in the CA observation period. Results No statistically significant associations were observed between infant leukemia and any CA (OR=1.2; 95% CI 0.8-1.9), birthmarks (OR=1.4, 95% CI 0.7-2.5), urogenital abnormalities (OR=0.7; 95% CI 0.2-2.0), or other CA (OR=1.4; 95% CI 0.7-2.8). Results were similar for acute lymphoblastic and myeloid leukemia cases. Fewer than five subjects were in the remaining CA categories precluding analysis. Conclusions Overall, we did not find evidence to support an association between CAs and infant leukemia. PMID:20486175

  10. Self-organization mechanisms in the assembly and maintenance of bipolar spindles

    NASA Astrophysics Data System (ADS)

    Burbank, Kendra Stewart

    Anastral, meiotic spindles are thought to be organized differently from astral, mitotic spindles, but the field has lacked basic structural information required to describe and model them, including the location of microtubule nucleating sites and minus ends. How the various components of spindles act together to establish and maintain the dynamic bipolar structure of spindles is not understood. We measure the distributions of oriented microtubules (MTs) in metaphase anastral spindles in Xenopus extracts by fluorescence speckle microscopy and cross-correlation analysis. We localized plus ends by tubulin incorporation and combined this with the orientation data to infer the localization of minus ends. We find that minus ends are localized throughout the spindle, sparsely at the equator and at higher concentrations near the poles. This dads to the surprising conclusion that spindles contained many short MTs, not connected to the spindle poles. Based on these data, we propose a slide-and-cluster model based on four known molecular activities: MT nucleation near chromosomes, the sliding of MTs by a plus-enddirected motor, the clustering of their minus ends by a minus-end-directed motor, and the loss of MTs by dynamic instability. This work demonstrates how the interplay between two types of motors together with continual nucleation of MTs by chromosomes could organize the MTs into spindles. Our model applies to overlapping, nonkinetochore MTs in anastral spindles, and perhaps also to interpolar MTs in astral spindles. We show mathematically that the slide-and-cluster mechanism robustly forms bipolar spindles a stable steady-state length, sometimes with sharp poles. This model accounts for several experimental observations that were difficult to explain with existing models, and is the first self contained model for anastral spindle assembly, MT sliding (known as poleward flux), and spindle bistability. Our experimental results support the slide-and-cluster scenario

  11. Physical Limits on the Precision of Mitotic Spindle Positioning by Microtubule Pushing forces: Mechanics of mitotic spindle positioning.

    PubMed

    Howard, Jonathon; Garzon-Coral, Carlos

    2017-11-01

    Tissues are shaped and patterned by mechanical and chemical processes. A key mechanical process is the positioning of the mitotic spindle, which determines the size and location of the daughter cells within the tissue. Recent force and position-fluctuation measurements indicate that pushing forces, mediated by the polymerization of astral microtubules against- the cell cortex, maintain the mitotic spindle at the cell center in Caenorhabditis elegans embryos. The magnitude of the centering forces suggests that the physical limit on the accuracy and precision of this centering mechanism is determined by the number of pushing microtubules rather than by thermally driven fluctuations. In cells that divide asymmetrically, anti-centering, pulling forces generated by cortically located dyneins, in conjunction with microtubule depolymerization, oppose the pushing forces to drive spindle displacements away from the center. Thus, a balance of centering pushing forces and anti-centering pulling forces localize the mitotic spindles within dividing C. elegans cells. © 2017 The Authors. BioEssays published by Wiley Periodicals, Inc.

  12. Estimating the numbers of pregnant women infected with Zika virus and infants with congenital microcephaly in Colombia, 2015-2017.

    PubMed

    Adamski, Alys; Bertolli, Jeanne; Castañeda-Orjuela, Carlos; Devine, Owen J; Johansson, Michael A; Duarte, Maritza Adegnis Gonzalez; Farr, Sherry L; Tinker, Sarah C; Reyes, Marcela Maria Mercado; Tong, Van T; Garcia, Oscar Eduardo Pacheco; Valencia, Diana; Ortiz, Diego Alberto Cuellar; Honein, Margaret A; Jamieson, Denise J; Martínez, Martha Lucía Ospina; Gilboa, Suzanne M

    2018-06-01

    Colombia experienced a Zika virus (ZIKV) outbreak in 2015-2016. To assist with planning for medical and supportive services for infants affected by prenatal ZIKV infection, we used a model to estimate the number of pregnant women infected with ZIKV and the number of infants with congenital microcephaly from August 2015 to August 2017. We used nationally reported cases of symptomatic ZIKV disease among pregnant women and information from the literature on the percent of asymptomatic infections to estimate the number of pregnant women with ZIKV infection occurring August 2015-December 2016. We then estimated the number of infants with congenital microcephaly expected to occur August 2015-August 2017. To compare to the observed counts of infants with congenital microcephaly due to all causes reported through the national birth defects surveillance system, the model was time limited to produce estimates for February-November 2016. We estimated 1140-2160 (interquartile range [IQR]) infants with congenital microcephaly in Colombia, during August 2015-August 2017, whereas 340-540 infants with congenital microcephaly would be expected in the absence of ZIKV. Based on the time limited version of the model, for February-November 2016, we estimated 650-1410 infants with congenital microcephaly in Colombia. The 95% uncertainty interval for the latter estimate encompasses the 476 infants with congenital microcephaly reported during that approximate time frame based on national birth defects surveillance. Based on modeled estimates, ZIKV infection during pregnancy in Colombia could lead to 3-4 times as many infants with congenital microcephaly in 2015-2017 as would have been expected in the absence of the ZIKV outbreak. This publication was made possible through support provided by the Bureau for Global Health, U.S. Agency for International Development under the terms of an Interagency Agreement with Centers for Disease Control and Prevention. Published by Elsevier Ltd.

  13. Population-Based Microcephaly Surveillance in the United States, 2009 to 2013: An Analysis of Potential Sources of Variation

    PubMed Central

    Cragan, Janet D.; Isenburg, Jennifer L.; Parker, Samantha E.; Alverson, C.J.; Meyer, Robert E.; Stallings, Erin B.; Kirby, Russell S.; Lupo, Philip J.; Liu, Jennifer S.; Seagroves, Amanda; Ethen, Mary K.; Cho, Sook Ja; Evans, MaryAnn; Liberman, Rebecca F.; Fornoff, Jane; Browne, Marilyn L.; Rutkowski, Rachel E.; Nance, Amy E.; Anderka, Marlene; Fox, Deborah J.; Steele, Amy; Copeland, Glenn; Romitti, Paul A.; Mai, Cara T.

    2017-01-01

    Background Congenital microcephaly has been linked to maternal Zika virus infection. However, ascertaining infants diagnosed with microcephaly can be challenging. Methods Thirty birth defects surveillance programs provided data on infants diagnosed with microcephaly born 2009 to 2013. The pooled prevalence of microcephaly per 10,000 live births was estimated overall and by maternal/infant characteristics. Variation in prevalence was examined across case finding methods. Nine programs provided data on head circumference and conditions potentially contributing to microcephaly. Results The pooled prevalence of microcephaly was 8.7 per 10,000 live births. Median prevalence (per 10,000 live births) was similar among programs using active (6.7) and passive (6.6) methods; the interdecile range of prevalence estimates was wider among programs using passive methods for all race/ethnicity categories except Hispanic. Prevalence (per 10,000 live births) was lowest among non-Hispanic Whites (6.5) and highest among non-Hispanic Blacks and Hispanics (11.2 and 11.9, respectively); estimates followed a U-shaped distribution by maternal age with the highest prevalence among mothers <20 years (11.5) and ≥40 years (13.2). For gestational age and birth weight, the highest prevalence was among infants <32 weeks gestation and infants <1500 gm. Case definitions varied; 41.8% of cases had an HC ≥ the 10th percentile for sex and gestational age. Conclusion Differences in methods, population distribution of maternal/infant characteristics, and case definitions for microcephaly can contribute to the wide range of observed prevalence estimates across individual birth defects surveillance programs. Addressing these factors in the setting of Zika virus infection can improve the quality of prevalence estimates. PMID:27891783

  14. Dimethyl Sulfoxide Perturbs Cell Cycle Progression and Spindle Organization in Porcine Meiotic Oocytes

    PubMed Central

    Li, Xuan; Wang, Yan-Kui; Song, Zhi-Qiang; Du, Zhi-Qiang; Yang, Cai-Xia

    2016-01-01

    Meiotic maturation of mammalian oocytes is a precisely orchestrated and complex process. Dimethyl sulfoxide (DMSO), a widely used solvent, drug, and cryoprotectant, is capable of disturbing asymmetric cytokinesis of oocyte meiosis in mice. However, in pigs, DMSO’s effect on oocyte meiosis still remains unknown. We aimed to evaluate if DMSO treatment will affect porcine oocyte meiosis and the underlying molecular changes as well. Interestingly, we did not observe the formation of the large first polar body and symmetric division for porcine oocytes treated with DMSO, contrary to findings reported in mice. 3% DMSO treatment could inhibit cumulus expansion, increase nuclear abnormality, disturb spindle organization, decrease reactive oxygen species level, and elevate mitochondrial membrane potential of porcine oocytes. There was no effect on germinal vesicle breakdown rate regardless of DMSO concentration. 3% DMSO treatment did not affect expression of genes involved in spindle organization (Bub1 and Mad2) and apoptosis (NF-κB, Pten, Bcl2, Caspase3 and Caspase9), however, it significantly decreased expression levels of pluripotency genes (Oct4, Sox2 and Lin28) in mature oocytes. Therefore, we demonstrated that disturbed cumulus expansion, chromosome alignment, spindle organization and pluripotency gene expression could be responsible for DMSO-induced porcine oocyte meiotic arrest and the lower capacity of subsequent embryo development. Our results provide new insights on DMSO’s effect on porcine oocyte meiosis and raise safety concerns over DMSO’s usage on female reproduction in both farm animals and humans. PMID:27348312

  15. Dimethyl Sulfoxide Perturbs Cell Cycle Progression and Spindle Organization in Porcine Meiotic Oocytes.

    PubMed

    Li, Xuan; Wang, Yan-Kui; Song, Zhi-Qiang; Du, Zhi-Qiang; Yang, Cai-Xia

    2016-01-01

    Meiotic maturation of mammalian oocytes is a precisely orchestrated and complex process. Dimethyl sulfoxide (DMSO), a widely used solvent, drug, and cryoprotectant, is capable of disturbing asymmetric cytokinesis of oocyte meiosis in mice. However, in pigs, DMSO's effect on oocyte meiosis still remains unknown. We aimed to evaluate if DMSO treatment will affect porcine oocyte meiosis and the underlying molecular changes as well. Interestingly, we did not observe the formation of the large first polar body and symmetric division for porcine oocytes treated with DMSO, contrary to findings reported in mice. 3% DMSO treatment could inhibit cumulus expansion, increase nuclear abnormality, disturb spindle organization, decrease reactive oxygen species level, and elevate mitochondrial membrane potential of porcine oocytes. There was no effect on germinal vesicle breakdown rate regardless of DMSO concentration. 3% DMSO treatment did not affect expression of genes involved in spindle organization (Bub1 and Mad2) and apoptosis (NF-κB, Pten, Bcl2, Caspase3 and Caspase9), however, it significantly decreased expression levels of pluripotency genes (Oct4, Sox2 and Lin28) in mature oocytes. Therefore, we demonstrated that disturbed cumulus expansion, chromosome alignment, spindle organization and pluripotency gene expression could be responsible for DMSO-induced porcine oocyte meiotic arrest and the lower capacity of subsequent embryo development. Our results provide new insights on DMSO's effect on porcine oocyte meiosis and raise safety concerns over DMSO's usage on female reproduction in both farm animals and humans.

  16. Spatial signals link exit from mitosis to spindle position

    PubMed Central

    Falk, Jill Elaine; Tsuchiya, Dai; Verdaasdonk, Jolien; Lacefield, Soni; Bloom, Kerry; Amon, Angelika

    2016-01-01

    In budding yeast, if the spindle becomes mispositioned, cells prevent exit from mitosis by inhibiting the mitotic exit network (MEN). The MEN is a signaling cascade that localizes to spindle pole bodies (SPBs) and activates the phosphatase Cdc14. There are two competing models that explain MEN regulation by spindle position. In the 'zone model', exit from mitosis occurs when a MEN-bearing SPB enters the bud. The 'cMT-bud neck model' posits that cytoplasmic microtubule (cMT)-bud neck interactions prevent MEN activity. Here we find that 1) eliminating cMT– bud neck interactions does not trigger exit from mitosis and 2) loss of these interactions does not precede Cdc14 activation. Furthermore, using binucleate cells, we show that exit from mitosis occurs when one SPB enters the bud despite the presence of a mispositioned spindle. We conclude that exit from mitosis is triggered by a correctly positioned spindle rather than inhibited by improper spindle position. DOI: http://dx.doi.org/10.7554/eLife.14036.001 PMID:27166637

  17. Sleep spindle activity and cognitive performance in healthy children.

    PubMed

    Chatburn, Alex; Coussens, Scott; Lushington, Kurt; Kennedy, Declan; Baumert, Mathias; Kohler, Mark

    2013-02-01

    To investigate the association between indices of sleep spindle activity and cognitive performance in a sample of healthy children. Correlational. Intelligence (Stanford-Binet) and neurocognitive functioning (NEPSY) were assessed, with sleep variables being measured during overnight polysomnography. Hospital sleep laboratory. Twenty-seven healthy children (mean age 8.19 y; 14 female, 13 male). N/A. Participants underwent a single night of overnight polysomnography after completing measures of intelligence and neurocognitive functioning. Sleep spindles were visually identified by an experienced sleep scoring technician and separated algorithmically into fast (> 13 Hz) and slow spindle (< 13 Hz) categories. The number of fast spindles was significantly correlated with narrative memory (r(s) = 0.38) and sensorimotor functioning (-0.43). Mean central frequency of spindles was also significantly correlated with sensorimotor functioning (-0.41), planning ability (-0.41), and working memory (-0.54). Basal sleep spindle activity is associated with different aspects of cognitive performance in children. To the extent that these associations in a pediatric population are different from what is known in adult sleep may play an important role in development.

  18. Measurement of Spindle Rigidity by using a Magnet Loader

    NASA Astrophysics Data System (ADS)

    Yamazaki, Taku; Matsubara, Atsushi; Fujita, Tomoya; Muraki, Toshiyuki; Asano, Kohei; Kawashima, Kazuyuki

    The static rigidity of a rotating spindle in the radial direction is investigated in this research. A magnetic loading device (magnet loader) has been developed for the measurement. The magnet loader, which has coils and iron cores, generates the electromagnetic force and attracts a dummy tool attached to the spindle. However, the eddy current is generated in the dummy tool with the spindle rotation and reduces the attractive force at high spindle speed. In order to understand the magnetic flux and eddy current in the dummy tool, the electromagnetic field analysis by FEM was carried out. Grooves on the attraction surface of the dummy tool were designed to cut the eddy current flow. The dimension of the groove were decided based on the FEM analysis, and the designed tool were manufactured and tested. The test result shows that the designed tool successfully reduces the eddy current and recovers the attractive force. By using the magnet loader and the grooved tool, the spindle rigidity can be measured when the spindle rotates with a speed up to 10,000 min-1.

  19. Establishing biorientation occurs with precocious separation of the sister kinetochores, but not the arms, in the early spindle of budding yeast.

    PubMed

    Goshima, G; Yanagida, M

    2000-03-17

    Sister kinetochores are bioriented toward the spindle poles in higher eukaryotic prometaphase before chromosome segregation. We show that, in budding yeast, the sister kinetochores are separated in the very early spindle, while the sister arms remain associated. Biorientation of the separated kinetochores is achieved already after replication. Mtw1p, a homolog of fission yeast Mis12 required for biorientation, locates at the centromeres in an Ndc10p-dependent manner. Mtw1p and the sequences 1.8 and 3.8 kb from CEN3 and CEN15, respectively, behave like the precociously separated kinetochores, whereas the sequences 23 and 35 kb distant from CEN3 and CEN5 previously used as the centromere markers behave like a part of the arm. Mtw1p and Ndc10p are identically located except for additional spindle localization of Ndc10p. A model explaining small centromeres and early spindle formation in budding yeast is proposed.

  20. The muscle spindle as a feedback element in muscle control

    NASA Technical Reports Server (NTRS)

    Andrews, L. T.; Iannone, A. M.; Ewing, D. J.

    1973-01-01

    The muscle spindle, the feedback element in the myotatic (stretch) reflex, is a major contributor to muscular control. Therefore, an accurate description of behavior of the muscle spindle during active contraction of the muscle, as well as during passive stretch, is essential to the understanding of muscle control. Animal experiments were performed in order to obtain the data necessary to model the muscle spindle. Spectral density functions were used to identify a linear approximation of the two types of nerve endings from the spindle. A model reference adaptive control system was used on a hybrid computer to optimize the anatomically defined lumped parameter estimate of the spindle. The derived nonlinear model accurately predicts the behavior of the muscle spindle both during active discharge and during its silent period. This model is used to determine the mechanism employed to control muscle movement.

  1. The crack effect on instability in a machine tool spindle with gas bearings

    NASA Astrophysics Data System (ADS)

    Huang, Bo-Wun

    2005-09-01

    Gas-bearing spindles are required for increased spindle speed in precise machining. Due to manufacturing flaws or cyclic loading, cracks frequently appear in a rotating spindle systems. Cracks markedly affect the dynamic characteristics of rotating machinery. Hence, in this study, high-speed spindles with gas bearings and the crack effect on the instability dynamics are considered. Most investigations on dynamic characteristics of the spindle system were confined to ball-bearing-type spindles. This work examines the dynamic instability in a cracked rotating spindle system with gas bearings. A round Euler-Bernoulli beam is used to approximate the spindle. The Hamilton principle is applied to derive the equation of motion for the spindle system. The effects of crack depth, rotation speed and provided air pressure on the dynamic instability of a rotating spindle system are studied

  2. Zika Virus (ZIKV): a review of proposed mechanisms of transmission and associated congenital abnormalities

    PubMed Central

    Desai, Sruti K; Hartman, Steven D; Jayarajan, Shilpa; Liu, Stephanie; Gallicano, G Ian

    2017-01-01

    Zika virus (ZIKV) has been of major international public health concern following large outbreaks in the Americas occurring in 2015-2016. Most notably, ZIKV has been seen to pose dangers in pregnancy due to its association with congenital abnormalities such as microcephaly. Numerous experimental approaches have been taken to address how the virus can cross the placenta, alter normal fetal development, and disrupt specific cellular functions. Many areas concerning the mechanisms of transmission, especially from mother to fetus, are largely unknown but demand further research. Several promising new studies are presented that provide insight into possible mechanisms of transmission, different cell types affected, and immune responses towards the virus. By aiming to better understand the processes behind altered fetal neuronal development due to ZIKV infection, the hope is to find ways to increase protection of the fetus and prevent congenital abnormalities such as microcephaly. As ZIKV infection is spreading to increasingly more areas and bringing harmful outcomes and birth defects with it, it is imperative to identify the mechanisms of transmitting this infectious agent, consider different genetic backgrounds of hosts and strain types, and navigate methods to protect those affected from the detrimental effects of this newly emerging virus. PMID:28804687

  3. Syndrome of microcephaly, Dandy-Walker malformation, and Wilms tumor caused by mosaic variegated aneuploidy with premature centromere division (PCD): report of a new case and review of the literature.

    PubMed

    Kawame, H; Sugio, Y; Fuyama, Y; Hayashi, Y; Suzuki, H; Kurosawa, K; Maekawa, K

    1999-01-01

    We report a male infant with multiple congenital anomalies and mosaic variegated aneuploidy; a rare cytogenetic abnormality characterized by mosaicism for several different aneuploidies involving many different chromosomes. He had prenatal-onset growth retardation, microcephaly, dysmorphic face, seizures, hypotonia, feeding difficulty, and developmental delay. In addition, he developed bilateral Wilms tumors. Neuroradiological examination revealed Dandy-Walker malformation and hypoplasia of the cerebral hemisphere and pons. Cytogenetic analysis revealed various multiple numerical aneuploidies in blood lymphocytes, fibroblasts, and bone marrow cells, together with premature centromere division (PCD). Peripheral blood chromosome analysis from his parents also showed PCD, but no aneuploid cells. The clinical phenotype and multiple aneuploidies of the patient may be a consequence of the homozygous PCD trait inherited from his parents. Comparison with previously reported cases of multiple aneuploidy suggests that mosaic variegated aneuploidy with PCD may be a clinically recognizable syndrome with major phenotypes being mental retardation, microcephaly, structural brain anomalies (including Dandy-Walker malformation), and possible cancer predisposition.

  4. Physical determinants of bipolar mitotic spindle assembly and stability in fission yeast

    PubMed Central

    Blackwell, Robert; Edelmaier, Christopher; Sweezy-Schindler, Oliver; Lamson, Adam; Gergely, Zachary R.; O’Toole, Eileen; Crapo, Ammon; Hough, Loren E.; McIntosh, J. Richard; Glaser, Matthew A.; Betterton, Meredith D.

    2017-01-01

    Mitotic spindles use an elegant bipolar architecture to segregate duplicated chromosomes with high fidelity. Bipolar spindles form from a monopolar initial condition; this is the most fundamental construction problem that the spindle must solve. Microtubules, motors, and cross-linkers are important for bipolarity, but the mechanisms necessary and sufficient for spindle assembly remain unknown. We describe a physical model that exhibits de novo bipolar spindle formation. We began with physical properties of fission-yeast spindle pole body size and microtubule number, kinesin-5 motors, kinesin-14 motors, and passive cross-linkers. Our model results agree quantitatively with our experiments in fission yeast, thereby establishing a minimal system with which to interrogate collective self-assembly. By varying the features of our model, we identify a set of functions essential for the generation and stability of spindle bipolarity. When kinesin-5 motors are present, their bidirectionality is essential, but spindles can form in the presence of passive cross-linkers alone. We also identify characteristic failed states of spindle assembly—the persistent monopole, X spindle, separated asters, and short spindle, which are avoided by the creation and maintenance of antiparallel microtubule overlaps. Our model can guide the identification of new, multifaceted strategies to induce mitotic catastrophes; these would constitute novel strategies for cancer chemotherapy. PMID:28116355

  5. Spinal spindle cell haemangioma: an atypical location.

    PubMed

    Talan-Hranilović, J; Vucić, M; Sajko, T; Bedek, D; Tomić, K; Lupret, V

    2007-03-01

    We present a case of the 31-year-old male patient who complained of weakness in both legs and progressed slowly. Neuroimagine of the thoracic spine showed an intraspinal, extradural mass lesion, measuring 5.3 x 1.2 cm at the Th1-Th3 level. Histologically the lesion was a spindle cell haemangioma composed of dilated vascular spaces and a proliferation of bland appearing interspersed spindle cells. Immunohistochemical analysis was diffusely positive for VIM, SMA and focally for CD34. This lesion is uncommon and shows a predilection for distal extremities. Spindle cell haemangioma within the spine has not been previously reported in the literature.

  6. A Role for the Chaperone Complex BAG3-HSPB8 in Actin Dynamics, Spindle Orientation and Proper Chromosome Segregation during Mitosis

    PubMed Central

    Fuchs, Margit; Lambert, Herman; Jetté, Alexandra; Elowe, Sabine; Landry, Jacques; Lavoie, Josée N.

    2015-01-01

    The co-chaperone BAG3, in complex with the heat shock protein HSPB8, plays a role in protein quality control during mechanical strain. It is part of a multichaperone complex that senses damaged cytoskeletal proteins and orchestrates their seclusion and/or degradation by selective autophagy. Here we describe a novel role for the BAG3-HSPB8 complex in mitosis, a process involving profound changes in cell tension homeostasis. BAG3 is hyperphosphorylated at mitotic entry and localizes to centrosomal regions. BAG3 regulates, in an HSPB8-dependent manner, the timely congression of chromosomes to the metaphase plate by influencing the three-dimensional positioning of the mitotic spindle. Depletion of BAG3 caused defects in cell rounding at metaphase and dramatic blebbing of the cortex associated with abnormal spindle rotations. Similar defects were observed upon silencing of the autophagic receptor p62/SQSTM1 that contributes to BAG3-mediated selective autophagy pathway. Mitotic cells depleted of BAG3, HSPB8 or p62/SQSTM1 exhibited disorganized actin-rich retraction fibres, which are proposed to guide spindle orientation. Proper spindle positioning was rescued in BAG3-depleted cells upon addition of the lectin concanavalin A, which restores cortex rigidity. Together, our findings suggest the existence of a so-far unrecognized quality control mechanism involving BAG3, HSPB8 and p62/SQSTM1 for accurate remodelling of actin-based mitotic structures that guide spindle orientation. PMID:26496431

  7. A Role for the Chaperone Complex BAG3-HSPB8 in Actin Dynamics, Spindle Orientation and Proper Chromosome Segregation during Mitosis.

    PubMed

    Fuchs, Margit; Luthold, Carole; Guilbert, Solenn M; Varlet, Alice Anaïs; Lambert, Herman; Jetté, Alexandra; Elowe, Sabine; Landry, Jacques; Lavoie, Josée N

    2015-10-01

    The co-chaperone BAG3, in complex with the heat shock protein HSPB8, plays a role in protein quality control during mechanical strain. It is part of a multichaperone complex that senses damaged cytoskeletal proteins and orchestrates their seclusion and/or degradation by selective autophagy. Here we describe a novel role for the BAG3-HSPB8 complex in mitosis, a process involving profound changes in cell tension homeostasis. BAG3 is hyperphosphorylated at mitotic entry and localizes to centrosomal regions. BAG3 regulates, in an HSPB8-dependent manner, the timely congression of chromosomes to the metaphase plate by influencing the three-dimensional positioning of the mitotic spindle. Depletion of BAG3 caused defects in cell rounding at metaphase and dramatic blebbing of the cortex associated with abnormal spindle rotations. Similar defects were observed upon silencing of the autophagic receptor p62/SQSTM1 that contributes to BAG3-mediated selective autophagy pathway. Mitotic cells depleted of BAG3, HSPB8 or p62/SQSTM1 exhibited disorganized actin-rich retraction fibres, which are proposed to guide spindle orientation. Proper spindle positioning was rescued in BAG3-depleted cells upon addition of the lectin concanavalin A, which restores cortex rigidity. Together, our findings suggest the existence of a so-far unrecognized quality control mechanism involving BAG3, HSPB8 and p62/SQSTM1 for accurate remodelling of actin-based mitotic structures that guide spindle orientation.

  8. Infection-related microcephaly after the 2015 and 2016 Zika virus outbreaks in Brazil: a surveillance-based analysis.

    PubMed

    de Oliveira, Wanderson Kleber; de França, Giovanny Vinícius Araújo; Carmo, Eduardo Hage; Duncan, Bruce Bartholow; de Souza Kuchenbecker, Ricardo; Schmidt, Maria Inês

    2017-08-26

    On Nov 11, 2015, the Brazilian Ministry of Health declared a Public Health Emergency of National Concern in response to an increased number of microcephaly cases, possibly related to previous Zika virus outbreaks. We describe the course of the dual epidemics of the Zika virus infection during pregnancy and microcephaly in Brazil up to Nov 12, 2016, the first anniversary of this declaration. We used secondary data for Zika virus and microcephaly cases obtained through the Brazilian Ministry of Health's surveillance systems from Jan 1, 2015, to Nov 12, 2016. We deemed possible Zika virus infections during pregnancy as all suspected cases of Zika virus disease and all initially suspected, but later discarded, cases of dengue and chikungunya fever. We defined confirmed infection-related microcephaly in liveborn infants as the presence of a head circumference of at least 2 SDs below the mean for their age and sex, accompanied by diagnostic imaging consistent with an infectious cause, or laboratory, clinical, or epidemiological results positive for Zika virus or STORCH (infectious agents known to cause congenital infection, mainly syphilis, toxoplasmosis, cytomegalovirus, and herpes simplex virus). We excluded cases of congenital anomalies or death without microcephaly. We analyse the spatial clustering of these diseases in Brazil to obtain the kernel density estimation. Two distinct waves of possible Zika virus infection extended across all Brazilian regions in 2015 and 2016. 1 673 272 notified cases were reported, of which 41 473 (2·5%) were in pregnant women. During this period, 1950 cases of infection-related microcephaly were confirmed. Most cases (1373 [70·4%]) occurred in the northeast region after the first wave of Zika virus infection, with peak monthly occurrence estimated at 49·9 cases per 10 000 livebirths. After a major, well documented second wave of Zika virus infection in all regions of Brazil from September, 2015, to September, 2016

  9. Assessing EEG sleep spindle propagation. Part 1: theory and proposed methodology.

    PubMed

    O'Reilly, Christian; Nielsen, Tore

    2014-01-15

    A convergence of studies has revealed sleep spindles to be associated with sleep-related cognitive processing and even with fundamental waking state capacities such as intelligence. However, some spindle characteristics, such as propagation direction and delay, may play a decisive role but are only infrequently investigated because of technical complexities. A new methodology for assessing sleep spindle propagation over the human scalp using noninvasive electroencephalography (EEG) is described. This approach is based on the alignment of time-frequency representations of spindle activity across recording channels. This first of a two-part series concentrates on framing theoretical considerations related to EEG spindle propagation and on detailing the methodology. A short example application is provided that illustrates the repeatability of results obtained with the new propagation measure in a sample of 32 night recordings. A more comprehensive experimental investigation is presented in part two of the series. Compared to existing methods, this approach is particularly well adapted for studying the propagation of sleep spindles because it estimates time delays rather than phase synchrony and it computes propagation properties for every individual spindle with windows adjusted to the specific spindle duration. The proposed methodology is effective in tracking the propagation of spindles across the scalp and may thus help in elucidating the temporal aspects of sleep spindle dynamics, as well as other transient EEG and MEG events. A software implementation (the Spyndle Python package) is provided as open source software. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Abnormal experimentally- and behaviorally-induced LTP-like plasticity in focal hand dystonia.

    PubMed

    Belvisi, Daniele; Suppa, Antonio; Marsili, Luca; Di Stasio, Flavio; Parvez, Ahmad Khandker; Agostino, Rocco; Fabbrini, Giovanni; Berardelli, Alfredo

    2013-02-01

    Idiopathic focal hand dystonia (FHD) arises from abnormal plasticity in the primary motor cortex (M1) possibly reflecting abnormal sensori-motor integration processes. In this transcranial magnetic stimulation (TMS) study in FHD, we evaluated changes in motor evoked potentials (MEPs) after intermittent theta burst stimulation (iTBS) and paired associative stimulation (PAS), techniques that elicit different forms of experimentally-induced long-term potentiation (LTP)-like plasticity in M1. We also examined behaviorally-induced LTP-like plasticity as reflected by early motor learning of a simple motor task. We studied 14 patients with FHD and 14 healthy subjects. MEPs were recorded before and after iTBS and PAS at the 25 ms interstimulus interval (PAS(25)) in separate sessions. Subjects did a simple motor task entailing repetitive index finger abductions. To measure early motor learning we tested practice-related improvement in peak velocity and peak acceleration. In FHD patients iTBS failed to elicit the expected MEP changes and PAS(25) induced abnormally increased MEPs in target and non-target muscles. In the experiment testing early motor learning, patients lacked the expected practice-related changes in kinematic variables. In FHD, the degree of early motor learning correlated with patients' clinical features. We conclude that experimentally-induced (iTBS and PAS) and behaviorally-induced LTP-like plasticity are both altered in FHD. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Dual mechanism controls asymmetric spindle position in ascidian germ cell precursors.

    PubMed

    Prodon, François; Chenevert, Janet; Hébras, Céline; Dumollard, Rémi; Faure, Emmanuel; Gonzalez-Garcia, Jose; Nishida, Hiroki; Sardet, Christian; McDougall, Alex

    2010-06-01

    Mitotic spindle orientation with respect to cortical polarity cues generates molecularly distinct daughter cells during asymmetric cell division (ACD). However, during ACD it remains unknown how the orientation of the mitotic spindle is regulated by cortical polarity cues until furrowing begins. In ascidians, the cortical centrosome-attracting body (CAB) generates three successive unequal cleavages and the asymmetric segregation of 40 localized postplasmic/PEM RNAs in germ cell precursors from the 8-64 cell stage. By combining fast 4D confocal fluorescence imaging with gene-silencing and classical blastomere isolation experiments, we show that spindle repositioning mechanisms are active from prometaphase until anaphase, when furrowing is initiated in B5.2 cells. We show that the vegetal-most spindle pole/centrosome is attracted towards the CAB during prometaphase, causing the spindle to position asymmetrically near the cortex. Next, during anaphase, the opposite spindle pole/centrosome is attracted towards the border with neighbouring B5.1 blastomeres, causing the spindle to rotate (10 degrees /minute) and migrate (3 microm/minute). Dynamic 4D fluorescence imaging of filamentous actin and plasma membrane shows that precise orientation of the cleavage furrow is determined by this second phase of rotational spindle displacement. Furthermore, in pairs of isolated B5.2 blastomeres, the second phase of rotational spindle displacement was lost. Finally, knockdown of PEM1, a protein localized in the CAB and required for unequal cleavage in B5.2 cells, completely randomizes spindle orientation. Together these data show that two separate mechanisms active during mitosis are responsible for spindle positioning, leading to precise orientation of the cleavage furrow during ACD in the cells that give rise to the germ lineage in ascidians.

  12. Microcephaly in north-east Brazil: a retrospective study on neonates born between 2012 and 2015.

    PubMed

    Soares de Araújo, Juliana Sousa; Regis, Cláudio Teixeira; Gomes, Renata Grigório Silva; Tavares, Thiago Ribeiro; Rocha Dos Santos, Cícera; Assunção, Patrícia Melo; Nóbrega, Renata Valéria; Pinto, Diana de Fátima Alves; Bezerra, Bruno Vinícius Dantas; Mattos, Sandra da Silva

    2016-11-01

    To assess the number of children born with microcephaly in the State of Paraíba, north-east Brazil. We contacted 21 maternity centres belonging to a paediatric cardiology network, with access to information regarding more than 100 000 neonates born between 1 January 2012 and 31 December 2015. For 10% of these neonates, nurses were requested to retrieve head circumference measurements data from delivery-room books. We used three separate criteria to classify whether a neonate had microcephaly: (i) the Brazilian Ministry of Health proposed criterion: term neonates (gestational age ≥ 37 weeks) with a head circumference of less than 32 cm; (ii) Fenton curves: neonates with a head circumference of less than -3 standard deviation for age and gender; or (iii) the proportionality criterion: neonates with a head circumference of less than ((height/2))+10) ± 2. Between 1 and 31 December 2015, nurses obtained data for 16 208 neonates. Depending on which criterion we used, the number of neonates with microcephaly varied from 678 to 1272 (4.2-8.2%). Two per cent (316) of the neonates fulfilled all three criteria. We observed temporal fluctuations of microcephaly prevalence from late 2012. The numbers of microcephaly reported here are much higher than the 6.4 per 10 000 live births reported by the Brazilian live birth information system. The results raise questions about the notification system, the appropriateness of the diagnostic criteria and future implications for the affected children and their families. More studies are needed to understand the epidemiology and the implications for the Brazilian health system.

  13. HDAC8 functions in spindle assembly during mouse oocyte meiosis

    PubMed Central

    Shu, Jing; Chen, Xueqin; Shi, Yingjiao; Wang, Ensheng; Wang, Li; Hu, Qinbo; Dai, Yibo; Xiong, Bo

    2017-01-01

    HDAC8 is a class I histone deacetylase that functions in a variety of biological processes through its non-histone substrates. However, its roles during oocyte meiosis remain elusive. Here, we document that HDAC8 localizes at spindle poles and positively participates in the regulation of microtubule organization and spindle assembly in mouse oocytes. Depletion of HDAC8 by siRNA-based gene silencing results in various spindle defects and chromosome misalignment during oocyte meiotic maturation, accompanied by impaired kinetochore-microtubule attachments. Consequently, a higher incidence of aneuploidy is generated in HDAC8-depleted MII eggs. In addition, inhibition of HDAC8 activity with its selective inhibitor PCI-34051 phenocopies the spindle/chromosome defects resulting from HDAC8 depletion by siRNA injection. Finally, we find that HDAC8 is required for the correct localization of ϕ-tubulin to spindle poles. Collectively, these data reveal that HDAC8 plays a significant role in regulating spindle assembly and thus ensuring the euploidy in mouse eggs. PMID:28223544

  14. Microcephaly Prevalence in Infants Born to Zika Virus-Infected Women: A Systematic Review and Meta-Analysis

    PubMed Central

    2017-01-01

    Zika virus is an emergent flavivirus transmitted by Aedes genus mosquitoes that recently reached the Americas and was soon implicated in an increase of microcephaly incidence. The objective of the present study is to systematically review the published data and perform a meta-analysis to estimate the prevalence of microcephaly in babies born to Zika virus-infected women during pregnancy. We searched PubMed and Cochrane databases, included cohort studies, and excluded case reports and case series publications. We extracted sample sizes and the number of microcephaly cases from eight studies, which permitted a calculation of prevalence rates that are pooled in a random-effects model meta-analysis. We estimated the prevalence of microcephaly of 2.3% (95% CI = 1.0–5.3%) among all pregnancies. Limitations include mixed samples of women infected at different pregnancy times, since it is known that infection at the first trimester is associated with higher risk to congenital anomalies. The estimates are deceptively low, given the devastating impact the infection causes over children and their families. We hope our study contributes to public health knowledge to fight Zika virus epidemics to protect mothers and their newborns. PMID:28783051

  15. Natural Loss of Mps1 Kinase in Nematodes Uncovers a Role for Polo-like Kinase 1 in Spindle Checkpoint Initiation.

    PubMed

    Espeut, Julien; Lara-Gonzalez, Pablo; Sassine, Mélanie; Shiau, Andrew K; Desai, Arshad; Abrieu, Ariane

    2015-07-07

    The spindle checkpoint safeguards against chromosome loss during cell division by preventing anaphase onset until all chromosomes are attached to spindle microtubules. Checkpoint signal is generated at kinetochores, the primary attachment site on chromosomes for spindle microtubules. Mps1 kinase initiates checkpoint signaling by phosphorylating the kinetochore-localized scaffold protein Knl1 to create phospho-docking sites for Bub1/Bub3. Mps1 is widely conserved but is surprisingly absent in many nematode species. Here, we show that PLK-1, which targets a substrate motif similar to that of Mps1, functionally substitutes for Mps1 in C. elegans by phosphorylating KNL-1 to direct BUB-1/BUB-3 kinetochore recruitment. This finding led us to re-examine checkpoint initiation in human cells, where we found that Plk1 co-inhibition significantly reduced Knl1 phosphorylation and Bub1 kinetochore recruitment relative to Mps1 inhibition alone. Thus, the finding that PLK-1 functionally substitutes for Mps1 in checkpoint initiation in C. elegans uncovered a role for Plk1 in species that have Mps1. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Physical determinants of bipolar mitotic spindle assembly and stability in fission yeast

    NASA Astrophysics Data System (ADS)

    Betterton, Meredith; Blackwell, Robert; Edelmaier, Christopher; Sweezy-Schindler, Oliver; Lamson, Adam; Gergely, Zachary; O'Toole, Eileen; Crapo, Ammon; Hough, Loren; McIntosh, J. Richard; Glaser, Matthew

    Mitotic spindles use an elegant bipolar architecture to segregate duplicated chromosomes with high fidelity. Bipolar spindles form from a monopolar initial condition; this is the most fundamental construction problem that the spindle must solve. Microtubules, motors, and crosslinkers are important for bipolarity, but the mechanisms necessary and sufficient for spindle assembly remain unknown. Here we describe a physical model that exhibits de novo bipolar spindle formation. We began with previously published data on fission-yeast spindle-pole-body size and microtubule number, kinesin-5 motors, kinesin-14 motors, and passive crosslinkers. Our model results agree quantitatively with our experiments in fission yeast, thereby establishing a minimal system with which to interrogate collective self assembly. By varying features of our model, we identify a set of functions essential for the generation and stability of spindle bipolarity. When kinesin-5 motors are present, their bidirectionality is essential, but spindles can form in the presence of passive crosslinkers alone. We also identify characteristic failed states of spindle assembly, which are avoided by creation and maintenance of antiparallel microtubule overlaps. DMR-0847685, DMR-1551095, DMR-1420736, K25GM110486, R01GM104976, R01GM033787.

  17. Topographical distribution of fast and slow sleep spindles in medicated depressive patients.

    PubMed

    Nishida, Masaki; Nakashima, Yusaku; Nishikawa, Toru

    2014-10-01

    To compare the properties of sleep spindles between healthy subjects and medicated patients with major depressive episode, including frequency range, spectra power, and spatial distribution of spindle power. Continuous 16-channel EEG was used to record nocturnal sleep in healthy control subjects and medicated depressive patients. Recordings were analyzed for changes in EEG power spectra and power topography. Additionally, we graphically demonstrated the pattern of spatial distribution of each type of sleep spindle, divided into fast (12.5-14 Hz) and slow spindles (11-12.5 Hz). Sleep EEG records of depressive subjects exhibited a significantly higher amplitude of slow spindles in the prefrontal region, compared with the healthy controls (P < 0.01). Fast spindles were dominant in the centroparietal region in both depressive patients and the control group. Enhanced slow spindles in the prefrontal region were observed in the medicated depressive patients and not in the healthy controls. The frequency of fast spindles in depressive patients was globally higher than that in healthy participants. The alteration in sleep spindles seen in medicated depressive subjects may reflect a pharmacological modulation of synaptic function involving the thalamic-reticular and thalamocortical mechanisms.

  18. Abnormal movements in first-episode, nonaffective psychosis: dyskinesias, stereotypies, and catatonic-like signs

    PubMed Central

    Compton, Michael T.; Fantes, Francisco; Wan, Claire Ramsay; Johnson, Stephanie; Walker, Elaine F.

    2015-01-01

    Motor abnormalities represent a neurobehavioral domain of signs intrinsic to schizophrenia-spectrum disorders, though they are commonly attributed to medication side effects and remain understudied. Individuals with first-episode psychosis represent an ideal group to study innate movement disorders due to minimal prior antipsychotic exposure. We measured dyskinesias, stereotypies, and catatonic-like signs and examined their associations with: (1) age at onset psychotic symptoms and duration of untreated psychosis; (2) positive, negative, and disorganized symptoms; (3) neurocognition; and (4) neurological soft signs. Among 47 predominantly African American first-episode psychosis patients in a public-sector hospital, the presence and severity of dyskinesias, stereotypies, and catatonic-like features were assessed using approximately 30-minute video recordings. Movement abnormalities were rated utilizing three scales (Dyskinesia Identification System Condensed User Scale, Stereotypy Checklist, and Catatonia Rating Scale). Correlational analyses were conducted. Scores for each of three movement abnormality types were modestly inter-correlated (r=.29-.40). Stereotypy score was significantly associated with age at onset of psychotic symptoms (r=.32) and positive symptom severity scores (r=.29–.41). There were no meaningful or consistent associations with negative symptom severity, neurocognition, or neurological soft signs. Abnormal movements appear to represent a relatively distinct phenotypic domain deserving of further research. PMID:25619434

  19. Sleep Spindles and Intellectual Ability: Epiphenomenon or Directly Related?

    PubMed

    Fang, Zhuo; Sergeeva, Valya; Ray, Laura B; Viczko, Jeremy; Owen, Adrian M; Fogel, Stuart M

    2017-01-01

    Sleep spindles-short, phasic, oscillatory bursts of activity that characterize non-rapid eye movement sleep-are one of the only electrophysiological oscillations identified as a biological marker of human intelligence (e.g., cognitive abilities commonly assessed using intelligence quotient tests). However, spindles are also important for sleep maintenance and are modulated by circadian factors. Thus, the possibility remains that the relationship between spindles and intelligence quotient may be an epiphenomenon of a putative relationship between good quality sleep and cognitive ability or perhaps modulated by circadian factors such as morningness-eveningness tendencies. We sought to ascertain whether spindles are directly or indirectly related to cognitive abilities using mediation analysis. Here, we show that fast (13.5-16 Hz) parietal but not slow (11-13.5 Hz) frontal spindles in both non-rapid eye movement stage 2 sleep and slow wave sleep are directly related to reasoning abilities (i.e., cognitive abilities that support "fluid intelligence," such as the capacity to identify complex patterns and relationships and the use of logic to solve novel problems) but not verbal abilities (i.e., cognitive abilities that support "crystalized intelligence"; accumulated knowledge and experience) or cognitive abilities that support STM (i.e., the capacity to briefly maintain information in an available state). The relationship between fast spindles and reasoning abilities is independent of the indicators of sleep maintenance and circadian chronotype, thus suggesting that spindles are indeed a biological marker of cognitive abilities and can serve as a window to further explore the physiological and biological substrates that give rise to human intelligence.

  20. Microcephaly in north-east Brazil: a retrospective study on neonates born between 2012 and 2015

    PubMed Central

    Soares de Araújo, Juliana Sousa; Regis, Cláudio Teixeira; Gomes, Renata Grigório Silva; Tavares, Thiago Ribeiro; Rocha dos Santos, Cícera; Assunção, Patrícia Melo; Nóbrega, Renata Valéria; Pinto, Diana de Fátima Alves; Bezerra, Bruno Vinícius Dantas

    2016-01-01

    Abstract Objective To assess the number of children born with microcephaly in the State of Paraíba, north-east Brazil. Methods We contacted 21 maternity centres belonging to a paediatric cardiology network, with access to information regarding more than 100 000 neonates born between 1 January 2012 and 31 December 2015. For 10% of these neonates, nurses were requested to retrieve head circumference measurements data from delivery-room books. We used three separate criteria to classify whether a neonate had microcephaly: (i) the Brazilian Ministry of Health proposed criterion: term neonates (gestational age ≥ 37 weeks) with a head circumference of less than 32 cm; (ii) Fenton curves: neonates with a head circumference of less than −3 standard deviation for age and gender; or (iii) the proportionality criterion: neonates with a head circumference of less than ((height/2))+10) ± 2. Findings Between 1 and 31 December 2015, nurses obtained data for 16 208 neonates. Depending on which criterion we used, the number of neonates with microcephaly varied from 678 to 1272 (4.2–8.2%). Two per cent (316) of the neonates fulfilled all three criteria. We observed temporal fluctuations of microcephaly prevalence from late 2012. Conclusion The numbers of microcephaly reported here are much higher than the 6.4 per 10 000 live births reported by the Brazilian live birth information system. The results raise questions about the notification system, the appropriateness of the diagnostic criteria and future implications for the affected children and their families. More studies are needed to understand the epidemiology and the implications for the Brazilian health system. PMID:27821886

  1. Decreased Axon Caliber Underlies Loss of Fiber Tract Integrity, Disproportional Reductions in White Matter Volume, and Microcephaly in Angelman Syndrome Model Mice

    PubMed Central

    Judson, Matthew C.; Burette, Alain C.; Shen, Mark D.; Rumple, Ashley M.; Del Cid, Wilmer A.; Paniagua, Beatriz

    2017-01-01

    Angelman syndrome (AS) is a debilitating neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A allele. It is currently unclear how the consequences of this genetic insult unfold to impair neurodevelopment. We reasoned that by elucidating the basis of microcephaly in AS, a highly penetrant syndromic feature with early postnatal onset, we would gain new insights into the mechanisms by which maternal UBE3A loss derails neurotypical brain growth and function. Detailed anatomical analysis of both male and female maternal Ube3a-null mice reveals that microcephaly in the AS mouse model is primarily driven by deficits in the growth of white matter tracts, which by adulthood are characterized by densely packed axons of disproportionately small caliber. Our results implicate impaired axon growth in the pathogenesis of AS and identify noninvasive structural neuroimaging as a potentially valuable tool for gauging therapeutic efficacy in the disorder. SIGNIFICANCE STATEMENT People who maternally inherit a deletion or nonfunctional copy of the UBE3A gene develop Angelman syndrome (AS), a severe neurodevelopmental disorder. To better understand how loss of maternal UBE3A function derails brain development, we analyzed brain structure in a maternal Ube3a knock-out mouse model of AS. We report that the volume of white matter (WM) is disproportionately reduced in AS mice, indicating that deficits in WM development are a major factor underlying impaired brain growth and microcephaly in the disorder. Notably, we find that axons within the WM pathways of AS model mice are abnormally small in caliber. This defect is associated with slowed nerve conduction, which could contribute to behavioral deficits in AS, including motor dysfunction. PMID:28663201

  2. Trivalent dimethylarsenic compound induces histone H3 phosphorylation and abnormal localization of Aurora B kinase in HepG2 cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Suzuki, Toshihide, E-mail: toshi-su@pharm.teikyo-u.ac.j; Miyazaki, Koichi; Kita, Kayoko

    2009-12-15

    Trivalent dimethylarsinous acid [DMA(III)] has been shown to induce mitotic abnormalities, such as centrosome abnormality, multipolar spindles, multipolar division, and aneuploidy, in several cell lines. In order to elucidate the mechanisms underlying these mitotic abnormalities, we investigated DMA(III)-mediated changes in histone H3 phosphorylation and localization of Aurora B kinase, which is a key molecule in cell mitosis. DMA(III) caused the phosphorylation of histone H3 (ser10) and was distributed predominantly in mitotic cells, especially in prometaphase cells. By contrast, most of the phospho-histone H3 was found to be localized in interphase cells after treatment with inorganic arsenite [iAs(III)], suggesting the involvementmore » of a different pathway in phosphorylation. DMA(III) activated Aurora B kinase and slightly activated ERK MAP kinase. Phosphorylation of histone H3 by DMA(III) was effectively reduced by ZM447439 (Aurora kinase inhibitor) and slightly reduced by U0126 (MEK inhibitor). By contrast, iAs(III)-dependent histone H3 phosphorylation was markedly reduced by U0126. Aurora B kinase is generally localized in the midbody during telophase and plays an important role in cytokinesis. However, in some cells treated with DMA(III), Aurora B was not localized in the midbody of telophase cells. These findings suggested that DMA(III) induced a spindle abnormality, thereby activating the spindle assembly checkpoint (SAC) through the Aurora B kinase pathway. In addition, cytokinesis was not completed because of the abnormal localization of Aurora B kinase by DMA(III), thereby resulting in the generation of multinucleated cells. These results provide insight into the mechanism of arsenic tumorigenesis.« less

  3. Sulfolobus Spindle-Shaped Virus 1 Contains Glycosylated Capsid Proteins, a Cellular Chromatin Protein, and Host-Derived Lipids

    PubMed Central

    Quemin, Emmanuelle R. J.; Pietilä, Maija K.; Oksanen, Hanna M.; Forterre, Patrick; Rijpstra, W. Irene C.; Schouten, Stefan; Bamford, Dennis H.; Prangishvili, David

    2015-01-01

    ABSTRACT Geothermal and hypersaline environments are rich in virus-like particles, among which spindle-shaped morphotypes dominate. Currently, viruses with spindle- or lemon-shaped virions are exclusive to Archaea and belong to two distinct viral families. The larger of the two families, the Fuselloviridae, comprises tail-less, spindle-shaped viruses, which infect hosts from phylogenetically distant archaeal lineages. Sulfolobus spindle-shaped virus 1 (SSV1) is the best known member of the family and was one of the first hyperthermophilic archaeal viruses to be isolated. SSV1 is an attractive model for understanding virus-host interactions in Archaea; however, the constituents and architecture of SSV1 particles remain only partially characterized. Here, we have conducted an extensive biochemical characterization of highly purified SSV1 virions and identified four virus-encoded structural proteins, VP1 to VP4, as well as one DNA-binding protein of cellular origin. The virion proteins VP1, VP3, and VP4 undergo posttranslational modification by glycosylation, seemingly at multiple sites. VP1 is also proteolytically processed. In addition to the viral DNA-binding protein VP2, we show that viral particles contain the Sulfolobus solfataricus chromatin protein Sso7d. Finally, we provide evidence indicating that SSV1 virions contain glycerol dibiphytanyl glycerol tetraether (GDGT) lipids, resolving a long-standing debate on the presence of lipids within SSV1 virions. A comparison of the contents of lipids isolated from the virus and its host cell suggests that GDGTs are acquired by the virus in a selective manner from the host cytoplasmic membrane, likely during progeny egress. IMPORTANCE Although spindle-shaped viruses represent one of the most prominent viral groups in Archaea, structural data on their virion constituents and architecture still are scarce. The comprehensive biochemical characterization of the hyperthermophilic virus SSV1 presented here brings novel and

  4. Nonimmune hydrops fetalis, hydramnios, microcephaly, and intracranial meningeal hemangioendothelioma.

    PubMed

    Drut, R; Sapia, S; Gril, D; Velasco, J C; Drut, R M

    1993-01-01

    Necropsy findings in a male stillborn at 31 weeks gestational age included nonimmune hydrops, hydramnios, and microcephaly secondary to a hemangioendotheliomatous malformation at the tentorium. The vascular lesion was composed by large and small tortuous endothelium-lined vessels and leiomuscular septa. The lesion is thought to be related to the more frequent arteriovenous malformation of the vein of Galen.

  5. Illusion caused by vibration of muscle spindles reveals an involvement of muscle spindle inputs in regulating isometric contraction of masseter muscles.

    PubMed

    Tsukiboshi, Taisuke; Sato, Hajime; Tanaka, Yuto; Saito, Mitsuru; Toyoda, Hiroki; Morimoto, Toshifumi; Türker, Kemal Sitki; Maeda, Yoshinobu; Kang, Youngnam

    2012-11-01

    Spindle Ia afferents may be differentially involved in voluntary isometric contraction, depending on the pattern of synaptic connections in spindle reflex pathways. We investigated how isometric contraction of masseter muscles is regulated through the activity of their muscle spindles that contain the largest number of intrafusal fibers among skeletal muscle spindles by examining the effects of vibration of muscle spindles on the voluntary isometric contraction. Subjects were instructed to hold the jaw at resting position by counteracting ramp loads applied on lower molar teeth. In response to the increasing-ramp load, the root mean square (RMS) of masseter EMG activity almost linearly increased under no vibration, while displaying a steep linear increase followed by a slower increase under vibration. The regression line of the relationship between the load and RMS was significantly steeper under vibration than under no vibration, suggesting that the subjects overestimated the ramp load and excessively counteracted it as reflected in the emergence of bite pressure. In response to the decreasing-ramp load applied following the increasing one, the RMS hardly decreased under vibration unlike under no vibration, leading to a generation of bite pressure even after the offset of the negative-ramp load until the vibration was ceased. Thus the subjects overestimated the increasing rate of the load while underestimating the decreasing rate of the load, due to the vibration-induced illusion of jaw opening. These observations suggest that spindle Ia/II inputs play crucial roles both in estimating the load and in controlling the isometric contraction of masseter muscles in the jaw-closed position.

  6. Equilibrium stellar systems with spindle singularities

    NASA Technical Reports Server (NTRS)

    Shapiro, Stuart L.; Teukolsky, Saul A.

    1992-01-01

    Equilibrium sequences of axisymmetric Newtonian clusters that tend toward singular states are constructed. The distribution functions are chosen to be of the form f = f(E, Jz). The numerical method then determines the density and gravitational potential self-consistently to satisfy Poisson's equation. For the prolate models, spindle singularities arise from the depletion of angular momentum near the symmetry axis. While the resulting density enhancement is confined to the region near the axis, the influence of the spindle extends much further out through its tidal gravitational field. Centrally condensed prolate clusters may contain strong-field regions even though the spindle mass is small and the mean cluster eccentricity is not extreme. While the calculations performed here are entirely Newtonian, the issue of singularities is an important topic in general relativity. Equilibrium solutions for relativistic star clusters can provide a testing ground for exploring this issue. The methods used in this paper for building nonspherical clusters can be extended to relativistic systems.

  7. Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.

    PubMed

    Innocenti, Paolo; Woodward, Hannah L; Solanki, Savade; Naud, Sébastien; Westwood, Isaac M; Cronin, Nora; Hayes, Angela; Roberts, Jennie; Henley, Alan T; Baker, Ross; Faisal, Amir; Mak, Grace Wing-Yan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; O'Fee, Lisa; Saville, Harry; Schmitt, Jessica; Matijssen, Berry; Burke, Rosemary; van Montfort, Rob L M; Raynaud, Florence I; Eccles, Suzanne A; Linardopoulos, Spiros; Blagg, Julian; Hoelder, Swen

    2016-04-28

    Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.

  8. Craniometaphyseal dysplasia with obvious biochemical abnormality and rickets-like features.

    PubMed

    Wu, Bo; Jiang, Yan; Wang, Ou; Li, Mei; Xing, Xiao-Ping; Xia, Wei-Bo

    2016-05-01

    Craniometaphyseal dysplasia (CMD) is a rare genetic disorder that is characterized by progressive sclerosis of the craniofacial bones and metaphyseal widening of long bones, and biochemical indexes were mostly normal. To further the understanding of the disease from a biochemical perspective, we reported a CMD case with obviously abnormal biochemical indexes. A 1-year-old boy was referred to our clinic. Biochemical test showed obviously increased alkaline phosphatase (ALP) and parathyroid hormone (PTH), mild hypocalcemia and hypophosphatemia. Moreover, significant elevated receptor activator of nuclear factor kappa-B ligand (RANKL) level, but normal β-C-terminal telopeptide of type I collagen (β-CTX) concentration were revealed. He was initially suspected of rickets, because the radiological examination also showed broadened epiphysis in his long bones. Supplementation with calcium and calcitriol alleviated biochemical abnormality. However, the patient gradually developed osteosclerosis which was inconformity with rickets. Considering that he was also presented with facial paralysis and nasal obstruction symptom, the diagnosis of craniometaphyseal dysplasia was suspected, and then was confirmed by the mutation analysis of ANKH of the proband and his family, which showed a de novo heterozygous mutation (C1124-1126delCCT) on exon 9. Our study revealed that obvious biochemical abnormality and rickets-like features might present as uncommon characteristics in CMD patients, and the calcium and calcitriol supplementation could alleviate biochemical abnormalities. Furthermore, although early osteoclast differentiation factor was excited in CMD patient, activity of osteoclast was still inert. Copyright © 2016. Published by Elsevier B.V.

  9. Clinical-epidemiological description of live births with microcephaly in the state of Sergipe, Brazil, 2015.

    PubMed

    Cabral, Cibelle Mendes; Nóbrega, Martha Elizabeth Brasil da; Leite, Priscila Leal E; Souza, Mércia Simone Feitosa de; Teixeira, Daniela Cabral Pizzi; Cavalcante, Taíse Ferreira; Lima, Raulinna Gomes de Souza; Tavares, Lúcia Maria Sayde de Azevedo; Souza, Priscila Bochi de; Saad, Eduardo

    2017-01-01

    to describe the clinical and epidemiological characteristics of microcephaly cases in live births in Sergipe, Brazil, and to calculate the prevalence in its municipalities. this is a descriptive study on live births from September 1st to November 30th, 2015, with data from medical records and interviews with mothers. 83 cases of microcephaly were confirmed, with three deaths; prevalence in the 26 municipalities with confirmed cases ranged from 18 to 185/10,000 live births; the median of head circumference was 31 cm (range: 22.5-33.0); agenesis of corpus callosum (26/43), lissencephaly (12/43), absence of midline (10/43) and ventriculomegaly (8/43) were observed in the transfontanellar ultrasound; 40 mothers reported rash in pregnancy, 23 in the first trimester, with pruritus, arthralgia and headache; seven were positive for infections potentially causing malformations. there was a high occurrence of cases of microcephaly, and reports of signs and symptoms compatible with Zika virus infection during pregnancy.

  10. Involvement of Spindles in Memory Consolidation Is Slow Wave Sleep-Specific

    ERIC Educational Resources Information Center

    Cox, Roy; Hofman, Winni F.; Talamini, Lucia M.

    2012-01-01

    Both sleep spindles and slow oscillations have been implicated in sleep-dependent memory consolidation. Whereas spindles occur during both light and deep sleep, slow oscillations are restricted to deep sleep, raising the possibility of greater consolidation-related spindle involvement during deep sleep. We assessed declarative memory retention…

  11. Mutation of the 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) Substrate-Docking Site in the Developing Brain Causes Microcephaly with Abnormal Brain Morphogenesis Independently of Akt, Leading to Impaired Cognition and Disruptive Behaviors

    PubMed Central

    Cordón-Barris, Lluís; Pascual-Guiral, Sònia; Yang, Shaobin; Giménez-Llort, Lydia; Lope-Piedrafita, Silvia; Niemeyer, Carlota; Claro, Enrique; Lizcano, Jose M.

    2016-01-01

    The phosphoinositide (PI) 3-kinase/Akt signaling pathway plays essential roles during neuronal development. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) coordinates the PI 3-kinase signals by activating 23 kinases of the AGC family, including Akt. Phosphorylation of a conserved docking site in the substrate is a requisite for PDK1 to recognize, phosphorylate, and activate most of these kinases, with the exception of Akt. We exploited this differential mechanism of regulation by generating neuron-specific conditional knock-in mice expressing a mutant form of PDK1, L155E, in which the substrate-docking site binding motif, termed the PIF pocket, was disrupted. As a consequence, activation of all the PDK1 substrates tested except Akt was abolished. The mice exhibited microcephaly, altered cortical layering, and reduced circuitry, leading to cognitive deficits and exacerbated disruptive behavior combined with diminished motivation. The abnormal patterning of the adult brain arises from the reduced ability of the embryonic neurons to polarize and extend their axons, highlighting the essential roles that the PDK1 signaling beyond Akt plays in mediating the neuronal responses that regulate brain development. PMID:27644329

  12. Abnormal movements in first-episode, nonaffective psychosis: dyskinesias, stereotypies, and catatonic-like signs.

    PubMed

    Compton, Michael T; Fantes, Francisco; Wan, Claire Ramsay; Johnson, Stephanie; Walker, Elaine F

    2015-03-30

    Motor abnormalities represent a neurobehavioral domain of signs intrinsic to schizophrenia-spectrum disorders, though they are commonly attributed to medication side effects and remain understudied. Individuals with first-episode psychosis represent an ideal group to study innate movement disorders due to minimal prior antipsychotic exposure. We measured dyskinesias, stereotypies, and catatonic-like signs and examined their associations with: (1) age at onset of psychotic symptoms and duration of untreated psychosis; (2) positive, negative, and disorganized symptoms; (3) neurocognition; and (4) neurological soft signs. Among 47 predominantly African American first-episode psychosis patients in a public-sector hospital, the presence and severity of dyskinesias, stereotypies, and catatonic-like features were assessed using approximately 30-min video recordings. Movement abnormalities were rated utilizing three scales (Dyskinesia Identification System Condensed User Scale, Stereotypy Checklist, and Catatonia Rating Scale). Correlational analyses were conducted. Scores for each of three movement abnormality types were modestly inter-correlated (r=0.29-0.40). Stereotypy score was significantly associated with age at onset of psychotic symptoms (r=0.32) and positive symptom severity scores (r=0.29-0.41). There were no meaningful or consistent associations with negative symptom severity, neurocognition, or neurological soft signs. Abnormal movements appear to represent a relatively distinct phenotypic domain deserving of further research. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Microcephaly-capillary malformation syndrome: Brothers with a homozygous STAMBP mutation, uncovered by exome sequencing.

    PubMed

    Naseer, Muhammad Imran; Sogaty, Sameera; Rasool, Mahmood; Chaudhary, Adeel G; Abutalib, Yousif Ahmed; Walker, Susan; Marshall, Christian R; Merico, Daniele; Carter, Melissa T; Scherer, Stephen W; Al-Qahtani, Mohammad H; Zarrei, Mehdi

    2016-11-01

    We describe two brothers from a consanguineous family of Egyptian ancestry, presenting with microcephaly, apparent global developmental delay, seizures, spasticity, congenital blindness, and multiple cutaneous capillary malformations. Through exome sequencing, we uncovered a homozygous missense variant in STAMBP (p.K303R) in the two siblings, inherited from heterozygous carrier parents. Mutations in STAMBP are known to cause microcephaly-capillary malformation syndrome (MIC-CAP) and the phenotype in this family is consistent with this diagnosis. We compared the findings in the present brothers with those of earlier reported patients. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  14. Microtubule Dynamics Scale with Cell Size to Set Spindle Length and Assembly Timing.

    PubMed

    Lacroix, Benjamin; Letort, Gaëlle; Pitayu, Laras; Sallé, Jérémy; Stefanutti, Marine; Maton, Gilliane; Ladouceur, Anne-Marie; Canman, Julie C; Maddox, Paul S; Maddox, Amy S; Minc, Nicolas; Nédélec, François; Dumont, Julien

    2018-05-21

    Successive cell divisions during embryonic cleavage create increasingly smaller cells, so intracellular structures must adapt accordingly. Mitotic spindle size correlates with cell size, but the mechanisms for this scaling remain unclear. Using live cell imaging, we analyzed spindle scaling during embryo cleavage in the nematode Caenorhabditis elegans and sea urchin Paracentrotus lividus. We reveal a common scaling mechanism, where the growth rate of spindle microtubules scales with cell volume, which explains spindle shortening. Spindle assembly timing is, however, constant throughout successive divisions. Analyses in silico suggest that controlling the microtubule growth rate is sufficient to scale spindle length and maintain a constant assembly timing. We tested our in silico predictions to demonstrate that modulating cell volume or microtubule growth rate in vivo induces a proportional spindle size change. Our results suggest that scalability of the microtubule growth rate when cell size varies adapts spindle length to cell volume. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Prevalence and clinical profile of microcephaly in South America pre-Zika, 2005-14: prevalence and case-control study

    PubMed Central

    Dolk, Helen; Lopez-Camelo, Jorge S; Mattos, Daniel; Poletta, Fernando A; Dutra, Maria G; Carvalho, Flavia M; Castilla, Eduardo E

    2017-01-01

    Objective To describe the prevalence and clinical spectrum of microcephaly in South America for the period 2005-14, before the start of the Zika epidemic in 2015, as a baseline for future surveillance as the Zika epidemic spreads and as other infectious causes may emerge in future. Design Prevalence and case-control study. Data sources ECLAMC (Latin American Collaborative Study of Congenital Malformations) database derived from 107 hospitals in 10 South American countries, 2005 to 2014. Data on microcephaly cases, four non-malformed controls per case, and all hospital births (all births for hospital based prevalence, resident within municipality for population based prevalence). For 2010-14, head circumference data were available and compared with Intergrowth charts. Results 552 microcephaly cases were registered, giving a hospital based prevalence of 4.4 (95% confidence interval 4.1 to 4.9) per 10 000 births and a population based prevalence of 3.0 (2.7 to 3.4) per 10 000. Prevalence varied significantly between countries and between regions and hospitals within countries. Thirty two per cent (n=175) of cases were prenatally diagnosed; 29% (n=159) were perinatal deaths. Twenty three per cent (n=128) were associated with a diagnosed genetic syndrome, 34% (n=189) polymalformed without a syndrome diagnosis, 12% (n=65) with associated neural malformations, and 26% (n=145) microcephaly only. In addition, 3.8% (n=21) had a STORCH (syphilis, toxoplasmosis, other including HIV, rubella, cytomegalovirus, and herpes simplex) infection diagnosis and 2.0% (n=11) had consanguineous parents. Head circumference measurements available for 184/235 cases in 2010-14 showed 45% (n=82) more than 3 SD below the mean, 24% (n=44) between 3 SD and 2 SD below the mean, and 32% (n=58) larger than −2 SD. Conclusion Extrapolated to the nearly 7 million annual births in South America, an estimated 2000-2500 microcephaly cases were diagnosed among births each year before the Zika

  16. Amphiastral Mitotic Spindle Assembly in Vertebrate Cells Lacking Centrosomes

    PubMed Central

    Hornick, Jessica E.; Mader, Christopher C.; Tribble, Emily K.; Bagne, Cydney C.; Vaughan, Kevin T.; Shaw, Sidney L.; Hinchcliffe, Edward H.

    2011-01-01

    Summary The role of centrosomes/centrioles during mitotic spindle assembly in vertebrates remains controversial. In cell-free extracts and experimentally derived acentrosomal cells, randomly oriented microtubules (MTs) self-organize around mitotic chromosomes and assemble anastral spindles [1, 2, 3]. However, vertebrate somatic cells normally assemble a connected pair of polarized, astral MT arrays – termed an amphiaster (“a star on both sides” [4]) – that is formed by the splitting and separation of the microtubule-organizing center (MTOC) well before nuclear envelope breakdown (NEB) [5]. Whether amphiaster formation requires splitting of duplicated centrosomes is not known. We found that when centrosomes were removed from living vertebrate cells early in their cell cycle, an acentriolar MTOC re-assembled, and prior to NEB, a functional amphiastral spindle formed. Cytoplasmic dynein, dynactin, and pericentrin are all recruited to the interphase aMTOC, and the activity of kinesin-5 is needed for amphiaster formation. Mitosis proceeded on time and these karyoplasts divided in two. However, ~35% of aMTOCs failed to split/separate before NEB, and these entered mitosis with persistent monastral spindles. The chromatin-mediated RAN-GTP pathway could not restore bipolarity to monastral spindles, and these cells exited mitosis as single daughters. Our data reveal the novel finding that MTOC separation and amphiaster formation does not absolutely require the centrosome, but in its absence, the fidelity of bipolar spindle assembly is highly compromised. PMID:21439826

  17. Coordination of Slow Waves With Sleep Spindles Predicts Sleep-Dependent Memory Consolidation in Schizophrenia.

    PubMed

    Demanuele, Charmaine; Bartsch, Ullrich; Baran, Bengi; Khan, Sheraz; Vangel, Mark G; Cox, Roy; Hämäläinen, Matti; Jones, Matthew W; Stickgold, Robert; Manoach, Dara S

    2017-01-01

    Schizophrenia patients have correlated deficits in sleep spindle density and sleep-dependent memory consolidation. In addition to spindle density, memory consolidation is thought to rely on the precise temporal coordination of spindles with slow waves (SWs). We investigated whether this coordination is intact in schizophrenia and its relation to motor procedural memory consolidation. Twenty-one chronic medicated schizophrenia patients and 17 demographically matched healthy controls underwent two nights of polysomnography, with training on the finger tapping motor sequence task (MST) on the second night and testing the following morning. We detected SWs (0.5-4 Hz) and spindles during non-rapid eye movement (NREM) sleep. We measured SW-spindle phase-amplitude coupling and its relation with overnight improvement in MST performance. Patients did not differ from controls in the timing of SW-spindle coupling. In both the groups, spindles peaked during the SW upstate. For patients alone, the later in the SW upstate that spindles peaked and the more reliable this phase relationship, the greater the overnight MST improvement. Regression models that included both spindle density and SW-spindle coordination predicted overnight improvement significantly better than either parameter alone, suggesting that both contribute to memory consolidation. Schizophrenia patients show intact spindle-SW temporal coordination, and these timing relationships, together with spindle density, predict sleep-dependent memory consolidation. These relations were seen only in patients suggesting that their memory is more dependent on optimal spindle-SW timing, possibly due to reduced spindle density. Interventions to improve memory may need to increase spindle density while preserving or enhancing the coordination of NREM oscillations. © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e

  18. Noninvasive three-dimensional live imaging methodology for the spindles at meiosis and mitosis

    NASA Astrophysics Data System (ADS)

    Zheng, Jing-gao; Huo, Tiancheng; Tian, Ning; Chen, Tianyuan; Wang, Chengming; Zhang, Ning; Zhao, Fengying; Lu, Danyu; Chen, Dieyan; Ma, Wanyun; Sun, Jia-lin; Xue, Ping

    2013-05-01

    The spindle plays a crucial role in normal chromosome alignment and segregation during meiosis and mitosis. Studying spindles in living cells noninvasively is of great value in assisted reproduction technology (ART). Here, we present a novel spindle imaging methodology, full-field optical coherence tomography (FF-OCT). Without any dye labeling and fixation, we demonstrate the first successful application of FF-OCT to noninvasive three-dimensional (3-D) live imaging of the meiotic spindles within the mouse living oocytes at metaphase II as well as the mitotic spindles in the living zygotes at metaphase and telophase. By post-processing of the 3-D dataset obtained with FF-OCT, the important morphological and spatial parameters of the spindles, such as short and long axes, spatial localization, and the angle of meiotic spindle deviation from the first polar body in the oocyte were precisely measured with the spatial resolution of 0.7 μm. Our results reveal the potential of FF-OCT as an imaging tool capable of noninvasive 3-D live morphological analysis for spindles, which might be useful to ART related procedures and many other spindle related studies.

  19. Syndecan defines precise spindle orientation by modulating Wnt signaling in C. elegans.

    PubMed

    Dejima, Katsufumi; Kang, Sukryool; Mitani, Shohei; Cosman, Pamela C; Chisholm, Andrew D

    2014-11-01

    Wnt signals orient mitotic spindles in development, but it remains unclear how Wnt signaling is spatially controlled to achieve precise spindle orientation. Here, we show that C. elegans syndecan (SDN-1) is required for precise orientation of a mitotic spindle in response to a Wnt cue. We find that SDN-1 is the predominant heparan sulfate (HS) proteoglycan in the early C. elegans embryo, and that loss of HS biosynthesis or of the SDN-1 core protein results in misorientation of the spindle of the ABar blastomere. The ABar and EMS spindles both reorient in response to Wnt signals, but only ABar spindle reorientation is dependent on a new cell contact and on HS and SDN-1. SDN-1 transiently accumulates on the ABar surface as it contacts C, and is required for local concentration of Dishevelled (MIG-5) in the ABar cortex adjacent to C. These findings establish a new role for syndecan in Wnt-dependent spindle orientation. © 2014. Published by The Company of Biologists Ltd.

  20. Telomeres and centromeres have interchangeable roles in promoting meiotic spindle formation

    PubMed Central

    Fennell, Alex; Fernández-Álvarez, Alfonso; Tomita, Kazunori

    2015-01-01

    Telomeres and centromeres have traditionally been considered to perform distinct roles. During meiotic prophase, in a conserved chromosomal configuration called the bouquet, telomeres gather to the nuclear membrane (NM), often near centrosomes. We found previously that upon disruption of the fission yeast bouquet, centrosomes failed to insert into the NM at meiosis I and nucleate bipolar spindles. Hence, the trans-NM association of telomeres with centrosomes during prophase is crucial for efficient spindle formation. Nonetheless, in approximately half of bouquet-deficient meiocytes, spindles form properly. Here, we show that bouquet-deficient cells can successfully undergo meiosis using centromere–centrosome contact instead of telomere–centrosome contact to generate spindle formation. Accordingly, forced association between centromeres and centrosomes fully rescued the spindle defects incurred by bouquet disruption. Telomeres and centromeres both stimulate focal accumulation of the SUN domain protein Sad1 beneath the centrosome, suggesting a molecular underpinning for their shared spindle-generating ability. Our observations demonstrate an unanticipated level of interchangeability between the two most prominent chromosomal landmarks. PMID:25688135

  1. Nek2A destruction marks APC/C activation at the prophase-to-prometaphase transition by spindle-checkpoint-restricted Cdc20.

    PubMed

    Boekhout, Michiel; Wolthuis, Rob

    2015-04-15

    Nek2 isoform A (Nek2A) is a presumed substrate of the anaphase-promoting complex/cyclosome containing Cdc20 (APC/C(Cdc20)). Nek2A, like cyclin A, is degraded in mitosis while the spindle checkpoint is active. Cyclin A prevents spindle checkpoint proteins from binding to Cdc20 and is recruited to the APC/C in prometaphase. We found that Nek2A and cyclin A avoid being stabilized by the spindle checkpoint in different ways. First, enhancing mitotic checkpoint complex (MCC) formation by nocodazole treatment inhibited the degradation of geminin and cyclin A, whereas Nek2A disappeared at a normal rate. Second, depleting Cdc20 effectively stabilized cyclin A but not Nek2A. Nevertheless, Nek2A destruction crucially depended on Cdc20 binding to the APC/C. Third, in contrast to cyclin A, Nek2A was recruited to the APC/C before the start of mitosis. Interestingly, the spindle checkpoint very effectively stabilized an APC/C-binding mutant of Nek2A, which required the Nek2A KEN box. Apparently, in cells, the spindle checkpoint primarily prevents Cdc20 from binding destruction motifs. Nek2A disappearance marks the prophase-to-prometaphase transition, when Cdc20, regardless of the spindle checkpoint, activates the APC/C. However, Mad2 depletion accelerated Nek2A destruction, showing that spindle checkpoint release further increases APC/C(Cdc20) catalytic activity. © 2015. Published by The Company of Biologists Ltd.

  2. Blastopathies and microcephaly in a Chornobyl impacted region of Ukraine

    PubMed Central

    Wertelecki, Wladimir; Yevtushok, Lyubov; Zymak-Zakutnia, Natalia; Wang, Bin; Sosyniuk, Zoriana; Lapchenko, Serhiy; Hobart, Holly H

    2014-01-01

    This population-based descriptive epidemiology study demonstrates that rates of conjoined twins, teratomas, neural tube defects, microcephaly, and microphthalmia in the Rivne province of Ukraine are among the highest in Europe. The province is 200 km distant from the Chornobyl site and its northern half, a region known as Polissia, is significantly polluted by ionizing radiation. The rates of neural tube defects, microcephaly and microphthalmia in Polissia are statistically significantly higher than in the rest of the province. A survey of at-birth head size showed that values were statistically smaller in males and females born in one Polissia county than among neonates born in the capital city. These observations provide clues for confirmatory and cause-effect prospective investigations. The strength of this study stems from a reliance on international standards prevalent in Europe and a decade-long population-based surveillance of congenital malformations in two distinct large populations. The limitations of this study, as those of other descriptive epidemiology investigations, is that identified cause-effect associations require further assessment by specific prospective investigations designed to address specific teratogenic factors. PMID:24666273

  3. Physical limits on kinesin-5–mediated chromosome congression in the smallest mitotic spindles

    PubMed Central

    McCoy, Kelsey M.; Tubman, Emily S.; Claas, Allison; Tank, Damien; Clancy, Shelly Applen; O’Toole, Eileen T.; Berman, Judith; Odde, David J.

    2015-01-01

    A characteristic feature of mitotic spindles is the congression of chromosomes near the spindle equator, a process mediated by dynamic kinetochore microtubules. A major challenge is to understand how precise, submicrometer-scale control of kinetochore micro­tubule dynamics is achieved in the smallest mitotic spindles, where the noisiness of microtubule assembly/disassembly will potentially act to overwhelm the spatial information that controls microtubule plus end–tip positioning to mediate congression. To better understand this fundamental limit, we conducted an integrated live fluorescence, electron microscopy, and modeling analysis of the polymorphic fungal pathogen Candida albicans, which contains one of the smallest known mitotic spindles (<1 μm). Previously, ScCin8p (kinesin-5 in Saccharomyces cerevisiae) was shown to mediate chromosome congression by promoting catastrophe of long kinetochore microtubules (kMTs). Using C. albicans yeast and hyphal kinesin-5 (Kip1p) heterozygotes (KIP1/kip1∆), we found that mutant spindles have longer kMTs than wild-type spindles, consistent with a less-organized spindle. By contrast, kinesin-8 heterozygous mutant (KIP3/kip3∆) spindles exhibited the same spindle organization as wild type. Of interest, spindle organization in the yeast and hyphal states was indistinguishable, even though yeast and hyphal cell lengths differ by two- to fivefold, demonstrating that spindle length regulation and chromosome congression are intrinsic to the spindle and largely independent of cell size. Together these results are consistent with a kinesin-5–mediated, length-dependent depolymerase activity that organizes chromosomes at the spindle equator in C. albicans to overcome fundamental noisiness in microtubule self-assembly. More generally, we define a dimensionless number that sets a fundamental physical limit for maintaining congression in small spindles in the face of assembly noise and find that C. albicans operates very close to

  4. Chromosome and mitotic spindle dynamics in fission yeast kinesin-8 mutants

    NASA Astrophysics Data System (ADS)

    Crapo, Ammon M.; Gergley, Zachary R.; McIntosh, J. Richard; Betterton, M. D.

    2014-03-01

    Fission yeast proteins Klp5p and Klp6p are plus-end directed motors of the kinesin-8 family which promote microtubule (MT) depolymerization and also affect chromosome segregation, but the mechanism of these activities is not well understood. Using live-cell time-lapse fluorescence microscopy of fission yeast wild-type (WT) and klp5/6 mutant strains, we quantify and compare the dynamics of kinetochore motion and mitotic spindle length in 3D. In WT cells, the spindle, once formed, remains a consistent size and chromosomes are correctly organized and segregated. In kinesin-8 mutants, spindles undergo large length fluctuations of several microns. Kinetochore motions are also highly fluctuating, with kinetochores frequently moving away from the spindle rather than toward it. We observe transient pushing of chromosomes away from the spindle by as much as 10 microns in distance.

  5. Slow Sleep Spindle Activity, Declarative Memory, and General Cognitive Abilities in Children

    PubMed Central

    Hoedlmoser, Kerstin; Heib, Dominik P.J.; Roell, Judith; Peigneux, Philippe; Sadeh, Avi; Gruber, Georg; Schabus, Manuel

    2014-01-01

    Study Objectives: Functional interactions between sleep spindle activity, declarative memory consolidation, and general cognitive abilities in school-aged children. Design: Healthy, prepubertal children (n = 63; mean age 9.56 ± 0.76 y); ambulatory all-night polysomnography (2 nights); investigating the effect of prior learning (word pair association task; experimental night) versus nonlearning (baseline night) on sleep spindle activity; general cognitive abilities assessed using the Wechsler Intelligence Scale for Children-IV (WISC-IV). Measurements and Results: Analysis of spindle activity during nonrapid eye movement sleep (N2 and N3) evidenced predominant peaks in the slow (11-13 Hz) but not in the fast (13-15 Hz) sleep spindle frequency range (baseline and experimental night). Analyses were restricted to slow sleep spindles. Changes in spindle activity from the baseline to the experimental night were not associated with the overnight change in the number of recalled words reflecting declarative memory consolidation. Children with higher sleep spindle activity as measured at frontal, central, parietal, and occipital sites during both baseline and experimental nights exhibited higher general cognitive abilities (WISC-IV) and declarative learning efficiency (i.e., number of recalled words before and after sleep). Conclusions: Slow sleep spindles (11-13 Hz) in children age 8–11 y are associated with inter-individual differences in general cognitive abilities and learning efficiency. Citation: Hoedlmoser K, Heib DPJ, Roell J, Peigneux P, Sadeh A, Gruber G, Schabus M. Slow sleep spindle activity, declarative memory, and general cognitive abilities in children. SLEEP 2014;37(9):1501-1512. PMID:25142558

  6. A yeast gene essential for regulation of spindle pole duplication.

    PubMed Central

    Baum, P; Yip, C; Goetsch, L; Byers, B

    1988-01-01

    In eucaryotic cells, duplication of spindle poles must be coordinated with other cell cycle functions. We report here the identification in Saccharomyces cerevisiae of a temperature-sensitive lethal mutation, esp1, that deregulates spindle pole duplication. Mutant cells transferred to the nonpermissive temperature became unable to continue DNA synthesis and cell division but displayed repeated duplication of their spindle pole bodies. Although entry into this state after transient challenge by the nonpermissive temperature was largely lethal, rare survivors were recovered and found to have become increased in ploidy. If the mutant cells were held in G0 or G1 during exposure to the elevated temperature, they remained viable and maintained normal numbers of spindle poles. These results suggest dual regulation of spindle pole duplication, including a mechanism that promotes duplication as cells enter the division cycle and a negative regulatory mechanism, controlled by ESP1, that limits duplication to a single occurrence in each cell division cycle. Tetrad analysis has revealed that ESP1 resides at a previously undescribed locus on the right arm of chromosome VII. Images PMID:3072479

  7. Intact perception but abnormal orientation towards face-like objects in young children with ASD

    PubMed Central

    Guillon, Quentin; Rogé, Bernadette; Afzali, Mohammad H.; Baduel, Sophie; Kruck, Jeanne; Hadjikhani, Nouchine

    2016-01-01

    There is ample behavioral evidence of diminished orientation towards faces as well as the presence of face perception impairments in autism spectrum disorder (ASD), but the underlying mechanisms of these deficits are still unclear. We used face-like object stimuli that have been shown to evoke pareidolia in typically developing (TD) individuals to test the effect of a global face-like configuration on orientation and perceptual processes in young children with ASD and age-matched TD controls. We show that TD children were more likely to look first towards upright face-like objects than children with ASD, showing that a global face-like configuration elicit a stronger orientation bias in TD children as compared to children with ASD. However, once they were looking at the stimuli, both groups spent more time exploring the upright face-like object, suggesting that they both perceived it as a face. Our results are in agreement with abnormal social orienting in ASD, possibly due to an abnormal tuning of the subcortical pathway, leading to poor orienting and attention towards faces. Our results also indicate that young children with ASD can perceive a generic face holistically, such as face-like objects, further demonstrating holistic processing of faces in ASD. PMID:26912096

  8. Intact perception but abnormal orientation towards face-like objects in young children with ASD.

    PubMed

    Guillon, Quentin; Rogé, Bernadette; Afzali, Mohammad H; Baduel, Sophie; Kruck, Jeanne; Hadjikhani, Nouchine

    2016-02-25

    There is ample behavioral evidence of diminished orientation towards faces as well as the presence of face perception impairments in autism spectrum disorder (ASD), but the underlying mechanisms of these deficits are still unclear. We used face-like object stimuli that have been shown to evoke pareidolia in typically developing (TD) individuals to test the effect of a global face-like configuration on orientation and perceptual processes in young children with ASD and age-matched TD controls. We show that TD children were more likely to look first towards upright face-like objects than children with ASD, showing that a global face-like configuration elicit a stronger orientation bias in TD children as compared to children with ASD. However, once they were looking at the stimuli, both groups spent more time exploring the upright face-like object, suggesting that they both perceived it as a face. Our results are in agreement with abnormal social orienting in ASD, possibly due to an abnormal tuning of the subcortical pathway, leading to poor orienting and attention towards faces. Our results also indicate that young children with ASD can perceive a generic face holistically, such as face-like objects, further demonstrating holistic processing of faces in ASD.

  9. Timely Endocytosis of Cytokinetic Enzymes Prevents Premature Spindle Breakage during Mitotic Exit

    PubMed Central

    Onishi, Masayuki; Yeong, Foong May

    2016-01-01

    Cytokinesis requires the spatio-temporal coordination of membrane deposition and primary septum (PS) formation at the division site to drive acto-myosin ring (AMR) constriction. It has been demonstrated that AMR constriction invariably occurs only after the mitotic spindle disassembly. It has also been established that Chitin Synthase II (Chs2p) neck localization precedes mitotic spindle disassembly during mitotic exit. As AMR constriction depends upon PS formation, the question arises as to how chitin deposition is regulated so as to prevent premature AMR constriction and mitotic spindle breakage. In this study, we propose that cells regulate the coordination between spindle disassembly and AMR constriction via timely endocytosis of cytokinetic enzymes, Chs2p, Chs3p, and Fks1p. Inhibition of endocytosis leads to over accumulation of cytokinetic enzymes during mitotic exit, which accelerates the constriction of the AMR, and causes spindle breakage that eventually could contribute to monopolar spindle formation in the subsequent round of cell division. Intriguingly, the mitotic spindle breakage observed in endocytosis mutants can be rescued either by deleting or inhibiting the activities of, CHS2, CHS3 and FKS1, which are involved in septum formation. The findings from our study highlight the importance of timely endocytosis of cytokinetic enzymes at the division site in safeguarding mitotic spindle integrity during mitotic exit. PMID:27447488

  10. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.

    PubMed

    Braun, Daniela A; Rao, Jia; Mollet, Geraldine; Schapiro, David; Daugeron, Marie-Claire; Tan, Weizhen; Gribouval, Olivier; Boyer, Olivia; Revy, Patrick; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Lawson, Jennifer A; Schanze, Denny; Ashraf, Shazia; Ullmann, Jeremy F P; Hoogstraten, Charlotte A; Boddaert, Nathalie; Collinet, Bruno; Martin, Gaëlle; Liger, Dominique; Lovric, Svjetlana; Furlano, Monica; Guerrera, I Chiara; Sanchez-Ferras, Oraly; Hu, Jennifer F; Boschat, Anne-Claire; Sanquer, Sylvia; Menten, Björn; Vergult, Sarah; De Rocker, Nina; Airik, Merlin; Hermle, Tobias; Shril, Shirlee; Widmeier, Eugen; Gee, Heon Yung; Choi, Won-Il; Sadowski, Carolin E; Pabst, Werner L; Warejko, Jillian K; Daga, Ankana; Basta, Tamara; Matejas, Verena; Scharmann, Karin; Kienast, Sandra D; Behnam, Babak; Beeson, Brendan; Begtrup, Amber; Bruce, Malcolm; Ch'ng, Gaik-Siew; Lin, Shuan-Pei; Chang, Jui-Hsing; Chen, Chao-Huei; Cho, Megan T; Gaffney, Patrick M; Gipson, Patrick E; Hsu, Chyong-Hsin; Kari, Jameela A; Ke, Yu-Yuan; Kiraly-Borri, Cathy; Lai, Wai-Ming; Lemyre, Emmanuelle; Littlejohn, Rebecca Okashah; Masri, Amira; Moghtaderi, Mastaneh; Nakamura, Kazuyuki; Ozaltin, Fatih; Praet, Marleen; Prasad, Chitra; Prytula, Agnieszka; Roeder, Elizabeth R; Rump, Patrick; Schnur, Rhonda E; Shiihara, Takashi; Sinha, Manish D; Soliman, Neveen A; Soulami, Kenza; Sweetser, David A; Tsai, Wen-Hui; Tsai, Jeng-Daw; Topaloglu, Rezan; Vester, Udo; Viskochil, David H; Vatanavicharn, Nithiwat; Waxler, Jessica L; Wierenga, Klaas J; Wolf, Matthias T F; Wong, Sik-Nin; Leidel, Sebastian A; Truglio, Gessica; Dedon, Peter C; Poduri, Annapurna; Mane, Shrikant; Lifton, Richard P; Bouchard, Maxime; Kannu, Peter; Chitayat, David; Magen, Daniella; Callewaert, Bert; van Tilbeurgh, Herman; Zenker, Martin; Antignac, Corinne; Hildebrandt, Friedhelm

    2017-10-01

    Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

  11. The chromokinesin Kid is required for maintenance of proper metaphase spindle size.

    PubMed

    Tokai-Nishizumi, Noriko; Ohsugi, Miho; Suzuki, Emiko; Yamamoto, Tadashi

    2005-11-01

    The human chromokinesin Kid/kinesin-10, a plus end-directed microtubule (MT)-based motor with both microtubule- and DNA-binding domains, is required for proper chromosome alignment at the metaphase plate. Here, we performed RNA interference experiments to deplete endogenous Kid from HeLa cells and confirmed defects in metaphase chromosome arm alignment in Kid-depleted cells. In addition, we noted a shortening of the spindle length, resulting in a pole-to-pole distance only 80% of wild type. The spindle microtubule-bundles with which Kid normally colocalize became less robust. Rescue of the two Kid deficiency phenotypes-imprecise chromosome alignment at metaphase and shortened spindles- exhibited distinct requirements. Mutants lacking either the DNA-binding domain or the MT motor ATPase failed to rescue the former defect, whereas rescue of the shortened spindle phenotype required neither activity. Kid also exhibits microtubule bundling activity in vitro, and rescue of the shortened spindle phenotype and the bundling activity displayed similar domain requirements, except that rescue required a coiled-coil domain not needed for bundling. These results suggest that distinct from its role in chromosome movement, Kid contributes to spindle morphogenesis by mediating spindle microtubules stabilization.

  12. Force encoding in muscle spindles during stretch of passive muscle

    PubMed Central

    Blum, Kyle P.; Zytnicki, Daniel

    2017-01-01

    Muscle spindle proprioceptive receptors play a primary role in encoding the effects of external mechanical perturbations to the body. During externally-imposed stretches of passive, i.e. electrically-quiescent, muscles, the instantaneous firing rates (IFRs) of muscle spindles are associated with characteristics of stretch such as length and velocity. However, even in passive muscle, there are history-dependent transients of muscle spindle firing that are not uniquely related to muscle length and velocity, nor reproduced by current muscle spindle models. These include acceleration-dependent initial bursts, increased dynamic response to stretch velocity if a muscle has been isometric, and rate relaxation, i.e., a decrease in tonic IFR when a muscle is held at a constant length after being stretched. We collected muscle spindle spike trains across a variety of muscle stretch kinematic conditions, including systematic changes in peak length, velocity, and acceleration. We demonstrate that muscle spindle primary afferents in passive muscle fire in direct relationship to muscle force-related variables, rather than length-related variables. Linear combinations of whole muscle-tendon force and the first time derivative of force (dF/dt) predict the entire time course of transient IFRs in muscle spindle Ia afferents during stretch (i.e., lengthening) of passive muscle, including the initial burst, the dynamic response to lengthening, and rate relaxation following lengthening. Similar to acceleration scaling found previously in postural responses to perturbations, initial burst amplitude scaled equally well to initial stretch acceleration or dF/dt, though later transients were only described by dF/dt. The transient increase in dF/dt at the onset of lengthening reflects muscle short-range stiffness due to cross-bridge dynamics. Our work demonstrates a critical role of muscle cross-bridge dynamics in history-dependent muscle spindle IFRs in passive muscle lengthening conditions

  13. Force encoding in muscle spindles during stretch of passive muscle.

    PubMed

    Blum, Kyle P; Lamotte D'Incamps, Boris; Zytnicki, Daniel; Ting, Lena H

    2017-09-01

    Muscle spindle proprioceptive receptors play a primary role in encoding the effects of external mechanical perturbations to the body. During externally-imposed stretches of passive, i.e. electrically-quiescent, muscles, the instantaneous firing rates (IFRs) of muscle spindles are associated with characteristics of stretch such as length and velocity. However, even in passive muscle, there are history-dependent transients of muscle spindle firing that are not uniquely related to muscle length and velocity, nor reproduced by current muscle spindle models. These include acceleration-dependent initial bursts, increased dynamic response to stretch velocity if a muscle has been isometric, and rate relaxation, i.e., a decrease in tonic IFR when a muscle is held at a constant length after being stretched. We collected muscle spindle spike trains across a variety of muscle stretch kinematic conditions, including systematic changes in peak length, velocity, and acceleration. We demonstrate that muscle spindle primary afferents in passive muscle fire in direct relationship to muscle force-related variables, rather than length-related variables. Linear combinations of whole muscle-tendon force and the first time derivative of force (dF/dt) predict the entire time course of transient IFRs in muscle spindle Ia afferents during stretch (i.e., lengthening) of passive muscle, including the initial burst, the dynamic response to lengthening, and rate relaxation following lengthening. Similar to acceleration scaling found previously in postural responses to perturbations, initial burst amplitude scaled equally well to initial stretch acceleration or dF/dt, though later transients were only described by dF/dt. The transient increase in dF/dt at the onset of lengthening reflects muscle short-range stiffness due to cross-bridge dynamics. Our work demonstrates a critical role of muscle cross-bridge dynamics in history-dependent muscle spindle IFRs in passive muscle lengthening conditions

  14. Prevalence and clinical profile of microcephaly in South America pre-Zika, 2005-14: prevalence and case-control study.

    PubMed

    Orioli, Iêda M; Dolk, Helen; Lopez-Camelo, Jorge S; Mattos, Daniel; Poletta, Fernando A; Dutra, Maria G; Carvalho, Flavia M; Castilla, Eduardo E

    2017-11-21

    Objective  To describe the prevalence and clinical spectrum of microcephaly in South America for the period 2005-14, before the start of the Zika epidemic in 2015, as a baseline for future surveillance as the Zika epidemic spreads and as other infectious causes may emerge in future. Design  Prevalence and case-control study. Data sources  ECLAMC (Latin American Collaborative Study of Congenital Malformations) database derived from 107 hospitals in 10 South American countries, 2005 to 2014. Data on microcephaly cases, four non-malformed controls per case, and all hospital births (all births for hospital based prevalence, resident within municipality for population based prevalence). For 2010-14, head circumference data were available and compared with Intergrowth charts. Results  552 microcephaly cases were registered, giving a hospital based prevalence of 4.4 (95% confidence interval 4.1 to 4.9) per 10 000 births and a population based prevalence of 3.0 (2.7 to 3.4) per 10 000. Prevalence varied significantly between countries and between regions and hospitals within countries. Thirty two per cent (n=175) of cases were prenatally diagnosed; 29% (n=159) were perinatal deaths. Twenty three per cent (n=128) were associated with a diagnosed genetic syndrome, 34% (n=189) polymalformed without a syndrome diagnosis, 12% (n=65) with associated neural malformations, and 26% (n=145) microcephaly only. In addition, 3.8% (n=21) had a STORCH (syphilis, toxoplasmosis, other including HIV, rubella, cytomegalovirus, and herpes simplex) infection diagnosis and 2.0% (n=11) had consanguineous parents. Head circumference measurements available for 184/235 cases in 2010-14 showed 45% (n=82) more than 3 SD below the mean, 24% (n=44) between 3 SD and 2 SD below the mean, and 32% (n=58) larger than -2 SD. Conclusion  Extrapolated to the nearly 7 million annual births in South America, an estimated 2000-2500 microcephaly cases were diagnosed among births each year before the Zika

  15. Systems cell biology of the mitotic spindle.

    PubMed

    Saleem, Ramsey A; Aitchison, John D

    2010-01-11

    Cell division depends critically on the temporally controlled assembly of mitotic spindles, which are responsible for the distribution of duplicated chromosomes to each of the two daughter cells. To gain insight into the process, Vizeacoumar et al., in this issue (Vizeacoumar et al. 2010. J. Cell Biol. doi:10.1083/jcb.200909013), have combined systems genetics with high-throughput and high-content imaging to comprehensively identify and classify novel components that contribute to the morphology and function of the mitotic spindle.

  16. Disruption of IFT Complex A Causes Cystic Kidneys without Mitotic Spindle Misorientation

    PubMed Central

    Jonassen, Julie A.; SanAgustin, Jovenal; Baker, Stephen P.

    2012-01-01

    Intraflagellar transport (IFT) complexes A and B build and maintain primary cilia. In the mouse, kidney-specific or hypomorphic mutant alleles of IFT complex B genes cause polycystic kidneys, but the influence of IFT complex A proteins on renal development is not well understood. In the present study, we found that HoxB7-Cre–driven deletion of the complex A gene Ift140 from collecting ducts disrupted, but did not completely prevent, cilia assembly. Mutant kidneys developed collecting duct cysts by postnatal day 5, with rapid cystic expansion and renal dysfunction by day 15 and little remaining parenchymal tissue by day 20. In contrast to many models of polycystic kidney disease, precystic Ift140-deleted collecting ducts showed normal centrosomal positioning and no misorientation of the mitotic spindle axis, suggesting that disruption of oriented cell division is not a prerequisite to cyst formation in these kidneys. Precystic collecting ducts had an increased mitotic index, suggesting that cell proliferation may drive cyst expansion even with normal orientation of the mitotic spindle. In addition, we observed significant increases in expression of canonical Wnt pathway genes and mediators of Hedgehog and tissue fibrosis in highly cystic, but not precystic, kidneys. Taken together, these studies indicate that loss of Ift140 causes pronounced renal cystic disease and suggest that abnormalities in several different pathways may influence cyst progression. PMID:22282595

  17. Spindle neurons of the human anterior cingulate cortex

    NASA Technical Reports Server (NTRS)

    Nimchinsky, E. A.; Vogt, B. A.; Morrison, J. H.; Hof, P. R.; Bloom, F. E. (Principal Investigator)

    1995-01-01

    The human anterior cingulate cortex is distinguished by the presence of an unusual cell type, a large spindle neuron in layer Vb. This cell has been noted numerous times in the historical literature but has not been studied with modern neuroanatomic techniques. For instance, details regarding the neuronal class to which these cells belong and regarding their precise distribution along both ventrodorsal and anteroposterior axes of the cingulate gyrus are still lacking. In the present study, morphological features and the anatomic distribution of this cell type were studied using computer-assisted mapping and immunocytochemical techniques. Spindle neurons are restricted to the subfields of the anterior cingulate cortex (Brodmann's area 24), exhibiting a greater density in anterior portions of this area than in posterior portions, and tapering off in the transition zone between anterior and posterior cingulate cortex. Furthermore, a majority of the spindle cells at any level is located in subarea 24b on the gyral surface. Immunocytochemical analysis revealed that the neurofilament protein triple was present in a large percentage of these neurons and that they did not contain calcium-binding proteins. Injections of the carbocyanine dye DiI into the cingulum bundle revealed that these cells are projection neurons. Finally, spindle cells were consistently affected in Alzheimer's disease cases, with an overall loss of about 60%. Taken together, these observations indicate that the spindle cells of the human cingulate cortex represent a morphological subpopulation of pyramidal neurons whose restricted distribution may be associated with functionally distinct areas.

  18. Fast and slow spindles during the sleep slow oscillation: disparate coalescence and engagement in memory processing.

    PubMed

    Mölle, Matthias; Bergmann, Til O; Marshall, Lisa; Born, Jan

    2011-10-01

    Thalamo-cortical spindles driven by the up-state of neocortical slow (< 1 Hz) oscillations (SOs) represent a candidate mechanism of memory consolidation during sleep. We examined interactions between SOs and spindles in human slow wave sleep, focusing on the presumed existence of 2 kinds of spindles, i.e., slow frontocortical and fast centro-parietal spindles. Two experiments were performed in healthy humans (24.5 ± 0.9 y) investigating undisturbed sleep (Experiment I) and the effects of prior learning (word paired associates) vs. non-learning (Experiment II) on multichannel EEG recordings during sleep. Only fast spindles (12-15 Hz) were synchronized to the depolarizing SO up-state. Slow spindles (9-12 Hz) occurred preferentially at the transition into the SO down-state, i.e., during waning depolarization. Slow spindles also revealed a higher probability to follow rather than precede fast spindles. For sequences of individual SOs, fast spindle activity was largest for "initial" SOs, whereas SO amplitude and slow spindle activity were largest for succeeding SOs. Prior learning enhanced this pattern. The finding that fast and slow spindles occur at different times of the SO cycle points to disparate generating mechanisms for the 2 kinds of spindles. The reported temporal relationships during SO sequences suggest that fast spindles, driven by the SO up-state feed back to enhance the likelihood of succeeding SOs together with slow spindles. By enforcing such SO-spindle cycles, particularly after prior learning, fast spindles possibly play a key role in sleep-dependent memory processing.

  19. Intercentrosomal angular separation during mitosis plays a crucial role for maintaining spindle stability

    NASA Astrophysics Data System (ADS)

    Sutradhar, S.; Basu, S.; Paul, R.

    2015-10-01

    Cell division through proper spindle formation is one of the key puzzles in cell biology. In most mammalian cells, chromosomes spontaneously arrange to achieve a stable bipolar spindle during metaphase which eventually ensures proper segregation of the DNA into the daughter cells. In this paper, we present a robust three-dimensional mechanistic model to investigate the formation and maintenance of a bipolar mitotic spindle in mammalian cells under different physiological constraints. Using realistic parameters, we test spindle viability by measuring the spindle length and studying the chromosomal configuration. The model strikingly predicts a feature of the spindle instability arising from the insufficient intercentrosomal angular separation and impaired sliding of the interpolar microtubules. In addition, our model successfully reproduces chromosomal patterns observed in mammalian cells, when activity of different motor proteins is perturbed.

  20. Rotating waves during human sleep spindles organize global patterns of activity that repeat precisely through the night

    PubMed Central

    Muller, Lyle; Piantoni, Giovanni; Koller, Dominik; Cash, Sydney S; Halgren, Eric; Sejnowski, Terrence J

    2016-01-01

    During sleep, the thalamus generates a characteristic pattern of transient, 11-15 Hz sleep spindle oscillations, which synchronize the cortex through large-scale thalamocortical loops. Spindles have been increasingly demonstrated to be critical for sleep-dependent consolidation of memory, but the specific neural mechanism for this process remains unclear. We show here that cortical spindles are spatiotemporally organized into circular wave-like patterns, organizing neuronal activity over tens of milliseconds, within the timescale for storing memories in large-scale networks across the cortex via spike-time dependent plasticity. These circular patterns repeat over hours of sleep with millisecond temporal precision, allowing reinforcement of the activity patterns through hundreds of reverberations. These results provide a novel mechanistic account for how global sleep oscillations and synaptic plasticity could strengthen networks distributed across the cortex to store coherent and integrated memories. DOI: http://dx.doi.org/10.7554/eLife.17267.001 PMID:27855061

  1. Relationship between focal penicillin spikes and cortical spindles in the cerveau isolé cat.

    PubMed

    McLachlan, R S; Kaibara, M; Girvin, J P

    1983-01-01

    Using the unanesthetized, cerveau isolé preparation in the cat, the association between artificially induced penicillin (PCN) spikes and spontaneously occurring electrocorticographic (ECoG) spindles was investigated. Spikes were elicited by surface application of small pledgets of PCN. After the application of PCN, there was a decrease in spindle amplitude but no change in frequency, duration, or spindle wave frequency in the area of the focus. Examination of the times of occurrence of the spikes and spindles disclosed that in the majority of cases, within a few minutes of the initiation of the foci, there was very high simultaneity, usually 100% between the occurrences of these two events. Examination of the times of occurrence of the spikes within the ECoG spindles failed to disclose any compelling evidence which would favor either the hypothesis that spikes "trigger" spindles or the hypothesis that spindles predispose to focal spikes. Thus, whether spikes trigger spindles, or spikes simply occur in a nonspecific manner during the occurrence of the spindle, or whether it is a combination of both these explanations, must remain an open question on the basis of the data available.

  2. Sleep Spindles and Intelligence in Early Childhood--Developmental and Trait-Dependent Aspects

    ERIC Educational Resources Information Center

    Ujma, Péter P.; Sándor, Piroska; Szakadát, Sára; Gombos, Ferenc; Bódizs, Róbert

    2016-01-01

    Sleep spindles act as a powerful marker of individual differences in cognitive ability. Sleep spindle parameters correlate with both age-related changes in cognitive abilities and with the age-independent concept of IQ. While some studies have specifically demonstrated the relationship between sleep spindles and intelligence in young children, our…

  3. Spindle-shaped Microstructures: Potential Models for Planktonic Life Forms on Other Worlds

    NASA Technical Reports Server (NTRS)

    Oehler, Dorothy Z.; Walsh, Maud M.; Sugitani, Kenichiro; House, Christopher H.

    2014-01-01

    Spindle-shaped, organic microstructures ("spindles") are now known from Archean cherts in three localities (Figs. 1-4): The 3 Ga Farrel Quartzite from the Pilbara of Australia [1]; the older, 3.3-3.4 Ga Strelley Pool Formation, also from the Pilbara of Australia [2]; and the 3.4 Ga Kromberg Formation of the Barberton Mountain Land of South Africa [3]. Though the spindles were previously speculated to be pseudofossils or epigenetic organic contaminants, a growing body of data suggests that these structures are bona fide microfossils and further, that they are syngenetic with the Archean cherts in which they occur [1-2, 4-10]. As such, the spindles are among some of the oldest-known organically preserved microfossils on Earth. Moreover, recent delta C-13 study of individual spindles from the Farrel Quartzite (using Secondary Ion Mass Spectrometry [SIMS]) suggests that the spindles may have been planktonic (living in open water), as opposed to benthic (living as bottom dwellers in contact with muds or sediments) [9]. Since most Precambrian microbiotas have been described from benthic, matforming communities, a planktonic lifestyle for the spindles suggests that these structures could represent a segment of the Archean biosphere that is poorly known. Here we synthesize the recent work on the spindles, and we add new observations regarding their geographic distribution, robustness, planktonic habit, and long-lived success. We then discuss their potential evolutionary and astrobiological significance.

  4. Sex-dependent association of common variants of microcephaly genes with brain structure.

    PubMed

    Rimol, Lars M; Agartz, Ingrid; Djurovic, Srdjan; Brown, Andrew A; Roddey, J Cooper; Kähler, Anna K; Mattingsdal, Morten; Athanasiu, Lavinia; Joyner, Alexander H; Schork, Nicholas J; Halgren, Eric; Sundet, Kjetil; Melle, Ingrid; Dale, Anders M; Andreassen, Ole A

    2010-01-05

    Loss-of-function mutations in the genes associated with primary microcephaly (MCPH) reduce human brain size by about two-thirds, without producing gross abnormalities in brain organization or physiology and leaving other organs largely unaffected [Woods CG, et al. (2005) Am J Hum Genet 76:717-728]. There is also evidence suggesting that MCPH genes have evolved rapidly in primates and humans and have been subjected to selection in recent human evolution [Vallender EJ, et al. (2008) Trends Neurosci 31:637-644]. Here, we show that common variants of MCPH genes account for some of the common variation in brain structure in humans, independently of disease status. We investigated the correlations of SNPs from four MCPH genes with brain morphometry phenotypes obtained with MRI. We found significant, sex-specific associations between common, nonexonic, SNPs of the genes CDK5RAP2, MCPH1, and ASPM, with brain volume or cortical surface area in an ethnically homogenous Norwegian discovery sample (n = 287), including patients with mental illness. The most strongly associated SNP findings were replicated in an independent North American sample (n = 656), which included patients with dementia. These results are consistent with the view that common variation in brain structure is associated with genetic variants located in nonexonic, presumably regulatory, regions.

  5. Fast and Slow Spindles during the Sleep Slow Oscillation: Disparate Coalescence and Engagement in Memory Processing

    PubMed Central

    Mölle, Matthias; Bergmann, Til O.; Marshall, Lisa; Born, Jan

    2011-01-01

    Study Objectives: Thalamo-cortical spindles driven by the up-state of neocortical slow (< 1 Hz) oscillations (SOs) represent a candidate mechanism of memory consolidation during sleep. We examined interactions between SOs and spindles in human slow wave sleep, focusing on the presumed existence of 2 kinds of spindles, i.e., slow frontocortical and fast centro-parietal spindles. Design: Two experiments were performed in healthy humans (24.5 ± 0.9 y) investigating undisturbed sleep (Experiment I) and the effects of prior learning (word paired associates) vs. non-learning (Experiment II) on multichannel EEG recordings during sleep. Measurements and Results: Only fast spindles (12-15 Hz) were synchronized to the depolarizing SO up-state. Slow spindles (9-12 Hz) occurred preferentially at the transition into the SO down-state, i.e., during waning depolarization. Slow spindles also revealed a higher probability to follow rather than precede fast spindles. For sequences of individual SOs, fast spindle activity was largest for “initial” SOs, whereas SO amplitude and slow spindle activity were largest for succeeding SOs. Prior learning enhanced this pattern. Conclusions: The finding that fast and slow spindles occur at different times of the SO cycle points to disparate generating mechanisms for the 2 kinds of spindles. The reported temporal relationships during SO sequences suggest that fast spindles, driven by the SO up-state feed back to enhance the likelihood of succeeding SOs together with slow spindles. By enforcing such SO-spindle cycles, particularly after prior learning, fast spindles possibly play a key role in sleep-dependent memory processing. Citation: Mölle M; Bergmann TO; Marshall L; Born J. Fast and slow spindles during the sleep slow oscillation: disparate coalescence and engagement in memory processing. SLEEP 2011;34(10):1411–1421. PMID:21966073

  6. Frequency Response Studies using Receptance Coupling Approach in High Speed Spindles

    NASA Astrophysics Data System (ADS)

    Shaik, Jakeer Hussain; Ramakotaiah, K.; Srinivas, J.

    2018-01-01

    In order to assess the stability of high speed machining, estimate the frequency response at the end of tool tip is of great importance. Evaluating dynamic response of several combinations of integrated spindle-tool holder-tool will consume a lot of time. This paper presents coupled field dynamic response at tool tip for the entire integrated spindle tool unit. The spindle unit is assumed to be relying over the front and rear bearings and investigated using the Timoshenko beam theory to arrive the receptances at different locations of the spindle-tool unit. The responses are further validated with conventional finite element model as well as with the experiments. This approach permits quick outputs without losing accuracy of solution and further these methods are utilized to analyze the various design variables on system dynamics. The results obtained through this analysis are needed to design the better spindle unit in an attempt to reduce the frequency amplitudes at the tool tip to improvise the milling stability during cutting process.

  7. Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss.

    PubMed

    Tanaka, Akemi J; Cho, Megan T; Millan, Francisca; Juusola, Jane; Retterer, Kyle; Joshi, Charuta; Niyazov, Dmitriy; Garnica, Adolfo; Gratz, Edward; Deardorff, Matthew; Wilkins, Alisha; Ortiz-Gonzalez, Xilma; Mathews, Katherine; Panzer, Karin; Brilstra, Eva; van Gassen, Koen L I; Volker-Touw, Catharina M L; van Binsbergen, Ellen; Sobreira, Nara; Hamosh, Ada; McKnight, Dianalee; Monaghan, Kristin G; Chung, Wendy K

    2015-09-03

    Using whole-exome sequencing, we have identified in ten families 14 individuals with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants in spermatogenesis-associated protein 5 (SPATA5). SPATA5 encodes a ubiquitously expressed member of the ATPase associated with diverse activities (AAA) protein family and is involved in mitochondrial morphogenesis during early spermatogenesis. It might also play a role in post-translational modification during cell differentiation in neuronal development. Mutations in SPATA5 might affect brain development and function, resulting in microcephaly, developmental delay, and intellectual disability. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  8. The Light Intermediate Chain 2 Subpopulation of Dynein Regulates Mitotic Spindle Orientation.

    PubMed

    Mahale, Sagar; Kumar, Megha; Sharma, Amit; Babu, Aswini; Ranjan, Shashi; Sachidanandan, Chetana; Mylavarapu, Sivaram V S

    2016-12-23

    Cytoplasmic dynein 1 is a multi-protein intracellular motor essential for mediating several mitotic functions, including the establishment of proper spindle orientation. The functional relevance and mechanistic distinctions between two discrete dynein subpopulations distinguished only by Light Intermediate Chain (LIC) homologues, LIC1 and LIC2 is unknown during mitosis. Here, we identify LIC2-dynein as the major mediator of proper spindle orientation and uncover its underlying molecular mechanism. Cortically localized dynein, essential for maintaining correct spindle orientation, consists majorly of LIC2-dynein, which interacts with cortical 14-3-3 ε- ζ and Par3, conserved proteins required for orienting the spindle. LIC2-dynein is also responsible for the majority of dynein-mediated asymmetric poleward transport of NuMA, helping focus microtubule minus ends. In addition, LIC2-dynein dominates in equatorially aligning chromosomes at metaphase and in regulating mitotic spindle length. Key mitotic functions of LIC2 were remarkably conserved in and essential for early embryonic divisions and development in zebrafish. Thus LIC2-dynein exclusively engages with two major cortical pathways to govern spindle orientation. Overall, we identify a novel selectivity of molecular interactions between the two LICs in mitosis as the underlying basis for their uneven distribution of labour in ensuring proper spindle orientation.

  9. Zika Virus IgG in Infants with Microcephaly, Guinea-Bissau, 2016.

    PubMed

    Rosenstierne, Maiken Worsøe; Schaltz-Buchholzer, Frederik; Bruzadelli, Fernanda; Có, Asson; Cardoso, Placido; Jørgensen, Charlotte Sværke; Michiels, Johan; Heyndrickx, Leo; Ariën, Kevin K; Fischer, Thea Kølsen; Fomsgaard, Anders

    2018-05-01

    We analyzed blood samples from infants born with microcephaly and their mothers in Guinea-Bissau in 2016 for pathogens associated with birth defects. No Zika virus RNA was detected, but Zika virus IgG was highly prevalent. We recommend implementing pathogen screening of infants with congenital defects in Guinea-Bissau.

  10. The responses of muscle spindles to small, slow movements in passive muscle and during fusimotor activity.

    PubMed

    Wise, A K; Gregory, J E; Proske, U

    1999-03-06

    We have previously shown that movement detection thresholds at the human elbow joint were less than a degree of joint rotation in the passive limb but were higher if they were measured while subjects co-contracted elbow muscles [A.K. Wise, J.E. Gregory, U. Proske, J. Physiol., 508 (1998) 325-330]. Here we report observations on the responses of muscle spindles of the soleus muscle of the anaesthetised cat to determine their ability to signal small length changes in the passive muscle and during a contraction, under conditions resembling those of the human experiments. After appropriate conditioning of the muscle to control for history effects, primary endings of muscle spindles showed thresholds to ramp stretch at 20 micrometers s-1 of between less than 5 micrometers and 15 micrometers, which translates to 0.05 degrees -0.15 degrees of human elbow joint rotation. Thresholds were much higher following conditioning to introduce slack in the muscle. Since during a voluntary contraction there is likely to be alpha:gamma co-activation, responses of spindles were also recorded during slow stretches (100 micrometers at 20 micrometers s-1) during static fusimotor stimulation, dynamic fusimotor stimulation, combined fusimotor stimulation and fusimotor plus skeletomotor stimulation. Invariably, responses to passive stretch were larger than during motor stimulation. It is concluded that spindles are sensitive enough to signal fractions of a degree of elbow joint rotation and that the rise in threshold observed during a voluntary contraction may be accounted for by the actions of fusimotor and skeletomotor axons on spindle stretch responses. Copyright 1999 Elsevier Science B.V.

  11. X-43A Rudder Spindle Fatigue Life Estimate and Testing

    NASA Technical Reports Server (NTRS)

    Glaessgen, Edward H.; Dawicke, David S.; Johnston, William M.; James, Mark A.; Simonsen, Micah; Mason, Brian H.

    2005-01-01

    Fatigue life analyses were performed using a standard strain-life approach and a linear cumulative damage parameter to assess the effect of a single accidental overload on the fatigue life of the Haynes 230 nickel-base superalloy X-43A rudder spindle. Because of a limited amount of information available about the Haynes 230 material, a series of tests were conducted to replicate the overload and in-service conditions for the spindle and corroborate the analysis. Both the analytical and experimental results suggest that the spindle will survive the anticipated flight loads.

  12. Sonographic assessment of normal and abnormal patterns of fetal cerebral lamination.

    PubMed

    Pugash, D; Hendson, G; Dunham, C P; Dewar, K; Money, D M; Prayer, D

    2012-12-01

    Prenatal development of the brain is characterized by gestational age-specific changes in the laminar structure of the brain parenchyma before 30 gestational weeks. Cerebral lamination patterns of normal fetal brain development have been described histologically, by postmortem in-vitro magnetic resonance imaging (MRI) and by in-vivo fetal MRI. The purpose of this study was to evaluate the sonographic appearance of laminar organization of the cerebral wall in normal and abnormal brain development. This was a retrospective study of ultrasound findings in 92 normal fetuses and 68 fetuses with abnormal cerebral lamination patterns for gestational age, at 17-38 weeks' gestation. We investigated the visibility of the subplate zone relative to the intermediate zone and correlated characteristic sonographic findings of cerebral lamination with gestational age in order to evaluate transient structures. In the normal cohort, the subplate zone-intermediate zone interface was identified as early as 17 weeks, and in all 57 fetuses examined up to 28 weeks. In all of these fetuses, the subplate zone appeared anechoic and the intermediate zone appeared homogeneously more echogenic than did the subplate zone. In the 22 fetuses between 28 and 34 weeks, there was a transition period when lamination disappeared in a variable fashion. The subplate zone-intermediate zone interface was not identified in any fetus after 34 weeks (n=13). There were three patterns of abnormal cerebral lamination: (1) no normal laminar pattern before 28 weeks (n=32), in association with severe ventriculomegaly, diffuse ischemia, microcephaly, teratogen exposure or lissencephaly; (2) focal disruption of lamination before 28 weeks (n=24), associated with hemorrhage, porencephaly, stroke, migrational abnormalities, thanatophoric dysplasia, meningomyelocele or encephalocele; (3) increased prominence and echogenicity of the intermediate zone before 28 weeks and/or persistence of a laminar pattern beyond 33 weeks

  13. Time Lags between Exanthematous Illness Attributed to Zika Virus, Guillain-Barré Syndrome, and Microcephaly, Salvador, Brazil

    PubMed Central

    Paploski, Igor A.D.; Prates, Ana Paula P.B.; Cardoso, Cristiane W.; Kikuti, Mariana; Silva, Monaise M. O.; Waller, Lance A.; Reis, Mitermayer G.; Kitron, Uriel

    2016-01-01

    Zika virus infection emerged as a public health emergency after increasing evidence for its association with neurologic disorders and congenital malformations. In Salvador, Brazil, outbreaks of acute exanthematous illness (AEI) attributed to Zika virus, Guillain-Barré syndrome (GBS), and microcephaly occurred in 2015. We investigated temporal correlations and time lags between these outbreaks to identify a common link between them by using epidemic curves and time series cross-correlations. Number of GBS cases peaked after a lag of 5–9 weeks from the AEI peak. Number of suspected cases of microcephaly peaked after a lag of 30–33 weeks from the AEI peak, which corresponded to time of potential infections of pregnant mothers during the first trimester. These findings support the association of GBS and microcephaly with Zika virus infection and provide evidence for a temporal relationship between timing of arboviral infection of pregnant women during the first trimester and birth outcome. PMID:27144515

  14. Spindle Oscillations in Sleep Disorders: A Systematic Review

    PubMed Central

    Weiner, Oren M.

    2016-01-01

    Measurement of sleep microarchitecture and neural oscillations is an increasingly popular technique for quantifying EEG sleep activity. Many studies have examined sleep spindle oscillations in sleep-disordered adults; however reviews of this literature are scarce. As such, our overarching aim was to critically review experimental studies examining sleep spindle activity between adults with and without different sleep disorders. Articles were obtained using a systematic methodology with a priori criteria. Thirty-seven studies meeting final inclusion criteria were reviewed, with studies grouped across three categories: insomnia, hypersomnias, and sleep-related movement disorders (including parasomnias). Studies of patients with insomnia and sleep-disordered breathing were more abundant relative to other diagnoses. All studies were cross-sectional. Studies were largely inconsistent regarding spindle activity differences between clinical and nonclinical groups, with some reporting greater or less activity, while many others reported no group differences. Stark inconsistencies in sample characteristics (e.g., age range and diagnostic criteria) and methods of analysis (e.g., spindle bandwidth selection, visual detection versus digital filtering, absolute versus relative spectral power, and NREM2 versus NREM3) suggest a need for greater use of event-based detection methods and increased research standardization. Hypotheses regarding the clinical and empirical implications of these findings, and suggestions for potential future studies, are also discussed. PMID:27034850

  15. Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephaly

    PubMed Central

    Cottee, Matthew A; Muschalik, Nadine; Wong, Yao Liang; Johnson, Christopher M; Johnson, Steven; Andreeva, Antonina; Oegema, Karen; Lea, Susan M; Raff, Jordan W; van Breugel, Mark

    2013-01-01

    Centrioles organise centrosomes and template cilia and flagella. Several centriole and centrosome proteins have been linked to microcephaly (MCPH), a neuro-developmental disease associated with small brain size. CPAP (MCPH6) and STIL (MCPH7) are required for centriole assembly, but it is unclear how mutations in them lead to microcephaly. We show that the TCP domain of CPAP constitutes a novel proline recognition domain that forms a 1:1 complex with a short, highly conserved target motif in STIL. Crystal structures of this complex reveal an unusual, all-β structure adopted by the TCP domain and explain how a microcephaly mutation in CPAP compromises complex formation. Through point mutations, we demonstrate that complex formation is essential for centriole duplication in vivo. Our studies provide the first structural insight into how the malfunction of centriole proteins results in human disease and also reveal that the CPAP–STIL interaction constitutes a conserved key step in centriole biogenesis. DOI: http://dx.doi.org/10.7554/eLife.01071.001 PMID:24052813

  16. Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study.

    PubMed

    de Fatima Vasco Aragao, Maria; van der Linden, Vanessa; Brainer-Lima, Alessandra Mertens; Coeli, Regina Ramos; Rocha, Maria Angela; Sobral da Silva, Paula; Durce Costa Gomes de Carvalho, Maria; van der Linden, Ana; Cesario de Holanda, Arthur; Valenca, Marcelo Moraes

    2016-04-13

    To report radiological findings observed in computed tomography (CT) and magnetic resonance imaging (MRI) scans of the first cases of congenital infection and microcephaly presumably associated with the Zika virus in the current Brazilian epidemic. Retrospective study with a case series. Association for Assistance of Disabled Children (AACD), Pernambuco state, Brazil. 23 children with a diagnosis of congenital infection presumably associated with the Zika virus during the Brazilian microcephaly epidemic. Types of abnormalities and the radiological pattern of lesions identified on CT and MRI brain scans. Six of the 23 children tested positive for IgM antibodies to Zika virus in cerebrospinal fluid. The other 17 children met the protocol criteria for congenital infection presumably associated with the Zika virus, even without being tested for IgM antibodies to the virus--the test was not yet available on a routine basis. Of the 23 children, 15 underwent CT, seven underwent both CT and MRI, and one underwent MRI. Of the 22 children who underwent CT, all had calcifications in the junction between cortical and subcortical white matter, 21 (95%) had malformations of cortical development, 20 (91%) had a decreased brain volume, 19 (86%) had ventriculomegaly, and 11 (50%) had hypoplasia of the cerebellum or brainstem. Of the eight children who underwent MRI, all had calcifications in the junction between cortical and subcortical white matter, malformations of cortical development occurring predominantly in the frontal lobes, and ventriculomegaly. Seven of the eight (88%) children had enlarged cisterna magna, seven (88%) delayed myelination, and six each (75%) a moderate to severe decrease in brain volume, simplified gyral pattern, and abnormalities of the corpus callosum (38% hypogenesis and 38% hypoplasia). Malformations were symmetrical in 75% of the cases. Severe cerebral damage was found on imaging in most of the children in this case series with congenital infection

  17. Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study

    PubMed Central

    van der Linden, Vanessa; Brainer-Lima, Alessandra Mertens; Coeli, Regina Ramos; Rocha, Maria Angela; Sobral da Silva, Paula; Durce Costa Gomes de Carvalho, Maria; van der Linden, Ana; Cesario de Holanda, Arthur; Valenca, Marcelo Moraes

    2016-01-01

    Objective To report radiological findings observed in computed tomography (CT) and magnetic resonance imaging (MRI) scans of the first cases of congenital infection and microcephaly presumably associated with the Zika virus in the current Brazilian epidemic. Design Retrospective study with a case series. Setting Association for Assistance of Disabled Children (AACD), Pernambuco state, Brazil. Participants 23 children with a diagnosis of congenital infection presumably associated with the Zika virus during the Brazilian microcephaly epidemic. Main outcome measures Types of abnormalities and the radiological pattern of lesions identified on CT and MRI brain scans. Results Six of the 23 children tested positive for IgM antibodies to Zika virus in cerebrospinal fluid. The other 17 children met the protocol criteria for congenital infection presumably associated with the Zika virus, even without being tested for IgM antibodies to the virus—the test was not yet available on a routine basis. Of the 23 children, 15 underwent CT, seven underwent both CT and MRI, and one underwent MRI. Of the 22 children who underwent CT, all had calcifications in the junction between cortical and subcortical white matter, 21 (95%) had malformations of cortical development, 20 (91%) had a decreased brain volume, 19 (86%) had ventriculomegaly, and 11 (50%) had hypoplasia of the cerebellum or brainstem. Of the eight children who underwent MRI, all had calcifications in the junction between cortical and subcortical white matter, malformations of cortical development occurring predominantly in the frontal lobes, and ventriculomegaly. Seven of the eight (88%) children had enlarged cisterna magna, seven (88%) delayed myelination, and six each (75%) a moderate to severe decrease in brain volume, simplified gyral pattern, and abnormalities of the corpus callosum (38% hypogenesis and 38% hypoplasia). Malformations were symmetrical in 75% of the cases. Conclusion Severe cerebral damage was

  18. Whole Exome Sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome

    PubMed Central

    Martinez, Fernando; Lee, Jeong Ho; Lee, Ji Eun; Blanco, Sandra; Nickerson, Elizabeth; Gabriel, Stacey; Frye, Michaela; Al-Gazali, Lihadh; Gleeson, Joseph G.

    2016-01-01

    Dubowitz Syndrome is an autosomal recessive disorder characterized by the constellation of mild microcephaly, growth and mental retardation, eczema and peculiar facies, but causes are still unknown. We studied a multiplex consanguineous family with many features of Dubowitz syndrome using whole exome sequencing and identified a splice mutation in NSUN2, encoding a conserved RNA methyltransferase. NSUN2 has been implicated in Myc-induced cell proliferation and mitotic spindle stability, which might help explain the varied clinical presentations that can include chromosomal instability and immunological defects. Patient cells displayed loss of NSUN2-specific methylation at two residues of the aspartate tRNA. Our findings establish NSUN2 as the first causal gene with relationship to the Dubowitz syndrome spectrum phenotype. PMID:22577224

  19. Nonequilibrium fluctuations in metaphase spindles: polarized light microscopy, image registration, and correlation functions

    NASA Astrophysics Data System (ADS)

    Brugués, Jan; Needleman, Daniel J.

    2010-02-01

    Metaphase spindles are highly dynamic, nonequilibrium, steady-state structures. We study the internal fluctuations of spindles by computing spatio-temporal correlation functions of movies obtained from quantitative polarized light microscopy. These correlation functions are only physically meaningful if corrections are made for the net motion of the spindle. We describe our image registration algorithm in detail and we explore its robustness. Finally, we discuss the expression used for the estimation of the correlation function in terms of the nematic order of the microtubules which make up the spindle. Ultimately, studying the form of these correlation functions will provide a quantitative test of the validity of coarse-grained models of spindle structure inspired from liquid crystal physics.

  20. The induction of chromosomal abnormalities by inhalational anaesthetics.

    PubMed

    Grant, C J; Powell, J N; Radford, S G

    1977-06-01

    When Vicia faba root tips are exposed for 2 h to clinically useful concentrations of halothane or methoxyflurane in air, or to halothane in 80% nitrous oxide/20% oxygen, there is a transient increase in mitotic index and then abnormal interphase cells are produced in proportion to the anaesthetic concentrations. After exposure there is a period of mitotic inhibition during which the cells become partially synchronised. When colchicine-metaphase cells collected 28 h after exposure are compared with controls and with metaphases collected only 4 h after exposure, they show a significant increase in the incidence of aneuploidy, tetraploidy and the results of chromosome breakage. It is suggested that all the abnormalities seen can be accounted for by the effects of the anaesthetics on spindle movements, and that at the concentrations used the anaesthetics have no mutagenic effects on chromosomes in interphase.

  1. An allometric analysis of the number of muscle spindles in mammalian skeletal muscles

    PubMed Central

    Banks, R W

    2006-01-01

    An allometric analysis of the number of muscle spindles in relation to muscle mass in mammalian (mouse, rat, guinea-pig, cat, human) skeletal muscles is presented. It is shown that the trend to increasing number as muscle mass increases follows an isometric (length) relationship between species, whereas within a species, at least for the only essentially complete sample (human), the number of spindles scales, on average, with the square root rather than the cube root of muscle mass. An attempt is made to reconcile these apparently discrepant relationships. Use of the widely accepted spindle density (number of spindles g−1 of muscle) as a measure of relative abundance of spindles in different muscles is shown to be grossly misleading. It is replaced with the residuals of the linear regression of ln spindle number against ln muscle mass. Significant differences in relative spindle abundance as measured by residuals were found between regional groups of muscles: the greatest abundance is in axial muscles, including those concerned with head position, whereas the least is in muscles of the shoulder girdle. No differences were found between large and small muscles operating in parallel, or between antigravity and non-antigravity muscles. For proximal vs. distal muscles, spindles were significantly less abundant in the hand than the arm, but there was no difference between the foot and the leg. PMID:16761976

  2. Systemic blockade of dopamine D2-like receptors increases high-voltage spindles in the globus pallidus and motor cortex of freely moving rats.

    PubMed

    Yang, Chen; Ge, Shun-Nan; Zhang, Jia-Rui; Chen, Lei; Yan, Zhi-Qiang; Heng, Li-Jun; Zhao, Tian-Zhi; Li, Wei-Xin; Jia, Dong; Zhu, Jun-Ling; Gao, Guo-Dong

    2013-01-01

    High-voltage spindles (HVSs) have been reported to appear spontaneously and widely in the cortical-basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP) and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D₁-like receptors or D₂-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1) in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D₂-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D₂-like receptor antagonists. On the contrary, the selective dopamine D₁-like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D₂-like receptors, but not D₁-like receptors, were involved in HVS regulation. This supports the important role of dopamine D₂-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion.

  3. Copb2 is essential for embryogenesis and hypomorphic mutations cause human microcephaly.

    PubMed

    DiStasio, Andrew; Driver, Ashley; Sund, Kristen; Donlin, Milene; Muraleedharan, Ranjith M; Pooya, Shabnam; Kline-Fath, Beth; Kaufman, Kenneth M; Prows, Cynthia A; Schorry, Elizabeth; Dasgupta, Biplab; Stottmann, Rolf W

    2017-12-15

    Primary microcephaly is a congenital brain malformation characterized by a head circumference less than three standard deviations below the mean for age and sex and results in moderate to severe mental deficiencies and decreased lifespan. We recently studied two children with primary microcephaly in an otherwise unaffected family. Exome sequencing identified an autosomal recessive mutation leading to an amino acid substitution in a WD40 domain of the highly conserved Coatomer Protein Complex, Subunit Beta 2 (COPB2). To study the role of Copb2 in neural development, we utilized genome-editing technology to generate an allelic series in the mouse. Two independent null alleles revealed that Copb2 is essential for early stages of embryogenesis. Mice homozygous for the patient variant (Copb2R254C/R254C) appear to have a grossly normal phenotype, likely due to differences in corticogenesis between the two species. Strikingly, mice heterozygous for the patient mutation and a null allele (Copb2R254C/Zfn) show a severe perinatal phenotype including low neonatal weight, significantly increased apoptosis in the brain, and death within the first week of life. Immunostaining of the Copb2R254C/Zfnbrain revealed a reduction in layer V (CTIP2+) neurons, while the overall cell density of the cortex is unchanged. Moreover, neurospheres derived from animals with Copb2 variants grew less than control. These results identify a general requirement for COPB2 in embryogenesis and a specific role in corticogenesis. We further demonstrate the utility of CRISPR-Cas9 generated mouse models in the study of potential pathogenicity of variants of potential clinical interest. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. A curved edge diffraction-utilized displacement sensor for spindle metrology

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lee, ChaBum, E-mail: clee@tntech.edu; Zhao, Rui; Jeon, Seongkyul

    This paper presents a new dimensional metrological sensing principle for a curved surface based on curved edge diffraction. Spindle error measurement technology utilizes a cylindrical or spherical target artifact attached to the spindle with non-contact sensors, typically a capacitive sensor (CS) or an eddy current sensor, pointed at the artifact. However, these sensors are designed for flat surface measurement. Therefore, measuring a target with a curved surface causes error. This is due to electric fields behaving differently between a flat and curved surface than between two flat surfaces. In this study, a laser is positioned incident to the cylindrical surfacemore » of the spindle, and a photodetector collects the total field produced by the diffraction around the target surface. The proposed sensor was compared with a CS within a range of 500 μm. The discrepancy between the proposed sensor and CS was 0.017% of the full range. Its sensing performance showed a resolution of 14 nm and a drift of less than 10 nm for 7 min of operation. This sensor was also used to measure dynamic characteristics of the spindle system (natural frequency 181.8 Hz, damping ratio 0.042) and spindle runout (22.0 μm at 2000 rpm). The combined standard uncertainty was estimated as 85.9 nm under current experiment conditions. It is anticipated that this measurement technique allows for in situ health monitoring of a precision spindle system in an accurate, convenient, and low cost manner.« less

  5. Thalamic Spindles Promote Memory Formation during Sleep through Triple Phase-Locking of Cortical, Thalamic, and Hippocampal Rhythms.

    PubMed

    Latchoumane, Charles-Francois V; Ngo, Hong-Viet V; Born, Jan; Shin, Hee-Sup

    2017-07-19

    While the interaction of the cardinal rhythms of non-rapid-eye-movement (NREM) sleep-the thalamo-cortical spindles, hippocampal ripples, and the cortical slow oscillations-is thought to be critical for memory consolidation during sleep, the role spindles play in this interaction is elusive. Combining optogenetics with a closed-loop stimulation approach in mice, we show here that only thalamic spindles induced in-phase with cortical slow oscillation up-states, but not out-of-phase-induced spindles, improve consolidation of hippocampus-dependent memory during sleep. Whereas optogenetically stimulated spindles were as efficient as spontaneous spindles in nesting hippocampal ripples within their excitable troughs, stimulation in-phase with the slow oscillation up-state increased spindle co-occurrence and frontal spindle-ripple co-occurrence, eventually resulting in increased triple coupling of slow oscillation-spindle-ripple events. In-phase optogenetic suppression of thalamic spindles impaired hippocampus-dependent memory. Our results suggest a causal role for thalamic sleep spindles in hippocampus-dependent memory consolidation, conveyed through triple coupling of slow oscillations, spindles, and ripples. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Intra-spindle Microtubule Assembly Regulates Clustering of Microtubule-Organizing Centers during Early Mouse Development.

    PubMed

    Watanabe, Sadanori; Shioi, Go; Furuta, Yasuhide; Goshima, Gohta

    2016-04-05

    Errors during cell division in oocytes and early embryos are linked to birth defects in mammals. Bipolar spindle assembly in early mouse embryos is unique in that three or more acentriolar microtubule-organizing centers (MTOCs) are initially formed and are then clustered into two spindle poles. Using a knockout mouse and live imaging of spindles in embryos, we demonstrate that MTOC clustering during the blastocyst stage requires augmin, a critical complex for MT-dependent MT nucleation within the spindle. Functional analyses in cultured cells with artificially increased numbers of centrosomes indicate that the lack of intra-spindle MT nucleation, but not loss of augmin per se or overall reduction of spindle MTs, is the cause of clustering failure. These data suggest that onset of mitosis with three or more MTOCs is turned into a typical bipolar division through augmin-dependent intra-spindle MT assembly. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Direct kinetochore–spindle pole connections are not required for chromosome segregation

    PubMed Central

    Sikirzhytski, Vitali; Magidson, Valentin; Steinman, Jonathan B.; He, Jie; Le Berre, Maël; Tikhonenko, Irina; Ault, Jeffrey G.; McEwen, Bruce F.; Chen, James K.; Sui, Haixin; Piel, Matthieu; Kapoor, Tarun M.

    2014-01-01

    Segregation of genetic material occurs when chromosomes move to opposite spindle poles during mitosis. This movement depends on K-fibers, specialized microtubule (MT) bundles attached to the chromosomes′ kinetochores. A long-standing assumption is that continuous K-fibers connect every kinetochore to a spindle pole and the force for chromosome movement is produced at the kinetochore and coupled with MT depolymerization. However, we found that chromosomes still maintained their position at the spindle equator during metaphase and segregated properly during anaphase when one of their K-fibers was severed near the kinetochore with a laser microbeam. We also found that, in normal fully assembled spindles, K-fibers of some chromosomes did not extend to the spindle pole. These K-fibers connected to adjacent K-fibers and/or nonkinetochore MTs. Poleward movement of chromosomes with short K-fibers was uncoupled from MT depolymerization at the kinetochore. Instead, these chromosomes moved by dynein-mediated transport of the entire K-fiber/kinetochore assembly. Thus, at least two distinct parallel mechanisms drive chromosome segregation in mammalian cells. PMID:25023516

  8. Direct kinetochore-spindle pole connections are not required for chromosome segregation.

    PubMed

    Sikirzhytski, Vitali; Magidson, Valentin; Steinman, Jonathan B; He, Jie; Le Berre, Maël; Tikhonenko, Irina; Ault, Jeffrey G; McEwen, Bruce F; Chen, James K; Sui, Haixin; Piel, Matthieu; Kapoor, Tarun M; Khodjakov, Alexey

    2014-07-21

    Segregation of genetic material occurs when chromosomes move to opposite spindle poles during mitosis. This movement depends on K-fibers, specialized microtubule (MT) bundles attached to the chromosomes' kinetochores. A long-standing assumption is that continuous K-fibers connect every kinetochore to a spindle pole and the force for chromosome movement is produced at the kinetochore and coupled with MT depolymerization. However, we found that chromosomes still maintained their position at the spindle equator during metaphase and segregated properly during anaphase when one of their K-fibers was severed near the kinetochore with a laser microbeam. We also found that, in normal fully assembled spindles, K-fibers of some chromosomes did not extend to the spindle pole. These K-fibers connected to adjacent K-fibers and/or nonkinetochore MTs. Poleward movement of chromosomes with short K-fibers was uncoupled from MT depolymerization at the kinetochore. Instead, these chromosomes moved by dynein-mediated transport of the entire K-fiber/kinetochore assembly. Thus, at least two distinct parallel mechanisms drive chromosome segregation in mammalian cells.

  9. Material Choice for spindle of machine tools

    NASA Astrophysics Data System (ADS)

    Gouasmi, S.; Merzoug, B.; Abba, G.; Kherredine, L.

    2012-02-01

    The requirements of contemporary industry and the flashing development of modern sciences impose restrictions on the majority of the elements of machines; the resulting financial constraints can be satisfied by a better output of the production equipment. As for those concerning the design, the resistance and the correct operation of the product, these require the development of increasingly precise parts, therefore the use of increasingly powerful tools [5]. The precision of machining and the output of the machine tools are generally determined by the precision of rotation of the spindle, indeed, more this one is large more the dimensions to obtain are in the zone of tolerance and the defects of shape are minimized. During the development of the machine tool, the spindle which by definition is a rotating shaft receiving and transmitting to the work piece or the cutting tool the rotational movement, must be designed according to certain optimal parameters to be able to ensure the precision required. This study will be devoted to the choice of the material of the spindle fulfilling the imposed requirements of precision.

  10. Simplified Dynamic Analysis of Grinders Spindle Node

    NASA Astrophysics Data System (ADS)

    Demec, Peter

    2014-12-01

    The contribution deals with the simplified dynamic analysis of surface grinding machine spindle node. Dynamic analysis is based on the use of the transfer matrix method, which is essentially a matrix form of method of initial parameters. The advantage of the described method, despite the seemingly complex mathematical apparatus, is primarily, that it does not require for solve the problem of costly commercial software using finite element method. All calculations can be made for example in MS Excel, which is advantageous especially in the initial stages of constructing of spindle node for the rapid assessment of the suitability its design. After detailing the entire structure of spindle node is then also necessary to perform the refined dynamic analysis in the environment of FEM, which it requires the necessary skills and experience and it is therefore economically difficult. This work was developed within grant project KEGA No. 023TUKE-4/2012 Creation of a comprehensive educational - teaching material for the article Production technique using a combination of traditional and modern information technology and e-learning.

  11. RED, a Spindle Pole-associated Protein, Is Required for Kinetochore Localization of MAD1, Mitotic Progression, and Activation of the Spindle Assembly Checkpoint*

    PubMed Central

    Yeh, Pei-Chi; Yeh, Chang-Ching; Chen, Yi-Cheng; Juang, Yue-Li

    2012-01-01

    The spindle assembly checkpoint (SAC) is essential for ensuring the proper attachment of kinetochores to the spindle and, thus, the precise separation of paired sister chromatids during mitosis. The SAC proteins are recruited to the unattached kinetochores for activation of the SAC in prometaphase. However, it has been less studied whether activation of the SAC also requires the proteins that do not localize to the kinetochores. Here, we show that the nuclear protein RED, also called IK, a down-regulator of human leukocyte antigen (HLA) II, interacts with the human SAC protein MAD1. Two RED-interacting regions identified in MAD1 are from amino acid residues 301–340 and 439–480, designated as MAD1(301–340) and MAD1(439–480), respectively. Our observations reveal that RED is a spindle pole-associated protein that colocalizes with MAD1 at the spindle poles in metaphase and anaphase. Depletion of RED can cause a shorter mitotic timing, a failure in the kinetochore localization of MAD1 in prometaphase, and a defect in the SAC. Furthermore, the RED-interacting peptides MAD1(301–340) and MAD1(439–480), fused to enhanced green fluorescence protein, can colocalize with RED at the spindle poles in prometaphase, and their expression can abrogate the SAC. Taken together, we conclude that RED is required for kinetochore localization of MAD1, mitotic progression, and activation of the SAC. PMID:22351768

  12. Exclusive destruction of mitotic spindles in human cancer cells.

    PubMed

    Visochek, Leonid; Castiel, Asher; Mittelman, Leonid; Elkin, Michael; Atias, Dikla; Golan, Talia; Izraeli, Shai; Peretz, Tamar; Cohen-Armon, Malka

    2017-03-28

    We identified target proteins modified by phenanthrenes that cause exclusive eradication of human cancer cells. The cytotoxic activity of the phenanthrenes in a variety of human cancer cells is attributed by these findings to post translational modifications of NuMA and kinesins HSET/kifC1 and kif18A. Their activity prevented the binding of NuMA to α-tubulin and kinesins in human cancer cells, and caused aberrant spindles. The most efficient cytotoxic activity of the phenanthridine PJ34, caused significantly smaller aberrant spindles with disrupted spindle poles and scattered extra-centrosomes and chromosomes. Concomitantly, PJ34 induced tumor growth arrest of human malignant tumors developed in athymic nude mice, indicating the relevance of its activity for cancer therapy.

  13. F-actin mechanics control spindle centring in the mouse zygote

    NASA Astrophysics Data System (ADS)

    Chaigne, Agathe; Campillo, Clément; Voituriez, Raphaël; Gov, Nir S.; Sykes, Cécile; Verlhac, Marie-Hélène; Terret, Marie-Emilie

    2016-01-01

    Mitotic spindle position relies on interactions between astral microtubules nucleated by centrosomes and a rigid cortex. Some cells, such as mouse oocytes, do not possess centrosomes and astral microtubules. These cells rely only on actin and on a soft cortex to position their spindle off-centre and undergo asymmetric divisions. While the first mouse embryonic division also occurs in the absence of centrosomes, it is symmetric and not much is known on how the spindle is positioned at the exact cell centre. Using interdisciplinary approaches, we demonstrate that zygotic spindle positioning follows a three-step process: (1) coarse centring of pronuclei relying on the dynamics of an F-actin/Myosin-Vb meshwork; (2) fine centring of the metaphase plate depending on a high cortical tension; (3) passive maintenance at the cell centre. Altogether, we show that F-actin-dependent mechanics operate the switch between asymmetric to symmetric division required at the oocyte to embryo transition.

  14. Pericentromere tension is self-regulated by spindle structure in metaphase

    PubMed Central

    Chacón, Jeremy M.; Mukherjee, Soumya; Schuster, Breanna M.; Clarke, Duncan J.

    2014-01-01

    During cell division, a mitotic spindle is built by the cell and acts to align and stretch duplicated sister chromosomes before their ultimate segregation into daughter cells. Stretching of the pericentromeric chromatin during metaphase is thought to generate a tension-based signal that promotes proper chromosome segregation. However, it is not known whether the mitotic spindle actively maintains a set point tension magnitude for properly attached sister chromosomes to facilitate robust mechanochemical checkpoint signaling. By imaging and tracking the thermal movements of pericentromeric fluorescent markers in Saccharomyces cerevisiae, we measured pericentromere stiffness and then used the stiffness measurements to quantitatively evaluate the tension generated by pericentromere stretch during metaphase in wild-type cells and in mutants with disrupted chromosome structure. We found that pericentromere tension in yeast is substantial (4–6 pN) and is tightly self-regulated by the mitotic spindle: through adjustments in spindle structure, the cell maintains wild-type tension magnitudes even when pericentromere stiffness is disrupted. PMID:24821839

  15. Pericentromere tension is self-regulated by spindle structure in metaphase.

    PubMed

    Chacón, Jeremy M; Mukherjee, Soumya; Schuster, Breanna M; Clarke, Duncan J; Gardner, Melissa K

    2014-05-12

    During cell division, a mitotic spindle is built by the cell and acts to align and stretch duplicated sister chromosomes before their ultimate segregation into daughter cells. Stretching of the pericentromeric chromatin during metaphase is thought to generate a tension-based signal that promotes proper chromosome segregation. However, it is not known whether the mitotic spindle actively maintains a set point tension magnitude for properly attached sister chromosomes to facilitate robust mechanochemical checkpoint signaling. By imaging and tracking the thermal movements of pericentromeric fluorescent markers in Saccharomyces cerevisiae, we measured pericentromere stiffness and then used the stiffness measurements to quantitatively evaluate the tension generated by pericentromere stretch during metaphase in wild-type cells and in mutants with disrupted chromosome structure. We found that pericentromere tension in yeast is substantial (4-6 pN) and is tightly self-regulated by the mitotic spindle: through adjustments in spindle structure, the cell maintains wild-type tension magnitudes even when pericentromere stiffness is disrupted.

  16. Oocyte spindle proteomics analysis leading to rescue of chromosome congression defects in cloned embryos

    PubMed Central

    Duan, Xunbao; Zhong, Zhisheng; Potireddy, Santhi; Moncada, Camilo; Merali, Salim; Latham, Keith E.

    2015-01-01

    Embryos produced by somatic cell nuclear transfer (SCNT) display low term developmental potential. This is associated with deficiencies in spindle composition prior to activation and at early mitotic divisions, including failure to assemble certain proteins on the spindle. The protein-deficient spindles are accompanied by chromosome congression defects prior to activation and during the first mitotic divisions of the embryo. The molecular basis for these deficiencies and how they might be avoided are unknown. Proteomic analyses of spindles isolated from normal metaphase II (MII) stage oocytes and SCNT constructs, along with a systematic immunofluorescent survey of known spindle-associated proteins were undertaken. This was the first proteomics study of mammalian oocyte spindles. The study revealed four proteins as being deficient in spindles of SCNT embryos in addition to those previously identified; these were clathrin heavy chain (CLTC), aurora B kinase, dynactin 4, and casein kinase 1 alpha. Due to substantial reduction in CLTC abundance after spindle removal, we undertook functional studies to explore the importance of CLTC in oocyte spindle function and in chromosome congression defects of cloned embryos. Using siRNA knockdown we demonstrated an essential role for CLTC in chromosome congression during oocyte maturation. We also demonstrated rescue of chromosome congression defects in SCNT embryos at the first mitosis using CLTC mRNA injection. These studies are the first to employ proteomics analyses coupled to functional interventions to rescue a specific molecular defect in cloned embryos. PMID:20883044

  17. Interactions between core and matrix thalamocortical projections in human sleep spindle synchronization

    PubMed Central

    Bonjean, Maxime; Baker, Tanya; Bazhenov, Maxim; Cash, Sydney; Halgren, Eric; Sejnowski, Terrence

    2012-01-01

    Sleep spindles, which are bursts of 11–15 Hz that occur during non-REM sleep, are highly synchronous across the scalp when measured with EEG, but have low spatial coherence and exhibit low correlation with EEG signals when simultaneously measured with MEG spindles in humans. We developed a computational model to explore the hypothesis that the spatial coherence of the EEG spindle is a consequence of diffuse matrix projections of the thalamus to layer 1 compared to the focal projections of the core pathway to layer 4 recorded by the MEG. Increasing the fanout of thalamocortical connectivity in the matrix pathway while keeping the core pathway fixed led to increased synchrony of the spindle activity in the superficial cortical layers in the model. In agreement with cortical recordings, the latency for spindles to spread from the core to the matrix was independent of the thalamocortical fanout but highly dependent on the probability of connections between cortical areas. PMID:22496571

  18. Sleep spindle and K-complex detection using tunable Q-factor wavelet transform and morphological component analysis

    PubMed Central

    Lajnef, Tarek; Chaibi, Sahbi; Eichenlaub, Jean-Baptiste; Ruby, Perrine M.; Aguera, Pierre-Emmanuel; Samet, Mounir; Kachouri, Abdennaceur; Jerbi, Karim

    2015-01-01

    A novel framework for joint detection of sleep spindles and K-complex events, two hallmarks of sleep stage S2, is proposed. Sleep electroencephalography (EEG) signals are split into oscillatory (spindles) and transient (K-complex) components. This decomposition is conveniently achieved by applying morphological component analysis (MCA) to a sparse representation of EEG segments obtained by the recently introduced discrete tunable Q-factor wavelet transform (TQWT). Tuning the Q-factor provides a convenient and elegant tool to naturally decompose the signal into an oscillatory and a transient component. The actual detection step relies on thresholding (i) the transient component to reveal K-complexes and (ii) the time-frequency representation of the oscillatory component to identify sleep spindles. Optimal thresholds are derived from ROC-like curves (sensitivity vs. FDR) on training sets and the performance of the method is assessed on test data sets. We assessed the performance of our method using full-night sleep EEG data we collected from 14 participants. In comparison to visual scoring (Expert 1), the proposed method detected spindles with a sensitivity of 83.18% and false discovery rate (FDR) of 39%, while K-complexes were detected with a sensitivity of 81.57% and an FDR of 29.54%. Similar performances were obtained when using a second expert as benchmark. In addition, when the TQWT and MCA steps were excluded from the pipeline the detection sensitivities dropped down to 70% for spindles and to 76.97% for K-complexes, while the FDR rose up to 43.62 and 49.09%, respectively. Finally, we also evaluated the performance of the proposed method on a set of publicly available sleep EEG recordings. Overall, the results we obtained suggest that the TQWT-MCA method may be a valuable alternative to existing spindle and K-complex detection methods. Paths for improvements and further validations with large-scale standard open-access benchmarking data sets are discussed. PMID

  19. Sleep spindles may predict response to cognitive-behavioral therapy for chronic insomnia.

    PubMed

    Dang-Vu, Thien Thanh; Hatch, Benjamin; Salimi, Ali; Mograss, Melodee; Boucetta, Soufiane; O'Byrne, Jordan; Brandewinder, Marie; Berthomier, Christian; Gouin, Jean-Philippe

    2017-11-01

    While cognitive-behavioral therapy for insomnia constitutes the first-line treatment for chronic insomnia, only few reports have investigated how sleep architecture relates to response to this treatment. In this pilot study, we aimed to determine whether pre-treatment sleep spindle density predicts treatment response to cognitive-behavioral therapy for insomnia. Twenty-four participants with chronic primary insomnia participated in a 6-week cognitive-behavioral therapy for insomnia performed in groups of 4-6 participants. Treatment response was assessed using the Pittsburgh Sleep Quality Index and the Insomnia Severity Index measured at pre- and post-treatment, and at 3- and 12-months' follow-up assessments. Secondary outcome measures were extracted from sleep diaries over 7 days and overnight polysomnography, obtained at pre- and post-treatment. Spindle density during stage N2-N3 sleep was extracted from polysomnography at pre-treatment. Hierarchical linear modeling analysis assessed whether sleep spindle density predicted response to cognitive-behavioral therapy. After adjusting for age, sex, and education level, lower spindle density at pre-treatment predicted poorer response over the 12-month follow-up, as reflected by a smaller reduction in Pittsburgh Sleep Quality Index over time. Reduced spindle density also predicted lower improvements in sleep diary sleep efficiency and wake after sleep onset immediately after treatment. There were no significant associations between spindle density and changes in the Insomnia Severity Index or polysomnography variables over time. These preliminary results suggest that inter-individual differences in sleep spindle density in insomnia may represent an endogenous biomarker predicting responsiveness to cognitive-behavioral therapy. Insomnia with altered spindle activity might constitute an insomnia subtype characterized by a neurophysiological vulnerability to sleep disruption associated with impaired responsiveness to

  20. Novel phosphorylation states of the yeast spindle pole body.

    PubMed

    Fong, Kimberly K; Zelter, Alex; Graczyk, Beth; Hoyt, Jill M; Riffle, Michael; Johnson, Richard; MacCoss, Michael J; Davis, Trisha N

    2018-06-14

    Phosphorylation regulates yeast spindle pole body (SPB) duplication and separation and likely regulates microtubule nucleation. We report a phosphoproteomic analysis using tandem mass spectrometry of enriched Saccharomyces cerevisiae SPBs for two cell cycle arrests, G1/S and the mitotic checkpoint, expanding on previously reported phosphoproteomic data sets. We present a novel phosphoproteomic state of SPBs arrested in G1/S by a cdc4-1 temperature sensitive mutation, with particular focus on phosphorylation events on the γ-tubulin small complex (γ-TuSC). The cdc4-1 arrest is the earliest arrest at which microtubule nucleation has occurred at the newly duplicated SPB. Several novel phosphorylation sites were identified in G1/S and during mitosis on the microtubule nucleating γ-TuSC. These sites were analyzed in vivo by fluorescence microscopy and were shown to be required for proper regulation of spindle length. Additionally, in vivo analysis of two mitotic sites in Spc97 found that phosphorylation of at least one of these sites is required for progression through the cell cycle. This phosphoproteomic data set not only broadens the scope of the phosphoproteome of SPBs, it also identifies several γ-TuSC phosphorylation sites that influence microtubule formation. © 2018. Published by The Company of Biologists Ltd.

  1. Topological defects in confined populations of spindle-shaped cells

    NASA Astrophysics Data System (ADS)

    Duclos, Guillaume; Erlenkämper, Christoph; Joanny, Jean-François; Silberzan, Pascal

    2017-01-01

    Most spindle-shaped cells (including smooth muscles and sarcomas) organize in vivo into well-aligned `nematic’ domains, creating intrinsic topological defects that may be used to probe the behaviour of these active nematic systems. Active non-cellular nematics have been shown to be dominated by activity, yielding complex chaotic flows. However, the regime in which live spindle-shaped cells operate, and the importance of cell-substrate friction in particular, remains largely unexplored. Using in vitro experiments, we show that these active cellular nematics operate in a regime in which activity is effectively damped by friction, and that the interaction between defects is controlled by the system’s elastic nematic energy. Due to the activity of the cells, these defects behave as self-propelled particles and pairwise annihilate until all displacements freeze as cell crowding increases. When confined in mesoscopic circular domains, the system evolves towards two identical +1/2 disclinations facing each other. The most likely reduced positions of these defects are independent of the size of the disk, the cells’ activity or even the cell type, but are well described by equilibrium liquid crystal theory. These cell-based systems thus operate in a regime more stable than other active nematics, which may be necessary for their biological function.

  2. Functioning and Disability Profile of Children with Microcephaly Associated with Congenital Zika Virus Infection.

    PubMed

    Ferreira, Haryelle Náryma Confessor; Schiariti, Veronica; Regalado, Isabelly Cristina Rodrigues; Sousa, Klayton Galante; Pereira, Silvana Alves; Fechine, Carla Patrícia Novaes Dos Santos; Longo, Egmar

    2018-05-29

    The increase in the number of cases of microcephaly in Brazil and its association with the Zika virus (ZIKV) is a global public health problem. The International Classification of Functioning Disability and Health (ICF) model is a powerful tool and extremely relevant in managing disability. Describe the functioning profile of children with microcephaly associated with ZIKV in two states of northeastern Brazil. This is a descriptive cross-sectional study. The sociodemographic characteristics, head circumference, and other clinical data were collected from medical charts, physical examinations, measuring instruments, and interviews with the children and their parents. The Brazilian Portuguese version of the Brief Common ICF Core Set for cerebral palsy (CP) was used. Each ICF category was assigned a qualifier, which ranged from 0 to 4 (no problem, mild problem, moderate problem, severe problem, complete problem). For environmental factors, 0 represents no barrier and 4 represents complete barrier; +0, no facilitator and +4, complete facilitator. A total of 34 children with microcephaly caused by ZIKV were recruited (18 girls and 16 boys) at four rehabilitation facilities in Rio Grande do Norte and Paraíba states, Brazil. The average age of the participants was 21 months, monthly income was ≈USD 300.00, and head circumference z-scores ranged between 0.92 and -5.51. The functioning profile revealed complete disability in most of the body function categories (b). The activity and participation areas (d) were highly impacted, particularly in mobility-related categories. With respect to environmental factors (e), most of the sample reported a complete facilitator for the immediate family, friends, and health services, systems, and policies, as well as a complete barrier to societal attitudes. This is the first study that describes the functioning profile of children with microcephaly associated with ZIKV, using a tool based on the ICF in Brazil. Our findings reinforce

  3. Topographic and sex-related differences in sleep spindles in major depressive disorder: a high-density EEG investigation.

    PubMed

    Plante, D T; Goldstein, M R; Landsness, E C; Peterson, M J; Riedner, B A; Ferrarelli, F; Wanger, T; Guokas, J J; Tononi, G; Benca, R M

    2013-03-20

    Sleep spindles are believed to mediate several sleep-related functions including maintaining disconnection from the external environment during sleep, cortical development, and sleep-dependent memory consolidation. Prior studies that have examined sleep spindles in major depressive disorder (MDD) have not demonstrated consistent differences relative to control subjects, which may be due to sex-related variation and limited spatial resolution of spindle detection. Thus, this study sought to characterize sleep spindles in MDD using high-density electroencephalography (hdEEG) to examine the topography of sleep spindles across the cortex in MDD, as well as sex-related variation in spindle topography in the disorder. All-night hdEEG recordings were collected in 30 unipolar MDD participants (19 women) and 30 age and sex-matched controls. Topography of sleep spindle density, amplitude, duration, and integrated spindle activity (ISA) were assessed to determine group differences. Spindle parameters were compared between MDD and controls, including analysis stratified by sex. As a group, MDD subjects demonstrated significant increases in frontal and parietal spindle density and ISA compared to controls. When stratified by sex, MDD women demonstrated increases in frontal and parietal spindle density, amplitude, duration, and ISA; whereas MDD men demonstrated either no differences or decreases in spindle parameters. Given the number of male subjects, this study may be underpowered to detect differences in spindle parameters in male MDD participants. This study demonstrates topographic and sex-related differences in sleep spindles in MDD. Further research is warranted to investigate the role of sleep spindles and sex in the pathophysiology of MDD. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Kinesin-5-independent mitotic spindle assembly requires the antiparallel microtubule crosslinker Ase1 in fission yeast

    PubMed Central

    Rincon, Sergio A.; Lamson, Adam; Blackwell, Robert; Syrovatkina, Viktoriya; Fraisier, Vincent; Paoletti, Anne; Betterton, Meredith D.; Tran, Phong T.

    2017-01-01

    Bipolar spindle assembly requires a balance of forces where kinesin-5 produces outward pushing forces to antagonize the inward pulling forces from kinesin-14 or dynein. Accordingly, Kinesin-5 inactivation results in force imbalance leading to monopolar spindle and chromosome segregation failure. In fission yeast, force balance is restored when both kinesin-5 Cut7 and kinesin-14 Pkl1 are deleted, restoring spindle bipolarity. Here we show that the cut7Δpkl1Δ spindle is fully competent for chromosome segregation independently of motor activity, except for kinesin-6 Klp9, which is required for anaphase spindle elongation. We demonstrate that cut7Δpkl1Δ spindle bipolarity requires the microtubule antiparallel bundler PRC1/Ase1 to recruit CLASP/Cls1 to stabilize microtubules. Brownian dynamics-kinetic Monte Carlo simulations show that Ase1 and Cls1 activity are sufficient for initial bipolar spindle formation. We conclude that pushing forces generated by microtubule polymerization are sufficient to promote spindle pole separation and the assembly of bipolar spindle in the absence of molecular motors. PMID:28513584

  5. Mathematical modeling and numerical simulation of the mitotic spindle orientation system.

    PubMed

    Ibrahim, Bashar

    2018-05-21

    The mitotic spindle orientation and position is crucial for the fidelity of chromosome segregation during asymmetric cell division to generate daughter cells with different sizes or fates. This mechanism is best understood in the budding yeast Saccharomyces cerevisiae, named the spindle position checkpoint (SPOC). The SPOC inhibits cells from exiting mitosis until the mitotic spindle is properly oriented along the mother-daughter polarity axis. Despite many experimental studies, the mechanisms underlying SPOC regulation remains elusive and unexplored theoretically. Here, a minimal mathematical is developed to describe SPOC activation and silencing having autocatalytic feedback-loop. Numerical simulations of the nonlinear ordinary differential equations (ODEs) model accurately reproduce the phenotype of SPOC mechanism. Bifurcation analysis of the nonlinear ODEs reveals the orientation dependency on spindle pole bodies, and how this dependence is altered by parameter values. These results provide for systems understanding on the molecular organization of spindle orientation system via mathematical modeling. The presented mathematical model is easy to understand and, within the above mentioned context, can be used as a base for further development of quantitative models in asymmetric cell-division. Copyright © 2018. Published by Elsevier Inc.

  6. Abnormal neurodevelopmental outcomes are very likely in cases of bilateral neonatal arterial ischaemic stroke.

    PubMed

    Jin, Ju Hyun; Shin, Jeong Eun; Lee, Soon Min; Eun, Ho Seon; Park, Min Soo; Park, Kook In; Namgung, Ran

    2017-02-01

    Neonatal arterial ischaemic stroke (AIS) is an important cause of severe neurological disability. This study aimed to analyse the clinical manifestations and outcomes of AIS patients. We enrolled neonates with AIS admitted to Severance Children's Hospital and Gangnam Severance Hospital between 2008 and 2015. AIS was confirmed using magnetic resonance imaging (MRI). We retrospectively reviewed the clinical manifestations, MRI findings, electroencephalography (EEG) findings and neurodevelopmental outcomes. The study comprised 29 neonates (18 boys). The mean follow-up period was 15.4 months (range 6-44 months), and the mean age at diagnosis was 8.1 days. Seizure was the most common symptom (66%). Bilateral involvement was more common than unilateral involvement (52%). The middle cerebral artery was the most commonly identified territory (79%). Abnormal EEG findings were noted in 93% of the cases. Neurodevelopment was normal in 11 (38%) patients, while cerebral palsy and delayed development were noted in eight (28%) and six (21%) patients, respectively. Patients with bilateral involvement were very likely to have abnormal neurodevelopmental outcomes. Our study showed that abnormal neurodevelopmental outcomes were very likely after cases of neonatal AIS with bilateral involvement, and clinicians should consider early and more effective interventions in such cases. ©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  7. Mitosis in Barbulanympha. I. Spindle structure, formation, and kinetochore engagement

    PubMed Central

    1978-01-01

    Successful culture of the obligatorily anaerobic symbionts residing in the hindgut of the wood-eating cockroach Cryptocercus punctulatus now permits continuous observation of mitosis in individual Barbulanympha cells. In Part I of this two-part paper, we report methods for culture of the protozoa, preparation of microscope slide cultures in which Barbulanympha survived and divided for up to 3 days, and an optical arrangement which permits observation and through-focus photographic recording of dividing cells, sequentially in differential interference contrast and rectified polarized light microscopy. We describe the following prophase events and structures: development of the astral rays and large extranuclear central spindle from the tips of the elongate-centrioles; the fine structure of spindle fibers and astral rays which were deduced in vivo from polarized light microscopy and seen as a particular array of microtubules in thin-section electron micrographs; formation of chromosomal spindle fibers by dynamic engagement of astral rays to the kinetochores embedded in the persistent nuclear envelope; and repetitive shortening of chromosomal spindle fibers which appear to hoist the nucleus to the spindle surface, cyclically jostle the kinetochores within the nuclear envelope, and churn the prophase chromosomes. The observations described here and in Part II have implications both for the evolution of mitosis and for understanding the mitotic process generally. PMID:681451

  8. Regulating positioning and orientation of mitotic spindles via cell size and shape

    NASA Astrophysics Data System (ADS)

    Li, Jingchen; Jiang, Hongyuan

    2018-01-01

    Proper location of the mitotic spindle is critical for chromosome segregation and the selection of the cell division plane. However, how mitotic spindles sense cell size and shape to regulate their own position and orientation is still largely unclear. To investigate this question systematically, we used a general model by considering chromosomes, microtubule dynamics, and forces of various molecular motors. Our results show that in cells of various sizes and shapes, spindles can always be centered and oriented along the long axis robustly in the absence of other specified mechanisms. We found that the characteristic time of positioning and orientation processes increases with cell size. Spindles sense the cell size mainly by the cortical force in small cells and by the cytoplasmic force in large cells. In addition to the cell size, the cell shape mainly influences the orientation process. We found that more slender cells have a faster orientation process, and the final orientation is not necessarily along the longest axis but is determined by the radial profile and the symmetry of the cell shape. Finally, our model also reproduces the separation and repositioning of the spindle poles during the anaphase. Therefore, our work provides a general tool for studying the mitotic spindle across the whole mitotic phase.

  9. Estimating the Number of Pregnant Women Infected With Zika Virus and Expected Infants With Microcephaly Following the Zika Virus Outbreak in Puerto Rico, 2016.

    PubMed

    Ellington, Sascha R; Devine, Owen; Bertolli, Jeanne; Martinez Quiñones, Alma; Shapiro-Mendoza, Carrie K; Perez-Padilla, Janice; Rivera-Garcia, Brenda; Simeone, Regina M; Jamieson, Denise J; Valencia-Prado, Miguel; Gilboa, Suzanne M; Honein, Margaret A; Johansson, Michael A

    2016-10-01

    Zika virus (ZIKV) infection during pregnancy is a cause of congenital microcephaly and severe fetal brain defects, and it has been associated with other adverse pregnancy and birth outcomes. To estimate the number of pregnant women infected with ZIKV in Puerto Rico and the number of associated congenital microcephaly cases. We conducted a modeling study from April to July 2016. Using parameters derived from published reports, outcomes were modeled probabilistically using Monte Carlo simulation. We used uncertainty distributions to reflect the limited information available for parameter values. Given the high level of uncertainty in model parameters, interquartile ranges (IQRs) are presented as primary results. Outcomes were modeled for pregnant women in Puerto Rico, which currently has more confirmed ZIKV cases than any other US location. Zika virus infection in pregnant women. Number of pregnant women infected with ZIKV and number of congenital microcephaly cases. We estimated an IQR of 5900 to 10 300 pregnant women (median, 7800) might be infected during the initial ZIKV outbreak in Puerto Rico. Of these, an IQR of 100 to 270 infants (median, 180) may be born with microcephaly due to congenital ZIKV infection from mid-2016 to mid-2017. In the absence of a ZIKV outbreak, an IQR of 9 to 16 cases (median, 12) of congenital microcephaly are expected in Puerto Rico per year. The estimate of 5900 to 10 300 pregnant women that might be infected with ZIKV provides an estimate for the number of infants that could potentially have ZIKV-associated adverse outcomes. Including baseline cases of microcephaly, we estimated that an IQR of 110 to 290 total cases of congenital microcephaly, mostly attributable to ZIKV infection, could occur from mid-2016 to mid-2017 in the absence of effective interventions. The primary limitation in this analysis is uncertainty in model parameters. Multivariate sensitivity analyses indicated that the cumulative incidence of ZIKV infection and

  10. Very High Load Capacity Air Bearing Spindle for Large Diamond Turning Machines

    DTIC Science & Technology

    2010-06-08

    testing and a surplus air bearing rotary table has been located. A prototype spindle has been designed to work with the table. 15. SUBJECT TERMS...MSFC) • PROTOTYPE SPINDLE DESIGN June 8, 2010Mirror Technology Workshop 3 Introduction • DT is a proven method of manufacturing aspheric off-axis... designed to hold in a strain-free condition. This spindle development is aimed at producing 3 meter diameter components. This requirement results in the

  11. Responses in Rat Core Auditory Cortex are Preserved during Sleep Spindle Oscillations

    PubMed Central

    Sela, Yaniv; Vyazovskiy, Vladyslav V.; Cirelli, Chiara; Tononi, Giulio; Nir, Yuval

    2016-01-01

    Study Objectives: Sleep is defined as a reversible state of reduction in sensory responsiveness and immobility. A long-standing hypothesis suggests that a high arousal threshold during non-rapid eye movement (NREM) sleep is mediated by sleep spindle oscillations, impairing thalamocortical transmission of incoming sensory stimuli. Here we set out to test this idea directly by examining sensory-evoked neuronal spiking activity during natural sleep. Methods: We compared neuronal (n = 269) and multiunit activity (MUA), as well as local field potentials (LFP) in rat core auditory cortex (A1) during NREM sleep, comparing responses to sounds depending on the presence or absence of sleep spindles. Results: We found that sleep spindles robustly modulated the timing of neuronal discharges in A1. However, responses to sounds were nearly identical for all measured signals including isolated neurons, MUA, and LFPs (all differences < 10%). Furthermore, in 10% of trials, auditory stimulation led to an early termination of the sleep spindle oscillation around 150–250 msec following stimulus onset. Finally, active ON states and inactive OFF periods during slow waves in NREM sleep affected the auditory response in opposite ways, depending on stimulus intensity. Conclusions: Responses in core auditory cortex are well preserved regardless of sleep spindles recorded in that area, suggesting that thalamocortical sensory relay remains functional during sleep spindles, and that sensory disconnection in sleep is mediated by other mechanisms. Citation: Sela Y, Vyazovskiy VV, Cirelli C, Tononi G, Nir Y. Responses in rat core auditory cortex are preserved during sleep spindle oscillations. SLEEP 2016;39(5):1069–1082. PMID:26856904

  12. Comparison of a Four-Section Spindle and Stomacher for Efficacy of Detaching Microorganisms from Fresh Vegetables.

    PubMed

    Kim, Do-Kyun; Kim, Soo-Ji; Kang, Dong-Hyun

    2015-07-01

    This study was undertaken to compare the effect of the spindle and stomacher for detaching microorganisms from fresh vegetables. The spindle is an apparatus for detaching microorganisms from food surfaces, which was developed in our laboratory. When processed with the spindle, food samples were barely disrupted, the original shape was maintained, and the diluent was clear, facilitating further detection analysis more easily than with stomacher treatment. The four-section spindle consists of four sample bag containers (A, B, C, and D) to economize time and effort by simultaneously processing four samples. The aerobic plate counts (APC) of 50 fresh vegetable samples were measured following spindle and stomacher treatment. Correlations between the two methods for each section of the spindle and stomacher were very high (R(2) = 0.9828 [spindle compartment A; Sp A], 0.9855 [Sp B], 0.9848 [Sp C], and 0.9851 [Sp D]). One-tenth milliliter of foodborne pathogens suspensions was inoculated onto surfaces of food samples, and ratios of spindle-to-stomacher enumerations were close to 1.00 log CFU/g between every section of the spindle and stomacher. One of the greatest features of the spindle is that it can treat large-sized samples that exceed 200 g. Uncut whole apples, green peppers, potatoes, and tomatoes were processed by the spindle and by hand massaging by 2 min. Large-sized samples were also assayed for aerobic plate count and recovery of the three foodborne pathogens, and the difference between each section of the spindle and hand massaging was not significant (P > 0.05). This study demonstrated that the spindle apparatus can be an alternative device for detaching microorganisms from all fresh vegetable samples for microbiological analysis by the food processing industry.

  13. Abnormal meiosis in an intersectional allotriploid of Populus L. and segregation of ploidy levels in 2x × 3x progeny

    PubMed Central

    Huo, Beibei; Liu, Wanting; Li, Daili; Liao, Ling

    2017-01-01

    Triploid plants are usually highly aborted owing to unbalanced meiotic chromosome segregation, but limited viable gametes can participate in the transition to different ploidy levels. In this study, numerous meiotic abnormalities were found with high frequency in an intersectional allotriploid poplar (Populus alba × P. berolinensis ‘Yinzhong’), including univalents, precocious chromosome migration, lagging chromosomes, chromosome bridges, micronuclei, and precocious cytokinesis, indicating high genetic imbalance in this allotriploid. Some micronuclei trigger mini-spindle formation in metaphase II and participate in cytokinesis to form polyads with microcytes. Unbalanced chromosome segregation and chromosome elimination resulted in the formation of microspores with aneuploid chromosome sets. Fusion of sister nuclei occurs in microsporocytes with precocious cytokinesis, which could form second meiotic division restitution (SDR)-type gametes. However, SDR-type gametes likely contain incomplete chromosome sets due to unbalanced segregation of homologous chromosomes during the first meiotic division in triploids. Misorientation of spindles during the second meiotic division, such as fused and tripolar spindles with low frequency, could result in the formation of first meiotic division restitution (FDR)-type unreduced gametes, which most likely contain three complete chromosome sets. Although ‘Yinzhong’ yields 88.7% stainable pollen grains with wide diameter variation from 23.9 to 61.3 μm, the pollen viability is poor (2.78% ± 0.38). A cross of ‘Yinzhong’ pollen with a diploid female clone produced progeny with extensive segregation of ploidy levels, including 29 diploids, 18 triploids, 4 tetraploids, and 48 aneuploids, suggesting the formation of viable aneuploidy and unreduced pollen in ‘Yinzhong’. Individuals with different chromosome compositions are potential to analyze chromosomal function and to integrate the chromosomal dosage variation into

  14. REM sleep behaviour disorder is associated with lower fast and higher slow sleep spindle densities.

    PubMed

    O'Reilly, Christian; Godin, Isabelle; Montplaisir, Jacques; Nielsen, Tore

    2015-12-01

    To investigate differences in sleep spindle properties and scalp topography between patients with rapid eye movement sleep behaviour disorder (RBD) and healthy controls, whole-night polysomnograms of 35 patients diagnosed with RBD and 35 healthy control subjects matched for age and sex were compared. Recordings included a 19-lead 10-20 electroencephalogram montage and standard electromyogram, electrooculogram, electrocardiogram and respiratory leads. Sleep spindles were automatically detected using a standard algorithm, and their characteristics (amplitude, duration, density, frequency and frequency slope) compared between groups. Topological analyses of group-discriminative features were conducted. Sleep spindles occurred at a significantly (e.g. t34 = -4.49; P = 0.00008 for C3) lower density (spindles ∙ min(-1) ) for RBD (mean ± SD: 1.61 ± 0.56 for C3) than for control (2.19 ± 0.61 for C3) participants. However, when distinguishing slow and fast spindles using thresholds individually adapted to the electroencephalogram spectrum of each participant, densities smaller (31-96%) for fast but larger (20-120%) for slow spindles were observed in RBD in all derivations. Maximal differences were in more posterior regions for slow spindles, but over the entire scalp for fast spindles. Results suggest that the density of sleep spindles is altered in patients with RBD and should therefore be investigated as a potential marker of future neurodegeneration in these patients. © 2015 European Sleep Research Society.

  15. Clinico-radiological and molecular characterization of a child with ring chromosome 2 presenting growth failure, microcephaly, kidney and brain malformations.

    PubMed

    Severino, Mariasavina; Accogli, Andrea; Gimelli, Giorgio; Rossi, Andrea; Kotzeva, Svetlana; Di Rocco, Maja; Ronchetto, Patrizia; Cuoco, Cristina; Tassano, Elisa

    2015-01-01

    Ring chromosome 2 is a rare constitutional abnormality that generally occurs de novo. About 14 cases have been described to date, but the vast majority of papers report exclusively conventional cytogenetic investigations and only two have been characterized by array-CGH. Here we describe the clinical, neuroradiological, and molecular features of a 5-year-old boy harbouring a ring chromosome 2 presenting with severe growth failure, facial and bone dysmorphisms, microcephaly, and renal malformation. Brain MR with diffusion tensor imaging revealed simplified cortical gyration, pontine hypoplasia, and abnormally thick posterior corpus callosum, suggesting an underlying axonal guidance defect. Cytogenetic investigations showed a karyotype with a ring chromosome 2 and FISH analysis with subtelomeric probes revealed the absence of signals on both arms. These results were confirmed by array-CGH showing terminal deletions on 2p25.3 (~439 kb) and 2q37.3 (~3.4 Mb). Our report describes a new patient with a ring chromosome 2 completely characterised by array-CGH providing additional information useful not only to study genotype-phenotype correlation but also to validate the role of already reported candidate genes and to suggest novel ones which could improve our understanding of the clinical features associated with ring chromosome 2.

  16. Expert and crowd-sourced validation of an individualized sleep spindle detection method employing complex demodulation and individualized normalization

    PubMed Central

    Ray, Laura B.; Sockeel, Stéphane; Soon, Melissa; Bore, Arnaud; Myhr, Ayako; Stojanoski, Bobby; Cusack, Rhodri; Owen, Adrian M.; Doyon, Julien; Fogel, Stuart M.

    2015-01-01

    A spindle detection method was developed that: (1) extracts the signal of interest (i.e., spindle-related phasic changes in sigma) relative to ongoing “background” sigma activity using complex demodulation, (2) accounts for variations of spindle characteristics across the night, scalp derivations and between individuals, and (3) employs a minimum number of sometimes arbitrary, user-defined parameters. Complex demodulation was used to extract instantaneous power in the spindle band. To account for intra- and inter-individual differences, the signal was z-score transformed using a 60 s sliding window, per channel, over the course of the recording. Spindle events were detected with a z-score threshold corresponding to a low probability (e.g., 99th percentile). Spindle characteristics, such as amplitude, duration and oscillatory frequency, were derived for each individual spindle following detection, which permits spindles to be subsequently and flexibly categorized as slow or fast spindles from a single detection pass. Spindles were automatically detected in 15 young healthy subjects. Two experts manually identified spindles from C3 during Stage 2 sleep, from each recording; one employing conventional guidelines, and the other, identifying spindles with the aid of a sigma (11–16 Hz) filtered channel. These spindles were then compared between raters and to the automated detection to identify the presence of true positives, true negatives, false positives and false negatives. This method of automated spindle detection resolves or avoids many of the limitations that complicate automated spindle detection, and performs well compared to a group of non-experts, and importantly, has good external validity with respect to the extant literature in terms of the characteristics of automatically detected spindles. PMID:26441604

  17. Spindle formation in the mouse embryo requires Plk4 in the absence of centrioles.

    PubMed

    Coelho, Paula A; Bury, Leah; Sharif, Bedra; Riparbelli, Maria G; Fu, Jingyan; Callaini, Giuliano; Glover, David M; Zernicka-Goetz, Magdalena

    2013-12-09

    During the first five rounds of cell division in the mouse embryo, spindles assemble in the absence of centrioles. Spindle formation initiates around chromosomes, but the microtubule nucleating process remains unclear. Here we demonstrate that Plk4, a protein kinase known as a master regulator of centriole formation, is also essential for spindle assembly in the absence of centrioles. Depletion of maternal Plk4 prevents nucleation and growth of microtubules and results in monopolar spindle formation. This leads to cytokinesis failure and, consequently, developmental arrest. We show that Plk4 function depends on its kinase activity and its partner protein, Cep152. Moreover, tethering Cep152 to cellular membranes sequesters Plk4 and is sufficient to trigger spindle assembly from ectopic membranous sites. Thus, the Plk4-Cep152 complex has an unexpected role in promoting microtubule nucleation in the vicinity of chromosomes to mediate bipolar spindle formation in the absence of centrioles. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Application of a novel prenatal vertical cranial biometric measurement can improve accuracy of microcephaly diagnosis in utero.

    PubMed

    Leibovitz, Z; Shiran, C; Haratz, K; Tamarkin, M; Gindes, L; Schreiber, L; Malinger, G; Ben-Sira, L; Lev, D; Shapiro, I; Bakry, H; Weizman, B; Zreik, A; Kidron, D; Egenburg, S; Arad, A; Lerman-Sagie, T

    2016-05-01

    To construct a reference range for a new vertical measurement of the fetal head and to assess whether its combination with fetal head circumference (HC) can prevent the misdiagnosis of microcephaly in fetuses with an acrocephalic-like head deformation. A new vertical cranial biometric measurement was defined: the foramen magnum-to-cranium distance (FCD), measured between the foramen magnum and the upper inner cranial border along the posterior wall of the brainstem. The measurement was performed in a precise mid-sagittal plane using a three-dimensional multiplanar display of a sagittally acquired sonographic volume of the fetal head. The normal reference range was developed by measuring 396 healthy fetuses of low-risk singleton pregnancies between 15 and 40 gestational weeks. This reference was applied to 25 fetuses with microcephaly diagnosed prenatally (Fmic) based on HC ≥ 3 SD below the mean for gestational age. We determined an optimal FCD cut-off for combination with HC to detect all cases found with microcephaly at birth (micB), while excluding the fetuses with normal head circumference at birth (NHCB), who were described postnatally as having an acrocephalic-like cranial deformation. In the healthy singleton fetuses, FCD increased with gestational age, with a quadratic equation providing an optimal fit to the data (adjusted R(2) = 0.934). The measurement could be assessed in 95.2% of cases. Of the 25 cases diagnosed with Fmic prenatally, on the basis of HC alone, 14 were micB and 11 were NHCB. We observed FCD below the mean - 2SD for gestational age in all 14 micB cases, but in only four of the 11 NHCB cases (P < 0.003). An acrocephalic-like cranial deformation was described at birth in five of the seven NHCB cases with normal FCD. The mean ± SD FCD Z-score of the micB cases was significantly lower (P < 0.001) than that of the false-positive ones: -3.85 ± 0.96 SD and -1.59 ± 1.45 SD, respectively. Based on HC measurement alone, the positive predictive

  19. Slow sleep spindle and procedural memory consolidation in patients with major depressive disorder

    PubMed Central

    Nishida, Masaki; Nakashima, Yusaku; Nishikawa, Toru

    2016-01-01

    Introduction Evidence has accumulated, which indicates that, in healthy individuals, sleep enhances procedural memory consolidation, and that sleep spindle activity modulates this process. However, whether sleep-dependent procedural memory consolidation occurs in patients medicated for major depressive disorder remains unclear, as are the pharmacological and physiological mechanisms that underlie this process. Methods Healthy control participants (n=17) and patients medicated for major depressive disorder (n=11) were recruited and subjected to a finger-tapping motor sequence test (MST; nondominant hand) paradigm to compare the averaged scores of different learning phases (presleep, postsleep, and overnight improvement). Participants’ brain activity was recorded during sleep with 16 electroencephalography channels (between MSTs). Sleep scoring and frequency analyses were performed on the electroencephalography data. Additionally, we evaluated sleep spindle activity, which divided the spindles into fast-frequency spindle activity (12.5–16 Hz) and slow-frequency spindle activity (10.5–12.5 Hz). Result Sleep-dependent motor memory consolidation in patients with depression was impaired in comparison with that in control participants. In patients with depression, age correlated negatively with overnight improvement. The duration of slow-wave sleep correlated with the magnitude of motor memory consolidation in patients with depression, but not in healthy controls. Slow-frequency spindle activity was associated with reduction in the magnitude of motor memory consolidation in both groups. Conclusion Because the changes in slow-frequency spindle activity affected the thalamocortical network dysfunction in patients medicated for depression, dysregulated spindle generation may impair sleep-dependent memory consolidation. Our findings may help to elucidate the cognitive deficits that occur in patients with major depression both in the waking state and during sleep. PMID

  20. Slow sleep spindle and procedural memory consolidation in patients with major depressive disorder.

    PubMed

    Nishida, Masaki; Nakashima, Yusaku; Nishikawa, Toru

    2016-01-01

    Evidence has accumulated, which indicates that, in healthy individuals, sleep enhances procedural memory consolidation, and that sleep spindle activity modulates this process. However, whether sleep-dependent procedural memory consolidation occurs in patients medicated for major depressive disorder remains unclear, as are the pharmacological and physiological mechanisms that underlie this process. Healthy control participants (n=17) and patients medicated for major depressive disorder (n=11) were recruited and subjected to a finger-tapping motor sequence test (MST; nondominant hand) paradigm to compare the averaged scores of different learning phases (presleep, postsleep, and overnight improvement). Participants' brain activity was recorded during sleep with 16 electroencephalography channels (between MSTs). Sleep scoring and frequency analyses were performed on the electroencephalography data. Additionally, we evaluated sleep spindle activity, which divided the spindles into fast-frequency spindle activity (12.5-16 Hz) and slow-frequency spindle activity (10.5-12.5 Hz). Sleep-dependent motor memory consolidation in patients with depression was impaired in comparison with that in control participants. In patients with depression, age correlated negatively with overnight improvement. The duration of slow-wave sleep correlated with the magnitude of motor memory consolidation in patients with depression, but not in healthy controls. Slow-frequency spindle activity was associated with reduction in the magnitude of motor memory consolidation in both groups. Because the changes in slow-frequency spindle activity affected the thalamocortical network dysfunction in patients medicated for depression, dysregulated spindle generation may impair sleep-dependent memory consolidation. Our findings may help to elucidate the cognitive deficits that occur in patients with major depression both in the waking state and during sleep.

  1. The Chromokinesin Kid Is Required for Maintenance of Proper Metaphase Spindle SizeD⃞

    PubMed Central

    Tokai-Nishizumi, Noriko; Ohsugi, Miho; Suzuki, Emiko; Yamamoto, Tadashi

    2005-01-01

    The human chromokinesin Kid/kinesin-10, a plus end-directed microtubule (MT)-based motor with both microtubule- and DNA-binding domains, is required for proper chromosome alignment at the metaphase plate. Here, we performed RNA interference experiments to deplete endogenous Kid from HeLa cells and confirmed defects in metaphase chromosome arm alignment in Kid-depleted cells. In addition, we noted a shortening of the spindle length, resulting in a pole-to-pole distance only 80% of wild type. The spindle microtubule-bundles with which Kid normally colocalize became less robust. Rescue of the two Kid deficiency phenotypes—imprecise chromosome alignment at metaphase and shortened spindles— exhibited distinct requirements. Mutants lacking either the DNA-binding domain or the MT motor ATPase failed to rescue the former defect, whereas rescue of the shortened spindle phenotype required neither activity. Kid also exhibits microtubule bundling activity in vitro, and rescue of the shortened spindle phenotype and the bundling activity displayed similar domain requirements, except that rescue required a coiled-coil domain not needed for bundling. These results suggest that distinct from its role in chromosome movement, Kid contributes to spindle morphogenesis by mediating spindle microtubules stabilization. PMID:16176979

  2. Kif2a regulates spindle organization and cell cycle progression in meiotic oocytes.

    PubMed

    Yi, Zi-Yun; Ma, Xue-Shan; Liang, Qiu-Xia; Zhang, Teng; Xu, Zhao-Yang; Meng, Tie-Gang; Ouyang, Ying-Chun; Hou, Yi; Schatten, Heide; Sun, Qing-Yuan; Quan, Song

    2016-12-19

    Kif2a is a member of the Kinesin-13 microtubule depolymerases. Here, we report the expression, subcellular localization and functions of Kif2a during mouse oocyte meiotic maturation. Immunoblotting analysis showed that Kif2a was gradually increased form GV to the M I stages, and then decreased slightly at the M II stage. Confocal microscopy identified that Kif2a localized to the meiotic spindle, especially concentrated at the spindle poles and inner centromeres in metaphase and translocated to the midbody at telophase. Kif2a depletion by siRNA microinjection generated severely defective spindles and misaligned chromosomes, reduced microtubule depolymerization, which led to significant pro-M I/M Iarrest and failure of first polar body (PB1) extrusion. Kif2a-depleted oocytes were also defective in spindle pole localization of γ-tubulin and showed spindle assembly checkpoint (SAC) protein Bub3 at the kinetochores even after 10 hr extended culture. These results demonstrate that Kif2a may act as a microtubule depolymerase, regulating microtubule dynamics, spindle assembly and chromosome congression, and thus cell cycle progression during mouse oocyte meiotic maturation.

  3. Response to apatinib in chemotherapy-failed advanced spindle cell breast carcinoma.

    PubMed

    Zhou, Na; Liu, Congmin; Hou, Helei; Zhang, Chuantao; Liu, Dong; Wang, Guanqun; Liu, Kewei; Zhu, Jingjuan; Lv, Hongying; Li, Tianjun; Zhang, Xiaochun

    2016-11-01

    Spindle cell carcinoma of the breast is a rare subtype of metaplastic carcinoma, and no effective chemotherapy special for metaplastic carcinoma exists until now. As spindle cell carcinomas of the breast are typically "Triple Negative", endocrine therapy and molecular therapy targeted to Her2 might not be favorable, resulting in poor prognosis. Apatinib is currently being tested in patients with breast or lung cancers. Here we report a successful case using Apatinib to treat spindle cell carcinoma of breast.A 52- year- old woman presented with a gradually enlarged lump in left breast, which was revealed to be a triple-negative spindle cell carcinoma, underwent a modified radical mastectomy. After the first line chemotherapy with Cyclophosphamide and Epirubicin, multiple metastases in bilateral lung and left anterior thoracic wall appeared. After disease progressed with therapy of Bevacizumab combined with Albumin-bound Paclitaxel and Cisplatin, we treated the patient with Apatinib according to her VEGFR expression, which showed nearly complete response and controllable and tolerated side effects. Next-generation sequencing analysis of the tumor specimen and real time ctDNA was performed to observe the mutated gene numbers matched with therapeutic effect. The present case can help to provide a new and effective therapy strategy to treat advanced spindle cell carcinoma.

  4. Response to apatinib in chemotherapy-failed advanced spindle cell breast carcinoma

    PubMed Central

    Zhou, Na; Liu, Congmin; Hou, Helei; Zhang, Chuantao; Liu, Dong; Wang, Guanqun; Liu, Kewei; Zhu, Jingjuan; Lv, Hongying; Li, Tianjun; Zhang, Xiaochun

    2016-01-01

    Spindle cell carcinoma of the breast is a rare subtype of metaplastic carcinoma, and no effective chemotherapy special for metaplastic carcinoma exists until now. As spindle cell carcinomas of the breast are typically “Triple Negative”, endocrine therapy and molecular therapy targeted to Her2 might not be favorable, resulting in poor prognosis. Apatinib is currently being tested in patients with breast or lung cancers. Here we report a successful case using Apatinib to treat spindle cell carcinoma of breast. A 52- year- old woman presented with a gradually enlarged lump in left breast, which was revealed to be a triple-negative spindle cell carcinoma, underwent a modified radical mastectomy. After the first line chemotherapy with Cyclophosphamide and Epirubicin, multiple metastases in bilateral lung and left anterior thoracic wall appeared. After disease progressed with therapy of Bevacizumab combined with Albumin-bound Paclitaxel and Cisplatin, we treated the patient with Apatinib according to her VEGFR expression, which showed nearly complete response and controllable and tolerated side effects. Next-generation sequencing analysis of the tumor specimen and real time ctDNA was performed to observe the mutated gene numbers matched with therapeutic effect. The present case can help to provide a new and effective therapy strategy to treat advanced spindle cell carcinoma. PMID:27738308

  5. Improving Abnormality Detection on Chest Radiography Using Game-Like Reinforcement Mechanics.

    PubMed

    Chen, Po-Hao; Roth, Howard; Galperin-Aizenberg, Maya; Ruutiainen, Alexander T; Gefter, Warren; Cook, Tessa S

    2017-11-01

    Despite their increasing prevalence, online textbooks, question banks, and digital references focus primarily on explicit knowledge. Implicit skills such as abnormality detection require repeated practice on clinical service and have few digital substitutes. Using mechanics traditionally deployed in video games such as clearly defined goals, rapid-fire levels, and narrow time constraints may be an effective way to teach implicit skills. We created a freely available, online module to evaluate the ability of individuals to differentiate between normal and abnormal chest radiographs by implementing mechanics, including instantaneous feedback, rapid-fire cases, and 15-second timers. Volunteer subjects completed the modules and were separated based on formal experience with chest radiography. Performance between training and testing sets were measured for each group, and a survey was administered after each session. The module contained 74 cases and took approximately 20 minutes to complete. Thirty-two cases were normal radiographs and 56 cases were abnormal. Of the 60 volunteers recruited, 25 were "never trained" and 35 were "previously trained." "Never trained" users scored 21.9 out of 37 during training and 24.0 out of 37 during testing (59.1% vs 64.9%, P value <.001). "Previously trained" users scored 28.0 out of 37 during training and 28.3 out of 37 during testing phases (75.6% vs 76.4%, P value = .56). Survey results showed that 87% of all subjects agreed the module is an efficient way of learning, and 83% agreed the rapid-fire module is valuable for medical students. A gamified online module may improve the abnormality detection rates of novice interpreters of chest radiography, although experienced interpreters are less likely to derive similar benefits. Users reviewed the educational module favorably. Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

  6. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause Microcephaly-Capillary Malformation syndrome

    PubMed Central

    McDonell, Laura M.; Mirzaa, Ghayda M.; Alcantara, Diana; Schwartzentruber, Jeremy; Carter, Melissa T.; Lee, Leo J.; Clericuzio, Carol L.; Graham, John M.; Morris-Rosendahl, Deborah J.; Polster, Tilman; Acsadi, Gyula; Townshend, Sharron; Williams, Simon; Halbert, Anne; Isidor, Bertrand; Smyser, Christopher D.; Paciorkowski, Alex R.; Willing, Marcia; Woulfe, John; Das, Soma; Beaulieu, Chandree L.; Marcadier, Janet; Geraghty, Michael T.; Frey, Brendan J.; Majewski, Jacek; Bulman, Dennis E.; Dobyns, William B.; O’Driscoll, Mark; Boycott, Kym M.

    2014-01-01

    Microcephaly-capillary malformation (MIC-CAP) syndrome exhibits severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We employed whole-exome sequencing of five patients with MIC-CAP syndrome and identified novel recessive mutations in STAMBP, a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein)/AMSH (Associated Molecule with the SH3 domain of STAM), that plays a key role in cell surface receptor-mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. The latter cellular phenotype is significant considering the established connection between these pathways and their association with vascular and capillary malformations. Furthermore, our findings of a congenital human disorder caused by a defective DUB protein that functions in endocytosis, implicates ubiquitin-conjugate aggregation and elevated apoptosis as factors potentially influencing the progressive neuronal loss underlying MIC-CAP. PMID:23542699

  7. Stimulus-induced transitions between spike-wave discharges and spindles with the modulation of thalamic reticular nucleus.

    PubMed

    Fan, Denggui; Wang, Qingyun; Su, Jianzhong; Xi, Hongguang

    2017-12-01

    It is believed that thalamic reticular nucleus (TRN) controls spindles and spike-wave discharges (SWD) in seizure or sleeping processes. The dynamical mechanisms of spatiotemporal evolutions between these two types of activity, however, are not well understood. In light of this, we first use a single-compartment thalamocortical neural field model to investigate the effects of TRN on occurrence of SWD and its transition. Results show that the increasing inhibition from TRN to specific relay nuclei (SRN) can lead to the transition of system from SWD to slow-wave oscillation. Specially, it is shown that stimulations applied in the cortical neuronal populations can also initiate the SWD and slow-wave oscillation from the resting states under the typical inhibitory intensity from TRN to SRN. Then, we expand into a 3-compartment coupled thalamocortical model network in linear and circular structures, respectively, to explore the spatiotemporal evolutions of wave states in different compartments. The main results are: (i) for the open-ended model network, SWD induced by stimulus in the first compartment can be transformed into sleep-like slow UP-DOWN and spindle states as it propagates into the downstream compartments; (ii) for the close-ended model network, weak stimulations performed in the first compartment can result in the consistent experimentally observed spindle oscillations in all three compartments; in contrast, stronger periodic single-pulse stimulations applied in the first compartment can induce periodic transitions between SWD and spindle oscillations. Detailed investigations reveal that multi-attractor coexistence mechanism composed of SWD, spindles and background state underlies these state evolutions. What's more, in order to demonstrate the state evolution stability with respect to the topological structures of neural network, we further expand the 3-compartment coupled network into 10-compartment coupled one, with linear and circular structures, and

  8. Meiosis-Specific Stable Binding of Augmin to Acentrosomal Spindle Poles Promotes Biased Microtubule Assembly in Oocytes

    PubMed Central

    Colombié, Nathalie; Głuszek, A. Agata; Meireles, Ana M.; Ohkura, Hiroyuki

    2013-01-01

    In the oocytes of many animals including humans, the meiotic spindle assembles without centrosomes. It is still unclear how multiple pathways contribute to spindle microtubule assembly, and whether they are regulated differently in mitosis and meiosis. Augmin is a γ-tubulin recruiting complex which “amplifies” spindle microtubules by generating new microtubules along existing ones in mitosis. Here we show that in Drosophila melanogaster oocytes Augmin is dispensable for chromatin-driven assembly of bulk spindle microtubules, but is required for full microtubule assembly near the poles. The level of Augmin accumulated at spindle poles is well correlated with the degree of chromosome congression. Fluorescence recovery after photobleaching shows that Augmin stably associates with the polar regions of the spindle in oocytes, unlike in mitotic cells where it transiently and uniformly associates with the metaphase spindle. This stable association is enhanced by γ-tubulin and the kinesin-14 Ncd. Therefore, we suggest that meiosis-specific regulation of Augmin compensates for the lack of centrosomes in oocytes by actively biasing sites of microtubule generation within the spindle. PMID:23785300

  9. Integrating high-throughput genetic interaction mapping and high-content screening to explore yeast spindle morphogenesis

    PubMed Central

    Vizeacoumar, Franco J.; van Dyk, Nydia; S.Vizeacoumar, Frederick; Cheung, Vincent; Li, Jingjing; Sydorskyy, Yaroslav; Case, Nicolle; Li, Zhijian; Datti, Alessandro; Nislow, Corey; Raught, Brian; Zhang, Zhaolei; Frey, Brendan; Bloom, Kerry

    2010-01-01

    We describe the application of a novel screening approach that combines automated yeast genetics, synthetic genetic array (SGA) analysis, and a high-content screening (HCS) system to examine mitotic spindle morphogenesis. We measured numerous spindle and cellular morphological parameters in thousands of single mutants and corresponding sensitized double mutants lacking genes known to be involved in spindle function. We focused on a subset of genes that appear to define a highly conserved mitotic spindle disassembly pathway, which is known to involve Ipl1p, the yeast aurora B kinase, as well as the cell cycle regulatory networks mitotic exit network (MEN) and fourteen early anaphase release (FEAR). We also dissected the function of the kinetochore protein Mcm21p, showing that sumoylation of Mcm21p regulates the enrichment of Ipl1p and other chromosomal passenger proteins to the spindle midzone to mediate spindle disassembly. Although we focused on spindle disassembly in a proof-of-principle study, our integrated HCS-SGA method can be applied to virtually any pathway, making it a powerful means for identifying specific cellular functions. PMID:20065090

  10. Multisensory integration and ADHD-like traits: Evidence for an abnormal temporal integration window in ADHD.

    PubMed

    Panagiotidi, Maria; Overton, Paul G; Stafford, Tom

    2017-11-01

    Abnormalities in multimodal processing have been found in many developmental disorders such as autism and dyslexia. However, surprisingly little empirical work has been conducted to test the integrity of multisensory integration in Attention Deficit Hyperactivity Disorder (ADHD). The main aim of the present study was to examine links between symptoms of ADHD (as measured using a self-report scale in a healthy adult population) and the temporal aspects of multisensory processing. More specifically, a Simultaneity Judgement (SJ) and a Temporal Order Judgement (TOJ) task were used in participants with low and high levels of ADHD-like traits to measure the temporal integration window and Just-Noticeable Difference (JND) (respectively) between the timing of an auditory beep and a visual pattern presented over a broad range of stimulus onset asynchronies. The Point of Subjective Similarity (PSS) was also measured in both cases. In the SJ task, participants with high levels of ADHD-like traits considered significantly fewer stimuli to be simultaneous than participants with high levels of ADHD-like traits, and the former were found to have significantly smaller temporal windows of integration (although no difference was found in the PSS in the SJ or TOJ tasks, or the JND in the latter). This is the first study to identify an abnormal temporal integration window in individuals with ADHD-like traits. Perceived temporal misalignment of two or more modalities can lead to distractibility (e.g., when the stimulus components from different modalities occur separated by too large of a temporal gap). Hence, an abnormality in the perception of simultaneity could lead to the increased distractibility seen in ADHD. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. EEG alpha spindle measures as indicators of driver fatigue under real traffic conditions.

    PubMed

    Simon, Michael; Schmidt, Eike A; Kincses, Wilhelm E; Fritzsche, Martin; Bruns, Andreas; Aufmuth, Claus; Bogdan, Martin; Rosenstiel, Wolfgang; Schrauf, Michael

    2011-06-01

    The purpose of this study is to show the effectiveness of EEG alpha spindles, defined by short narrowband bursts in the alpha band, as an objective measure for assessing driver fatigue under real driving conditions. An algorithm for the identification of alpha spindles is described. The performance of the algorithm is tested based on simulated data. The method is applied to real data recorded under real traffic conditions and compared with the performance of traditional EEG fatigue measures, i.e. alpha-band power. As a highly valid fatigue reference, the last 20 min of driving from participants who aborted the drive due to heavy fatigue were used in contrast to the initial 20 min of driving. Statistical analysis revealed significant increases from the first to the last driving section of several alpha spindle parameters and among all traditional EEG frequency bands, only of alpha-band power; with larger effect sizes for the alpha spindle based measures. An increased level of fatigue over the same time periods for drop-outs, as compared to participants who did not abort the drive, was observed only by means of alpha spindle parameters. EEG alpha spindle parameters increase both fatigue detection sensitivity and specificity as compared to EEG alpha-band power. It is demonstrated that alpha spindles are superior to EEG band power measures for assessing driver fatigue under real traffic conditions. Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  12. On the Dynamics of Rocking Motion of the Hard-Disk Drive Spindle Motor System

    NASA Astrophysics Data System (ADS)

    Wang, Joseph

    Excessive rocking motion of the spindle motor system can cause track misregistration resulting in poor throughput or even drive failure. The chance of excessive disk stack rocking increases as a result of decreasing torsional stiffness of spindle motor bearing system due to the market demand for low profile hard drives. As the track density increases and the vibration specification becomes increasingly stringent, rocking motion of a spindle motor system deserves even more attention and has become a primary challenge for a spindle motor system designer. Lack of understanding of the rocking phenomenon combined with misleading paradox has presented a great difficulty in the effort of avoiding the rocking motion in the hard-disk drive industry. This paper aims to provide fundamental understanding of the rocking phenomenon of a rotating spindle motor system, to clarify the paradox in disk-drive industry and to provide a design guide to an optimized spindle system. This paper, theoretically and experimentally, covers a few important areas of industrial interest including the prediction of rocking natural frequencies and mode shape of a rotating spindle, free vibration, and frequency response under common forcing functions such as rotating and fixed-plane forcing functions. The theory presented here meets with agreeable experimental observation.

  13. NuMA-microtubule interactions are critical for spindle orientation and the morphogenesis of diverse epidermal structures

    PubMed Central

    Seldin, Lindsey; Muroyama, Andrew; Lechler, Terry

    2016-01-01

    Mitotic spindle orientation is used to generate cell fate diversity and drive proper tissue morphogenesis. A complex of NuMA and dynein/dynactin is required for robust spindle orientation in a number of cell types. Previous research proposed that cortical dynein/dynactin was sufficient to generate forces on astral microtubules (MTs) to orient the spindle, with NuMA acting as a passive tether. In this study, we demonstrate that dynein/dynactin is insufficient for spindle orientation establishment in keratinocytes and that NuMA’s MT-binding domain, which targets MT tips, is also required. Loss of NuMA-MT interactions in skin caused defects in spindle orientation and epidermal differentiation, leading to neonatal lethality. In addition, we show that NuMA-MT interactions are also required in adult mice for hair follicle morphogenesis and spindle orientation within the transit-amplifying cells of the matrix. Loss of spindle orientation in matrix cells results in defective differentiation of matrix-derived lineages. Our results reveal an additional and direct function of NuMA during mitotic spindle positioning, as well as a reiterative use of spindle orientation in the skin to build diverse structures. DOI: http://dx.doi.org/10.7554/eLife.12504.001 PMID:26765568

  14. A primary microcephaly protein complex forms a ring around parental centrioles.

    PubMed

    Sir, Joo-Hee; Barr, Alexis R; Nicholas, Adeline K; Carvalho, Ofelia P; Khurshid, Maryam; Sossick, Alex; Reichelt, Stefanie; D'Santos, Clive; Woods, C Geoffrey; Gergely, Fanni

    2011-10-09

    Autosomal recessive primary microcephaly (MCPH) is characterized by a substantial reduction in prenatal human brain growth without alteration of the cerebral architecture and is caused by biallelic mutations in genes coding for a subset of centrosomal proteins. Although at least three of these proteins have been implicated in centrosome duplication, the nature of the centrosome dysfunction that underlies the neurodevelopmental defect in MCPH is unclear. Here we report a homozygous MCPH-causing mutation in human CEP63. CEP63 forms a complex with another MCPH protein, CEP152, a conserved centrosome duplication factor. Together, these two proteins are essential for maintaining normal centrosome numbers in cells. Using super-resolution microscopy, we found that CEP63 and CEP152 co-localize in a discrete ring around the proximal end of the parental centriole, a pattern specifically disrupted in CEP63-deficient cells derived from patients with MCPH. This work suggests that the CEP152-CEP63 ring-like structure ensures normal neurodevelopment and that its impairment particularly affects human cerebral cortex growth.

  15. Mto2 multisite phosphorylation inactivates non-spindle microtubule nucleation complexes during mitosis

    PubMed Central

    Borek, Weronika E.; Groocock, Lynda M.; Samejima, Itaru; Zou, Juan; de Lima Alves, Flavia; Rappsilber, Juri; Sawin, Kenneth E.

    2015-01-01

    Microtubule nucleation is highly regulated during the eukaryotic cell cycle, but the underlying molecular mechanisms are largely unknown. During mitosis in fission yeast Schizosaccharomyces pombe, cytoplasmic microtubule nucleation ceases simultaneously with intranuclear mitotic spindle assembly. Cytoplasmic nucleation depends on the Mto1/2 complex, which binds and activates the γ-tubulin complex and also recruits the γ-tubulin complex to both centrosomal (spindle pole body) and non-centrosomal sites. Here we show that the Mto1/2 complex disassembles during mitosis, coincident with hyperphosphorylation of Mto2 protein. By mapping and mutating multiple Mto2 phosphorylation sites, we generate mto2-phosphomutant strains with enhanced Mto1/2 complex stability, interaction with the γ-tubulin complex and microtubule nucleation activity. A mutant with 24 phosphorylation sites mutated to alanine, mto2[24A], retains interphase-like behaviour even in mitotic cells. This provides a molecular-level understanding of how phosphorylation ‘switches off' microtubule nucleation complexes during the cell cycle and, more broadly, illuminates mechanisms regulating non-centrosomal microtubule nucleation. PMID:26243668

  16. Kinesin-8 effects on mitotic microtubule dynamics contribute to spindle function in fission yeast

    PubMed Central

    Gergely, Zachary R.; Crapo, Ammon; Hough, Loren E.; McIntosh, J. Richard; Betterton, Meredith D.

    2016-01-01

    Kinesin-8 motor proteins destabilize microtubules. Their absence during cell division is associated with disorganized mitotic chromosome movements and chromosome loss. Despite recent work studying effects of kinesin-8s on microtubule dynamics, it remains unclear whether the kinesin-8 mitotic phenotypes are consequences of their effect on microtubule dynamics, their well-established motor activity, or additional, unknown functions. To better understand the role of kinesin-8 proteins in mitosis, we studied the effects of deletion of the fission yeast kinesin-8 proteins Klp5 and Klp6 on chromosome movements and spindle length dynamics. Aberrant microtubule-driven kinetochore pushing movements and tripolar mitotic spindles occurred in cells lacking Klp5 but not Klp6. Kinesin-8–deletion strains showed large fluctuations in metaphase spindle length, suggesting a disruption of spindle length stabilization. Comparison of our results from light microscopy with a mathematical model suggests that kinesin-8–induced effects on microtubule dynamics, kinetochore attachment stability, and sliding force in the spindle can explain the aberrant chromosome movements and spindle length fluctuations seen. PMID:27146110

  17. Anterior uveal spindle cell tumor in a cat.

    PubMed

    Evans, Paige M; Lynch, Gwendolyn L; Dubielzig, Richard R

    2010-11-01

    To describe a case of anterior uveal spindle cell tumor in a cat with features similar to spindle cell tumor of blue eyed dogs. A 10-year-old female spayed domestic short-haired cat was referred for an iris mass OS. The mass was solitary, nodular, nonpigmented, located medially, and causing dyscoria. A diagnosis of a benign epithelial tumor was suggested by a FNA of the mass. The cat was lost to follow-up for 2 years, after which time she re-presented with glaucoma, blindness and grossly evident iridal mass enlargement OS. Transconjunctival enucleation was performed and the globe submitted for histopathology. Histopathology of the enucleated globe revealed the superior iris to be infiltrated and effaced by a large population of neoplastic spindle cells. The cells were arranged in streams and bundles and exhibited Antoni-A and Antoni-B tissue patterns, which are characteristic of Schwann cell tumors. Mitotic figures were rare and cellular pleomorphism moderate. Immunohistochemical staining was positive for S-100 protein and glial fibrillary acidic protein (GFAP), and negative for Melan-A. Interestingly, there was no histological evidence of glaucoma. Based on its histopathologic characteristics, this iris tumor was diagnosed as a Schwann cell variant of a peripheral nerve sheath tumor (PNST) closely resembling the spindle cell tumor of blue-eyed dogs. Anterior uveal PNST has not been previously reported in cats to the authors' knowledge. The presence of Antoni type A and type B tissue patterns along with immunohistochemical staining may facilitate a diagnosis of PNST and rule out malignant melanoma. © 2010 American College of Veterinary Ophthalmologists.

  18. Spindled and hollow spars

    NASA Technical Reports Server (NTRS)

    Blyth, J D

    1926-01-01

    The most usual method of arriving at the maximum amount of spindling or hollowing out permissible in the case of any particular spar section is by trial and error, a process which is apt to become laborious in the absence of good guessing - or luck. The following tables have been got out with the object of making it possible to arrive with certainty at a suitable section at the first attempt.

  19. Electro-Acoustic Behavior of the Mitotic Spindle: A Semi-Classical Coarse-Grained Model

    PubMed Central

    Havelka, Daniel; Kučera, Ondřej; Deriu, Marco A.; Cifra, Michal

    2014-01-01

    The regulation of chromosome separation during mitosis is not fully understood yet. Microtubules forming mitotic spindles are targets of treatment strategies which are aimed at (i) the triggering of the apoptosis or (ii) the interruption of uncontrolled cell division. Despite these facts, only few physical models relating to the dynamics of mitotic spindles exist up to now. In this paper, we present the first electromechanical model which enables calculation of the electromagnetic field coupled to acoustic vibrations of the mitotic spindle. This electromagnetic field originates from the electrical polarity of microtubules which form the mitotic spindle. The model is based on the approximation of resonantly vibrating microtubules by a network of oscillating electric dipoles. Our computational results predict the existence of a rapidly changing electric field which is generated by either driven or endogenous vibrations of the mitotic spindle. For certain values of parameters, the intensity of the electric field and its gradient reach values which may exert a not-inconsiderable force on chromosomes which are aligned in the spindle midzone. Our model may describe possible mechanisms of the effects of ultra-short electrical and mechanical pulses on dividing cells—a strategy used in novel methods for cancer treatment. PMID:24497952

  20. Age-dependent seizures of absence epilepsy and sleep spindles dynamics in WAG/Rij rats

    NASA Astrophysics Data System (ADS)

    Grubov, Vadim V.; Sitnikova, Evgenia Y.; Pavlov, Alexey N.; Khramova, Marina V.; Koronovskii, Alexey A.; Hramov, Alexander E.

    2015-03-01

    In the given paper, a relation between time-frequency characteristics of sleep spindles and the age-dependent epileptic activity in WAG/Rij rats is discussed. Analysis of sleep spindles based on the continuous wavelet transform is performed for rats of different ages. It is shown that the epileptic activity affects the time-frequency intrinsic dynamics of sleep spindles.

  1. Sequential activities of Dynein, Mud and Asp in centrosome-spindle coupling maintain centrosome number upon mitosis.

    PubMed

    Bosveld, Floris; Ainslie, Anna; Bellaïche, Yohanns

    2017-10-15

    Centrosomes nucleate microtubules and are tightly coupled to the bipolar spindle to ensure genome integrity, cell division orientation and centrosome segregation. While the mechanisms of centrosome-dependent microtubule nucleation and bipolar spindle assembly have been the focus of numerous works, less is known about the mechanisms ensuring the centrosome-spindle coupling. The conserved NuMA protein (Mud in Drosophila ) is best known for its role in spindle orientation. Here, we analyzed the role of Mud and two of its interactors, Asp and Dynein, in the regulation of centrosome numbers in Drosophila epithelial cells. We found that Dynein and Mud mainly initiate centrosome-spindle coupling prior to nuclear envelope breakdown (NEB) by promoting correct centrosome positioning or separation, while Asp acts largely independently of Dynein and Mud to maintain centrosome-spindle coupling. Failure in the centrosome-spindle coupling leads to mis-segregation of the two centrosomes into one daughter cell, resulting in cells with supernumerary centrosomes during subsequent divisions. Altogether, we propose that Dynein, Mud and Asp operate sequentially during the cell cycle to ensure efficient centrosome-spindle coupling in mitosis, thereby preventing centrosome mis-segregation to maintain centrosome number. © 2017. Published by The Company of Biologists Ltd.

  2. Analysis of static and dynamic characteristic of spindle system and its structure optimization in camshaft grinding machine

    NASA Astrophysics Data System (ADS)

    Feng, Jianjun; Li, Chengzhe; Wu, Zhi

    2017-08-01

    As an important part of the valve opening and closing controller in engine, camshaft has high machining accuracy requirement in designing. Taking the high-speed camshaft grinder spindle system as the research object and the spindle system performance as the optimizing target, this paper firstly uses Solidworks to establish the three-dimensional finite element model (FEM) of spindle system, then conducts static analysis and the modal analysis by applying the established FEM in ANSYS Workbench, and finally uses the design optimization function of the ANSYS Workbench to optimize the structure parameter in the spindle system. The study results prove that the design of the spindle system fully meets the production requirements, and the performance of the optimized spindle system is promoted. Besides, this paper provides an analysis and optimization method for other grinder spindle systems.

  3. Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis

    PubMed Central

    Martin, Carol-Anne; Murray, Jennie E.; Carroll, Paula; Leitch, Andrea; Mackenzie, Karen J.; Halachev, Mihail; Fetit, Ahmed E.; Keith, Charlotte; Bicknell, Louise S.; Fluteau, Adeline; Gautier, Philippe; Hall, Emma A.; Joss, Shelagh; Soares, Gabriela; Silva, João; Bober, Michael B.; Duker, Angela; Wise, Carol A.; Quigley, Alan J.; Phadke, Shubha R.; Wood, Andrew J.; Vagnarelli, Paola; Jackson, Andrew P.

    2016-01-01

    Compaction of chromosomes is essential for accurate segregation of the genome during mitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid disentanglement, and maintenance of mitotic chromosome structure. Here, we report that biallelic mutations in NCAPD2, NCAPH, or NCAPD3, encoding subunits of these complexes, cause microcephaly. In addition, hypomorphic Ncaph2 mice have significantly reduced brain size, with frequent anaphase chromatin bridge formation observed in apical neural progenitors during neurogenesis. Such DNA bridges also arise in condensin-deficient patient cells, where they are the consequence of failed sister chromatid disentanglement during chromosome compaction. This results in chromosome segregation errors, leading to micronucleus formation and increased aneuploidy in daughter cells. These findings establish “condensinopathies” as microcephalic disorders, with decatenation failure as an additional disease mechanism for microcephaly, implicating mitotic chromosome condensation as a key process ensuring mammalian cerebral cortex size. PMID:27737959

  4. Characterization of the Arabidopsis Augmin Complex Uncovers Its Critical Function in the Assembly of the Acentrosomal Spindle and Phragmoplast Microtubule Arrays[W

    PubMed Central

    Hotta, Takashi; Kong, Zhaosheng; Ho, Chin-Min Kimmy; Zeng, Cui Jing Tracy; Horio, Tetsuya; Fong, Sophia; Vuong, Trang; Lee, Yuh-Ru Julie; Liu, Bo

    2012-01-01

    Plant cells assemble the bipolar spindle and phragmoplast microtubule (MT) arrays in the absence of the centrosome structure. Our recent findings in Arabidopsis thaliana indicated that AUGMIN subunit3 (AUG3), a homolog of animal dim γ-tubulin 3, plays a critical role in γ-tubulin–dependent MT nucleation and amplification during mitosis. Here, we report the isolation of the entire plant augmin complex that contains eight subunits. Among them, AUG1 to AUG6 share low sequence similarity with their animal counterparts, but AUG7 and AUG8 share homology only with proteins of plant origin. Genetic analyses indicate that the AUG1, AUG2, AUG4, and AUG5 genes are essential, as stable mutations in these genes could only be transmitted to heterozygous plants. The sterile aug7-1 homozygous mutant in which AUG7 expression is significantly reduced exhibited pleiotropic phenotypes of seriously retarded vegetative and reproductive growth. The aug7-1 mutation caused delocalization of γ-tubulin in the mitotic spindle and phragmoplast. Consequently, spindles were abnormally elongated, and their poles failed to converge, as MTs were splayed to discrete positions rendering deformed arrays. In addition, the mutant phragmoplasts often had disorganized MT bundles with uneven edges. We conclude that assembly of MT arrays during plant mitosis depends on the augmin complex, which includes two plant-specific subunits. PMID:22505726

  5. Kinesin-5–dependent Poleward Flux and Spindle Length Control in Drosophila Embryo Mitosis

    PubMed Central

    Brust-Mascher, Ingrid; Sommi, Patrizia; Cheerambathur, Dhanya K.

    2009-01-01

    We used antibody microinjection and genetic manipulations to dissect the various roles of the homotetrameric kinesin-5, KLP61F, in astral, centrosome-controlled Drosophila embryo spindles and to test the hypothesis that it slides apart interpolar (ip) microtubules (MT), thereby controlling poleward flux and spindle length. In wild-type and Ncd null mutant embryos, anti-KLP61F dissociated the motor from spindles, producing a spatial gradient in the KLP61F content of different spindles, which was visible in KLP61F-GFP transgenic embryos. The resulting mitotic defects, supported by gene dosage experiments and time-lapse microscopy of living klp61f mutants, reveal that, after NEB, KLP61F drives persistent MT bundling and the outward sliding of antiparallel MTs, thereby contributing to several processes that all appear insensitive to cortical disruption. KLP61F activity contributes to the poleward flux of both ipMTs and kinetochore MTs and to the length of the metaphase spindle. KLP61F activity maintains the prometaphase spindle by antagonizing Ncd and another unknown force-generator and drives anaphase B, although the rate of spindle elongation is relatively insensitive to the motor's concentration. Finally, KLP61F activity contributes to normal chromosome congression, kinetochore spacing, and anaphase A rates. Thus, a KLP61F-driven sliding filament mechanism contributes to multiple aspects of mitosis in this system. PMID:19158379

  6. Occurrence of maternal and paternal spindles in unfertilized human oocytes: possible relationship to nucleation defects after silent fertilization.

    PubMed

    Van Blerkom, Jonathan; Davis, Patrick; Alexander, Samuel

    2004-04-01

    Experience with conventional clinical IVF indicates that a first cleavage can occur in the absence of detectable pronuclear formation (so-called silent fertilization). In these instances, the first division is often asymmetrical and delayed when compared with normally fertilized siblings. In this study, DNA configurations and spindle organization were examined by fluorescence microscopy in metaphase II human oocytes that remained unfertilized after conventional IVF and were considered likely candidates for silent fertilization. The results show comparatively high frequencies of penetration in the absence of detectable pronuclear evolution, and that both a maternal meiotic and a sperm-derived mitotic-like spindle can coexist in the same oocyte. Patterns of cell division and blastomere nucleation in silent fertilizations suggest the possibility that this division may involve uniparental chromosomal segregation in which maternal and paternal DNA is differentially partitioned into daughter blastomeres. This pattern of inheritance may generate certain types of ploidy and nucleation defects detected at the 2- to 4-cell stage.

  7. Mounting arrangement for the drive system of an air-bearing spindle on a machine tool

    DOEpatents

    Lunsford, J.S.; Crisp, D.W.; Petrowski, P.L.

    1987-12-07

    The present invention is directed to a mounting arrangement for the drive system of an air-bearing spindle utilized on a machine tool such as a lathe. The mounting arrangement of the present invention comprises a housing which is secured to the casing of the air bearing in such a manner that the housing position can be selectively adjusted to provide alignment of the air-bearing drive shaft supported by the housing and the air-bearing spindle. Once this alignment is achieved the air between spindle and the drive arrangement is maintained in permanent alignment so as to overcome misalignment problems encountered in the operation of the machine tool between the air-bearing spindle and the shaft utilized for driving the air-bearing spindle.

  8. Elucidating an Adverse Outcome Pathway of Microcephaly for use in Computational Toxicology (SOT Annual Meeting)

    EPA Science Inventory

    While evidence now supports a causal link between maternal Zika viral infection and microcephaly, genetic errors and chemical stressors may also precipitate this malformation through disruption of neuroprogenitor cell (NPC) proliferation, migration and differentiation in the earl...

  9. Autocatalytic microtubule nucleation determines the size and mass of Xenopus laevis egg extract spindles

    PubMed Central

    Decker, Franziska; Oriola, David; Dalton, Benjamin

    2018-01-01

    Regulation of size and growth is a fundamental problem in biology. A prominent example is the formation of the mitotic spindle, where protein concentration gradients around chromosomes are thought to regulate spindle growth by controlling microtubule nucleation. Previous evidence suggests that microtubules nucleate throughout the spindle structure. However, the mechanisms underlying microtubule nucleation and its spatial regulation are still unclear. Here, we developed an assay based on laser ablation to directly probe microtubule nucleation events in Xenopus laevis egg extracts. Combining this method with theory and quantitative microscopy, we show that the size of a spindle is controlled by autocatalytic growth of microtubules, driven by microtubule-stimulated microtubule nucleation. The autocatalytic activity of this nucleation system is spatially regulated by the limiting amounts of active microtubule nucleators, which decrease with distance from the chromosomes. This mechanism provides an upper limit to spindle size even when resources are not limiting. PMID:29323637

  10. Rat isolated phrenic nerve-diaphragm preparation for pharmacological study of muscle spindle afferent activity: effect of oxotremorine.

    PubMed Central

    Ganguly, D K; Nath, D N; Ross, H G; Vedasiromoni, J R

    1978-01-01

    1. Muscle spindle afferent discharges exhibiting an approximately linear length-frequency relation could be recorded from the phrenic nerve in the isolated phrenic nerve-diaphragm preparation of the rat. 2. Muscle spindle afferent discharges could be identified by their characteristic "spindle pause" during muscle contraction and by their response to succinylcholine. 3. Cholinergic influence on spontaneous and stretch-induced afferent discharges was indicated by the augmentation produced by physostigmine and acetylcholine. (+)-Tubocurarine, but not atropine, prevented this augmentation indicating the presence of curariform cholinoceptors in muscle spindles. 4. Acetylcholine did not appear to be involved in the genesis of spindle afferent discharges as incubation with hemicholinium-3 and (+)-tubocurarine failed to affect the rate of spontaneous and stretch-induced spindle discharges. 5. Oxotremorine markedly increased the rate of spontaneous and stretch-induced spindle afferent discharges and this effect was prevented in the presence of hemicholinium-3 and (+)-tubocurarine. 6. These results with oxotremorine are of interest in connection with the observation that muscle spindle afferents and hyperactive in Parkinsonian patients. PMID:151569

  11. Plk1 and Mps1 Cooperatively Regulate the Spindle Assembly Checkpoint in Human Cells.

    PubMed

    von Schubert, Conrad; Cubizolles, Fabien; Bracher, Jasmine M; Sliedrecht, Tale; Kops, Geert J P L; Nigg, Erich A

    2015-07-07

    Equal mitotic chromosome segregation is critical for genome integrity and is monitored by the spindle assembly checkpoint (SAC). We have previously shown that the consensus phosphorylation motif of the essential SAC kinase Monopolar spindle 1 (Mps1) is very similar to that of Polo-like kinase 1 (Plk1). This prompted us to ask whether human Plk1 cooperates with Mps1 in SAC signaling. Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. We conclude that Plk1 strengthens the robustness of SAC establishment at the onset of mitosis and supports SAC maintenance during prolonged mitotic arrest. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Evaluating and Improving Automatic Sleep Spindle Detection by Using Multi-Objective Evolutionary Algorithms

    PubMed Central

    Liu, Min-Yin; Huang, Adam; Huang, Norden E.

    2017-01-01

    Sleep spindles are brief bursts of brain activity in the sigma frequency range (11–16 Hz) measured by electroencephalography (EEG) mostly during non-rapid eye movement (NREM) stage 2 sleep. These oscillations are of great biological and clinical interests because they potentially play an important role in identifying and characterizing the processes of various neurological disorders. Conventionally, sleep spindles are identified by expert sleep clinicians via visual inspection of EEG signals. The process is laborious and the results are inconsistent among different experts. To resolve the problem, numerous computerized methods have been developed to automate the process of sleep spindle identification. Still, the performance of these automated sleep spindle detection methods varies inconsistently from study to study. There are two reasons: (1) the lack of common benchmark databases, and (2) the lack of commonly accepted evaluation metrics. In this study, we focus on tackling the second problem by proposing to evaluate the performance of a spindle detector in a multi-objective optimization context and hypothesize that using the resultant Pareto fronts for deriving evaluation metrics will improve automatic sleep spindle detection. We use a popular multi-objective evolutionary algorithm (MOEA), the Strength Pareto Evolutionary Algorithm (SPEA2), to optimize six existing frequency-based sleep spindle detection algorithms. They include three Fourier, one continuous wavelet transform (CWT), and two Hilbert-Huang transform (HHT) based algorithms. We also explore three hybrid approaches. Trained and tested on open-access DREAMS and MASS databases, two new hybrid methods of combining Fourier with HHT algorithms show significant performance improvement with F1-scores of 0.726–0.737. PMID:28572762

  13. Automated High-Throughput Quantification of Mitotic Spindle Positioning from DIC Movies of Caenorhabditis Embryos

    PubMed Central

    Cluet, David; Spichty, Martin; Delattre, Marie

    2014-01-01

    The mitotic spindle is a microtubule-based structure that elongates to accurately segregate chromosomes during anaphase. Its position within the cell also dictates the future cell cleavage plan, thereby determining daughter cell orientation within a tissue or cell fate adoption for polarized cells. Therefore, the mitotic spindle ensures at the same time proper cell division and developmental precision. Consequently, spindle dynamics is the matter of intensive research. Among the different cellular models that have been explored, the one-cell stage C. elegans embryo has been an essential and powerful system to dissect the molecular and biophysical basis of spindle elongation and positioning. Indeed, in this large and transparent cell, spindle poles (or centrosomes) can be easily detected from simple DIC microscopy by human eyes. To perform quantitative and high-throughput analysis of spindle motion, we developed a computer program ACT for Automated-Centrosome-Tracking from DIC movies of C. elegans embryos. We therefore offer an alternative to the image acquisition and processing of transgenic lines expressing fluorescent spindle markers. Consequently, experiments on large sets of cells can be performed with a simple setup using inexpensive microscopes. Moreover, analysis of any mutant or wild-type backgrounds is accessible because laborious rounds of crosses with transgenic lines become unnecessary. Last, our program allows spindle detection in other nematode species, offering the same quality of DIC images but for which techniques of transgenesis are not accessible. Thus, our program also opens the way towards a quantitative evolutionary approach of spindle dynamics. Overall, our computer program is a unique macro for the image- and movie-processing platform ImageJ. It is user-friendly and freely available under an open-source licence. ACT allows batch-wise analysis of large sets of mitosis events. Within 2 minutes, a single movie is processed and the accuracy of

  14. Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis.

    PubMed

    Martin, Carol-Anne; Murray, Jennie E; Carroll, Paula; Leitch, Andrea; Mackenzie, Karen J; Halachev, Mihail; Fetit, Ahmed E; Keith, Charlotte; Bicknell, Louise S; Fluteau, Adeline; Gautier, Philippe; Hall, Emma A; Joss, Shelagh; Soares, Gabriela; Silva, João; Bober, Michael B; Duker, Angela; Wise, Carol A; Quigley, Alan J; Phadke, Shubha R; Wood, Andrew J; Vagnarelli, Paola; Jackson, Andrew P

    2016-10-01

    Compaction of chromosomes is essential for accurate segregation of the genome during mitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid disentanglement, and maintenance of mitotic chromosome structure. Here, we report that biallelic mutations in NCAPD2, NCAPH, or NCAPD3, encoding subunits of these complexes, cause microcephaly. In addition, hypomorphic Ncaph2 mice have significantly reduced brain size, with frequent anaphase chromatin bridge formation observed in apical neural progenitors during neurogenesis. Such DNA bridges also arise in condensin-deficient patient cells, where they are the consequence of failed sister chromatid disentanglement during chromosome compaction. This results in chromosome segregation errors, leading to micronucleus formation and increased aneuploidy in daughter cells. These findings establish "condensinopathies" as microcephalic disorders, with decatenation failure as an additional disease mechanism for microcephaly, implicating mitotic chromosome condensation as a key process ensuring mammalian cerebral cortex size. © 2016 Martin et al.; Published by Cold Spring Harbor Laboratory Press.

  15. Autocatalytic microtubule nucleation determines the size and mass of Xenopus laevis egg extract spindles.

    PubMed

    Decker, Franziska; Oriola, David; Dalton, Benjamin; Brugués, Jan

    2018-01-11

    Regulation of size and growth is a fundamental problem in biology. A prominent example is the formation of the mitotic spindle, where protein concentration gradients around chromosomes are thought to regulate spindle growth by controlling microtubule nucleation. Previous evidence suggests that microtubules nucleate throughout the spindle structure. However, the mechanisms underlying microtubule nucleation and its spatial regulation are still unclear. Here, we developed an assay based on laser ablation to directly probe microtubule nucleation events in Xenopus laevis egg extracts. Combining this method with theory and quantitative microscopy, we show that the size of a spindle is controlled by autocatalytic growth of microtubules, driven by microtubule-stimulated microtubule nucleation. The autocatalytic activity of this nucleation system is spatially regulated by the limiting amounts of active microtubule nucleators, which decrease with distance from the chromosomes. This mechanism provides an upper limit to spindle size even when resources are not limiting. © 2018, Decker et al.

  16. Ase1/Prc1-dependent spindle elongation corrects merotely during anaphase in fission yeast

    PubMed Central

    Courtheoux, Thibault; Gay, Guillaume; Tournier, Sylvie

    2009-01-01

    Faithful segregation of sister chromatids requires the attachment of each kinetochore (Kt) to microtubules (MTs) that extend from opposite spindle poles. Merotelic Kt orientation is a Kt–MT misattachment in which a single Kt binds MTs from both spindle poles rather than just one. Genetic induction of merotelic Kt attachment during anaphase in fission yeast resulted in intra-Kt stretching followed by either correction or Kt disruption. Laser ablation of spindle MTs revealed that intra-Kt stretching and merotelic correction were dependent on MT forces. The presence of multiple merotelic chromosomes linearly antagonized the spindle elongation rate, and this phenomenon could be solved numerically using a simple force balance model. Based on the predictions of our mechanical model, we provide in vivo evidence that correction of merotelic attachment in anaphase is tension dependent and requires an Ase1/Prc1-dependent mechanism that prevents spindle collapse and thus asymmetric division and/or the appearance of the cut phenotype. PMID:19948483

  17. Spindle cell sarcoma of the vulva with myofibroblastic differentiation.

    PubMed

    Adeleye, Amanda J; Palmeri, Nicholas; Wang, Shih-Hsiu J; Liu-Jarin, Xiaolin; Wright, Jason D

    2015-04-01

    Primary vulvar sarcomas are rare lesions of the lower genital tract. We report the case of a patient with a spindle cell sarcoma of the vulva. A 44-year-old woman presented with a painless vulvar mass. Vulvar biopsy demonstrated a spindle cell sarcoma with myofibroblastic differentiation. Pretreatment evaluation revealed no evidence of metastatic disease, and magnetic resonance imaging found no local masses. The patient underwent right radical vulvectomy with negative margins and tolerated the procedure well. Women undergoing gynecologic care should have routine evaluation of the vulva to detect these rare neoplasms.

  18. Cortical dendritic activity correlates with spindle-rich oscillations during sleep in rodents.

    PubMed

    Seibt, Julie; Richard, Clément J; Sigl-Glöckner, Johanna; Takahashi, Naoya; Kaplan, David I; Doron, Guy; de Limoges, Denis; Bocklisch, Christina; Larkum, Matthew E

    2017-09-25

    How sleep influences brain plasticity is not known. In particular, why certain electroencephalographic (EEG) rhythms are linked to memory consolidation is poorly understood. Calcium activity in dendrites is known to be necessary for structural plasticity changes, but this has never been carefully examined during sleep. Here, we report that calcium activity in populations of neocortical dendrites is increased and synchronised during oscillations in the spindle range in naturally sleeping rodents. Remarkably, the same relationship is not found in cell bodies of the same neurons and throughout the cortical column. Spindles during sleep have been suggested to be important for brain development and plasticity. Our results provide evidence for a physiological link of spindles in the cortex specific to dendrites, the main site of synaptic plasticity.Different stages of sleep, marked by particular electroencephalographic (EEG) signatures, have been linked to memory consolidation, but underlying mechanisms are poorly understood. Here, the authors show that dendritic calcium synchronisation correlates with spindle-rich sleep phases.

  19. Sleep Spindles in the Right Hemisphere Support Awareness of Regularities and Reflect Pre-Sleep Activations.

    PubMed

    Yordanova, Juliana; Kolev, Vasil; Bruns, Eike; Kirov, Roumen; Verleger, Rolf

    2017-11-01

    The present study explored the sleep mechanisms which may support awareness of hidden regularities. Before sleep, 53 participants learned implicitly a lateralized variant of the serial response-time task in order to localize sensorimotor encoding either in the left or right hemisphere and induce implicit regularity representations. Electroencephalographic (EEG) activity was recorded at multiple electrodes during both task performance and sleep, searching for lateralized traces of the preceding activity during learning. Sleep EEG analysis focused on region-specific slow (9-12 Hz) and fast (13-16 Hz) sleep spindles during nonrapid eye movement sleep. Fast spindle activity at those motor regions that were activated during learning increased with the amount of postsleep awareness. Independently of side of learning, spindle activity at right frontal and fronto-central regions was involved: there, fast spindles increased with the transformation of sequence knowledge from implicit before sleep to explicit after sleep, and slow spindles correlated with individual abilities of gaining awareness. These local modulations of sleep spindles corresponded to regions with greater presleep activation in participants with postsleep explicit knowledge. Sleep spindle mechanisms are related to explicit awareness (1) by tracing the activation of motor cortical and right-hemisphere regions which had stronger involvement already during learning and (2) by recruitment of individually consolidated processing modules in the right hemisphere. The integration of different sleep spindle mechanisms with functional states during wake collectively supports the gain of awareness of previously experienced regularities, with a special role for the right hemisphere. © Sleep Research Society 2017. Published by Oxford University Press [on behalf of the Sleep Research Society].

  20. Warts phosphorylates Mud to promote Pins-mediated mitotic spindle orientation in Drosophila independent of Yorkie

    PubMed Central

    Dewey, Evan B.; Sanchez, Desiree; Johnston, Christopher A.

    2015-01-01

    SUMMARY Multicellular animals have evolved conserved signaling pathways that translate cell polarity cues into mitotic spindle positioning to control the orientation of cell division within complex tissue structures. These oriented cell divisions are essential for the development of cell diversity and the maintenance of tissue homeostasis. Despite intense efforts, the molecular mechanisms that control spindle orientation remain incompletely defined. Here we describe a role for the Hippo (Hpo) kinase complex in promoting Partner of Inscuteable (Pins)-mediated spindle orientation. Knockdown of Hpo, Salvador (Sav), or Warts (Wts) each result in a partial loss of spindle orientation, a phenotype previously described following loss of the Pins-binding protein Mushroom body defect (Mud). Similar to orthologs spanning yeast to mammals, Wts kinase localizes to mitotic spindle poles, a prominent site of Mud localization. Wts directly phosphorylates Mud in vitro within its C-terminal coiled-coil domain. This Mud coiled-coil domain directly binds the adjacent Pins-binding domain to dampen the Pins/Mud interaction, and Wts-mediated phosphorylation uncouples this intramolecular Mud interaction. Loss of Wts prevents cortical Pins/Mud association without affecting Mud accumulation at spindle poles, suggesting phosphorylation acts as a molecular switch to specifically activate cortical Mud function. Finally, loss of Wts in Drosophila imaginal disc epithelial cells results in diminished cortical Mud and defective planar spindle orientation. Our results provide new insights into the molecular basis for dynamic regulation of the cortical Pins/Mud spindle positioning complex and highlight a novel link with an essential, evolutionarily-conserved cell proliferation pathway. PMID:26592339

  1. Warts phosphorylates mud to promote pins-mediated mitotic spindle orientation in Drosophila, independent of Yorkie.

    PubMed

    Dewey, Evan B; Sanchez, Desiree; Johnston, Christopher A

    2015-11-02

    Multicellular animals have evolved conserved signaling pathways that translate cell polarity cues into mitotic spindle positioning to control the orientation of cell division within complex tissue structures. These oriented cell divisions are essential for the development of cell diversity and the maintenance of tissue homeostasis. Despite intense efforts, the molecular mechanisms that control spindle orientation remain incompletely defined. Here, we describe a role for the Hippo (Hpo) kinase complex in promoting Partner of Inscuteable (Pins)-mediated spindle orientation. Knockdown of Hpo, Salvador (Sav), or Warts (Wts) each result in a partial loss of spindle orientation, a phenotype previously described following loss of the Pins-binding protein Mushroom body defect (Mud). Similar to orthologs spanning yeast to mammals, Wts kinase localizes to mitotic spindle poles, a prominent site of Mud localization. Wts directly phosphorylates Mud in vitro within its C-terminal coiled-coil domain. This Mud coiled-coil domain directly binds the adjacent Pins-binding domain to dampen the Pins/Mud interaction, and Wts-mediated phosphorylation uncouples this intramolecular Mud interaction. Loss of Wts prevents cortical Pins/Mud association without affecting Mud accumulation at spindle poles, suggesting phosphorylation acts as a molecular switch to specifically activate cortical Mud function. Finally, loss of Wts in Drosophila imaginal disc epithelial cells results in diminished cortical Mud and defective planar spindle orientation. Our results provide new insights into the molecular basis for dynamic regulation of the cortical Pins/Mud spindle positioning complex and highlight a novel link with an essential, evolutionarily conserved cell proliferation pathway. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Loss of the arginine methyltranserase PRMT7 causes syndromic intellectual disability with microcephaly and brachydactyly.

    PubMed

    Kernohan, K D; McBride, A; Xi, Y; Martin, N; Schwartzentruber, J; Dyment, D A; Majewski, J; Blaser, S; Boycott, K M; Chitayat, D

    2017-05-01

    Post-translational protein modifications exponentially expand the functional complement of proteins encoded by the human genome. One such modification is the covalent addition of a methyl group to arginine or lysine residues, which is used to regulate a substantial proportion of the proteome. Arginine and lysine methylation are catalyzed by protein arginine methyltransferase (PRMTs) and protein lysine methyltransferase proteins (PKMTs), respectively; each methyltransferase has a specific set of target substrates. Here, we report a male with severe intellectual disability, facial dysmorphism, microcephaly, short stature, brachydactyly, cryptorchidism and seizures who was found to have a homozygous 15,309 bp deletion encompassing the transcription start site of PRMT7, which we confirmed is functionally a null allele. We show that the patient's cells have decreased levels of protein arginine methylation, and that affected proteins include the essential histones, H2B and H4. Finally, we demonstrate that patient cells have altered Wnt signaling, which may have contributed to the skeletal abnormalities. Our findings confirm the recent disease association of PRMT7, expand the phenotypic manifestations of this disorder and provide insight into the molecular pathogenesis of this new condition. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Drosophila Klp67A binds prophase kinetochores to subsequently regulate congression and spindle length.

    PubMed

    Savoian, Matthew S; Glover, David M

    2010-03-01

    The kinesin-8 proteins are a family of microtubule-depolymerising motor molecules, which, despite their highly conserved roles in chromosome alignment and spindle dynamics, remain poorly characterised. Here, we report that the Drosophila kinesin-8 protein, Klp67A, exists in two spatially and functionally separable metaphase pools: at kinetochores and along the spindle. Fixed and live-cell analyses of different Klp67A recombinant variants indicate that this kinesin-8 first collects at kinetochores during prophase and, by metaphase, localises to the kinetochore outerplate. Although the catalytic motor activity of Klp67A is required for efficient kinetochore recruitment at all times, microtubules are entirely dispensable for this process. The tail of Klp67A does not play a role in kinetochore accumulation, but is both necessary and sufficient for spindle association. Using functional assays, we reveal that chromosome position and spindle length are determined by the microtubule-depolymerising motor activity of Klp67A exclusively when located at kinetochores, but not along the spindle. These data reveal that, unlike other metazoan kinesin-8 proteins, Klp67A binds the nascent prophase and mature metaphase kinetochore. From this location, Klp67A uses its motor activity to ensure chromosome alignment and proper spindle length.

  4. Characterization of a Putative Spindle Assembly Checkpoint Kinase Mps1, Suggests Its Involvement in Cell Division, Morphogenesis and Oxidative Stress Tolerance in Candida albicans

    PubMed Central

    Ruhela, Deepa; Kamthan, Ayushi; Maiti, Protiti; Datta, Asis

    2014-01-01

    In Saccharomyces cerevisiae MPS1 is one of the major protein kinase that governs the spindle checkpoint pathway. The S. cerevisiae structural homolog of opportunistic pathogen Candida albicans CaMPS1, is indispensable for the cell viability. The essentiality of Mps1 was confirmed by Homozygote Trisome test. To determine its biological function in this pathogen conditional mutant was generated through regulatable MET3 promoter. Examination of heterozygous and conditional (+Met/Cys) mps1 mutants revealed a mitosis specific arrest phenotype, where mutants showed large buds with undivided nuclei. Flowcytometry analysis revealed abnormal ploidy levels in mps1mutant. In presence of anti-microtubule drug Nocodazole, mps1 mutant showed a dramatic loss of viability suggesting a role of Mps1 in Spindle Assembly Checkpoint (SAC) activation. These mutants were also defective in microtubule organization. Moreover, heterozygous mutant showed defective in-vitro yeast to hyphae morphological transition. Growth defect in heterozygous mutant suggest haploinsufficiency of this gene. qRT PCR analysis showed around 3 fold upregulation of MPS1 in presence of serum. This expression of MPS1 is dependent on Efg1and is independent of other hyphal regulators like Ras1 and Tpk2. Furthermore, mps1 mutants were also sensitive to oxidative stress. Heterozygous mps1 mutant did not undergo morphological transition and showed 5-Fold reduction in colony forming units in response to macrophage. Thus, the vital checkpoint kinase, Mps1 besides cell division also has a role in morphogenesis and oxidative stress tolerance, in this pathogenic fungus. PMID:25025778

  5. Characterization of a putative spindle assembly checkpoint kinase Mps1, suggests its involvement in cell division, morphogenesis and oxidative stress tolerance in Candida albicans.

    PubMed

    Kamthan, Mohan; Nalla, Vijaya Kumar; Ruhela, Deepa; Kamthan, Ayushi; Maiti, Protiti; Datta, Asis

    2014-01-01

    In Saccharomyces cerevisiae MPS1 is one of the major protein kinase that governs the spindle checkpoint pathway. The S. cerevisiae structural homolog of opportunistic pathogen Candida albicans CaMPS1, is indispensable for the cell viability. The essentiality of Mps1 was confirmed by Homozygote Trisome test. To determine its biological function in this pathogen conditional mutant was generated through regulatable MET3 promoter. Examination of heterozygous and conditional (+Met/Cys) mps1 mutants revealed a mitosis specific arrest phenotype, where mutants showed large buds with undivided nuclei. Flowcytometry analysis revealed abnormal ploidy levels in mps1 mutant. In presence of anti-microtubule drug Nocodazole, mps1 mutant showed a dramatic loss of viability suggesting a role of Mps1 in Spindle Assembly Checkpoint (SAC) activation. These mutants were also defective in microtubule organization. Moreover, heterozygous mutant showed defective in-vitro yeast to hyphae morphological transition. Growth defect in heterozygous mutant suggest haploinsufficiency of this gene. qRT PCR analysis showed around 3 fold upregulation of MPS1 in presence of serum. This expression of MPS1 is dependent on Efg1 and is independent of other hyphal regulators like Ras1 and Tpk2. Furthermore, mps1 mutants were also sensitive to oxidative stress. Heterozygous mps1 mutant did not undergo morphological transition and showed 5-Fold reduction in colony forming units in response to macrophage. Thus, the vital checkpoint kinase, Mps1 besides cell division also has a role in morphogenesis and oxidative stress tolerance, in this pathogenic fungus.

  6. Fusimotor control of spindle sensitivity regulates central and peripheral coding of joint angles.

    PubMed

    Lan, Ning; He, Xin

    2012-01-01

    Proprioceptive afferents from muscle spindles encode information about peripheral joint movements for the central nervous system (CNS). The sensitivity of muscle spindle is nonlinearly dependent on the activation of gamma (γ) motoneurons in the spinal cord that receives inputs from the motor cortex. How fusimotor control of spindle sensitivity affects proprioceptive coding of joint position is not clear. Furthermore, what information is carried in the fusimotor signal from the motor cortex to the muscle spindle is largely unknown. In this study, we addressed the issue of communication between the central and peripheral sensorimotor systems using a computational approach based on the virtual arm (VA) model. In simulation experiments within the operational range of joint movements, the gamma static commands (γ(s)) to the spindles of both mono-articular and bi-articular muscles were hypothesized (1) to remain constant, (2) to be modulated with joint angles linearly, and (3) to be modulated with joint angles nonlinearly. Simulation results revealed a nonlinear landscape of Ia afferent with respect to both γ(s) activation and joint angle. Among the three hypotheses, the constant and linear strategies did not yield Ia responses that matched the experimental data, and therefore, were rejected as plausible strategies of spindle sensitivity control. However, if γ(s) commands were quadratically modulated with joint angles, a robust linear relation between Ia afferents and joint angles could be obtained in both mono-articular and bi-articular muscles. With the quadratic strategy of spindle sensitivity control, γ(s) commands may serve as the CNS outputs that inform the periphery of central coding of joint angles. The results suggest that the information of joint angles may be communicated between the CNS and muscles via the descending γ(s) efferent and Ia afferent signals.

  7. MAPK-Activated Protein Kinase 2 Is Required for Mouse Meiotic Spindle Assembly and Kinetochore-Microtubule Attachment

    PubMed Central

    Qi, Shu-Tao; Tong, Jing-Shan; Wei, Liang; Li, Mo; Ouyang, Ying-Chun; Hou, Yi; Schatten, Heide; Sun, Qing-Yuan

    2010-01-01

    MAPK-activated protein kinase 2 (MK2), a direct substrate of p38 MAPK, plays key roles in multiple physiological functions in mitosis. Here, we show for the first time the unique distribution pattern of MK2 in meiosis. Phospho-MK2 was localized on bipolar spindle minus ends and along the interstitial axes of homologous chromosomes extending over centromere regions and arm regions at metaphase of first meiosis (MI stage) in mouse oocytes. At metaphase of second meiosis (MII stage), p-MK2 was localized on the bipolar spindle minus ends and at the inner centromere region of sister chromatids as dots. Knockdown or inhibition of MK2 resulted in spindle defects. Spindles were surrounded by irregular nondisjunction chromosomes, which were arranged in an amphitelic or syntelic/monotelic manner, or chromosomes detached from the spindles. Kinetochore–microtubule attachments were impaired in MK2-deficient oocytes because spindle microtubules became unstable in response to cold treatment. In addition, homologous chromosome segregation and meiosis progression were inhibited in these oocytes. Our data suggest that MK2 may be essential for functional meiotic bipolar spindle formation, chromosome segregation and proper kinetochore–microtubule attachments. PMID:20596525

  8. Cdc2-mediated phosphorylation of Kid controls its distribution to spindle and chromosomes

    PubMed Central

    Ohsugi, Miho; Tokai-Nishizumi, Noriko; Shiroguchi, Katsuyuki; Toyoshima, Yoko Y.; Inoue, Jun-ichiro; Yamamoto, Tadashi

    2003-01-01

    The chromokinesin Kid is important in chromosome alignment at the metaphase plate. Here, we report that Kid function is regulated by phosphorylation. We identify Ser427 and Thr463 as M phase-specific phosphorylation sites and Cdc2–cyclin B as a Thr463 kinase. Kid with a Thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind DNA or chromosomes. Localization of rigor-type mutant Kid, which shows nucleotide-independent microtubule association, is also confined to the spindle, implying that strong association of Kid with the spindle can sequester it from chromosomes. T463A substitution in DNA-binding domain-truncated Kid consistently enhances its spindle localization. At physiological ionic strength, unphosphorylated Kid shows ATP-independent microtubule association, whereas Thr463-phosphorylated Kid shows ATP dependency. Moreover, the stalk region of unphosphorylated Kid interacts with microtubules and the interaction is weakened when Thr463 is phosphorylated. Our data suggest that phosphorylation on Thr463 of Kid downregulates its affinity for microtubules to ensure reversible association with spindles, allowing Kid to bind chromosomes and exhibit its function. PMID:12727876

  9. The 5α-reductase inhibitor finasteride is not associated with alterations in sleep spindles in men referred for polysomnography

    PubMed Central

    Goldstein, Michael R.; Cook, Jesse D.; Plante, David T.

    2015-01-01

    Objective Endogenous neurosteroids that potentiate the GABAA receptor are thought to enhance the generation of sleep spindles. This study tested the hypothesis that the 5α-reductase inhibitor finasteride, an agent associated with reductions in neurosteroids, would be associated with reduced sleep spindles in men referred for polysomnography. Methods Spectral analysis and spindle waveform detection were performed on electroencephalographic (EEG) sleep data in the 11–16Hz sigma band, as well as several subranges, from 27 men taking finasteride and 27 matched comparison patients (ages 18 to 81 years). Results No significant differences between groups were observed for spectral power or sleep spindle morphology measures, including spindle density, amplitude, duration, and integrated spindle activity. Conclusions Contrary to our hypothesis, these findings demonstrate that finasteride is not associated with alterations in sleep spindle range activity or spindle morphology parameters. PMID:26494125

  10. The Drosophila Microtubule-Associated Protein Mars Stabilizes Mitotic Spindles by Crosslinking Microtubules through Its N-Terminal Region

    PubMed Central

    Zhang, Gang; Beati, Hamze; Nilsson, Jakob; Wodarz, Andreas

    2013-01-01

    Correct segregation of genetic material relies on proper assembly and maintenance of the mitotic spindle. How the highly dynamic microtubules (MTs) are maintained in stable mitotic spindles is a key question to be answered. Motor and non-motor microtubule associated proteins (MAPs) have been reported to stabilize the dynamic spindle through crosslinking adjacent MTs. Mars, a novel MAP, is essential for the early development of Drosophila embryos. Previous studies showed that Mars is required for maintaining an intact mitotic spindle but did not provide a molecular mechanism for this function. Here we show that Mars is able to stabilize the mitotic spindle in vivo. Both in vivo and in vitro data reveal that the N-terminal region of Mars functions in the stabilization of the mitotic spindle by crosslinking adjacent MTs. PMID:23593258

  11. Spindle speed variation technique in turning operations: Modeling and real implementation

    NASA Astrophysics Data System (ADS)

    Urbikain, G.; Olvera, D.; de Lacalle, L. N. López; Elías-Zúñiga, A.

    2016-11-01

    Chatter is still one of the most challenging problems in machining vibrations. Researchers have focused their efforts to prevent, avoid or reduce chatter vibrations by introducing more accurate predictive physical methods. Among them, the techniques based on varying the rotational speed of the spindle (or SSV, Spindle Speed ​​Variation) have gained great relevance. However, several problems need to be addressed due to technical and practical reasons. On one hand, they can generate harmful overheating of the spindle especially at high speeds. On the other hand, the machine may be unable to perform the interpolation properly. Moreover, it is not trivial to select the most appropriate tuning parameters. This paper conducts a study of the real implementation of the SSV technique in turning systems. First, a stability model based on perturbation theory was developed for simulation purposes. Secondly, the procedure to realistically implement the technique in a conventional turning center was tested and developed. The balance between the improved stability margins and acceptable behavior of the spindle is ensured by energy consumption measurements. Mathematical model shows good agreement with experimental cutting tests.

  12. Mitotic Spindle Positioning in the EMS Cell of Caenorhabditis elegans Requires LET-99 and LIN-5/NuMA.

    PubMed

    Liro, Małgorzata J; Rose, Lesilee S

    2016-11-01

    Asymmetric divisions produce daughter cells with different fates, and thus are critical for animal development. During asymmetric divisions, the mitotic spindle must be positioned on a polarized axis to ensure the differential segregation of cell fate determinants into the daughter cells. In many cell types, a cortically localized complex consisting of Gα, GPR-1/2, and LIN-5 (Gαi/Pins/Mud, Gαi/LGN/NuMA) mediates the recruitment of dynactin/dynein, which exerts pulling forces on astral microtubules to physically position the spindle. The conserved PAR polarity proteins are known to regulate both cytoplasmic asymmetry and spindle positioning in many cases. However, spindle positioning also occurs in response to cell signaling cues that appear to be PAR-independent. In the four-cell Caenorhabditis elegans embryo, Wnt and Mes-1/Src-1 signaling pathways act partially redundantly to align the spindle on the anterior/posterior axis of the endomesodermal (EMS) precursor cell. It is unclear how those extrinsic signals individually contribute to spindle positioning and whether either pathway acts via conserved spindle positioning regulators. Here, we genetically test the involvement of Gα, LIN-5, and their negative regulator LET-99, in transducing EMS spindle positioning polarity cues. We also examined whether the C. elegans ortholog of another spindle positioning regulator, DLG-1, is required. We show that LET-99 acts in the Mes-1/Src-1 pathway for spindle positioning. LIN-5 is also required for EMS spindle positioning, possibly through a Gα- and DLG-1-independent mechanism. Copyright © 2016 by the Genetics Society of America.

  13. Mitotic Spindle Positioning in the EMS Cell of Caenorhabditis elegans Requires LET-99 and LIN-5/NuMA

    PubMed Central

    Liro, Małgorzata J.; Rose, Lesilee S.

    2016-01-01

    Asymmetric divisions produce daughter cells with different fates, and thus are critical for animal development. During asymmetric divisions, the mitotic spindle must be positioned on a polarized axis to ensure the differential segregation of cell fate determinants into the daughter cells. In many cell types, a cortically localized complex consisting of Gα, GPR-1/2, and LIN-5 (Gαi/Pins/Mud, Gαi/LGN/NuMA) mediates the recruitment of dynactin/dynein, which exerts pulling forces on astral microtubules to physically position the spindle. The conserved PAR polarity proteins are known to regulate both cytoplasmic asymmetry and spindle positioning in many cases. However, spindle positioning also occurs in response to cell signaling cues that appear to be PAR-independent. In the four-cell Caenorhabditis elegans embryo, Wnt and Mes-1/Src-1 signaling pathways act partially redundantly to align the spindle on the anterior/posterior axis of the endomesodermal (EMS) precursor cell. It is unclear how those extrinsic signals individually contribute to spindle positioning and whether either pathway acts via conserved spindle positioning regulators. Here, we genetically test the involvement of Gα, LIN-5, and their negative regulator LET-99, in transducing EMS spindle positioning polarity cues. We also examined whether the C. elegans ortholog of another spindle positioning regulator, DLG-1, is required. We show that LET-99 acts in the Mes-1/Src-1 pathway for spindle positioning. LIN-5 is also required for EMS spindle positioning, possibly through a Gα- and DLG-1-independent mechanism. PMID:27672093

  14. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study.

    PubMed

    Calvet, Guilherme; Aguiar, Renato S; Melo, Adriana S O; Sampaio, Simone A; de Filippis, Ivano; Fabri, Allison; Araujo, Eliane S M; de Sequeira, Patricia C; de Mendonça, Marcos C L; de Oliveira, Louisi; Tschoeke, Diogo A; Schrago, Carlos G; Thompson, Fabiano L; Brasil, Patricia; Dos Santos, Flavia B; Nogueira, Rita M R; Tanuri, Amilcar; de Filippis, Ana M B

    2016-06-01

    The incidence of microcephaly in Brazil in 2015 was 20 times higher than in previous years. Congenital microcephaly is associated with genetic factors and several causative agents. Epidemiological data suggest that microcephaly cases in Brazil might be associated with the introduction of Zika virus. We aimed to detect and sequence the Zika virus genome in amniotic fluid samples of two pregnant women in Brazil whose fetuses were diagnosed with microcephaly. In this case study, amniotic fluid samples from two pregnant women from the state of Paraíba in Brazil whose fetuses had been diagnosed with microcephaly were obtained, on the recommendation of the Brazilian health authorities, by ultrasound-guided transabdominal amniocentesis at 28 weeks' gestation. The women had presented at 18 weeks' and 10 weeks' gestation, respectively, with clinical manifestations that could have been symptoms of Zika virus infection, including fever, myalgia, and rash. After the amniotic fluid samples were centrifuged, DNA and RNA were extracted from the purified virus particles before the viral genome was identified by quantitative reverse transcription PCR and viral metagenomic next-generation sequencing. Phylogenetic reconstruction and investigation of recombination events were done by comparing the Brazilian Zika virus genome with sequences from other Zika strains and from flaviviruses that occur in similar regions in Brazil. We detected the Zika virus genome in the amniotic fluid of both pregnant women. The virus was not detected in their urine or serum. Tests for dengue virus, chikungunya virus, Toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, HIV, Treponema pallidum, and parvovirus B19 were all negative. After sequencing of the complete genome of the Brazilian Zika virus isolated from patient 1, phylogenetic analyses showed that the virus shares 97-100% of its genomic identity with lineages isolated during an outbreak in French Polynesia in 2013, and that in

  15. Abnormal mitosis triggers p53-dependent cell cycle arrest in human tetraploid cells.

    PubMed

    Kuffer, Christian; Kuznetsova, Anastasia Yurievna; Storchová, Zuzana

    2013-08-01

    Erroneously arising tetraploid mammalian cells are chromosomally instable and may facilitate cell transformation. An increasing body of evidence shows that the propagation of mammalian tetraploid cells is limited by a p53-dependent arrest. The trigger of this arrest has not been identified so far. Here we show by live cell imaging of tetraploid cells generated by an induced cytokinesis failure that most tetraploids arrest and die in a p53-dependent manner after the first tetraploid mitosis. Furthermore, we found that the main trigger is a mitotic defect, in particular, chromosome missegregation during bipolar mitosis or spindle multipolarity. Both a transient multipolar spindle followed by efficient clustering in anaphase as well as a multipolar spindle followed by multipolar mitosis inhibited subsequent proliferation to a similar degree. We found that the tetraploid cells did not accumulate double-strand breaks that could cause the cell cycle arrest after tetraploid mitosis. In contrast, tetraploid cells showed increased levels of oxidative DNA damage coinciding with the p53 activation. To further elucidate the pathways involved in the proliferation control of tetraploid cells, we knocked down specific kinases that had been previously linked to the cell cycle arrest and p53 phosphorylation. Our results suggest that the checkpoint kinase ATM phosphorylates p53 in tetraploid cells after abnormal mitosis and thus contributes to proliferation control of human aberrantly arising tetraploids.

  16. Molecular basis of APC/C regulation by the spindle assembly checkpoint

    PubMed Central

    Zhang, Ziguo; Yang, Jing; Maslen, Sarah; Skehel, Mark; Barford, David

    2016-01-01

    In the dividing eukaryotic cell the spindle assembly checkpoint (SAC) ensures each daughter cell inherits an identical set of chromosomes. The SAC coordinates the correct attachment of sister chromatid kinetochores to the mitotic spindle with activation of the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that initiates chromosome separation. In response to unattached kinetochores, the SAC generates the mitotic checkpoint complex (MCC), a multimeric assembly that inhibits the APC/C, delaying chromosome segregation. Here, using cryo-electron microscopy we determined the near-atomic resolution structure of an APC/C-MCC complex (APC/CMCC). We reveal how degron-like sequences of the MCC subunit BubR1 block degron recognition sites on Cdc20, the APC/C coactivator subunit (Cdc20APC/C) responsible for substrate interactions. BubR1 also obstructs binding of UbcH10 (APC/C’s initiating E2) to repress APC/C ubiquitination activity. Conformational variability of the complex allows for UbcH10 association, and we show from a structure of APC/CMCC in complex with UbcH10 how the Cdc20 subunit intrinsic to the MCC (Cdc20MCC) is ubiquitinated, a process that results in APC/C reactivation when the SAC is silenced. PMID:27509861

  17. Stage-independent, single lead EEG sleep spindle detection using the continuous wavelet transform and local weighted smoothing.

    PubMed

    Tsanas, Athanasios; Clifford, Gari D

    2015-01-01

    Sleep spindles are critical in characterizing sleep and have been associated with cognitive function and pathophysiological assessment. Typically, their detection relies on the subjective and time-consuming visual examination of electroencephalogram (EEG) signal(s) by experts, and has led to large inter-rater variability as a result of poor definition of sleep spindle characteristics. Hitherto, many algorithmic spindle detectors inherently make signal stationarity assumptions (e.g., Fourier transform-based approaches) which are inappropriate for EEG signals, and frequently rely on additional information which may not be readily available in many practical settings (e.g., more than one EEG channels, or prior hypnogram assessment). This study proposes a novel signal processing methodology relying solely on a single EEG channel, and provides objective, accurate means toward probabilistically assessing the presence of sleep spindles in EEG signals. We use the intuitively appealing continuous wavelet transform (CWT) with a Morlet basis function, identifying regions of interest where the power of the CWT coefficients corresponding to the frequencies of spindles (11-16 Hz) is large. The potential for assessing the signal segment as a spindle is refined using local weighted smoothing techniques. We evaluate our findings on two databases: the MASS database comprising 19 healthy controls and the DREAMS sleep spindle database comprising eight participants diagnosed with various sleep pathologies. We demonstrate that we can replicate the experts' sleep spindles assessment accurately in both databases (MASS database: sensitivity: 84%, specificity: 90%, false discovery rate 83%, DREAMS database: sensitivity: 76%, specificity: 92%, false discovery rate: 67%), outperforming six competing automatic sleep spindle detection algorithms in terms of correctly replicating the experts' assessment of detected spindles.

  18. Distinct chromosome segregation roles for spindle checkpoint proteins.

    PubMed

    Warren, Cheryl D; Brady, D Michelle; Johnston, Raymond C; Hanna, Joseph S; Hardwick, Kevin G; Spencer, Forrest A

    2002-09-01

    The spindle checkpoint plays a central role in the fidelity of chromosome transmission by ensuring that anaphase is initiated only after kinetochore-microtubule associations of all sister chromatid pairs are complete. In this study, we find that known spindle checkpoint proteins do not contribute equally to chromosome segregation fidelity in Saccharomyces cerevisiae. Loss of Bub1 or Bub3 protein elicits the largest effect. Analysis of Bub1p reveals the presence of two molecular functions. An N-terminal 608-amino acid (nonkinase) portion of the protein supports robust checkpoint activity, and, as expected, contributes to chromosome segregation. A C-terminal kinase-encoding segment independently contributes to chromosome segregation through an unknown mechanism. Both molecular functions depend on association with Bub3p. A 156-amino acid fragment of Bub1p functions in Bub3p binding and in kinetochore localization by one-hybrid assay. An adjacent segment is required for Mad1p binding, detected by deletion analysis and coimmunoprecipitation. Finally, overexpression of wild-type BUB1 or MAD3 genes leads to chromosome instability. Analysis of this activity indicates that the Bub3p-binding domain of Bub1p contributes to this phenotype through disruption of checkpoint activity as well as through introduction of kinetochore or spindle damage.

  19. Distinct Chromosome Segregation Roles for Spindle Checkpoint Proteins

    PubMed Central

    Warren, Cheryl D.; Brady, D. Michelle; Johnston, Raymond C.; Hanna, Joseph S.; Hardwick, Kevin G.; Spencer, Forrest A.

    2002-01-01

    The spindle checkpoint plays a central role in the fidelity of chromosome transmission by ensuring that anaphase is initiated only after kinetochore-microtubule associations of all sister chromatid pairs are complete. In this study, we find that known spindle checkpoint proteins do not contribute equally to chromosome segregation fidelity in Saccharomyces cerevisiae. Loss of Bub1 or Bub3 protein elicits the largest effect. Analysis of Bub1p reveals the presence of two molecular functions. An N-terminal 608-amino acid (nonkinase) portion of the protein supports robust checkpoint activity, and, as expected, contributes to chromosome segregation. A C-terminal kinase-encoding segment independently contributes to chromosome segregation through an unknown mechanism. Both molecular functions depend on association with Bub3p. A 156-amino acid fragment of Bub1p functions in Bub3p binding and in kinetochore localization by one-hybrid assay. An adjacent segment is required for Mad1p binding, detected by deletion analysis and coimmunoprecipitation. Finally, overexpression of wild-type BUB1 or MAD3 genes leads to chromosome instability. Analysis of this activity indicates that the Bub3p-binding domain of Bub1p contributes to this phenotype through disruption of checkpoint activity as well as through introduction of kinetochore or spindle damage. PMID:12221113

  20. Spinning Wool with a Hand Spindle.

    ERIC Educational Resources Information Center

    Kren, Margo

    1982-01-01

    Describes an eight-week program in which 8- to 14-year-olds learned to spin raw wool into yarn. Students observed wool shearing at a sheep farm, learned to prepare wool for spinning, and spun their own yarn. Detail directions for carding and use of hand spindles are included. (AM)

  1. 5p14 deletion associated with microcephaly and seizures

    PubMed Central

    Johnson, E.; Marinescu, R; Punnett, H.; Tenenholz, B.; Overhauser, J.

    2000-01-01

    We report on a father and son who have an interstitial deletion of 5p14. The father is clinically and mentally normal while the son has significant clinical involvement including microcephaly, seizures, and global developmental delay. The extent of the 5p14 deletion was determined using fluorescence in situ hybridisation (FISH). The deletion in this present family is smaller than a deletion previously described in a multigenerational family that lacks any clinical phenotype. This report shows that a 5p14 deletion does not always lead to a normal phenotype.


Keywords: interstitial deletion; chromosome 5; fluorescence in situ hybridisation; cri du chat syndrome PMID:10662813

  2. Synthesis, structural and optical properties of ZnO spindle/reduced graphene oxide composites with enhanced photocatalytic activity under visible light irradiation

    NASA Astrophysics Data System (ADS)

    Prabhu, S.; Pudukudy, M.; Sohila, S.; Harish, S.; Navaneethan, M.; Navaneethan, D.; Ramesh, R.; Hayakawa, Y.

    2018-05-01

    In the present work, spindle-shaped ZnO and reduced graphene oxide sheets were successfully synthesized by a hydrothermal method and then ZnO/r-GO composite was prepared by a direct solution mixing method. Various characterization results confirmed the interior and surface decoration of spindle-shaped ZnO on the reduced graphene oxide sheets. The phase formation, crystalline structure, morphology, surface states and optical properties were characterized using Powder X-ray diffraction (XRD), Field emission scanning electron microscopy (FESEM), Transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), Fourier Transform Infrared Spectroscopy (FTIR) and UV-Vis spectroscopy. The X-ray diffraction analysis showed the formation of the hexagonal wurtzite crystalline structure of ZnO with high crystalline quality. The band gap of the ZnO/r-GO composite was found to be low (3.03eV) compared to the band gap of spindle shaped ZnO (3.13 eV), as calculated from optical studies. The spindle-like morphology of the single crystalline ZnO was clearly shown in the electron microscopic images. The chemical bonding and surface states of the samples were studied using XPS measurement. Moreover, a possible growth mechanism for the ZnO spindle was proposed. The catalytic activity of the as-synthesized samples was evaluated for the photodegradation of methylene blue under visible light irradiation. Among the synthesized samples, the ZnO/r-GO composite showed higher degradation efficiency of 93% and successfully reused for four consecutive run without any activity loss.

  3. White Matter Structure in Older Adults Moderates the Benefit of Sleep Spindles on Motor Memory Consolidation.

    PubMed

    Mander, Bryce A; Zhu, Alyssa H; Lindquist, John R; Villeneuve, Sylvia; Rao, Vikram; Lu, Brandon; Saletin, Jared M; Ancoli-Israel, Sonia; Jagust, William J; Walker, Matthew P

    2017-11-29

    Sleep spindles promote the consolidation of motor skill memory in young adults. Older adults, however, exhibit impoverished sleep-dependent motor memory consolidation. The underlying pathophysiological mechanism(s) explaining why motor memory consolidation in older adults fails to benefit from sleep remains unclear. Here, we demonstrate that male and female older adults show impoverished overnight motor skill memory consolidation relative to young adults, with the extent of impairment being associated with the degree of reduced frontal fast sleep spindle density. The magnitude of the loss of frontal fast sleep spindles in older adults was predicted by the degree of reduced white matter integrity throughout multiple white matter tracts known to connect subcortical and cortical brain regions. We further demonstrate that the structural integrity of selective white matter fiber tracts, specifically within right posterior corona radiata, right tapetum, and bilateral corpus callosum, statistically moderates whether sleep spindles promoted overnight consolidation of motor skill memory. Therefore, white matter integrity within tracts known to connect cortical sensorimotor control regions dictates the functional influence of sleep spindles on motor skill memory consolidation in the elderly. The deterioration of white matter fiber tracts associated with human brain aging thus appears to be one pathophysiological mechanism influencing subcortical-cortical propagation of sleep spindles and their related memory benefits. SIGNIFICANCE STATEMENT Numerous studies have shown that sleep spindle expression is reduced and sleep-dependent motor memory is impaired in older adults. However, the mechanisms underlying these alterations have remained unknown. The present study reveals that age-related degeneration of white matter within select fiber tracts is associated with reduced sleep spindles in older adults. We further demonstrate that, within these same fiber tracts, the degree of

  4. White Matter Structure in Older Adults Moderates the Benefit of Sleep Spindles on Motor Memory Consolidation

    PubMed Central

    Zhu, Alyssa H.; Lindquist, John R.; Villeneuve, Sylvia; Rao, Vikram; Lu, Brandon; Ancoli-Israel, Sonia

    2017-01-01

    Sleep spindles promote the consolidation of motor skill memory in young adults. Older adults, however, exhibit impoverished sleep-dependent motor memory consolidation. The underlying pathophysiological mechanism(s) explaining why motor memory consolidation in older adults fails to benefit from sleep remains unclear. Here, we demonstrate that male and female older adults show impoverished overnight motor skill memory consolidation relative to young adults, with the extent of impairment being associated with the degree of reduced frontal fast sleep spindle density. The magnitude of the loss of frontal fast sleep spindles in older adults was predicted by the degree of reduced white matter integrity throughout multiple white matter tracts known to connect subcortical and cortical brain regions. We further demonstrate that the structural integrity of selective white matter fiber tracts, specifically within right posterior corona radiata, right tapetum, and bilateral corpus callosum, statistically moderates whether sleep spindles promoted overnight consolidation of motor skill memory. Therefore, white matter integrity within tracts known to connect cortical sensorimotor control regions dictates the functional influence of sleep spindles on motor skill memory consolidation in the elderly. The deterioration of white matter fiber tracts associated with human brain aging thus appears to be one pathophysiological mechanism influencing subcortical–cortical propagation of sleep spindles and their related memory benefits. SIGNIFICANCE STATEMENT Numerous studies have shown that sleep spindle expression is reduced and sleep-dependent motor memory is impaired in older adults. However, the mechanisms underlying these alterations have remained unknown. The present study reveals that age-related degeneration of white matter within select fiber tracts is associated with reduced sleep spindles in older adults. We further demonstrate that, within these same fiber tracts, the degree of

  5. A new method to measure circular runout of end-milling spindle based on cutting mark

    NASA Astrophysics Data System (ADS)

    Zhou, Jianlai; Liu, Shuchun

    2008-12-01

    A practical method is introduced to measure the circular runout of a end-milling spindle system at high speed rotations without the need of a reference sphere. A workpiece is held on a linear slide which moves along the axial direction of the spindle. The spindle is then programmed to run at a specific speed. A very sharp edge cutter must be used and the depth of cut will be very shallow in order to keep the cutting force very small. The workpiece is then fed into the end mill in order to make a cutting mark of teens μm in depth. The cutting marks are circular, and their diameters are related to the circular runout of the spindle system. The cutting mark that is generated at a specific speed is expected to contain information about the spindle circular runout at this speed. In practice the cutting marks are not perfectly circular. Therefore, a best-fit circle of a cutting mark is needed to determine its diameter. A high-resolution edge detector machine is used for this purpose. Quantitative precision analysis was carried out to confirm the accuracy and repeatability of this new measurement technique. It is demonstrated that this technique for the measurement of spindle circular runout is an effective tool in verifying the actual running accuracy of spindles at their actual operating speeds and can be accomplished without the need for a reference sphere.

  6. The pacemaker role of thalamic reticular nucleus in controlling spike-wave discharges and spindles.

    PubMed

    Fan, Denggui; Liao, Fucheng; Wang, Qingyun

    2017-07-01

    Absence epilepsy, characterized by 2-4 Hz spike-wave discharges (SWDs), can be caused by pathological interactions within the thalamocortical system. Cortical spindling oscillations are also demonstrated to involve the oscillatory thalamocortical rhythms generated by the synaptic circuitry of the thalamus and cortex. This implies that SWDs and spindling oscillations can share the common thalamocortical mechanism. Additionally, the thalamic reticular nucleus (RE) is hypothesized to regulate the onsets and propagations of both the epileptic SWDs and sleep spindles. Based on the proposed single-compartment thalamocortical neural field model, we firstly investigate the stimulation effect of RE on the initiations, terminations, and transitions of SWDs. It is shown that the activations and deactivations of RE triggered by single-pulse stimuli can drive the cortical subsystem to behave as the experimentally observed onsets and self-abatements of SWDs, as well as the transitions from 2-spike and wave discharges (2-SWDs) to SWDs. In particular, with increasing inhibition from RE to the specific relay nucleus (TC), rich transition behaviors in cortex can be obtained through the upstream projection path, RE→TC→Cortex. Although some of the complex dynamical patterns can be expected from the earlier single compartment thalamocortical model, the effect of brain network topology on the emergence of SWDs and spindles, as well as the transitions between them, has not been fully investigated. We thereby develop a spatially extended 3-compartment coupled network model with open-/closed-end connective configurations, to investigate the spatiotemporal effect of RE on the SWDs and spindles. Results show that the degrees of activations of RE 1 can induce the rich spatiotemporal evolution properties including the propagations from SWDs to spindles within different compartments and the transitions between them, through the RE 1 →TC 1 →Cortex 1 and Cortex 1 →Cortex 2 →Cortex 3

  7. The pacemaker role of thalamic reticular nucleus in controlling spike-wave discharges and spindles

    NASA Astrophysics Data System (ADS)

    Fan, Denggui; Liao, Fucheng; Wang, Qingyun

    2017-07-01

    Absence epilepsy, characterized by 2-4 Hz spike-wave discharges (SWDs), can be caused by pathological interactions within the thalamocortical system. Cortical spindling oscillations are also demonstrated to involve the oscillatory thalamocortical rhythms generated by the synaptic circuitry of the thalamus and cortex. This implies that SWDs and spindling oscillations can share the common thalamocortical mechanism. Additionally, the thalamic reticular nucleus (RE) is hypothesized to regulate the onsets and propagations of both the epileptic SWDs and sleep spindles. Based on the proposed single-compartment thalamocortical neural field model, we firstly investigate the stimulation effect of RE on the initiations, terminations, and transitions of SWDs. It is shown that the activations and deactivations of RE triggered by single-pulse stimuli can drive the cortical subsystem to behave as the experimentally observed onsets and self-abatements of SWDs, as well as the transitions from 2-spike and wave discharges (2-SWDs) to SWDs. In particular, with increasing inhibition from RE to the specific relay nucleus (TC), rich transition behaviors in cortex can be obtained through the upstream projection path, RE → TC → Cortex . Although some of the complex dynamical patterns can be expected from the earlier single compartment thalamocortical model, the effect of brain network topology on the emergence of SWDs and spindles, as well as the transitions between them, has not been fully investigated. We thereby develop a spatially extended 3-compartment coupled network model with open-/closed-end connective configurations, to investigate the spatiotemporal effect of RE on the SWDs and spindles. Results show that the degrees of activations of RE 1 can induce the rich spatiotemporal evolution properties including the propagations from SWDs to spindles within different compartments and the transitions between them, through the RE 1 → TC 1 → Cortex 1 and Cortex 1 → Cortex 2

  8. Achilles tendon shape and echogenicity on ultrasound among active badminton players.

    PubMed

    Malliaras, P; Voss, C; Garau, G; Richards, P; Maffulli, N

    2012-04-01

    The relationship between Achilles tendon ultrasound abnormalities, including a spindle shape and heterogeneous echogenicity, is unclear. This study investigated the relationship between these abnormalities, tendon thickness, Doppler flow and pain. Sixty-one badminton players (122 tendons, 36 men, and 25 women) were recruited. Achilles tendon thickness, shape (spindle, parallel), echogenicity (heterogeneous, homogeneous) and Doppler flow (present or absent) were measured bilaterally with ultrasound. Achilles tendon pain (during or after activity over the last week) and pain and function [Victorian Institute of Sport Achilles Assessment (VISA-A)] were measured. Sixty-eight (56%) tendons were parallel with homogeneous echogenicity (normal), 22 (18%) were spindle shaped with homogeneous echogenicity, 16 (13%) were parallel with heterogeneous echogenicity and 16 (13%) were spindle shaped with heterogeneous echogenicity. Spindle shape was associated with self-reported pain (P<0.05). Heterogeneous echogenicity was associated with lower VISA-A scores than normal tendon (P<0.05). There was an ordinal relationship between normal tendon, parallel and heterogeneous and spindle shaped and heterogeneous tendons with regard to increasing thickness and likelihood of Doppler flow. Heterogeneous echogenicity with a parallel shape may be a physiological phase and may develop into heterogeneous echogenicity with a spindle shape that is more likely to be pathological. © 2010 John Wiley & Sons A/S.

  9. De Novo Generation and Characterization of New Zika Virus Isolate Using Sequence Data from a Microcephaly Case

    PubMed Central

    Setoh, Yin Xiang; Prow, Natalie A.; Peng, Nias; Hugo, Leon E.; Devine, Gregor; Hazlewood, Jessamine E.

    2017-01-01

    ABSTRACT Zika virus (ZIKV) has recently emerged and is the etiological agent of congenital Zika syndrome (CZS), a spectrum of congenital abnormalities arising from neural tissue infections in utero. Herein, we describe the de novo generation of a new ZIKV isolate, ZIKVNatal, using a modified circular polymerase extension reaction protocol and sequence data obtained from a ZIKV-infected fetus with microcephaly. ZIKVNatal thus has no laboratory passage history and is unequivocally associated with CZS. ZIKVNatal could be used to establish a fetal brain infection model in IFNAR−/− mice (including intrauterine growth restriction) without causing symptomatic infections in dams. ZIKVNatal was also able to be transmitted by Aedes aegypti mosquitoes. ZIKVNatal thus retains key aspects of circulating pathogenic ZIKVs and illustrates a novel methodology for obtaining an authentic functional viral isolate by using data from deep sequencing of infected tissues. IMPORTANCE The major complications of an ongoing Zika virus outbreak in the Americas and Asia are congenital defects caused by the virus’s ability to cross the placenta and infect the fetal brain. The ability to generate molecular tools to analyze viral isolates from the current outbreak is essential for furthering our understanding of how these viruses cause congenital defects. The majority of existing viral isolates and infectious cDNA clones generated from them have undergone various numbers of passages in cell culture and/or suckling mice, which is likely to result in the accumulation of adaptive mutations that may affect viral properties. The approach described herein allows rapid generation of new, fully functional Zika virus isolates directly from deep sequencing data from virus-infected tissues without the need for prior virus passaging and for the generation and propagation of full-length cDNA clones. The approach should be applicable to other medically important flaviviruses and perhaps other positive

  10. De Novo Generation and Characterization of New Zika Virus Isolate Using Sequence Data from a Microcephaly Case.

    PubMed

    Setoh, Yin Xiang; Prow, Natalie A; Peng, Nias; Hugo, Leon E; Devine, Gregor; Hazlewood, Jessamine E; Suhrbier, Andreas; Khromykh, Alexander A

    2017-01-01

    Zika virus (ZIKV) has recently emerged and is the etiological agent of congenital Zika syndrome (CZS), a spectrum of congenital abnormalities arising from neural tissue infections in utero . Herein, we describe the de novo generation of a new ZIKV isolate, ZIKV Natal , using a modified circular polymerase extension reaction protocol and sequence data obtained from a ZIKV-infected fetus with microcephaly. ZIKV Natal thus has no laboratory passage history and is unequivocally associated with CZS. ZIKV Natal could be used to establish a fetal brain infection model in IFNAR -/- mice (including intrauterine growth restriction) without causing symptomatic infections in dams. ZIKV Natal was also able to be transmitted by Aedes aegypti mosquitoes. ZIKV Natal thus retains key aspects of circulating pathogenic ZIKVs and illustrates a novel methodology for obtaining an authentic functional viral isolate by using data from deep sequencing of infected tissues. IMPORTANCE The major complications of an ongoing Zika virus outbreak in the Americas and Asia are congenital defects caused by the virus's ability to cross the placenta and infect the fetal brain. The ability to generate molecular tools to analyze viral isolates from the current outbreak is essential for furthering our understanding of how these viruses cause congenital defects. The majority of existing viral isolates and infectious cDNA clones generated from them have undergone various numbers of passages in cell culture and/or suckling mice, which is likely to result in the accumulation of adaptive mutations that may affect viral properties. The approach described herein allows rapid generation of new, fully functional Zika virus isolates directly from deep sequencing data from virus-infected tissues without the need for prior virus passaging and for the generation and propagation of full-length cDNA clones. The approach should be applicable to other medically important flaviviruses and perhaps other positive-strand RNA

  11. [Concordance between a head circumference growth function and intellectual disability in relation with the cause of microcephaly].

    PubMed

    Coronado, R; Macaya Ruíz, A; Giraldo Arjonilla, J; Roig-Quilis, M

    2015-08-01

    Our aim was to investigate the correlations between patterns of head growth and intellectual disability among distinct aetiological presentations of microcephaly. 3,269 head circumference (HC) charts of patients from a tertiary neuropediatric unit were reviewed and 136 microcephalic participants selected. Using the Z-scores of registered HC measurements we defined the variables: HC Minimum, HC Drop and HC Catch-up. We classified patients according to the presence or absence of intellectual disability (IQ below 71) and according to the cause of microcephaly (idiopathic, familial, syndromic, symptomatic and mixed). Using Discriminant Analysis a C-function was defined as C=HC Minimum + HC Drop with a cut-off level of C=-4.32 Z-score. In our sample 95% of patients scoring below this level, severe microcephaly, were classified in the disabled group while the overall concordance was 66%. In the symptomatic-mixed group the concordance between HC function and outcome reached 82% in contrast to only 54% in the idiopathic-syndromic group (P-value=0.0002). We defined a HC growth function which discriminates intellectual disability of microcephalic patients better than isolated HC measurements, especially for those with secondary and mixed aetiologies. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  12. The effects of eszopiclone on sleep spindles and memory consolidation in schizophrenia: a randomized placebo-controlled trial.

    PubMed

    Wamsley, Erin J; Shinn, Ann K; Tucker, Matthew A; Ono, Kim E; McKinley, Sophia K; Ely, Alice V; Goff, Donald C; Stickgold, Robert; Manoach, Dara S

    2013-09-01

    In schizophrenia there is a dramatic reduction of sleep spindles that predicts deficient sleep-dependent memory consolidation. Eszopiclone (Lunesta), a non-benzodiazepine hypnotic, acts on γ-aminobutyric acid (GABA) neurons in the thalamic reticular nucleus where spindles are generated. We investigated whether eszopiclone could increase spindles and thereby improve memory consolidation in schizophrenia. In a double-blind design, patients were randomly assigned to receive either placebo or 3 mg of eszopiclone. Patients completed Baseline and Treatment visits, each consisting of two consecutive nights of polysomnography. On the second night of each visit, patients were trained on the motor sequence task (MST) at bedtime and tested the following morning. Academic research center. Twenty-one chronic, medicated schizophrenia outpatients. We compared the effects of two nights of eszopiclone vs. placebo on stage 2 sleep spindles and overnight changes in MST performance. Eszopiclone increased the number and density of spindles over baseline levels significantly more than placebo, but did not significantly enhance overnight MST improvement. In the combined eszopiclone and placebo groups, spindle number and density predicted overnight MST improvement. Eszopiclone significantly increased sleep spindles, which correlated with overnight motor sequence task improvement. These findings provide partial support for the hypothesis that the spindle deficit in schizophrenia impairs sleep-dependent memory consolidation and may be ameliorated by eszopiclone. Larger samples may be needed to detect a significant effect on memory. Given the general role of sleep spindles in cognition, they offer a promising novel potential target for treating cognitive deficits in schizophrenia.

  13. Scalp defects, polythelia, microcephaly, and developmental delay: a new syndrome with apparent autosomal dominant inheritance.

    PubMed

    Marble, Michael; Pridjian, Gabriella

    2002-04-01

    We report a family with apparent autosomal dominant inheritance of scalp defects, polythelia, microcephaly, and developmental delay. A review of the literature revealed no previous report of this combination of anomalies. We conclude that these patients have a new autosomal dominant syndrome. Copyright 2002 Wiley-Liss, Inc.

  14. Spindle Thermal Error Optimization Modeling of a Five-axis Machine Tool

    NASA Astrophysics Data System (ADS)

    Guo, Qianjian; Fan, Shuo; Xu, Rufeng; Cheng, Xiang; Zhao, Guoyong; Yang, Jianguo

    2017-05-01

    Aiming at the problem of low machining accuracy and uncontrollable thermal errors of NC machine tools, spindle thermal error measurement, modeling and compensation of a two turntable five-axis machine tool are researched. Measurement experiment of heat sources and thermal errors are carried out, and GRA(grey relational analysis) method is introduced into the selection of temperature variables used for thermal error modeling. In order to analyze the influence of different heat sources on spindle thermal errors, an ANN (artificial neural network) model is presented, and ABC(artificial bee colony) algorithm is introduced to train the link weights of ANN, a new ABC-NN(Artificial bee colony-based neural network) modeling method is proposed and used in the prediction of spindle thermal errors. In order to test the prediction performance of ABC-NN model, an experiment system is developed, the prediction results of LSR (least squares regression), ANN and ABC-NN are compared with the measurement results of spindle thermal errors. Experiment results show that the prediction accuracy of ABC-NN model is higher than LSR and ANN, and the residual error is smaller than 3 μm, the new modeling method is feasible. The proposed research provides instruction to compensate thermal errors and improve machining accuracy of NC machine tools.

  15. "Atypical" Pleomorphic Lipomatous Tumor: A Clinicopathologic, Immunohistochemical and Molecular Study of 21 Cases, Emphasizing its Relationship to Atypical Spindle Cell Lipomatous Tumor and Suggesting a Morphologic Spectrum (Atypical Spindle Cell/Pleomorphic Lipomatous Tumor).

    PubMed

    Creytens, David; Mentzel, Thomas; Ferdinande, Liesbeth; Lecoutere, Evelyne; van Gorp, Joost; Atanesyan, Lilit; de Groot, Karel; Savola, Suvi; Van Roy, Nadine; Van Dorpe, Jo; Flucke, Uta

    2017-11-01

    The classification of the until recently poorly explored group of atypical adipocytic neoplasms with spindle cell features, for which recently the term atypical spindle cell lipomatous tumor (ASLT) has been proposed, remains challenging. Recent studies have proposed ASLT as a unique entity with (in at least a significant subset of cases) a specific genetic background, namely deletions/losses of 13q14, including RB1 and its flanking genes RCBTB2, DLEU1, and ITM2B. Similar genetic aberrations have been reported in pleomorphic liposarcomas (PLSs). This prompted us to investigate a series of 21 low-grade adipocytic neoplasms with a pleomorphic lipoma-like appearance, but with atypical morphologic features (including atypical spindle cells, pleomorphic [multinucleated] cells, pleomorphic lipoblasts and poor circumscription), for which we propose the term "atypical" pleomorphic lipomatous tumor (APLT). Five cases of PLS were also included in this study. We used multiplex ligation-dependent probe amplification to evaluate genetic changes of 13q14. In addition, array-based comparative genomic hybridization was performed on 4 APLTs and all PLSs. Multiplex ligation-dependent probe amplification showed consistent loss of RB1 and its flanking gene RCBTB2 in all cases of APLT. This genetic alteration was also present in all PLSs, suggesting genetic overlap, in addition to morphologic overlap, with APLTs. However, array-based comparative genomic hybridization demonstrated more complex genetic alterations with more losses and gains in PLSs compared with APLTs. APLTs arose in the subcutis (67%) more frequently than in the deep (subfascial) soft tissues (33%). With a median follow-up of 42 months, recurrences were documented in 2 of 12 APLTs for which a long follow-up was available. Herein, we also demonstrate that APLTs share obvious overlapping morphologic, immunohistochemical, genetic and clinical characteristics with the recently defined ASLT, suggesting that they are related

  16. Human chromokinesins promote chromosome congression and spindle microtubule dynamics during mitosis

    PubMed Central

    Wandke, Cornelia; Barisic, Marin; Sigl, Reinhard; Rauch, Veronika; Wolf, Frank; Amaro, Ana C.; Tan, Chia H.; Pereira, Antonio J.; Kutay, Ulrike; Maiato, Helder; Meraldi, Patrick

    2012-01-01

    Chromokinesins are microtubule plus end–directed motor proteins that bind to chromosome arms. In Xenopus egg cell-free extracts, Xkid and Xklp1 are essential for bipolar spindle formation but the functions of the human homologues, hKID (KIF22) and KIF4A, are poorly understood. By using RNAi-mediated protein knockdown in human cells, we find that only co-depletion delayed progression through mitosis in a Mad2-dependent manner. Depletion of hKID caused abnormal chromosome arm orientation, delayed chromosome congression, and sensitized cells to nocodazole. Knockdown of KIF4A increased the number and length of microtubules, altered kinetochore oscillations, and decreased kinetochore microtubule flux. These changes were associated with failures in establishing a tight metaphase plate and an increase in anaphase lagging chromosomes. Co-depletion of both chromokinesins aggravated chromosome attachment failures, which led to mitotic arrest. Thus, hKID and KIF4A contribute independently to the rapid and correct attachment of chromosomes by controlling the positioning of chromosome arms and the dynamics of microtubules, respectively. PMID:22945934

  17. Multiple Duties for Spindle Assembly Checkpoint Kinases in Meiosis

    PubMed Central

    Marston, Adele L.; Wassmann, Katja

    2017-01-01

    Cell division in mitosis and meiosis is governed by evolutionary highly conserved protein kinases and phosphatases, controlling the timely execution of key events such as nuclear envelope breakdown, spindle assembly, chromosome attachment to the spindle and chromosome segregation, and cell cycle exit. In mitosis, the spindle assembly checkpoint (SAC) controls the proper attachment to and alignment of chromosomes on the spindle. The SAC detects errors and induces a cell cycle arrest in metaphase, preventing chromatid separation. Once all chromosomes are properly attached, the SAC-dependent arrest is relieved and chromatids separate evenly into daughter cells. The signaling cascade leading to checkpoint arrest depends on several protein kinases that are conserved from yeast to man. In meiosis, haploid cells containing new genetic combinations are generated from a diploid cell through two specialized cell divisions. Though apparently less robust, SAC control also exists in meiosis. Recently, it has emerged that SAC kinases have additional roles in executing accurate chromosome segregation during the meiotic divisions. Here, we summarize the main differences between mitotic and meiotic cell divisions, and explain why meiotic divisions pose special challenges for correct chromosome segregation. The less-known meiotic roles of the SAC kinases are described, with a focus on two model systems: yeast and mouse oocytes. The meiotic roles of the canonical checkpoint kinases Bub1, Mps1, the pseudokinase BubR1 (Mad3), and Aurora B and C (Ipl1) will be discussed. Insights into the molecular signaling pathways that bring about the special chromosome segregation pattern during meiosis will help us understand why human oocytes are so frequently aneuploid. PMID:29322045

  18. Clathrin heavy chain 1 is required for spindle assembly and chromosome congression in mouse oocytes.

    PubMed

    Zhao, Jie; Wang, Lu; Zhou, Hong-Xia; Liu, Li; Lu, Angeleem; Li, Guang-Peng; Schatten, Heide; Liang, Cheng-Guang

    2013-10-01

    Clathrin heavy chain 1 (CLTC) has been considered a “moonlighting protein” which acts in membrane trafficking during interphase and in stabilizing spindle fibers during mitosis. However, its roles in meiosis, especially in mammalian oocyte maturation, remain unclear. This study investigated CLTC expression and function in spindle formation and chromosome congression during mouse oocyte meiotic maturation. Our results showed that the expression level of CLTC increased after germinal vesicle breakdown (GVBD) and peaked in the M phase. Immunostaining results showed CLTC distribution throughout the cytoplasm in a cell cycle-dependent manner. Appearance and disappearance of CLTC along with β-tubulin (TUBB) could be observed during spindle dynamic changes. To explore the relationship between CLTC and microtubule dynamics, oocytes at metaphase were treated with taxol or nocodazole. CLTC colocalized with TUBB at the enlarged spindle and with cytoplasmic asters after taxol treatment; it disassembled and distributed into the cytoplasm along with TUBB after nocodazole treatment. Disruption of CLTC function using stealth siRNA caused a decreased first polar body extrusion rate and extensive spindle formation and chromosome congression defects. Taken together, these results show that CLTC plays an important role in spindle assembly and chromosome congression through a microtubule correlation mechanism during mouse oocyte maturation.

  19. Newly recognized recessive syndrome characterized by dysmorphic features, hypogonadotropic hypogonadism, severe microcephaly, and sensorineural hearing loss maps to 3p21.3.

    PubMed

    Jenkinson, Emma M; Kingston, Helen; Urquhart, Jill; Khan, Naz; Melville, Athalie; Swinton, Martin; Crow, Yanick J; Davis, Julian R E; Trump, Dorothy; Newman, William G

    2011-12-01

    We present a newly recognized, likely autosomal recessive, pleiotropic disorder seen in four individuals (three siblings and their nephew) from a consanguineous family of Pakistani origin. The condition is characterized by hypogonadotropic hypogonadism, severe microcephaly, sensorineural deafness, moderate learning disability, and distinctive facial dysmorphic features. Autozygosity mapping using SNP array genotyping defined a single, large autozygous region of 13.1 Mb on chromosome 3p21 common to the affected individuals. The critical region contains 227 genes and initial sequence analysis of a functional candidate gene has not identified causative mutations. Copyright © 2011 Wiley Periodicals, Inc.

  20. A new theory of the origin of cancer: quantum coherent entanglement, centrioles, mitosis, and differentiation.

    PubMed

    Hameroff, Stuart R

    2004-11-01

    Malignant cells are characterized by abnormal segregation of chromosomes during mitosis ("aneuploidy"), generally considered a result of malignancy originating in genetic mutations. However, recent evidence supports a century-old concept that maldistribution of chromosomes (and resultant genomic instability) due to abnormalities in mitosis itself is the primary cause of malignancy rather than a mere byproduct. In normal mitosis chromosomes replicate into sister chromatids which are then precisely separated and transported into mirror-like sets by structural protein assemblies called mitotic spindles and centrioles, both composed of microtubules. The elegant yet poorly understood ballet-like movements and geometric organization occurring in mitosis have suggested guidance by some type of organizing field, however neither electromagnetic nor chemical gradient fields have been demonstrated or shown to be sufficient. It is proposed here that normal mirror-like mitosis is organized by quantum coherence and quantum entanglement among microtubule-based centrioles and mitotic spindles which ensure precise, complementary duplication of daughter cell genomes and recognition of daughter cell boundaries. Evidence and theory supporting organized quantum states in cytoplasm/nucleoplasm (and quantum optical properties of centrioles in particular) at physiological temperature are presented. Impairment of quantum coherence and/or entanglement among microtubule-based mitotic spindles and centrioles can result in abnormal distribution of chromosomes, abnormal differentiation and uncontrolled growth, and account for all aspects of malignancy. New approaches to cancer therapy and stem cell production are suggested via non-thermal laser-mediated effects aimed at quantum optical states of centrioles.

  1. Microtubule-dependent path to the cell cortex for cytoplasmic dynein in mitotic spindle orientation

    PubMed Central

    Markus, Steven M.; Lee, Wei-Lih

    2011-01-01

    During animal development, microtubules (MTs) play a major role in directing cellular and subcellular patterning, impacting cell polarization and subcellular organization, thereby affecting cell fate determination and tissue architecture. In particular, when progenitor cells divide asymmetrically along an anterior-posterior or apical-basal axis, MTs must coordinate the position of the mitotic spindle with the site of cell division to ensure normal distribution of cell fate determinants and equal sequestration of genetic material into the two daughter cells. Emerging data from diverse model systems have led to the prevailing view that, during mitotic spindle positioning, polarity cues at the cell cortex signal for the recruitment of NuMA and the minus-end directed MT motor cytoplasmic dynein.1 The NuMA/dynein complex is believed to connect, in turn, to the mitotic spindle via astral MTs, thus aligning and tethering the spindle, but how this connection is achieved faithfully is unclear. Do astral MTs need to search for and then capture cortical NuMA/dynein? How does dynein capture the astral MTs emanating from the correct spindle pole? Recently, using the classical model of asymmetric cell division—budding yeast S. cerevisiae—we successfully demonstrated that astral MTs assume an active role in cortical dynein targeting, in that astral MTs utilize their distal plus ends to deliver dynein to the daughter cell cortex, the site where dynein activity is needed to perform its spindle alignment function. This observation introduced the novel idea that, during mitotic spindle orientation processes, polarity cues at the cell cortex may actually signal to prime the cortical receptors for MT-dependent dynein delivery. This model is consistent with the observation that dynein/dynactin accumulate prominently at the astral MT plus ends during metaphase in a wide range of cultured mammalian cells. PMID:22754610

  2. Suspended animation in C. elegans requires the spindle checkpoint.

    PubMed

    Nystul, Todd G; Goldmark, Jesse P; Padilla, Pamela A; Roth, Mark B

    2003-11-07

    In response to environmental signals such as anoxia, many organisms enter a state of suspended animation, an extreme form of quiescence in which microscopically visible movement ceases. We have identified a gene, san-1, that is required for suspended animation in Caenorhabditis elegans embryos. We show that san-1 functions as a spindle checkpoint component in C. elegans. During anoxia-induced suspended animation, embryos lacking functional SAN-1 or a second spindle checkpoint component, MDF-2, failed to arrest the cell cycle, exhibited chromosome missegregation, and showed reduced viability. These data provide a model for how a dynamic biological process is arrested in suspended animation.

  3. Prediction of microcephaly at birth using three reference ranges for fetal head circumference: can we improve prenatal diagnosis?

    PubMed

    Leibovitz, Z; Daniel-Spiegel, E; Malinger, G; Haratz, K; Tamarkin, M; Gindes, L; Schreiber, L; Ben-Sira, L; Lev, D; Shapiro, I; Bakry, H; Weizman, B; Zreik, A; Egenburg, S; Arad, A; Tepper, R; Kidron, D; Lerman-Sagie, T

    2016-05-01

    To evaluate the prediction of microcephaly at birth (micB) using established and two new reference ranges for fetal head circumference (HC) and to assess whether integrating additional parameters can improve prediction. Microcephaly in utero was defined as a fetal HC 3SD below the mean for gestational age according to Jeanty et al.'s reference range. The records of cases with fetal microcephaly (Fmic) were evaluated for medical history, imaging findings, biometry and postnatal examination/autopsy findings. Microcephaly was confirmed at birth (micB) by an occipitofrontal circumference (OFC) or a brain weight at autopsy 2SD below the mean for gestational age. The new INTERGROWTH-21(st) Project and a recent Israeli reference for fetal growth were applied for evaluation of the Fmic positive predictive value (PPV) for diagnosis of micB cases. Optimal HC cut-offs were determined for each of the new references with the aim of detecting all micB cases whilst minimizing the number of false positives found to have a normal HC at birth. We also assessed the difference between the Z-scores of the prenatal HC and the corresponding OFC at birth, the frequency of small-for-gestational age (SGA), decreased HC/abdominal circumference (AC) and HC/femur length (FL) ratios, the prevalence of associated malformations and family history. Forty-two fetuses were diagnosed as having Fmic according to the Jeanty reference, but micB was confirmed in only 24 (PPV, 57.1%). The optimal INTERGROWTH and Israeli reference HC cut-offs for micB diagnosis were mean - 3SD and mean - 2.3SD, resulting in a statistically non-significant improvement in PPV to 61.5% and 66.7%, respectively. The presence of a family history of microcephaly, SGA, associated malformations and application of stricter HC cut-offs resulted in a higher PPV of micB, although not statistically significant and with a concurrent increase in the number of false-negative results. The deviation of the HC from the mean, by all references

  4. The Spindle Positioning Protein Kar9p Interacts With the Sumoylation Machinery in Saccharomyces cerevisiae

    PubMed Central

    Meednu, Nida; Hoops, Harold; D'Silva, Sonia; Pogorzala, Leah; Wood, Schuyler; Farkas, David; Sorrentino, Mark; Sia, Elaine; Meluh, Pam; Miller, Rita K.

    2008-01-01

    Accurate positioning of the mitotic spindle is important for the genetic material to be distributed evenly in dividing cells, but little is known about the mechanisms that regulate this process. Here we report that two microtubule-associated proteins important for spindle positioning interact with several proteins in the sumoylation pathway. By two-hybrid analysis, Kar9p and Bim1p interact with the yeast SUMO Smt3p, the E2 enzyme Ubc9p, an E3 Nfi1p, as well as Wss1p, a weak suppressor of a temperature-sensitive smt3 allele. The physical interaction between Kar9p and Ubc9p was confirmed by in vitro binding assays. A single-amino-acid substitution in Kar9p, L304P disrupted its two-hybrid interaction with proteins in the sumoylation pathway, but retained its interactions with the spindle positioning proteins Bim1p, Stu2p, Bik1p, and Myo2p. The kar9-L304P mutant showed defects in positioning the mitotic spindle, with the spindle located more distally than normal. Whereas wild-type Kar9p-3GFP normally localizes to only the bud-directed spindle pole body (SPB), Kar9p-L304P-3GFP was mislocalized to both SPBs. Using a reconstitution assay, Kar9p was sumoylated in vitro. We propose a model in which sumoylation regulates spindle positioning by restricting Kar9p to one SPB. These findings raise the possibility that sumoylation could regulate other microtubule-dependent processes. PMID:18832349

  5. A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly

    PubMed Central

    Abdulkarim, Baroj; Igoillo-Esteve, Mariana; Daures, Mathilde; Romero, Sophie; Philippi, Anne; Senée, Valérie; Lopes, Miguel; Cunha, Daniel A.; Harding, Heather P.; Derbois, Céline; Bendelac, Nathalie; Hattersley, Andrew T.; Eizirik, Décio L.; Ron, David

    2015-01-01

    Dysregulated endoplasmic reticulum stress and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) are associated with pancreatic β-cell failure and diabetes. Here, we report the first homozygous mutation in the PPP1R15B gene (also known as constitutive repressor of eIF2α phosphorylation [CReP]) encoding the regulatory subunit of an eIF2α-specific phosphatase in two siblings affected by a novel syndrome of diabetes of youth with short stature, intellectual disability, and microcephaly. The R658C mutation in PPP1R15B affects a conserved amino acid within the domain important for protein phosphatase 1 (PP1) binding. The R658C mutation decreases PP1 binding and eIF2α dephosphorylation and results in β-cell apoptosis. Our findings support the concept that dysregulated eIF2α phosphorylation, whether decreased by mutation of the kinase (EIF2AK3) in Wolcott-Rallison syndrome or increased by mutation of the phosphatase (PPP1R15B), is deleterious to β-cells and other secretory tissues, resulting in diabetes associated with multisystem abnormalities. PMID:26159176

  6. Adverse factors increase preeclampsia-like changes in pregnant mice with abnormal lipid metabolism.

    PubMed

    Ding, Xiaoyan; Yang, Zi; Han, Yiwei; Yu, Huan

    2014-01-01

    Preeclampsia (PE) is a multifactorial pregnancy complication. Maternal underlying condition and adverse factors both influence the pathogenesis of PE. Abnormal lipid metabolism as a maternal underlying disease may participate in the occurrence and development of PE. This study aimed to observe the effects of adverse factors on PE-like symptoms of pregnant mice with genetic abnormal lipid metabolism. Apolipoprotein C-III (ApoC3) transgenic mice with abnormal lipid metabolism were subcutaneously injected with L-arginine methyl ester (L-NAME) or normal saline (NS) daily starting at Day 7 or 16 of pregnancy (ApoC3+L-NA and ApoC3+NS groups), and wild-type (WT) mice served as a control (WT+L-NA and WT+NS groups). All mice were subdivided into early and late subgroups by injection time. The mean arterial pressure (MAP) and urinary protein were measured. Pregnancy outcomes, including fetal weight, placental weight, live birth rate, and fetal absorption rate, were analyzed. Pathologic changes in the placenta were observed by hematoxylin-eosin staining. One-way analysis of variance, t-test, and χ(2) test were used for statistical analysis. MAP significantly increased for ApoC3+NS groups compared with WT+NS groups (P < 0.05), without significant difference in urine protein. Following L-NAME injection, MAP and urinary protein significantly increased for ApoC3+L-NA and WT+L-NA compared with the corresponding NS groups (P < 0.05), and the increase for ApoC3+L-NA was more obvious. Urinary protein levels in early ApoC3+L-NA and WT+L-NA significantly increased compared with the corresponding late groups (P < 0.05). Fetal absorption rate significantly increased and fetal and placental weights significantly decreased in early ApoC3+L-NA and WT+L-NA compared with the corresponding NS groups (P < 0.05), without significant difference in late ApoC3+L-NA and WT+L-NA groups. Fetal weight in early ApoC3+L-NA was significantly lower than in early WT+L-NA group (P < 0.05). Morphologic

  7. Spindle checkpoint–independent inhibition of mitotic chromosome segregation by Drosophila Mps1

    PubMed Central

    Althoff, Friederike; Karess, Roger E.; Lehner, Christian F.

    2012-01-01

    Monopolar spindle 1 (Mps1) is essential for the spindle assembly checkpoint (SAC), which prevents anaphase onset in the presence of misaligned chromosomes. Moreover, Mps1 kinase contributes in a SAC-independent manner to the correction of erroneous initial attachments of chromosomes to the spindle. Our characterization of the Drosophila homologue reveals yet another SAC-independent role. As in yeast, modest overexpression of Drosophila Mps1 is sufficient to delay progression through mitosis during metaphase, even though chromosome congression and metaphase alignment do not appear to be affected. This delay in metaphase depends on the SAC component Mad2. Although Mps1 overexpression in mad2 mutants no longer causes a metaphase delay, it perturbs anaphase. Sister kinetochores barely move apart toward spindle poles. However, kinetochore movements can be restored experimentally by separase-independent resolution of sister chromatid cohesion. We propose therefore that Mps1 inhibits sister chromatid separation in a SAC-independent manner. Moreover, we report unexpected results concerning the requirement of Mps1 dimerization and kinase activity for its kinetochore localization in Drosophila. These findings further expand Mps1's significance for faithful mitotic chromosome segregation and emphasize the importance of its careful regulation. PMID:22553353

  8. Spindle checkpoint-independent inhibition of mitotic chromosome segregation by Drosophila Mps1.

    PubMed

    Althoff, Friederike; Karess, Roger E; Lehner, Christian F

    2012-06-01

    Monopolar spindle 1 (Mps1) is essential for the spindle assembly checkpoint (SAC), which prevents anaphase onset in the presence of misaligned chromosomes. Moreover, Mps1 kinase contributes in a SAC-independent manner to the correction of erroneous initial attachments of chromosomes to the spindle. Our characterization of the Drosophila homologue reveals yet another SAC-independent role. As in yeast, modest overexpression of Drosophila Mps1 is sufficient to delay progression through mitosis during metaphase, even though chromosome congression and metaphase alignment do not appear to be affected. This delay in metaphase depends on the SAC component Mad2. Although Mps1 overexpression in mad2 mutants no longer causes a metaphase delay, it perturbs anaphase. Sister kinetochores barely move apart toward spindle poles. However, kinetochore movements can be restored experimentally by separase-independent resolution of sister chromatid cohesion. We propose therefore that Mps1 inhibits sister chromatid separation in a SAC-independent manner. Moreover, we report unexpected results concerning the requirement of Mps1 dimerization and kinase activity for its kinetochore localization in Drosophila. These findings further expand Mps1's significance for faithful mitotic chromosome segregation and emphasize the importance of its careful regulation.

  9. The relationship between sleep and glucagon-like peptide 1 in patients with abnormal glucose tolerance.

    PubMed

    Reutrakul, Sirimon; Sumritsopak, Rungtip; Saetung, Sunee; Chanprasertyothin, Suwannee; Anothaisintawee, Thunyarat

    2017-12-01

    Glucagon-like peptide 1 plays a role in glucose regulation. Sleep disturbances (obstructive sleep apnea, insufficient or poor sleep quality) have been shown to adversely affect glucose metabolism. This study aimed to explore the relationship between sleep and glucagon-like peptide 1 regulation in patients with abnormal glucose tolerance. Seventy-one adults with haemoglobin A1c levels between 5.7% and < 6.5% and no history of diabetes participated. Habitual sleep duration and efficiency were obtained from 7-day actigraphy recordings. Obstructive sleep apnea was assessed using an overnight home monitor. Glucagon-like peptide 1 levels were measured during a 75-g glucose tolerance. The area under the curve of glucagon-like peptide 1 was calculated. The mean age (SD) was 55.1 (8.3) years and median (interquartile range) haemoglobin A1c was 5.97% (5.86, 6.23). There was no relationship between sleep duration or efficiency and fasting or area under the curve glucagon-like peptide 1. Glucagon-like peptide 1 levels did not differ among those sleeping ≤ 5.75, > 5.75-< 6.5 or ≥ 6.5 h per night. Increasing apnea-hypopnea index, an indicator of obstructive sleep apnea severity, correlated with lower area under the curve glucagon-like peptide 1 (B -0.242, P = 0.045), but not with fasting glucagon-like peptide 1 (B -0.213, P = 0.079). After adjusting for sex, haemoglobin A1c and body mass index, increasing apnea-hypopnea index was negatively associated with having area under the curve glucagon-like peptide 1 in the highest quartile (odds ratio 0.581, P = 0.028, 95% CI 0.359, 0.942). This study demonstrated that increasing obstructive sleep apnea severity was associated with lower glucagon-like peptide 1 response to glucose challenge. This could possibly be an additional mechanism by which obstructive sleep apnea affects glucose metabolism. Whether raising glucagon-like peptide 1 levels in patients with abnormal glucose tolerance with more severe obstructive sleep

  10. The budding yeast RSC complex maintains ploidy by promoting spindle pole body insertion.

    PubMed

    Sing, Tina L; Hung, Minnie P; Ohnuki, Shinsuke; Suzuki, Godai; San Luis, Bryan-Joseph; McClain, Melainia; Unruh, Jay R; Yu, Zulin; Ou, Jiongwen; Marshall-Sheppard, Jesse; Huh, Won-Ki; Costanzo, Michael; Boone, Charles; Ohya, Yoshikazu; Jaspersen, Sue L; Brown, Grant W

    2018-06-06

    Ploidy is tightly regulated in eukaryotic cells and is critical for cell function and survival. Cells coordinate multiple pathways to ensure replicated DNA is segregated accurately to prevent abnormal changes in chromosome number. In this study, we characterize an unanticipated role for the Saccharomyces cerevisiae "remodels the structure of chromatin" (RSC) complex in ploidy maintenance. We show that deletion of any of six nonessential RSC genes causes a rapid transition from haploid to diploid DNA content because of nondisjunction events. Diploidization is accompanied by diagnostic changes in cell morphology and is stably maintained without further ploidy increases. We find that RSC promotes chromosome segregation by facilitating spindle pole body (SPB) duplication. More specifically, RSC plays a role in distributing two SPB insertion factors, Nbp1 and Ndc1, to the new SPB. Thus, we provide insight into a role for a SWI/SNF family complex in SPB duplication and ploidy maintenance. © 2018 Sing et al.

  11. 27 T ultra-high static magnetic field changes orientation and morphology of mitotic spindles in human cells

    PubMed Central

    Zhang, Lei; Hou, Yubin; Li, Zhiyuan; Ji, Xinmiao; Wang, Ze; Wang, Huizhen; Tian, Xiaofei; Yu, Fazhi; Yang, Zhenye; Pi, Li; Mitchison, Timothy J; Lu, Qingyou; Zhang, Xin

    2017-01-01

    Purified microtubules have been shown to align along the static magnetic field (SMF) in vitro because of their diamagnetic anisotropy. However, whether mitotic spindle in mammalian cells can be aligned by magnetic field has not been experimentally proved. In particular, the biological effects of SMF of above 20 T (Tesla) on mammalian cells have never been reported. Here we found that in both CNE-2Z and RPE1 human cells spindle orients in 27 T SMF. The direction of spindle alignment depended on the extent to which chromosomes were aligned to form a planar metaphase plate. Our results show that the magnetic torque acts on both microtubules and chromosomes, and the preferred direction of spindle alignment relative to the field depends more on chromosome alignment than microtubules. In addition, spindle morphology was also perturbed by 27 T SMF. This is the first reported study that investigated the mammalian cellular responses to ultra-high magnetic field of above 20 T. Our study not only found that ultra-high magnetic field can change the orientation and morphology of mitotic spindles, but also provided a tool to probe the role of spindle orientation and perturbation in developmental and cancer biology. DOI: http://dx.doi.org/10.7554/eLife.22911.001 PMID:28244368

  12. Regulation of kinetochore recruitment of two essential mitotic spindle checkpoint proteins by Mps1 phosphorylation.

    PubMed

    Xu, Quanbin; Zhu, Songcheng; Wang, Wei; Zhang, Xiaojuan; Old, William; Ahn, Natalie; Liu, Xuedong

    2009-01-01

    Mps1 is a protein kinase that plays essential roles in spindle checkpoint signaling. Unattached kinetochores or lack of tension triggers recruitment of several key spindle checkpoint proteins to the kinetochore, which delays anaphase onset until proper attachment or tension is reestablished. Mps1 acts upstream in the spindle checkpoint signaling cascade, and kinetochore targeting of Mps1 is required for subsequent recruitment of Mad1 and Mad2 to the kinetochore. The mechanisms that govern recruitment of Mps1 or other checkpoint proteins to the kinetochore upon spindle checkpoint activation are incompletely understood. Here, we demonstrate that phosphorylation of Mps1 at T12 and S15 is required for Mps1 recruitment to the kinetochore. Mps1 kinetochore recruitment requires its kinase activity and autophosphorylation at T12 and S15. Mutation of T12 and S15 severely impairs its kinetochore association and markedly reduces recruitment of Mad2 to the kinetochore. Our studies underscore the importance of Mps1 autophosphorylation in kinetochore targeting and spindle checkpoint signaling.

  13. Declarative memory performance is associated with the number of sleep spindles in elderly women.

    PubMed

    Seeck-Hirschner, Mareen; Baier, Paul Christian; Weinhold, Sara Lena; Dittmar, Manuela; Heiermann, Steffanie; Aldenhoff, Josef B; Göder, Robert

    2012-09-01

    Recent evidence suggests that the sleep-dependent consolidation of declarative memory relies on the nonrapid eye movement rather than the rapid eye movement phase of sleep. In addition, it is known that aging is accompanied by changes in sleep and memory processes. Hence, the purpose of this study was to investigate the overnight consolidation of declarative memory in healthy elderly women. Sleep laboratory of University. Nineteen healthy elderly women (age range: 61-74 years). We used laboratory-based measures of sleep. To test declarative memory, the Rey-Osterrieth Complex Figure Test was performed. Declarative memory performance in elderly women was associated with Stage 2 sleep spindle density. Women characterized by high memory performance exhibited significantly higher numbers of sleep spindles and higher spindle density compared with women with generally low memory performance. The data strongly support theories suggesting a link between sleep spindle activity and declarative memory consolidation.

  14. Microtubule Flux and Sliding in Mitotic Spindles of Drosophila EmbryosV⃞

    PubMed Central

    Brust-Mascher, Ingrid; Scholey, Jonathan M.

    2002-01-01

    We proposed that spindle morphogenesis in Drosophila embryos involves progression through four transient isometric structures in which a constant spacing of the spindle poles is maintained by a balance of forces generated by multiple microtubule (MT) motors and that tipping this balance drives pole-pole separation. Here we used fluorescent speckle microscopy to evaluate the influence of MT dynamics on the isometric state that persists through metaphase and anaphase A and on pole-pole separation in anaphase B. During metaphase and anaphase A, fluorescent punctae on kinetochore and interpolar MTs flux toward the poles at 0.03 μm/s, too slow to drive chromatid-to-pole motion at 0.11 μm/s, and during anaphase B, fluorescent punctae on interpolar MTs move away from the spindle equator at the same rate as the poles, consistent with MT-MT sliding. Loss of Ncd, a candidate flux motor or brake, did not affect flux in the metaphase/anaphase A isometric state or MT sliding in anaphase B but decreased the duration of the isometric state. Our results suggest that, throughout this isometric state, an outward force exerted on the spindle poles by MT sliding motors is balanced by flux, and that suppression of flux could tip the balance of forces at the onset of anaphase B, allowing MT sliding and polymerization to push the poles apart. PMID:12429839

  15. Characteristics of Paraspinal Muscle Spindle Response to Mechanically Assisted Spinal Manipulation: A Preliminary Report.

    PubMed

    Reed, William R; Pickar, Joel G; Sozio, Randall S; Liebschner, Michael A K; Little, Joshua W; Gudavalli, Maruti R

    The purpose of this preliminary study is to determine muscle spindle response characteristics related to the use of 2 solenoid powered clinical mechanically assisted manipulation (MAM) devices. L6 muscle spindle afferents with receptive fields in paraspinal muscles were isolated in 6 cats. Neural recordings were made during L7 MAM thrusts using the Activator V (Activator Methods Int. Ltd., Phoenix, AZ) and/or Pulstar (Sense Technology Inc., Pittsburgh, PA) devices at their 3 lowest force settings. Mechanically assisted manipulation response measures included (a) the time required post-thrust until the first action potential, (b) differences in mean frequency (MF) and mean instantaneous frequency (MIF) 2 seconds before and after MAM, and (c) the time required for muscle spindle discharge (MF and MIF) to return to 95% of baseline after MAM. Depending on device setting, between 44% to 80% (Pulstar) and 11% to 63% (Activator V) of spindle afferents required >6 seconds to return to within 95% of baseline MF values; whereas 66% to 89% (Pulstar) and 75% to 100% (Activator V) of spindle responses returned to within 95% of baseline MIF in <6 seconds after MAM. Nonparametric comparisons between the 22 N and 44 N settings of the Pulstar yielded significant differences for the time required to return to baseline MF and MIF. Short duration (<10 ms) MAM thrusts decrease muscle spindle discharge with a majority of afferents requiring prolonged periods (>6 seconds) to return to baseline MF activity. Physiological consequences and clinical relevance of described MAM mechanoreceptor responses will require additional investigation. Copyright © 2017. Published by Elsevier Inc.

  16. Method for automated building of spindle thermal model with use of CAE system

    NASA Astrophysics Data System (ADS)

    Kamenev, S. V.

    2018-03-01

    The spindle is one of the most important units of the metal-cutting machine tool. Its performance is critical to minimize the machining error, especially the thermal error. Various methods are applied to improve the thermal behaviour of spindle units. One of the most important methods is mathematical modelling based on the finite element analysis. The most common approach for its realization is the use of CAE systems. This approach, however, is not capable to address the number of important effects that need to be taken into consideration for proper simulation. In the present article, the authors propose the solution to overcome these disadvantages using automated thermal model building for the spindle unit utilizing the CAE system ANSYS.

  17. Micromanipulation studies of chromosome movement. II. Birefringent chromosomal fibers and the mechanical attachment of chromosomes to the spindle

    PubMed Central

    1979-01-01

    The degree of mechanical coupling of chromosomes to the spindles of Nephrotoma and Trimeratropis primary spermatocytes varies with the stage of meiosis and the birefringent retardation of the chromosomal fibers. In early prometaphase, before birefringent chromosomal fibers have formed, a bivalent can be displaced toward a spindle pole by a single, continuous pull with a microneedle. Resistance to poleward displacement increases with increased development of the chromosomal fibers, reaching a maximum at metaphase. At this stage kinetochores cannot be displaced greater than 1 micrometer toward either spindle pole, even by a force which is sufficient to displace the entire spindle within the cell. The abolition of birefringence with either colcemid or vinblastine results in the loss of chromosome-spindle attachment. In the absence of birefringent fibers a chromosome can be displaced anywhere within the cell. The photochemical inactivation of colcemid by irradiation with 366-nm light results in the reformation of birefringent chromosomal fibers and the concomitant re-establishment of chromosome attachment to the spindle. These results support the hypothesis that the birefringent chromosomal fibers anchor the chromosomes to the spindle and transmit the force for anaphase chromosome movement. PMID:479316

  18. Short-term treatment with VEGF receptor inhibitors induces retinopathy of prematurity-like abnormal vascular growth in neonatal rats.

    PubMed

    Nakano, Ayuki; Nakahara, Tsutomu; Mori, Asami; Ushikubo, Hiroko; Sakamoto, Kenji; Ishii, Kunio

    2016-02-01

    Retinal arterial tortuosity and venous dilation are hallmarks of plus disease, which is a severe form of retinopathy of prematurity (ROP). In this study, we examined whether short-term interruption of vascular endothelial growth factor (VEGF) signals leads to the formation of severe ROP-like abnormal retinal blood vessels. Neonatal rats were treated subcutaneously with the VEGF receptor (VEGFR) tyrosine kinase inhibitors, KRN633 (1, 5, or 10 mg/kg) or axitinib (10 mg/kg), on postnatal day (P) 7 and P8. The retinal vasculatures were examined on P9, P14, or P21 in retinal whole-mounts stained with an endothelial cell marker. Prevention of vascular growth and regression of some preformed capillaries were observed on P9 in retinas of rats treated with KRN633. However, on P14 and P21, density of capillaries, tortuosity index of arterioles, and diameter of veins significantly increased in KRN633-treated rats, compared to vehicle (0.5% methylcellulose)-treated animals. Similar observations were made with axitinib-treated rats. Expressions of VEGF and VEGFR-2 were enhanced on P14 in KRN633-treated rat retinas. The second round of KRN633 treatment on P11 and P12 completely blocked abnormal retinal vascular growth on P14, but thereafter induced ROP-like abnormal retinal blood vessels by P21. These results suggest that an interruption of normal retinal vascular development in neonatal rats as a result of short-term VEGFR inhibition causes severe ROP-like abnormal retinal vascular growth in a VEGF-dependent manner. Rats treated postnatally with VEGFR inhibitors could serve as an animal model for studying the mechanisms underlying the development of plus disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. JMJD5 (Jumonji Domain-containing 5) Associates with Spindle Microtubules and Is Required for Proper Mitosis.

    PubMed

    He, Zhimin; Wu, Junyu; Su, Xiaonan; Zhang, Ye; Pan, Lixia; Wei, Huimin; Fang, Qiang; Li, Haitao; Wang, Da-Liang; Sun, Fang-Lin

    2016-02-26

    Precise mitotic spindle assembly is a guarantee of proper chromosome segregation during mitosis. Chromosome instability caused by disturbed mitosis is one of the major features of various types of cancer. JMJD5 has been reported to be involved in epigenetic regulation of gene expression in the nucleus, but little is known about its function in mitotic process. Here we report the unexpected localization and function of JMJD5 in mitotic progression. JMJD5 partially accumulates on mitotic spindles during mitosis, and depletion of JMJD5 results in significant mitotic arrest, spindle assembly defects, and sustained activation of the spindle assembly checkpoint (SAC). Inactivating SAC can efficiently reverse the mitotic arrest caused by JMJD5 depletion. Moreover, JMJD5 is found to interact with tubulin proteins and associate with microtubules during mitosis. JMJD5-depleted cells show a significant reduction of α-tubulin acetylation level on mitotic spindles and fail to generate enough interkinetochore tension to satisfy the SAC. Further, JMJD5 depletion also increases the susceptibility of HeLa cells to the antimicrotubule agent. Taken together, these results suggest that JMJD5 plays an important role in regulating mitotic progression, probably by modulating the stability of spindle microtubules. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Zika virus disease, microcephaly and Guillain-Barré syndrome in Colombia: epidemiological situation during 21 months of the Zika virus outbreak, 2015-2017.

    PubMed

    Méndez, Nelson; Oviedo-Pastrana, Misael; Mattar, Salim; Caicedo-Castro, Isaac; Arrieta, German

    2017-01-01

    The Zika virus disease (ZVD) has had a huge impact on public health in Colombia for the numbers of people affected and the presentation of Guillain-Barre syndrome (GBS) and microcephaly cases associated to ZVD. A retrospective descriptive study was carried out, we analyze the epidemiological situation of ZVD and its association with microcephaly and GBS during a 21-month period, from October 2015 to June 2017. The variables studied were: (i) ZVD cases, (ii) ZVD cases in pregnant women, (iii) laboratory-confirmed ZVD in pregnant women, (iv) ZVD cases associated with microcephaly, (v) laboratory-confirmed ZVD associated with microcephaly, and (vi) ZVD associated to GBS cases. Average number of cases, attack rates (AR) and proportions were also calculated. The studied variables were plotted by epidemiological weeks and months. The distribution of ZVD cases in Colombia was mapped across the time using Kernel density estimator and QGIS software; we adopted Kernel Ridge Regression (KRR) and the Gaussian Kernel to estimate the number of Guillain Barre cases given the number of ZVD cases. One hundred eight thousand eighty-seven ZVD cases had been reported in Colombia, including 19,963 (18.5%) in pregnant women, 710 (0.66%) associated with microcephaly (AR, 4.87 cases per 10,000 live births) and 453 (0.42%) ZVD associated to GBS cases (AR, 41.9 GBS cases per 10,000 ZVD cases). It appears the cases of GBS increased in parallel with the cases of ZVD, cases of microcephaly appeared 5 months after recognition of the outbreak. The kernel density map shows that throughout the study period, the states most affected by the Zika outbreak in Colombia were mainly San Andrés and Providencia islands, Casanare, Norte de Santander, Arauca and Huila. The KRR shows that there is no proportional relationship between the number of GBS and ZVD cases. During the cross validation, the RMSE achieved for the second order polynomial kernel, the linear kernel, the sigmoid kernel, and the Gaussian

  1. Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes.

    PubMed

    Carvalho, Claudia M B; Vasanth, Shivakumar; Shinawi, Marwan; Russell, Chad; Ramocki, Melissa B; Brown, Chester W; Graakjaer, Jesper; Skytte, Anne-Bine; Vianna-Morgante, Angela M; Krepischi, Ana C V; Patel, Gayle S; Immken, LaDonna; Aleck, Kyrieckos; Lim, Cynthia; Cheung, Sau Wai; Rosenberg, Carla; Katsanis, Nicholas; Lupski, James R

    2014-11-06

    The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  2. A Functional Relationship between NuMA and Kid Is Involved in Both Spindle Organization and Chromosome Alignment in Vertebrate CellsV⃞

    PubMed Central

    Levesque, Aime A.; Howard, Louisa; Gordon, Michael B.; Compton, Duane A.

    2003-01-01

    We examined spindle morphology and chromosome alignment in vertebrate cells after simultaneous perturbation of the chromokinesin Kid and either NuMA, CENP-E, or HSET. Spindle morphology and chromosome alignment after simultaneous perturbation of Kid and either HSET or CENP-E were no different from when either HSET or CENP-E was perturbed alone. However, short bipolar spindles with organized poles formed after perturbation of both Kid and NuMA in stark contrast to splayed spindle poles observed after perturbation of NuMA alone. Spindles were disorganized if Kid, NuMA, and HSET were perturbed, indicating that HSET is sufficient for spindle organization in the absence of Kid and NuMA function. In addition, chromosomes failed to align efficiently at the spindle equator after simultaneous perturbation of Kid and NuMA despite appropriate kinetochore-microtubule interactions that generated chromosome movement at normal velocities. These data indicate that a functional relationship between the chromokinesin Kid and the spindle pole organizing protein NuMA influences spindle morphology, and we propose that this occurs because NuMA forms functional linkages between kinetochore and nonkinetochore microtubules at spindle poles. In addition, these data show that both Kid and NuMA contribute to chromosome alignment in mammalian cells. PMID:12972545

  3. Changes in muscle spindle firing in response to length changes of neighboring muscles

    PubMed Central

    Smilde, Hiltsje A.; Vincent, Jake A.; Baan, Guus C.; Nardelli, Paul; Lodder, Johannes C.; Mansvelder, Huibert D.; Cope, Tim C.

    2016-01-01

    Skeletal muscle force can be transmitted to the skeleton, not only via its tendons of origin and insertion but also through connective tissues linking the muscle belly to surrounding structures. Through such epimuscular myofascial connections, length changes of a muscle may cause length changes within an adjacent muscle and hence, affect muscle spindles. The aim of the present study was to investigate the effects of epimuscular myofascial forces on feedback from muscle spindles in triceps surae muscles of the rat. We hypothesized that within an intact muscle compartment, muscle spindles not only signal length changes of the muscle in which they are located but can also sense length changes that occur as a result of changing the length of synergistic muscles. Action potentials from single afferents were measured intra-axonally in response to ramp-hold release (RHR) stretches of an agonistic muscle at different lengths of its synergist, as well as in response to synergist RHRs. A decrease in force threshold was found for both soleus (SO) and lateral gastrocnemius afferents, along with an increase in length threshold for SO afferents. In addition, muscle spindle firing could be evoked by RHRs of the synergistic muscle. We conclude that muscle spindles not only signal length changes of the muscle in which they are located but also local length changes that occur as a result of changing the length and relative position of synergistic muscles. PMID:27075540

  4. Dynactin Function in Mitotic Spindle Positioning

    PubMed Central

    Moore, Jeffrey K.; Li, Jun; Cooper, John A.

    2008-01-01

    Dynactin is a multisubunit protein complex necessary for dynein function. Here, we investigated the function of dynactin in budding yeast. Loss of dynactin impaired movement and positioning of the mitotic spindle, similar to loss of dynein. Dynactin subunits required for function included p150Glued, dynamitin, actin-related protein (Arp) 1 and p24. Arp10 and capping protein were dispensable, even in combination. All dynactin subunits tested localized to dynamic plus ends of cytoplasmic microtubules, to stationary foci on the cell cortex and to spindle pole bodies. The number of molecules of dynactin in those locations was small, less than five. In the absence of dynactin, dynein accumulated at plus ends and did not appear at the cell cortex, consistent with a role for dynactin in offloading dynein from the plus end to the cortex. Dynein at the plus end was necessary for dynactin plus-end targeting. p150Glued was the only dynactin subunit sufficient for plus-end targeting. Interactions among the subunits support a molecular model that resembles the current model for brain dynactin in many respects; however, three subunits at the pointed end of brain dynactin appear to be absent from yeast. PMID:18221362

  5. In-series compliance of gastrocnemius muscle in cat step cycle: do spindles signal origin-to-insertion length?

    PubMed Central

    Elek, J; Prochazka, A; Hulliger, M; Vincent, S

    1990-01-01

    1. It has been claimed that stretch in the non-contractile (extramysial) portion of muscles is substantial, and may produce large discrepancies between the origin-to-insertion muscle length and the internal length variations 'seen' by muscle spindle endings. 2. In eight pentobarbitone-anaesthetized cats, we estimated stretch in the extramysial portion of medial gastrocnemius (MG) muscle with a method similar to the spindle null technique. 3. Length variations of MG previously monitored in a normal step cycle were reproduced with a computer-controlled length servo. The responses of test MG spindle endings were monitored in dorsal root filaments. Distributed stimulation of ventral root filaments, rate-modulated by the step-cycle EMG envelope, served to reproduce step-cycle forces. The filaments were selected so as to have no fusimotor action on the test spindle. 4. Spindle responses in active cycles were compared with those in passive cycles (stretch, but no distributed stimulation). In some cases concomitant tonic fusimotor stimulation was used to maintain spindle responsiveness throughout the cycle, both in active and passive trials. Generally, small discrepancies in spindle firing were seen. The passive trials were now repeated, with iterative adjustments of the length function, until the response matched the spindle firing profile in the active trial. The spindle 'saw' the same internal length change in the final passive trial as in the active trial. Any difference between the corresponding length profiles was attributed to extramysial displacement. 5. Extramysial displacement estimated in this was was maximal at short mean muscle lengths, reaching about 0.5 mm in a typical step cycle (force rising from 0 to 10 N). At longer mean muscle lengths where muscle force rose from say 2 to 12 N in the cycle, extramysial displacement was in the range 0.2-0.4 mm. 6. Except at very short lengths, the displacement was probably mainly tendinous. On this assumption, our

  6. Sleep Spindle Density Predicts the Effect of Prior Knowledge on Memory Consolidation

    PubMed Central

    Lambon Ralph, Matthew A.; Kempkes, Marleen; Cousins, James N.; Lewis, Penelope A.

    2016-01-01

    Information that relates to a prior knowledge schema is remembered better and consolidates more rapidly than information that does not. Another factor that influences memory consolidation is sleep and growing evidence suggests that sleep-related processing is important for integration with existing knowledge. Here, we perform an examination of how sleep-related mechanisms interact with schema-dependent memory advantage. Participants first established a schema over 2 weeks. Next, they encoded new facts, which were either related to the schema or completely unrelated. After a 24 h retention interval, including a night of sleep, which we monitored with polysomnography, participants encoded a second set of facts. Finally, memory for all facts was tested in a functional magnetic resonance imaging scanner. Behaviorally, sleep spindle density predicted an increase of the schema benefit to memory across the retention interval. Higher spindle densities were associated with reduced decay of schema-related memories. Functionally, spindle density predicted increased disengagement of the hippocampus across 24 h for schema-related memories only. Together, these results suggest that sleep spindle activity is associated with the effect of prior knowledge on memory consolidation. SIGNIFICANCE STATEMENT Episodic memories are gradually assimilated into long-term memory and this process is strongly influenced by sleep. The consolidation of new information is also influenced by its relationship to existing knowledge structures, or schemas, but the role of sleep in such schema-related consolidation is unknown. We show that sleep spindle density predicts the extent to which schemas influence the consolidation of related facts. This is the first evidence that sleep is associated with the interaction between prior knowledge and long-term memory formation. PMID:27030764

  7. The function of the sleep spindle: a physiological index of intelligence and a mechanism for sleep-dependent memory consolidation.

    PubMed

    Fogel, Stuart M; Smith, Carlyle T

    2011-04-01

    Until recently, the electrophysiological mechanisms involved in strengthening new memories into a more permanent form during sleep have been largely unknown. The sleep spindle is an event in the electroencephalogram (EEG) characterizing Stage 2 sleep. Sleep spindles may reflect, at the electrophysiological level, an ideal mechanism for inducing long-term synaptic changes in the neocortex. Recent evidence suggests the spindle is highly correlated with tests of intellectual ability (e.g.; IQ tests) and may serve as a physiological index of intelligence. Further, spindles increase in number and duration in sleep following new learning and are correlated with performance improvements. Spindle density and sigma (14-16Hz) spectral power have been found to be positively correlated with performance following a daytime nap, and animal studies suggest the spindle is involved in a hippocampal-neocortical dialogue necessary for memory consolidation. The findings reviewed here collectively provide a compelling body of evidence that the function of the sleep spindle is related to intellectual ability and memory consolidation. Copyright © 2010 Elsevier Ltd. All rights reserved.

  8. TFG-MET fusion in an infantile spindle cell sarcoma with neural features.

    PubMed

    Flucke, Uta; van Noesel, Max M; Wijnen, Marc; Zhang, Lei; Chen, Chun-Liang; Sung, Yun-Shao; Antonescu, Cristina R

    2017-09-01

    An increasing number of congenital and infantile sarcomas displaying a primitive, monomorphic spindle cell phenotype have been characterized to harbor recurrent gene fusions, including infantile fibrosarcoma and congenital spindle cell rhabdomyosarcoma. Here, we report an unusual spindle cell sarcoma presenting as a large and infiltrative pelvic soft tissue mass in a 4-month-old girl, which revealed a novel TFG-MET gene fusion by whole transcriptome RNA sequencing. The tumor resembled the morphology of an infantile fibrosarcoma with both fascicular and patternless growth, however, it expressed strong S100 protein immunoreactivity, while lacking SOX10 staining and retaining H3K27me3 expression. Although this immunoprofile suggested partial neural/neuroectodermal differentiation, overall features were unusual and did not fit into any known tumor types (cellular schwannoma, MPNST), raising the possibility of a novel pathologic entity. The TFG-MET gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital spindle cell sarcomas, with yet another example of kinase oncogenic activation through chromosomal translocation. The discovery of this new fusion is significant since the resulting MET activation can potentially be inhibited by targeted therapy, as MET inhibitors are presently available in clinical trials. © 2017 Wiley Periodicals, Inc.

  9. Time-frequency dynamics during sleep spindles on the EEG in rodents with a genetic predisposition to absence epilepsy (WAG/Rij rats)

    NASA Astrophysics Data System (ADS)

    Hramov, Alexander E.; Sitnikova, Evgenija Y.; Pavlov, Alexey N.; Grubov, Vadim V.; Koronovskii, Alexey A.; Khramova, Marina V.

    2015-03-01

    Sleep spindles are known to appear spontaneously in the thalamocortical neuronal network of the brain during slow-wave sleep; pathological processes in the thalamocortical network may be the reason of the absence epilepsy. The aim of the present work is to study developed changes in the time-frequency structure of sleep spindles during the progressive development of the absence epilepsy in WAG/Rij rats. EEG recordings were made at age 7 and 9 months. Automatic recognition and subsequent analysis of sleep spindles on the EEG were performed using the continuous wavelet transform. The duration of epileptic discharges and the total duration of epileptic activity were found to increase with age, while the duration of sleep spindles, conversely, decreased. In terms of the mean frequency, sleep spindles could be divided into three classes: `slow' (mean frequency 9.3Hz), `medium' (11.4Hz), and `fast' (13.5Hz). Slow and medium (transitional) spindles in five-month-old animals showed increased frequency from the beginning to the end of the spindle. The more intense the epilepsy is, the shorter are the durations of spindles of all types. The mean frequencies of `medium' and `fast' spindles were higher in rats with more intense signs of epilepsy. Overall, high epileptic activity in WAG/Rij rats was linked with significant changes in spindles of the transitional type, with less marked changes in the two traditionally identified types of spindle, slow and fast.

  10. Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication

    PubMed Central

    Kodani, Andrew; Yu, Timothy W; Johnson, Jeffrey R; Jayaraman, Divya; Johnson, Tasha L; Al-Gazali, Lihadh; Sztriha, Lāszló; Partlow, Jennifer N; Kim, Hanjun; Krup, Alexis L; Dammermann, Alexander; Krogan, Nevan J; Walsh, Christopher A; Reiter, Jeremy F

    2015-01-01

    Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. Thus, centriolar satellites build a MCPH complex critical for human neurodevelopment that promotes CDK2 centrosomal localization and centriole duplication. DOI: http://dx.doi.org/10.7554/eLife.07519.001 PMID:26297806

  11. Radmis, a Novel Mitotic Spindle Protein that Functions in Cell Division of Neural Progenitors

    PubMed Central

    Yumoto, Takahito; Nakadate, Kazuhiko; Nakamura, Yuki; Sugitani, Yoshinobu; Sugitani-Yoshida, Reiko; Ueda, Shuichi; Sakakibara, Shin-ichi

    2013-01-01

    Developmental dynamics of neural stem/progenitor cells (NSPCs) are crucial for embryonic and adult neurogenesis, but its regulatory factors are not fully understood. By differential subtractive screening with NSPCs versus their differentiated progenies, we identified the radmis (radial fiber and mitotic spindle)/ckap2l gene, a novel microtubule-associated protein (MAP) enriched in NSPCs. Radmis is a putative substrate for the E3-ubiquitin ligase, anaphase promoting complex/cyclosome (APC/C), and is degraded via the KEN box. Radmis was highly expressed in regions of active neurogenesis throughout life, and its distribution was dynamically regulated during NSPC division. In embryonic and perinatal brains, radmis localized to bipolar mitotic spindles and radial fibers (basal processes) of dividing NSPCs. As central nervous system development proceeded, radmis expression was lost in most brain regions, except for several neurogenic regions. In adult brain, radmis expression persisted in the mitotic spindles of both slowly-dividing stem cells and rapid amplifying progenitors. Overexpression of radmis in vitro induced hyper-stabilization of microtubules, severe defects in mitotic spindle formation, and mitotic arrest. In vivo gain-of-function using in utero electroporation revealed that radmis directed a reduction in NSPC proliferation and a concomitant increase in cell cycle exit, causing a reduction in the Tbr2-positive basal progenitor population and shrinkage of the embryonic subventricular zone. Besides, radmis loss-of-function by shRNAs induced the multipolar mitotic spindle structure, accompanied with the catastrophe of chromosome segregation including the long chromosome bridge between two separating daughter nuclei. These findings uncover the indispensable role of radmis in mitotic spindle formation and cell-cycle progression of NSPCs. PMID:24260314

  12. Microcephaly Case Fatality Rate Associated with Zika Virus Infection in Brazil: Current Estimates.

    PubMed

    Cunha, Antonio José Ledo Alves da; de Magalhães-Barbosa, Maria Clara; Lima-Setta, Fernanda; Medronho, Roberto de Andrade; Prata-Barbosa, Arnaldo

    2017-05-01

    Considering the currently confirmed cases of microcephaly and related deaths associated with Zika virus in Brazil, the estimated case fatality rate is 8.3% (95% confidence interval: 7.2-9.6). However, a third of the reported cases remain under investigation. If the confirmation rates of cases and deaths are the same in the future, the estimated case fatality rate will be as high as 10.5% (95% confidence interval: 9.5-11.7).

  13. EEG alpha spindles and prolonged brake reaction times during auditory distraction in an on-road driving study.

    PubMed

    Sonnleitner, Andreas; Treder, Matthias Sebastian; Simon, Michael; Willmann, Sven; Ewald, Arne; Buchner, Axel; Schrauf, Michael

    2014-01-01

    Driver distraction is responsible for a substantial number of traffic accidents. This paper describes the impact of an auditory secondary task on drivers' mental states during a primary driving task. N=20 participants performed the test procedure in a car following task with repeated forced braking on a non-public test track. Performance measures (provoked reaction time to brake lights) and brain activity (EEG alpha spindles) were analyzed to describe distracted drivers. Further, a classification approach was used to investigate whether alpha spindles can predict drivers' mental states. Results show that reaction times and alpha spindle rate increased with time-on-task. Moreover, brake reaction times and alpha spindle rate were significantly higher while driving with auditory secondary task opposed to driving only. In single-trial classification, a combination of spindle parameters yielded a median classification error of about 8% in discriminating the distracted from the alert driving. Reduced driving performance (i.e., prolonged brake reaction times) during increased cognitive load is assumed to be indicated by EEG alpha spindles, enabling the quantification of driver distraction in experiments on public roads without verbally assessing the drivers' mental states. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Role of Rad23 and Dsk2 in Nucleotide Excision Repair and Spindle Pole Body Duplication

    DTIC Science & Technology

    2006-03-01

    AD Award Number: W81XWH-05-1-0310 TITLE: Role of Rad23 and Dsk2 in Nucleotide Excision Repair and Spindle Pole Body Duplication PRINCIPAL...Feb 2006 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Role of Rad23 and Dsk2 in Nucleotide Excision Repair and Spindle Pole Body Duplication Sb. GRANT...Degradation, Cell Cycle, Spindle Pole Body 16. SECURITY CLASSIFICATION OF: 17. LIMITATION 18. NUMBER 19a. NAME OF RESPONSIBLE PERSON OF ABSTRACT OF

  15. Zika Virus Infection in Pregnancy, Microcephaly, and Maternal and Fetal Health: What We Think, What We Know, and What We Think We Know.

    PubMed

    Alvarado, Maria Gabriela; Schwartz, David A

    2017-01-01

    -The global epidemic of Zika virus (ZIKV) infection has emerged as an important public health problem affecting pregnant women and their infants. -To review the causal association between ZIKV infection during pregnancy and intrauterine fetal infection, microcephaly, brain damage, congenital malformation syndrome, and experimental laboratory models of fetal infection. Many questions remain regarding the risk factors, pathophysiology, epidemiology, and timing of maternal-fetal transmission and disease. These include mechanisms of fetal brain damage and microcephaly; the role of covariables, such as viral burden, duration of viremia, and host genetics, on vertical transmission; and the clinical and pathologic spectrum of congenital Zika syndrome. Additional questions include defining the potential long-term physical and neurobehavioral outcomes for infected infants, whether maternal or fetal host genetics influence the clinical outcome, and whether ZIKV infection can cause maternal morbidity. Finally, are experimental laboratory and animal models of ZIKV infection helpful in addressing maternal-fetal viral transmission and the development of congenital microcephaly? This communication provides current information and attempts to address some of these important questions. -Comprehensive review of published scientific literature. -Recent advances in epidemiology, clinical medicine, pathology, and experimental studies have provided a great amount of new information regarding vertical ZIKV transmission and the mechanisms of congenital microcephaly, brain damage, and congenital Zika syndrome in a relatively short time. However, much work still needs to be performed to more completely understand the maternal and fetal aspects of this new and emerging viral disease.

  16. Birth Defects Among Fetuses and Infants of US Women With Evidence of Possible Zika Virus Infection During Pregnancy.

    PubMed

    Honein, Margaret A; Dawson, April L; Petersen, Emily E; Jones, Abbey M; Lee, Ellen H; Yazdy, Mahsa M; Ahmad, Nina; Macdonald, Jennifer; Evert, Nicole; Bingham, Andrea; Ellington, Sascha R; Shapiro-Mendoza, Carrie K; Oduyebo, Titilope; Fine, Anne D; Brown, Catherine M; Sommer, Jamie N; Gupta, Jyoti; Cavicchia, Philip; Slavinski, Sally; White, Jennifer L; Owen, S Michele; Petersen, Lyle R; Boyle, Coleen; Meaney-Delman, Dana; Jamieson, Denise J

    2017-01-03

    Understanding the risk of birth defects associated with Zika virus infection during pregnancy may help guide communication, prevention, and planning efforts. In the absence of Zika virus, microcephaly occurs in approximately 7 per 10 000 live births. To estimate the preliminary proportion of fetuses or infants with birth defects after maternal Zika virus infection by trimester of infection and maternal symptoms. Completed pregnancies with maternal, fetal, or infant laboratory evidence of possible recent Zika virus infection and outcomes reported in the continental United States and Hawaii from January 15 to September 22, 2016, in the US Zika Pregnancy Registry, a collaboration between the CDC and state and local health departments. Laboratory evidence of possible recent Zika virus infection in a maternal, placental, fetal, or infant sample. Birth defects potentially Zika associated: brain abnormalities with or without microcephaly, neural tube defects and other early brain malformations, eye abnormalities, and other central nervous system consequences. Among 442 completed pregnancies in women (median age, 28 years; range, 15-50 years) with laboratory evidence of possible recent Zika virus infection, birth defects potentially related to Zika virus were identified in 26 (6%; 95% CI, 4%-8%) fetuses or infants. There were 21 infants with birth defects among 395 live births and 5 fetuses with birth defects among 47 pregnancy losses. Birth defects were reported for 16 of 271 (6%; 95% CI, 4%-9%) pregnant asymptomatic women and 10 of 167 (6%; 95% CI, 3%-11%) symptomatic pregnant women. Of the 26 affected fetuses or infants, 4 had microcephaly and no reported neuroimaging, 14 had microcephaly and brain abnormalities, and 4 had brain abnormalities without microcephaly; reported brain abnormalities included intracranial calcifications, corpus callosum abnormalities, abnormal cortical formation, cerebral atrophy, ventriculomegaly, hydrocephaly, and cerebellar abnormalities

  17. Exposure of spermatozoa to dibutyl phthalate induces abnormal embryonic development in a marine invertebrate Galeolaria caespitosa (Polychaeta: Serpulidae).

    PubMed

    Lu, Yonggang; Lin, Minjie; Aitken, Robert John

    2017-10-01

    In this study, we have investigated the impact of dibutyl phthalate (DBP) on early embryogenesis in a sessile marine invertebrate, Galeolaria caespitosa. DBP was found to induce sperm dysfunction as well as impaired and defective embryogenesis characterised by a particular pattern of abnormality. Thus, after the first cleavage, one blastomere in these abnormal embryos was able to carry out further mitoses, while the other arrested. Analysis of microtubules, chromosomes and actin filaments demonstrated that the mitotic spindles in the abnormal embryos were irregularly bent, shortened and unable to anchor to the cortex, resulting in the defective segregation of chromosomes. Within the non-dividing blastomeres, karyokinesis was found to continue at a slow pace as indicated by the presence of multiple sets of abnormal mitotic spindles. However, cytokinesis had been disrupted in these arrested cells due to a failure to assemble the contractile actin ring, as a result of which one pole of the embryos remained as one large, undivided cell. DBP was found to suppress the activity of superoxide dismutase in spermatozoa and, in association with this change, DBP-treated cells experienced oxidative stress as indicated by the presence of lipid aldehydes, such as 4-hydroxynonenal (4-HNE) in the sperm acrosome and neck. Adduction of lipid aldehydes at the level of the acrosome would be expected to impede the acrosome reaction and account for the significant decrease in fertilisation rates. 4-HNE generated as a consequence of lipid peroxidation in the sperm neck resulted in alkylation of the sperm centrioles. Such paternally damaged centrioles were inherited by the embryos and disrupted cytoskeletal protein organisation during early cleavage, generating the observed abnormalities in embryonic development. This research emphasises the vulnerability of spermatozoa to oxidative damage and highlights novel potential mechanisms for reproductive toxicity involving the alkylation of

  18. Muscle spindle autogenetic inhibition in the extraocular muscles of lamb.

    PubMed

    Pettorossi, V E; Filippi, G M

    1981-09-01

    The role of extraocular muscle (EOM) proprioceptors on eye motility has been investigated in lambs on "encéphale isolé", by evaluating the tension of EOMs at various lengths and velocities of stretch before and after proprioceptive blocks. The EOM tension, in the absence of proprioceptive input, was higher than in normal conditions. Such an effect occurred at lengthening values greater than 3 mm of stretch from resting muscle length, corresponding to 18 degrees of eye deviation and was dependent on the velocity of the stretch, being more effective at high velocity. The muscle receptors responsible for this effect was determined by comparing the sensitivity to vibratory stimulation of spindles and tendon organs to the amount of inhibition provoked by the same stimulation on an EOM electromyographic activity. The tension inhibition appeared to be correlated to muscle spindle activation. Thus, the presence of muscle spindles can determine a reduction of the tension within the stretched muscles. This result suggests that the EOM length and velocity signals operate moment to moment reduction on the stiffness of the muscle which antagonizes eye displacement, thus facilitating the ocular movements.

  19. Sleep spindle detection using deep learning: A validation study based on crowdsourcing.

    PubMed

    Dakun Tan; Rui Zhao; Jinbo Sun; Wei Qin

    2015-08-01

    Sleep spindles are significant transient oscillations observed on the electroencephalogram (EEG) in stage 2 of non-rapid eye movement sleep. Deep belief network (DBN) gaining great successes in images and speech is still a novel method to develop sleep spindle detection system. In this paper, crowdsourcing replacing gold standard was applied to generate three different labeled samples and constructed three classes of datasets with a combination of these samples. An F1-score measure was estimated to compare the performance of DBN to other three classifiers on classifying these samples, with the DBN obtaining an result of 92.78%. Then a comparison of two feature extraction methods based on power spectrum density was made on same dataset using DBN. In addition, the DBN trained in dataset was applied to detect sleep spindle from raw EEG recordings and performed a comparable capacity to expert group consensus.

  20. Genome-wide haploinsufficiency screen reveals a novel role for γ-TuSC in spindle organization and genome stability

    PubMed Central

    Choy, John S.; O'Toole, Eileen; Schuster, Breanna M.; Crisp, Matthew J.; Karpova, Tatiana S.; McNally, James G.; Winey, Mark; Gardner, Melissa K.; Basrai, Munira A.

    2013-01-01

    How subunit dosage contributes to the assembly and function of multimeric complexes is an important question with implications in understanding biochemical, evolutionary, and disease mechanisms. Toward identifying pathways that are susceptible to decreased gene dosage, we performed a genome-wide screen for haploinsufficient (HI) genes that guard against genome instability in Saccharomyces cerevisiae. This led to the identification of all three genes (SPC97, SPC98, and TUB4) encoding the evolutionarily conserved γ-tubulin small complex (γ-TuSC), which nucleates microtubule assembly. We found that hemizygous γ-TuSC mutants exhibit higher rates of chromosome loss and increases in anaphase spindle length and elongation velocities. Fluorescence microscopy, fluorescence recovery after photobleaching, electron tomography, and model convolution simulation of spc98/+ mutants revealed improper regulation of interpolar (iMT) and kinetochore (kMT) microtubules in anaphase. The underlying cause is likely due to reduced levels of Tub4, as overexpression of TUB4 suppressed the spindle and chromosome segregation defects in spc98/+ mutants. We propose that γ-TuSC is crucial for balanced assembly between iMTs and kMTs for spindle organization and accurate chromosome segregation. Taken together, the results show how gene dosage studies provide critical insights into the assembly and function of multisubunit complexes that may not be revealed by using traditional studies with haploid gene deletion or conditional alleles. PMID:23825022

  1. Genome-wide haploinsufficiency screen reveals a novel role for γ-TuSC in spindle organization and genome stability.

    PubMed

    Choy, John S; O'Toole, Eileen; Schuster, Breanna M; Crisp, Matthew J; Karpova, Tatiana S; McNally, James G; Winey, Mark; Gardner, Melissa K; Basrai, Munira A

    2013-09-01

    How subunit dosage contributes to the assembly and function of multimeric complexes is an important question with implications in understanding biochemical, evolutionary, and disease mechanisms. Toward identifying pathways that are susceptible to decreased gene dosage, we performed a genome-wide screen for haploinsufficient (HI) genes that guard against genome instability in Saccharomyces cerevisiae. This led to the identification of all three genes (SPC97, SPC98, and TUB4) encoding the evolutionarily conserved γ-tubulin small complex (γ-TuSC), which nucleates microtubule assembly. We found that hemizygous γ-TuSC mutants exhibit higher rates of chromosome loss and increases in anaphase spindle length and elongation velocities. Fluorescence microscopy, fluorescence recovery after photobleaching, electron tomography, and model convolution simulation of spc98/+ mutants revealed improper regulation of interpolar (iMT) and kinetochore (kMT) microtubules in anaphase. The underlying cause is likely due to reduced levels of Tub4, as overexpression of TUB4 suppressed the spindle and chromosome segregation defects in spc98/+ mutants. We propose that γ-TuSC is crucial for balanced assembly between iMTs and kMTs for spindle organization and accurate chromosome segregation. Taken together, the results show how gene dosage studies provide critical insights into the assembly and function of multisubunit complexes that may not be revealed by using traditional studies with haploid gene deletion or conditional alleles.

  2. The Making of SPINdle

    NASA Astrophysics Data System (ADS)

    Lam, Ho-Pun; Governatori, Guido

    We present the design and implementation of SPINdle - an open source Java based defeasible logic reasoner capable to perform efficient and scalable reasoning on defeasible logic theories (including theories with over 1 million rules). The implementation covers both the standard and modal extensions to defeasible logics. It can be used as a standalone theory prover and can be embedded into any applications as a defeasible logic rule engine. It allows users or agents to issues queries, on a given knowledge base or a theory generated on the fly by other applications, and automatically produces the conclusions of its consequences. The theory can also be represented using XML.

  3. The Kinesin-Related Protein, Hset, Opposes the Activity of Eg5 and Cross-Links Microtubules in the Mammalian Mitotic Spindle

    PubMed Central

    Mountain, Vicki; Simerly, Calvin; Howard, Louisa; Ando, Asako; Schatten, Gerald; Compton, Duane A.

    1999-01-01

    We have prepared antibodies specific for HSET, the human homologue of the KAR3 family of minus end-directed motors. Immuno-EM with these antibodies indicates that HSET frequently localizes between microtubules within the mammalian metaphase spindle consistent with a microtubule cross-linking function. Microinjection experiments show that HSET activity is essential for meiotic spindle organization in murine oocytes and taxol-induced aster assembly in cultured cells. However, inhibition of HSET did not affect mitotic spindle architecture or function in cultured cells, indicating that centrosomes mask the role of HSET during mitosis. We also show that (acentrosomal) microtubule asters fail to assemble in vitro without HSET activity, but simultaneous inhibition of HSET and Eg5, a plus end-directed motor, redresses the balance of forces acting on microtubules and restores aster organization. In vivo, centrosomes fail to separate and monopolar spindles assemble without Eg5 activity. Simultaneous inhibition of HSET and Eg5 restores centrosome separation and, in some cases, bipolar spindle formation. Thus, through microtubule cross-linking and oppositely oriented motor activity, HSET and Eg5 participate in spindle assembly and promote spindle bipolarity, although the activity of HSET is not essential for spindle assembly and function in cultured cells because of centrosomes. PMID:10525540

  4. Germline-Specific MATH-BTB Substrate Adaptor MAB1 Regulates Spindle Length and Nuclei Identity in Maize[W

    PubMed Central

    Juranić, Martina; Srilunchang, Kanok-orn; Krohn, Nádia Graciele; Leljak-Levanić, Dunja; Sprunck, Stefanie; Dresselhaus, Thomas

    2012-01-01

    Germline and early embryo development constitute ideal model systems to study the establishment of polarity, cell identity, and asymmetric cell divisions (ACDs) in plants. We describe here the function of the MATH-BTB domain protein MAB1 that is exclusively expressed in the germ lineages and the zygote of maize (Zea mays). mab1 (RNA interference [RNAi]) mutant plants display chromosome segregation defects and short spindles during meiosis that cause insufficient separation and migration of nuclei. After the meiosis-to-mitosis transition, two attached nuclei of similar identity are formed in mab1 (RNAi) mutants leading to an arrest of further germline development. Transient expression studies of MAB1 in tobacco (Nicotiana tabacum) Bright Yellow-2 cells revealed a cell cycle–dependent nuclear localization pattern but no direct colocalization with the spindle apparatus. MAB1 is able to form homodimers and interacts with the E3 ubiquitin ligase component Cullin 3a (CUL3a) in the cytoplasm, likely as a substrate-specific adapter protein. The microtubule-severing subunit p60 of katanin was identified as a candidate substrate for MAB1, suggesting that MAB1 resembles the animal key ACD regulator Maternal Effect Lethal 26 (MEL-26). In summary, our findings provide further evidence for the importance of posttranslational regulation for asymmetric divisions and germline progression in plants and identified an unstable key protein that seems to be involved in regulating the stability of a spindle apparatus regulator(s). PMID:23250449

  5. A THERMODYNAMIC ANALYSIS OF MITOTIC SPINDLE EQUILIBRIUM AT ACTIVE METAPHASE

    PubMed Central

    Stephens, R. E.

    1973-01-01

    The mitotic apparatus of first-division metaphase eggs of the sea urchin Strongylocentrotus drobachiensis was observed by means of polarization microscopy under controlled temperature conditions. Eggs were fertilized and grown at two temperature extremes in order to produce two different sizes of available spindle pool. Slow division time allowed successive samples of such cells to be observed at the same point in metaphase but at different equilibrium temperatures, yielding curves of metaphase equilibrium birefringence vs. observational temperature. Using the plateau value of birefringence at higher temperatures as a measure of total available spindle pool and the observed birefringence at lower temperatures as a measure of polymerized material at equilibrium, the spindle protein association was evaluated according to the method of Inoué. Both pool conditions produced linear van't Hoff functions. Analysis of these functions yielded enthalpy and entropy changes of +55–65 kcal/mol and +197–233 entropy units (eu), respectively. These values for active mitotic metaphase are quite comparable to those obtained by Inoué and co-workers for arrested meiotic metaphase cells. When other equilibrium treatments were considered, the best fit to the experimental data was still that of Inoué, a treatment which theoretically involves first-order polymerization and dissociation kinetics. Treatment of metaphase cells with D2O by direct immersion drove the equilibrium to completion regardless of temperature, attaining or exceeding a birefringence value equal to the cell's characteristic pool size; perfusion with D2O appeared to erase the original temperature-determined pool size differences for the two growth conditions, attaining a maximum value characteristic of the larger pool condition. These data confirm Inoué's earlier contention that D2O treatment can modify the available spindle pool. PMID:4734864

  6. Perinatal findings of Seckel syndrome: a case report of a fetus showing primordial dwarfism and severe microcephaly.

    PubMed

    Takikawa, Keiko Miyachi; Kikuchi, Akihiko; Yokoyama, Akiko; Ono, Kyoko; Iwasawa, Yuki; Sunagawa, Sorahiro; Takagi, Kimiyo; Kawame, Hiroshi; Nakamura, Tomohiko

    2008-01-01

    Seckel syndrome is a rare form of primordial dwarfism and most of the previous reports have been limited to postnatal findings. We report on a fetus showing severe microcephaly, intrauterine growth restriction and a few gyri with shallow sulci on the fetal brain suggesting cortical dysplasia, followed by ultrasound and magnetic resonance imaging in the prenatal period. Cardiotocograph revealed a reassuring fetal status throughout the whole pregnancy period. A male infant weighing 1,556 g was delivered at 39 weeks' gestation, and a diagnosis of Seckel syndrome was made based on postnatal typical findings. Although previous reports on prenatal findings of Seckel syndrome are quite limited, we think that our case presents typical features of a fetus affected by this syndrome. When prenatal ultrasound shows severe microcephaly and intrauterine growth restriction, this rare syndrome should be included in the differential diagnosis. Moreover, magnetic resonance imaging of the affected fetal brain provides further diagnostic clues. Copyright 2008 S. Karger AG, Basel.

  7. Identified Cellular Correlates of Neocortical Ripple and High-Gamma Oscillations during Spindles of Natural Sleep.

    PubMed

    Averkin, Robert G; Szemenyei, Viktor; Bordé, Sándor; Tamás, Gábor

    2016-11-23

    Ultra-high-frequency network events in the hippocampus are instrumental in a dialogue with the neocortex during memory formation, but the existence of transient ∼200 Hz network events in the neocortex is not clear. Our recordings from neocortical layer II/III of freely behaving rats revealed field potential events at ripple and high-gamma frequencies repeatedly occurring at troughs of spindle oscillations during sleep. Juxtacellular recordings identified subpopulations of fast-spiking, parvalbumin-containing basket cells with epochs of firing at ripple (∼200 Hz) and high-gamma (∼120 Hz) frequencies detected during spindles and centered with millisecond precision at the trough of spindle waves in phase with field potential events but phase shifted relative to pyramidal cell firing. The results suggest that basket cell subpopulations are involved in spindle-nested, high-frequency network events that hypothetically provide repeatedly occurring neocortical temporal reference states potentially involved in mnemonic processes. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Activin Decoy Receptor ActRIIB:Fc Lowers FSH and Therapeutically Restores Oocyte Yield, Prevents Oocyte Chromosome Misalignments and Spindle Aberrations, and Increases Fertility in Midlife Female SAMP8 Mice.

    PubMed

    Bernstein, Lori R; Mackenzie, Amelia C L; Lee, Se-Jin; Chaffin, Charles L; Merchenthaler, István

    2016-03-01

    Women of advanced maternal age (AMA) (age ≥ 35) have increased rates of infertility, miscarriages, and trisomic pregnancies. Collectively these conditions are called "egg infertility." A root cause of egg infertility is increased rates of oocyte aneuploidy with age. AMA women often have elevated endogenous FSH. Female senescence-accelerated mouse-prone-8 (SAMP8) has increased rates of oocyte spindle aberrations, diminished fertility, and rising endogenous FSH with age. We hypothesize that elevated FSH during the oocyte's FSH-responsive growth period is a cause of abnormalities in the meiotic spindle. We report that eggs from SAMP8 mice treated with equine chorionic gonadotropin (eCG) for the period of oocyte growth have increased chromosome and spindle misalignments. Activin is a molecule that raises FSH, and ActRIIB:Fc is an activin decoy receptor that binds and sequesters activin. We report that ActRIIB:Fc treatment of midlife SAMP8 mice for the duration of oocyte growth lowers FSH, prevents egg chromosome and spindle misalignments, and increases litter sizes. AMA patients can also have poor responsiveness to FSH stimulation. We report that although eCG lowers yields of viable oocytes, ActRIIB:Fc increases yields of viable oocytes. ActRIIB:Fc and eCG cotreatment markedly reduces yields of viable oocytes. These data are consistent with the hypothesis that elevated FSH contributes to egg aneuploidy, declining fertility, and poor ovarian response and that ActRIIB:Fc can prevent egg aneuploidy, increase fertility, and improve ovarian response. Future studies will continue to examine whether ActRIIB:Fc works via FSH and/or other pathways and whether ActRIIB:Fc can prevent aneuploidy, increase fertility, and improve stimulation responsiveness in AMA women.

  9. Prader-Willi-like phenotypes: a systematic review of their chromosomal abnormalities.

    PubMed

    Rocha, C F; Paiva, C L A

    2014-03-31

    Prader-Willi syndrome (PWS) is caused by the lack of expression of genes located on paternal chromosome 15q11-q13. This lack of gene expression may be due to a deletion in this chromosomal segment, to maternal uniparental disomy of chromosome 15, or to a defect in the imprinting center on 15q11-q13. PWS is characterized by hypotonia during the neonatal stage and in childhood, accompanied by a delay in neuropsychomotor development. Overeating, obesity, and mental deficiency arise later on. The syndrome has a clinical overlap with other diseases, which makes it difficult to accurately diagnose. The purpose of this article is to review the Prader-Willi-like phenotype in the scientific literature from 2000 to 2013, i.e., to review the cases of PWS caused by chromosomal abnormalities different from those found on chromosome 15. A search was carried out using the "National Center for Biotechnology Information" (www.pubmed.com) and "Scientific Electronic Library Online (www.scielo.br) databases and combinations of key words such as "Prader-Willi-like phenotype" and "Prader-Willi syndrome phenotype". Editorials, letters, reviews, and guidelines were excluded. Articles chosen contained descriptions of patients diagnosed with the PWS phenotype but who were negative for alterations on 15q11-q13. Our search found 643 articles about PWS, but only 14 of these matched with the Prader-Willi-like phenotype and with the selected years of publication (2000-2013). If two or more articles reported the same chromosomal alterations for Prader-Willi-like phenotype, the most recent was chosen. Twelve articles of 14 were case reports and 2 reported series of cases.

  10. Flies without centrioles.

    PubMed

    Basto, Renata; Lau, Joyce; Vinogradova, Tatiana; Gardiol, Alejandra; Woods, C Geoffrey; Khodjakov, Alexey; Raff, Jordan W

    2006-06-30

    Centrioles and centrosomes have an important role in animal cell organization, but it is uncertain to what extent they are essential for animal development. The Drosophila protein DSas-4 is related to the human microcephaly protein CenpJ and the C. elegans centriolar protein Sas-4. We show that DSas-4 is essential for centriole replication in flies. DSas-4 mutants start to lose centrioles during embryonic development, and, by third-instar larval stages, no centrioles or centrosomes are detectable. Mitotic spindle assembly is slow in mutant cells, and approximately 30% of the asymmetric divisions of larval neuroblasts are abnormal. Nevertheless, mutant flies develop with near normal timing into morphologically normal adults. These flies, however, have no cilia or flagella and die shortly after birth because their sensory neurons lack cilia. Thus, centrioles are essential for the formation of centrosomes, cilia, and flagella, but, remarkably, they are not essential for most aspects of Drosophila development.

  11. Chloroquine, a FDA-approved Drug, Prevents Zika Virus Infection and its Associated Congenital Microcephaly in Mice.

    PubMed

    Li, Chunfeng; Zhu, Xingliang; Ji, Xue; Quanquin, Natalie; Deng, Yong-Qiang; Tian, Min; Aliyari, Roghiyh; Zuo, Xiangyang; Yuan, Ling; Afridi, Shabbir Khan; Li, Xiao-Feng; Jung, Jae U; Nielsen-Saines, Karin; Qin, Frank Xiao-Feng; Qin, Cheng-Feng; Xu, Zhiheng; Cheng, Genhong

    2017-10-01

    Zika virus (ZIKV) has become a global public health emergency due to its rapidly expanding range and its ability to cause severe congenital defects such as microcephaly. However, there are no FDA-approved therapies or vaccines against ZIKV infection. Through our screening of viral entry inhibitors, we found that chloroquine (CQ), a commonly used antimalarial and a FDA-approved drug that has also been repurposed against other pathogens, could significantly inhibit ZIKV infection in vitro, by blocking virus internalization. We also demonstrated that CQ attenuates ZIKV-associated morbidity and mortality in mice. Finally, we proved that CQ protects fetal mice from microcephaly caused by ZIKV infection. Our methodology of focusing on previously identified antivirals in screens for effectiveness against ZIKV proved to be a rapid and efficient means of discovering new ZIKV therapeutics. Selecting drugs that were previously FDA-approved, such as CQ, also improves the likelihood that they may more quickly reach stages of clinical testing and use by the public. Copyright © 2017. Published by Elsevier B.V.

  12. Regional Slow Waves and Spindles in Human Sleep

    PubMed Central

    Nir, Yuval; Staba, Richard J.; Andrillon, Thomas; Vyazovskiy, Vladyslav V.; Cirelli, Chiara; Fried, Itzhak; Tononi, Giulio

    2011-01-01

    SUMMARY The most prominent EEG events in sleep are slow waves, reflecting a slow (<1 Hz) oscillation between up and down states in cortical neurons. It is unknown whether slow oscillations are synchronous across the majority or the minority of brain regions—are they a global or local phenomenon? To examine this, we recorded simultaneously scalp EEG, intracerebral EEG, and unit firing in multiple brain regions of neurosurgical patients. We find that most sleep slow waves and the underlying active and inactive neuronal states occur locally. Thus, especially in late sleep, some regions can be active while others are silent. We also find that slow waves can propagate, usually from medial prefrontal cortex to the medial temporal lobe and hippocampus. Sleep spindles, the other hallmark of NREM sleep EEG, are likewise predominantly local. Thus, intracerebral communication during sleep is constrained because slow and spindle oscillations often occur out-of-phase in different brain regions. PMID:21482364

  13. Haploinsufficiency of a Spliceosomal GTPase Encoded by EFTUD2 Causes Mandibulofacial Dysostosis with Microcephaly

    PubMed Central

    Lines, Matthew A.; Huang, Lijia; Schwartzentruber, Jeremy; Douglas, Stuart L.; Lynch, Danielle C.; Beaulieu, Chandree; Guion-Almeida, Maria Leine; Zechi-Ceide, Roseli Maria; Gener, Blanca; Gillessen-Kaesbach, Gabriele; Nava, Caroline; Baujat, Geneviève; Horn, Denise; Kini, Usha; Caliebe, Almuth; Alanay, Yasemin; Utine, Gulen Eda; Lev, Dorit; Kohlhase, Jürgen; Grix, Arthur W.; Lohmann, Dietmar R.; Hehr, Ute; Böhm, Detlef; Majewski, Jacek; Bulman, Dennis E.; Wieczorek, Dagmar; Boycott, Kym M.

    2012-01-01

    Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EFTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the first multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome. PMID:22305528

  14. Mutations in the evolutionarily highly conserved KEOPS complex genes cause nephrotic syndrome with microcephaly

    PubMed Central

    Braun, Daniela A.; Rao, Jia; Mollet, Geraldine; Schapiro, David; Daugeron, Marie-Claire; Tan, Weizhen; Gribouval, Olivier; Boyer, Olivia; Revy, Patrick; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Lawson, Jennifer A.; Schanze, Denny; Ashraf, Shazia; Boddaert, Nathalie; Collinet, Bruno; Martin, Gaëlle; Liger, Dominique; Lovric, Svjetlana; Furlano, Monica; Guerrera, I. Chiara; Sanchez-Ferras, Oraly; Menten, Björn; Vergult, Sarah; De Rocker, Nina; Airik, Merlin; Hermle, Tobias; Shril, Shirlee; Widmeier, Eugen; Gee, Heon Yung; Choi, Won-Il; Sadowski, Carolin E.; Pabst, Werner L.; Warejko, Jillian; Daga, Ankana; LeBerre, Tamara Basta; Matejas, Verena; Behnam, Babak; Beeson, Brendan; Begtrup, Amber; Bruce, Malcolm; Ch'ng, Gaik-Siew; Lin, Shuan-Pei; Chang, Jui-Hsing; Chen, Chao-Huei; Cho, Megan T.; Gipson, Patrick E.; Hsu, Chyong-Hsin; Kari, Jameela A.; Ke, Yu-Yuan; Kiraly-Borri, Cathy; Lai, Wai-ming; Lemyre, Emmanuelle; Littlejohn, Rebecca Okasha; Masri, Amira; Moghtaderi, Mastaneh; Nakamura, Kazuyuki; Praet, Marleen; Prasad, Chitra; Prytula, Agnieszka; Roeder, Elizabeth; Rump, Patrick; Schnur, Rhonda E.; Shiihara, Takashi; Sinha, Manish; Soliman, Neveen A; Soulami, Kenza; Sweetser, David A.; Tsai, Wen-Hui; Tsai, Jeng-Daw; Vester, Udo; Viskochil, David H.; Vatanavicharn, Nithiwat; Waxler, Jessica L.; Wolf, Matthias T.F.; Wong, Sik-Nin; Poduri, Annapurna; Truglio, Gessica; Mane, Shrikant; Lifton, Richard P.; Bouchard, Maxime; Kannu, Peter; Chitayat, David; Magen, Daniella; Calleweart, Bert; van Tilbeurgh, Herman; Zenker, Martin; Antignac, Corinne; Hildebrandt, Friedhelm

    2018-01-01

    Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in zebrafish and mice recapitulates the human phenotype of microcephaly and results in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibits cell proliferation, which human mutations fail to rescue, and knockdown of either gene activates DNA damage response signaling and induces apoptosis. OSGEP and TP53RK molecularly interact and co-localize with the actin-regulating ARP2/3 complex. Furthermore, knockdown of OSGEP and TP53RK induces defects of the actin cytoskeleton and reduces migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identify 4 novel monogenic causes of GAMOS, describe the first link between KEOPS function and human disease, and delineate potential pathogenic mechanisms. PMID:28805828

  15. Acute effect of carbamazepine on corticothalamic 5-9-Hz and thalamocortical spindle (10-16-Hz) oscillations in the rat.

    PubMed

    Zheng, Thomas W; O'Brien, Terence J; Kulikova, Sofya P; Reid, Christopher A; Morris, Margaret J; Pinault, Didier

    2014-03-01

    A major side effect of carbamazepine (CBZ), a drug used to treat neurological and neuropsychiatric disorders, is drowsiness, a state characterized by increased slow-wave oscillations with the emergence of sleep spindles in the electroencephalogram (EEG). We conducted cortical EEG and thalamic cellular recordings in freely moving or lightly anesthetized rats to explore the impact of CBZ within the intact corticothalamic (CT)-thalamocortical (TC) network, more specifically on CT 5-9-Hz and TC spindle (10-16-Hz) oscillations. Two to three successive 5-9-Hz waves were followed by a spindle in the cortical EEG. A single systemic injection of CBZ (20 mg/kg) induced a significant increase in the power of EEG 5-9-Hz oscillations and spindles. Intracellular recordings of glutamatergic TC neurons revealed 5-9-Hz depolarizing wave-hyperpolarizing wave sequences prolonged by robust, rhythmic spindle-frequency hyperpolarizing waves. This hybrid sequence occurred during a slow hyperpolarizing trough, and was at least 10 times more frequent under the CBZ condition than under the control condition. The hyperpolarizing waves reversed at approximately -70 mV, and became depolarizing when recorded with KCl-filled intracellular micropipettes, indicating that they were GABAA receptor-mediated potentials. In neurons of the GABAergic thalamic reticular nucleus, the principal source of TC GABAergic inputs, CBZ augmented both the number and the duration of sequences of rhythmic spindle-frequency bursts of action potentials. This indicates that these GABAergic neurons are responsible for the generation of at least the spindle-frequency hyperpolarizing waves in TC neurons. In conclusion, CBZ potentiates GABAA receptor-mediated TC spindle oscillations. Furthermore, we propose that CT 5-9-Hz waves can trigger TC spindles. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  16. CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination.

    PubMed

    Marjanović, Marko; Sánchez-Huertas, Carlos; Terré, Berta; Gómez, Rocío; Scheel, Jan Frederik; Pacheco, Sarai; Knobel, Philip A; Martínez-Marchal, Ana; Aivio, Suvi; Palenzuela, Lluís; Wolfrum, Uwe; McKinnon, Peter J; Suja, José A; Roig, Ignasi; Costanzo, Vincenzo; Lüders, Jens; Stracker, Travis H

    2015-07-09

    CEP63 is a centrosomal protein that facilitates centriole duplication and is regulated by the DNA damage response. Mutations in CEP63 cause Seckel syndrome, a human disease characterized by microcephaly and dwarfism. Here we demonstrate that Cep63-deficient mice recapitulate Seckel syndrome pathology. The attrition of neural progenitor cells involves p53-dependent cell death, and brain size is rescued by the deletion of p53. Cell death is not the result of an aberrant DNA damage response but is triggered by centrosome-based mitotic errors. In addition, Cep63 loss severely impairs meiotic recombination, leading to profound male infertility. Cep63-deficient spermatocytes display numerical and structural centrosome aberrations, chromosome entanglements and defective telomere clustering, suggesting that a reduction in centrosome-mediated chromosome movements underlies recombination failure. Our results provide novel insight into the molecular pathology of microcephaly and establish a role for the centrosome in meiotic recombination.

  17. The C. elegans RSA complex localizes protein phosphatase 2A to centrosomes and regulates mitotic spindle assembly.

    PubMed

    Schlaitz, Anne-Lore; Srayko, Martin; Dammermann, Alexander; Quintin, Sophie; Wielsch, Natalie; MacLeod, Ian; de Robillard, Quentin; Zinke, Andrea; Yates, John R; Müller-Reichert, Thomas; Shevchenko, Andrei; Oegema, Karen; Hyman, Anthony A

    2007-01-12

    Microtubule behavior changes during the cell cycle and during spindle assembly. However, it remains unclear how these changes are regulated and coordinated. We describe a complex that targets the Protein Phosphatase 2A holoenzyme (PP2A) to centrosomes in C. elegans embryos. This complex includes Regulator of Spindle Assembly 1 (RSA-1), a targeting subunit for PP2A, and RSA-2, a protein that binds and recruits RSA-1 to centrosomes. In contrast to the multiple functions of the PP2A catalytic subunit, RSA-1 and RSA-2 are specifically required for microtubule outgrowth from centrosomes and for spindle assembly. The centrosomally localized RSA-PP2A complex mediates these functions in part by regulating two critical mitotic effectors: the microtubule destabilizer KLP-7 and the C. elegans regulator of spindle assembly TPXL-1. By regulating a subset of PP2A functions at the centrosome, the RSA complex could therefore provide a means of coordinating microtubule outgrowth from centrosomes and kinetochore microtubule stability during mitotic spindle assembly.

  18. Contractile Ring-independent Localization of DdINCENP, a Protein Important for Spindle Stability and CytokinesisD⃞V⃞

    PubMed Central

    Chen, Qian; Li, Hui; De Lozanne, Arturo

    2006-01-01

    Dictyostelium DdINCENP is a chromosomal passenger protein associated with centromeres, the spindle midzone, and poles during mitosis and the cleavage furrow during cytokinesis. Disruption of the single DdINCENP gene revealed important roles for this protein in mitosis and cytokinesis. DdINCENP null cells lack a robust spindle midzone and are hypersensitive to microtubule-depolymerizing drugs, suggesting that their spindles may not be stable. Furthermore DdCP224, a protein homologous to the microtubule-stabilizing protein TOGp/XMAP215, was absent from the spindle midzone of DdINCENP null cells. Overexpression of DdCP224 rescued the weak spindle midzone defect of DdINCENP null cells. Although not required for the localization of the myosin II contractile ring and subsequent formation of a cleavage furrow, DdINCENP is important for the abscission of daughter cells at the end of cytokinesis. Finally, we show that the localization of DdINCENP at the cleavage furrow is modulated by myosin II but it occurs by a mechanism different from that controlling the formation of the contractile ring. PMID:16339076

  19. Effect of spinal manipulation on the development of history-dependent responsiveness of lumbar paraspinal muscle spindles in the cat

    PubMed Central

    Cao, Dong-Yuan; Pickar, Joel G.

    2014-01-01

    We determined whether spinal manipulation could prevent and/or reverse the decrease and increase in paraspinal muscle spindle responsiveness caused respectively by lengthening and shortening histories of the lumbar muscles. Single unit spindle activity from multifidus and longissimus muscles was recorded in the L6 dorsal root in anesthetized cats. Muscle history was created and spinal manipulation delivered (thrust amplitude: 1.0mm, duration: 100ms) using a feedback-controlled motor attached to the L6 spinous process. Muscle spindle discharge to a fixed vertebral position (static test) and to vertebral movement (dynamic test) was evaluated following the lengthening and shortening histories. For the static test, changes in muscle spindle responsiveness were significantly less when spinal manipulation followed muscle history (p<0.01), but not when spinal manipulation preceded it (p>0.05). For the dynamic test, spinal manipulation did not significantly affect the history-induced change in muscle spindle responsiveness. Spinal manipulation may partially reverse the effects of muscle history on muscle spindle signaling of vertebral position. PMID:24932019

  20. Dynamic maintenance of asymmetric meiotic spindle position through Arp2/3 complex-driven cytoplasmic streaming in mouse oocytes

    PubMed Central

    Yi, Kexi; Unruh, Jay R.; Deng, Manqi; Slaughter, Brian D.; Rubinstein, Boris; Li, Rong

    2012-01-01

    Mature mammalian oocytes are poised for the completion of second polar body extrusion upon fertilization by positioning the metaphase spindle in close proximity to an actomyosin-rich cortical cap. Loss of this spindle position asymmetry is often associated with poor oocyte quality and infertility 1–3. Here, we report a novel role for the Arp2/3 actin nucleation complex in the maintenance of asymmetric spindle position in mature mouse oocytes. The Arp2/3 complex localizes to the cortical cap in a Ran GTPase-dependent manner and accounts for the nucleation of the majority of actin filaments in both the cortical cap and a cytoplasmic actin network. Inhibition of Arp2/3 complex activity or localization leads to rapid dissociation of the spindle from the cortex. High resolution live imaging and spatiotemporal image correlation spectroscopy (STICS) analysis reveal that in normal oocytes actin filaments flow continuously away from the Arp2/3-rich cortex, generating a cytoplamic streaming that results in a net pushing force on the spindle toward the actomyosin cap. Arp2/3 inhibition not only diminishes this actin flow and cytoplamic streaming but also enables a reverse streaming driven by myosin-II-based cortical contraction, leading to spindle movement away from the cortex. We conclude that the Arp2/3 complex maintains asymmetric meiotic spindle position by generating an actin polymerization-driven cytoplamic streaming and by suppressing a counteracting force from myosin-II-based contractility. PMID:21874009

  1. Spindle disturbances in human-hamster hybrid (AL) cells induced by mobile communication frequency range signals.

    PubMed

    Schrader, Thorsten; Münter, Klaus; Kleine-Ostmann, Thomas; Schmid, Ernst

    2008-12-01

    The production of spindle disturbances in FC2 cells, a human-hamster hybrid (A(L)) cell line, by non-ionizing radiation was studied using an electromagnetic field with a field strength of 90 V/m at a frequency of 835 MHz. Due to the given experimental conditions slide flask cultures were exposed at room temperature in a microTEM (transversal electromagnetic field) cell, which allows optimal experimental conditions for small samples of biological material. Numerical calculations suggest that specific absorption rates of up to 60 mW/kg are reached for maximum field exposure. All exposure field parameters--either measured or calculable--are precisely defined and, for the first time, traceable to the standards of the SI system of physical units. Compared with co-incident negative controls, the results of two independently performed experiments suggest that exposure periods of time from 0.5 to 2 h with an electric field strength of 90 V/m are spindle acting agents as predominately indicated by the appearance of spindle disturbances at the ana- and telophase stages (especially lagging and non-disjunction of single chromosomes) of cell divisions. The spindle disturbances do not change the fraction of mitotic cells with increasing exposure time up to 2 h. Due to the applied experimental conditions an influence of temperature as a confounder parameter for spindle disturbances can be excluded.

  2. SPINDLE: A 2-Stage Nuclear-Powered Cryobot for Ocean World Exploration

    NASA Astrophysics Data System (ADS)

    Stone, W.; Hogan, B.; Siegel, V. L.; Howe, T.; Howe, S.; Harman, J.; Richmond, K.; Flesher, C.; Clark, E.; Lelievre, S.; Moor, J.; Rothhammer, B.

    2016-12-01

    SPINDLE (Sub-glacial Polar Ice Navigation, Descent, and Lake Exploration) is a 2-stage autonomous vehicle system consisting of a robotic ice-penetrating carrier vehicle (cryobot) and a marsupial, hovering autonomous underwater vehicle (HAUV). The cryobot will descend through an ice body into a sub-ice aqueous environment and deploy the HAUV to conduct long range reconnaissance, life search, and sample collection. The HAUV will return to, and auto-dock with, the cryobot at the conclusion of the mission for subsequent data uplink and sample return to the surface. The SPINDLE cryobot has been currently designed for a 1.5 kilometer penetration through a terrestrial ice sheet and the HAUV has been designed for persistent exploration and science presence in for deployments up to a kilometer radius from the cryobot. Importantly, the cryobot is bi-directional and vertically controllable both in an ice sheet as well as following breakthrough into a subglacial water cavity / ocean. The vehicle has been designed for long-duration persistent science in subglacial cavities and to allow for subsequent return-to-surface at a much later date or subsequent season. Engineering designs for the current SPINDLE cryobot will be presented in addition to current designs for autonomous rendezvous, docking, and storing of the HAUV system into the cryobot for subsequent recovery of the entire system to the surface. Taken to completion in a three-phase program, SPINDLE will deliver an integrated and field-tested system that will be directly transferable into a Flagship-class mission to either the hypothesized shallow lakes of Europa, the sub-surface ocean of Ganymede, or the geyser/plume sources on both Europa and Enceladus. We present the results of several parallel laboratory investigations into advanced power transmission systems (laser, high voltage) as well as onboard systems that enable the SPINDLE vehicle to access any subglacial lake on earth while using non-nuclear surrogate, surface

  3. Casein kinase II is required for the spindle assembly checkpoint by regulating Mad2p in fission yeast

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shimada, Midori; Yamamoto, Ayumu; Murakami-Tonami, Yuko

    2009-10-23

    The spindle checkpoint is a surveillance mechanism that ensures the fidelity of chromosome segregation in mitosis. Here we show that fission yeast casein kinase II (CK2) is required for this checkpoint function. In the CK2 mutants mitosis occurs in the presence of a spindle defect, and the spindle checkpoint protein Mad2p fails to localize to unattached kinetochores. The CK2 mutants are sensitive to the microtubule depolymerising drug thiabendazole, which is counteracted by ectopic expression of mad2{sup +}. The level of Mad2p is low in the CK2 mutants. These results suggest that CK2 has a role in the spindle checkpoint bymore » regulating Mad2p.« less

  4. The human Ino80 binds to microtubule via the E-hook of tubulin: Implications for the role in spindle assembly

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Park, Eun-Jung; Hur, Shin-Kyoung; Lee, Han-Sae

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer The N-terminal domain of hIno80 is important for binding to the spindle. Black-Right-Pointing-Pointer The hIno80 N-terminal domain binds to tubulin and microtubule in vitro. Black-Right-Pointing-Pointer The E-hook of tubulin is critical for hIno80 binding to tubulin and microtubule. Black-Right-Pointing-Pointer Tip49a does not bind to microtubule and dispensable for spindle formation. -- Abstract: The human INO80 chromatin remodeling complex, comprising the Ino80 ATPase (hIno80) and the associated proteins such as Tip49a, has been implicated in a variety of nuclear processes other than transcription. We previously have found that hIno80 interacts with tubulin and co-localizes with the mitotic spindle andmore » is required for spindle formation. To better understand the role of hIno80 in spindle formation, we further investigated the interaction between hIno80 and microtubule. Here, we show that the N-terminal domain, dispensable for the nucleosome remodeling activity, is important for hIno80 to interact with tubulin and co-localize with the spindle. The hIno80 N-terminal domain binds to monomeric tubulin and polymerized microtubule in vitro, and the E-hook of tubulin, involved in the polymerization of microtubule, is critical for this binding. Tip49a, which has been reported to associate with the spindle, does not bind to microtubule in vitro and dispensable for spindle formation in vivo. These results suggest that hIno80 can play a direct role in the spindle assembly independent of its chromatin remodeling activity.« less

  5. Properties of the spindle-to-cusp transition in extensional capsule dynamics

    NASA Astrophysics Data System (ADS)

    Dodson, W. R., III; Dimitrakopoulos, P.

    2014-05-01

    Our earlier letter (Dodson W. R. III and Dimitrakopoulos P., Phys. Rev. Lett., 101 (2008) 208102) revealed that a (strain-hardening) Skalak capsule in a planar extensional Stokes flow develops for stability reasons steady-state shapes whose edges from spindled become cusped with increasing flow rate owing to a transition of the edge tensions from tensile to compressive. A bifurcation in the steady-state shapes was also found (i.e. existence of both spindled and cusped edges for a range of high flow rates) by implementing different transient processes, owing to the different evolution of the membrane tensions. In this paper we show that the bifurcation range is wider at higher viscosity ratio (owing to the lower transient membrane tensions accompanied the slower capsule deformation starting from the quiescent capsule shape), while it contracts and eventually disappears as the viscosity ratio decreases. The spindle-to-cusp transition is shown to represent a self-similar finite-time singularity formation which for real capsules with very small but finite thickness is expected to be an apparent singularity, i.e. formation of very large (but finite) positive and negative edge curvatures.

  6. 5-Mehtyltetrahydrofolate rescues alcohol-induced neural crest cell migration abnormalities.

    PubMed

    Shi, Yu; Li, Jiejing; Chen, Chunjiang; Gong, Manzi; Chen, Yuan; Liu, Youxue; Chen, Jie; Li, Tingyu; Song, Weihong

    2014-09-16

    Alcohol is detrimental to early development. Fetal alcohol spectrum disorders (FASD) due to maternal alcohol abuse results in a series of developmental abnormalities including cranial facial dysmorphology, ocular anomalies, congenital heart defects, microcephaly and intellectual disabilities. Previous studies have been shown that ethanol exposure causes neural crest (NC) apoptosis and perturbation of neural crest migration. However, the underlying mechanism remains elusive. In this report we investigated the fetal effect of alcohol on the process of neural crest development in the Xenopus leavis. Pre-gastrulation exposure of 2-4% alcohol induces apoptosis in Xenopus embryo whereas 1% alcohol specifically impairs neural crest migration without observing discernible apoptosis. Additionally, 1% alcohol treatment considerably increased the phenotype of small head (43.4% ± 4.4%, total embryo n = 234), and 1.5% and 2.0% dramatically augment the deformation to 81.2% ± 6.5% (n = 205) and 91.6% ± 3.0% (n = 235), respectively (P < 0.05). Significant accumulation of Homocysteine was caused by alcohol treatment in embryos and 5-mehtyltetrahydrofolate restores neural crest migration and alleviates homocysteine accumulation, resulting in inhibition of the alcohol-induced neurocristopathies. Our study demonstrates that prenatal alcohol exposure causes neural crest cell migration abnormality and 5-mehtyltetrahydrofolate could be beneficial for treating FASD.

  7. Extreme Mutation Tolerance: Nearly Half of the Archaeal Fusellovirus Sulfolobus Spindle-Shaped Virus 1 Genes Are Not Required for Virus Function, Including the Minor Capsid Protein Gene vp3

    PubMed Central

    Iverson, Eric A.; Goodman, David A.; Gorchels, Madeline E.

    2017-01-01

    ABSTRACT Viruses infecting the Archaea harbor a tremendous amount of genetic diversity. This is especially true for the spindle-shaped viruses of the family Fuselloviridae, where >90% of the viral genes do not have detectable homologs in public databases. This significantly limits our ability to elucidate the role of viral proteins in the infection cycle. To address this, we have developed genetic techniques to study the well-characterized fusellovirus Sulfolobus spindle-shaped virus 1 (SSV1), which infects Sulfolobus solfataricus in volcanic hot springs at 80°C and pH 3. Here, we present a new comparative genome analysis and a thorough genetic analysis of SSV1 using both specific and random mutagenesis and thereby generate mutations in all open reading frames. We demonstrate that almost half of the SSV1 genes are not essential for infectivity, and the requirement for a particular gene correlates well with its degree of conservation within the Fuselloviridae. The major capsid gene vp1 is essential for SSV1 infectivity. However, the universally conserved minor capsid gene vp3 could be deleted without a loss in infectivity and results in virions with abnormal morphology. IMPORTANCE Most of the putative genes in the spindle-shaped archaeal hyperthermophile fuselloviruses have no sequences that are clearly similar to characterized genes. In order to determine which of these SSV genes are important for function, we disrupted all of the putative genes in the prototypical fusellovirus, SSV1. Surprisingly, about half of the genes could be disrupted without destroying virus function. Even deletions of one of the known structural protein genes that is present in all known fuselloviruses, vp3, allows the production of infectious viruses. However, viruses lacking vp3 have abnormal shapes, indicating that the vp3 gene is important for virus structure. Identification of essential genes will allow focused research on minimal SSV genomes and further understanding of the structure

  8. Extreme Mutation Tolerance: Nearly Half of the Archaeal Fusellovirus Sulfolobus Spindle-Shaped Virus 1 Genes Are Not Required for Virus Function, Including the Minor Capsid Protein Gene vp3.

    PubMed

    Iverson, Eric A; Goodman, David A; Gorchels, Madeline E; Stedman, Kenneth M

    2017-05-15

    Viruses infecting the Archaea harbor a tremendous amount of genetic diversity. This is especially true for the spindle-shaped viruses of the family Fuselloviridae , where >90% of the viral genes do not have detectable homologs in public databases. This significantly limits our ability to elucidate the role of viral proteins in the infection cycle. To address this, we have developed genetic techniques to study the well-characterized fusellovirus Sulfolobus spindle-shaped virus 1 (SSV1), which infects Sulfolobus solfataricus in volcanic hot springs at 80°C and pH 3. Here, we present a new comparative genome analysis and a thorough genetic analysis of SSV1 using both specific and random mutagenesis and thereby generate mutations in all open reading frames. We demonstrate that almost half of the SSV1 genes are not essential for infectivity, and the requirement for a particular gene correlates well with its degree of conservation within the Fuselloviridae The major capsid gene vp1 is essential for SSV1 infectivity. However, the universally conserved minor capsid gene vp3 could be deleted without a loss in infectivity and results in virions with abnormal morphology. IMPORTANCE Most of the putative genes in the spindle-shaped archaeal hyperthermophile fuselloviruses have no sequences that are clearly similar to characterized genes. In order to determine which of these SSV genes are important for function, we disrupted all of the putative genes in the prototypical fusellovirus, SSV1. Surprisingly, about half of the genes could be disrupted without destroying virus function. Even deletions of one of the known structural protein genes that is present in all known fuselloviruses, vp3 , allows the production of infectious viruses. However, viruses lacking vp3 have abnormal shapes, indicating that the vp3 gene is important for virus structure. Identification of essential genes will allow focused research on minimal SSV genomes and further understanding of the structure of

  9. TIME COURSE FOR THE DEVELOPMENT OF MUSCLE HISTORY IN LUMBAR PARASPINAL MUSCLE SPINDLES ARISING FROM CHANGES IN VERTEBRAL POSITION

    PubMed Central

    Pickar, Joel G.; Ge, Weiqing

    2008-01-01

    Background Context In neutral spinal postures with low loading moments the lumbar spine is not inherently stable. Small compromises in paraspinal muscle activity may affect lumbar spinal biomechanics. Proprioceptive feedback from muscle spindles is considered important for control of muscle activity. Because skeletal muscle and muscle spindles are thixotropic, their length history changes their physical properties. The present study explores a mechanism that can affect the responsiveness of paraspinal muscle spindles in the lumbar spine. Purpose This study had two aims: to extend our previous findings demonstrating the history dependent effects of vertebral position on the responsiveness of lumbar paraspinal muscle spindles; and to determine the time course for these effects. Based upon previous studies, if a crossbridge mechanism underlies these thixotropic effects, then the relationship between the magnitude of spindle discharge and the duration of the vertebral position will be one of exponential decay or growth. Study Design/Setting A neurophysiological study using the lumbar spine of a feline model. Methods The discharge from individual muscle spindles afferents innervating lumbar paraspinal muscles in response to the duration and direction of vertebral position were obtained from teased filaments in the L6 dorsal roots of 30 Nembutal-anesthetized cats. The L6 vertebra was controlled using a displacement-controlled feedback motor and was held in each of 3 different conditioning positions for durations of 0, 0.5, 1, 1.5, and 2 seconds. Two of the conditioning positions stretched or shortened the lumbar muscles relative to an intermediate conditioning position. Conditioning positions for all cats ranged from 0.9 – 2.0 mm dorsal and ventralward relative to the intermediate position. These magnitudes were determined based upon the displacement that loaded the L6 vertebra to 50–60% of the cat’s body weight. Conditioning was thought to simulate a motion

  10. Transient synchronization of hippocampo-striato-thalamo-cortical networks during sleep spindle oscillations induces motor memory consolidation.

    PubMed

    Boutin, Arnaud; Pinsard, Basile; Boré, Arnaud; Carrier, Julie; Fogel, Stuart M; Doyon, Julien

    2018-04-01

    Sleep benefits motor memory consolidation. This mnemonic process is thought to be mediated by thalamo-cortical spindle activity during NREM-stage2 sleep episodes as well as changes in striatal and hippocampal activity. However, direct experimental evidence supporting the contribution of such sleep-dependent physiological mechanisms to motor memory consolidation in humans is lacking. In the present study, we combined EEG and fMRI sleep recordings following practice of a motor sequence learning (MSL) task to determine whether spindle oscillations support sleep-dependent motor memory consolidation by transiently synchronizing and coordinating specialized cortical and subcortical networks. To that end, we conducted EEG source reconstruction on spindle epochs in both cortical and subcortical regions using novel deep-source localization techniques. Coherence-based metrics were adopted to estimate functional connectivity between cortical and subcortical structures over specific frequency bands. Our findings not only confirm the critical and functional role of NREM-stage2 sleep spindles in motor skill consolidation, but provide first-time evidence that spindle oscillations [11-17 Hz] may be involved in sleep-dependent motor memory consolidation by locally reactivating and functionally binding specific task-relevant cortical and subcortical regions within networks including the hippocampus, putamen, thalamus and motor-related cortical regions. Copyright © 2018 Elsevier Inc. All rights reserved.

  11. Altered Sleep Spindles in Delayed Encephalopathy after Acute Carbon Monoxide Poisoning.

    PubMed

    Yoshiike, Takuya; Nishida, Masaki; Yagishita, Kazuyoshi; Nariai, Tadashi; Ishii, Kenji; Nishikawa, Toru

    2016-06-15

    Delayed encephalopathy (DE) affects not only the cerebral white matter and globus pallidus but also the cortex and thalamus. However, it remains unknown whether these brain lesions alter sleep along with clinical manifestations of DE. A 46-year-old man with DE underwent repetitive hyperbaric oxygen therapy. The patient was evaluated by not only neuropsychological and neuroimaging testing but polysomnography over the clinical course. Neurological symptoms improved markedly; however, profound frontal cognitive deficits continued. The polysomnography revealed prolonged absence and delayed recovery of sleep spindles across recordings. Alterations in spindle oscillations in DE could provide further insight into sleep regulatory networks. © 2016 American Academy of Sleep Medicine.

  12. Thresholds of cortical activation of muscle spindles and α motoneurones of the baboon's hand

    PubMed Central

    Koeze, T. H.; Phillips, C. G.; Sheridan, J. D.

    1968-01-01

    1. Much current thinking about voluntary movement assumes that the segmental γ loops can function as a servomechanism operated by the brain. However, the α motoneurones of the baboon's hand receive a powerful monosynaptic (CM) projection from the precentral gyrus. If servo-driving from the same cortical area is to be possible, it must project independently to the fusimotor neurones and have sufficient power to increase the afferent signalling from the muscle spindles. The cortical thresholds for contraction of m. extensor digitorum communis and for acceleration of the discharges of its muscle spindles have therefore been compared. 2. Significant results in this context require that the spindles studied be coupled in parallel with the responding extrafusal muscle fibres. Many spindles were not unloaded by the submaximal contractions evoked by cortical stimulation, although all so tested were unloaded by maximal motor nerve twitches. Reasons are given for thinking that such apparent lack of parallel coupling is an artifact of complex intramuscular anatomy and limitation of shortening by `isometric' myography. 3. A brief burst of corticospinal volleys at 500/sec, which is specially effective in exciting α motoneurones over the CM projection, failed to excite spindle afferents at or below the threshold for a cortical `twitch'. 4. In a few epileptiform discharges, bursts of spindle acceleration occurred independently of the clonic contractions. A relatively direct and independent cortico-fusimotor (CF) projection may therefore exist. 5. Prolonged near-threshold stimulation at 50-100/sec, which allows time for temporal summation in the less direct projections (e.g. cortico-interneuronal, cortico-rubro-spinal) and does not cause frequency-potentiation at CM synapses, gives abundant evidence of independent α and fusimotor projections, whose actions hardly outlast the stimulation period. 6. Although independent CF projections would permit servo-driving in natural

  13. Expression of Spindle and Kinetochore-Associated Protein 1 Is Associated with Poor Prognosis in Papillary Thyroid Carcinoma

    PubMed Central

    Dong, Chao; Wang, Xiao-li; Ma, Bin-lin

    2015-01-01

    Aim. Spindle and kinetochore-associated protein 1 (SKA1) is one subtype of SKA, whose protein can make spindle microtubules attach steadily to the kinetochore in the middle of mitosis. At present, there are fewer researches on the relationship between SKA1 expression and tumor development. Methods. In this study, immunohistochemical analysis was used to determine the expression of SKA1 in papillary thyroid carcinoma (PTC) and adjacent tissues. We used quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis to further verify the results. Results. We found that SKA1 expression was significantly higher in PTC tissues than normal adjacent tissues (P < 0.05). There existed a significant correlation among a higher SKA1 expression, including lymphoid node (P = 0.005), clinical stage (P = 0.015), and extrathyroid invasion (P = 0.004). Survival analysis showed high SKA1 expression in PTC patients more likely to relapse after surgery. Conclusion. High SKA1 expression is predictive of poor prognosis of PTC, implying that SKA1 may be a promising new target for targeted therapies for PTC. PMID:26063960

  14. A role for the Rab6A′ GTPase in the inactivation of the Mad2-spindle checkpoint

    PubMed Central

    Miserey-Lenkei, Stéphanie; Couëdel-Courteille, Anne; Del Nery, Elaine; Bardin, Sabine; Piel, Matthieu; Racine, Victor; Sibarita, Jean-Baptiste; Perez, Franck; Bornens, Michel; Goud, Bruno

    2006-01-01

    The two isoforms of the Rab6 GTPase, Rab6A and Rab6A′, regulate a retrograde transport route connecting early endosomes and the endoplasmic reticulum via the Golgi complex in interphasic cells. Here we report that when Rab6A′ function is altered cells are unable to progress normally through mitosis. Such cells are blocked in metaphase, despite displaying a normal Golgi fragmentation and with the Mad2-spindle checkpoint activated. Furthermore, the Rab6 effector p150Glued, a subunit of the dynein/dynactin complex, remains associated with some kinetochores. A similar phenotype was observed when GAPCenA, a GTPase-activating protein of Rab6, was depleted from cells. Our results suggest that Rab6A′ likely regulates the dynamics of the dynein/dynactin complex at the kinetochores and consequently the inactivation of the Mad2-spindle checkpoint. Rab6A′, through its interaction with p150Glued and GAPCenA, may thus participate in a pathway involved in the metaphase/anaphase transition. PMID:16395330

  15. Evaluation of micro-organism-detaching efficacy from meat samples by spindle or stomacher treatment and quality analysis of suspensions.

    PubMed

    Kim, S-J; Kim, D-K; Kang, D-H

    2016-04-01

    We investigated and compared the efficacy of a new apparatus for detaching micro-organisms from meat samples. The efficacy of Spindle and stomacher in detaching micro-organisms from meat samples was evaluated. Also, evaluation of appropriateness of suspensions generated by both methods for carrying out molecular biological analysis was implemented. A nearly identical correlation and high R(2) were obtained between Spindle and stomacher in Aerobic Plate Count (APC), and no significant differences were observed in detachment of three major foodborne pathogens. The suspension generated by the Spindle showed lower turbidity and total protein concentration. Also, significantly different threshold cycles were observed in Real-time PCR analysis using suspensions generated by both methods. The Spindle shows nearly identical efficacy with stomacher treatment in detaching micro-organisms from meat samples. Furthermore, the high quality of suspensions generated by the Spindle, in terms of turbidity and total protein assay, allows for a lower threshold cycle than stomached suspension in Real-time PCR. The Spindle could be an alternative method for detaching micro-organisms, yielding a higher quality of suspensions which may be better suited for further molecular microbiological analysis. © 2016 The Society for Applied Microbiology.

  16. CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination

    PubMed Central

    Marjanović, Marko; Sánchez-Huertas, Carlos; Terré, Berta; Gómez, Rocío; Scheel, Jan Frederik; Pacheco, Sarai; Knobel, Philip A.; Martínez-Marchal, Ana; Aivio, Suvi; Palenzuela, Lluís; Wolfrum, Uwe; McKinnon, Peter J.; Suja, José A.; Roig, Ignasi; Costanzo, Vincenzo; Lüders, Jens; Stracker, Travis H.

    2015-01-01

    CEP63 is a centrosomal protein that facilitates centriole duplication and is regulated by the DNA damage response. Mutations in CEP63 cause Seckel syndrome, a human disease characterized by microcephaly and dwarfism. Here we demonstrate that Cep63 deficient mice recapitulate Seckel syndrome pathology. The attrition of neural progenitor cells involves p53-dependent cell death and brain size is rescued by the deletion of p53. Cell death is not the result of an aberrant DNA damage response but is triggered by centrosome-based mitotic errors. In addition, Cep63 loss severely impairs meiotic recombination, leading to profound male infertility. Cep63 deficient spermatocytes display numerical and structural centrosome aberrations, chromosome entanglements and defective telomere clustering, suggesting that a reduction in centrosome-mediated chromosome movements underlies recombination failure. Our results provide novel insight into the molecular pathology of microcephaly and establish a role for the centrosome in meiotic recombination. PMID:26158450

  17. The Effect of Functional Mandibular Shift on the Muscle Spindle Systems in Head-Neck Muscles and the Related Neurotransmitter Histamine.

    PubMed

    Du, Bing-Li; Li, Jiang-Ning; Guo, Hong-Ming; Li, Song; Liu, Biao

    2017-09-01

    The aim of this study is to explore the effects of abnormal occlusion and functional recovery caused by functional mandible deviation on the head and neck muscles and muscle spindle sensory-motor system by electrophysiological response and endogenous monoamine neurotransmitters' distribution in the nucleus of the spinal tract. Seven-week-old male Wistar rats were randomly divided into 7 groups: normal control group, 2W experimental control group, 2W functional mandible deviation group, 2W functional mandible deviation recovery group, 4W experimental control group, 4W functional mandible deviation group, 4W functional mandible deviation recovery group. Chewing muscles, digastric muscle, splenius, and trapezius muscle spindles electrophysiological response activities at the opening and closing state were recorded. And then the chewing muscles, digastric, splenius, trapezius, and neck trigeminal nucleus were taken for histidine decarboxylase (HDC) detection by high performance liquid chromatography (HPLC), immunofluorescence, and reverse-transcription polymerase chain reaction (RT-PCR). Histamine receptor proteins in the neck nucleus of the spinal tract were also examined by immunofluorescence and RT-PCR. Electromyography activity of chewing muscles, digastric, and splenius muscle was significantly asymmetric; the abnormal muscle electromyography activity was mainly detected at the ipsilateral side. After functional mandibular deviation, muscle sensitivity on the ipsilateral sides of the chewing muscle and splenius decreased, muscle excitement weakened, modulation depth decreased, and the muscle spindle afferent impulses of excitation transmission speed slowed down. Changes for digastric muscle electrical activity were contrary. The functions recovered at different extents after removing the deflector. However, trapezius in all the experimental groups and recovery groups exhibited bilateral symmetry electrophysiological responses, and no significant difference

  18. The Development of a Monitoring System Using a Wireless and Powerless Sensing Node Deployed Inside a Spindle

    PubMed Central

    Chang, Liang-Cheng; Lee, Da-Sheng

    2012-01-01

    Installation of a Wireless and Powerless Sensing Node (WPSN) inside a spindle enables the direct transmission of monitoring signals through a metal case of a certain thickness instead of the traditional method of using connecting cables. Thus, the node can be conveniently installed inside motors to measure various operational parameters. This study extends this earlier finding by applying this advantage to the monitoring of spindle systems. After over 2 years of system observation and optimization, the system has been verified to be superior to traditional methods. The innovation of fault diagnosis in this study includes the unmatched assembly dimensions of the spindle system, the unbalanced system, and bearing damage. The results of the experiment demonstrate that the WPSN provides a desirable signal-to-noise ratio (SNR) in all three of the simulated faults, with the difference of SNR reaching a maximum of 8.6 dB. Following multiple repetitions of the three experiment types, 80% of the faults were diagnosed when the spindle revolved at 4,000 rpm, significantly higher than the 30% fault recognition rate of traditional methods. The experimental results of monitoring of the spindle production line indicated that monitoring using the WPSN encounters less interference from noise compared to that of traditional methods. Therefore, this study has successfully developed a prototype concept into a well-developed monitoring system, and the monitoring can be implemented in a spindle production line or real-time monitoring of machine tools. PMID:22368456

  19. The development of a monitoring system using a Wireless and Powerless Sensing Node deployed inside a spindle.

    PubMed

    Chang, Liang-Cheng; Lee, Da-Sheng

    2012-01-01

    Installation of a Wireless and Powerless Sensing Node (WPSN) inside a spindle enables the direct transmission of monitoring signals through a metal case of a certain thickness instead of the traditional method of using connecting cables. Thus, the node can be conveniently installed inside motors to measure various operational parameters. This study extends this earlier finding by applying this advantage to the monitoring of spindle systems. After over 2 years of system observation and optimization, the system has been verified to be superior to traditional methods. The innovation of fault diagnosis in this study includes the unmatched assembly dimensions of the spindle system, the unbalanced system, and bearing damage. The results of the experiment demonstrate that the WPSN provides a desirable signal-to-noise ratio (SNR) in all three of the simulated faults, with the difference of SNR reaching a maximum of 8.6 dB. Following multiple repetitions of the three experiment types, 80% of the faults were diagnosed when the spindle revolved at 4,000 rpm, significantly higher than the 30% fault recognition rate of traditional methods. The experimental results of monitoring of the spindle production line indicated that monitoring using the WPSN encounters less interference from noise compared to that of traditional methods. Therefore, this study has successfully developed a prototype concept into a well-developed monitoring system, and the monitoring can be implemented in a spindle production line or real-time monitoring of machine tools.

  20. Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas.

    PubMed

    Arai, Eri; Gotoh, Masahiro; Tian, Ying; Sakamoto, Hiromi; Ono, Masaya; Matsuda, Akio; Takahashi, Yoriko; Miyata, Sayaka; Totsuka, Hirohiko; Chiku, Suenori; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Matsumoto, Kenji; Yamada, Tesshi; Yoshida, Teruhiko; Kanai, Yae

    2015-12-01

    CpG-island methylator phenotype (CIMP)-positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP-positive renal carcinogenesis. Genome (whole-exome and copy number), transcriptome and proteome (two-dimensional image converted analysis of liquid chromatography-mass spectrometry) analyses were performed using tissue specimens of 87 CIMP-negative and 14 CIMP-positive clear cell RCCs and corresponding specimens of non-cancerous renal cortex. Genes encoding microtubule-associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non-synonymous single-nucleotide mutations and insertions/deletions) in CIMP-positive RCCs, whereas CIMP-negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP-positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the "The metaphase checkpoint (p = 1.427 × 10(-6))," "Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10(-6))" and "Spindle assembly and chromosome separation (p = 9.260 × 10(-6))" pathways. Quantitative RT-PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP-positive than in CIMP-negative RCCs. All CIMP-positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP-positive renal carcinogenesis, and that AURKA and AURKB may be potential therapeutic targets in more aggressive CIMP-positive RCCs.

  1. Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

    PubMed Central

    Arai, Eri; Gotoh, Masahiro; Tian, Ying; Sakamoto, Hiromi; Ono, Masaya; Matsuda, Akio; Takahashi, Yoriko; Miyata, Sayaka; Totsuka, Hirohiko; Chiku, Suenori; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Matsumoto, Kenji; Yamada, Tesshi; Yoshida, Teruhiko

    2015-01-01

    CpG‐island methylator phenotype (CIMP)‐positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP‐positive renal carcinogenesis. Genome (whole‐exome and copy number), transcriptome and proteome (two‐dimensional image converted analysis of liquid chromatography‐mass spectrometry) analyses were performed using tissue specimens of 87 CIMP‐negative and 14 CIMP‐positive clear cell RCCs and corresponding specimens of non‐cancerous renal cortex. Genes encoding microtubule‐associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non‐synonymous single‐nucleotide mutations and insertions/deletions) in CIMP‐positive RCCs, whereas CIMP‐negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP‐positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the “The metaphase checkpoint (p = 1.427 × 10−6),” “Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10−6)” and “Spindle assembly and chromosome separation (p = 9.260 × 10−6)” pathways. Quantitative RT‐PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP‐positive than in CIMP‐negative RCCs. All CIMP‐positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP‐positive renal carcinogenesis, and that AURKA and AURKB may be potential

  2. The chromokinesin Kid is necessary for chromosome arm orientation and oscillation, but not congression, on mitotic spindles

    PubMed Central

    Levesque, Aime A.; Compton, Duane A.

    2001-01-01

    Chromokinesins have been postulated to provide the polar ejection force needed for chromosome congression during mitosis. We have evaluated that possibility by monitoring chromosome movement in vertebrate-cultured cells using time-lapse differential interference contrast microscopy after microinjection with antibodies specific for the chromokinesin Kid. 17.5% of cells injected with Kid-specific antibodies have one or more chromosomes that remain closely opposed to a spindle pole and fail to enter anaphase. In contrast, 82.5% of injected cells align chromosomes in metaphase, progress to anaphase, and display chromosome velocities not significantly different from control cells. However, injected cells lack chromosome oscillations, and chromosome orientation is atypical because chromosome arms extend toward spindle poles during both congression and metaphase. Furthermore, chromosomes cluster into a mass and fail to oscillate when Kid is perturbed in cells containing monopolar spindles. These data indicate that Kid generates the polar ejection force that pushes chromosome arms away from spindle poles in vertebrate-cultured cells. This force increases the efficiency with which chromosomes make bipolar spindle attachments and regulates kinetochore activities necessary for chromosome oscillation, but is not essential for chromosome congression. PMID:11564754

  3. Upregulated Op18/stathmin activity causes chromosomal instability through a mechanism that evades the spindle assembly checkpoint

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Holmfeldt, Per; Sellin, Mikael E.; Gullberg, Martin, E-mail: Martin.Gullberg@molbiol.umu.se

    2010-07-15

    Op18/stathmin (Op18) is a microtubule-destabilizing protein that is phosphorylation-inactivated during mitosis and its normal function is to govern tubulin subunit partitioning during interphase. Human tumors frequently overexpress Op18 and a tumor-associated Q18{yields}E mutation has been identified that confers hyperactivity, destabilizes spindle microtubules, and causes mitotic aberrancies, polyploidization, and chromosome loss in K562 leukemia cells. Here we determined whether wild-type and mutant Op18 have the potential to cause chromosomal instability by some means other than interference with spindle assembly, and thereby bypassing the spindle assembly checkpoint. Our approach was based on Op18 derivatives with distinct temporal order of activity during mitosis,more » conferred either by differential phosphorylation inactivation or by anaphase-specific degradation through fusion with the destruction box of cyclin B1. We present evidence that excessive Op18 activity generates chromosomal instability through interference occurring subsequent to the metaphase-to-anaphase transition, which reduces the fidelity of chromosome segregation to spindle poles during anaphase. Similar to uncorrected merotelic attachment, this mechanism evades detection by the spindle assembly checkpoint and thus provides an additional route to chromosomal instability.« less

  4. Phosphorylation by Cdk1 Increases the Binding of Eg5 to Microtubules In Vitro and in Xenopus Egg Extract Spindles

    PubMed Central

    Cahu, Julie; Olichon, Aurelien; Hentrich, Christian; Schek, Henry; Drinjakovic, Jovana; Zhang, Cunjie; Doherty-Kirby, Amanda; Lajoie, Gilles; Surrey, Thomas

    2008-01-01

    Background Motor proteins from the kinesin-5 subfamily play an essential role in spindle assembly during cell division of most organisms. These motors crosslink and slide microtubules in the spindle. Kinesin-5 motors are phosphorylated at a conserved site by Cyclin-dependent kinase 1 (Cdk1) during mitosis. Xenopus laevis kinesin-5 has also been reported to be phosphorylated by Aurora A in vitro. Methodology/Principal Findings We investigate here the effect of these phosphorylations on kinesin-5 from Xenopus laevis, called Eg5. We find that phosphorylation at threonine 937 in the C-terminal tail of Eg5 by Cdk1 does not affect the velocity of Eg5, but strongly increases its binding to microtubules assembled in buffer. Likewise, this phosphorylation promotes binding of Eg5 to microtubules in Xenopus egg extract spindles. This enhancement of binding elevates the amount of Eg5 in spindles above a critical level required for bipolar spindle formation. We find furthermore that phosphorylation of Xenopus laevis Eg5 by Aurora A at serine 543 in the stalk is not required for spindle formation. Conclusions/Significance These results show that phosphorylation of Eg5 by Cdk1 has a direct effect on the interaction of this motor with microtubules. In egg extract, phosphorylation of Eg5 by Cdk1 ensures that the amount of Eg5 in the spindle is above a level that is required for spindle formation. This enhanced targeting to the spindle appears therefore to be, at least in part, a direct consequence of the enhanced binding of Eg5 to microtubules upon phosphorylation by Cdk1. These findings advance our understanding of the regulation of this essential mitotic motor protein. PMID:19079595

  5. WAVE2 regulates meiotic spindle stability, peripheral positioning and polar body emission in mouse oocytes.

    PubMed

    Sun, Shao-Chen; Xu, Yong-Nan; Li, Ying-Hua; Lee, Seung-Eun; Jin, Yong-Xun; Cui, Xiang-Shun; Kim, Nam-Hyung

    2011-06-01

    During oocyte meiotic maturation, meiotic spindles form in the central cytoplasm and then migrate to the cortex to extrude a small polar body, forming a highly polarized cell through a process involving actin and actin-related molecules. The mechanisms underlying oocyte polarization are still unclear. The Arp2/3 complex regulates oocyte polarization but it is not known whether the WASP family of proteins, a known regulator of the Arp2/3 complex, is involved in this context. In the present study, the role of WASP family member WAVE2 in mouse oocyte asymmetric division was investigated. (1) WAVE2 mRNA and protein were detected during mouse oocyte meiosis. (2) siRNA-mediated and antibody-mediated disruption of WAVE2 resulted in the failure of chromosome congression, spindle formation, spindle positioning and polar body extrusion. (3) WAVE2 regulated actin-driven chromosome migration since chromosomes were arrested in the central cytoplasm by WAVE2 RNAi in the absence of microtubules. (4) Localization of γ-tubulin and MAPK was disrupted after RNAi, confirming the effect of WAVE2 on spindle formation. (5) Actin cap and cortical granule-free domain (CGFD) formation was also disrupted, further confirming the failure of oocyte polarization. Our data suggest that WAVE2 regulates oocyte polarization by regulating meiotic spindle, peripheral positioning, probably via an actin-mediated pathway, and is involved in polar body emission during mouse oocyte meiotic maturation.

  6. Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities.

    PubMed

    Katayama, K; Yamada, K; Ornthanalai, V G; Inoue, T; Ota, M; Murphy, N P; Aruga, J

    2010-02-01

    Mutations in SLITRK1 are found in patients with Tourette's syndrome and trichotillomania. SLITRK1 encodes a transmembrane protein containing leucine-rich repeats that is produced predominantly in the nervous system. However, the role of this protein is largely unknown, except that it can modulate neurite outgrowth in vitro. To clarify the role of Slitrk1 in vivo, we developed Slitrk1-knockout mice and analyzed their behavioral and neurochemical phenotypes. Slitrk1-deficient mice exhibited elevated anxiety-like behavior in the elevated plus-maze test as well as increased immobility time in forced swimming and tail suspension tests. Neurochemical analysis revealed that Slitrk1-knockout mice had increased levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol. Administration of clonidine, an alpha2-adrenergic agonist that is frequently used to treat patients with Tourette's syndrome, attenuated the anxiety-like behavior of Slitrk1-deficient mice in the elevated plus-maze test. These results lead us to conclude that noradrenergic mechanisms are involved in the behavioral abnormalities of Slitrk1-deficient mice. Elevated anxiety due to Slitrk1 dysfunction may contribute to the pathogenesis of neuropsychiatric diseases such as Tourette's syndrome and trichotillomania.

  7. Muscle spindle feedback directs locomotor recovery and circuit reorganization after spinal cord injury.

    PubMed

    Takeoka, Aya; Vollenweider, Isabel; Courtine, Grégoire; Arber, Silvia

    2014-12-18

    Spinal cord injuries alter motor function by disconnecting neural circuits above and below the lesion, rendering sensory inputs a primary source of direct external drive to neuronal networks caudal to the injury. Here, we studied mice lacking functional muscle spindle feedback to determine the role of this sensory channel in gait control and locomotor recovery after spinal cord injury. High-resolution kinematic analysis of intact mutant mice revealed proficient execution in basic locomotor tasks but poor performance in a precision task. After injury, wild-type mice spontaneously recovered basic locomotor function, whereas mice with deficient muscle spindle feedback failed to regain control over the hindlimb on the lesioned side. Virus-mediated tracing demonstrated that mutant mice exhibit defective rearrangements of descending circuits projecting to deprived spinal segments during recovery. Our findings reveal an essential role for muscle spindle feedback in directing basic locomotor recovery and facilitating circuit reorganization after spinal cord injury. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Bilateral neuroblastoma in situ associated with microcephaly.

    PubMed Central

    Park, W. S.; Chi, J. G.

    1993-01-01

    We present an autopsy case of a two-day-old female infant with a very unusual combination of neuroblastoma in situ in both adrenals and microcephaly. This baby was born to a 28-year-old mother after 38 weeks of gestation, and died of respiratory difficulty 2 days later. At autopsy, the baby weighted 1,840gm, and the brain was extraordinarily small with a weight of 125gm. The gyral pattern was simplified and irregular. Microscopically massive migration defects, pachygyria, micropolygyria, leptomeningeal glioneuronal islands, small corticospinal tract and heterotopic Purkinje cells in the cerebellum were found. In addition, there were medullary nodules in both adrenals. They measured 0.7 x 0.4cm and 0.7 x 0.3cm, respectively. These nodules showed the typical histological features of undifferentiated neuroblastoma. The tumor nodules were confined to the medullary portion and did not extend to the cortex or contiguous structures meeting the criteria of neuroblastoma in situ. Based on these unusual and seemingly unrelated sets of findings, it is suggested that the histogenesis of neuroblastoma in situ could be a part of the generalized dysontogenic process. PMID:8397936

  9. Lateralised sleep spindles relate to false memory generation.

    PubMed

    Shaw, John J; Monaghan, Padraic

    2017-12-01

    Sleep is known to enhance false memories: After presenting participants with lists of semantically related words, sleeping before recalling these words results in a greater acceptance of unseen "lure" words related in theme to previously seen words. Furthermore, the right hemisphere (RH) seems to be more prone to false memories than the left hemisphere (LH). In the current study, we investigated the sleep architecture associated with these false memory and lateralisation effects in a nap study. Participants viewed lists of related words, then stayed awake or slept for approximately 90min, and were then tested for recognition of previously seen-old, unseen-new, or unseen-lure words presented either to the LH or RH. Sleep increased acceptance of unseen-lure words as previously seen compared to the wake group, particularly for RH presentations of word lists. RH lateralised stage 2 sleep spindle density relative to the LH correlated with this increase in false memories, suggesting that RH sleep spindles enhanced false memories in the RH. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Kinetochore Dynein Is Required for Chromosome Motion and Congression Independent of the Spindle Checkpoint

    PubMed Central

    Yang, Zhenye; Tulu, U. Serdar; Wadsworth, Patricia; Rieder, Conly L.

    2008-01-01

    Summary During mitosis, the motor molecule cytoplasmic dynein plays key direct and indirect roles in organizing microtubules (MTs) into a functional spindle. At this time, dynein is also recruited to kinetochores, but its role or roles at these organelles remain vague, partly because inhibiting dynein globally disrupts spindle assembly [1-4]. However, dynein can be selectively depleted from kinetochores by disruption of ZW10 [5], and recent studies with this approach conclude that kinetochore-associated dynein (KD) functions to silence the spindle-assembly checkpoint (SAC) [6]. Here we use dynein-antibody microinjection and the RNAi of ZW10 to explore the role of KD in chromosome behavior during mitosis in mammals. We find that depleting or inhibiting KD prevents the rapid poleward motion of attaching kinetochores but not kinetochore fiber (K fiber) formation. However, after kinetochores attach to the spindle, KD is required for stabilizing kinetochore MTs, which it probably does by generating tension on the kinetochore, and in its absence, chromosome congression is defective. Finally, depleting KD reduces the velocity of anaphase chromosome motion by ∼40%, without affecting the rate of poleward MT flux. Thus, in addition to its role in silencing the SAC, KD is important for forming and stabilizing K fibers and in powering chromosome motion. PMID:17509882

  11. Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly.

    PubMed

    Lines, Matthew A; Huang, Lijia; Schwartzentruber, Jeremy; Douglas, Stuart L; Lynch, Danielle C; Beaulieu, Chandree; Guion-Almeida, Maria Leine; Zechi-Ceide, Roseli Maria; Gener, Blanca; Gillessen-Kaesbach, Gabriele; Nava, Caroline; Baujat, Geneviève; Horn, Denise; Kini, Usha; Caliebe, Almuth; Alanay, Yasemin; Utine, Gulen Eda; Lev, Dorit; Kohlhase, Jürgen; Grix, Arthur W; Lohmann, Dietmar R; Hehr, Ute; Böhm, Detlef; Majewski, Jacek; Bulman, Dennis E; Wieczorek, Dagmar; Boycott, Kym M

    2012-02-10

    Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EFTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the first multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  12. Transcriptional and post-transcriptional regulation of Cdc20 during the spindle assembly checkpoint in S. cerevisiae

    PubMed Central

    Wang, Ruiwen; Burton, Janet L.; Solomon, Mark J.

    2017-01-01

    The anaphase-promoting complex (APC) is a ubiquitin ligase responsible for promoting the degradation of many cell cycle regulators. One of the activators and substrate-binding proteins for the APC is Cdc20. It has been shown previously that Cdc20 can promote its own degradation by the APC in normal cycling cells mainly through a cis-degradation mode (i.e. via an intramolecular mechanism). However, how Cdc20 is degraded during the spindle assembly checkpoint (SAC) is still not fully clear. In this study, we used a dual-Cdc20 system to investigate this issue and found that the cis-degradation mode is also the major pathway responsible for Cdc20 degradation during the SAC. In addition, we found that there is an inverse relationship between APCCdc20 activity and the transcriptional activity of the CDC20 promoter, which likely occurs through feedback regulation by APCCdc20 substrates, such as the cyclins Clb2 and Clb5. These findings contribute to our understanding of how the inhibition of APCCdc20 activity and enhanced Cdc20 degradation are required for proper spindle checkpoint arrest. PMID:28189585

  13. Spindle assembly in the oocytes of mouse and Drosophila--similar solutions to a problem.

    PubMed

    Doubilet, Susan; McKim, Kim S

    2007-01-01

    In the oocytes of many organisms a bipolar spindle is assembled in the absence of centrosomes. In this article we review how this occurs in two model organisms, Drosophila melanogaster and Mus musculus. Common themes include an important role for the chromosomes but paradoxically, organization of a bipolar spindle may not involve kinetochore microtubules. Some comparisons are not yet possible, however, since the same genes have usually not been studied in both systems.

  14. A time-frequency analysis of the dynamics of cortical networks of sleep spindles from MEG-EEG recordings

    PubMed Central

    Zerouali, Younes; Lina, Jean-Marc; Sekerovic, Zoran; Godbout, Jonathan; Dube, Jonathan; Jolicoeur, Pierre; Carrier, Julie

    2014-01-01

    Sleep spindles are a hallmark of NREM sleep. They result from a widespread thalamo-cortical loop and involve synchronous cortical networks that are still poorly understood. We investigated whether brain activity during spindles can be characterized by specific patterns of functional connectivity among cortical generators. For that purpose, we developed a wavelet-based approach aimed at imaging the synchronous oscillatory cortical networks from simultaneous MEG-EEG recordings. First, we detected spindles on the EEG and extracted the corresponding frequency-locked MEG activity under the form of an analytic ridge signal in the time-frequency plane (Zerouali et al., 2013). Secondly, we performed source reconstruction of the ridge signal within the Maximum Entropy on the Mean framework (Amblard et al., 2004), yielding a robust estimate of the cortical sources producing observed oscillations. Lastly, we quantified functional connectivity among cortical sources using phase-locking values. The main innovations of this methodology are (1) to reveal the dynamic behavior of functional networks resolved in the time-frequency plane and (2) to characterize functional connectivity among MEG sources through phase interactions. We showed, for the first time, that the switch from fast to slow oscillatory mode during sleep spindles is required for the emergence of specific patterns of connectivity. Moreover, we show that earlier synchrony during spindles was associated with mainly intra-hemispheric connectivity whereas later synchrony was associated with global long-range connectivity. We propose that our methodology can be a valuable tool for studying the connectivity underlying neural processes involving sleep spindles, such as memory, plasticity or aging. PMID:25389381

  15. Fetal and neonatal abnormalities due to congenital rubella syndrome: a review of literature.

    PubMed

    Yazigi, Alexandre; De Pecoulas, Aurelia Eldin; Vauloup-Fellous, Christelle; Grangeot-Keros, Liliane; Ayoubi, Jean-Marc; Picone, Olivier

    2017-02-01

    Rubella virus infection during the first trimester of pregnancy can cause congenital rubella syndrome (CRS). We aimed to describe the abnormalities in order to define the ultrasound features to look for when performing prenatal scans. The goal of this review is to focus specifically on the signs of CRS accessible to prenatal diagnosis. We analyzed every case of CRS described before and/or after birth that we identified in the Pubmed database and classified them as accessible or not to prenatal diagnosis. The most frequently reported malformations accessible to prenatal diagnosis were: cardiac septal defects, pulmonary artery stenosis, microcephaly, cataract, microphtalmia, and hepatosplenomegaly. This extensive literature review shows that the ultrasound features of CRS are not well known, even though rubella was the first teratogenic virus described. This review will help clinicians in the management of rubella during pregnancy by clarifying the findings to be sought.

  16. Overexpression of Mps1 in colon cancer cells attenuates the spindle assembly checkpoint and increases aneuploidy.

    PubMed

    Ling, Youguo; Zhang, Xiaojuan; Bai, Yuanyuan; Li, Ping; Wei, Congwen; Song, Ting; Zheng, Zirui; Guan, Kai; Zhang, Yanhong; Zhang, Buchang; Liu, Xuedong; Ma, Runlin Z; Cao, Cheng; Zhong, Hui; Xu, Quanbin

    2014-08-08

    The spindle assembly checkpoint kinase Mps1 is highly expressed in several types of cancers, but its cellular involvement in tumorigenesis is less defined. Herein, we confirm that Mps1 is overexpressed in colon cancer tissues. Further, we find that forced expression of Mps1 in the colon cancer cell line SW480 enables cells to become resistant to both Mps1 inhibition-induced checkpoint depletion and cell death. Overexpression of Mps1 also increases genome instability in tumor cells owing to a weakened spindle assembly checkpoint. Collectively, our findings suggest that high levels of Mps1 contribute to tumorigenesis by attenuating the spindle assembly checkpoint. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development

    PubMed Central

    Jiang, Jihong; Kuan, Chia-Wei; Fotovati, Abbas; Chu, Tony LH; He, Zhengcheng; Lengyell, Tess C; Li, Huaibiao; Kroll, Torsten; Li, Amanda M; Goldowitz, Daniel; Frappart, Lucien; Ploubidou, Aspasia; Patel, Millan S; Pilarski, Linda M; Simpson, Elizabeth M; Lange, Philipp F; Allan, Douglas W

    2017-01-01

    Oriented cell division is one mechanism progenitor cells use during development and to maintain tissue homeostasis. Common to most cell types is the asymmetric establishment and regulation of cortical NuMA-dynein complexes that position the mitotic spindle. Here, we discover that HMMR acts at centrosomes in a PLK1-dependent pathway that locates active Ran and modulates the cortical localization of NuMA-dynein complexes to correct mispositioned spindles. This pathway was discovered through the creation and analysis of Hmmr-knockout mice, which suffer neonatal lethality with defective neural development and pleiotropic phenotypes in multiple tissues. HMMR over-expression in immortalized cancer cells induces phenotypes consistent with an increase in active Ran including defects in spindle orientation. These data identify an essential role for HMMR in the PLK1-dependent regulatory pathway that orients progenitor cell division and supports neural development. PMID:28994651

  18. Aurora-A-Dependent Control of TACC3 Influences the Rate of Mitotic Spindle Assembly

    PubMed Central

    Joseph, Nimesh; Cavazza, Tommaso; Vernos, Isabelle; Pfuhl, Mark; Gergely, Fanni; Bayliss, Richard

    2015-01-01

    The essential mammalian gene TACC3 is frequently mutated and amplified in cancers and its fusion products exhibit oncogenic activity in glioblastomas. TACC3 functions in mitotic spindle assembly and chromosome segregation. In particular, phosphorylation on S558 by the mitotic kinase, Aurora-A, promotes spindle recruitment of TACC3 and triggers the formation of a complex with ch-TOG-clathrin that crosslinks and stabilises kinetochore microtubules. Here we map the Aurora-A-binding interface in TACC3 and show that TACC3 potently activates Aurora-A through a domain centered on F525. Vertebrate cells carrying homozygous F525A mutation in the endogenous TACC3 loci exhibit defects in TACC3 function, namely perturbed localization, reduced phosphorylation and weakened interaction with clathrin. The most striking feature of the F525A cells however is a marked shortening of mitosis, at least in part due to rapid spindle assembly. F525A cells do not exhibit chromosome missegregation, indicating that they undergo fast yet apparently faithful mitosis. By contrast, mutating the phosphorylation site S558 to alanine in TACC3 causes aneuploidy without a significant change in mitotic duration. Our work has therefore defined a regulatory role for the Aurora-A-TACC3 interaction beyond the act of phosphorylation at S558. We propose that the regulatory relationship between Aurora-A and TACC3 enables the transition from the microtubule-polymerase activity of TACC3-ch-TOG to the microtubule-crosslinking activity of TACC3-ch-TOG-clathrin complexes as mitosis progresses. Aurora-A-dependent control of TACC3 could determine the balance between these activities, thereby influencing not only spindle length and stability but also the speed of spindle formation with vital consequences for chromosome alignment and segregation. PMID:26134678

  19. Research on a power management system for thermoelectric generators to drive wireless sensors on a spindle unit.

    PubMed

    Li, Sheng; Yao, Xinhua; Fu, Jianzhong

    2014-07-16

    Thermoelectric energy harvesting is emerging as a promising alternative energy source to drive wireless sensors in mechanical systems. Typically, the waste heat from spindle units in machine tools creates potential for thermoelectric generation. However, the problem of low and fluctuant ambient temperature differences in spindle units limits the application of thermoelectric generation to drive a wireless sensor. This study is devoted to presenting a transformer-based power management system and its associated control strategy to make the wireless sensor work stably at different speeds of the spindle. The charging/discharging time of capacitors is optimized through this energy-harvesting strategy. A rotating spindle platform is set up to test the performance of the power management system at different speeds. The experimental results show that a longer sampling cycle time will increase the stability of the wireless sensor. The experiments also prove that utilizing the optimal time can make the power management system work more effectively compared with other systems using the same sample cycle.

  20. Research on a Power Management System for Thermoelectric Generators to Drive Wireless Sensors on a Spindle Unit

    PubMed Central

    Li, Sheng; Yao, Xinhua; Fu, Jianzhong

    2014-01-01

    Thermoelectric energy harvesting is emerging as a promising alternative energy source to drive wireless sensors in mechanical systems. Typically, the waste heat from spindle units in machine tools creates potential for thermoelectric generation. However, the problem of low and fluctuant ambient temperature differences in spindle units limits the application of thermoelectric generation to drive a wireless sensor. This study is devoted to presenting a transformer-based power management system and its associated control strategy to make the wireless sensor work stably at different speeds of the spindle. The charging/discharging time of capacitors is optimized through this energy-harvesting strategy. A rotating spindle platform is set up to test the performance of the power management system at different speeds. The experimental results show that a longer sampling cycle time will increase the stability of the wireless sensor. The experiments also prove that utilizing the optimal time can make the power management system work more effectively compared with other systems using the same sample cycle. PMID:25033189