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Sample records for abnormal polyglutamine expansion

  1. Monomeric, Oligomeric and Polymeric Proteins in Huntington Disease and Other Diseases of Polyglutamine Expansion

    PubMed Central

    Hoffner, Guylaine; Djian, Philippe

    2014-01-01

    Huntington disease and other diseases of polyglutamine expansion are each caused by a different protein bearing an excessively long polyglutamine sequence and are associated with neuronal death. Although these diseases affect largely different brain regions, they all share a number of characteristics, and, therefore, are likely to possess a common mechanism. In all of the diseases, the causative protein is proteolyzed, becomes abnormally folded and accumulates in oligomers and larger aggregates. The aggregated and possibly the monomeric expanded polyglutamine are likely to play a critical role in the pathogenesis and there is increasing evidence that the secondary structure of the protein influences its toxicity. We describe here, with special attention to huntingtin, the mechanisms of polyglutamine aggregation and the modulation of aggregation by the sequences flanking the polyglutamine. We give a comprehensive picture of the characteristics of monomeric and aggregated polyglutamine, including morphology, composition, seeding ability, secondary structure, and toxicity. The structural heterogeneity of aggregated polyglutamine may explain why polyglutamine-containing aggregates could paradoxically be either toxic or neuroprotective. PMID:24961702

  2. Polyglutamine expansion in huntingtin increases its insertion into lipid bilayers.

    PubMed

    Kegel, Kimberly B; Schewkunow, Vitali; Sapp, Ellen; Masso, Nicholas; Wanker, Erich E; DiFiglia, Marian; Goldmann, Wolfgang H

    2009-09-25

    An expanded polyglutamine (Q) tract (>37Q) in huntingtin (htt) causes Huntington disease. Htt associates with membranes and polyglutamine expansion in htt may alter membrane function in Huntington disease through a mechanism that is not known. Here we used differential scanning calorimetry to examine the effects of polyQ expansion in htt on its insertion into lipid bilayers. We prepared synthetic lipid vesicles composed of phosphatidylcholine and phosphatidylethanolamine and tested interactions of htt amino acids 1-89 with 20Q, 32Q or 53Q with the vesicles. GST-htt1-89 with 53Q inserted into synthetic lipid vesicles significantly more than GST-htt1-89 with 20Q or 32Q. We speculate that by inserting more into cell membranes, mutant huntingtin could increase disorder within the lipid bilayer and thereby disturb cellular membrane function.

  3. Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity

    PubMed Central

    Suzuki, Eriko; Zhao, Yue; Ito, Saya; Sawatsubashi, Shun; Murata, Takuya; Furutani, Takashi; Shirode, Yuko; Yamagata, Kaoru; Tanabe, Masahiko; Kimura, Shuhei; Ueda, Takashi; Fujiyama, Sally; Lim, Jinseon; Matsukawa, Hiroyuki; Kouzmenko, Alexander P.; Aigaki, Toshiro; Tabata, Tetsuya; Takeyama, Ken-ichi; Kato, Shigeaki

    2009-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by a polyglutamine repeat (polyQ) expansion within the human androgen receptor (AR). Unlike other neurodegenerative diseases caused by abnormal polyQ expansion, the onset of SBMA depends on androgen binding to mutant human polyQ-AR proteins. This is also observed in Drosophila eyes ectopically expressing the polyQ-AR mutants. We have genetically screened mediators of androgen-induced neurodegeneration caused by polyQ-AR mutants in Drosophila eyes. We identified Rbf (Retinoblastoma-family protein), the Drosophila homologue of human Rb (Retinoblastoma protein), as a neuroprotective factor. Androgen-dependent association of Rbf or Rb with AR was remarkably potentiated by aberrant polyQ expansion. Such potentiated Rb association appeared to attenuate recruitment of histone deacetyltransferase 1 (HDAC1), a corepressor of E2F function. Either overexpression of Rbf or E2F deficiency in fly eyes reduced the neurotoxicity of the polyQ-AR mutants. Induction of E2F function by polyQ-AR-bound androgen was suppressed by Rb in human neuroblastoma cells. We conclude that abnormal expansion of polyQ may potentiate innate androgen-dependent association of AR with Rb. This appears to lead to androgen-dependent onset of SBMA through aberrant E2F transactivation caused by suppressed histone deacetylation. PMID:19237573

  4. Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity.

    PubMed

    Suzuki, Eriko; Zhao, Yue; Ito, Saya; Sawatsubashi, Shun; Murata, Takuya; Furutani, Takashi; Shirode, Yuko; Yamagata, Kaoru; Tanabe, Masahiko; Kimura, Shuhei; Ueda, Takashi; Fujiyama, Sally; Lim, Jinseon; Matsukawa, Hiroyuki; Kouzmenko, Alexander P; Aigaki, Toshiro; Tabata, Tetsuya; Takeyama, Ken-ichi; Kato, Shigeaki

    2009-03-10

    Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by a polyglutamine repeat (polyQ) expansion within the human androgen receptor (AR). Unlike other neurodegenerative diseases caused by abnormal polyQ expansion, the onset of SBMA depends on androgen binding to mutant human polyQ-AR proteins. This is also observed in Drosophila eyes ectopically expressing the polyQ-AR mutants. We have genetically screened mediators of androgen-induced neurodegeneration caused by polyQ-AR mutants in Drosophila eyes. We identified Rbf (Retinoblastoma-family protein), the Drosophila homologue of human Rb (Retinoblastoma protein), as a neuroprotective factor. Androgen-dependent association of Rbf or Rb with AR was remarkably potentiated by aberrant polyQ expansion. Such potentiated Rb association appeared to attenuate recruitment of histone deacetyltransferase 1 (HDAC1), a corepressor of E2F function. Either overexpression of Rbf or E2F deficiency in fly eyes reduced the neurotoxicity of the polyQ-AR mutants. Induction of E2F function by polyQ-AR-bound androgen was suppressed by Rb in human neuroblastoma cells. We conclude that abnormal expansion of polyQ may potentiate innate androgen-dependent association of AR with Rb. This appears to lead to androgen-dependent onset of SBMA through aberrant E2F transactivation caused by suppressed histone deacetylation.

  5. CAG Expansions Are Genetically Stable and Form Nontoxic Aggregates in Cells Lacking Endogenous Polyglutamine Proteins

    PubMed Central

    Zurawel, Ashley A.; Kabeche, Ruth; DiGregorio, Sonja E.; Deng, Lin; Menon, Kartikeya M.; Opalko, Hannah

    2016-01-01

    ABSTRACT Proteins containing polyglutamine (polyQ) regions are found in almost all eukaryotes, albeit with various frequencies. In humans, proteins such as huntingtin (Htt) with abnormally expanded polyQ regions cause neurodegenerative diseases such as Huntington’s disease (HD). To study how the presence of endogenous polyQ aggregation modulates polyQ aggregation and toxicity, we expressed polyQ expanded Htt fragments (polyQ Htt) in Schizosaccharomyces pombe. In stark contrast to other unicellular fungi, such as Saccharomyces cerevisiae, S. pombe is uniquely devoid of proteins with more than 10 Q repeats. We found that polyQ Htt forms aggregates within S. pombe cells only with exceedingly long polyQ expansions. Surprisingly, despite the presence of polyQ Htt aggregates in both the cytoplasm and nucleus, no significant growth defect was observed in S. pombe cells. Further, PCR analysis showed that the repetitive polyQ-encoding DNA region remained constant following transformation and after multiple divisions in S. pombe, in contrast to the genetic instability of polyQ DNA sequences in other organisms. These results demonstrate that cells with a low content of polyQ or other aggregation-prone proteins can show a striking resilience with respect to polyQ toxicity and that genetic instability of repetitive DNA sequences may have played an important role in the evolutionary emergence and exclusion of polyQ expansion proteins in different organisms. PMID:27677791

  6. Polyglutamine expansion in huntingtin alters its interaction with phospholipids.

    PubMed

    Kegel, Kimberly B; Sapp, Ellen; Alexander, Jonathan; Valencia, Antonio; Reeves, Patrick; Li, Xueyi; Masso, Nicholas; Sobin, Lindsay; Aronin, Neil; DiFiglia, Marian

    2009-09-01

    Huntingtin has an expanded polyglutamine tract in patients with Huntington's disease. Huntingtin localizes to intracellular and plasma membranes but the function of huntingtin at membranes is unknown. Previously we reported that exogenously expressed huntingtin bound pure phospholipids using protein-lipid overlays. Here we show that endogenous huntingtin from normal (Hdh(7Q/7Q)) mouse brain and mutant huntingtin from Huntington's disease (Hdh(140Q/140Q)) mouse brain bound to large unilamellar vesicles containing phosphoinositol (PI) PI 3,4-bisphosphate, PI 3,5-bisphosphate, and PI 3,4,5-triphosphate [PI(3,4,5)P3]. Huntingtin interactions with multivalent phospholipids were similar to those of dynamin. Mutant huntingtin associated more with phosphatidylethanolamine and PI(3,4,5)P3 than did wild-type huntingtin, and associated with other phospholipids not recognized by wild-type huntingtin. Wild-type and mutant huntingtin also bound to large unilamellar vesicles containing cardiolipin, a phospholipid specific to mitochondrial membranes. Maximal huntingtin-phospholipid association required inclusion of huntingtin amino acids 171-287. Endogenous huntingtin recruited to the plasma membrane in cells that incorporated exogenous PI 3,4-bisphosphate and PI(3,4,5)P3 or were stimulated by platelet-derived growth factor or insulin growth factor 1, which both activate PI 3-kinase. These data suggest that huntingtin interacts with membranes through specific phospholipid associations and that mutant huntingtin may disrupt membrane trafficking and signaling at membranes.

  7. Effects of androgen receptor polyglutamine tract expansion on proliferation of NG108-15 cells.

    PubMed

    Nakajima, H; Kimura, F; Nakagawa, T; Ikemoto, T; Furutama, D; Shinoda, K; Kato, S; Shimizu, A; Ohsawa, N

    1997-01-31

    Expansion of the polyglutamine tracts in the androgen receptor (AR) has been recognized as a cause of X-linked spinal and bulbar muscular atrophy (SBMA). In the present study, NG108-15 cells were stably transfected with expression vectors coding for either the wild type (WT) AR gene (CAG repeat number = 22) or a mutated (MT) AR gene (CAG repeat number = 52). Cells proliferation and cell cycle parameters were evaluated for NG108-15-WT and NG108-15-MT cells in the presence or absence of androgen. NG108-15-WT cells demonstrated an androgen-dependent increase in cell number, while NG108-15-MT cells did not. Our results demonstrate that expansion of polyglutamine tracts in the AR may affect the proliferation and differentiation of nerve cells.

  8. Examination of Ataxin-3 (atx-3) Aggregation by Structural Mass Spectrometry Techniques: A Rationale for Expedited Aggregation upon Polyglutamine (polyQ) Expansion*

    PubMed Central

    Scarff, Charlotte A.; Almeida, Bruno; Fraga, Joana; Macedo-Ribeiro, Sandra; Radford, Sheena E.; Ashcroft, Alison E.

    2015-01-01

    Expansion of polyglutamine stretches leads to the formation of polyglutamine-containing neuronal aggregates and neuronal death in nine diseases for which there currently are no treatments or cures. This is largely due to a lack in understanding of the mechanisms by which expanded polyglutamine regions contribute to aggregation and disease. To complicate matters further, several of the polyglutamine-disease related proteins, including ataxin-3, have a multistage aggregation mechanism in which flanking domain self-assembly precedes polyglutamine aggregation yet is influenced by polyglutamine expansion. How polyglutamine expansion influences flanking domain aggregation is poorly understood. Here, we use a combination of mass spectrometry and biophysical approaches to investigate this issue for ataxin-3. We show that the conformational dynamics of the flanking Josephin domain in ataxin-3 with an expanded polyglutamine tract are altered in comparison to those exhibited by its nonexpanded counterpart, specifically within the aggregation-prone region of the Josephin domain (amino acid residues 73–96). Expansion thus exposes this region more frequently in ataxin-3 containing an expanded polyglutamine tract, providing a molecular explanation of why aggregation is accelerated upon polyglutamine expansion. Here, harnessing the power of ion mobility spectrometry-mass spectrometry, oligomeric species formed during aggregation are characterized and a model for oligomer growth proposed. The results suggest that a conformational change occurs at the dimer level that initiates self-assembly. New insights into ataxin-3 fibril architecture are also described, revealing the region of the Josephin domain involved in protofibril formation and demonstrating that polyglutamine aggregation proceeds as a distinct second step after protofibril formation without requiring structural rearrangement of the protofibril core. Overall, the results enable the effect of polyglutamine expansion on

  9. Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death.

    PubMed

    Parker, J A; Connolly, J B; Wellington, C; Hayden, M; Dausset, J; Neri, C

    2001-11-06

    Huntington's disease (HD) is a dominant neurodegenerative disease caused by polyglutamine (polyQ) expansion in the protein huntingtin (htt). HD pathogenesis appears to involve the production of mutated N-terminal htt, cytoplasmic and nuclear aggregation of htt, and abnormal activity of htt interactor proteins essential to neuronal survival. Before cell death, neuronal dysfunction may be an important step of HD pathogenesis. To explore polyQ-mediated neuronal toxicity, we expressed the first 57 amino acids of human htt containing normal [19 Gln residues (Glns)] and expanded (88 or 128 Glns) polyQ fused to fluorescent marker proteins in the six touch receptor neurons of Caenorhabditis elegans. Expanded polyQ produced touch insensitivity in young adults. Noticeably, only 28 +/- 6% of animals with 128 Glns were touch sensitive in the tail, as mediated by the PLM neurons. Similar perinuclear deposits and faint nuclear accumulation of fusion proteins with 19, 88, and 128 Glns were observed. In contrast, significant deposits and morphological abnormalities in PLM cell axons were observed with expanded polyQ (128 Glns) and partially correlated with touch insensitivity. PLM cell death was not detected in young or old adults. These animals indicate that significant neuronal dysfunction without cell death may be induced by expanded polyQ and may correlate with axonal insults, and not cell body aggregates. These animals also provide a suitable model to perform in vivo suppression of polyQ-mediated neuronal dysfunction.

  10. Polyglutamine expansion inhibits respiration by increasing reactive oxygen species in isolated mitochondria

    SciTech Connect

    Puranam, Kasturi L.; Wu, Guanghong; Strittmatter, Warren J.; Burke, James R. . E-mail: james.burke@duke.edu

    2006-03-10

    Huntington's disease results from expansion of the polyglutamine (PolyQ) domain in the huntingtin protein. Although the cellular mechanism by which pathologic-length PolyQ protein causes neurodegeneration is unclear, mitochondria appear central in pathogenesis. We demonstrate in isolated mitochondria that pathologic-length PolyQ protein directly inhibits ADP-dependent (state 3) mitochondrial respiration. Inhibition of mitochondrial respiration by PolyQ protein is not due to reduction in the activities of electron transport chain complexes, mitochondrial ATP synthase, or the adenine nucleotide translocase. We show that pathologic-length PolyQ protein increases the production of reactive oxygen species in isolated mitochondria. Impairment of state 3 mitochondrial respiration by PolyQ protein is reversed by addition of the antioxidants N-acetyl-L-cysteine or cytochrome c. We propose a model in which pathologic-length PolyQ protein directly inhibits mitochondrial function by inducing oxidative stress.

  11. Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1

    PubMed Central

    Ni, Chun-Lun; Seth, Divya; Fonseca, Fabio Vasconcelos; Wang, Liwen; Xiao, Tsan Sam; Gruber, Phillip; Sy, Man-Sun; Stamler, Jonathan S.

    2016-01-01

    Expansion of the polyglutamine (polyQ) tract in the huntingtin (Htt) protein causes Huntington’s disease (HD), a fatal inherited movement disorder linked to neurodegeneration in the striatum and cortex. S-nitrosylation and S-acylation of cysteine residues regulate many functions of cytosolic proteins. We therefore used a resin-assisted capture approach to identify these modifications in Htt. In contrast to many proteins that have only a single S-nitrosylation or S-acylation site, we identified sites along much of the length of Htt. Moreover, analysis of cells expressing full-length Htt or a large N-terminal fragment of Htt shows that polyQ expansion strongly increases Htt S-nitrosylation. This effect appears to be general since it is also observed in Ataxin-1, which causes spinocerebellar ataxia type 1 (SCA1) when its polyQ tract is expanded. Overexpression of nitric oxide synthase increases the S-nitrosylation of normal Htt and the frequency of conspicuous juxtanuclear inclusions of Htt N-terminal fragments in transfected cells. Taken together with the evidence that S-nitrosylation of Htt is widespread and parallels polyQ expansion, these subcellular changes show that S-nitrosylation affects the biology of this protein in vivo. PMID:27658206

  12. Polyglutamine expansion alters the dynamics and molecular architecture of aggregates in dentatorubropallidoluysian atrophy.

    PubMed

    Hinz, Justyna; Lehnhardt, Lothar; Zakrzewski, Silke; Zhang, Gong; Ignatova, Zoya

    2012-01-13

    Preferential accumulation of mutant proteins in the nucleus has been suggested to be the molecular culprit that confers cellular toxicity in the neurodegenerative disorders caused by polyglutamine (polyQ) expansion. Here, we use dynamic imaging approaches, orthogonal cross-seeding, and composition analysis to examine the dynamics and structure of nuclear and cytoplasmic inclusions of atrophin-1, implicated in dentatorubropallidoluysian atrophy, a polyQ-based disease with complex clinical features. Our results reveal a large heterogeneity in the dynamics of the nuclear inclusions compared with the compact and immobile cytoplasmic aggregates. At least two types of inclusions of expanded atrophin-1 with different mobility of the molecular species and ability to exchange with the surrounding monomer pool coexist in the nucleus. Intriguingly, the enrichment of nuclear inclusions with slow dynamics parallels changes in the aggregate core architecture that are dominated by the polyQ stretch. We propose that the observed complexity in the dynamics of the nuclear inclusions provides a molecular explanation for the enhanced cellular toxicity of the nuclear aggregates in polyQ-based neurodegeneration.

  13. Polyglutamine Expansion Alters the Dynamics and Molecular Architecture of Aggregates in Dentatorubropallidoluysian Atrophy*

    PubMed Central

    Hinz, Justyna; Lehnhardt, Lothar; Zakrzewski, Silke; Zhang, Gong; Ignatova, Zoya

    2012-01-01

    Preferential accumulation of mutant proteins in the nucleus has been suggested to be the molecular culprit that confers cellular toxicity in the neurodegenerative disorders caused by polyglutamine (polyQ) expansion. Here, we use dynamic imaging approaches, orthogonal cross-seeding, and composition analysis to examine the dynamics and structure of nuclear and cytoplasmic inclusions of atrophin-1, implicated in dentatorubropallidoluysian atrophy, a polyQ-based disease with complex clinical features. Our results reveal a large heterogeneity in the dynamics of the nuclear inclusions compared with the compact and immobile cytoplasmic aggregates. At least two types of inclusions of expanded atrophin-1 with different mobility of the molecular species and ability to exchange with the surrounding monomer pool coexist in the nucleus. Intriguingly, the enrichment of nuclear inclusions with slow dynamics parallels changes in the aggregate core architecture that are dominated by the polyQ stretch. We propose that the observed complexity in the dynamics of the nuclear inclusions provides a molecular explanation for the enhanced cellular toxicity of the nuclear aggregates in polyQ-based neurodegeneration. PMID:22134925

  14. Polyglutamine Aggregation in Huntington Disease: Does Structure Determine Toxicity?

    PubMed

    Hoffner, Guylaine; Djian, Philippe

    2015-12-01

    Huntington disease is a dominantly inherited disease of the central nervous system. The mutational expansion of polyglutamine beyond a critical length produces a toxic gain of function in huntingtin and results in neuronal death. In the course of the disease, expanded huntingtin is proteolyzed, becomes abnormally folded, and accumulates in oligomers, fibrils, and microscopic inclusions. The aggregated forms of the expanded protein are structurally diverse. Structural heterogeneity may explain why polyglutamine-containing aggregates could paradoxically be either toxic or neuroprotective. When defined, the toxic structures could then specifically be targeted by prophylactic or therapeutic drugs aimed at inhibiting polyglutamine aggregation.

  15. Azadiradione ameliorates polyglutamine expansion disease in Drosophila by potentiating DNA binding activity of heat shock factor 1

    PubMed Central

    Dutta, Naibedya; Ghosh, Suvranil; Jana, Manas; Ganguli, Arnab; Komarov, Andrei; Paul, Soumyadip; Dwivedi, Vibha; Chatterjee, Subhrangsu; Jana, Nihar R.; Lakhotia, Subhash C.; Chakrabarti, Gopal; Misra, Anup K.; Mandal, Subhash C.; Pal, Mahadeb

    2016-01-01

    Aggregation of proteins with the expansion of polyglutamine tracts in the brain underlies progressive genetic neurodegenerative diseases (NDs) like Huntington's disease and spinocerebellar ataxias (SCA). An insensitive cellular proteotoxic stress response to non-native protein oligomers is common in such conditions. Indeed, upregulation of heat shock factor 1 (HSF1) function and its target protein chaperone expression has shown promising results in animal models of NDs. Using an HSF1 sensitive cell based reporter screening, we have isolated azadiradione (AZD) from the methanolic extract of seeds of Azadirachta indica, a plant known for its multifarious medicinal properties. We show that AZD ameliorates toxicity due to protein aggregation in cell and fly models of polyglutamine expansion diseases to a great extent. All these effects are correlated with activation of HSF1 function and expression of its target protein chaperone genes. Notably, HSF1 activation by AZD is independent of cellular HSP90 or proteasome function. Furthermore, we show that AZD directly interacts with purified human HSF1 with high specificity, and facilitates binding of HSF1 to its recognition sequence with higher affinity. These unique findings qualify AZD as an ideal lead molecule for consideration for drug development against NDs that affect millions worldwide. PMID:27835876

  16. The role of polyglutamine expansion and protein context in disease-related huntingtin/lipid interactions

    NASA Astrophysics Data System (ADS)

    Burke, Kathleen Anne

    Huntington's Disease (HD) is a neurodegenerative disorder that is defined by the accumulation of nanoscale aggregates comprised of the huntingtin (htt) protein. Aggregation is directly caused by an expanded polyglutamine (polyQ) domain in htt, leading to a diverse population of aggregate species, such as oligomers, fibrils, and annular aggregates. Furthermore, the length of this polyQ domain is directly related to onset and severity of disease. The first 17 amino acids on the N-terminus (N17) and the polyproline domain on the C-terminal side of the polyQ domain have been shown to further modulate the aggregation process. Additionally, N17 appears to have lipid binding properties as htt interacts with a variety of membrane-containing structures present in cells, such as organelles, and interactions with these membrane surfaces may further modulate htt aggregation. To investigate the interaction between htt exon1 and lipid bilayers, in situ atomic force microscopy (AFM) was used to directly monitor the aggregation of htt exon1 constructs with varying Q-length (35Q, 46Q, 51Q, and myc- 53Q) or synthetic peptides with different polyQ domain flanking sequences (KK-Q35-KK, KK-Q 35-P10-KK, N17-Q35-KK, and N 17-Q35-P10-KK) on supported lipid membranes comprised of total brain lipid extract. The exon1 fragments accumulated on the lipid membranes, causing disruption of the membrane, in a polyQ dependent manner. By adding N-terminal tags to the htt exon1 fragments, the interaction with the lipid bilayer was impeded. The KK-Q35-KK and KK-Q 35-P10-KK peptides had no appreciable interaction with lipid bilayers. Interestingly, polyQ peptides with the N17 flanking sequence interacted with the bilayer. N17-Q35-KK formed discrete aggregates on the bilayer, but there was minimal membrane disruption. The N17-Q35-P10-KK peptide interacted more aggressively with the lipid bilayer in a manner reminiscent of the htt exon1 proteins.

  17. Large-scale assessment of polyglutamine repeat expansions in Parkinson disease

    PubMed Central

    Wang, Lisa; Aasly, Jan O.; Annesi, Grazia; Bardien, Soraya; Bozi, Maria; Brice, Alexis; Carr, Jonathan; Chung, Sun J.; Clarke, Carl; Crosiers, David; Deutschländer, Angela; Eckstein, Gertrud; Farrer, Matthew J.; Goldwurm, Stefano; Garraux, Gaetan; Hadjigeorgiou, Georgios M.; Hicks, Andrew A.; Hattori, Nobutaka; Klein, Christine; Jeon, Beom; Kim, Yun J.; Lesage, Suzanne; Lin, Juei-Jueng; Lynch, Timothy; Lichtner, Peter; Lang, Anthony E.; Mok, Vincent; Jasinska-Myga, Barbara; Mellick, George D.; Morrison, Karen E.; Opala, Grzegorz; Pihlstrøm, Lasse; Pramstaller, Peter P.; Park, Sung S.; Quattrone, Aldo; Rogaeva, Ekaterina; Ross, Owen A.; Stefanis, Leonidas; Stockton, Joanne D.; Silburn, Peter A.; Theuns, Jessie; Tan, Eng K.; Tomiyama, Hiroyuki; Toft, Mathias; Van Broeckhoven, Christine; Uitti, Ryan J.; Wirdefeldt, Karin; Wszolek, Zbigniew; Xiromerisiou, Georgia; Yueh, Kuo-Chu; Zhao, Yi; Gasser, Thomas; Maraganore, Demetrius M.; Krüger, Rejko

    2015-01-01

    Objectives: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). Methods: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. Results: We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. Conclusions: Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD. PMID:26354989

  18. Studying Polyglutamine Diseases in Drosophila

    PubMed Central

    Xu, Zhen; Tito, Antonio; Rui, Yan-Ning; Zhang, Sheng

    2015-01-01

    Polyglutamine (polyQ) diseases are a family of dominantly transmitted neurodegenerative disorders caused by an abnormal expansion of CAG trinucleotide repeats in the protein-coding regions of the respective disease-causing genes. Despite their simple genetic basis, the etiology of these diseases is far from clear. Over the past two decades, Drosophila has proven to be successful in modeling this family of neurodegenerative disorders, including the faithful recapitulation of pathological features such as polyQ length-dependent formation of protein aggregates and progressive neuronal degeneration. Additionally, it has been valuable in probing the pathogenic mechanisms, in identifying and evaluating disease modifiers, and in helping elucidate the normal functions of disease-causing genes. Knowledge learned from this simple invertebrate organism has had a large impact on our understanding of these devastating brain diseases. PMID:26257024

  19. Aggregation Kinetics of Interrupted Polyglutamine Peptides

    PubMed Central

    Walters, Robert H.; Murphy, Regina M.

    2011-01-01

    Abnormally expanded polyglutamine domains are associated with at least nine neurodegenerative diseases, including Huntington’s disease. Expansion of the glutamine region facilitates aggregation of the impacted protein, and aggregation has been linked to neurotoxicity. Studies of synthetic peptides have contributed substantially to our understanding of the mechanism of aggregation, because the underlying biophysics of polyglutamine-mediated association can be probed independent of their context within a larger protein. In this report, interrupting residues were inserted into polyglutamine peptides (Q20), and the impact on conformational and aggregation properties was examined. A peptide with 2 alanine residues formed laterally-aligned fibrillar aggregates which were similar to the uninterrupted Q20 peptide. Insertion of 2 proline residues resulted in soluble, nonfibrillar aggregates, which did not mature into insoluble aggregates. In contrast, insertion of a β-turn template DPG rapidly accelerated aggregation and resulted in a fibrillar aggregate morphology with little lateral alignment between fibrils. These results are interpreted to indicate that (a) long-range nonspecific interactions lead to the formation of soluble oligomers, while maturation of oligomers into fibrils requires conformational conversion, and (b) that soluble oligomers dynamically interact with each other, while insoluble aggregates are relatively inert. Kinetic analysis revealed that the increase in aggregation caused by the DPG insert is inconsistent with the nucleation-elongation mechanism of aggregation featuring a monomeric β-sheet nucleus. Rather, the data support a mechanism of polyglutamine aggregation by which monomers associate into soluble oligomers, which then undergo slow structural rearrangement to form sedimentable aggregates. PMID:21821045

  20. From Pathways to Targets: Understanding the Mechanisms behind Polyglutamine Disease

    PubMed Central

    Weber, Jonasz Jeremiasz; Sowa, Anna Sergeevna

    2014-01-01

    The history of polyglutamine diseases dates back approximately 20 years to the discovery of a polyglutamine repeat in the androgen receptor of SBMA followed by the identification of similar expansion mutations in Huntington's disease, SCA1, DRPLA, and the other spinocerebellar ataxias. This common molecular feature of polyglutamine diseases suggests shared mechanisms in disease pathology and neurodegeneration of disease specific brain regions. In this review, we discuss the main pathogenic pathways including proteolytic processing, nuclear shuttling and aggregation, mitochondrial dysfunction, and clearance of misfolded polyglutamine proteins and point out possible targets for treatment. PMID:25309920

  1. Analysis of polyglutamine-coding repeats in the TATA-binding protein in different human populations and in patients with schizophrenia an bipolar affective disorder

    SciTech Connect

    Rubinsztein, D.C.; Leggo, J.; Crow, T.J.

    1996-09-20

    A new class of disease (including Huntington disease, Kennedy disease, and spinocerebellar ataxias types 1 and 3) results from abnormal expansions of CAG trinucleotides in the coding regions of genes. In all of these diseases the CAG repeats are thought to be translated into polyglutamine tracts. There is accumulating evidence arguing for CAG trinucleotide expansions as one of the causative disease mutations in schizophrenia and bipolar affective disorder. We and others believe that the TATA-binding protein (TBP) is an important candidate to investigate in these diseases as it contains a highly polymorphic stretch of glutamine codons, which are close to the threshold length where the polyglutamine tracts start to be associated with disease. Thus, we examined the lengths of this polyglutamine repeat in normal unrelated East Anglians, South African Blacks, sub-Saharan Africans mainly from Nigeria, and Asian Indians. We also examined 43 bipolar affective disorder patients and 65 schizophrenic patients. The range of polyglutamine tract-lengths that we found in humans was from 26-42 codons. No patients with bipolar affective disorder and schizophrenia had abnormal expansions at this locus. 22 refs., 1 tab.

  2. Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease.

    PubMed

    Adegbuyiro, Adewale; Sedighi, Faezeh; Pilkington, Albert W; Groover, Sharon; Legleiter, Justin

    2017-03-07

    Several hereditary neurological and neuromuscular diseases are caused by an abnormal expansion of trinucleotide repeats. To date, there have been 10 of these trinucleotide repeat disorders associated with an expansion of the codon CAG encoding glutamine (Q). For these polyglutamine (polyQ) diseases, there is a critical threshold length of the CAG repeat required for disease, and further expansion beyond this threshold is correlated with age of onset and symptom severity. PolyQ expansion in the translated proteins promotes their self-assembly into a variety of oligomeric and fibrillar aggregate species that accumulate into the hallmark proteinaceous inclusion bodies associated with each disease. Here, we review aggregation mechanisms of proteins with expanded polyQ-tracts, structural consequences of expanded polyQ ranging from monomers to fibrillar aggregates, the impact of protein context and post-translational modifications on aggregation, and a potential role for lipid membranes in aggregation. As the pathogenic mechanisms that underlie these disorders are often classified as either a gain of toxic function or loss of normal protein function, some toxic mechanisms associated with mutant polyQ tracts will also be discussed.

  3. Folding of polyglutamine chains

    NASA Astrophysics Data System (ADS)

    Chopra, Manan; Reddy, Allam S.; Abbott, N. L.; de Pablo, J. J.

    2008-10-01

    Long polyglutamine chains have been associated with a number of neurodegenerative diseases. These include Huntington's disease, where expanded polyglutamine (PolyQ) sequences longer than 36 residues are correlated with the onset of symptoms. In this paper we study the folding pathway of a 54-residue PolyQ chain into a β-helical structure. Transition path sampling Monte Carlo simulations are used to generate unbiased reactive pathways between unfolded configurations and the folded β-helical structure of the polyglutamine chain. The folding process is examined in both explicit water and an implicit solvent. Both models reveal that the formation of a few critical contacts is necessary and sufficient for the molecule to fold. Once the primary contacts are formed, the fate of the protein is sealed and it is largely committed to fold. We find that, consistent with emerging hypotheses about PolyQ aggregation, a stable β-helical structure could serve as the nucleus for subsequent polymerization of amyloid fibrils. Our results indicate that PolyQ sequences shorter than 36 residues cannot form that nucleus, and it is also shown that specific mutations inferred from an analysis of the simulated folding pathway exacerbate its stability.

  4. Cell-autonomous and non-cell-autonomous toxicity in polyglutamine diseases.

    PubMed

    Sambataro, Fabio; Pennuto, Maria

    2012-05-01

    Polyglutamine diseases are neurodegenerative disorders caused by expansion of polyglutamine tracts in the coding regions of specific genes. One of the most important features of polyglutamine diseases is that, despite the widespread and in some cases ubiquitous expression of the polyglutamine proteins, specific populations of neurons degenerate in each disease. This finding has led to the idea that polyglutamine diseases are cell-autonomous diseases, in which selective neuronal dysfunction and death result from damage caused by the mutant protein within the targeted neuronal population itself. Development of animal models for conditional expression of polyglutamine proteins, along with new pharmacologic manipulation of polyglutamine protein expression and toxicity, has led to a remarkable change of the current view of polyglutamine diseases as cell-autonomous disorders. It is becoming evident that toxicity in the neighboring non-neuronal cells contributes to selective neuronal damage. This observation implies non-cell-autonomous mechanisms of neurodegeneration in polyglutamine diseases. Here, we describe cell-autonomous and non-cell-autonomous mechanisms of polyglutamine disease pathogenesis, including toxicity in neurons, skeletal muscle, glia, germinal cells, and other cell types.

  5. Huntingtin’s spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function

    PubMed Central

    Vijayvargia, Ravi; Epand, Raquel; Leitner, Alexander; Jung, Tae-Yang; Shin, Baehyun; Jung, Roy; Lloret, Alejandro; Singh Atwal, Randy; Lee, Hyeongseok; Lee, Jong-Min; Aebersold, Ruedi; Hebert, Hans; Song, Ji-Joon; Seong, Ihn Sik

    2016-01-01

    The polyglutamine expansion in huntingtin protein causes Huntington’s disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including circular dichroism, single-particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical α-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to contain a circumscribed central cavity. Interestingly, we showed that the polyglutamine expansion increases α-helical properties of huntingtin and affects the intramolecular interactions among the domains. Our work delineates the structural characteristics of full-length huntingtin, which are affected by the polyglutamine expansion, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal polyglutamine tract confers a novel property on huntingtin, causing the disease. DOI: http://dx.doi.org/10.7554/eLife.11184.001 PMID:27003594

  6. Spontaneous formation of polyglutamine nanotubes with molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Laghaei, Rozita; Mousseau, Normand

    2010-04-01

    Expansion of polyglutamine (polyQ) beyond the pathogenic threshold (35-40 Gln) is associated with several neurodegenerative diseases including Huntington's disease, several forms of spinocerebellar ataxias and spinobulbar muscular atrophy. To determine the structure of polyglutamine aggregates we perform replica-exchange molecular dynamics simulations coupled with the optimized potential for effective peptide forcefield. Using a range of temperatures from 250 to 700 K, we study the aggregation kinetics of the polyglutamine monomer and dimer with chain lengths from 30 to 50 residues. All monomers show a similar structural change at the same temperature from α-helical structure to random coil, without indication of any significant β-strand. For dimers, by contrast, starting from random structures, we observe spontaneous formation of antiparallel β-sheets and triangular and circular β-helical structures for polyglutamine with 40 residues in a 400 ns 50 temperature replica-exchange molecular dynamics simulation (total integrated time 20 μs). This ˜32 Å diameter structure reorganizes further into a tight antiparallel double-stranded ˜22 Å nanotube with 22 residues per turn close to Perutz' model for amyloid fibers as water-filled nanotubes. This diversity of structures suggests the existence of polymorphism for polyglutamine with possibly different pathways leading to the formation of toxic oligomers and to fibrils.

  7. Cryogenic abnormal thermal expansion properties of carbon-doped La(Fe,Si)13 compounds.

    PubMed

    Li, Shaopeng; Huang, Rongjin; Zhao, Yuqiang; Wang, Wei; Li, Laifeng

    2015-12-14

    Recently, La(Fe,Si)13-based compounds have attracted much attention due to their isotropic and tunable abnormal thermal expansion (ATE) properties as well as bright prospects for practical applications. In this research, we have prepared cubic NaZn13-type carbon-doped La(Fe,Si)13 compounds by the arc-melting method, and their ATE and magnetic properties were investigated by means of variable-temperature X-ray diffraction, strain gauge and the physical property measurement system (PPMS). The experimental results indicate that both micro and macro negative thermal expansion (NTE) behaviors gradually weaken with the increase of interstitial carbon atoms. Moreover, the temperature region with the most remarkable NTE properties has been broadened and near zero thermal expansion (NZTE) behavior occurs in the bulk carbon-doped La(Fe,Si)13 compounds.

  8. Examining Polyglutamine Peptide Length: A Connection between Collapsed Conformations and Increased Aggregation

    PubMed Central

    Walters, Robert H.; Murphy, Regina M.

    2009-01-01

    Abnormally expanded polyglutamine domains in proteins are associated with several neurodegenerative diseases, of which the best known is Huntington’s. Expansion of the polyglutamine domain facilitates aggregation of the affected protein, and several studies directly link aggregation to neurotoxicity. The age of onset of disease is inversely correlated with the length of the polyglutamine domain; this correlation motivates an examination of the role of the length of the domain on aggregation. In this investigation, peptides containing 8 to 24 glutamines were synthesized, and their conformational and aggregation properties were examined. All peptides lacked secondary structure. Fluorescence resonance energy transfer (FRET) studies revealed that the peptides became increasingly collapsed as the number of glutamine residues increased. The effective persistence length was estimated to decrease from ~11 Å to ~7 Å as the number of glutamines increased from 8 to 24. A comparison of our data with theoretical results suggests that phosphate-buffered saline is a good solvent for Q8 and Q12, a theta solvent for Q16, and a poor solvent for Q20 and Q24. By dynamic light scattering, we observed that Q16, Q20 and Q24, but not Q8 or Q12, immediately formed soluble aggregates upon dilution into phosphate buffered saline at 37°C. Thus, Q16 stands at the transition point between good and poor solvent, and between stable and aggregation-prone peptide. Examination of aggregates by transmission electron microscopy, along with kinetic assays for sedimentation, provided evidence indicating that soluble aggregates mature into sedimentable aggregates. Together, the data support a mechanism of aggregation in which monomer collapse is accompanied by formation of soluble oligomers; these soluble species lack regular secondary structure but appear morphologically similar to the sedimentable aggregates into which they eventually mature. PMID:19699209

  9. Abnormal thermal expansion properties of cubic NaZn13-type La(Fe,Al)13 compounds.

    PubMed

    Li, Wen; Huang, Rongjin; Wang, Wei; Zhao, Yuqiang; Li, Shaopeng; Huang, Chuanjun; Li, Laifeng

    2015-02-28

    The cubic NaZn13-type La(Fe,Al)13 compounds were synthesized, and their linear thermal expansion properties were investigated in the temperature range of 4.2-300 K. It was found that these compounds exhibit abnormal thermal expansion behavior, i.e., pronounced negative thermal expansion (NTE) or zero thermal expansion (ZTE) behavior, below the Curie temperature due to the magnetovolume effect (MVE). Moreover, in the La(Fe,Al)13 compounds, the modification of the coefficient of thermal expansion (CTE) as well as the abnormal thermal expansion (ATE) temperature-window is achieved through optimizing the proportion of Fe and Al. Typically, the average CTE of the LaFe13-xAlx compounds with x = 1.8 reaches as large as -10.47 × 10(-6) K(-1) between 100 and 225 K (ΔT = 125 K). Also, the ZTE temperature-window of the LaFe13-xAlx compounds with x = 2.5 and x = 2.7 could be broadened to 245 K (from 5 to 250 K). Besides, the magnetic properties of these compounds were measured and correlated with the abnormal thermal expansion behavior. The present results highlight the potential application of such La(Fe,Al)13 compounds with abnormal thermal expansion properties in cryogenic engineering.

  10. Abnormal volumetric thermal expansion in the hourglass fermion materials KHgAs and KHgSb

    NASA Astrophysics Data System (ADS)

    Chang, Dahu; Niu, Chun-Yao; Huang, Xiaowei; Sun, Qiang; Cho, Jun-Hyung; Jia, Yu

    2017-03-01

    Using first principles density functional theory calculations combined with quasi-harmonic approximation, we demonstrate that the recently reported nonsymmorphic "hourglass fermion" materials KHgX (X =As , Sb) belong to a type of negative thermal expansion (NTE) material with an abnormal volumetric thermal expansion. It is revealed that the NTE is caused by the peculiar layered structures of KHgAs and KHgSb, composed of alternately arranged alkali metal and Hg-X atomic layers with residual tensions. Specifically, the coefficients of negative thermal expansion (CNTE) of KHgAs and KHgSb can reach up to -2.7 ×10-6K-1 and -4.9 ×10-6K-1 along the a axis, respectively, as well as a larger volumetric CNTE of -4.98 ×10-6K-1 for KHgSb. The analyses of Grüneisen parameters and vibrational modes show that the NTE of KHgX is driven by the cooperation of membrane and tension effects. It is most likely that the weaker bonds in the Hg-X layer and the smaller mass of alkali metal facilitate the membrane and tension effects, therefore producing a large NTE. Our findings offer insights for understanding the underlying mechanism of NTE behavior in the hourglass fermion materials KHgX .

  11. Huntingtin exon 1 fibrils feature an interdigitated β-hairpin-based polyglutamine core.

    PubMed

    Hoop, Cody L; Lin, Hsiang-Kai; Kar, Karunakar; Magyarfalvi, Gábor; Lamley, Jonathan M; Boatz, Jennifer C; Mandal, Abhishek; Lewandowski, Józef R; Wetzel, Ronald; van der Wel, Patrick C A

    2016-02-09

    Polyglutamine expansion within the exon1 of huntingtin leads to protein misfolding, aggregation, and cytotoxicity in Huntington's disease. This incurable neurodegenerative disease is the most prevalent member of a family of CAG repeat expansion disorders. Although mature exon1 fibrils are viable candidates for the toxic species, their molecular structure and how they form have remained poorly understood. Using advanced magic angle spinning solid-state NMR, we directly probe the structure of the rigid core that is at the heart of huntingtin exon1 fibrils and other polyglutamine aggregates, via measurements of long-range intramolecular and intermolecular contacts, backbone and side-chain torsion angles, relaxation measurements, and calculations of chemical shifts. These experiments reveal the presence of β-hairpin-containing β-sheets that are connected through interdigitating extended side chains. Despite dramatic differences in aggregation behavior, huntingtin exon1 fibrils and other polyglutamine-based aggregates contain identical β-strand-based cores. Prior structural models, derived from X-ray fiber diffraction and computational analyses, are shown to be inconsistent with the solid-state NMR results. Internally, the polyglutamine amyloid fibrils are coassembled from differently structured monomers, which we describe as a type of "intrinsic" polymorphism. A stochastic polyglutamine-specific aggregation mechanism is introduced to explain this phenomenon. We show that the aggregation of mutant huntingtin exon1 proceeds via an intramolecular collapse of the expanded polyglutamine domain and discuss the implications of this observation for our understanding of its misfolding and aggregation mechanisms.

  12. Repeat expansion and autosomal dominant neurodegenerative disorders: consensus and controversy.

    PubMed

    Rudnicki, Dobrila D; Margolis, Russell L

    2003-08-22

    Repeat-expansion mutations cause 13 autosomal dominant neurodegenerative disorders falling into three groups. Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs) types 1, 2, 3, 7 and 17 are each caused by a CAG repeat expansion that encodes polyglutamine. Convergent lines of evidence demonstrate that neurodegeneration in these diseases is a consequence of the neurotoxic effects of abnormally long stretches of glutamines. How polyglutamine induces neurodegeneration, and why neurodegeneration occurs in only select neuronal populations, remains a matter of intense investigation. SCA6 is caused by a CAG repeat expansion in CACNA1A, a gene that encodes a subunit of the P/Q-type calcium channel. The threshold length at which the repeat causes disease is much shorter than in the other polyglutamine diseases, and neurodegeneration may arise from expansion-induced change of function in the calcium channel. Huntington's disease-like 2 (HDL2) and SCAs 8, 10 and 12 are rare disorders in which the repeats (CAG, CTG or ATTCT) are not in protein-coding regions. Investigation into these diseases is still at an early stage, but it is now reasonable to hypothesise that the net effect of each expansion is to alter gene expression. The different pathogenic mechanisms in these three groups of diseases have important implications for the development of rational therapeutics.

  13. The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease

    PubMed Central

    Nath, Samir R.; Lieberman, Andrew P.

    2017-01-01

    Polyglutamine disorders are chronic, progressive neurodegenerative diseases caused by expansion of a glutamine tract in widely expressed genes. Despite excellent models of disease, a well-documented clinical history and progression, and established genetic causes, there are no FDA approved, disease modifying treatments for these disorders. Downstream of the mutant protein, several divergent pathways of toxicity have been identified over the last several decades, supporting the idea that targeting only one of these pathways of toxicity is unlikely to robustly alleviate disease progression. As a result, a vast body of research has focused on eliminating the mutant protein to broadly prevent downstream toxicity, either by silencing mutant protein expression or leveraging the endogenous protein quality control machinery. In the latter approach, a focus has been placed on four critical components of mutant protein degradation that are active in the nucleus, a key site of toxicity: disaggregation, ubiquitination, deubiquitination, and proteasomal activity. These machineries have unique functional components, but work together as a cellular defense system that can be successfully leveraged to alleviate disease phenotypes in several models of polyglutamine toxicity. This review will highlight recent advances in understanding both the potential and role of these components of the protein quality control machinery in polyglutamine disease pathophysiology. PMID:28381987

  14. The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease.

    PubMed

    Nath, Samir R; Lieberman, Andrew P

    2017-01-01

    Polyglutamine disorders are chronic, progressive neurodegenerative diseases caused by expansion of a glutamine tract in widely expressed genes. Despite excellent models of disease, a well-documented clinical history and progression, and established genetic causes, there are no FDA approved, disease modifying treatments for these disorders. Downstream of the mutant protein, several divergent pathways of toxicity have been identified over the last several decades, supporting the idea that targeting only one of these pathways of toxicity is unlikely to robustly alleviate disease progression. As a result, a vast body of research has focused on eliminating the mutant protein to broadly prevent downstream toxicity, either by silencing mutant protein expression or leveraging the endogenous protein quality control machinery. In the latter approach, a focus has been placed on four critical components of mutant protein degradation that are active in the nucleus, a key site of toxicity: disaggregation, ubiquitination, deubiquitination, and proteasomal activity. These machineries have unique functional components, but work together as a cellular defense system that can be successfully leveraged to alleviate disease phenotypes in several models of polyglutamine toxicity. This review will highlight recent advances in understanding both the potential and role of these components of the protein quality control machinery in polyglutamine disease pathophysiology.

  15. Extended polyglutamine tracts cause aggregation and structural perturbation of an adjacent beta barrel protein.

    PubMed

    Ignatova, Zoya; Gierasch, Lila M

    2006-05-05

    Formation of fibrillar intranuclear inclusions and related neuropathologies of the CAG-repeat disorders are linked to the expansion of a polyglutamine tract. Despite considerable effort, the etiology of these devastating diseases remains unclear. Although polypeptides with glutamine tracts recapitulate many of the observed characteristics of the gene products with CAG repeats, such as in vitro and in vivo aggregation and toxicity in model organisms, extended polyglutamine segments have also been reported to structurally perturb proteins into which they are inserted. Additionally, the sequence context of a polyglutamine tract has recently been shown to modulate its propensity to aggregate. These findings raise the possibility that indirect influences of the repeat tract on adjacent protein domains are contributory to pathologies. Destabilization of an adjacent domain may lead to loss of function, as well as favoring non-native structures in the neighboring domain causing them to be prone to intermolecular association and consequent aggregation. To explore these phenomena, we have used chimeras of a well studied globular protein and exon 1 of huntingtin. We find that expansion of the polyglutamine segment beyond the pathological threshold (>35 glutamines) results in structural perturbation of the neighboring protein whether the huntingtin exon is N- or C-terminal. Elongation of the polyglutamine region also substantially increases the propensity of the chimera to aggregate, both in vitro and in vivo, and in vitro aggregation kinetics of a chimera with a 53-glutamine repeat follow a nucleation polymerization mechanism with a monomeric nucleus.

  16. Elongation kinetics of polyglutamine peptide fibrils: a quartz crystal microbalance with dissipation study.

    PubMed

    Walters, Robert H; Jacobson, Kurt H; Pedersen, Joel A; Murphy, Regina M

    2012-08-10

    Abnormally expanded polyglutamine domains in proteins are associated with several neurodegenerative diseases, including Huntington's disease. Expansion of the polyglutamine (polyQ) domain facilitates aggregation of the affected protein, and several studies directly link aggregation to neurotoxicity. Studies of synthetic polyQ peptides have contributed substantially to our understanding of the mechanism of aggregation. In this report, polyQ fibrils were immobilized onto a sensor, and their elongation by polyQ peptides of various length and conformation was examined using quartz crystal microbalance with dissipation monitoring (QCM-D). The rate of elongation increased as the peptide length increased from 8 to 24 glutamines (Q8, Q20, and Q24). Monomer conformation affected elongation rates: insertion of a β-turn template d-Pro-Gly in the center of the peptide increased elongation rates several-fold, while insertion of Pro-Pro dramatically slowed elongation. Dissipation measurements of the QCM-D provided qualitative information about mechanical properties of the elongating fibrils. These data showed clear differences in the characteristics of the elongating aggregates, depending on the specific identity of the associating polyQ peptide. Elongation rates were sensitive to the pH and ionic strength of the buffer. Comparison of QCM-D data with those obtained by optical waveguide lightmode spectroscopy revealed that very little water was associated with the elongation of fibrils by the peptide containing d-Pro-Gly, but a significant amount of water was associated when the fibrils were elongated by Q20. Together, the data indicate that elongation of polyQ fibrils can occur without full consolidation to the fibril structure, resulting in variations to the aggregate structure during elongation.

  17. The expanding role for chromatin and transcription in polyglutamine disease

    PubMed Central

    Mohan, Ryan D.; Abmayr, Susan M.; Workman, Jerry L.

    2014-01-01

    Nine genetic diseases arise from expansion of CAG repeats in seemingly unrelated genes. They are referred to as polyglutamine (polyQ) diseases due to the presence of elongated glutamine tracts in the corresponding proteins. The pathologic consequences of polyQ expansion include progressive spinal, cerebellar, and neural degeneration. These pathologies are not identical, however, suggesting that disruption of protein-specific functions is critical to establish and maintain each disease. A closer examination of protein function reveals that several act as regulators of gene expression. Here we examine the roles these proteins play in regulating gene expression, discuss how polyQ expansion may disrupt these functions to cause disease, and speculate on the neural specificity of perturbing ubiquitous gene regulators. PMID:25108806

  18. Expression of expanded polyglutamine targets profilin for degradation and alters actin dynamics

    PubMed Central

    Burnett, Barrington G.; Andrews, Jaime; Ranganathan, Srikanth; Fischbeck, Kenneth H.; Di Prospero, Nicholas A.

    2008-01-01

    Huntington’s disease is caused by polyglutamine expansion in the huntingtin protein. Huntingtin directly interacts with profilin, a major actin monomer sequestering protein and a key integrator of signals leading to actin polymerization. We observed a progressive loss of profilin in the cerebral cortex of Huntington’s disease patients, and in cell culture and Drosophila models of polyglutamine disease. This loss of profilin is likely due to increased degradation through the ubiquitin-proteasome system. Profilin loss reduces the F/G actin ratio, indicating a shift in actin polymerization. Overexpression of profilin abolishes mutant huntingtin toxicity in cells and partially ameliorates the morphological and functional eye phenotype and extends lifespan in a transgenic polyglutamine Drosophila model. These results indicate a link between huntingtin and profilin and implicate profilin in Huntington’s disease pathogenesis. PMID:18417352

  19. From The Cover: Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation

    NASA Astrophysics Data System (ADS)

    Nollen, Ellen A. A.; Garcia, Susana M.; van Haaften, Gijs; Kim, Soojin; Chavez, Alejandro; Morimoto, Richard I.; Plasterk, Ronald H. A.

    2004-04-01

    Protein misfolding and the formation of aggregates are increasingly recognized components of the pathology of human genetic disease and hallmarks of many neurodegenerative disorders. As exemplified by polyglutamine diseases, the propensity for protein misfolding is associated with the length of polyglutamine expansions and age-dependent changes in protein-folding homeostasis, suggesting a critical role for a protein homeostatic buffer. To identify the complement of protein factors that protects cells against the formation of protein aggregates, we tested transgenic Caenorhabditis elegans strains expressing polyglutamine expansion yellow fluorescent protein fusion proteins at the threshold length associated with the age-dependent appearance of protein aggregation. We used genome-wide RNA interference to identify genes that, when suppressed, resulted in the premature appearance of protein aggregates. Our screen identified 186 genes corresponding to five principal classes of polyglutamine regulators: genes involved in RNA metabolism, protein synthesis, protein folding, and protein degradation; and those involved in protein trafficking. We propose that each of these classes represents a molecular machine collectively comprising the protein homeostatic buffer that responds to the expression of damaged proteins to prevent their misfolding and aggregation. protein misfolding | neurodegenerative diseases

  20. Glycogen synthase kinase 3β suppresses polyglutamine aggregation by inhibiting Vaccinia-related kinase 2 activity

    PubMed Central

    Lee, Eunju; Ryu, Hye Guk; Kim, Sangjune; Lee, Dohyun; Jeong, Young-Hun; Kim, Kyong-Tai

    2016-01-01

    Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the N-terminal of huntingtin. The amount of aggregate-prone protein is controlled by various mechanisms, including molecular chaperones. Vaccinia-related kinase 2 (VRK2) is known to negatively regulate chaperonin TRiC, and VRK2-facilitated degradation of TRiC increases polyQ protein aggregation, which is involved in HD. We found that VRK2 activity was negatively controlled by glycogen synthase kinase 3β (GSK3β). GSK3β directly bound to VRK2 and inhibited the catalytic activity of VRK2 in a kinase activity-independent manner. Furthermore, GSK3β increased the stability of TRiC and decreased the formation of HttQ103-GFP aggregates by inhibiting VRK2. These results indicate that GSK3β signaling may be a regulatory mechanism of HD progression and suggest targets for further therapeutic trials for HD. PMID:27377031

  1. Pharmacological Tuning of Heat Shock Protein 70 Modulates Polyglutamine Toxicity and Aggregation

    PubMed Central

    Chafekar, Sidhartha M.; Wisén, Susanne; Thompson, Andrea D.; Echeverria, AnaLisa; Walter, Gladis M.; Evans, Christopher G.; Makley, Leah N.; Gestwicki, Jason E.; Duennwald, Martin L.

    2012-01-01

    Nine neurodegenerative disorders are caused by the abnormal expansion of polyglutamine (polyQ) regions within distinct proteins. Genetic and biochemical evidence has documented that the molecular chaperone, heat shock protein 70 (Hsp70), modulates polyQ toxicity and aggregation, yet it remains unclear how Hsp70 might be used as a potential target in polyQ-related diseases. We have utilized a pair of membrane-permeable compounds that tune the activity of Hsp70 by either stimulating or by inhibiting its ATPase functions. Using these two pharmacological agents in both yeast and PC12 cell models of polyQ aggregation and toxicity, we were surprised to find that stimulating Hsp70 solubilized polyQ conformers and simultaneously exacerbated polyQ-mediated toxicity. By contrast, inhibiting Hsp70’s ATPase activity protected against polyQ toxicity and promoted aggregation. These findings clarify Hsp70’s role as a possible drug target in polyQ disorders and suggest that Hsp70 uses ATP hydrolysis to help partition polyQ proteins into structures with varying levels of proteotoxicity. Our results thus support an emerging concept in which certain kinds of polyQ aggregates may be protective, while more soluble polyQ species are toxic. PMID:22709427

  2. The polyglutamine-expanded androgen receptor responsible for spinal and bulbar muscular atrophy inhibits the APC/CCdh1 ubiquitin ligase complex

    PubMed Central

    Bott, Laura C.; Salomons, Florian A.; Maric, Dragan; Liu, Yuhong; Merry, Diane; Fischbeck, Kenneth H.; Dantuma, Nico P.

    2016-01-01

    Polyglutamine expansion in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA), an X-linked neuromuscular disease that is fully manifest only in males. It has been suggested that proteins with expanded polyglutamine tracts impair ubiquitin-dependent proteolysis due to their propensity to aggregate, but recent studies indicate that the overall activity of the ubiquitin-proteasome system is preserved in SBMA models. Here we report that AR selectively interferes with the function of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which, together with its substrate adaptor Cdh1, is critical for cell cycle arrest and neuronal architecture. We show that both wild-type and mutant AR physically interact with the APC/CCdh1 complex in a ligand-dependent fashion without being targeted for proteasomal degradation. Inhibition of APC/CCdh1 by mutant but not wild-type AR in PC12 cells results in enhanced neurite outgrowth which is typically followed by rapid neurite retraction and mitotic entry. Our data indicate a role of AR in neuronal differentiation through regulation of APC/CCdh1 and suggest abnormal cell cycle reactivation as a pathogenic mechanism in SBMA. PMID:27312068

  3. Early-Aggregation Studies of Polyglutamine in Solution

    NASA Astrophysics Data System (ADS)

    Fluitt, Aaron; de Pablo, Juan

    2012-02-01

    Several neurodegenerative diseases, notably Huntington's disease, are associated with certain proteins containing extended polyglutamine tracts. In all polyglutamine diseases, the age of onset is inversely correlated with the length of the polyglutamine domain beyond some pathological threshold. Diseased cells are characterized by intranuclear inclusions rich in aggregated polyglutamine. Experimental evidence suggests that oligomeric aggregate species, not mature amyloid fibrils, are the species most toxic to the cell. Little is known about the structures and aggregation dynamics of polyglutamine oligomers due to their short lifetimes. A better understanding of the pathway through which polyglutamine peptides form oligomeric aggregates will aid the design of therapies to inhibit their toxic activity. In this work, we report structural characterization of polyglutamine monomers and dimers from atomistic molecular dynamics simulations in explicit water. Umbrella sampling simulations reveal that the stability of the dimer species with respect to the disassociated monomers is an increasing function of the chain length.

  4. Abnormalities induced by the mutant gene Ipr: expansion of a unique lymphocyte subset.

    PubMed

    Morse, H C; Davidson, W F; Yetter, R A; Murphy, E D; Roths, J B; Coffman, R L

    1982-12-01

    Mice carrying the Ipr mutation develop massive lymphoadenopathy and severe autoimmune disease. The characteristics of the cell population that proliferates in lymphoid tissues were evaluated by the use of a) monoclonal antibodies and FMF, and b) molecular genetic studies of Ig heavy chain genes. The lymph node cells of different strains of mice homozygous for the Ipr mutation were shown to be almost uniformly Thy-1+, Ly-1+, Ly-2-, H-11+, Ly-5+, sIg-, ThB-, 2C2+, I-A-, 6B2+, and therefore to have surface characteristics of both T and B cells. Molecular genetic studies of the arrangements of Ig heavy chain genes showed that they were not rearranged as in pre-B and B cells. These results suggest that an abnormal proliferating population of T cells in Ipr/Ipr mice aberrantly express B cell surface markers.

  5. Abnormal ion content, hydration and granule expansion of the secretory granules from cystic fibrosis airway glandular cells

    SciTech Connect

    Baconnais, S.; Delavoie, F. |; Zahm, J.M.; Milliot, M.; Castillon, N.; Terryn, C.; Banchet, V.; Michel, J.; Danos, O.; Merten, M.; Chinet, T.; Zierold, K.; Bonnet, N.; Puchelle, E. , E-Mail: edith.puchelle@univ-reims.fr; Balossier, G.

    2005-10-01

    The absence or decreased expression of cystic fibrosis transmembrane conductance regulator (CFTR) induces increased Na{sup +} absorption and hyperabsorption of the airway surface liquid (ASL) resulting in a dehydrated and hyperviscous ASL. Although the implication of abnormal airway submucosal gland function has been suggested, the ion and water content in the Cystic Fibrosis (CF) glandular secretory granules, before exocytosis, is unknown. We analyzed, in non-CF and CF human airway glandular cell lines (MM-39 and KM4, respectively), the ion content in the secretory granules by electron probe X-ray microanalysis and the water content by quantitative dark field imaging on freeze-dried cryosections. We demonstrated that the ion content (Na{sup +}, Mg{sup 2+}, P, S and Cl{sup -}) is significantly higher and the water content significantly lower in secretory granules from the CF cell line compared to the non-CF cell line. Using videomicroscopy, we observed that the secretory granule expansion was deficient in CF glandular cells. Transfection of CF cells with CFTR cDNA or inhibition of non-CF cells with CFTR{sub inh}-172, respectively restored or decreased the water content and granule expansion, in parallel with changes in ion content. We hypothesize that the decreased water and increased ion content in glandular secretory granules may contribute to the dehydration and increased viscosity of the ASL in CF.

  6. Protein Arginine Methyltransferase 6 Enhances Polyglutamine-Expanded Androgen Receptor Function and Toxicity in Spinal and Bulbar Muscular Atrophy

    PubMed Central

    Scaramuzzino, Chiara; Casci, Ian; Parodi, Sara; Lievens, Patricia M.J.; Polanco, Maria J.; Milioto, Carmelo; Chivet, Mathilde; Monaghan, John; Mishra, Ashutosh; Badders, Nisha; Aggarwal, Tanya; Grunseich, Christopher; Sambataro, Fabio; Basso, Manuela; Fackelmayer, Frank O.; Taylor, J. Paul; Pandey, Udai Bhan; Pennuto, Maria

    2015-01-01

    Summary Polyglutamine expansion in androgen receptor (AR) is responsible for spinobulbar muscular atrophy (SBMA) that leads to selective loss of lower motor neurons. Using SBMA as a model, we explored the relationship between protein structure/function and neurodegeneration in polyglutamine diseases. We show here that protein arginine methyltransferase 6 (PRMT6) is a specific co-activator of normal and mutant AR and that the interaction of PRMT6 with AR is significantly enhanced in the AR mutant. AR and PRMT6 interaction occurs through the PRMT6 steroid receptor interaction motif, LXXLL, and the AR activating function 2 surface. AR transactivation requires PRMT6 catalytic activity and involves methylation of arginine residues at Akt consensus site motifs, which is mutually exclusive with serine phosphorylation by Akt. The enhanced interaction of PRMT6 and mutant AR leads to neurodegeneration in cell and fly models of SBMA. These findings demonstrate a direct role of arginine methylation in polyglutamine disease pathogenesis. PMID:25569348

  7. Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch

    PubMed Central

    Kuiper, E. F. E.; de Mattos, Eduardo P.; Jardim, Laura B.; Kampinga, Harm H.; Bergink, Steven

    2017-01-01

    Expanded polyglutamine (polyQ) stretches in at least nine unrelated proteins lead to inherited neuronal dysfunction and degeneration. The expansion size in all diseases correlates with age at onset (AO) of disease and with polyQ protein aggregation, indicating that the expanded polyQ stretch is the main driving force for the disease onset. Interestingly, there is marked interpatient variability in expansion thresholds for a given disease. Between different polyQ diseases the repeat length vs. AO also indicates the existence of modulatory effects on aggregation of the upstream and downstream amino acid sequences flanking the Q expansion. This can be either due to intrinsic modulation of aggregation by the flanking regions, or due to differential interaction with other proteins, such as the components of the cellular protein quality control network. Indeed, several lines of evidence suggest that molecular chaperones have impact on the handling of different polyQ proteins. Here, we review factors differentially influencing polyQ aggregation: the Q-stretch itself, modulatory flanking sequences, interaction partners, cleavage of polyQ-containing proteins, and post-translational modifications, with a special focus on the role of molecular chaperones. By discussing typical examples of how these factors influence aggregation, we provide more insight on the variability of AO between different diseases as well as within the same polyQ disorder, on the molecular level. PMID:28386214

  8. Explaining the length threshold of polyglutamine aggregation

    NASA Astrophysics Data System (ADS)

    De Los Rios, Paolo; Hafner, Marc; Pastore, Annalisa

    2012-06-01

    The existence of a length threshold, of about 35 residues, above which polyglutamine repeats can give rise to aggregation and to pathologies, is one of the hallmarks of polyglutamine neurodegenerative diseases such as Huntington’s disease. The reason why such a minimal length exists at all has remained one of the main open issues in research on the molecular origins of such classes of diseases. Following the seminal proposals of Perutz, most research has focused on the hunt for a special structure, attainable only above the minimal length, able to trigger aggregation. Such a structure has remained elusive and there is growing evidence that it might not exist at all. Here we review some basic polymer and statistical physics facts and show that the existence of a threshold is compatible with the modulation that the repeat length imposes on the association and dissociation rates of polyglutamine polypeptides to and from oligomers. In particular, their dramatically different functional dependence on the length rationalizes the very presence of a threshold and hints at the cellular processes that might be at play, in vivo, to prevent aggregation and the consequent onset of the disease.

  9. The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway

    PubMed Central

    Ciura, Sorana; Sellier, Chantal; Campanari, Maria-Letizia; Charlet-Berguerand, Nicolas; Kabashi, Edor

    2016-01-01

    ABSTRACT The most common genetic cause for amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) is repeat expansion of a hexanucleotide sequence (GGGGCC) within the C9orf72 genomic sequence. To elucidate the functional role of C9orf72 in disease pathogenesis, we identified certain molecular interactors of this factor. We determined that C9orf72 exists in a complex with SMCR8 and WDR41 and that this complex acts as a GDP/GTP exchange factor for RAB8 and RAB39, 2 RAB GTPases involved in macroautophagy/autophagy. Consequently, C9orf72 depletion in neuronal cultures leads to accumulation of unresolved aggregates of SQSTM1/p62 and phosphorylated TARDBP/TDP-43. However, C9orf72 reduction does not lead to major neuronal toxicity, suggesting that a second stress may be required to induce neuronal cell death. An intermediate size of polyglutamine repeats within ATXN2 is an important genetic modifier of ALS-FTD. We found that coexpression of intermediate polyglutamine repeats (30Q) of ATXN2 combined with C9orf72 depletion increases the aggregation of ATXN2 and neuronal toxicity. These results were confirmed in zebrafish embryos where partial C9orf72 knockdown along with intermediate (but not normal) repeat expansions in ATXN2 causes locomotion deficits and abnormal axonal projections from spinal motor neurons. These results demonstrate that C9orf72 plays an important role in the autophagy pathway while genetically interacting with another major genetic risk factor, ATXN2, to contribute to ALS-FTD pathogenesis. PMID:27245636

  10. Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila.

    PubMed

    Lessing, Derek; Bonini, Nancy M

    2008-02-01

    The expansion of polyglutamine tracts in a variety of proteins causes devastating, dominantly inherited neurodegenerative diseases, including six forms of spinal cerebellar ataxia (SCA). Although a polyglutamine expansion encoded in a single allele of each of the responsible genes is sufficient for the onset of each disease, clinical observations suggest that interactions between these genes may affect disease progression. In a screen for modifiers of neurodegeneration due to SCA3 in Drosophila, we isolated atx2, the fly ortholog of the human gene that causes a related ataxia, SCA2. We show that the normal activity of Ataxin-2 (Atx2) is critical for SCA3 degeneration and that Atx2 activity hastens the onset of nuclear inclusions associated with SCA3. These activities depend on a conserved protein interaction domain of Atx2, the PAM2 motif, which mediates binding of cytoplasmic poly(A)-binding protein (PABP). We show here that PABP also influences SCA3-associated neurodegeneration. These studies indicate that the toxicity of one polyglutamine disease protein can be dramatically modulated by the normal activity of another. We propose that functional links between these genes are critical to disease severity and progression, such that therapeutics for one disease may be applicable to others.

  11. Interaction with polyglutamine-expanded huntingtin alters cellular distribution and RNA processing of huntingtin yeast two-hybrid protein A (HYPA).

    PubMed

    Jiang, Ya-Jun; Che, Mei-Xia; Yuan, Jin-Qiao; Xie, Yuan-Yuan; Yan, Xian-Zhong; Hu, Hong-Yu

    2011-07-15

    Huntington disease (HD) is an autosomal inherited disorder that causes the deterioration of brain cells. The polyglutamine (polyQ) expansion of huntingtin (Htt) is implicated in the pathogenesis of HD via interaction with an RNA splicing factor, Htt yeast two-hybrid protein A/forming-binding protein 11 (HYPA/FBP11). Besides the pathogenic polyQ expansion, Htt also contains a proline-rich region (PRR) located exactly in the C terminus to the polyQ tract. However, how the polyQ expansion influences the PRR-mediated protein interaction and how this abnormal interaction leads to the biological consequence remain elusive. Our NMR structural analysis indicates that the PRR motif of Htt cooperatively interacts with the tandem WW domains of HYPA through domain chaperoning effect of WW1 on WW2. The polyQ-expanded Htt sequesters HYPA to the cytosolic location and then significantly reduces the efficiency of pre-mRNA splicing. We propose that the toxic gain-of-function of the polyQ-expanded Htt that causes dysfunction of cellular RNA processing contributes to the pathogenesis of HD.

  12. Polyglutamine length-dependent toxicity from α1ACT in Drosophila models of spinocerebellar ataxia type 6

    PubMed Central

    Tsou, Wei-Ling; Qiblawi, Sultan H.; Hosking, Ryan R.; Gomez, Christopher M.

    2016-01-01

    ABSTRACT Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that results from abnormal expansion of a polyglutamine (polyQ) repeat. SCA6 is caused by CAG triplet repeat expansion in the gene CACNA1A, resulting in a polyQ tract of 19-33 in patients. CACNA1A, a bicistronic gene, encodes the α1A calcium channel subunit and the transcription factor, α1ACT. PolyQ expansion in α1ACT causes degeneration in mice. We recently described the first Drosophila models of SCA6 that express α1ACT with a normal (11Q) or hyper-expanded (70Q) polyQ. Here, we report additional α1ACT transgenic flies, which express full-length α1ACT with a 33Q repeat. We show that α1ACT33Q is toxic in Drosophila, but less so than the 70Q version. When expressed everywhere, α1ACT33Q-expressing adults die earlier than flies expressing the normal allele. α1ACT33Q causes retinal degeneration and leads to aggregated species in an age-dependent manner, but at a slower pace than the 70Q counterpart. According to western blots, α1ACT33Q localizes less readily in the nucleus than α1ACT70Q, providing clues into the importance of polyQ tract length on α1ACT localization and its site of toxicity. We expect that these new lines will be highly valuable for future work on SCA6. PMID:27979829

  13. Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport.

    PubMed

    Gasset-Rosa, Fatima; Chillon-Marinas, Carlos; Goginashvili, Alexander; Atwal, Ranjit Singh; Artates, Jonathan W; Tabet, Ricardos; Wheeler, Vanessa C; Bang, Anne G; Cleveland, Don W; Lagier-Tourenne, Clotilde

    2017-04-05

    Onset of neurodegenerative disorders, including Huntington's disease, is strongly influenced by aging. Hallmarks of aged cells include compromised nuclear envelope integrity, impaired nucleocytoplasmic transport, and accumulation of DNA double-strand breaks. We show that mutant huntingtin markedly accelerates all of these cellular phenotypes in a dose- and age-dependent manner in cortex and striatum of mice. Huntingtin-linked polyglutamine initially accumulates in nuclei, leading to disruption of nuclear envelope architecture, partial sequestration of factors essential for nucleocytoplasmic transport (Gle1 and RanGAP1), and intranuclear accumulation of mRNA. In aged mice, accumulation of RanGAP1 together with polyglutamine is shifted to perinuclear and cytoplasmic areas. Consistent with findings in mice, marked alterations in nuclear envelope morphology, abnormal localization of RanGAP1, and nuclear accumulation of mRNA were found in cortex of Huntington's disease patients. Overall, our findings identify polyglutamine-dependent inhibition of nucleocytoplasmic transport and alteration of nuclear integrity as a central component of Huntington's disease.

  14. Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration.

    PubMed

    Katsuno, Masahisa; Adachi, Hiroaki; Minamiyama, Makoto; Waza, Masahiro; Tokui, Keisuke; Banno, Haruhiko; Suzuki, Keisuke; Onoda, Yu; Tanaka, Fumiaki; Doyu, Manabu; Sobue, Gen

    2006-11-22

    Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease caused by an expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the androgen receptor (AR) gene. To elucidate the pathogenesis of polyglutamine-mediated motor neuron dysfunction, we investigated histopathological and biological alterations in a transgenic mouse model of SBMA carrying human pathogenic AR. In affected mice, neurofilaments and synaptophysin accumulated at the distal motor axon. A similar intramuscular accumulation of neurofilament was detected in the skeletal muscle of SBMA patients. Fluoro-gold labeling and sciatic nerve ligation demonstrated an impaired retrograde axonal transport in the transgenic mice. The mRNA level of dynactin 1, an axon motor for retrograde transport, was significantly reduced in the SBMA mice resulting from pathogenic AR-induced transcriptional dysregulation. These pathological events were observed before the onset of neurological symptoms, but were reversed by castration, which prevents nuclear accumulation of pathogenic AR. Overexpression of dynactin 1 mitigated neuronal toxicity of the pathogenic AR in a cell culture model of SBMA. These observations indicate that polyglutamine-dependent transcriptional dysregulation of dynactin 1 plays a crucial role in the reversible neuronal dysfunction in the early stage of SBMA.

  15. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

    PubMed Central

    Bettencourt, Conceição; Hensman‐Moss, Davina; Flower, Michael; Wiethoff, Sarah; Brice, Alexis; Goizet, Cyril; Stevanin, Giovanni; Koutsis, Georgios; Karadima, Georgia; Panas, Marios; Yescas‐Gómez, Petra; García‐Velázquez, Lizbeth Esmeralda; Alonso‐Vilatela, María Elisa; Lima, Manuela; Raposo, Mafalda; Traynor, Bryan; Sweeney, Mary; Wood, Nicholas; Giunti, Paola; Durr, Alexandra; Holmans, Peter; Houlden, Henry; Tabrizi, Sarah J.

    2016-01-01

    Objective The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases. Methods We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study. Results In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS. Interpretation We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990 PMID:27044000

  16. Stable polyglutamine dimers can contain β-hairpins with interdigitated side chains-but not α-helices, β-nanotubes, β-pseudohelices, or steric zippers.

    PubMed

    Miettinen, Markus S; Monticelli, Luca; Nedumpully-Govindan, Praveen; Knecht, Volker; Ignatova, Zoya

    2014-04-15

    A common thread connecting nine fatal neurodegenerative protein aggregation diseases is an abnormally expanded polyglutamine tract found in the respective proteins. Although the structure of this tract in the large mature aggregates is increasingly well described, its structure in the small early aggregates remains largely unknown. As experimental evidence suggests that the most toxic species along the aggregation pathway are the small early ones, developing strategies to alleviate disease pathology calls for understanding the structure of polyglutamine peptides in the early stages of aggregation. Here, we present a criterion, grounded in available experimental data, that allows for using kinetic stability of dimers to assess whether a given polyglutamine conformer can be on the aggregation path. We then demonstrate that this criterion can be assessed using present-day molecular dynamics simulations. We find that although the α-helical conformer of polyglutamine is very stable, dimers of α-helices lack the kinetic stability necessary to support further oligomerization. Dimers of steric zipper, β-nanotube, and β-pseudohelix conformers are also too short-lived to initiate aggregation. The β-hairpin-containing conformers, instead, invariably form very stable dimers when their side chains are interdigitated. Combining these findings with the implications of recent solid-state NMR data on mature fibrils, we propose a possible pathway for the initial stages of polyglutamine aggregation, in which β-hairpin-containing conformers act as templates for fibril formation.

  17. Stable Polyglutamine Dimers Can Contain β-Hairpins with Interdigitated Side Chains—But Not α-Helices, β-Nanotubes, β-Pseudohelices, or Steric Zippers

    PubMed Central

    Miettinen, Markus S.; Monticelli, Luca; Nedumpully-Govindan, Praveen; Knecht, Volker; Ignatova, Zoya

    2014-01-01

    A common thread connecting nine fatal neurodegenerative protein aggregation diseases is an abnormally expanded polyglutamine tract found in the respective proteins. Although the structure of this tract in the large mature aggregates is increasingly well described, its structure in the small early aggregates remains largely unknown. As experimental evidence suggests that the most toxic species along the aggregation pathway are the small early ones, developing strategies to alleviate disease pathology calls for understanding the structure of polyglutamine peptides in the early stages of aggregation. Here, we present a criterion, grounded in available experimental data, that allows for using kinetic stability of dimers to assess whether a given polyglutamine conformer can be on the aggregation path. We then demonstrate that this criterion can be assessed using present-day molecular dynamics simulations. We find that although the α-helical conformer of polyglutamine is very stable, dimers of α-helices lack the kinetic stability necessary to support further oligomerization. Dimers of steric zipper, β-nanotube, and β-pseudohelix conformers are also too short-lived to initiate aggregation. The β-hairpin-containing conformers, instead, invariably form very stable dimers when their side chains are interdigitated. Combining these findings with the implications of recent solid-state NMR data on mature fibrils, we propose a possible pathway for the initial stages of polyglutamine aggregation, in which β-hairpin-containing conformers act as templates for fibril formation. PMID:24739171

  18. Abnormal thermal expansion, multiple transitions, magnetocaloric effect, and electronic structure of Gd{sub 6}Co{sub 4.85}

    SciTech Connect

    Zhang, Jiliang; Zheng, Zhigang; Shan, Guangcun E-mail: bobev@udel.edu; Bobev, Svilen E-mail: bobev@udel.edu; Shek, Chan Hung E-mail: bobev@udel.edu

    2015-10-07

    The structure of known Gd{sub 4}Co{sub 3} compound is re-determined as Gd{sub 6}Co{sub 4.85}, adopting the Gd{sub 6}Co{sub 1.67}Si{sub 3} structure type, which is characterized by two disorder Co sites filling the Gd octahedral and a short Gd-Gd distance within the octahedra. The compound shows uniaxial negative thermal expansion in paramagnetic state, significant negative expansion in ferromagnetic state, and positive expansion below ca. 140 K. It also exhibits large magnetocaloric effect, with an entropy change of −6.4 J kg{sup −1} K{sup −1} at 50 kOe. In the lattice of the compound, Co atoms at different sites show different spin states. It was confirmed by the X-ray photoelectron spectra and calculation of electronic structure and shed lights on the abnormal thermal expansion. The stability of such compound and the origin of its magnetism are also discussed based on measured and calculated electronic structures.

  19. Chaperone-like N-methyl Peptide Inhibitors of Polyglutamine Aggregation†

    PubMed Central

    Lanning, Jennifer D.; Hawk, Andrew J.; Derryberry, JohnMark; Meredith, Stephen C.

    2010-01-01

    Polyglutamine expansion in the exon 1 domain of huntingtin leads to aggregation into β-sheet-rich insoluble aggregates associated with Huntington’s Disease. We assessed eight polyglutamine peptides with different permutations of N-methylation of backbone and side chain amides as potential inhibitors of polyglutamine aggregation. Surprisingly, the most effective inhibitor, 5QMe2 (Anth-K-Q-Q(Me2)-Q-Q(Me2)-Q-CONH2, Anth = N-methyl anthranilic acid, Q(Me2) = side chain N-methyl Q) has only side chain methylations at alternate residues, highlighting the importance of side chain interactions in polyglutamine fibrillogenesis. Above a 1:1 stoichiometric ratio, 5QMe2 can completely prevent fibrillation of a synthetic aggregating peptide YAQ12A; it also shows significant inhibition at substoichiometric ratios. Surface plasmon resonance (SPR) measurements show a moderate Kd with very fast kon and koff. Sedimentation equilibrium analytical ultracentrifugation indicates that 5QMe2 is predominantly or entirely monomeric at concentrations up to 1 mM, and that it forms a 1:1 stoichiometric complex with a fibril-forming target, YAQ12A. 5QMe2 inhibits not only nucleation of YAQ12A, but also fibril extension, as shown by the fact that it also inhibits seeded fibril growth where the nucleation steps are bypassed. 5QMe2 acts on its targets only when they are in the PPII-like conformation, but not after they undergo a transition to β-sheets. Thus 5QMe2 does not disassemble pre-formed YAQ12A; this contrasts with our previously described, backbone N-methylated inhibitors of β-amyloid aggregation (16,17). The mode of action of 5QMe2 is reminiscent of chaperones, since it binds and releases its targets very rapidly, and maintains them in a non-aggregation-prone, monomeric state, in this case, the polyproline II (PPII)-like conformation, as shown by CD spectroscopy. PMID:20583779

  20. Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability.

    PubMed

    Ansar, Muhammad; Jan, Abid; Santos-Cortez, Regie Lyn P; Wang, Xin; Suliman, Muhammad; Acharya, Anushree; Habib, Rabia; Abbe, Izoduwa; Ali, Ghazanfar; Lee, Kwanghyuk; Smith, Joshua D; Nickerson, Deborah A; Shendure, Jay; Bamshad, Michael J; Ahmad, Wasim; Leal, Suzanne M

    2016-08-01

    Alopecia with mental retardation (APMR) is a very rare disorder. In this study, we report on a consanguineous Pakistani family (AP91) with mild-to-moderate intellectual disability, adolescent alopecia and dentogingival abnormalities. Using homozygosity mapping, linkage analysis and exome sequencing, we identified a novel rare missense variant c.898G>A (p.(Glu300Lys)) in ITGB6, which co-segregates with the phenotype within the family and is predicted to be deleterious. Structural modeling shows that Glu300 lies in the β-propeller domain, and is surrounded by several residues that are important for heterodimerization with α integrin. Previous studies showed that ITGB6 variants can cause amelogenesis imperfecta in humans, but patients from family AP91 who are homozygous for the c.898G>A variant present with neurological and dermatological features, indicating a role for ITGB6 beyond enamel formation. Our study demonstrates that a rare deleterious variant within ITGB6 causes not only dentogingival anomalies but also intellectual disability and alopecia.

  1. Comparative analysis of anti-polyglutamine Fab crystals grown on Earth and in microgravity

    PubMed Central

    Owens, Gwen E.; New, Danielle M.; Olvera, Alejandra I.; Manzella, Julia Ashlyn; Macon, Brittney L.; Dunn, Joshua C.; Cooper, David A.; Rouleau, Robyn L.; Connor, Daniel S.; Bjorkman, Pamela J.

    2016-01-01

    Huntington’s disease is one of nine neurodegenerative diseases caused by a polyglutamine (polyQ)-repeat expansion. An anti-polyQ antigen-binding fragment, MW1 Fab, was crystallized both on Earth and on the International Space Station, a microgravity environment where convection is limited. Once the crystals returned to Earth, the number, size and morphology of all crystals were recorded, and X-ray data were collected from representative crystals. The results generally agreed with previous microgravity crystallization studies. On average, microgravity-grown crystals were 20% larger than control crystals grown on Earth, and microgravity-grown crystals had a slightly improved mosaicity (decreased by 0.03°) and diffraction resolution (decreased by 0.2 Å) compared with control crystals grown on Earth. However, the highest resolution and lowest mosaicity crystals were formed on Earth, and the highest-quality crystal overall was formed on Earth after return from microgravity. PMID:27710941

  2. Comparative analysis of anti-polyglutamine Fab crystals grown on Earth and in microgravity.

    PubMed

    Owens, Gwen E; New, Danielle M; Olvera, Alejandra I; Manzella, Julia Ashlyn; Macon, Brittney L; Dunn, Joshua C; Cooper, David A; Rouleau, Robyn L; Connor, Daniel S; Bjorkman, Pamela J

    2016-10-01

    Huntington's disease is one of nine neurodegenerative diseases caused by a polyglutamine (polyQ)-repeat expansion. An anti-polyQ antigen-binding fragment, MW1 Fab, was crystallized both on Earth and on the International Space Station, a microgravity environment where convection is limited. Once the crystals returned to Earth, the number, size and morphology of all crystals were recorded, and X-ray data were collected from representative crystals. The results generally agreed with previous microgravity crystallization studies. On average, microgravity-grown crystals were 20% larger than control crystals grown on Earth, and microgravity-grown crystals had a slightly improved mosaicity (decreased by 0.03°) and diffraction resolution (decreased by 0.2 Å) compared with control crystals grown on Earth. However, the highest resolution and lowest mosaicity crystals were formed on Earth, and the highest-quality crystal overall was formed on Earth after return from microgravity.

  3. Expanded polyglutamine stretches lead to aberrant transcriptional regulation in polyglutamine diseases.

    PubMed

    Shimohata, T; Onodera, O; Tsuji, S

    2001-03-01

    At least nine neurodegenerative diseases are known to be caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches have been suggested, the molecular mechanisms of neurodegeneration remain unclear. We demonstrated that the nuclear translocation of mutant proteins containing expanded polyQ stretches is a prerequisite for the expression of their cytotoxicity. Hypothesizing that nuclear proteins that interact with mutant proteins, particularly, those that bind to the expanded polyQ stretches, are involved in the pathogenetic mechanisms underlying neurodegeneration, we screened nuclear proteins for their capability of binding to expanded polyQ stretches. We found that expanded polyQ stretches preferentially bind to TAF[symbol: see text]130, a coactivator involved in CREB-dependent transcriptional activation. The binding of TAF[symbol: see text]130 with expanded polyQ stretches strongly suppress CREB-dependent transcriptional activation, suggesting that interference with transcription due to the binding of expanded polyQ stretches with TAF[symbol: see text]130 and redistribution of TAF[symbol: see text]130 are involved in the pathogenetic mechanisms underlying neurodegeneration.

  4. D-polyglutamine amyloid recruits L-polyglutamine monomers and kills cells.

    PubMed

    Kar, Karunakar; Arduini, Irene; Drombosky, Kenneth W; van der Wel, Patrick C A; Wetzel, Ronald

    2014-02-20

    Polyglutamine (polyQ) amyloid fibrils are observed in disease tissue and have been implicated as toxic agents responsible for neurodegeneration in expanded CAG repeat diseases such as Huntington's disease. Despite intensive efforts, the mechanism of amyloid toxicity remains unknown. As a novel approach to probing polyQ toxicity, we investigate here how some cellular and physical properties of polyQ amyloid vary with the chirality of the glutamine residues in the polyQ. We challenged PC12 cells with small amyloid fibrils composed of either L- or D-polyQ peptides and found that D-fibrils are as cytotoxic as L-fibrils. We also found using fluorescence microscopy that both aggregates effectively seed the aggregation of cell-produced L-polyQ proteins, suggesting a surprising lack of stereochemical restriction in seeded elongation of polyQ amyloid. To investigate this effect further, we studied chemically synthesized D- and L-polyQ in vitro. We found that, as expected, D-polyQ monomers are not recognized by proteins that recognize L-polyQ monomers. However, amyloid fibrils prepared from D-polyQ peptides can efficiently seed the aggregation of L-polyQ monomers in vitro, and vice versa. This result is consistent with our cell results on polyQ recruitment but is inconsistent with previous literature reports on the chiral specificity of amyloid seeding. This chiral cross-seeding can be rationalized by a model for seeded elongation featuring a "rippled β-sheet" interface between seed fibril and docked monomers of opposite chirality. The lack of chiral discrimination in polyQ amyloid cytotoxicity is consistent with several toxicity mechanisms, including recruitment of cellular polyQ proteins.

  5. Neurodegenerative Models in Drosophila: Polyglutamine Disorders, Parkinson Disease, and Amyotrophic Lateral Sclerosis

    PubMed Central

    Ambegaokar, Surendra S.; Roy, Bidisha; Jackson, George R.

    2010-01-01

    Neurodegenerative diseases encompass a large group of neurological disorders. Clinical symptoms can include memory loss, cognitive impairment, loss of movement or loss of control of movement, and loss of sensation. Symptoms are typically adult onset (although severe cases can occur in adolescents) and are reflective of neuronal and glial cell loss in the central nervous system. Neurodegenerative diseases also are considered progressive, with increased severity of symptoms over time, also reflective of increased neuronal cell death. However, various neurodegenerative diseases differentially affect certain brain regions or neuronal or glial cell types. As an example, Alzheimer disease (AD) primarily affects the temporal lobe, whereas neuronal loss in Parkinson disease (PD) is largely (although not exclusively) confined to the nigrostriatal system. Neuronal loss is almost invariably accompanied by abnormal insoluble aggregates, either intra- or extracellular. Thus, neurodegenerative diseases are categorized by (a) the composite of clinical symptoms, (b) the brain regions or types of brain cells primarily affected, and (c) the types of protein aggregates found in the brain. Here we review the methods by which Drosophila melanogaster has been used to model aspects of polyglutamine diseases, Parkinson disease, and amyotrophic lateral sclerosis and key insights into that have been gained from these models; Alzheimer disease and the tauopathies are covered elsewhere in this special issue. PMID:20561920

  6. Structural motif of polyglutamine amyloid fibrils discerned with mixed-isotope infrared spectroscopy

    PubMed Central

    Buchanan, Lauren E.; Carr, Joshua K.; Fluitt, Aaron M.; Hoganson, Andrew J.; Moran, Sean D.; de Pablo, Juan J.; Skinner, James L.; Zanni, Martin T.

    2014-01-01

    Polyglutamine (polyQ) sequences are found in a variety of proteins, and mutational expansion of the polyQ tract is associated with many neurodegenerative diseases. We study the amyloid fibril structure and aggregation kinetics of K2Q24K2W, a model polyQ sequence. Two structures have been proposed for amyloid fibrils formed by polyQ peptides. By forming fibrils composed of both 12C and 13C monomers, made possible by protein expression in Escherichia coli, we can restrict vibrational delocalization to measure 2D IR spectra of individual monomers within the fibrils. The spectra are consistent with a β-turn structure in which each monomer forms an antiparallel hairpin and donates two strands to a single β-sheet. Calculated spectra from atomistic molecular-dynamics simulations of the two proposed structures confirm the assignment. No spectroscopically distinct intermediates are observed in rapid-scan 2D IR kinetics measurements, suggesting that aggregation is highly cooperative. Although 2D IR spectroscopy has advantages over linear techniques, the isotope-mixing strategy will also be useful with standard Fourier transform IR spectroscopy. PMID:24550484

  7. Prefoldin Protects Neuronal Cells from Polyglutamine Toxicity by Preventing Aggregation Formation*

    PubMed Central

    Tashiro, Erika; Zako, Tamotsu; Muto, Hideki; Itoo, Yoshinori; Sörgjerd, Karin; Terada, Naofumi; Abe, Akira; Miyazawa, Makoto; Kitamura, Akira; Kitaura, Hirotake; Kubota, Hiroshi; Maeda, Mizuo; Momoi, Takashi; Iguchi-Ariga, Sanae M. M.; Kinjo, Masataka; Ariga, Hiroyoshi

    2013-01-01

    Huntington disease is caused by cell death after the expansion of polyglutamine (polyQ) tracts longer than ∼40 repeats encoded by exon 1 of the huntingtin (HTT) gene. Prefoldin is a molecular chaperone composed of six subunits, PFD1–6, and prevents misfolding of newly synthesized nascent polypeptides. In this study, we found that knockdown of PFD2 and PFD5 disrupted prefoldin formation in HTT-expressing cells, resulting in accumulation of aggregates of a pathogenic form of HTT and in induction of cell death. Dead cells, however, did not contain inclusions of HTT, and analysis by a fluorescence correlation spectroscopy indicated that knockdown of PFD2 and PFD5 also increased the size of soluble oligomers of pathogenic HTT in cells. In vitro single molecule observation demonstrated that prefoldin suppressed HTT aggregation at the small oligomer (dimer to tetramer) stage. These results indicate that prefoldin inhibits elongation of large oligomers of pathogenic Htt, thereby inhibiting subsequent inclusion formation, and suggest that soluble oligomers of polyQ-expanded HTT are more toxic than are inclusion to cells. PMID:23720755

  8. Multiple discrete soluble aggregates influence polyglutamine toxicity in a Huntington’s disease model system

    PubMed Central

    Xi, Wen; Wang, Xin; Laue, Thomas M.; Denis, Clyde L.

    2016-01-01

    Huntington’s disease (HD) results from expansions of polyglutamine stretches (polyQ) in the huntingtin protein (Htt) that promote protein aggregation, neurodegeneration, and death. Since the diversity and sizes of the soluble Htt-polyQ aggregates that have been linked to cytotoxicity are unknown, we investigated soluble Htt-polyQ aggregates using analytical ultracentrifugation. Soon after induction in a yeast HD model system, non-toxic Htt-25Q and cytotoxic Htt-103Q both formed soluble aggregates 29S to 200S in size. Because current models indicate that Htt-25Q does not form soluble aggregates, reevaluation of previous studies may be necessary. Only Htt-103Q aggregation behavior changed, however, with time. At 6 hr mid-sized aggregates (33S to 84S) and large aggregates (greater than 100S) became present while at 24 hr primarily only mid-sized aggregates (20S to 80S) existed. Multiple factors that decreased cytotoxicity of Htt-103Q (changing the length of or sequences adjacent to the polyQ, altering ploidy or chaperone dosage, or deleting anti-aging factors) altered the Htt-103Q aggregation pattern in which the suite of mid-sized aggregates at 6 hr were most correlative with cytotoxicity. Hence, the amelioration of HD and other neurodegenerative diseases may require increased attention to and discrimination of the dynamic alterations in soluble aggregation processes. PMID:27721444

  9. Assessing polyglutamine conformation in the nucleating event by molecular dynamics simulations.

    PubMed

    Miettinen, Markus S; Knecht, Volker; Monticelli, Luca; Ignatova, Zoya

    2012-08-30

    Polyglutamine (polyQ) diseases comprise a group of dominantly inherited pathology caused by an expansion of an unstable polyQ stretch which is presumed to form β-sheets. Similar to other amyloid pathologies, polyQ amyloidogenesis occurs via a nucleated polymerization mechanism, and proceeds through energetically unfavorable nucleus whose existence and structure are difficult to detect. Here, we use atomistic molecular dynamics simulations in explicit solvent to assess the conformation of the polyQ stretch in the nucleus that initiates polyQ fibrillization. Comparison of the kinetic stability of various structures of polyQ peptide with a Q-length in the pathological range (Q40) revealed that steric zipper or nanotube-like structures (β-nanotube or β-pseudohelix) are not kinetically stable enough to serve as a template to initiate polyQ fibrillization as opposed to β-hairpin-based (β-sheet and β-sheetstack) or α-helical conformations. The selection of different structures of the polyQ stretch in the aggregation-initiating event may provide an alternative explanation for polyQ aggregate polymorphism.

  10. Fluorescence lifetime dynamics of enhanced green fluorescent protein in protein aggregates with expanded polyglutamine.

    PubMed

    Ghukasyan, Vladimir; Hsu, Chih-Chun; Liu, Chia-Rung; Kao, Fu-Jen; Cheng, Tzu-Hao

    2010-01-01

    Protein aggregation is one of the characteristic steps in a number of neurodegenerative diseases eventually leading to neuronal death and thorough study of aggregation is required for the development of effective therapy. We apply fluorescence lifetime imaging for the characterization of the fluorescence dynamics of the enhanced green fluorescent protein (eGFP) in fusion with the polyQ-expanded polyglutamine stretch. At the expansion of polyQ above 39 residues, it has an inherent propensity to form amyloid-like fibrils and aggregates, and is responsible for Huntington's disease. The results of the experiments show that expression of the eGFP in fusion with the 97Q protein leads to the decrease of the eGFP fluorescence lifetime by approximately 300 ps. This phenomenon does not appear in Hsp104-deficient cells, where the aggregation in polyQ is prevented. We demonstrate that the lifetime decrease observed is related to the aggregation per se and discuss the possible role of refractive index and homo-FRET in these dynamics.

  11. A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells

    PubMed Central

    Hsieh, Chang Heng; Lee, Li-Ching; Leong, Wai-Yin; Yang, Tsai-Chen; Yao, Ching-Fa; Fang, Kang

    2016-01-01

    Trinucleotide CAG repeat expansion in the coding region of genes has a propensity to form polyglutamine (polyQ) aggregates that contribute to neuronal disorders. Strategies in elevating autophagy to disintegrate the insoluble aggregates without injuring cells have become a major goal for therapy. In this work, a triazole derivative, OC-13, was found accelerating autophagic clearance of polyQ aggregation in human neuroblastoma cells following induction of the enhanced green fluorescence-conjugated chimeric protein that enclosed 79 polyQ repeats (Q79-EGFP). OC-13 accelerated autophagy development and removed nuclear Q79-EGFP aggregates. The increase of Beclin-1, turnover of LC3-I to LC3-II and degradation of p62 supported autophagy activation. Pretreatment of autophagy inhibitor, bafilomycin A1, not only suppressed autophagolysome fusion, but also impeded aggregate eradication. The study also showed that c-Jun N-terminal kinase/Beclin-1 pathway was activated during OC-13 treatment and c-Jun N-terminal kinase inhibitor impaired autophagy and final breakdown. Autophagic clearance of the insoluble aggregates demonstrated the feasibility of OC-13 in alleviating neuronal disorders because of expanded glutamine stretches. PMID:27695292

  12. Fluorescence lifetime dynamics of enhanced green fluorescent protein in protein aggregates with expanded polyglutamine

    NASA Astrophysics Data System (ADS)

    Ghukasyan, Vladimir; Hsu, Chih-Chun; Liu, Chia-Rung; Kao, Fu-Jen; Cheng, Tzu-Hao

    2010-01-01

    Protein aggregation is one of the characteristic steps in a number of neurodegenerative diseases eventually leading to neuronal death and thorough study of aggregation is required for the development of effective therapy. We apply fluorescence lifetime imaging for the characterization of the fluorescence dynamics of the enhanced green fluorescent protein (eGFP) in fusion with the polyQ-expanded polyglutamine stretch. At the expansion of polyQ above 39 residues, it has an inherent propensity to form amyloid-like fibrils and aggregates, and is responsible for Huntington's disease. The results of the experiments show that expression of the eGFP in fusion with the 97Q protein leads to the decrease of the eGFP fluorescence lifetime by ~300 ps. This phenomenon does not appear in Hsp104-deficient cells, where the aggregation in polyQ is prevented. We demonstrate that the lifetime decrease observed is related to the aggregation per se and discuss the possible role of refractive index and homo-FRET in these dynamics.

  13. Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor–mediated disease

    PubMed Central

    Chua, Jason P.; Reddy, Satya L.; Yu, Zhigang; Giorgetti, Elisa; Montie, Heather L.; Mukherjee, Sarmistha; Higgins, Jake; McEachin, Richard C.; Robins, Diane M.; Merry, Diane E.; Iñiguez-Lluhí, Jorge A.; Lieberman, Andrew P.

    2015-01-01

    Expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from polyQ-mediated proteotoxicity by enhancing the transcriptional activity of polyQ AR. To accomplish this, we bypassed the inhibitory effect of AR SUMOylation (where SUMO indicates small ubiquitin-like modifier) by mutating conserved lysines in the polyQ AR that are sites of SUMOylation. We determined that replacement of these residues by arginine enhances polyQ AR activity as a hormone-dependent transcriptional regulator. In a murine model, disruption of polyQ AR SUMOylation rescued exercise endurance and type I muscle fiber atrophy; it also prolonged survival. These changes occurred without overt alterations in polyQ AR expression or aggregation, revealing the favorable trophic support exerted by the ligand-activated receptor. Our findings demonstrate beneficial effects of enhancing the transcriptional function of the ligand-activated polyQ AR and indicate that the SUMOylation pathway may be a potential target for therapeutic intervention in SBMA. PMID:25607844

  14. Verification of Inter-laboratorial Genotyping Consistency in the Molecular Diagnosis of Polyglutamine Spinocerebellar Ataxias.

    PubMed

    Ramos, Amanda; Raposo, Mafalda; Milà, Montserrat; Bettencourt, Conceição; Houlden, Henry; Cisneros, Bulmaro; Magaña, Jonathan J; Bettencourt, Bruno Filipe; Bruges-Armas, Jácome; Santos, Cristina; Lima, Manuela

    2016-01-01

    The polyglutamine spinocerebellar ataxias (SCAs) constitute a clinically and genetically heterogeneous group of rare late-onset neurodegenerative disorders, caused by CAG expansions in the coding region of the respective genes. Given their considerable clinical overlapping, differential diagnosis relies on molecular testing. Laboratory best practice guidelines for molecular genetic testing of the SCAs were released in 2010 by the European Molecular Genetics Quality Network, following the recognition of gross genotyping errors by some diagnostic laboratories. The main goal of this study was to verify the existence of inter-laboratorial consistency comparing genotypes for SCA1, SCA2, SCA3, SCA6 and SCA7 obtained by independent diagnostic laboratories. The individual impact of different methodological issues on the genotype for the several SCAs was also analysed. Four international collaborative diagnostic laboratories provided 79 samples and the respective SCA genotypes. Samples were genotyped in-house for all SCAs using an independent methodology; comparison of the allele size obtained with the one provided by the collaborative laboratories was performed. Globally, no significant differences were identified, a result which could be reflecting the fulfilment of recommendations for the molecular testing of SCAs and demonstrating an improvement in genotyping accuracy.

  15. Nanoscale studies link amyloid maturity with polyglutamine diseases onset

    NASA Astrophysics Data System (ADS)

    Ruggeri, F. S.; Vieweg, S.; Cendrowska, U.; Longo, G.; Chiki, A.; Lashuel, H. A.; Dietler, G.

    2016-08-01

    The presence of expanded poly-glutamine (polyQ) repeats in proteins is directly linked to the pathogenesis of several neurodegenerative diseases, including Huntington’s disease. However, the molecular and structural basis underlying the increased toxicity of aggregates formed by proteins containing expanded polyQ repeats remain poorly understood, in part due to the size and morphological heterogeneity of the aggregates they form in vitro. To address this knowledge gap and technical limitations, we investigated the structural, mechanical and morphological properties of fibrillar aggregates at the single molecule and nanometer scale using the first exon of the Huntingtin protein as a model system (Exon1). Our findings demonstrate a direct correlation of the morphological and mechanical properties of Exon1 aggregates with their structural organization at the single aggregate and nanometric scale and provide novel insights into the molecular and structural basis of Huntingtin Exon1 aggregation and toxicity.

  16. Nanoscale studies link amyloid maturity with polyglutamine diseases onset

    PubMed Central

    Ruggeri, F. S.; Vieweg, S.; Cendrowska, U.; Longo, G.; Chiki, A.; Lashuel, H. A.; Dietler, G.

    2016-01-01

    The presence of expanded poly-glutamine (polyQ) repeats in proteins is directly linked to the pathogenesis of several neurodegenerative diseases, including Huntington’s disease. However, the molecular and structural basis underlying the increased toxicity of aggregates formed by proteins containing expanded polyQ repeats remain poorly understood, in part due to the size and morphological heterogeneity of the aggregates they form in vitro. To address this knowledge gap and technical limitations, we investigated the structural, mechanical and morphological properties of fibrillar aggregates at the single molecule and nanometer scale using the first exon of the Huntingtin protein as a model system (Exon1). Our findings demonstrate a direct correlation of the morphological and mechanical properties of Exon1 aggregates with their structural organization at the single aggregate and nanometric scale and provide novel insights into the molecular and structural basis of Huntingtin Exon1 aggregation and toxicity. PMID:27499269

  17. Picosecond pulsed infrared laser tuned to amide I band dissociates polyglutamine fibrils in cells.

    PubMed

    Kawasaki, Takayasu; Ohori, Gaku; Chiba, Tomoyuki; Tsukiyama, Koichi; Nakamura, Kazuhiro

    2016-09-01

    Amyloid fibrils are causal substances for serious neurodegenerative disorders and amyloidosis. Among them, polyglutamine fibrils seen in multiple polyglutamine diseases are toxic to neurons. Although much efforts have been made to explore the treatments of polyglutamine diseases, there are no effective drugs to block progression of the diseases. We recently found that a free electron laser (FEL), which has an oscillation wavelength at the amide I band (C = O stretch vibration mode) and picosecond pulse width, was effective for conversion of the fibril forms of insulin, lysozyme, and calcitonin peptide into their monomer forms. However, it is not known if that is also the case in polyglutamine fibrils in cells. We found in this study that the fibril-specific β-sheet conformation of polyglutamine peptide was converted into nonfibril form, as evidenced by the infrared microscopy and scanning-electron microscopy after the irradiation tuned to 6.08 μm. Furthermore, irradiation at this wavelength also changed polyglutamine fibrils to their nonfibril state in cultured cells, as shown by infrared mapping image of protein secondary structure. Notably, infrared thermography analysis showed that temperature increase of the cells during the irradiation was within 1 K, excluding thermal damage of cells. These results indicate that the picosecond pulsed infrared laser can safely reduce amyloid fibril structure to the nonfibril form even in cells.

  18. Congenital Abnormalities

    MedlinePlus

    ... Listen Español Text Size Email Print Share Congenital Abnormalities Page Content Article Body About 3% to 4% ... of congenital abnormalities earlier. 5 Categories of Congenital Abnormalities Chromosome Abnormalities Chromosomes are structures that carry genetic ...

  19. Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice

    PubMed Central

    Huang, Shanshan; Yang, Su; Guo, Jifeng; Yan, Sen; Gaertig, Marta A.; Li, Shihua; Li, Xiao-Jiang

    2015-01-01

    SUMMARY In polyglutamine (polyQ) diseases, large polyQ repeats cause juvenile cases with different symptoms than adult-onset patients, who carry smaller expanded polyQ repeats. The mechanisms behind the differential pathology mediated by different polyQ repeat lengths remain unknown. By studying knock-in mouse models of spinal cerebellar ataxia-17 (SCA17), we found that a large polyQ (105 glutamines) in the TATA box-binding protein (TBP) preferentially causes muscle degeneration and reduces the expression of muscle-specific genes. Direct expression of TBP with different polyQ repeats in mouse muscle revealed that muscle degeneration is mediated only by the large polyQ repeats. Different polyQ repeats differentially alter TBP’s interaction with neuronal and muscle-specific transcription factors. As a result, the large polyQ repeat decreases the association of MyoD with TBP and DNA promoters. Our findings suggest that specific alterations in protein interactions by large polyQ repeats may account for the unique pathology in juvenile polyQ diseases. PMID:26387956

  20. Oligomeric and polymeric aggregates formed by proteins containing expanded polyglutamine

    PubMed Central

    Iuchi, S.; Hoffner, G.; Verbeke, P.; Djian, P.; Green, H.

    2003-01-01

    Neurological diseases resulting from proteins containing expanded polyglutamine (polyQ) are characteristically associated with insoluble neuronal inclusions, usually intranuclear, and neuronal death. We describe here oligomeric and polymeric aggregates formed in cells by expanded polyQ. These aggregates are not dissociated by concentrated formic acid, an extremely effective solvent for otherwise insoluble proteins. Perinuclear inclusions formed in cultured cells by expanded polyQ can be completely dissolved in concentrated formic acid, but a soluble protein oligomer containing the expanded polyQ and released by the formic acid is not dissociated to monomer. In Huntington's disease, a formic acid-resistant oligomer is present in cerebral cortex, but not in cerebellum. Cortical nuclei contain a polymeric aggregate of expanded polyQ that is insoluble in formic acid, does not enter polyacrylamide gels, but is retained on filters. This finding shows that the process of polymerization is more advanced in the cerebral cortex than in cultured cells. The resistance of oligomer and polymer to formic acid suggests the participation of covalent bonds in their stabilization. PMID:12591956

  1. Candida albicans Is Resistant to Polyglutamine Aggregation and Toxicity

    PubMed Central

    Leach, Michelle D.; Kim, TaeHyung; DiGregorio, Sonja E.; Collins, Cathy; Zhang, Zhaolei; Duennwald, Martin L.; Cowen, Leah E.

    2016-01-01

    Disruption of protein quality control can be detrimental, having toxic effects on single cell organisms and contributing to neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s in humans. Here, we examined the effects of polyglutamine (polyQ) aggregation in a major fungal pathogen of humans, Candida albicans, with the goal of identifying new approaches to disable this fungus. However, we discovered that expression of polyQ stretches up to 230Q had no effect on C. albicans ability to grow and withstand proteotoxic stress. Bioinformatics analysis demonstrates that C. albicans has a similarly glutamine-rich proteome to the unicellular fungus Saccharomyces cerevisiae, which exhibits polyQ toxicity with as few as 72Q. Surprisingly, global transcriptional profiles indicated no significant change upon induction of up to 230Q. Proteomic analysis highlighted two key interactors of 230Q, Sis1 and Sgt2; however, loss of either protein had no additional effect on C. albicans toxicity. Our data suggest that C. albicans has evolved powerful mechanisms to overcome the toxicity associated with aggregation-prone proteins, providing a unique model for studying polyQ-associated diseases. PMID:27807047

  2. Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

    PubMed Central

    Ishibashi, Hidetoshi; Minakawa, Eiko N.; Motohashi, Hideyuki H.; Takayama, Osamu; Popiel, H. Akiko; Puentes, Sandra; Owari, Kensuke; Nakatani, Terumi; Nogami, Naotake; Yamamoto, Kazuhiro; Yonekawa, Takahiro; Tanaka, Yoko; Fujita, Naoko; Suzuki, Hikaru; Aizawa, Shu; Nagano, Seiichi; Yamada, Daisuke; Wada, Keiji; Kohsaka, Shinichi

    2017-01-01

    Abstract Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases. PMID:28374014

  3. An Analysis of Biomolecular Force Fields for Simulations of Polyglutamine in Solution

    SciTech Connect

    Fluitt, Aaron M.; de Pablo, Juan J.

    2015-09-01

    Polyglutamine (polyQ) peptides are a useful model system for biophysical studies of protein folding and aggregation, both for their intriguing aggregation properties and their own relevance to human disease. The genetic expansion of a polyQ tract triggers the formation of amyloid aggregates associated with nine neurodegenerative diseases. Several clearly identifiable and separable factors, notably the length of the polyQ tract, influence the mechanism of aggregation, its associated kinetics, and the ensemble of structures formed. Atomistic simulations are well positioned to answer open questions regarding the thermodynamics and kinetics of polyQ folding and aggregation. The additional, explicit representation of water permits deeper investigation of the role of solvent dynamics, and it permits a direct comparison of simulation results with infrared spectroscopy experiments. The generation of meaningful simulation results hinges on satisfying two essential criteria: achieving sufficient conformational sampling to draw statistically valid conclusions, and accurately reproducing the intermolecular forces that govern system structure and dynamics. In this work, we examine the ability of 12 biomolecular force fields to reproduce the properties of a simple, 30-residue polyQ peptide (Q30) in explicit water. In addition to secondary and tertiary structure, we consider generic structural properties of polymers that provide additional dimensions for analysis of the highly degenerate disordered states of the molecule. We find that the 12 force fields produce a wide range of predictions. We identify AMBER ff99SB, AMBER ff99SB*, and OPLS-AA/L to be most suitable for studies of polyQ folding and aggregation.

  4. Architecture of Polyglutamine-containing Fibrils from Time-resolved Fluorescence Decay

    PubMed Central

    Röthlein, Christoph; Miettinen, Markus S.; Borwankar, Tejas; Bürger, Jörg; Mielke, Thorsten; Kumke, Michael U.; Ignatova, Zoya

    2014-01-01

    The disease risk and age of onset of Huntington disease (HD) and nine other repeat disorders strongly depend on the expansion of CAG repeats encoding consecutive polyglutamines (polyQ) in the corresponding disease protein. PolyQ length-dependent misfolding and aggregation are the hallmarks of CAG pathologies. Despite intense effort, the overall structure of these aggregates remains poorly understood. Here, we used sensitive time-dependent fluorescent decay measurements to assess the architecture of mature fibrils of huntingtin (Htt) exon 1 implicated in HD pathology. Varying the position of the fluorescent labels in the Htt monomer with expanded 51Q (Htt51Q) and using structural models of putative fibril structures, we generated distance distributions between donors and acceptors covering all possible distances between the monomers or monomer dimensions within the polyQ amyloid fibril. Using Monte Carlo simulations, we systematically scanned all possible monomer conformations that fit the experimentally measured decay times. Monomers with four-stranded 51Q stretches organized into five-layered β-sheets with alternating N termini of the monomers perpendicular to the fibril axis gave the best fit to our data. Alternatively, the core structure of the polyQ fibrils might also be a zipper layer with antiparallel four-stranded stretches as this structure showed the next best fit. All other remaining arrangements are clearly excluded by the data. Furthermore, the assessed dimensions of the polyQ stretch of each monomer provide structural evidence for the observed polyQ length threshold in HD pathology. Our approach can be used to validate the effect of pharmacological substances that inhibit or alter amyloid growth and structure. PMID:25092288

  5. Architecture of polyglutamine-containing fibrils from time-resolved fluorescence decay.

    PubMed

    Röthlein, Christoph; Miettinen, Markus S; Borwankar, Tejas; Bürger, Jörg; Mielke, Thorsten; Kumke, Michael U; Ignatova, Zoya

    2014-09-26

    The disease risk and age of onset of Huntington disease (HD) and nine other repeat disorders strongly depend on the expansion of CAG repeats encoding consecutive polyglutamines (polyQ) in the corresponding disease protein. PolyQ length-dependent misfolding and aggregation are the hallmarks of CAG pathologies. Despite intense effort, the overall structure of these aggregates remains poorly understood. Here, we used sensitive time-dependent fluorescent decay measurements to assess the architecture of mature fibrils of huntingtin (Htt) exon 1 implicated in HD pathology. Varying the position of the fluorescent labels in the Htt monomer with expanded 51Q (Htt51Q) and using structural models of putative fibril structures, we generated distance distributions between donors and acceptors covering all possible distances between the monomers or monomer dimensions within the polyQ amyloid fibril. Using Monte Carlo simulations, we systematically scanned all possible monomer conformations that fit the experimentally measured decay times. Monomers with four-stranded 51Q stretches organized into five-layered β-sheets with alternating N termini of the monomers perpendicular to the fibril axis gave the best fit to our data. Alternatively, the core structure of the polyQ fibrils might also be a zipper layer with antiparallel four-stranded stretches as this structure showed the next best fit. All other remaining arrangements are clearly excluded by the data. Furthermore, the assessed dimensions of the polyQ stretch of each monomer provide structural evidence for the observed polyQ length threshold in HD pathology. Our approach can be used to validate the effect of pharmacological substances that inhibit or alter amyloid growth and structure.

  6. Correlation of Inter-Locus Polyglutamine Toxicity with CAG•CTG Triplet Repeat Expandability and Flanking Genomic DNA GC Content

    PubMed Central

    Nestor, Colm E.; Monckton, Darren G.

    2011-01-01

    Dynamic expansions of toxic polyglutamine (polyQ)-encoding CAG repeats in ubiquitously expressed, but otherwise unrelated, genes cause a number of late-onset progressive neurodegenerative disorders, including Huntington disease and the spinocerebellar ataxias. As polyQ toxicity in these disorders increases with repeat length, the intergenerational expansion of unstable CAG repeats leads to anticipation, an earlier age-at-onset in successive generations. Crucially, disease associated alleles are also somatically unstable and continue to expand throughout the lifetime of the individual. Interestingly, the inherited polyQ length mediating a specific age-at-onset of symptoms varies markedly between disorders. It is widely assumed that these inter-locus differences in polyQ toxicity are mediated by protein context effects. Previously, we demonstrated that the tendency of expanded CAG•CTG repeats to undergo further intergenerational expansion (their ‘expandability’) also differs between disorders and these effects are strongly correlated with the GC content of the genomic flanking DNA. Here we show that the inter-locus toxicity of the expanded polyQ tracts of these disorders also correlates with both the expandability of the underlying CAG repeat and the GC content of the genomic DNA flanking sequences. Inter-locus polyQ toxicity does not correlate with properties of the mRNA or protein sequences, with polyQ location within the gene or protein, or steady state transcript levels in the brain. These data suggest that the observed inter-locus differences in polyQ toxicity are not mediated solely by protein context effects, but that genomic context is also important, an effect that may be mediated by modifying the rate at which somatic expansion of the DNA delivers proteins to their cytotoxic state. PMID:22163004

  7. The Social Amoeba Dictyostelium discoideum Is Highly Resistant to Polyglutamine Aggregation.

    PubMed

    Santarriaga, Stephanie; Petersen, Amber; Ndukwe, Kelechi; Brandt, Anthony; Gerges, Nashaat; Bruns Scaglione, Jamie; Scaglione, Kenneth Matthew

    2015-10-16

    The expression, misfolding, and aggregation of long repetitive amino acid tracts are a major contributing factor in a number of neurodegenerative diseases, including C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia, fragile X tremor ataxia syndrome, myotonic dystrophy type 1, spinocerebellar ataxia type 8, and the nine polyglutamine diseases. Protein aggregation is a hallmark of each of these diseases. In model organisms, including yeast, worms, flies, mice, rats, and human cells, expression of proteins with the long repetitive amino acid tracts associated with these diseases recapitulates the protein aggregation that occurs in human disease. Here we show that the model organism Dictyostelium discoideum has evolved to normally encode long polyglutamine tracts and express these proteins in a soluble form. We also show that Dictyostelium has the capacity to suppress aggregation of a polyglutamine-expanded Huntingtin construct that aggregates in other model organisms tested. Together, these data identify Dictyostelium as a novel model organism with the capacity to suppress aggregation of proteins with long polyglutamine tracts.

  8. Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy.

    PubMed

    Polanco, Maria Josè; Parodi, Sara; Piol, Diana; Stack, Conor; Chivet, Mathilde; Contestabile, Andrea; Miranda, Helen C; Lievens, Patricia M-J; Espinoza, Stefano; Jochum, Tobias; Rocchi, Anna; Grunseich, Christopher; Gainetdinov, Raul R; Cato, Andrew C B; Lieberman, Andrew P; La Spada, Albert R; Sambataro, Fabio; Fischbeck, Kenneth H; Gozes, Illana; Pennuto, Maria

    2016-12-21

    Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. SBMA belongs to the family of polyQ diseases, which are fatal neurodegenerative disorders mainly caused by protein-mediated toxic gain-of-function mechanisms and characterized by deposition of misfolded proteins in the form of aggregates. The neurotoxicity of the polyQ proteins can be modified by phosphorylation at specific sites, thereby providing the rationale for the development of disease-specific treatments. We sought to identify signaling pathways that modulate polyQ-AR phosphorylation for therapy development. We report that cyclin-dependent kinase 2 (CDK2) phosphorylates polyQ-AR specifically at Ser(96) Phosphorylation of polyQ-AR by CDK2 increased protein stabilization and toxicity and is negatively regulated by the adenylyl cyclase (AC)/protein kinase A (PKA) signaling pathway. To translate these findings into therapy, we developed an analog of pituitary adenylyl cyclase activating polypeptide (PACAP), a potent activator of the AC/PKA pathway. Chronic intranasal administration of the PACAP analog to knock-in SBMA mice reduced Ser(96) phosphorylation, promoted polyQ-AR degradation, and ameliorated disease outcome. These results provide proof of principle that noninvasive therapy based on the use of PACAP analogs is a therapeutic option for SBMA.

  9. Effects of the enlargement of polyglutamine segments on the structure and folding of ataxin-2 and ataxin-3 proteins.

    PubMed

    Wen, Jingran; Scoles, Daniel R; Facelli, Julio C

    2017-02-01

    Spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) are two common autosomal-dominant inherited ataxia syndromes, both of which are related to the unstable expansion of trinucleotide CAG repeats in the coding region of the related ATXN2 and ATXN3 genes, respectively. The poly-glutamine (poly-Q) tract encoded by the CAG repeats has long been recognized as an important factor in disease pathogenesis and progress. In this study, using the I-TASSER method for 3D structure prediction, we investigated the effect of poly-Q tract enlargement on the structure and folding of ataxin-2 and ataxin-3 proteins. Our results show good agreement with the known experimental structures of the Josephin and UIM domains providing credence to the simulation results presented here, which show that the enlargement of the poly-Q region not only affects the local structure of these regions but also affects the structures of functional domains as well as the whole protein. The changes observed in the predicted models of the UIM domains in ataxin-3 when the poly-Q track is enlarged provide new insights on possible pathogenic mechanisms.

  10. Alveolar abnormalities

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/001093.htm Alveolar abnormalities To use the sharing features on this page, please enable JavaScript. Alveolar abnormalities are changes in the tiny air sacs in ...

  11. Nail abnormalities

    MedlinePlus

    Beau's lines; Fingernail abnormalities; Spoon nails; Onycholysis; Leukonychia; Koilonychia; Brittle nails ... 2012:chap 71. Zaiac MN, Walker A. Nail abnormalities associated with systemic pathologies. Clin Dermatol . 2013;31: ...

  12. Expansion, mosaicism and interruption: mechanisms of the CAG repeat mutation in spinocerebellar ataxia type 1.

    PubMed

    Kraus-Perrotta, Cara; Lagalwar, Sarita

    2016-01-01

    Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that primarily affects the cerebellum and brainstem. The genetic mutation is an expansion of CAG trinucleotide repeats within the coding region of the ataxin-1 gene, characterizing SCA1 as a polyglutamine expansion disease like Huntington's. As with most polyglutamine expansion diseases, SCA1 follows the rules of genetic anticipation: the larger the expansion, the earlier and more rapid the symptoms. Unlike the majority of polyglutamine expansion diseases, the presence of histidine interruptions within the polyglutamine tract of ataxin-1 protein can prevent or mitigate disease. The present review aims to synthesize three decades of research on the ataxin-1 polyglutamine expansion mutation that causes SCA1. Data from genetic population studies and case studies is gathered along with data from manipulation studies in animal models. Specifically, we examine the molecular mechanisms that cause tract expansions and contractions, the molecular pathways that confer instability of tract length in gametic and somatic cells resulting in gametic and somatic mosaicism, the influence of maternal or paternal factors in inheritance of the expanded allele, and the effects of CAT/histidine interruptions to the ataxin-1 allele and protein product. Our review of existing data supports the following conclusions. First, polyCAG expansion of gametic alleles occur due to the failure of gap repair mechanisms for single or double strand breaks during the transition from an immature haploid spermatid to a mature haploid sperm cell. Equivalent failures were not detected in female gametic cells. Second, polyCAG expansion of somatic alleles occur due to hairpins formed on Okazaki fragments and slipped strand structures due to failures in mismatch repair and transcription-coupled nucleotide excision repair mechanisms. Third, CAT trinucleotide interruptions, which code for histidines in the translated

  13. Transformation between α-helix and β-sheet structures of one and two polyglutamine peptides in explicit water molecules by replica-exchange molecular dynamics simulations.

    PubMed

    Chiang, Hsin-Lin; Chen, Chun-Jung; Okumura, Hisashi; Hu, Chin-Kun

    2014-07-15

    Aggregation of polyglutamine peptides with β-sheet structures is related to some important neurodegenerative diseases such as Huntington's disease. However, it is not clear how polyglutamine peptides form the β-sheets and aggregate. To understand this problem, we performed all-atom replica-exchange molecular dynamics simulations of one and two polyglutamine peptides with 10 glutamine residues in explicit water molecules. Our results show that two polyglutamine peptides mainly formed helix or coil structures when they are separated, as in the system with one-polyglutamine peptide. As the interpeptide distance decreases, the intrapeptide β-sheet structure sometimes appear as an intermediate state, and finally the interpeptide β-sheets are formed. We also find that the polyglutamine dimer tends to form the antiparallel β-sheet conformations rather than the parallel β-sheet, which is consistent with previous experiments and a coarse-grained molecular dynamics simulation.

  14. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  15. Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology

    PubMed Central

    Yang, Hui; Li, Jing-Jing; Liu, Shuai; Zhao, Jian; Jiang, Ya-Jun; Song, Ai-Xin; Hu, Hong-Yu

    2014-01-01

    Expansion of polyglutamine (polyQ) tract may cause protein misfolding and aggregation that lead to cytotoxicity and neurodegeneration, but the underlying mechanism remains to be elucidated. We applied ataxin-3 (Atx3), a polyQ tract-containing protein, as a model to study sequestration of normal cellular proteins. We found that the aggregates formed by polyQ-expanded Atx3 sequester its interacting partners, such as P97/VCP and ubiquitin conjugates, into the protein inclusions through specific interactions both in vitro and in cells. Moreover, this specific sequestration impairs the normal cellular function of P97 in down-regulating neddylation. However, expansion of polyQ tract in Atx3 does not alter the conformation of its surrounding regions and the interaction affinities with the interacting partners, although it indeed facilitates misfolding and aggregation of the Atx3 protein. Thus, we propose a loss-of-function pathology for polyQ diseases that sequestration of the cellular essential proteins via specific interactions into inclusions by the polyQ aggregates causes dysfunction of the corresponding proteins, and consequently leads to neurodegeneration. PMID:25231079

  16. Leukocyte abnormalities.

    PubMed

    Gabig, T G

    1980-07-01

    Certain qualitative abnormalities in neutrophils and blood monocytes are associated with frequent, severe, and recurrent bacterial infections leading to fatal sepsis, while other qualitative defects demonstrated in vitro may have few or no clinical sequelae. These qualitative defects are discussed in terms of the specific functions of locomotion, phagocytosis, degranulation, and bacterial killing.

  17. Genomic landscape of transcriptional and epigenetic dysregulation in early onset polyglutamine disease.

    PubMed

    Valor, Luis M; Guiretti, Deisy; Lopez-Atalaya, Jose P; Barco, Angel

    2013-06-19

    Transcriptional dysregulation is an important early feature of polyglutamine diseases. One of its proposed causes is defective neuronal histone acetylation, but important aspects of this hypothesis, such as the precise genomic topography of acetylation deficits and the relationship between transcriptional and acetylation alterations at the whole-genome level, remain unknown. The new techniques for the mapping of histone post-translational modifications at genomic scale enable such global analyses and are challenging some assumptions about the role of specific histone modifications in gene expression. We examined here the genome-wide correlation of histone acetylation and gene expression defects in a mouse model of early onset Huntington's disease. Our analyses identified hundreds of loci that were hypoacetylated for H3K9,14 and H4K12 in the chromatin of these mice. Surprisingly, few genes with altered transcript levels in mutant mice showed significant changes in these acetylation marks and vice versa. Our screen, however, identified a subset of genes in which H3K9,14 deacetylation and transcriptional dysregulation concur. Genes in this group were consistently affected in different brain areas, mouse models, and tissue from patients, which suggests a role in the etiology of this pathology. Overall, the combination of histone acetylation and gene expression screenings demonstrates that histone deacetylation and transcriptional dysregulation are two early, largely independent, manifestations of polyglutamine disease and suggests that additional epigenetic marks or mechanisms are required for explaining the full range of transcriptional alterations associated with this disorder.

  18. Abnormal pressure in hydrocarbon environments

    USGS Publications Warehouse

    Law, B.E.; Spencer, C.W.

    1998-01-01

    Abnormal pressures, pressures above or below hydrostatic pressures, occur on all continents in a wide range of geological conditions. According to a survey of published literature on abnormal pressures, compaction disequilibrium and hydrocarbon generation are the two most commonly cited causes of abnormally high pressure in petroleum provinces. In young (Tertiary) deltaic sequences, compaction disequilibrium is the dominant cause of abnormal pressure. In older (pre-Tertiary) lithified rocks, hydrocarbon generation, aquathermal expansion, and tectonics are most often cited as the causes of abnormal pressure. The association of abnormal pressures with hydrocarbon accumulations is statistically significant. Within abnormally pressured reservoirs, empirical evidence indicates that the bulk of economically recoverable oil and gas occurs in reservoirs with pressure gradients less than 0.75 psi/ft (17.4 kPa/m) and there is very little production potential from reservoirs that exceed 0.85 psi/ft (19.6 kPa/m). Abnormally pressured rocks are also commonly associated with unconventional gas accumulations where the pressuring phase is gas of either a thermal or microbial origin. In underpressured, thermally mature rocks, the affected reservoirs have most often experienced a significant cooling history and probably evolved from an originally overpressured system.

  19. Flanking Polyproline Sequences Inhibit [beta]-Sheet Structure in Polyglutamine Segments by Inducing PPII-like Helix Structure

    SciTech Connect

    Darnell, Gregory; Orgel, Joseph P.R.O.; Pahl, Reinhard; Meredith, Stephen C.

    2008-06-24

    Polyglutamine (poly(Q)) expansion is associated with protein aggregation into {beta}-sheet amyloid fibrils and neuronal cytotoxicity. In the mutant poly(Q) protein huntingtin, associated with Huntington's disease, both aggregation and cytotoxicity may be abrogated by a polyproline (poly(P)) domain flanking the C terminus of the poly(Q) region. To understand structural changes that may occur with the addition of the poly(P) sequence, we synthesized poly(Q) peptides with 3-15 glutamine residues and a corresponding set of poly(Q) peptides flanked on the C terminus by 11 proline residues (poly(Q)-poly(P)), as occurs in the huntingtin sequence. The shorter soluble poly(Q) peptides (three or six glutamine residues) showed polyproline type II-like (PPII)-like helix conformation when examined by circular dichroism spectroscopy and were monomers as judged by size-exclusion chromatography (SEC), while the longer poly(Q) peptides (nine or 15 glutamine residues) showed a {beta}-sheet conformation by CD and defined oligomers by SEC. Soluble poly(Q)-poly(P) peptides showed PPII-like content but SEC showed poorly defined, overlapping oligomeric peaks, and as judged by CD these peptides retained significant PPII-like structure with increasing poly(Q) length. More importantly, addition of the poly(P) domain increased the threshold for fibril formation to {approx} 15 glutamine residues. X-ray diffraction, electron microscopy, and film CD showed that, while poly(Q) peptides with {ge} 6 glutamine residues formed {beta}-sheet-rich fibrils, only the longest poly(Q)-poly(P) peptide (15 glutamine residues) did so. From these and other observations, we propose that poly(Q) domains exist in a 'tug-of-war' between two conformations, a PPII-like helix and a {beta}-sheet, while the poly(P) domain is conformationally constrained into a proline type II helix (PPII). Addition of poly(P) to the C terminus of a poly(Q) domain induces a PPII-like structure, which opposes the aggregation-prone {beta

  20. Expanded polyglutamine domain possesses nuclear export activity which modulates subcellular localization and toxicity of polyQ disease protein via exportin-1.

    PubMed

    Chan, Wing Man; Tsoi, Ho; Wu, Chi Chung; Wong, Chi Hang; Cheng, Tat Cheung; Li, Hoi Yeung; Lau, Kwok Fai; Shaw, Pang Chui; Perrimon, Norbert; Chan, Ho Yin Edwin

    2011-05-01

    Polyglutamine (polyQ) diseases are a group of late-onset, progressive neurodegenerative disorders caused by CAG trinucleotide repeat expansion in the coding region of disease genes. The cell nucleus is an important site of pathology in polyQ diseases, and transcriptional dysregulation is one of the pathologic hallmarks observed. In this study, we showed that exportin-1 (Xpo1) regulates the nucleocytoplasmic distribution of expanded polyQ protein. We found that expanded polyQ protein, but not its unexpanded form, possesses nuclear export activity and interacts with Xpo1. Genetic manipulation of Xpo1 expression levels in transgenic Drosophila models of polyQ disease confirmed the specific nuclear export role of Xpo1 on expanded polyQ protein. Upon Xpo1 knockdown, the expanded polyQ protein was retained in the nucleus. The nuclear disease protein enhanced polyQ toxicity by binding to heat shock protein (hsp) gene promoter and abolished hsp gene induction. Further, we uncovered a developmental decline of Xpo1 protein levels in vivo that contributes to the accumulation of expanded polyQ protein in the nucleus of symptomatic polyQ transgenic mice. Taken together, we first showed that Xpo1 is a nuclear export receptor for expanded polyQ domain, and our findings establish a direct link between protein nuclear export and the progressive nature of polyQ neurodegeneration.

  1. Universal Expansion.

    ERIC Educational Resources Information Center

    McArdle, Heather K.

    1997-01-01

    Describes a week-long activity for general to honors-level students that addresses Hubble's law and the universal expansion theory. Uses a discrepant event-type activity to lead up to the abstract principles of the universal expansion theory. (JRH)

  2. A stable G-quartet binds to a huntingtin protein fragment containing expanded polyglutamine tracks.

    PubMed

    Yerkes, Sarah; Vesenka, James; Kmiec, Eric B

    2010-02-01

    Huntington's disease (HD) is a progressive neurodegenerative disorder that is inherited in an autosomal dominant fashion. The disease is the result of an expanded CAG repeat in exon 1 of the HD gene, which encodes an elongated polyglutamine tract in the mutant form of the protein, huntingtin. Disease pathogenesis is linked to intracellular aggregates that form because of the tendency of the mutant protein to misfold. The role of huntingtin aggregates in disease pathology is unclear; it has been proposed that the aggregates themselves are toxic because of their ability to sequester intracellular proteins and disrupt normal cellular function. In addition, the mechanistic steps that lead to aggregate formation appear to be central to HD pathology. We have previously reported that guanosine-rich oligonucleotides with the ability to fold into a G-quartet are effective inhibitors of the aggregation process of a huntingtin protein fragment with an elongated polyglutamine tract, Htn 1-171(Q58). The most active molecule is composed of 20 guanosine residues, which adopt a G-wire conformation. Here we establish that G20 inhibits protein aggregation as judged by native gel electrophoresis, an agarose gel electrophoresis for resolving aggregates (AGERA) assay, and an immunoblotting assay. We also visualize the G20-Htn1-171(Q58) protein complex by using a streptavidin-biotin pull-down assay as well as atomic force microscopy (AFM). The G20 molecule also interacts with Htn1-171(Q23), a fusion protein that contains 23 glutamine residues instead of 58 (Q58), but in a more degenerate and nonspecific fashion. Taken together, our data support the notion that G20 exhibits some selectivity in binding to specific protein species that assemble along the aggregation pathway.

  3. A cell-based assay for aggregation inhibitors as therapeutics of polyglutamine-repeat disease and validation in Drosophila

    NASA Astrophysics Data System (ADS)

    Apostol, Barbara L.; Kazantsev, Alexsey; Raffioni, Simona; Illes, Katalin; Pallos, Judit; Bodai, Laszlo; Slepko, Natalia; Bear, James E.; Gertler, Frank B.; Hersch, Steven; Housman, David E.; Marsh, J. Lawrence; Michels Thompson, Leslie

    2003-05-01

    The formation of polyglutamine-containing aggregates and inclusions are hallmarks of pathogenesis in Huntington's disease that can be recapitulated in model systems. Although the contribution of inclusions to pathogenesis is unclear, cell-based assays can be used to screen for chemical compounds that affect aggregation and may provide therapeutic benefit. We have developed inducible PC12 cell-culture models to screen for loss of visible aggregates. To test the validity of this approach, compounds that inhibit aggregation in the PC12 cell-based screen were tested in a Drosophila model of polyglutamine-repeat disease. The disruption of aggregation in PC12 cells strongly correlates with suppression of neuronal degeneration in Drosophila. Thus, the engineered PC12 cells coupled with the Drosophila model provide a rapid and effective method to screen and validate compounds.

  4. Oxidative stress is increased in C. elegans models of Huntington's disease but does not contribute to polyglutamine toxicity phenotypes.

    PubMed

    Machiela, Emily; Dues, Dylan J; Senchuk, Megan M; Van Raamsdonk, Jeremy M

    2016-12-01

    Huntington's disease (HD) is an adult onset neurodegenerative disorder for which there is currently no cure. While HD patients and animal models of the disease exhibit increased oxidative damage, it is currently uncertain to what extent oxidative stress contributes to disease pathogenesis. In this work, we use a genetic approach to define the role of oxidative stress in HD. We find that a C. elegans model of HD expressing a disease-length polyglutamine tract in the body wall muscle is hypersensitive to oxidative stress and shows an upregulation of antioxidant defense genes, indicating that the HD worm model has increased levels of oxidative stress. To determine whether this increase in oxidative stress contributes to the development of polyglutamine-toxicity phenotypes in this HD model, we examined the effect of deleting individual superoxide dismutase (sod) genes in the HD worm model. As predicted, we found that deletion of sod genes in the HD worm model resulted in a clear increase in sensitivity to oxidative stress. However, we found that increasing oxidative stress in the HD worm model did not exacerbate deficits caused by polyglutamine toxicity. We confirmed these observations in two worm models expressing disease-length polyglutamine tracts in neurons. Furthermore, we found that treatment with antioxidants failed to rescue movement deficits or decrease aggregation in HD worm models. Combined, this suggests that the increase in oxidative stress in worm models of HD does not contribute to the phenotypic deficits observed in these worms, and provides a possible explanation for the failure of antioxidants in HD clinical trials.

  5. Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation.

    PubMed

    Wang, Adrienne M; Miyata, Yoshinari; Klinedinst, Susan; Peng, Hwei-Ming; Chua, Jason P; Komiyama, Tomoko; Li, Xiaokai; Morishima, Yoshihiro; Merry, Diane E; Pratt, William B; Osawa, Yoichi; Collins, Catherine A; Gestwicki, Jason E; Lieberman, Andrew P

    2013-02-01

    We sought new strategies to reduce amounts of the polyglutamine androgen receptor (polyQ AR) and achieve benefits in models of spinobulbar muscular atrophy, a protein aggregation neurodegenerative disorder. Proteostasis of the polyQ AR is controlled by the heat shock protein 90 (Hsp90)- and Hsp70-based chaperone machinery, but mechanisms regulating the protein's turnover are incompletely understood. We demonstrate that overexpression of Hsp70 interacting protein (Hip), a co-chaperone that enhances binding of Hsp70 to its substrates, promotes client protein ubiquitination and polyQ AR clearance. Furthermore, we identify a small molecule that acts similarly to Hip by allosterically promoting Hsp70 binding to unfolded substrates. Like Hip, this synthetic co-chaperone enhances client protein ubiquitination and polyQ AR degradation. Both genetic and pharmacologic approaches targeting Hsp70 alleviate toxicity in a Drosophila model of spinobulbar muscular atrophy. These findings highlight the therapeutic potential of allosteric regulators of Hsp70 and provide new insights into the role of the chaperone machinery in protein quality control.

  6. Nanoparticulate strategies for the treatment of polyglutamine diseases by halting the protein aggregation process (†).

    PubMed

    Escalona-Rayo, Oscar; Fuentes-Vázquez, Paulina; Leyva-Gómez, Gerardo; Cisneros, Bulmaro; Villalobos, Rafael; Magaña, Jonathan J; Quintanar-Guerrero, David

    2017-06-01

    Polyglutamine (polyQ) diseases are a class of neurodegenerative disorders that cause cellular dysfunction and, eventually, neuronal death in specific regions of the brain. Neurodegeneration is linked to the misfolding and aggregation of expanded polyQ-containing proteins, and their inhibition is one of major therapeutic strategies used commonly. However, successful treatment has been limited to date because of the intrinsic properties of therapeutic agents (poor water solubility, low bioavailability, poor pharmacokinetic properties), and difficulty in crossing physiological barriers, including the blood-brain barrier (BBB). In order to solve these problems, nanoparticulate systems with dimensions of 1-1000 nm able to incorporate small and macromolecules with therapeutic value, to protect and deliver them directly to the brain, have recently been developed, but their use for targeting polyQ disease-mediated protein misfolding and aggregation remains scarce. This review provides an update of the polyQ protein aggregation process and the development of therapeutic strategies for halting it. The main features that a nanoparticulate system should possess in order to enhance brain delivery are discussed, as well as the different types of materials utilized to produce them. The final part of this review focuses on the potential application of nanoparticulate system strategies to improve the specific and efficient delivery of therapeutic agents to the brain for the treatment of polyQ diseases.

  7. Valosin-containing protein immunoreactivity in tauopathies, synucleinopathies, polyglutamine diseases and intranuclear inclusion body disease.

    PubMed

    Mori, Fumiaki; Tanji, Kunikazu; Toyoshima, Yasuko; Sasaki, Hidenao; Yoshida, Mari; Kakita, Akiyoshi; Takahashi, Hitoshi; Wakabayashi, Koichi

    2013-12-01

    Valosin-containing protein (VCP) is associated with multiple cellular functions, including ubiquitin-dependent protein degradation. Mutations in VCP are known to cause inclusion body myopathy with Paget's disease and frontotemporal dementia and familial amyotrophic lateral sclerosis (fALS; ALS14), both of which are characterized by trans-activation response DNA protein 43 (TDP-43)-positive neuronal cytoplasmic and nuclear inclusions. Recently, immunoreactivity for fALS-associated proteins (TDP-43, fused in sarcoma (FUS), optineurin and ubiquilin-2) were reported to be present in cytoplasmic and nuclear inclusions in various neurodegenerative diseases. However, the extent and frequency of VCP-immunoreactive structures in these neurodegenerative diseases are uncertain. We immunohistochemically examined the brains of 72 cases with neurodegenerative diseases and five control cases. VCP immunoreactivity was present in Lewy bodies in Parkinson's disease and dementia with Lewy bodies, and neuronal nuclear inclusions in five polyglutamine diseases and intranuclear inclusion body disease, as well as in Marinesco bodies in aged control subjects. However, other neuronal and glial cytoplasmic inclusions in tauopathies and TDP-43 proteinopathies were unstained. These findings suggest that VCP may have common mechanisms in the formation or degradation of cytoplasmic and nuclear inclusions of neurons, but not of glial cells, in several neurodegenerative conditions.

  8. Post-translational Modifications and Protein Quality Control in Motor Neuron and Polyglutamine Diseases

    PubMed Central

    Sambataro, Fabio; Pennuto, Maria

    2017-01-01

    Neurodegenerative diseases, including motor neuron and polyglutamine (polyQ) diseases, are a broad class of neurological disorders. These diseases are characterized by neuronal dysfunction and death, and by the accumulation of toxic aggregation-prone proteins in the forms of inclusions and micro-aggregates. Protein quality control is a cellular mechanism to reduce the burden of accumulation of misfolded proteins, a function that results from the coordinated actions of chaperones and degradation systems, such as the ubiquitin-proteasome system (UPS) and autophagy-lysosomal degradation system. The rate of turnover, aggregation and degradation of the disease-causing proteins is modulated by post-translational modifications (PTMs), such as phosphorylation, arginine methylation, palmitoylation, acetylation, SUMOylation, ubiquitination, and proteolytic cleavage. Here, we describe how PTMs of proteins linked to motor neuron and polyQ diseases can either enhance or suppress protein quality control check and protein aggregation and degradation. The identification of molecular strategies targeting these modifications may offer novel avenues for the treatment of these yet incurable diseases.

  9. Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA.

    PubMed

    Cortes, Constanza J; Miranda, Helen C; Frankowski, Harald; Batlevi, Yakup; Young, Jessica E; Le, Amy; Ivanov, Nishi; Sopher, Bryce L; Carromeu, Cassiano; Muotri, Alysson R; Garden, Gwenn A; La Spada, Albert R

    2014-09-01

    Macroautophagy (hereafter autophagy) is a key pathway in neurodegeneration. Despite protective actions, autophagy may contribute to neuron demise when dysregulated. Here we consider X-linked spinal and bulbar muscular atrophy (SBMA), a repeat disorder caused by polyglutamine-expanded androgen receptor (polyQ-AR). We found that polyQ-AR reduced long-term protein turnover and impaired autophagic flux in motor neuron-like cells. Ultrastructural analysis of SBMA mice revealed a block in autophagy pathway progression. We examined the transcriptional regulation of autophagy and observed a functionally significant physical interaction between transcription factor EB (TFEB) and AR. Normal AR promoted, but polyQ-AR interfered with, TFEB transactivation. To evaluate physiological relevance, we reprogrammed patient fibroblasts to induced pluripotent stem cells and then to neuronal precursor cells (NPCs). We compared multiple SBMA NPC lines and documented the metabolic and autophagic flux defects that could be rescued by TFEB. Our results indicate that polyQ-AR diminishes TFEB function to impair autophagy and promote SBMA pathogenesis.

  10. Self-assembly and sequence length dependence on nanofibrils of polyglutamine peptides.

    PubMed

    Inayathullah, Mohammed; Tan, Aaron; Jeyaraj, Rebecca; Lam, James; Cho, Nam-Joon; Liu, Corey W; Manoukian, Martin A C; Ashkan, Keyoumars; Mahmoudi, Morteza; Rajadas, Jayakumar

    2016-06-01

    Huntington's disease (HD) is recognized as a currently incurable, inherited neurodegenerative disorder caused by the accumulation of misfolded polyglutamine (polyQ) peptide aggregates in neuronal cells. Yet, the mechanism by which newly formed polyQ chains interact and assemble into toxic oligomeric structures remains a critical, unresolved issue. In order to shed further light on the matter, our group elected to investigate the folding of polyQ peptides - examining glutamine repeat lengths ranging from 3 to 44 residues. To characterize these aggregates we employed a diverse array of technologies, including: nuclear magnetic resonance; circular dichroism; Fourier transform infrared spectroscopy; fluorescence resonance energy transfer (FRET), and atomic force microscopy. The data we obtained suggest that an increase in the number of glutamine repeats above 14 residues results in disordered loop structures, with different repeat lengths demonstrating unique folding characteristics. This differential folding manifests in the formation of distinct nano-sized fibrils, and on this basis, we postulate the idea of 14 polyQ repeats representing a critical loop length for neurotoxicity - a property that we hope may prove amenable to future therapeutic intervention. Furthermore, FRET measurements on aged assemblages indicate an increase in the end-to-end distance of the peptide with time, most probably due to the intermixing of individual peptide strands within the nanofibril. Further insight into this apparent time-dependent reorganization of aggregated polyQ peptides may influence future disease modeling of polyQ-related proteinopathies, in addition to directing novel clinical innovations.

  11. An Efficient Kinetic Model for Assemblies of Amyloid Fibrils and Its Application to Polyglutamine Aggregation

    PubMed Central

    Prigent, Stéphanie; Ballesta, Annabelle; Charles, Frédérique; Lenuzza, Natacha; Gabriel, Pierre; Tine, Léon Matar; Rezaei, Human; Doumic, Marie

    2012-01-01

    Protein polymerization consists in the aggregation of single monomers into polymers that may fragment. Fibrils assembly is a key process in amyloid diseases. Up to now, protein aggregation was commonly mathematically simulated by a polymer size-structured ordinary differential equations (ODE) system, which is infinite by definition and therefore leads to high computational costs. Moreover, this Ordinary Differential Equation-based modeling approach implies biological assumptions that may be difficult to justify in the general case. For example, whereas several ordinary differential equation models use the assumption that polymerization would occur at a constant rate independently of polymer size, it cannot be applied to certain protein aggregation mechanisms. Here, we propose a novel and efficient analytical method, capable of modelling and simulating amyloid aggregation processes. This alternative approach consists of an integro-Partial Differential Equation (PDE) model of coalescence-fragmentation type that was mathematically derived from the infinite differential system by asymptotic analysis. To illustrate the efficiency of our approach, we applied it to aggregation experiments on polyglutamine polymers that are involved in Huntington’s disease. Our model demonstrates the existence of a monomeric structural intermediate acting as a nucleus and deriving from a non polymerizing monomer (). Furthermore, we compared our model to previously published works carried out in different contexts and proved its accuracy to describe other amyloid aggregation processes. PMID:23152746

  12. Expansive Cements

    DTIC Science & Technology

    1970-10-01

    either burned simultaneously with a portland ce4nt or !r;terground with portland cement clinker ; Type M - a mixture of portland cement, calcium-aluminate... clinker that is interground with portland clinker or blended with portland cement or, alternately, it may be formed simul- taneously vrith the portland ... clinker compounds during the burning process. 3. Expansive cement, Type M is either a mixture of portland cement, calcium aluminate cement, and calcium

  13. Somatic instability of the DNA sequences encoding the polymorphic polyglutamine tract of the AIB1 gene

    PubMed Central

    Dai, P; Wong, L

    2003-01-01

    Background: AIB1 contains a polymorphic polyglutamine tract (poly Q) that is encoded by a trinucleotide CAG repeat. Previously there have been conflicting results regarding the effect of the poly Q tract length on breast cancer. Since poly Q is not encoded by a perfect CAG repeat, the heterozygous polymorphic alleles need to be resolved, to understand the exact DNA sequences encoding poly Q. Methods: Poly Q encoding sequences of AIB1 from 107 DNA samples, including breast cancer cell lines, sporadic primary breast tumours, and blood samples from BRCA1/BRCA2 mutation carriers and the general population, were resolved by PCR/cloning followed by sequencing of each individual clone. Results: 25 distinct poly Q encoding sequence patterns were found. More than two distinct sequence patterns were found in a significantly higher proportion of tumours and cell lines than that of the general population, suggesting somatic instability. A significantly higher proportion of cancer cell lines or primary breast tumours than that of the general population contained rare sequence patterns. The proportion of sporadic breast tumours having at least one allele ⩽27 repeats is significantly higher than that in the blood of BRCA1/BRCA2 mutation carrier breast cancer patients or the general population. Conclusion: The poly Q encoding DNA sequences are somatically unstable in tumour tissues and cell lines. A missense mutation and a very short glutamine repeat in primary tumours suggests that AIB1 activity may be modulated through poly Q, which in turn plays a role in the cotransactivation of gene expressions in breast cancers. PMID:14684685

  14. The interaction of polyglutamine peptides with lipid membranes is regulated by flanking sequences associated with huntingtin.

    PubMed

    Burke, Kathleen A; Kauffman, Karlina J; Umbaugh, C Samuel; Frey, Shelli L; Legleiter, Justin

    2013-05-24

    Huntington disease (HD) is caused by an expanded polyglutamine (poly(Q)) repeat near the N terminus of the huntingtin (htt) protein. Expanded poly(Q) facilitates formation of htt aggregates, eventually leading to deposition of cytoplasmic and intranuclear inclusion bodies containing htt. Flanking sequences directly adjacent to the poly(Q) domain, such as the first 17 amino acids on the N terminus (Nt17) and the polyproline (poly(P)) domain on the C-terminal side of the poly(Q) domain, heavily influence aggregation. Additionally, htt interacts with a variety of membraneous structures within the cell, and Nt17 is implicated in lipid binding. To investigate the interaction between htt exon1 and lipid membranes, a combination of in situ atomic force microscopy, Langmuir trough techniques, and vesicle permeability assays were used to directly monitor the interaction of a variety of synthetic poly(Q) peptides with different combinations of flanking sequences (KK-Q35-KK, KK-Q35-P10-KK, Nt17-Q35-KK, and Nt17-Q35-P10-KK) on model membranes and surfaces. Each peptide aggregated on mica, predominately forming extended, fibrillar aggregates. In contrast, poly(Q) peptides that lacked the Nt17 domain did not appreciably aggregate on or insert into lipid membranes. Nt17 facilitated the interaction of peptides with lipid surfaces, whereas the poly(P) region enhanced this interaction. The aggregation of Nt17-Q35-P10-KK on the lipid bilayer closely resembled that of a htt exon1 construct containing 35 repeat glutamines. Collectively, this data suggests that the Nt17 domain plays a critical role in htt binding and aggregation on lipid membranes, and this lipid/htt interaction can be further modulated by the presence of the poly(P) domain.

  15. Repeat expansion disease: Progress and puzzles in disease pathogenesis

    PubMed Central

    La Spada, Albert R.; Taylor, J. Paul

    2015-01-01

    Repeat expansion mutations cause at least 22 inherited neurological diseases. The complexity of repeat disease genetics and pathobiology has revealed unexpected shared themes and mechanistic pathways among the diseases, for example, RNA toxicity. Also, investigation of the polyglutamine diseases has identified post-translational modification as a key step in the pathogenic cascade, and has shown that the autophagy pathway plays an important role in the degradation of misfolded proteins – two themes likely to be relevant to the entire neurodegeneration field. Insights from repeat disease research are catalyzing new lines of study that should not only elucidate molecular mechanisms of disease, but also highlight opportunities for therapeutic intervention for these currently untreatable disorders. PMID:20177426

  16. XL PCR for the detection of large trinucleotide expansions in juvenile Huntington's disease.

    PubMed

    Milunsky, J M; Maher, T A; Loose, B A; Darras, B T; Ito, M

    2003-07-01

    Juvenile Huntington's disease (HD) becomes clinically manifest before 20 years of age. The diagnosis of HD is based on family history, characteristic clinical findings, and the detection of an expansion of a CAG polyglutamine tract in the Huntingtin gene. Juvenile HD is characterized by paternal anticipation and large CAG expansions that may be missed using routine molecular analysis. We have developed an easy, rapid, and reliable modified PCR method using XL (Extra Long) PCR that allowed us to diagnose one of the youngest children reported with juvenile HD. Without this innovation we would not have been able to demonstrate the large CAG expansion. This assay could become part of a standard protocol for HD testing in molecular diagnostic laboratories.

  17. Expansion Microscopy

    PubMed Central

    Chen, Fei; Tillberg, Paul W.; Boyden, Edward S.

    2014-01-01

    In optical microscopy, fine structural details are resolved by using refraction to magnify images of a specimen. Here we report the discovery that, by synthesizing a swellable polymer network within a specimen, it can be physically expanded, resulting in physical magnification. By covalently anchoring specific labels located within the specimen directly to the polymer network, labels spaced closer than the optical diffraction limit can be isotropically separated and optically resolved, a process we call expansion microscopy (ExM). Thus, this process can be used to perform scalable super-resolution microscopy with diffraction-limited microscopes. We demonstrate ExM with effective ~70 nm lateral resolution in both cultured cells and brain tissue, performing three-color super-resolution imaging of ~107 μm3 of the mouse hippocampus with a conventional confocal microscope. PMID:25592419

  18. In-cell aggregation of a polyglutamine-containing chimera is a multistep process initiated by the flanking sequence.

    PubMed

    Ignatova, Zoya; Thakur, Ashwani K; Wetzel, Ronald; Gierasch, Lila M

    2007-12-14

    Toxicity in amyloid diseases is intimately linked to the nature of aggregates, with early oligomeric species believed to be more cytotoxic than later fibrillar aggregates. Yet mechanistic understanding of how aggregating species evolve with time is currently lacking. We have explored the aggregation process of a chimera composed of a globular protein (cellular retinoic acid-binding protein, CRABP) and huntingtin exon 1 with polyglutamine tracts either above (Q53) or below (Q20) the pathological threshold using Escherichia coli cells as a model intracellular environment. Previously we showed that fusion of the huntingtin exon 1 sequence with >40Q led to structural perturbation and decreased stability of CRABP (Ignatova, Z., and Gierasch, L. M. (2006) J. Biol. Chem. 281, 12959-12967). Here we report that the Q53 chimera aggregates in cells via a multistep process: early stage aggregates are spherical and detergent-soluble, characteristics of prefibrillar aggregates, and appear to be dominated structurally by CRABP, in that they can promote aggregation of a CRABP variant but not oligoglutamine aggregation, and the CRABP domain is relatively sequestered based on its protection from proteolysis. Late stage aggregates appear to be dominated by polyGln; they are fibrillar, detergent-resistant, capable of seeding aggregation of oligoglutamine but not the CRABP variant, and show relative protection of the polyglutamine-exon1 domain from proteolysis. These results point to an evolution of the dominant sequences in intracellular aggregates and may provide molecular insight into origins of toxic prefibrillar aggregates.

  19. Thermal Expansion

    NASA Astrophysics Data System (ADS)

    Ventura, Guglielmo; Perfetti, Mauro

    All solid materials, when cooled to low temperatures experience a change in physical dimensions which called "thermal contraction" and is typically lower than 1 % in volume in the 4-300 K temperature range. Although the effect is small, it can have a heavy impact on the design of cryogenic devices. The thermal contraction of different materials may vary by as much as an order of magnitude: since cryogenic devices are constructed at room temperature with a lot of different materials, one of the major concerns is the effect of the different thermal contraction and the resulting thermal stress that may occur when two dissimilar materials are bonded together. In this chapter, theory of thermal contraction is reported in Sect. 1.2 . Section 1.3 is devoted to the phenomenon of negative thermal expansion and its applications.

  20. Urine - abnormal color

    MedlinePlus

    ... medlineplus.gov/ency/article/003139.htm Urine - abnormal color To use the sharing features on this page, please enable JavaScript. The usual color of urine is straw-yellow. Abnormally colored urine ...

  1. Tooth - abnormal colors

    MedlinePlus

    ... medlineplus.gov/ency/article/003065.htm Tooth - abnormal colors To use the sharing features on this page, please enable JavaScript. Abnormal tooth color is any color other than white to yellowish- ...

  2. Abnormal Head Position

    MedlinePlus

    ... cause. Can a longstanding head turn lead to any permanent problems? Yes, a significant abnormal head posture could cause permanent ... occipitocervical synostosis and unilateral hearing loss. Are there any ... postures? Yes. Abnormal head postures can usually be improved depending ...

  3. Skeletal limb abnormalities

    MedlinePlus

    ... medlineplus.gov/ency/article/003170.htm Skeletal limb abnormalities To use the sharing features on this page, please enable JavaScript. Skeletal limb abnormalities refers to a variety of bone structure problems ...

  4. Abnormal Uterine Bleeding FAQ

    MedlinePlus

    ... PROBLEMS Abnormal Uterine Bleeding • What is a normal menstrual cycle? • When is bleeding abnormal? • At what ages is ... treat abnormal bleeding? •Glossary What is a normal menstrual cycle? The normal length of the menstrual cycle is ...

  5. Proteasome-mediated Proteolysis of the Polyglutamine-expanded Androgen Receptor Is a Late Event in Spinal and Bulbar Muscular Atrophy (SBMA) Pathogenesis*

    PubMed Central

    Heine, Erin M.; Berger, Tamar R.; Pluciennik, Anna; Orr, Christopher R.; Zboray, Lori; Merry, Diane E.

    2015-01-01

    Proteolysis of polyglutamine-expanded proteins is thought to be a required step in the pathogenesis of several neurodegenerative diseases. The accepted view for many polyglutamine proteins is that proteolysis of the mutant protein produces a “toxic fragment” that induces neuronal dysfunction and death in a soluble form; toxicity of the fragment is buffered by its incorporation into amyloid-like inclusions. In contrast to this view, we show that, in the polyglutamine disease spinal and bulbar muscular atrophy, proteolysis of the mutant androgen receptor (AR) is a late event. Immunocytochemical and biochemical analyses revealed that the mutant AR aggregates as a full-length protein, becoming proteolyzed to a smaller fragment through a process requiring the proteasome after it is incorporated into intranuclear inclusions. Moreover, the toxicity-predicting conformational antibody 3B5H10 bound to soluble full-length AR species but not to fragment-containing nuclear inclusions. These data suggest that the AR is toxic as a full-length protein, challenging the notion of polyglutamine protein fragment-associated toxicity by redefining the role of AR proteolysis in spinal and bulbar muscular atrophy pathogenesis. PMID:25795778

  6. Proteasome-mediated proteolysis of the polyglutamine-expanded androgen receptor is a late event in spinal and bulbar muscular atrophy (SBMA) pathogenesis.

    PubMed

    Heine, Erin M; Berger, Tamar R; Pluciennik, Anna; Orr, Christopher R; Zboray, Lori; Merry, Diane E

    2015-05-15

    Proteolysis of polyglutamine-expanded proteins is thought to be a required step in the pathogenesis of several neurodegenerative diseases. The accepted view for many polyglutamine proteins is that proteolysis of the mutant protein produces a "toxic fragment" that induces neuronal dysfunction and death in a soluble form; toxicity of the fragment is buffered by its incorporation into amyloid-like inclusions. In contrast to this view, we show that, in the polyglutamine disease spinal and bulbar muscular atrophy, proteolysis of the mutant androgen receptor (AR) is a late event. Immunocytochemical and biochemical analyses revealed that the mutant AR aggregates as a full-length protein, becoming proteolyzed to a smaller fragment through a process requiring the proteasome after it is incorporated into intranuclear inclusions. Moreover, the toxicity-predicting conformational antibody 3B5H10 bound to soluble full-length AR species but not to fragment-containing nuclear inclusions. These data suggest that the AR is toxic as a full-length protein, challenging the notion of polyglutamine protein fragment-associated toxicity by redefining the role of AR proteolysis in spinal and bulbar muscular atrophy pathogenesis.

  7. Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy.

    PubMed

    Montie, Heather L; Cho, Maria S; Holder, Latia; Liu, Yuhong; Tsvetkov, Andrey S; Finkbeiner, Steven; Merry, Diane E

    2009-06-01

    The nucleus is the primary site of protein aggregation in many polyglutamine diseases, suggesting a central role in pathogenesis. In SBMA, the nucleus is further implicated by the critical role for disease of androgens, which promote the nuclear translocation of the mutant androgen receptor (AR). To clarify the importance of the nucleus in SBMA, we genetically manipulated the nuclear localization signal of the polyglutamine-expanded AR. Transgenic mice expressing this mutant AR displayed inefficient nuclear translocation and substantially improved motor function compared with SBMA mice. While we found that nuclear localization of polyglutamine-expanded AR is required for SBMA, we also discovered, using cell models of SBMA, that it is insufficient for both aggregation and toxicity and requires androgens for these disease features. Through our studies of cultured motor neurons, we further found that the autophagic pathway was able to degrade cytoplasmically retained expanded AR and represents an endogenous neuroprotective mechanism. Moreover, pharmacologic induction of autophagy rescued motor neurons from the toxic effects of even nuclear-residing mutant AR, suggesting a therapeutic role for autophagy in this nucleus-centric disease. Thus, our studies firmly establish that polyglutamine-expanded AR must reside within nuclei in the presence of its ligand to cause SBMA. They also highlight a mechanistic basis for the requirement for nuclear localization in SBMA neurotoxicity, namely the lack of mutant AR removal by the autophagic protein degradation pathway.

  8. Ectoine alters subcellular localization of inclusions and reduces apoptotic cell death induced by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch.

    PubMed

    Furusho, Kentaro; Yoshizawa, Toshihiro; Shoji, Shinichi

    2005-10-01

    Protein misfolding is considered a key event in the pathogenesis of polyglutamine disease such as Machado-Joseph disease (MJD). Overexpression of chaperone proteins and the application of chemical chaperones are reported to suppress polyglutamine induced cytotoxicity in vitro and in vivo. The effects of compatible solutes, which are osmoprotectants in bacteria and possess the action in stabilizing proteins under stress, have not, to our knowledge, been studied. We explored the protective effects of the compatible solutes ectoine, hydroxyectoine, and betaine on apoptotic cell death produced by the truncated MJD gene product with an expanded polyglutamine tract in cultured neuro2a cells. Ectoine, but not hydroxyectoine or betaine, decreased large cytoplasmic inclusions and increased the frequency of nuclear inclusions. Immunoblot analysis showed that ectoine reduced the total amount of aggregates. Despite the presence of nuclear inclusions, apoptotic features were less frequently observed after ectoine application. Our findings suggest that ectoine, a natural osmoprotectant in bacteria, may function as a novel molecule protecting cells from polyglutamine-induced toxicity.

  9. Fluorodeoxyuridine enhances the heat shock response and decreases polyglutamine aggregation in an HSF-1-dependent manner in Caenorhabditis elegans.

    PubMed

    Brunquell, Jessica; Bowers, Philip; Westerheide, Sandy D

    2014-01-01

    The heat shock response (HSR) protects cells from protein-denaturing stress through the induction of chaperones. The HSR is conserved in all organisms and is mediated by the transcription factor HSF-1. We show here that a compound commonly used to prevent larval development in Caenorhabditis elegans, 5-fluoro-2'-deoxyuridine (FUdR), can enhance heat shock induction of hsp mRNA in an HSF-1-dependent manner. Treatment with FUdR can also decrease age-dependent polyglutamine aggregation in a Huntington's disease model, and this effect depends on HSF-1 as well. Therefore, FUdR treatment can modulate the HSR and proteostasis, and should be used with caution when used to inhibit reproduction.

  10. Inhibition of hsp70 by methylene blue affects signaling protein function and ubiquitination and modulates polyglutamine protein degradation.

    PubMed

    Wang, Adrienne M; Morishima, Yoshihiro; Clapp, Kelly M; Peng, Hwei-Ming; Pratt, William B; Gestwicki, Jason E; Osawa, Yoichi; Lieberman, Andrew P

    2010-05-21

    The Hsp90/Hsp70-based chaperone machinery regulates the activity and degradation of many signaling proteins. Cycling with Hsp90 stabilizes client proteins, whereas Hsp70 interacts with chaperone-dependent E3 ubiquitin ligases to promote protein degradation. To probe these actions, small molecule inhibitors of Hsp70 would be extremely useful; however, few have been identified. Here we test the effects of methylene blue, a recently described inhibitor of Hsp70 ATPase activity, in three well established systems of increasing complexity. First, we demonstrate that methylene blue inhibits the ability of the purified Hsp90/Hsp70-based chaperone machinery to enable ligand binding by the glucocorticoid receptor and show that this effect is due to specific inhibition of Hsp70. Next, we establish that ubiquitination of neuronal nitric-oxide synthase by the native ubiquitinating system of reticulocyte lysate is dependent upon both Hsp70 and the E3 ubiquitin ligase CHIP and is blocked by methylene blue. Finally, we demonstrate that methylene blue impairs degradation of the polyglutamine expanded androgen receptor, an Hsp90 client mutated in spinal and bulbar muscular atrophy. In contrast, degradation of an amino-terminal fragment of the receptor, which lacks the ligand binding domain and, therefore, is not a client of the Hsp90/Hsp70-based chaperone machinery, is enhanced through homeostatic induction of autophagy that occurs when Hsp70-dependent proteasomal degradation is inhibited by methylene blue. Our data demonstrate the utility of methylene blue in defining Hsp70-dependent functions and reveal divergent effects on polyglutamine protein degradation depending on whether the substrate is an Hsp90 client.

  11. Glyceraldehyde 3-phosphate dehydrogenase augments the intercellular transmission and toxicity of polyglutamine aggregates in a cell model of Huntington disease.

    PubMed

    Mikhaylova, Elena R; Lazarev, Vladimir F; Nikotina, Alina D; Margulis, Boris A; Guzhova, Irina V

    2016-03-01

    The common feature of Huntington disease is the accumulation of oligomers or aggregates of mutant huntingtin protein (mHTT), which causes the death of a subset of striatal neuronal populations. The cytotoxic species can leave neurons and migrate to other groups of cells penetrating and damaging them in a prion-like manner. We hypothesized that the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH), previously shown to elevate the aggregation of mHTT, is associated with an increased efficiency of intercellular propagation of mHTT. GAPDH, on its own or together with polyglutamine species, was shown to be released into the extracellular milieu mainly from dying cells as assessed by a novel enzyme immunoassay, western blotting, and ultrafiltration. The conditioned medium of cells with growing GAPDH-polyQ aggregates was toxic to naïve cells, whereas depletion of the aggregates from the medium lowered this cytotoxicity. The GAPDH component of the aggregates was found to increase their toxicity by two-fold in comparison with polyQ alone. Furthermore, GAPDH-polyQ complexes were shown to penetrate acceptor cells and to increase the capacity of polyQ to prionize its intracellular homolog containing a repeat of 25 glutamine residues. Finally, inhibitors of intracellular transport showed that polyQ-GAPDH complexes, as well as GAPDH itself, penetrated cells using clathrin-mediated endocytosis. This suggested a pivotal role of the enzyme in the intercellular transmission of Huntington disease pathogenicity. In conclusion, GAPDH occurring in complexes with polyglutamine strengthens the prion-like activity and toxicity of the migrating aggregates. Aggregating polygluatmine tracts were shown to release from the cells over-expressing mutant huntingtin in a complex with glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The enzyme enhances the intracellular transport of aggregates to healthy cells, prionization of normal cellular proteins and finally cell death, thus

  12. Fluorescence anisotropy uncovers changes in protein packing with inclusion growth in a cellular model of polyglutamine aggregation.

    PubMed

    Bhardwaj, Vishal; Panicker, Mitradas M; Udgaonkar, Jayant B

    2014-06-10

    The aggregation of polyglutamine-rich proteins is closely linked with numerous neurodegenerative disorders. In pathological and cellular models, the appearance of protein-rich inclusions in cells acts as a read out of protein aggregation. The precise organization of aggregated protein in these inclusions and their mode of growth are still poorly understood. Here, fluorescence anisotropy-based measurements have been used to probe protein packing across inclusions of varying brightness, formed by an monomeric enhanced green fluorescent protein (mEGFP)-tagged polyglutamine model peptide in cells. High-resolution, confocal-based steady-state anisotropy measurements report a large depolarization, consistent with extensive homo-Förster (fluorescence) resonance energy transfer (FRET) between the sequestered mEGFP-tagged protein molecules. An inverse correlation of fluorescence anisotropy with intensity is seen across inclusions, which becomes emphasized when the observed fluorescence anisotropy values of inclusions are corrected for the fluorescence contribution of the diffusible protein, present within and around smaller inclusions. Homo-FRET becomes enhanced as inclusion size increases. This enhancement is confirmed by two-photon excitation-based time-resolved fluorescence anisotropy decay measurements, which also suggest that the mEGFP-tagged protein molecules are arranged in multiple ways within inclusions. Bright inclusions display faster FRET rates with a larger number of mEGFP moieties participating in homo-FRET than faint inclusions do. These results are consistent with a model in which the protein is more closely packed in the brighter inclusions. In such a possible mechanism, the higher packing density of protein molecules in brighter inclusions would suggest that inclusion growth could involve an intermolecular compaction event within the inclusion, as more monomers and aggregates are recruited into the growing inclusion.

  13. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  14. Morphological abnormalities among lampreys

    USGS Publications Warehouse

    Manion, Patrick J.

    1967-01-01

    The experimental control of the sea lamprey (Petromyzon marinus) in the Great Lakes has required the collection of thousands of lampreys. Representatives of each life stage of the four species of the Lake Superior basin were examined for structural abnormalities. The most common aberration was the presence of additional tails. The accessory tails were always postanal and smaller than the normal tail. The point of origin varied; the extra tails occurred on dorsal, ventral, or lateral surfaces. Some of the extra tails were misshaped and curled, but others were normal in shape and pigment pattern. Other abnormalities in larval sea lampreys were malformed or twisted tails and bodies. The cause of the structural abnormalities is unknown. The presence of extra caudal fins could be genetically controlled, or be due to partial amputation or injury followed by abnormal regeneration. Few if any lampreys with structural abnormalities live to sexual maturity.

  15. Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease.

    PubMed

    Reddy, P Hemachandra; Shirendeb, Ulziibat P

    2012-02-01

    Huntington's disease (HD) is a progressive, fatal neurodegenerative disease caused by expanded polyglutamine repeats in the HD gene. HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment and emotional disturbances. Research into mutant huntingtin (Htt) and mitochondria has found that mutant Htt interacts with the mitochondrial protein dynamin-related protein 1 (Drp1), enhances GTPase Drp1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. This article summarizes latest developments in HD research and focuses on the role of abnormal mitochondrial dynamics and defective axonal transport in HD neurons. This article also discusses the therapeutic strategies that decrease mitochondrial fragmentation and neuronal damage in HD.

  16. "Jeopardy" in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  17. [Abnormal absence of displacement of the cerebral median line].

    PubMed

    de Tribolet, N; Oberson, R

    1975-03-08

    The angiographic cerebral midline is described. It is pointed out that the midline may be abnormally undisplaced despite the presence of a unilateral or bilateral expansive lesion. The causes of such abnormal non-displacement of the midline are reviewed in the light of examples, and the importance is stressed of bilateral carotid angiograms, sometimes with oblique series, in the case of head injuries and certain tumors.

  18. Attenuation of polyglutamine-induced toxicity by enhancement of mitochondrial OXPHOS in yeast and fly models of aging

    PubMed Central

    Ruetenik, Andrea L.; Ocampo, Alejandro; Ruan, Kai; Zhu, Yi; Li, Chong; Zhai, R. Grace; Barrientos, Antoni

    2016-01-01

    Defects in mitochondrial biogenesis and function are common in many neurodegenerative disorders, including Huntington’s disease (HD). We have previously shown that in yeast models of HD, enhancement of mitochondrial biogenesis through overexpression of Hap4, the catalytic subunit of the transcriptional complex that regulates mitochondrial gene expression, alleviates the growth arrest induced by expanded polyglutamine (polyQ) tract peptides in rapidly dividing cells. However, the mechanism through which HAP4 overexpression exerts this protection remains unclear. Furthermore, it remains unexplored whether HAP4 overexpression and increased respiratory function during growth can also protect against polyQ-induced toxicity during yeast chronological lifespan. Here, we show that in yeast, mitochondrial respiration and oxidative phosphorylation (OXPHOS) are essential for protection against the polyQ-induced growth defect by HAP4 overexpression. In addition, we show that not only increased HAP4 levels, but also alternative interventions, including calorie restriction, that result in enhanced mitochondrial biogenesis confer protection against polyQ toxicity during stationary phase. The data obtained in yeast models guided experiments in a fly model of HD, where we show that enhancement of mitochondrial biogenesis can also protect against neurodegeneration and behavioral deficits. Our results suggest that therapeutic interventions aiming at the enhancement of mitochondrial respiration and OXPHOS could reduce polyQ toxicity and delay disease onset. PMID:28357370

  19. Hsp104 Suppresses Polyglutamine-Induced Degeneration Post Onset in a Drosophila MJD/SCA3 Model

    PubMed Central

    Cushman-Nick, Mimi; Bonini, Nancy M.; Shorter, James

    2013-01-01

    There are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ) disorders, including Spinocerebellar Ataxia Type-3 (SCA3). Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase from yeast, which is bafflingly absent from metazoa. Hsp104 suppressed eye degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, but unexpectedly enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 suppressed toxicity of MJD variants lacking a portion of the N-terminal deubiquitylase domain and full-length MJD variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 modalities. Importantly, in staging experiments, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression. PMID:24039611

  20. Inhibition of polyglutamine aggregation by SIMILAR huntingtin N-terminal sequences: Prospective molecules for preclinical evaluation in Huntington's disease.

    PubMed

    Burra, Gunasekhar; Thakur, Ashwani Kumar

    2017-04-12

    The mutant huntingtin protein (mHtt) fragments with expanded polyglutamine sequence forms microscopically visible aggregates in neurons, a hallmark of Huntington's disease (HD). The aggregation process and aggregates are possible targets of therapeutic intervention in HD. Due to lack of treatment and cure, the patients die within 15-20 years after the disease onset. Therefore, discovering therapeutic molecules that may either inhibit the aggregation mechanism or downregulate the toxic effects of mhtt are highly needed. The present study demonstrates the design and use of peptide inhibitors based on the role played by the N-terminal seventeen amino acid sequence (NT17 ) of huntingtin fragment in its aggregation. Fug-NT17 (Fugu), Xen-NT17 (Xenopus), Dro-NT17 (Drosophila), Aib-NT17 , and Pro-NT17 sequences were tested for their ability to inhibit aggregation. Among them, the first three are the sequence variants of human NT17 from evolutionarily distant organisms and the latter two are the analogs of human NT17 containing aminoisobutyric acid (Aib) and proline (Pro). Four out of five inhibited the aggregation of huntingtin fragment, NT17 Q35 P10 K2 polypeptide. Data indicates that the physicochemical properties of the inhibitors play a crucial role in exhibiting the inhibitory effect. These inhibitors can be tested in cell and animal models for the preclinical evaluation in the treating of HD. This article is protected by copyright. All rights reserved.

  1. 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse.

    PubMed

    Tokui, Keisuke; Adachi, Hiroaki; Waza, Masahiro; Katsuno, Masahisa; Minamiyama, Makoto; Doi, Hideki; Tanaka, Keiji; Hamazaki, Jun; Murata, Shigeo; Tanaka, Fumiaki; Sobue, Gen

    2009-03-01

    The ubiquitin-proteasome system (UPS) is the principal protein degradation system that tags and targets short-lived proteins, as well as damaged or misfolded proteins, for destruction. In spinal and bulbar muscular atrophy (SBMA), the androgen receptor (AR), an Hsp90 client protein, is such a misfolded protein that tends to aggregate in neurons. Hsp90 inhibitors promote the degradation of Hsp90 client proteins via the UPS. In a transgenic mouse model of SBMA, we examined whether a functioning UPS is preserved, if it was capable of degrading polyglutamine-expanded mutant AR, and what might be the therapeutic effects of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), an oral Hsp90 inhibitor. Ubiquitin-proteasomal function was well preserved in SBMA mice and was even increased during advanced stages when the mice developed severe phenotypes. Administration of 17-DMAG markedly ameliorated motor impairments in SBMA mice without detectable toxicity and reduced amounts of monomeric and nuclear-accumulated mutant AR. Mutant AR was preferentially degraded in the presence of 17-DMAG in both SBMA cell and mouse models when compared with wild-type AR. 17-DMAG also significantly induced Hsp70 and Hsp40. Thus, 17-DMAG would exert a therapeutic effect on SBMA via preserved proteasome function.

  2. Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons

    PubMed Central

    2012-01-01

    Background A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD. Results Here, we performed a large-scale RNA interference screen in C. elegans strains that express N-terminal huntingtin (htt) in touch receptor neurons. These neurons control the response to light touch. Their function is strongly impaired by expanded polyglutamines (128Q) as shown by the nearly complete loss of touch response in adult animals, providing an in vivo model in which to manipulate the early phases of expanded-polyQ neurotoxicity. In total, 6034 genes were examined, revealing 662 gene inactivations that either reduce or aggravate defective touch response in 128Q animals. Several genes were previously implicated in HD or neurodegenerative disease, suggesting that this screen has effectively identified candidate targets for HD. Network-based analysis emphasized a subset of high-confidence modifier genes in pathways of interest in HD including metabolic, neurodevelopmental and pro-survival pathways. Finally, 49 modifiers of 128Q-neuron dysfunction that are dysregulated in the striatum of either R/2 or CHL2 HD mice, or both, were identified. Conclusions Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD. PMID:22413862

  3. Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2.

    PubMed

    Vinther-Jensen, Tua; Ek, Jakob; Duno, Morten; Skovby, Flemming; Hjermind, Lena E; Nielsen, Jørgen E; Nielsen, Troels Tolstrup

    2013-06-01

    The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective genes leading to pathogenic expansions of polyglutamine stretches in the encoded proteins. In general, unstable CAG repeats have an uninterrupted CAG repeat, whereas stable CAG repeats are either short or interrupted by CAA codons, which - like CAG codons - code for glutamine. Here we report on an infantile SCA2 patient who, due to germ-line CAG repeat instability in her father, inherited an extremely expanded CAG repeat in the SCA2 locus. Surprisingly, the expanded allele of the father was an interrupted CAG repeat sequence. Furthermore, analyses of single spermatozoa showed a high frequency of paternal germ-line repeat sequence instability of the expanded SCA2 locus.

  4. [The relativity of abnormity].

    PubMed

    Nilson, Annika

    2006-01-01

    In the late 19th century and in the beginning of the 20th century, mental diseases and abnormal behavior was considered to be a great danger to culture and society. "Degeneration" was the buzzword of the time, used and misused by artists and scientists alike. At the same time, some scientists saw abnormity as the key to unlock the mysteries of the ordinary mind. Naturalistic curiosity left Pandoras box open when religion declined in Darwins wake. Two swedish scientists, the physician Bror Gadelius (1862-1938) and his friend the philosopher Axel Herrlin (1870-1937), inspired by the French psychologist Theodule Ribots (1839-1916) "psychology without a soul", denied all fixed demarcation lines between abnormity and normality. All humans are natures creatures ruled by physiological laws, not ruled by God or convention. Even ordinary morality was considered to be an utterly backward explanation and guideline for complex human behavior. Different forms of therapy, not various kinds of penalties for wicked and disturbing behavior, are the now the solution for lots of people, "normal" as well as "abnormal". Psychiatry is expanding.

  5. Abnormalities of gonadal differentiation.

    PubMed

    Berkovitz, G D; Seeherunvong, T

    1998-04-01

    Gonadal differentiation involves a complex interplay of developmental pathways. The sex determining region Y (SRY) gene plays a key role in testis determination, but its interaction with other genes is less well understood. Abnormalities of gonadal differentiation result in a range of clinical problems. 46,XY complete gonadal dysgenesis is defined by an absence of testis determination. Subjects have female external genitalia and come to clinical attention because of delayed puberty. Individuals with 46,XY partial gonadal dysgenesis usually present in the newborn period for the valuation of ambiguous genitalia. Gonadal histology always shows an abnormality of seminiferous tubule formation. A diagnosis of 46,XY true hermaphroditism is made if the gonads contain well-formed testicular and ovarian elements. Despite the pivotal role of the SRY gene in testis development, mutations of SRY are unusual in subjects with a 46,XY karyotype and abnormal gonadal development. 46,XX maleness is defined by testis determination in an individual with a 46,XX karyotype. Most affected individuals have a phenotype similar to that of Klinefelter syndrome. In contrast, subjects with 46,XX true hermaphroditism usually present with ambiguous genitalia. The majority of subjects with 46,XX maleness have Y sequences including SRY in genomic DNA. However, only rare subjects with 46,XX true hermaphroditism have translocated sequences encoding SRY. Mosaicism and chimaerism involving the Y chromosome can also be associated with abnormal gonadal development. However, the vast majority of subjects with 45,X/46,XY mosaicism have normal testes and normal male external genitalia.

  6. Heritable bovine fetal abnormalities.

    PubMed

    Whitlock, B K; Kaiser, L; Maxwell, H S

    2008-08-01

    The etiologies for congenital bovine fetal anomalies can be divided into heritable, toxic, nutritional, and infectious categories. Although uncommon in most herds, inherited congenital anomalies are probably present in all breeds of cattle and propagated as a result of specific trait selection that inadvertently results in propagation of the defect. In some herds, the occurrence of inherited anomalies has become frequent, and economically important. Anomalous traits can affect animals in a range of ways, some being lethal or requiring euthanasia on humane grounds, others altering structure, function, or performance of affected animals. Veterinary practitioners should be aware of the potential for inherited defects, and be prepared to investigate and report animals exhibiting abnormal characteristics. This review will discuss the morphologic characteristics, mode of inheritance, breeding lines affected, and the availability of genetic testing for selected heritable bovine fetal abnormalities.

  7. Liver abnormalities in pregnancy.

    PubMed

    Than, Nwe Ni; Neuberger, James

    2013-08-01

    Abnormalities of liver function (notably rise in alkaline phosphatase and fall in serum albumin) are common in normal pregnancy, whereas rise in serum bilirubin and aminotransferase suggest either exacerbation of underlying pre-existing liver disease, liver disease related to pregnancy or liver disease unrelated to pregnancy. Pregnant women appear to have a worse outcome when infected with Hepatitis E virus. Liver diseases associated with pregnancy include abnormalities associated hyperemesis gravidarum, acute fatty liver disease, pre-eclampsia, cholestasis of pregnancy and HELLP syndrome. Prompt investigation and diagnosis is important in ensuring a successful maternal and foetal outcome. In general, prompt delivery is the treatment of choice for acute fatty liver, pre-eclampsia and HELLP syndrome and ursodeoxycholic acid is used for cholestasis of pregnancy although it is not licenced for this indication.

  8. Morphological abnormalities in elasmobranchs.

    PubMed

    Moore, A B M

    2015-08-01

    A total of 10 abnormal free-swimming (i.e., post-birth) elasmobranchs are reported from The (Persian-Arabian) Gulf, encompassing five species and including deformed heads, snouts, caudal fins and claspers. The complete absence of pelvic fins in a milk shark Rhizoprionodon acutus may be the first record in any elasmobranch. Possible causes, including the extreme environmental conditions and the high level of anthropogenic pollution particular to The Gulf, are briefly discussed.

  9. Anatomical Abnormalities in Autism?

    PubMed

    Haar, Shlomi; Berman, Sigal; Behrmann, Marlene; Dinstein, Ilan

    2016-04-01

    Substantial controversy exists regarding the presence and significance of anatomical abnormalities in autism spectrum disorders (ASD). The release of the Autism Brain Imaging Data Exchange (∼1000 participants, age 6-65 years) offers an unprecedented opportunity to conduct large-scale comparisons of anatomical MRI scans across groups and to resolve many of the outstanding questions. Comprehensive univariate analyses using volumetric, thickness, and surface area measures of over 180 anatomically defined brain areas, revealed significantly larger ventricular volumes, smaller corpus callosum volume (central segment only), and several cortical areas with increased thickness in the ASD group. Previously reported anatomical abnormalities in ASD including larger intracranial volumes, smaller cerebellar volumes, and larger amygdala volumes were not substantiated by the current study. In addition, multivariate classification analyses yielded modest decoding accuracies of individuals' group identity (<60%), suggesting that the examined anatomical measures are of limited diagnostic utility for ASD. While anatomical abnormalities may be present in distinct subgroups of ASD individuals, the current findings show that many previously reported anatomical measures are likely to be of low clinical and scientific significance for understanding ASD neuropathology as a whole in individuals 6-35 years old.

  10. Abnormal pressures as hydrodynamic phenomena

    USGS Publications Warehouse

    Neuzil, C.E.

    1995-01-01

    So-called abnormal pressures, subsurface fluid pressures significantly higher or lower than hydrostatic, have excited speculation about their origin since subsurface exploration first encountered them. Two distinct conceptual models for abnormal pressures have gained currency among earth scientists. The static model sees abnormal pressures generally as relict features preserved by a virtual absence of fluid flow over geologic time. The hydrodynamic model instead envisions abnormal pressures as phenomena in which flow usually plays an important role. This paper develops the theoretical framework for abnormal pressures as hydrodynamic phenomena, shows that it explains the manifold occurrences of abnormal pressures, and examines the implications of this approach. -from Author

  11. [Molecular abnormalities in lymphomas].

    PubMed

    Delsol, G

    2010-11-01

    Numerous molecular abnormalities have been described in lymphomas. They are of diagnostic and prognostic value and are taken into account for the WHO classification of these tumors. They also shed some light on the underlying molecular mechanisms involved in lymphomas. Overall, four types of molecular abnormalities are involved: mutations, translocations, amplifications and deletions of tumor suppressor genes. Several techniques are available to detect these molecular anomalies: conventional cytogenetic analysis, multicolor FISH, CGH array or gene expression profiling using DNA microarrays. In some lymphomas, genetic abnormalities are responsible for the expression of an abnormal protein (e.g. tyrosine-kinase, transcription factor) detectable by immunohistochemistry. In the present review, molecular abnormalities observed in the most frequent B, T or NK cell lymphomas are discussed. In the broad spectrum of diffuse large B-cell lymphomas microarray analysis shows mostly two subgroups of tumors, one with gene expression signature corresponding to germinal center B-cell-like (GCB: CD10+, BCL6 [B-Cell Lymphoma 6]+, centerine+, MUM1-) and a subgroup expressing an activated B-cell-like signature (ABC: CD10-, BCL6-, centerine-, MUM1+). Among other B-cell lymphomas with well characterized molecular abnormalies are follicular lymphoma (BCL2 deregulation), MALT lymphoma (Mucosa Associated Lymphoid Tissue) [API2-MALT1 (mucosa-associated-lymphoid-tissue-lymphoma-translocation-gene1) fusion protein or deregulation BCL10, MALT1, FOXP1. MALT1 transcription factors], mantle cell lymphoma (cycline D1 [CCND1] overexpression) and Burkitt lymphoma (c-Myc expression). Except for ALK (anaplastic lymphoma kinase)-positive anaplastic large cell lymphoma, well characterized molecular anomalies are rare in lymphomas developed from T or NK cells. Peripheral T cell lymphomas not otherwise specified are a heterogeneous group of tumors with frequent but not recurrent molecular abnormalities

  12. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    ERIC Educational Resources Information Center

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  13. Exercises to Improve Gait Abnormalities

    MedlinePlus

    ... Home About iChip Articles Directories Videos Resources Contact Exercises to Improve Gait Abnormalities Home » Article Categories » Exercise and Fitness Font Size: A A A A Exercises to Improve Gait Abnormalities Next Page The manner ...

  14. Abnormal human sex chromosome constitutions

    SciTech Connect

    1993-12-31

    Chapter 22, discusses abnormal human sex chromosome constitution. Aneuploidy of X chromosomes with a female phenotype, sex chromosome aneuploidy with a male phenotype, and various abnormalities in X chromosome behavior are described. 31 refs., 2 figs.

  15. Common origin of pure and interrupted repeat expansions in spinocerebellar ataxia type 2 (SCA2).

    PubMed

    Ramos, Eliana Marisa; Martins, Sandra; Alonso, Isabel; Emmel, Vanessa E; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach; Coutinho, Paula; Sequeiros, Jorge; Silveira, Isabel

    2010-03-05

    The spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by gait and limb ataxia. This disease is caused by the expansion of a (CAG)(n) located in the ATXN2, that encodes a polyglutamine tract of more than 34 repeats. Lately, alleles with 32-33 CAGs have been associated to late-onset disease cases. Repeat interruptions by CAA triplets are common in normal alleles, while expanded alleles usually contain a pure repeat tract. To investigate the mutational origin and the instability associated to the ATXN2 repeat, we performed an extensive haplotype study and sequencing of the CAG/CAA repeat, in a cohort of families of different geographic origins and phenotypes. Our results showed (1) CAA interruptions also in expanded ATXN2 alleles; (2) that pathological CAA interrupted alleles shared an ancestral haplotype with pure expanded alleles; and (3) higher genetic diversity in European SCA2 families, suggesting an older European ancestry of SCA2. In conclusion, we found instability towards expansion in interrupted ATXN2 alleles and a shared ancestral ATXN2 haplotype for pure and interrupted expanded alleles; this finding has strong implications in mutation diagnosis and counseling. Our results indicate that interrupted alleles, below the pathological threshold, may be a reservoir of mutable alleles, prone to expansion in subsequent generations, leading to full disease mutation.

  16. Epilepsy and chromosomal abnormalities

    PubMed Central

    2010-01-01

    Background Many chromosomal abnormalities are associated with Central Nervous System (CNS) malformations and other neurological alterations, among which seizures and epilepsy. Some of these show a peculiar epileptic and EEG pattern. We describe some epileptic syndromes frequently reported in chromosomal disorders. Methods Detailed clinical assessment, electrophysiological studies, survey of the literature. Results In some of these congenital syndromes the clinical presentation and EEG anomalies seems to be quite typical, in others the manifestations appear aspecific and no strictly linked with the chromosomal imbalance. The onset of seizures is often during the neonatal period of the infancy. Conclusions A better characterization of the electro clinical patterns associated with specific chromosomal aberrations could give us a valuable key in the identification of epilepsy susceptibility of some chromosomal loci, using the new advances in molecular cytogenetics techniques - such as fluorescent in situ hybridization (FISH), subtelomeric analysis and CGH (comparative genomic hybridization) microarray. However further studies are needed to understand the mechanism of epilepsy associated with chromosomal abnormalities. PMID:20438626

  17. Optimal Electric Utility Expansion

    SciTech Connect

    1989-10-10

    SAGE-WASP is designed to find the optimal generation expansion policy for an electrical utility system. New units can be automatically selected from a user-supplied list of expansion candidates which can include hydroelectric and pumped storage projects. The existing system is modeled. The calculational procedure takes into account user restrictions to limit generation configurations to an area of economic interest. The optimization program reports whether the restrictions acted as a constraint on the solution. All expansion configurations considered are required to pass a user supplied reliability criterion. The discount rate and escalation rate are treated separately for each expansion candidate and for each fuel type. All expenditures are separated into local and foreign accounts, and a weighting factor can be applied to foreign expenditures.

  18. Weakly relativistic plasma expansion

    SciTech Connect

    Fermous, Rachid Djebli, Mourad

    2015-04-15

    Plasma expansion is an important physical process that takes place in laser interactions with solid targets. Within a self-similar model for the hydrodynamical multi-fluid equations, we investigated the expansion of both dense and under-dense plasmas. The weakly relativistic electrons are produced by ultra-intense laser pulses, while ions are supposed to be in a non-relativistic regime. Numerical investigations have shown that relativistic effects are important for under-dense plasma and are characterized by a finite ion front velocity. Dense plasma expansion is found to be governed mainly by quantum contributions in the fluid equations that originate from the degenerate pressure in addition to the nonlinear contributions from exchange and correlation potentials. The quantum degeneracy parameter profile provides clues to set the limit between under-dense and dense relativistic plasma expansions at a given density and temperature.

  19. Pen Branch delta expansion

    SciTech Connect

    Nelson, E.A.; Christensen, E.J.; Mackey, H.E.; Sharitz, R.R.; Jensen, J.R.; Hodgson, M.E.

    1984-02-01

    Since 1954, cooling water discharges from K Reactor ({anti X} = 370 cfs {at} 59 C) to Pen Branch have altered vegetation and deposited sediment in the Savannah River Swamp forming the Pen Branch delta. Currently, the delta covers over 300 acres and continues to expand at a rate of about 16 acres/yr. Examination of delta expansion can provide important information on environmental impacts to wetlands exposed to elevated temperature and flow conditions. To assess the current status and predict future expansion of the Pen Branch delta, historic aerial photographs were analyzed using both basic photo interpretation and computer techniques to provide the following information: (1) past and current expansion rates; (2) location and changes of impacted areas; (3) total acreage presently affected. Delta acreage changes were then compared to historic reactor discharge temperature and flow data to see if expansion rate variations could be related to reactor operations.

  20. Thermal Expansion "Paradox."

    ERIC Educational Resources Information Center

    Fakhruddin, Hasan

    1993-01-01

    Describes a paradox in the equation for thermal expansion. If the calculations for heating a rod and subsequently cooling a rod are determined, the new length of the cool rod is shorter than expected. (PR)

  1. Skeletal abnormalities in homocystinuria.

    PubMed Central

    Brenton, D. P.

    1977-01-01

    The skeletal changes of thirty-four patients with the biochemical and clinical features of cystathionine synthase deficiency are described. It is emphasized that there is clinical evidence of excessive bone growth and the formation for bone which is structurally weaker than normal. The similarities and differences between this condition and Marfan's syndrome are stressed and the possible nature of the connective tissue defect leading to the skeletal changes discussed. The most characteristic skeletal changes in homocystinuria are the skeletal disproportion (pubis-heel length greater than crown-pubis length), the abnormal vertebrae, sternal deformities, genu valgum and large metaphyses and epiphyses. Images Fig. 2 Fig. 3 Fig. 4 Fig. 8 Fig. 9 Fig. 10 PMID:917963

  2. Eye movement abnormalities.

    PubMed

    Moncayo, Jorge; Bogousslavsky, Julien

    2012-01-01

    Generation and control of eye movements requires the participation of the cortex, basal ganglia, cerebellum and brainstem. The signals of this complex neural network finally converge on the ocular motoneurons of the brainstem. Infarct or hemorrhage at any level of the oculomotor system (though more frequent in the brain-stem) may give rise to a broad spectrum of eye movement abnormalities (EMAs). Consequently, neurologists and particularly stroke neurologists are routinely confronted with EMAs, some of which may be overlooked in the acute stroke setting and others that, when recognized, may have a high localizing value. The most complex EMAs are due to midbrain stroke. Horizontal gaze disorders, some of them manifesting unusual patterns, may occur in pontine stroke. Distinct varieties of nystagmus occur in cerebellar and medullary stroke. This review summarizes the most representative EMAs from the supratentorial level to the brainstem.

  3. Drosophila melanogaster As a Model Organism to Study RNA Toxicity of Repeat Expansion-Associated Neurodegenerative and Neuromuscular Diseases

    PubMed Central

    Koon, Alex C.; Chan, Ho Yin Edwin

    2017-01-01

    For nearly a century, the fruit fly, Drosophila melanogaster, has proven to be a valuable tool in our understanding of fundamental biological processes, and has empowered our discoveries, particularly in the field of neuroscience. In recent years, Drosophila has emerged as a model organism for human neurodegenerative and neuromuscular disorders. In this review, we highlight a number of recent studies that utilized the Drosophila model to study repeat-expansion associated diseases (READs), such as polyglutamine diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), myotonic dystrophy type 1 (DM1) and type 2 (DM2), and C9ORF72-associated amyotrophic lateral sclerosis/frontotemporal dementia (C9-ALS/FTD). Discoveries regarding the possible mechanisms of RNA toxicity will be focused here. These studies demonstrate Drosophila as an excellent in vivo model system that can reveal novel mechanistic insights into human disorders, providing the foundation for translational research and therapeutic development. PMID:28377694

  4. The great human expansion.

    PubMed

    Henn, Brenna M; Cavalli-Sforza, L L; Feldman, Marcus W

    2012-10-30

    Genetic and paleoanthropological evidence is in accord that today's human population is the result of a great demic (demographic and geographic) expansion that began approximately 45,000 to 60,000 y ago in Africa and rapidly resulted in human occupation of almost all of the Earth's habitable regions. Genomic data from contemporary humans suggest that this expansion was accompanied by a continuous loss of genetic diversity, a result of what is called the "serial founder effect." In addition to genomic data, the serial founder effect model is now supported by the genetics of human parasites, morphology, and linguistics. This particular population history gave rise to the two defining features of genetic variation in humans: genomes from the substructured populations of Africa retain an exceptional number of unique variants, and there is a dramatic reduction in genetic diversity within populations living outside of Africa. These two patterns are relevant for medical genetic studies mapping genotypes to phenotypes and for inferring the power of natural selection in human history. It should be appreciated that the initial expansion and subsequent serial founder effect were determined by demographic and sociocultural factors associated with hunter-gatherer populations. How do we reconcile this major demic expansion with the population stability that followed for thousands years until the inventions of agriculture? We review advances in understanding the genetic diversity within Africa and the great human expansion out of Africa and offer hypotheses that can help to establish a more synthetic view of modern human evolution.

  5. Virial Expansion Bounds

    NASA Astrophysics Data System (ADS)

    Tate, Stephen James

    2013-10-01

    In the 1960s, the technique of using cluster expansion bounds in order to achieve bounds on the virial expansion was developed by Lebowitz and Penrose (J. Math. Phys. 5:841, 1964) and Ruelle (Statistical Mechanics: Rigorous Results. Benjamin, Elmsford, 1969). This technique is generalised to more recent cluster expansion bounds by Poghosyan and Ueltschi (J. Math. Phys. 50:053509, 2009), which are related to the work of Procacci (J. Stat. Phys. 129:171, 2007) and the tree-graph identity, detailed by Brydges (Phénomènes Critiques, Systèmes Aléatoires, Théories de Jauge. Les Houches 1984, pp. 129-183, 1986). The bounds achieved by Lebowitz and Penrose can also be sharpened by doing the actual optimisation and achieving expressions in terms of the Lambert W-function. The different bound from the cluster expansion shows some improvements for bounds on the convergence of the virial expansion in the case of positive potentials, which are allowed to have a hard core.

  6. Expansion of CAG triplet repeats by human DNA polymerases λ and β in vitro, is regulated by flap endonuclease 1 and DNA ligase 1.

    PubMed

    Crespan, Emmanuele; Hübscher, Ulrich; Maga, Giovanni

    2015-05-01

    Huntington's disease (HD) is a neurological genetic disorder caused by the expansion of the CAG trinucleotide repeats (TNR) in the N-terminal region of coding sequence of the Huntingtin's (HTT) gene. This results in the addition of a poly-glutamine tract within the Huntingtin protein, resulting in its pathological form. The mechanism by which TRN expansion takes place is not yet fully understood. We have recently shown that DNA polymerase (Pol) β can promote the microhomology-mediated end joining and triplet expansion of a substrate mimicking a double strand break in the TNR region of the HTT gene. Here we show that TNR expansion is dependent on the structure of the DNA substrate, as well as on the two essential Pol β co-factors: flap endonuclease 1 (Fen1) and DNA ligase 1 (Lig1). We found that Fen1 significantly stimulated TNR expansion by Pol β, but not by the related enzyme Pol λ, and subsequent ligation of the DNA products by Lig1. Interestingly, the deletion of N-terminal domains of Pol λ, resulted in an enzyme which displayed properties more similar to Pol β, suggesting a possible evolutionary mechanism. These results may suggest a novel mechanism for somatic TNR expansion in HD.

  7. AUTO-EXPANSIVE FLOW

    EPA Science Inventory

    Physics suggests that the interplay of momentum, continuity, and geometry in outward radial flow must produce density and concomitant pressure reductions. In other words, this flow is intrinsically auto-expansive. It has been proposed that this process is the key to understanding...

  8. Static gas expansion cooler

    DOEpatents

    Guzek, J.C.; Lujan, R.A.

    1984-01-01

    Disclosed is a cooler for television cameras and other temperature sensitive equipment. The cooler uses compressed gas ehich is accelerated to a high velocity by passing it through flow passageways having nozzle portions which expand the gas. This acceleration and expansion causes the gas to undergo a decrease in temperature thereby cooling the cooler body and adjacent temperature sensitive equipment.

  9. Expansion of Pannes

    EPA Science Inventory

    For the Long Island, New Jersey, and southern New England region, one facet of marsh drowning as a result of accelerated sea level rise is the expansion of salt marsh ponds and pannes. Over the past century, marsh ponds and pannes have formed and expanded in areas of poor drainag...

  10. A Special Trinomial Expansion

    ERIC Educational Resources Information Center

    Ayoub, Ayoub B.

    2006-01-01

    In this article, the author takes up the special trinomial (1 + x + x[squared])[superscript n] and shows that the coefficients of its expansion are entries of a Pascal-like triangle. He also shows how to calculate these entries recursively and explicitly. This article could be used in the classroom for enrichment. (Contains 1 table.)

  11. Urban Expansion Study

    NASA Technical Reports Server (NTRS)

    1985-01-01

    Under an Egyptian government contract, PADCO studies urban growth in the Nile Area. They were assisted by LANDSAT survey maps and measurements provided by TAC. TAC had classified the raw LANDSAT data and processed it into various categories to detail urban expansion. PADCO crews spot checked the results, and correlations were established.

  12. Systemic abnormalities in liver disease

    PubMed Central

    Minemura, Masami; Tajiri, Kazuto; Shimizu, Yukihiro

    2009-01-01

    Systemic abnormalities often occur in patients with liver disease. In particular, cardiopulmonary or renal diseases accompanied by advanced liver disease can be serious and may determine the quality of life and prognosis of patients. Therefore, both hepatologists and non-hepatologists should pay attention to such abnormalities in the management of patients with liver diseases. PMID:19554648

  13. The great human expansion

    PubMed Central

    Henn, Brenna M.; Cavalli-Sforza, L. L.; Feldman, Marcus W.

    2012-01-01

    Genetic and paleoanthropological evidence is in accord that today’s human population is the result of a great demic (demographic and geographic) expansion that began approximately 45,000 to 60,000 y ago in Africa and rapidly resulted in human occupation of almost all of the Earth’s habitable regions. Genomic data from contemporary humans suggest that this expansion was accompanied by a continuous loss of genetic diversity, a result of what is called the “serial founder effect.” In addition to genomic data, the serial founder effect model is now supported by the genetics of human parasites, morphology, and linguistics. This particular population history gave rise to the two defining features of genetic variation in humans: genomes from the substructured populations of Africa retain an exceptional number of unique variants, and there is a dramatic reduction in genetic diversity within populations living outside of Africa. These two patterns are relevant for medical genetic studies mapping genotypes to phenotypes and for inferring the power of natural selection in human history. It should be appreciated that the initial expansion and subsequent serial founder effect were determined by demographic and sociocultural factors associated with hunter-gatherer populations. How do we reconcile this major demic expansion with the population stability that followed for thousands years until the inventions of agriculture? We review advances in understanding the genetic diversity within Africa and the great human expansion out of Africa and offer hypotheses that can help to establish a more synthetic view of modern human evolution. PMID:23077256

  14. Trinucleotide repeat expansion and DRPLA (Smith`s disease): Molecular characterization of atrophin-1

    SciTech Connect

    Margolis, R.L.; Li, S.H.; Li, X.J.; Ross, C.A.

    1994-09-01

    Smith`s disease (also known as dentatorubral pallidoluysian atrophy or DRPLA) is a rare, progressive, fatal neuropsychiatric disorder similar to Huntington`s disease (HD). Smith`s disease is characterized by ataxia, choreoathetosis, myoclonic epilepsy, dementia, and genetic anticipation. Neuropathological findings include prominent cell loss in the dentate nucleus of the cerebellum, the globus pallidus, the red nucleus, and the subthalamic nucleus. An expansion of a CAG trinucleotide repeat encoding polyglutamine in a gene originally identified in our laboratory as part of a program to clone candidate genes for disorders with anticipation has recently been found to cause this disorder. We have identified two families that demonstrate the pathological and genetic features (expanded CAG repeat and anticipation) of this disease. Northern analysis indicates that the gene, which we have termed atrophin-1, is widely expressed as a 5 kb mRNA in normal human brain and peripheral tissues. Brain expression is highest in the cerebellum. The developmental expression of the rat homologues of IT-15 (the gene in which a CAG expansion causes HD) and atrophin-1 were compared. Atrophin-1 was most highly expressed in early rat embryo brain (E16), whereas the greatest expression of IT-15 was in the adult rat brain. Cloning and sequencing of the open reading frame from inserts contained in brain cDNA libraries is in progress. In addition to the CAG repeat, the ORF contains an unusual region of alternating acidic and basic amino acids. Further characterization of atrophin-1, and comparison of it to other genes in which trinucleotide repeat expansion leads to neuropsychiatric disorders, should lead to a better understanding of the pathophysiology by which CAG repeat expansion causes human disease.

  15. Chromosomal abnormalities and mental illness.

    PubMed

    MacIntyre, D J; Blackwood, D H R; Porteous, D J; Pickard, B S; Muir, W J

    2003-03-01

    Linkage studies of mental illness have provided suggestive evidence of susceptibility loci over many broad chromosomal regions. Pinpointing causative gene mutations by conventional linkage strategies alone is problematic. The breakpoints of chromosomal abnormalities occurring in patients with mental illness may be more direct pointers to the relevant gene locus. Publications that describe patients where chromosomal abnormalities co-exist with mental illness are reviewed along with supporting evidence that this may amount to an association. Chromosomal abnormalities are considered to be of possible significance if (a) the abnormality is rare and there are independent reports of its coexistence with psychiatric illness, or (b) there is colocalisation of the abnormality with a region of suggestive linkage findings, or (c) there is an apparent cosegregation of the abnormality with psychiatric illness within the individual's family. Breakpoints have been described within many of the loci suggested by linkage studies and these findings support the hypothesis that shared susceptibility factors for schizophrenia and bipolar disorder may exist. If these abnormalities directly disrupt coding regions, then combining molecular genetic breakpoint cloning with bioinformatic sequence analysis may be a method of rapidly identifying candidate genes. Full karyotyping of individuals with psychotic illness especially where this coexists with mild learning disability, dysmorphism or a strong family history of mental disorder is encouraged.

  16. Chromosomal abnormalities in human sperm

    SciTech Connect

    Martin, R.H.

    1985-01-01

    The ability to analyze human sperm chromosome complements after penetration of zona pellucida-free hamster eggs provides the first opportunity to study the frequency and type of chromosomal abnormalities in human gametes. Two large-scale studies have provided information on normal men. We have studied 1,426 sperm complements from 45 normal men and found an abnormality rate of 8.9%. Brandriff et al. (5) found 8.1% abnormal complements in 909 sperm from 4 men. The distribution of numerical and structural abnormalities was markedly dissimilar in the 2 studies. The frequency of aneuploidy was 5% in our sample and only 1.6% in Brandriff's, perhaps reflecting individual variability among donors. The frequency of 24,YY sperm was low: 0/1,426 and 1/909. This suggests that the estimates of nondisjunction based on fluorescent Y body data (1% to 5%) are not accurate. We have also studied men at increased risk of sperm chromosomal abnormalities. The frequency of chromosomally unbalanced sperm in 6 men heterozygous for structural abnormalities varied dramatically: 77% for t11;22, 32% for t6;14, 19% for t5;18, 13% for t14;21, and 0% for inv 3 and 7. We have also studied 13 cancer patients before and after radiotherapy and demonstrated a significant dose-dependent increase of sperm chromosome abnormalities (numerical and structural) 36 months after radiation treatment.

  17. Bigravity from gradient expansion

    SciTech Connect

    Yamashita, Yasuho; Tanaka, Takahiro

    2016-05-04

    We discuss how the ghost-free bigravity coupled with a single scalar field can be derived from a braneworld setup. We consider DGP two-brane model without radion stabilization. The bulk configuration is solved for given boundary metrics, and it is substituted back into the action to obtain the effective four-dimensional action. In order to obtain the ghost-free bigravity, we consider the gradient expansion in which the brane separation is supposed to be sufficiently small so that two boundary metrics are almost identical. The obtained effective theory is shown to be ghost free as expected, however, the interaction between two gravitons takes the Fierz-Pauli form at the leading order of the gradient expansion, even though we do not use the approximation of linear perturbation. We also find that the radion remains as a scalar field in the four-dimensional effective theory, but its coupling to the metrics is non-trivial.

  18. Range expansion of mutualists

    NASA Astrophysics Data System (ADS)

    Muller, Melanie J. I.; Korolev, Kirill S.; Murray, Andrew W.; Nelson, David R.

    2012-02-01

    The expansion of a species into new territory is often strongly influenced by the presence of other species. This effect is particularly striking for the case of mutualistic species that enhance each other's proliferation. Examples range from major events in evolutionary history, such as the spread and diversification of flowering plants due to their mutualism with pollen-dispersing insects, to modern examples like the surface colonisation of multi-species microbial biofilms. Here, we investigate the spread of cross-feeding strains of the budding yeast Saccharomyces cerevisiae on an agar surface as a model system for expanding mutualists. Depending on the degree of mutualism, the two strains form distinctive spatial patterns during their range expansion. This change in spatial patterns can be understood as a phase transition within a stepping stone model generalized to two mutualistic species.

  19. Haematological abnormalities in mitochondrial disorders

    PubMed Central

    Finsterer, Josef; Frank, Marlies

    2015-01-01

    INTRODUCTION This study aimed to assess the kind of haematological abnormalities that are present in patients with mitochondrial disorders (MIDs) and the frequency of their occurrence. METHODS The blood cell counts of a cohort of patients with syndromic and non-syndromic MIDs were retrospectively reviewed. MIDs were classified as ‘definite’, ‘probable’ or ‘possible’ according to clinical presentation, instrumental findings, immunohistological findings on muscle biopsy, biochemical abnormalities of the respiratory chain and/or the results of genetic studies. Patients who had medical conditions other than MID that account for the haematological abnormalities were excluded. RESULTS A total of 46 patients (‘definite’ = 5; ‘probable’ = 9; ‘possible’ = 32) had haematological abnormalities attributable to MIDs. The most frequent haematological abnormality in patients with MIDs was anaemia. 27 patients had anaemia as their sole haematological problem. Anaemia was associated with thrombopenia (n = 4), thrombocytosis (n = 2), leucopenia (n = 2), and eosinophilia (n = 1). Anaemia was hypochromic and normocytic in 27 patients, hypochromic and microcytic in six patients, hyperchromic and macrocytic in two patients, and normochromic and microcytic in one patient. Among the 46 patients with a mitochondrial haematological abnormality, 78.3% had anaemia, 13.0% had thrombopenia, 8.7% had leucopenia and 8.7% had eosinophilia, alone or in combination with other haematological abnormalities. CONCLUSION MID should be considered if a patient’s abnormal blood cell counts (particularly those associated with anaemia, thrombopenia, leucopenia or eosinophilia) cannot be explained by established causes. Abnormal blood cell counts may be the sole manifestation of MID or a collateral feature of a multisystem problem. PMID:26243978

  20. Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease.

    PubMed

    Gomez-Pastor, Rocio; Burchfiel, Eileen T; Neef, Daniel W; Jaeger, Alex M; Cabiscol, Elisa; McKinstry, Spencer U; Doss, Argenia; Aballay, Alejandro; Lo, Donald C; Akimov, Sergey S; Ross, Christopher A; Eroglu, Cagla; Thiele, Dennis J

    2017-02-13

    Huntington's Disease (HD) is a neurodegenerative disease caused by poly-glutamine expansion in the Htt protein, resulting in Htt misfolding and cell death. Expression of the cellular protein folding and pro-survival machinery by heat shock transcription factor 1 (HSF1) ameliorates biochemical and neurobiological defects caused by protein misfolding. We report that HSF1 is degraded in cells and mice expressing mutant Htt, in medium spiny neurons derived from human HD iPSCs and in brain samples from patients with HD. Mutant Htt increases CK2α' kinase and Fbxw7 E3 ligase levels, phosphorylating HSF1 and promoting its proteasomal degradation. An HD mouse model heterozygous for CK2α' shows increased HSF1 and chaperone levels, maintenance of striatal excitatory synapses, clearance of Htt aggregates and preserves body mass compared with HD mice homozygous for CK2α'. These results reveal a pathway that could be modulated to prevent neuronal dysfunction and muscle wasting caused by protein misfolding in HD.

  1. Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease

    PubMed Central

    Gomez-Pastor, Rocio; Burchfiel, Eileen T.; Neef, Daniel W.; Jaeger, Alex M.; Cabiscol, Elisa; McKinstry, Spencer U.; Doss, Argenia; Aballay, Alejandro; Lo, Donald C.; Akimov, Sergey S.; Ross, Christopher A.; Eroglu, Cagla; Thiele, Dennis J.

    2017-01-01

    Huntington's Disease (HD) is a neurodegenerative disease caused by poly-glutamine expansion in the Htt protein, resulting in Htt misfolding and cell death. Expression of the cellular protein folding and pro-survival machinery by heat shock transcription factor 1 (HSF1) ameliorates biochemical and neurobiological defects caused by protein misfolding. We report that HSF1 is degraded in cells and mice expressing mutant Htt, in medium spiny neurons derived from human HD iPSCs and in brain samples from patients with HD. Mutant Htt increases CK2α′ kinase and Fbxw7 E3 ligase levels, phosphorylating HSF1 and promoting its proteasomal degradation. An HD mouse model heterozygous for CK2α′ shows increased HSF1 and chaperone levels, maintenance of striatal excitatory synapses, clearance of Htt aggregates and preserves body mass compared with HD mice homozygous for CK2α′. These results reveal a pathway that could be modulated to prevent neuronal dysfunction and muscle wasting caused by protein misfolding in HD. PMID:28194040

  2. Thermal expansion of glassy polymers.

    PubMed

    Davy, K W; Braden, M

    1992-01-01

    The thermal expansion of a number of glassy polymers of interest in dentistry has been studied using a quartz dilatometer. In some cases, the expansion was linear and therefore the coefficient of thermal expansion readily determined. Other polymers exhibited non-linear behaviour and values appropriate to different temperature ranges are quoted. The linear coefficient of thermal expansion was, to a first approximation, a function of both the molar volume and van der Waal's volume of the repeating unit.

  3. Congenital abnormalities and selective abortion.

    PubMed

    Seller, M J

    1976-09-01

    The technique of amniocentesis, by which an abnormal fetus can be detected in utero, has brought a technological advance in medical science but attendant medical and moral problems. Dr Seller describes those congenital disabilities which can be detected in the fetus before birth, for which the "remedy" is selective abortion. She then discusses the arguments for and against selective abortion, for the issue is not simple, even in the strictly genetic sense of attempting to ensure a population free of congenital abnormality.

  4. Expansion: A Plan for Success.

    ERIC Educational Resources Information Center

    Callahan, A.P.

    This report provides selling brokers' guidelines for the successful expansion of their operations outlining a basic method of preparing an expansion plan. Topic headings are: The Pitfalls of Expansion (The Language of Business, Timely Financial Reporting, Regulatory Agencies of Government, Preoccupation with the Facade of Business, A Business Is a…

  5. Load regulating expansion fixture

    DOEpatents

    Wagner, Lawrence M.; Strum, Michael J.

    1998-01-01

    A free standing self contained device for bonding ultra thin metallic films, such as 0.001 inch beryllium foils. The device will regulate to a predetermined load for solid state bonding when heated to a bonding temperature. The device includes a load regulating feature, whereby the expansion stresses generated for bonding are regulated and self adjusting. The load regulator comprises a pair of friction isolators with a plurality of annealed copper members located therebetween. The device, with the load regulator, will adjust to and maintain a stress level needed to successfully and economically complete a leak tight bond without damaging thin foils or other delicate components.

  6. Load regulating expansion fixture

    DOEpatents

    Wagner, L.M.; Strum, M.J.

    1998-12-15

    A free standing self contained device for bonding ultra thin metallic films, such as 0.001 inch beryllium foils is disclosed. The device will regulate to a predetermined load for solid state bonding when heated to a bonding temperature. The device includes a load regulating feature, whereby the expansion stresses generated for bonding are regulated and self adjusting. The load regulator comprises a pair of friction isolators with a plurality of annealed copper members located therebetween. The device, with the load regulator, will adjust to and maintain a stress level needed to successfully and economically complete a leak tight bond without damaging thin foils or other delicate components. 1 fig.

  7. Expansible quantum secret sharing network

    NASA Astrophysics Data System (ADS)

    Sun, Ying; Xu, Sheng-Wei; Chen, Xiu-Bo; Niu, Xin-Xin; Yang, Yi-Xian

    2013-08-01

    In the practical applications, member expansion is a usual demand during the development of a secret sharing network. However, there are few consideration and discussion on network expansibility in the existing quantum secret sharing schemes. We propose an expansible quantum secret sharing scheme with relatively simple and economical quantum resources and show how to split and reconstruct the quantum secret among an expansible user group in our scheme. Its trait, no requirement of any agent's assistant during the process of member expansion, can help to prevent potential menaces of insider cheating. We also give a discussion on the security of this scheme from three aspects.

  8. [Diagnosticum of abnormalities of plant meiotic division].

    PubMed

    Shamina, N V

    2006-01-01

    Abnormalities of plant meiotic division leading to abnormal meiotic products are summarized schematically in the paper. Causes of formation of monads, abnormal diads, triads, pentads, polyads, etc. have been observed in meiosis with both successive and simultaneous cytokinesis.

  9. Abnormal insulin levels and vertigo.

    PubMed

    Proctor, C A

    1981-10-01

    Fifty patients with unexplained vertigo (36) or lightheadedness (14) are evaluated, all of whom had abnormal ENGs and normal audiograms. Five hour insulin glucose tolerance tests were performance on all patients, with insulin levels being obtained fasting and at one-half, one, two, and three hours. The results of this investigation were remarkable. Borderline or abnormal insulin levels were discovered in 82% of patients; 90% were found to have either an abnormal glucose tolerance test or at least borderline insulin levels. The response to treatment in these dizzy patients was also startling, with appropriate low carbohydrate diets improving the patient's symptoms in 90% of cases. It is, therefore, apparent that the earliest identification of carbohydrate imbalance with an insulin glucose tolerance test is extremely important in the work-up of the dizzy patients.

  10. Complex patterns of abnormal heartbeats

    NASA Technical Reports Server (NTRS)

    Schulte-Frohlinde, Verena; Ashkenazy, Yosef; Goldberger, Ary L.; Ivanov, Plamen Ch; Costa, Madalena; Morley-Davies, Adrian; Stanley, H. Eugene; Glass, Leon

    2002-01-01

    Individuals having frequent abnormal heartbeats interspersed with normal heartbeats may be at an increased risk of sudden cardiac death. However, mechanistic understanding of such cardiac arrhythmias is limited. We present a visual and qualitative method to display statistical properties of abnormal heartbeats. We introduce dynamical "heartprints" which reveal characteristic patterns in long clinical records encompassing approximately 10(5) heartbeats and may provide information about underlying mechanisms. We test if these dynamics can be reproduced by model simulations in which abnormal heartbeats are generated (i) randomly, (ii) at a fixed time interval following a preceding normal heartbeat, or (iii) by an independent oscillator that may or may not interact with the normal heartbeat. We compare the results of these three models and test their limitations to comprehensively simulate the statistical features of selected clinical records. This work introduces methods that can be used to test mathematical models of arrhythmogenesis and to develop a new understanding of underlying electrophysiologic mechanisms of cardiac arrhythmia.

  11. Large-scale microfluidics providing high-resolution and high-throughput screening of Caenorhabditis elegans poly-glutamine aggregation model

    PubMed Central

    Mondal, Sudip; Hegarty, Evan; Martin, Chris; Gökçe, Sertan Kutal; Ghorashian, Navid; Ben-Yakar, Adela

    2016-01-01

    Next generation drug screening could benefit greatly from in vivo studies, using small animal models such as Caenorhabditis elegans for hit identification and lead optimization. Current in vivo assays can operate either at low throughput with high resolution or with low resolution at high throughput. To enable both high-throughput and high-resolution imaging of C. elegans, we developed an automated microfluidic platform. This platform can image 15 z-stacks of ∼4,000 C. elegans from 96 different populations using a large-scale chip with a micron resolution in 16 min. Using this platform, we screened ∼100,000 animals of the poly-glutamine aggregation model on 25 chips. We tested the efficacy of ∼1,000 FDA-approved drugs in improving the aggregation phenotype of the model and identified four confirmed hits. This robust platform now enables high-content screening of various C. elegans disease models at the speed and cost of in vitro cell-based assays. PMID:27725672

  12. Large-scale microfluidics providing high-resolution and high-throughput screening of Caenorhabditis elegans poly-glutamine aggregation model

    NASA Astrophysics Data System (ADS)

    Mondal, Sudip; Hegarty, Evan; Martin, Chris; Gökçe, Sertan Kutal; Ghorashian, Navid; Ben-Yakar, Adela

    2016-10-01

    Next generation drug screening could benefit greatly from in vivo studies, using small animal models such as Caenorhabditis elegans for hit identification and lead optimization. Current in vivo assays can operate either at low throughput with high resolution or with low resolution at high throughput. To enable both high-throughput and high-resolution imaging of C. elegans, we developed an automated microfluidic platform. This platform can image 15 z-stacks of ~4,000 C. elegans from 96 different populations using a large-scale chip with a micron resolution in 16 min. Using this platform, we screened ~100,000 animals of the poly-glutamine aggregation model on 25 chips. We tested the efficacy of ~1,000 FDA-approved drugs in improving the aggregation phenotype of the model and identified four confirmed hits. This robust platform now enables high-content screening of various C. elegans disease models at the speed and cost of in vitro cell-based assays.

  13. Characterization of C-terminal adaptors, UFD-2 and UFD-3, of CDC-48 on the polyglutamine aggregation in C. elegans.

    PubMed

    Murayama, Yuki; Ogura, Teru; Yamanaka, Kunitoshi

    2015-03-27

    CDC-48 (also called VCP or p97 in mammals and Cdc48p in yeast) is a AAA (ATPases associated with diverse cellular activities) chaperone and participates in a wide range of cellular activities including modulation of protein complexes and protein aggregates. UFD-2 and UFD-3, C-terminal adaptors for CDC-48, reportedly bind to CDC-48 in a mutually exclusive manner and they may modulate the fate of substrates for CDC-48. However, their cellular functions have not yet been elucidated. In this study, we found that CDC-48 preferentially interacts with UFD-3 in Caenorhabditis elegans. We also found that the number of polyglutamine (polyQ) aggregates was reduced in the ufd-3 deletion mutant but not in the ufd-2 deletion mutant. Furthermore, the lifespan and motility of the ufd-3 deletion mutant, where polyQ40::GFP was expressed, were greatly decreased. Taken together, we propose that UFD-3 may promote the formation of polyQ aggregates to reduce the polyQ toxicity in C. elegans.

  14. Structure-function analysis of mouse Sry reveals dual essential roles of the C-terminal polyglutamine tract in sex determination.

    PubMed

    Zhao, Liang; Ng, Ee Ting; Davidson, Tara-Lynne; Longmuss, Enya; Urschitz, Johann; Elston, Marlee; Moisyadi, Stefan; Bowles, Josephine; Koopman, Peter

    2014-08-12

    The mammalian sex-determining factor SRY comprises a conserved high-mobility group (HMG) box DNA-binding domain and poorly conserved regions outside the HMG box. Mouse Sry is unusual in that it includes a C-terminal polyglutamine (polyQ) tract that is absent in nonrodent SRY proteins, and yet, paradoxically, is essential for male sex determination. To dissect the molecular functions of this domain, we generated a series of Sry mutants, and studied their biochemical properties in cell lines and transgenic mouse embryos. Sry protein lacking the polyQ domain was unstable, due to proteasomal degradation. Replacing this domain with irrelevant sequences stabilized the protein but failed to restore Sry's ability to up-regulate its key target gene SRY-box 9 (Sox9) and its sex-determining function in vivo. These functions were restored only when a VP16 transactivation domain was substituted. We conclude that the polyQ domain has important roles in protein stabilization and transcriptional activation, both of which are essential for male sex determination in mice. Our data disprove the hypothesis that the conserved HMG box domain is the only functional domain of Sry, and highlight an evolutionary paradox whereby mouse Sry has evolved a novel bifunctional module to activate Sox9 directly, whereas SRY proteins in other taxa, including humans, seem to lack this ability, presumably making them dependent on partner proteins(s) to provide this function.

  15. Quantitative relationships between huntingtin levels, polyglutamine length, inclusion body formation, and neuronal death provide novel insight into Huntington’s disease molecular pathogenesis

    PubMed Central

    Miller, Jason; Arrasate, Montserrat; Shaby, Benjamin A.; Mitra, Siddhartha; Masliah, Eliezer; Finkbeiner, Steven

    2010-01-01

    An expanded polyglutamine (polyQ) stretch in the protein huntingtin (htt) induces self-aggregation into inclusion bodies (IBs) and causes Huntington’s disease (HD). Defining precise relationships between early observable variables and neuronal death at the molecular and cellular levels should improve our understanding of HD pathogenesis. Here, we utilized an automated microscope that can track thousands of neurons individually over their entire lifetime to quantify interconnected relationships between early variables, such as htt levels, polyQ length, and IB formation, and neuronal death in a primary striatal model of HD. The resulting model revealed that: mutant htt increases the risk of death by tonically interfering with homeostatic coping mechanisms rather than producing accumulated damage to the neuron; htt toxicity is saturable; the rate limiting steps for inclusion body formation and death can be traced to different conformational changes in monomeric htt; and IB formation reduces the impact of a neuron’s starting levels of htt on its risk of death. Finally, the model that emerges from our quantitative measurements places critical limits on the potential mechanisms by which mutant htt might induce neurodegeneration, which should help direct future research. PMID:20685997

  16. Activity and cellular functions of the deubiquitinating enzyme and polyglutamine disease protein ataxin-3 are regulated by ubiquitination at lysine 117.

    PubMed

    Todi, Sokol V; Scaglione, K Matthew; Blount, Jessica R; Basrur, Venkatesha; Conlon, Kevin P; Pastore, Annalisa; Elenitoba-Johnson, Kojo; Paulson, Henry L

    2010-12-10

    Deubiquitinating enzymes (DUbs) play important roles in many ubiquitin-dependent pathways, yet how DUbs themselves are regulated is not well understood. Here, we provide insight into the mechanism by which ubiquitination directly enhances the activity of ataxin-3, a DUb implicated in protein quality control and the disease protein in the polyglutamine neurodegenerative disorder, Spinocerebellar Ataxia Type 3. We identify Lys-117, which resides near the catalytic triad, as the primary site of ubiquitination in wild type and pathogenic ataxin-3. Further studies indicate that ubiquitin-dependent activation of ataxin-3 at Lys-117 is important for its ability to reduce high molecular weight ubiquitinated species in cells. Ubiquitination at Lys-117 also facilitates the ability of ataxin-3 to induce aggresome formation in cells. Finally, structure-function studies support a model of activation whereby ubiquitination at Lys-117 enhances ataxin-3 activity independent of the known ubiquitin-binding sites in ataxin-3, most likely through a direct conformational change in or near the catalytic domain.

  17. Ectodermal dysplasia and abnormal thumbs.

    PubMed

    Lucky, A W; Esterly, N B; Tunnessen, W W

    1980-05-01

    Two unrelated children, a girl and a boy, with alopecia, anomalous cutaneous pigmentation, abnormal thumbs, and endocrine disorders, including short stature and delayed bone age in one patient and juvenile onset diabetes mellitus in the other, are described. In one instance, the mother and the maternal grandmother had similar abnormalities, although of a less severe nature. Both children had normal nails and no unusual susceptibility to infections. We believe these two patients represent a previously undescribed syndrome of ectodermal dysplasia that may be inherited as an autosomal-dominant trait.

  18. Optical imaging. Expansion microscopy.

    PubMed

    Chen, Fei; Tillberg, Paul W; Boyden, Edward S

    2015-01-30

    In optical microscopy, fine structural details are resolved by using refraction to magnify images of a specimen. We discovered that by synthesizing a swellable polymer network within a specimen, it can be physically expanded, resulting in physical magnification. By covalently anchoring specific labels located within the specimen directly to the polymer network, labels spaced closer than the optical diffraction limit can be isotropically separated and optically resolved, a process we call expansion microscopy (ExM). Thus, this process can be used to perform scalable superresolution microscopy with diffraction-limited microscopes. We demonstrate ExM with apparent ~70-nanometer lateral resolution in both cultured cells and brain tissue, performing three-color superresolution imaging of ~10(7) cubic micrometers of the mouse hippocampus with a conventional confocal microscope.

  19. Cryogenic expansion machine

    DOEpatents

    Pallaver, Carl B.; Morgan, Michael W.

    1978-01-01

    A cryogenic expansion engine includes intake and exhaust poppet valves each controlled by a cam having adjustable dwell, the valve seats for the valves being threaded inserts in the valve block. Each cam includes a cam base and a ring-shaped cam insert disposed at an exterior corner of the cam base, the cam base and cam insert being generally circular but including an enlarged cam dwell, the circumferential configuration of the cam base and cam dwell being identical, the cam insert being rotatable with respect to the cam base. GI CONTRACTUAL ORIGIN OF THE INVENTION The invention described herein was made in the course of, or under, a contract with the UNITED STATES ENERGY RESEARCH AND DEVELOPMENT ADMINISTRATION.

  20. Indicator Expansion with Analysis Pipeline

    DTIC Science & Technology

    2015-01-13

    2014 Carnegie Mellon University Indicator Expansion with Analysis Pipeline Dan Ruef 1/13/15 Report Documentation Page Form ApprovedOMB No. 0704...4. TITLE AND SUBTITLE Indicator Expansion with Analysis Pipeline 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...Mellon®, CERT® and FloCon® are registered marks of Carnegie Mellon University. DM-0002067 3 Definition “Indicator expansion is a process of using one or

  1. Huntington disease: new insights into the relationship between CAG expansion and disease.

    PubMed

    Nasir, J; Goldberg, Y P; Hayden, M R

    1996-01-01

    The mutation underlying Huntington disease (HD) is CAG expansion beyond 35 repeats within a novel gene. Recently, new insights into the role of the HD protein (huntingtin) in the pathogenesis of HD have emerged. The CAG is translated and expression of mutant huntingtin is essential for neuronal death. Huntingtin is crucial for normal development and may be regarded as a cell survival gene. Huntingtin is specifically cleaved during apoptosis by a key cysteine protease, apopain, known to play a pivotal role in apoptotic cell death. The rate of cleavage is enhanced by longer polyglutamine tracts, suggesting that inappropriate apoptosis underlies HD. Recently, three proteins have been identified and have been shown specifically to interact with huntingtin, two of these interactions being influenced by CAG length. Several different approaches to develop an animal model for HD include cDNA and YAC transgenics, as well as 'knock-in' strategies. Such a model will be critical for the understanding of the natural history of HD and for the testing of new therapeutic modalities.

  2. Vestibular abnormalities in congenital disorders.

    PubMed

    Sando, I; Orita, Y; Miura, M; Balaban, C D

    2001-10-01

    This paper reviews the histopathologic features of vestibular abnormalities in congenital disorders affecting the inner ear, based upon a comprehensive literature survey and a review of cases in our temporal bone collection. The review proceeds in three systematic steps. First, we surveyed associated diseases with the major phenotypic features of congenital abnormalities of the inner ear (including the internal auditory canal and otic capsule). Second, the vestibular anomalies are examined specifically. Finally, the anomalies are discussed from a developmental perspective. Among vestibular anomalies, a hypoplastic endolymphatic duct and sac are observed most frequently. Anomalies of the semicircular canals are also often observed. From embryological and clinical viewpoints, many of these resemble the structural features from fetal stages and appear to be associated with vestibular dysfunction. It is expected that progress in genetic analysis and accumulation of temporal bone specimens with vestibular abnormalities in congenital diseases will provide crucial information not only for pathology of those diseases, but also for genetic factors that are responsible for the specific vestibular abnormalities.

  3. Burial Ground Expansion Hydrogeologic Characterization

    SciTech Connect

    Gaughan , T.F.

    1999-02-26

    Sirrine Environmental Consultants provided technical oversight of the installation of eighteen groundwater monitoring wells and six exploratory borings around the location of the Burial Ground Expansion.

  4. Relativistic Sommerfeld Low Temperature Expansion

    NASA Astrophysics Data System (ADS)

    Lourenço, O.; Dutra, M.; Delfino, A.; Sá Martins, J. S.

    We derive a relativistic Sommerfeld expansion for thermodynamic quantities in many-body fermionic systems. The expansion is used to generate the equation of state of the Walecka model and its isotherms. We find that these results are in good agreement with numerical calculations, even when the expansion is truncated at its lowest order, in the low temperature regime, defined by T/xf ≪ 1. Although the interesting region near the liquid-gas phase transition is excluded by this criterion, the expansion may still find usefulness in the study of very cold nuclear matter systems, such as neutron stars.

  5. Effectively control negative thermal expansion of single-phase ferroelectrics of PbTiO3-(Bi,La)FeO3 over a giant range.

    PubMed

    Chen, Jun; Wang, Fangfang; Huang, Qingzhen; Hu, Lei; Song, Xiping; Deng, Jinxia; Yu, Ranbo; Xing, Xianran

    2013-01-01

    Control of negative thermal expansion is a fundamentally interesting topic in the negative thermal expansion materials in order for the future applications. However, it is a challenge to control the negative thermal expansion in individual pure materials over a large scale. Here, we report an effective way to control the coefficient of thermal expansion from a giant negative to a near zero thermal expansion by means of adjusting the spontaneous volume ferroelectrostriction (SVFS) in the system of PbTiO3-(Bi,La)FeO3 ferroelectrics. The adjustable range of thermal expansion contains most negative thermal expansion materials. The abnormal property of negative or zero thermal expansion previously observed in ferroelectrics is well understood according to the present new concept of spontaneous volume ferroelectrostriction. The present studies could be useful to control of thermal expansion of ferroelectrics, and could be extended to multiferroic materials whose properties of both ferroelectricity and magnetism are coupled with thermal expansion.

  6. Effectively control negative thermal expansion of single-phase ferroelectrics of PbTiO3-(Bi,La)FeO3 over a giant range

    PubMed Central

    Chen, Jun; Wang, Fangfang; Huang, Qingzhen; Hu, Lei; Song, Xiping; Deng, Jinxia; Yu, Ranbo; Xing, Xianran

    2013-01-01

    Control of negative thermal expansion is a fundamentally interesting topic in the negative thermal expansion materials in order for the future applications. However, it is a challenge to control the negative thermal expansion in individual pure materials over a large scale. Here, we report an effective way to control the coefficient of thermal expansion from a giant negative to a near zero thermal expansion by means of adjusting the spontaneous volume ferroelectrostriction (SVFS) in the system of PbTiO3-(Bi,La)FeO3 ferroelectrics. The adjustable range of thermal expansion contains most negative thermal expansion materials. The abnormal property of negative or zero thermal expansion previously observed in ferroelectrics is well understood according to the present new concept of spontaneous volume ferroelectrostriction. The present studies could be useful to control of thermal expansion of ferroelectrics, and could be extended to multiferroic materials whose properties of both ferroelectricity and magnetism are coupled with thermal expansion. PMID:23949238

  7. Lattice harmonics expansion revisited

    NASA Astrophysics Data System (ADS)

    Kontrym-Sznajd, G.; Holas, A.

    2017-04-01

    The main subject of the work is to provide the most effective way of determining the expansion of some quantities into orthogonal polynomials, when these quantities are known only along some limited number of sampling directions. By comparing the commonly used Houston method with the method based on the orthogonality relation, some relationships, which define the applicability and correctness of these methods, are demonstrated. They are verified for various sets of sampling directions applicable for expanding quantities having the full symmetry of the Brillouin zone of cubic and non-cubic lattices. All results clearly show that the Houston method is always better than the orthogonality-relation one. For the cubic symmetry we present a few sets of special directions (SDs) showing how their construction and, next, a proper application depend on the choice of various sets of lattice harmonics. SDs are important mainly for experimentalists who want to reconstruct anisotropic quantities from their measurements, performed at a limited number of sampling directions.

  8. Singularity Expansion Method

    NASA Astrophysics Data System (ADS)

    Riggs, Lloyd Stephen

    In this work the transient currents induced on an arbitrary system of thin linear scatterers by an electromagnetic plane wave are solved by using an electric field integral equation (EFIE) formulation. The transient analysis is carried out using the singularity expansion method (SEM). The general analysis developed here is useful for assessing the vulnerability of military aircraft to a nuclear generated electromagnetic pulse (EMP). It is also useful as a modal synthesis tool in the analysis and design of frequency selective surfaces (FSS). SEM parameters for a variety of thin cylindrical geometries have been computed. Specifically, SEM poles, modes, coupling coefficients, and transient currents are given for the two and three element planar array. Poles and modes for planar arrays with a larger number (as many as eight) of identical equally spaced elements are also considered. SEM pole-mode results are given for identical parallel elements with ends located at the vertices of a regular N-agon. Pole-mode patterns are found for symmetric (and slightly perturbed) single junction N-arm elements and for the five junction Jerusalem cross. The Jerusalem cross element has been used extensively in FSS.

  9. Local Adaptation Interacts with Expansion Load during Range Expansion: Maladaptation Reduces Expansion Load.

    PubMed

    Gilbert, Kimberly J; Sharp, Nathaniel P; Angert, Amy L; Conte, Gina L; Draghi, Jeremy A; Guillaume, Frédéric; Hargreaves, Anna L; Matthey-Doret, Remi; Whitlock, Michael C

    2017-04-01

    The biotic and abiotic factors that facilitate or hinder species range expansions are many and complex. We examine the impact of two genetic processes and their interaction on fitness at expanding range edges: local maladaptation resulting from the presence of an environmental gradient and expansion load resulting from increased genetic drift at the range edge. Results from spatially explicit simulations indicate that the presence of an environmental gradient during range expansion reduces expansion load; conversely, increasing expansion load allows only locally adapted populations to persist at the range edge. Increased maladaptation reduces the speed of range expansion, resulting in less genetic drift at the expanding front and more immigration from the range center, therefore reducing expansion load at the range edge. These results may have ramifications for species being forced to shift their ranges because of climate change or other anthropogenic changes. If rapidly changing climate leads to faster expansion as populations track their shifting climatic optima, populations may suffer increased expansion load beyond previous expectations.

  10. Isotropic Negative Thermal Expansion Metamaterials.

    PubMed

    Wu, Lingling; Li, Bo; Zhou, Ji

    2016-07-13

    Negative thermal expansion materials are important and desirable in science and engineering applications. However, natural materials with isotropic negative thermal expansion are rare and usually unsatisfied in performance. Here, we propose a novel method to achieve two- and three-dimensional negative thermal expansion metamaterials via antichiral structures. The two-dimensional metamaterial is constructed with unit cells that combine bimaterial strips and antichiral structures, while the three-dimensional metamaterial is fabricated by a multimaterial 3D printing process. Both experimental and simulation results display isotropic negative thermal expansion property of the samples. The effective coefficient of negative thermal expansion of the proposed models is demonstrated to be dependent on the difference between the thermal expansion coefficient of the component materials, as well as on the circular node radius and the ligament length in the antichiral structures. The measured value of the linear negative thermal expansion coefficient of the three-dimensional sample is among the largest achieved in experiments to date. Our findings provide an easy and practical approach to obtaining materials with tunable negative thermal expansion on any scale.

  11. Endocrine abnormalities in anorexia nervosa.

    PubMed

    Lawson, Elizabeth A; Klibanski, Anne

    2008-07-01

    Anorexia nervosa (AN) is a psychiatric disease associated with notable medical complications and increased mortality. Endocrine abnormalities, including hypogonadotropic hypogonadism, hypercortisolemia, growth hormone resistance and sick euthyroid syndrome, mediate the clinical manifestations of this disease. Alterations in anorexigenic and orexigenic appetite-regulating pathways have also been described. Decreases in fat mass result in adipokine abnormalities. Although most of the endocrine changes that occur in AN represent physiologic adaptation to starvation, some persist after recovery and might contribute to susceptibility to AN recurrence. In this Review, we summarize key endocrine alterations in AN, with a particular focus on the profound bone loss that can occur in this disease. Although AN is increasingly prevalent among boys and men, the disorder predominantly affects girls and women who are, therefore, the focus of this Review.

  12. Eye abnormalities in Fryns syndrome.

    PubMed

    Pierson, Diane M; Taboada, Eugenio; Butler, Merlin G

    2004-03-15

    Fryns syndrome is a rare, generally lethal, autosomal recessive multiple congenital anomaly (MCA) syndrome first described in 1979. Patients with the syndrome present with the classical findings of cloudy cornea, brain malformations, diaphragmatic defects, and distal limb deformities. Over 70 patients have been reported revealing a wide variety of phenotypic features. Although initially considered a major feature of Fryns syndrome, cloudy cornea has been relegated as a minor diagnostic sign and not commonly reported in patients since the original description. However, eye findings per se are not uncommon. Abnormal eye findings occasionally reported in Fryns syndrome potentially result in amblyopia and blindness, profoundly affecting neurologic outcome of those who survive the neonatal period. We reviewed 77 reported patients with Fryns syndrome and summarized the abnormal eye findings identified in 12 of the reported cases. In addition, we contribute three new patients with Fryns syndrome, one of which demonstrated unilateral microphthalmia and cloudy cornea.

  13. [Chromosome abnormalities in human cancer].

    PubMed

    Salamanca-Gómez, F

    1995-01-01

    Recent investigation on the presence of chromosome abnormalities in neoplasias has allowed outstanding advances in the knowledge of malignant transformation mechanisms and important applications in the clinical diagnosis and prognosis of leukaemias, lymphomas and solid tumors. The purpose of the present paper is to discuss the most relevant cytogenetic aberrations, some of them described at the Unidad de Investigación Médica en Genética Humana, Instituto Mexicano del Seguro Social, and to correlate these abnormalities with recent achievements in the knowledge of oncogenes, suppressor genes or antioncogenes, their chromosome localization, and their mutations in human neoplasia; as well as their perspectives in prevention and treatment of cancer that such findings permit to anticipate.

  14. Neuroendocrine abnormalities in Parkinson's disease.

    PubMed

    De Pablo-Fernández, Eduardo; Breen, David P; Bouloux, Pierre M; Barker, Roger A; Foltynie, Thomas; Warner, Thomas T

    2017-02-01

    Neuroendocrine abnormalities are common in Parkinson's disease (PD) and include disruption of melatonin secretion, disturbances of glucose, insulin resistance and bone metabolism, and body weight changes. They have been associated with multiple non-motor symptoms in PD and have important clinical consequences, including therapeutics. Some of the underlying mechanisms have been implicated in the pathogenesis of PD and represent promising targets for the development of disease biomarkers and neuroprotective therapies. In this systems-based review, we describe clinically relevant neuroendocrine abnormalities in Parkinson's disease to highlight their role in overall phenotype. We discuss pathophysiological mechanisms, clinical implications, and pharmacological and non-pharmacological interventions based on the current evidence. We also review recent advances in the field, focusing on the potential targets for development of neuroprotective drugs in Parkinson's disease and suggest future areas for research.

  15. Linear and extended: a common polyglutamine conformation recognized by the three antibodies MW1, 1C2 and 3B5H10.

    PubMed

    Klein, Fabrice A C; Zeder-Lutz, Gabrielle; Cousido-Siah, Alexandra; Mitschler, André; Katz, Aline; Eberling, Pascal; Mandel, Jean-Louis; Podjarny, Alberto; Trottier, Yvon

    2013-10-15

    A long-standing pathomechanistic model proposes that the polyglutamine (polyQ)-length-dependent toxicity threshold observed in all polyQ diseases is triggered by a conformational change within the monomer that occurs only above a certain polyQ length. If true, this yet undefined and elusive mutant-specific toxic conformation would constitute a direct therapeutic target. Three anti-polyQ antibodies-MW1, 1C2 and 3B5H10-have been extensively used to probe the conformation of polyQ. The crystal structure of the MW1 epitope reveals a linear, non-pathogenic polyQ. In contrast, although the detailed structure of its epitope is unknown, the 3B5H10 antibody is widely advertised and used as a conformational antibody that recognizes the toxic conformation of expanded polyQ. We solved the crystal structure of the 1C2 antigen-binding domain (1C2-Fab) and performed a direct comparison between the 1C2, MW1 and 3B5H10 structures. The MW1 and 1C2 antibodies have similar sequences and structures, consistent with their binding to short polyQ and their polyQ length-discrimination properties. Unexpectedly, the 3B5H10 antibody also shares striking features with MW1 and 1C2, which prompted us to revisit its binding properties. We show that the 3B5H10 epitope is actually a short, non-pathogenic polyQ. All three antibodies MW1, 1C2 and 3B5H10 interact similarly with polyQ of various lengths, and bind small polyQ epitopes in similar linear and extended conformations. Together with studies published during the recent years, our work argues against the hypothesis that a mutant-specific conformation in monomeric polyQ molecules is the toxic entity responsible for polyQ diseases.

  16. Congenital abnormalities of the goat.

    PubMed

    Basrur, P K

    1993-03-01

    Congenital abnormalities of genetic and environmental causes constitute a striking proportion of the afflictions seen in goats. These include a variety of malformations and metabolic diseases that could occur in all breeds but tend to exhibit predisposition in some breeds of goats. Genetic abnormalities for which the carrier state is detectable with the aid of enzymes and surface protein markers can be eliminated from goat populations, whereas common polygenic disorders including udder problems in does and gynecomastia in bucks are more difficult to eradicate because the mutant genes responsible for these traits generally do not declare themselves until inbreeding brings together a critical concentration of liability genes to create a crisis. A substantial reduction of common abnormalities in this species, such as intersexuality in dairy breeds, abortion in Angora breed, and arthritis in the Pygmy breed, will require a change in breeders' preference and selection practice. In making these changes, however, the beneficial traits will have to be balanced against the undesirable effects of the selected mutant genes (pleiotropy), which hold the key to success or failure of a breed under domestication.

  17. Meiotic abnormalities in infertile males.

    PubMed

    Egozcue, J; Sarrate, Z; Codina-Pascual, M; Egozcue, S; Oliver-Bonet, M; Blanco, J; Navarro, J; Benet, J; Vidal, F

    2005-01-01

    Meiotic anomalies, as reviewed here, are synaptic chromosome abnormalities, limited to germ cells that cannot be detected through the study of the karyotype. Although the importance of synaptic errors has been underestimated for many years, their presence is related to many cases of human male infertility. Synaptic anomalies can be studied by immunostaining of synaptonemal complexes (SCs), but in this case their frequency is probably underestimated due to the phenomenon of synaptic adjustment. They can also be studied in classic meiotic preparations, which, from a clinical point of view, is still the best approach, especially if multiplex fluorescence in situ hybridization is at hand to solve difficult cases. Sperm chromosome FISH studies also provide indirect evidence of their presence. Synaptic anomalies can affect the rate of recombination of all bivalents, produce achiasmate small univalents, partially achiasmate medium-sized or large bivalents, or affect all bivalents in the cell. The frequency is variable, interindividually and intraindividually. The baseline incidence of synaptic anomalies is 6-8%, which may be increased to 17.6% in males with a severe oligozoospermia, and to 27% in normozoospermic males with one or more previous IVF failures. The clinical consequences are the production of abnormal spermatozoa that will produce a higher number of chromosomally abnormal embryos. The indications for a meiotic study in testicular biopsy are provided.

  18. Visual pathway abnormalities in tuberculous meningitis.

    PubMed

    Maurya, Pradeep Kumar; Singh, Ajai Kumar; Sharma, Lalit; Kulshreshtha, Dinkar; Thacker, Anup Kumar

    2016-11-01

    Ophthalmological complications are common and disabling in patients with tuberculous meningitis. We aimed to study the visual pathway abnormalities in patients with tuberculous meningitis. Forty-three patients with tuberculous meningitis were subjected to visual evoked responses (VER) and neuroophthalmologic assessment. Neuroophthalmologic assessment revealed abnormalities in 22 (51.3%) patients. VER were found to be abnormal in 27 (62.8%) patients. The VER abnormalities included prolonged P100 latencies with relatively normal amplitude and significant interocular latency differences. Visual pathways abnormalities are common in patients with tuberculous meningitis and are often subclinical. Pathophysiologic explanations for electrophysiological abnormalities on VER in these patients are incompletely understood and needs further exploration.

  19. Atom cooling by nonadiabatic expansion

    SciTech Connect

    Chen Xi; Muga, J. G.; Campo, A. del; Ruschhaupt, A.

    2009-12-15

    Motivated by the recent discovery that a reflecting wall moving with a square-root-in-time trajectory behaves as a universal stopper of classical particles regardless of their initial velocities, we compare linear-in-time and square-root-in-time expansions of a box to achieve efficient atom cooling. For the quantum single-atom wave functions studied the square-root-in-time expansion presents important advantages: asymptotically it leads to zero average energy whereas any linear-in-time (constant box-wall velocity) expansion leaves a nonzero residual energy, except in the limit of an infinitely slow expansion. For finite final times and box lengths we set a number of bounds and cooling principles which again confirm the superior performance of the square-root-in-time expansion, even more clearly for increasing excitation of the initial state. Breakdown of adiabaticity is generally fatal for cooling with the linear expansion but not so with the square-root-in-time expansion.

  20. Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington's disease.

    PubMed

    Laforet, G A; Sapp, E; Chase, K; McIntyre, C; Boyce, F M; Campbell, M; Cadigan, B A; Warzecki, L; Tagle, D A; Reddy, P H; Cepeda, C; Calvert, C R; Jokel, E S; Klapstein, G J; Ariano, M A; Levine, M S; DiFiglia, M; Aronin, N

    2001-12-01

    Neurons in Huntington's disease exhibit selective morphological and subcellular alterations in the striatum and cortex. The link between these neuronal changes and behavioral abnormalities is unclear. We investigated relationships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behavioral phenotypes. We therefore generated heterozygote mice expressing the N-terminal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 months. The age of onset depended on an expanded polyglutamine length; phenotype severity correlated with increasing age. Neuronal changes in the striatum (nuclear inclusions) preceded the onset of phenotype, whereas cortical changes, especially the accumulation of huntingtin in the nucleus and cytoplasm and the appearance of dysmorphic dendrites, predicted the onset and severity of behavioral deficits. Striatal neurons in the HD mice displayed altered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca(2+) levels in HD100 neurons compared with wild-type neurons. Results suggest that motor deficits in Huntington's disease arise from cumulative morphological and physiological changes in neurons that impair corticostriatal circuitry.

  1. Thermal Expansion of Polyurethane Foam

    NASA Technical Reports Server (NTRS)

    Lerch, Bradley A.; Sullivan, Roy M.

    2006-01-01

    Closed cell foams are often used for thermal insulation. In the case of the Space Shuttle, the External Tank uses several thermal protection systems to maintain the temperature of the cryogenic fuels. A few of these systems are polyurethane, closed cell foams. In an attempt to better understand the foam behavior on the tank, we are in the process of developing and improving thermal-mechanical models for the foams. These models will start at the microstructural level and progress to the overall structural behavior of the foams on the tank. One of the key properties for model characterization and verification is thermal expansion. Since the foam is not a material, but a structure, the modeling of the expansion is complex. It is also exacerbated by the anisoptropy of the material. During the spraying and foaming process, the cells become elongated in the rise direction and this imparts different properties in the rise direction than in the transverse directions. Our approach is to treat the foam as a two part structure consisting of the polymeric cell structure and the gas inside the cells. The polymeric skeleton has a thermal expansion of its own which is derived from the basic polymer chemistry. However, a major contributor to the thermal expansion is the volume change associated with the gas inside of the closed cells. As this gas expands it exerts pressure on the cell walls and changes the shape and size of the cells. The amount that this occurs depends on the elastic and viscoplastic properties of the polymer skeleton. The more compliant the polymeric skeleton, the more influence the gas pressure has on the expansion. An additional influence on the expansion process is that the polymeric skeleton begins to breakdown at elevated temperatures and releases additional gas species into the cell interiors, adding to the gas pressure. The fact that this is such a complex process makes thermal expansion ideal for testing the models. This report focuses on the thermal

  2. Micromechanics of expansive mechanisms in expansive cement concretes

    NASA Astrophysics Data System (ADS)

    Cohen, M. D.

    The kinetics of hydration were studied by monitoring the presence of various compounds by X-ray diffractometer, a chemical extraction method, and scanning electron microscope. These studies indicated that the rates of depletion of the expanding particles and sulfates are higher in the finer blends, which is why expansion stops earlier in these blends. It is shown that the double curvature phenomenon (strength-drop and sudden increase in the rate of expansion) is caused by mechanical failure (e.g., microcracking) of the matrix surrounding the expanding particles that are producing ettringite crystals. The theory of protective and partial protective coating is reviewed. A hypothesis is introduced which assumes that monosulfate is not formed immediately when ettringite stops forming but is preceded by an intermediate phase. Shrinkage studies show that expansive cements shrink more than portland cements. The results of these studies were used to develop a modified model of the expansive process. It was shown theoretically that the time of expansion is inversely proportional to the surface area of the expansive clinker and directly proportional to the amount of sulfate used.

  3. C9orf72 repeat expansions that cause frontotemporal dementia are detectable among patients with psychosis.

    PubMed

    Watson, Annie; Pribadi, Mochtar; Chowdari, Kodavali; Clifton, Sue; Joel Wood; Miller, Bruce L; Coppola, Giovanni; Nimgaonkar, Vishwajit

    2016-01-30

    A pathologic hexanucleotide repeat expansion in C9orf72 causes frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). Behavioral abnormalities can also occur among mutation carriers with FTD, but it is uncertain whether such mutations occur among persons with psychoses per se. Among participants in a genetic study of psychoses (N=739), two pairs of related individuals had C9orf72 expansions, of whom three were diagnosed with schizophrenia (SZ) / schizoaffective disorder (SZA), but their clinical features did not suggest dementia or ALS. A few patients with SZ/SZA carry C9orf72 repeat expansions; such individuals are highly likely to develop FTD/ALS.

  4. Low-set ears and pinna abnormalities

    MedlinePlus

    Low-set ears; Microtia; "Lop" ear; Pinna abnormalities; Genetic defect-pinna; Congenital defect-pinna ... most cases, a health care provider finds pinna abnormalities during the first well-baby exam. This exam ...

  5. Abnormalities of the erythrocyte membrane.

    PubMed

    Gallagher, Patrick G

    2013-12-01

    Primary abnormalities of the erythrocyte membrane are characterized by clinical, laboratory, and genetic heterogeneity. Among this group, hereditary spherocytosis patients are more likely to experience symptomatic anemia. Treatment of hereditary spherocytosis with splenectomy is curative in most patients. Growing recognition of the long-term risks of splenectomy has led to re-evaluation of the role of splenectomy. Management guidelines acknowledge these considerations and recommend discussion between health care providers, patient, and family. The hereditary elliptocytosis syndromes are the most common primary disorders of erythrocyte membrane proteins. However, most elliptocytosis patients are asymptomatic and do not require therapy.

  6. Foot abnormalities of wild birds

    USGS Publications Warehouse

    Herman, C.M.; Locke, L.N.; Clark, G.M.

    1962-01-01

    The various foot abnormalities that occur in birds, including pox, scaly-leg, bumble-foot, ergotism and freezing are reviewed. In addition, our findings at the Patuxent Wildlife Research Center include pox from dove, mockingbird, cowbird, grackle and several species of sparrows. Scaly-leg has been particularly prevalent on icterids. Bumble foot has been observed in a whistling swan and in a group of captive woodcock. Ergotism is reported from a series of captive Canada geese from North Dakota. Several drug treatments recommended by others are presented.

  7. Lower extremity abnormalities in children.

    PubMed

    Sass, Pamela; Hassan, Ghinwa

    2003-08-01

    Rotational and angular problems are two types of lower extremity abnormalities common in children. Rotational problems include intoeing and out-toeing. Intoeing is caused by one of three types of deformity: metatarsus adductus, internal tibial torsion, and increased femoral anteversion. Out-toeing is less common than intoeing, and its causes are similar but opposite to those of intoeing. These include femoral retroversion and external tibial torsion. Angular problems include bowlegs and knock-knees. An accurate diagnosis can be made with careful history and physical examination, which includes torsional profile (a four-component composite of measurements of the lower extremities). Charts of normal values and values with two standard deviations for each component of the torsional profile are available. In most cases, the abnormality improves with time. A careful physical examination, explanation of the natural history, and serial measurements are usually reassuring to the parents. Treatment is usually conservative. Special shoes, cast, or braces are rarely beneficial and have no proven efficacy. Surgery is reserved for older children with deformity from three to four standard deviations from the normal.

  8. Normal and abnormal lid function.

    PubMed

    Rucker, Janet C

    2011-01-01

    This chapter on lid function is comprised of two primary sections, the first on normal eyelid anatomy, neurological innervation, and physiology, and the second on abnormal eyelid function in disease states. The eyelids serve several important ocular functions, the primary objectives of which are protection of the anterior globe from injury and maintenance of the ocular tear film. Typical eyelid behaviors to perform these functions include blinking (voluntary, spontaneous, or reflexive), voluntary eye closure (gentle or forced), partial lid lowering during squinting, normal lid retraction during emotional states such as surprise or fear (startle reflex), and coordination of lid movements with vertical eye movements for maximal eye protection. Detailed description of the neurological innervation patterns and neurophysiology of each of these lid behaviors is provided. Abnormal lid function is divided by conditions resulting in excessive lid closure (cerebral ptosis, apraxia of lid opening, blepharospasm, oculomotor palsy, Horner's syndrome, myasthenia gravis, and mechanical) and those resulting in excessive lid opening (midbrain lid retraction, facial nerve palsy, and lid retraction due to orbital disease).

  9. Rock expansion caused by ultrasound

    NASA Astrophysics Data System (ADS)

    Hedberg, C.; Gray, A.

    2013-12-01

    It has during many years been reported that materials' elastic modulus decrease when exposed to influences like mechanical impacts, ultrasound, magnetic fields, electricity and even humidity. Non-perfect atomic structures like rocks, concrete, or damaged metals exhibit a larger effect. This softening has most often been recorded by wave resonance measurements. The motion towards equilibrium is slow - often taking hours or days, which is why the effect is called Slow Dynamics [1]. The question had been raised, if a material expansion also occurs. 'The most fundamental parameter to consider is the volume expansion predicted to occur when positive hole charge carriers become activated, causing a decrease of the electron density in the O2- sublattice of the rock-forming minerals. This decrease of electron density should affect essentially all physical parameters, including the volume.' [2]. A new type of configuration has measured expansion of a rock subjected to ultrasound. A PZT was used as a pressure sensor while the combined thickness of the rock sample and the PZT sensor was held fixed. The expansion increased the stress in both the rock and the PZT, which gave an out-put voltage from the PZT. Knowing its material properties then made it possible to calculate the rock expansion. The equivalent strain caused by the ultrasound was approximately 3 x 10-5. The temperature was monitored and accounted for during the tests and for the maximum expansion the increase was 0.7 C, which means the expansion is at least to some degree caused by heating of the material by the ultrasound. The fraction of bonds activated by ultrasound was estimated to be around 10-5. References: [1] Guyer, R.A., Johnson, P.A.: Nonlinear Mesoscopic Elasticity: The Complex Behaviour of Rocks, Soils, Concrete. Wiley-VCH 2009 [2] M.M. Freund, F.F. Freund, Manipulating the Toughness of Rocks through Electric Potentials, Final Report CIF 2011 Award NNX11AJ84A, NAS Ames 2012.

  10. Asymptotic Expansions, 1/Z Expansions, and the Critical Nuclear Charge

    NASA Astrophysics Data System (ADS)

    Drake, Gordon

    2014-03-01

    The quantum mechanical three-body problem defies analytic solution, and so computationally intensive approximation methods involving, for example, variational calculations with large correlated basis sets must be used. This talk will review recent work to explore the outer fringes of the quantum mechanical three-body problem for heliumlike atoms. Asymptotic expansions provide a surprisingly simple and accurate account of highly excited Rydberg states with high angular momentum. 1 / Z expansions, where Z is the nuclear charge, provide results for an entire isoelectronic sequence within a single calculation. Its radius of convergence is thought to be related to the critical nuclear charge Zc for a state to be bound. For Z expansions and the critical nuclear charge. Research suppoted by the Natural Sciences and Engineering Research Council of Canada, and by SHARCNET.

  11. Thermal expansion measurements in Fe-base invar alloys

    NASA Astrophysics Data System (ADS)

    Ono, F.; Kittaka, T.; Maeta, H.

    1983-04-01

    By using the X-ray Bond method, measurements of thermal expansion curves have been made in Fe-Ni and Fe-Pd Invar alloys in the temperature range between 4.2 K and room temperatures. A minimum in the thermal expansion curve was observed for each alloy. This anomaly could be explained by considering the magnetovolume coupling term caused by the longitudinal spin fluctuation and the contribution due to the anharmonic terms in the normal lattice vibration energy. In 34.2 at% Pd-Fe alloy an abnormal increase of the linewidth of the (400) X-ray peak was observed with decreasing temperature from room temperature down to 4.2 K, while in Fe-Ni and Fe-Pt Invar alloys no such increase in linewidth was observed.

  12. Mechanical waves during tissue expansion

    NASA Astrophysics Data System (ADS)

    Serra-Picamal, Xavier; Conte, Vito; Vincent, Romaric; Anon, Ester; Tambe, Dhananjay T.; Bazellieres, Elsa; Butler, James P.; Fredberg, Jeffrey J.; Trepat, Xavier

    2012-08-01

    The processes by which an organism develops its shape and heals wounds involve expansion of a monolayer sheet of cells. The mechanism underpinning this epithelial expansion remains obscure, despite the fact that its failure is known to contribute to several diseases, including carcinomas, which account for about 90% of all human cancers. Here, using the micropatterned epithelial monolayer as a model system, we report the discovery of a mechanical wave that propagates slowly to span the monolayer, traverses intercellular junctions in a cooperative manner and builds up differentials of mechanical stress. Essential features of this wave generation and propagation are captured by a minimal model based on sequential fronts of cytoskeletal reinforcement and fluidization. These findings establish a mechanism of long-range cell guidance, symmetry breaking and pattern formation during monolayer expansion.

  13. Thermal Expansion of Hafnium Carbide

    NASA Technical Reports Server (NTRS)

    Grisaffe, Salvatore J.

    1960-01-01

    Since hafnium carbide (HfC) has a melting point of 7029 deg. F, it may have many high-temperature applications. A literature search uncovered very little information about the properties of HfC, and so a program was initiated at the Lewis Research Center to determine some of the physical properties of this material. This note presents the results of the thermal expansion investigation. The thermal-expansion measurements were made with a Gaertner dilatation interferometer calibrated to an accuracy of +/- 1 deg. F. This device indicates expansion by the movement of fringes produced by the cancellation and reinforcement of fixed wave-length light rays which are reflected from the surfaces of two parallel quartz glass disks. The test specimens which separate these disks are three small cones, each approximately 0.20 in. high.

  14. Expansion-based passive ranging

    NASA Technical Reports Server (NTRS)

    Barniv, Yair

    1993-01-01

    A new technique of passive ranging which is based on utilizing the image-plane expansion experienced by every object as its distance from the sensor decreases is described. This technique belongs in the feature/object-based family. The motion and shape of a small window, assumed to be fully contained inside the boundaries of some object, is approximated by an affine transformation. The parameters of the transformation matrix are derived by initially comparing successive images, and progressively increasing the image time separation so as to achieve much larger triangulation baseline than currently possible. Depth is directly derived from the expansion part of the transformation. To a first approximation, image-plane expansion is independent of image-plane location with respect to the focus of expansion (FOE) and of platform maneuvers. Thus, an expansion-based method has the potential of providing a reliable range in the difficult image area around the FOE. In areas far from the FOE the shift parameters of the affine transformation can provide more accurate depth information than the expansion alone, and can thus be used similarly to the way they were used in conjunction with the Inertial Navigation Unit (INU) and Kalman filtering. However, the performance of a shift-based algorithm, when the shifts are derived from the affine transformation, would be much improved compared to current algorithms because the shifts - as well as the other parameters - can be obtained between widely separated images. Thus, the main advantage of this new approach is that, allowing the tracked window to expand and rotate, in addition to moving laterally, enables one to correlate images over a very long time span which, in turn, translates into a large spatial baseline - resulting in a proportionately higher depth accuracy.

  15. Expansion-based passive ranging

    NASA Technical Reports Server (NTRS)

    Barniv, Yair

    1993-01-01

    This paper describes a new technique of passive ranging which is based on utilizing the image-plane expansion experienced by every object as its distance from the sensor decreases. This technique belongs in the feature/object-based family. The motion and shape of a small window, assumed to be fully contained inside the boundaries of some object, is approximated by an affine transformation. The parameters of the transformation matrix are derived by initially comparing successive images, and progressively increasing the image time separation so as to achieve much larger triangulation baseline than currently possible. Depth is directly derived from the expansion part of the transformation. To a first approximation, image-plane expansion is independent of image-plane location with respect to the focus of expansion (FOE) and of platform maneuvers. Thus, an expansion-based method has the potential of providing a reliable range in the difficult image area around the FOE. In areas far from the FOE the shift parameters of the affine transformation can provide more accurate depth information than the expansion alone, and can thus be used similarly to the way they have been used in conjunction with the Inertial Navigation Unit (INU) and Kalman filtering. However, the performance of a shift-based algorithm, when the shifts are derived from the affine transformation, would be much improved compared to current algorithms because the shifts--as well as the other parameters--can be obtained between widely separated images. Thus, the main advantage of this new approach is that, allowing the tracked window to expand and rotate, in addition to moving laterally, enables one to correlate images over a very long time span which, in turn, translates into a large spatial baseline resulting in a proportionately higher depth accuracy.

  16. Relativistic effects on plasma expansion

    SciTech Connect

    Benkhelifa, El-Amine; Djebli, Mourad

    2014-07-15

    The expansion of electron-ion plasma is studied through a fully relativistic multi-fluids plasma model which includes thermal pressure, ambipolar electrostatic potential, and internal energy conversion. Numerical investigation, based on quasi-neutral assumption, is performed for three different regimes: nonrelativistic, weakly relativistic, and relativistic. Ions' front in weakly relativistic regime exhibits spiky structure associated with a break-down of quasi-neutrality at the expanding front. In the relativistic regime, ion velocity is found to reach a saturation limit which occurs at earlier stages of the expansion. This limit is enhanced by higher electron velocity.

  17. 18 CFR 154.309 - Incremental expansions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Incremental expansions... Changes § 154.309 Incremental expansions. (a) For every expansion for which incremental rates are charged... costs and revenues associated with the expansion, until the Commission authorizes the costs of...

  18. 18 CFR 154.309 - Incremental expansions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Incremental expansions... Changes § 154.309 Incremental expansions. (a) For every expansion for which incremental rates are charged... costs and revenues associated with the expansion, until the Commission authorizes the costs of...

  19. 48 CFR 570.403 - Expansion requests.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 4 2012-10-01 2012-10-01 false Expansion requests. 570... Continued Space Requirements 570.403 Expansion requests. (a) If the expansion space is in the general scope... justification under FAR 6.3. (b) If the expansion space needed is outside the general scope of the lease,...

  20. 18 CFR 154.309 - Incremental expansions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Incremental expansions... Changes § 154.309 Incremental expansions. (a) For every expansion for which incremental rates are charged... costs and revenues associated with the expansion, until the Commission authorizes the costs of...

  1. 18 CFR 154.309 - Incremental expansions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Incremental expansions... Changes § 154.309 Incremental expansions. (a) For every expansion for which incremental rates are charged... costs and revenues associated with the expansion, until the Commission authorizes the costs of...

  2. 48 CFR 570.403 - Expansion requests.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 4 2011-10-01 2011-10-01 false Expansion requests. 570... Continued Space Requirements 570.403 Expansion requests. (a) If the expansion space is in the general scope... justification under FAR 6.3. (b) If the expansion space needed is outside the general scope of the lease,...

  3. 48 CFR 570.403 - Expansion requests.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 4 2013-10-01 2013-10-01 false Expansion requests. 570... Continued Space Requirements 570.403 Expansion requests. (a) If the expansion space is in the general scope... justification under FAR 6.3. (b) If the expansion space needed is outside the general scope of the lease,...

  4. 48 CFR 570.403 - Expansion requests.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 4 2014-10-01 2014-10-01 false Expansion requests. 570... Continued Space Requirements 570.403 Expansion requests. (a) If the expansion space is in the general scope... justification under FAR 6.3. (b) If the expansion space needed is outside the general scope of the lease,...

  5. 18 CFR 154.309 - Incremental expansions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Incremental expansions... Changes § 154.309 Incremental expansions. (a) For every expansion for which incremental rates are charged... costs and revenues associated with the expansion, until the Commission authorizes the costs of...

  6. 48 CFR 570.403 - Expansion requests.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Expansion requests. 570... Continued Space Requirements 570.403 Expansion requests. (a) If the expansion space is in the general scope... FAR 6.3. (b) If the expansion space needed is outside the general scope of the lease,...

  7. Bearing-Mounting Concept Accommodates Thermal Expansion

    NASA Technical Reports Server (NTRS)

    Nespodzany, Robert; Davis, Toren S.

    1995-01-01

    Pins or splines allow radial expansion without slippage. Design concept for mounting rotary bearing accommodates differential thermal expansion between bearing and any structure(s) to which bearing connected. Prevents buildup of thermal stresses by allowing thermal expansion to occur freely but accommodating expansion in such way not to introduce looseness. Pin-in-slot configuration also maintains concentricity.

  8. The Thermal Expansion Of Feldspars

    NASA Astrophysics Data System (ADS)

    Hovis, G. L.; Medford, A.; Conlon, M.

    2009-12-01

    Hovis and others (1) investigated the thermal expansion of natural and synthetic AlSi3 feldspars and demonstrated that the coefficient of thermal expansion (α) decreases significantly, and linearly, with increasing room-temperature volume (VRT). In all such feldspars, therefore, chemical expansion limits thermal expansion. The scope of this work now has been broadened to include plagioclase and Ba-K feldspar crystalline solutions. X-ray powder diffraction data have been collected between room temperature and 925 °C on six plagioclase specimens ranging in composition from anorthite to oligoclase. When combined with thermal expansion data for albite (2,3,4) a steep linear trend of α as a function of VRT emerges, reflecting how small changes in composition dramatically affect expansion behavior. The thermal expansion data for five synthetic Ba-K feldspars ranging in composition from 20 to 100 mole percent celsian, combined with data for pure K-feldspar (3,4), show α-VRT relationships similar in nature to the plagioclase series, but with a slope and intercept different from the latter. Taken as a group all Al2Si2 feldspars, including anorthite and celsian from the present study along with Sr- (5) and Pb-feldspar (6) from other workers, show very limited thermal expansion that, unlike AlSi3 feldspars, has little dependence on the divalent-ion (or M-) site occupant. This apparently is due to the necessitated alternation of Al and Si in the tetrahedral sites of these minerals (7), which in turn locks the tetrahedral framework and makes the M-site occupant nearly irrelevant to expansion behavior. Indeed, in feldspar series with coupled chemical substitution it is the change away from a 1:1 Al:Si ratio that gives feldspars greater freedom to expand. Overall, the relationships among α, chemical composition, and room-temperature volume provide useful predictive tools for estimating feldspar thermal expansion and give insight into the controls of expansion behavior in

  9. Removable Type Expansion Bolt Innovative Design

    NASA Astrophysics Data System (ADS)

    Wang, Feng-Lan; Zhang, Bo; Gao, Bo; Liu, Yan-Xin; Gao, Bo

    2016-05-01

    Expansion bolt is a kind of the most common things in our daily life. Currently, there are many kinds of expansion bolts in the market. However, they have some shortcomings that mainly contain underuse and unremovement but our innovation of design makes up for these shortcomings very well. Principle of working follows this: expansion tube is fixed outside of bolt, steel balls and expansion covers are fixed inside. Meanwhile, the steel balls have 120° with each other. When using it ,expansion cover is moved in the direction of its internal part. So the front part of expansion bolt cover is increasingly becoming big and steel halls is moved outside. Only in this way can it be fixed that steel balls make expansion tube expand. When removing them, expansion bolt is moved outside. So the front part of expansion bolt cover is gradually becoming small and steel balls moves inside, after expansion tube shrinks, we can detach them.

  10. Electrocardiographic abnormalities in patients with Lassa fever.

    PubMed

    Cummins, D; Bennett, D; Fisher-Hoch, S P; Farrar, B; McCormick, J B

    1989-10-01

    Electrocardiograms from 32 patients with acute Lassa fever were abnormal in over 70% of cases. The changes noted included non-specific ST-segment and T-wave abnormalities, ST-segment elevation, generalized low-voltage complexes, and changes reflecting electrolyte disturbance. None of the abnormalities correlated with clinical severity of infection, serum transaminase levels, or eventual outcome. ECG changes are common in Lassa fever, but usually unassociated with clinical manifestations of myocarditis.

  11. [Renal abnormalities in ankylosing spondylitis].

    PubMed

    Samia, Barbouch; Hazgui, Faiçal; Abdelghani, Khaoula Ben; Hamida, Fethi Ben; Goucha, Rym; Hedri, Hafedh; Taarit, Chokri Ben; Maiz, Hedi Ben; Kheder, Adel

    2012-07-01

    We will study the epidemiologic, clinical, biological, therapeutic, prognostic characteristics and predictive factors of development of nephropathy in ankylosing spondylitis patients. We retrospectively reviewed the medical record of 32 cases with renal involvement among 212 cases of ankylosing spondylitis followed in our service during the period spread out between 1978 and 2006. The renal involvement occurred in all patients a mean of 12 years after the clinical onset of the rheumatic disease. Thirty-two patients presented one or more signs of renal involvement: microscopic hematuria in 22 patients, proteinuria in 23 patients, nephrotic syndrome in 11 patients and decreased renal function in 24 patients (75%). Secondary renal amyloidosis (13 patients), which corresponds to a prevalence of 6,1% and tubulointerstitial nephropathy (7 patients) were the most common cause of renal involvement in ankylosing spondylitis followed by IgA nephropathy (4 patients). Seventeen patients evolved to the end stage renal disease after an average time of 29.8 ± 46 months. The average follow-up of the patients was 4,4 years. By comparing the 32 patients presenting a SPA and renal disease to 88 with SPA and without nephropathy, we detected the predictive factors of occurred of nephropathy: tobacco, intense inflammatory syndrome, sacroileite stage 3 or 4 and presence of column bamboo. The finding of 75% of the patients presented a renal failure at the time of the diagnosis of renal involvement suggests that evidence of renal abnormality involvement should be actively sought in this disease.

  12. Abnormal band of lateral meniscus.

    PubMed

    Giordano, Brian; Goldblatt, John

    2009-01-01

    This article describes a case of an "abnormal band" of the lateral meniscus, extending from the posterior horn of the true lateral meniscus to its antero-mid portion, observed during arthroscopy in a 45-year-old white man of Bosnian descent. The periphery of the aberrant lateral meniscus was freely mobile, and not connected to the underlying true lateral meniscus. Preoperative physical examination findings were consistent with medial-sided meniscal pathology only; however, evidence of an anomalous lateral meniscus was seen with magnetic resonance imaging. This anatomical pattern is rare and has been reported in the literature only once, in a report of 2 Asian patients. This article illustrates an anatomical variant of the lateral meniscus in a non-Asian patient with a clinical presentation that has not been previously described. In addition to the case report, the article presents a comprehensive review of the existing body of literature on anomalous lateral meniscus patterns. We believe that the definitions of the types of aberrant meniscus can be clarified to establish improved accuracy in reporting.

  13. Biochemical abnormalities in Pearson syndrome.

    PubMed

    Crippa, Beatrice Letizia; Leon, Eyby; Calhoun, Amy; Lowichik, Amy; Pasquali, Marzia; Longo, Nicola

    2015-03-01

    Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the severe bone marrow dysfunction in childhood develop Kearns-Sayre syndrome later in life. Here we report on four new cases with this condition and define their biochemical abnormalities. Three out of four patients presented with failure to thrive, with most of them having normal development and head size. All patients had evidence of bone marrow involvement that spontaneously improved in three out of four patients. Unique findings in our patients were acute pancreatitis (one out of four), renal Fanconi syndrome (present in all patients, but symptomatic only in one), and an unusual organic aciduria with 3-hydroxyisobutyric aciduria in one patient. Biochemical analysis indicated low levels of plasma citrulline and arginine, despite low-normal ammonia levels. Regression analysis indicated a significant correlation between each intermediate of the urea cycle and the next, except between ornithine and citrulline. This suggested that the reaction catalyzed by ornithine transcarbamylase (that converts ornithine to citrulline) might not be very efficient in patients with Pearson syndrome. In view of low-normal ammonia levels, we hypothesize that ammonia and carbamylphosphate could be diverted from the urea cycle to the synthesis of nucleotides in patients with Pearson syndrome and possibly other mitochondrial disorders.

  14. Radiologic atlas of pulmonary abnormalities in children

    SciTech Connect

    Singleton, E.B.; Wagner, M.L.; Dutton, R.V.

    1988-01-01

    This book is an atlas about thoracic abnormalities in infants and children. The authors include computed tomographic, digital subtraction angiographic, ultrasonographic, and a few magnetic resonance (MR) images. They recognize and discuss how changes in the medical treatment of premature infants and the management of infection and pediatric tumors have altered some of the appearances and considerations in these diseases. Oriented toward all aspects of pulmonary abnormalities, the book starts with radiographic techniques and then discusses the normal chest, the newborn, infections, tumors, and pulmonary vascular diseases. There is comprehensive treatment of mediastinal abnormalities and a discussion of airway abnormalities.

  15. Expansive Openness in Teacher Practice

    ERIC Educational Resources Information Center

    Kimmons, Royce

    2016-01-01

    Background/Context: Previous work on the use of open educational resources in K-12 classrooms has generally focused on issues related to cost. The current study takes a more expansive view of openness that also accounts for adaptation and sharing in authentic classroom contexts. Purpose/Objective/Research Question/Focus of Study The study seeks to…

  16. Clamshell Thermal-Expansion Bellows

    NASA Technical Reports Server (NTRS)

    Fesmire, J.; Moore, W. I.; Dipasquale, S. D.

    1993-01-01

    Improved bellows serves as thermal-expansion joint in vacuum-jacketed cyrogenic piping system. Made of Hastelloy C-22 and fabricated in field by welding two clam-shell-like half bellows. No protective paint or maintenance needed. Design modified to fit most thin-wall bellows.

  17. Effective Expansion: Balance between Shrinkage and Hygroscopic Expansion.

    PubMed

    Suiter, E A; Watson, L E; Tantbirojn, D; Lou, J S B; Versluis, A

    2016-05-01

    The purpose of this study was to investigate the relationship between hygroscopic expansion and polymerization shrinkage for compensation of polymerization shrinkage stresses in a restored tooth. One resin-modified glass-ionomer (RMGI) (Ketac Nano, 3M ESPE), 2 compomers (Dyract, Dentsply; Compoglass, Ivoclar), and a universal resin-based composite (Esthet•X HD, Dentsply) were tested. Volumetric change after polymerization ("total shrinkage") and during 4 wk of water storage at 37°C was measured using an optical method (n= 10). Post-gel shrinkage was measured during polymerization using a strain gauge method (n= 10). Extracted human molars with large mesio-occluso-distal slot preparations were restored with the tested restorative materials. Tooth surfaces at baseline (preparation), after restoration, and during 4 wk of 37°C water storage were scanned with an optical scanner to determine cuspal flexure (n= 8). Occlusal interface integrity was measured using dye penetration. Data were analyzed using analysis of variance and post hoc tests (significance level 0.05). All tested materials shrunk after polymerization. RMGI had the highest total shrinkage (4.65%) but lowest post-gel shrinkage (0.35%). Shrinkage values dropped significantly during storage in water but had not completely compensated polymerization shrinkage after 4 wk. All restored teeth initially exhibited inward (negative) cuspal flexure due to polymerization shrinkage. Cuspal flexure with the RMGI restoration was significantly less (-6.4 µm) than with the other materials (-12.1 to -14.1 µm). After 1 d, cuspal flexure reversed to +5.0 µm cuspal expansion with the RMGI and increased to +9.3 µm at 4 wk. After 4 wk, hygroscopic expansion compensated cuspal flexure in a compomer (Compoglass) and reduced flexure with Dyract and resin-based composite. Marginal integrity (93.7% intact restoration wall) was best for the Compoglass restorations and lowest (73.1%) for the RMGI restorations. Hygroscopic

  18. An Abnormal Psychology Community Based Interview Assignment

    ERIC Educational Resources Information Center

    White, Geoffry D.

    1977-01-01

    A course option in abnormal psychology involves students in interviewing and observing the activities of individuals in the off-campus community who are concerned with some aspect of abnormal psychology. The technique generates student interest in the field when they interview people about topics such as drug abuse, transsexualism, and abuse of…

  19. Immune Abnormalities in Patients with Autism.

    ERIC Educational Resources Information Center

    Warren, Reed P.; And Others

    1986-01-01

    A study of 31 autistic patients (3-28 years old) has revealed several immune-system abnormalities, including decreased numbers of T lymphocytes and an altered ratio of helper-to-suppressor T cells. Immune-system abnormalities may be directly related to underlying biologic processes of autism or an indirect reflection of the actual pathologic…

  20. Nail abnormalities in patients with vitiligo*

    PubMed Central

    Topal, Ilteris Oguz; Gungor, Sule; Kocaturk, Ozgur Emek; Duman, Hatice; Durmuscan, Mustafa

    2016-01-01

    Background Vitiligo is an acquired pigmentary skin disorder affecting 0.1-4% of the general population. The nails may be affected in patients with an autoimmune disease such as psoriasis, and in those with alopecia areata. It has been suggested that nail abnormalities should be apparent in vitiligo patients. Objective We sought to document the frequency and clinical presentation of nail abnormalities in vitiligo patients compared to healthy volunteers. We also examined the correlations between nail abnormalities and various clinical parameters. Methods This study included 100 vitiligo patients and 100 healthy subjects. Full medical histories were collected from the subjects, who underwent thorough general and nail examinations. All nail changes were noted. In the event of clinical suspicion of a fungal infection, additional mycological investigations were performed. Results Nail abnormalities were more prevalent in the patients (78%) than in the controls (55%) (p=0.001). Longitudinal ridging was the most common finding (42%), followed by (in descending order): leukonychia, an absent lunula, onycholysis, nail bed pallor, onychomycosis, splinter hemorrhage and nail plate thinning. The frequency of longitudinal ridging was significantly higher in patients than in controls (p<0.001). Conclusions Nail abnormalities were more prevalent in vitiligo patients than in controls. Systematic examination of the nails in such patients is useful because nail abnormalities are frequent. However, the causes of such abnormalities require further study. Longitudinal ridging and leukonychia were the most common abnormalities observed in this study. PMID:27579738

  1. Can transcutaneous recordings detect gastric electrical abnormalities?

    PubMed Central

    Familoni, B O; Bowes, K L; Kingma, Y J; Cote, K R

    1991-01-01

    The ability of transcutaneous recordings of gastric electrical activity to detect gastric electrical abnormalities was determined by simultaneous measurements of gastric electrical activity with surgically implanted serosal electrodes and cutaneous electrodes in six patients undergoing abdominal operations. Transient abnormalities in gastric electrical activity were seen in five of the six patients during the postoperative period. Recognition of normal gastric electrical activity by visual analysis was possible 67% of the time and with computer analysis 95% of the time. Ninety four per cent of abnormalities in frequency were detected by visual analysis and 93.7% by computer analysis. Abnormalities involving a loss of coupling, however, were not recognised by transcutaneous recordings. Transcutaneous recordings of gastric electrical activity assessed by computer analysis can usually recognise normal gastric electrical activity and tachygastria. Current techniques, however, are unable to detect abnormalities in electrical coupling. PMID:1864531

  2. Multipole expansions and intense fields

    NASA Astrophysics Data System (ADS)

    Reiss, Howard R.

    1984-02-01

    In the context of two-body bound-state systems subjected to a plane-wave electromagnetic field, it is shown that high field intensity introduces a distinction between long-wavelength approximation and electric dipole approximation. This distinction is gauge dependent, since it is absent in Coulomb gauge, whereas in "completed" gauges of Göppert-Mayer type the presence of high field intensity makes electric quadrupole and magnetic dipole terms of importance equal to electric dipole at long wavelengths. Another consequence of high field intensity is that multipole expansions lose their utility in view of the equivalent importance of a number of low-order multipole terms and the appearance of large-magnitude terms which defy multipole categorization. This loss of the multipole expansion is gauge independent. Also gauge independent is another related consequence of high field intensity, which is the intimate coupling of center-of-mass and relative coordinate motions in a two-body system.

  3. Expansive Cements and Their Use

    DTIC Science & Technology

    1972-10-01

    made available from the Office, Chief of Research and Development, Army, f- operation of the Concrete Technology Inxormation Aalysis Center (CTIAC...Ths is CTIAC Report No. 8. This report was prepared by Mr. George C. Hoff, Chief Materials Properties V Section of the Concrete iabcraLory, U. S. Army...compensating expansive cement concrete is to minimize cracking in concrete pavements and structures caused by drying shrinkage. The paper reviews the

  4. Femtosecond dynamics of cluster expansion

    NASA Astrophysics Data System (ADS)

    Gao, Xiaohui; Wang, Xiaoming; Shim, Bonggu; Arefiev, Alexey; Tushentsov, Mikhail; Breizman, Boris; Downer, Mike

    2010-03-01

    Noble gas clusters irradiated by intense ultrafast laser expand quickly and become typical plasma in picosecond time scale. During the expansion, the clustered plasma demonstrates unique optical properties such as strong absorption and positive contribution to the refractive index. Here we studied cluster expansion dynamics by fs-time-resolved refractive index and absorption measurements in cluster gas jets after ionization and heating by an intense pump pulse. The refractive index measured by frequency domain interferometry (FDI) shows the transient positive peak of refractive index due to clustered plasma. By separating it from the negative contribution of the monomer plasma, we are able to determine the cluster fraction. The absorption measured by a delayed probe shows the contribution from clusters of various sizes. The plasma resonances in the cluster explain the enhancement of the absorption in our isothermal expanding cluster model. The cluster size distribution can be determined. A complete understanding of the femtosecond dynamics of cluster expansion is essential in the accurate interpretation and control of laser-cluster experiments such as phase-matched harmonic generation in cluster medium.

  5. 78 FR 36165 - Reorganization/Expansion of Foreign-Trade Zone 104; (Expansion of Service Area and Expansion of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-17

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE Foreign-Trade Zones Board Reorganization/Expansion of Foreign-Trade Zone 104; (Expansion of Service Area and Expansion of Zone); Under Alternative Site Framework, Savannah, Georgia Pursuant to its...

  6. The role of the FTD-ALS associated C9orf72 expansion in suicide victims.

    PubMed

    Solje, Eino; Riipinen, Pirkko; Helisalmi, Seppo; Särkioja, Terttu; Laitinen, Marjo; Hiltunen, Mikko; Hakko, Helinä; Remes, Anne M

    Impulsive and aggressive traits are not only common features displayed by patients with behavioural variant frontotemporal dementia (bvFTD), they may well be the first clinical manifestations of the disease. In addition, suicidal behaviour has been postulated to be a symptom of bvFTD. A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the major genetic cause for familial bvFTD. During recent years, several genetic factors predisposing to suicide have been identified, but there are no previous studies analysing the role of the C9orf72 expansion in suicides. In the present study, we aimed to analyse the prevalence of the C9orf72 expansion in unselected suicide victims. The prevalence of the C9orf72 expansion was analysed in a cohort of 109 Finnish victims of suicide (mean age at death 46.1 years; range 18-86 years). The C9orf72 expansion was analysed from the post mortem blood samples. Results showed that no abnormal length C9orf72 expansions were detected in the study cohort. In conclusion, even though suicidal behaviour may be encountered in bvFTD patients, the C9orf72 expansion is not a common genetic finding in unselected suicide victims.

  7. Nonlinear effects on composite laminate thermal expansion

    NASA Technical Reports Server (NTRS)

    Hashin, Z.; Rosen, B. W.; Pipes, R. B.

    1979-01-01

    Analyses of Graphite/Polyimide laminates shown that the thermomechanical strains cannot be separated into mechanical strain and free thermal expansion strain. Elastic properties and thermal expansion coefficients of unidirectional Graphite/Polyimide specimens were measured as a function of temperature to provide inputs for the analysis. The + or - 45 degrees symmetric Graphite/Polyimide laminates were tested to obtain free thermal expansion coefficients and thermal expansion coefficients under various uniaxial loads. The experimental results demonstrated the effects predicted by the analysis, namely dependence of thermal expansion coefficients on load, and anisotropy of thermal expansion under load. The significance of time dependence on thermal expansion was demonstrated by comparison of measured laminate free expansion coefficients with and without 15 day delay at intermediate temperature.

  8. Chemical recombination in an expansion tube

    NASA Technical Reports Server (NTRS)

    Bakos, Robert J.; Morgan, Richard G.

    1994-01-01

    The note describes the theoretical basis of chemical recombination in an expansion tube which simulates energy, Reynolds number, and stream chemistry at near-orbital velocities. Expansion tubes can satisfy ground-based hypersonic propulsion and aerothermal testing requirements.

  9. A Power Series Expansion and Its Applications

    ERIC Educational Resources Information Center

    Chen, Hongwei

    2006-01-01

    Using the power series solution of a differential equation and the computation of a parametric integral, two elementary proofs are given for the power series expansion of (arcsin x)[squared], as well as some applications of this expansion.

  10. A Case of Complex Facial Clefts Treated with Staged-tissue Expansion

    PubMed Central

    Shigemura, Yuka; Nuri, Takashi; Iwanaga, Hiroyuki; Seno, Takaya

    2014-01-01

    Summary: Craniofacial clefts involve all soft tissue and skeletal elements throughout the cleft. Usefulness of tissue expansion in craniofacial clefts is reported. Surgery for a complex type of facial clefts is more difficult and more extensive than for a simple one. We experienced a primary case of complex facial clefts (Tessier No. 2 and 12 on the right and 3, 11, and 5 on the left). Soft-tissue closure of all clefts could be completed by using 4 tissue expanders and 7 operations. Because multiple tissue deficiencies and abnormalities exist in craniofacial clefts, especially complex type, a planned, staged, sequential approach by tissue expansion is necessary to produce ideal results. PMID:25587498

  11. Sleep Physiology, Abnormal States, and Therapeutic Interventions

    PubMed Central

    Wickboldt, Alvah T.; Bowen, Alex F.; Kaye, Aaron J.; Kaye, Adam M.; Rivera Bueno, Franklin; Kaye, Alan D.

    2012-01-01

    Sleep is essential. Unfortunately, a significant portion of the population experiences altered sleep states that often result in a multitude of health-related issues. The regulation of sleep and sleep-wake cycles is an area of intense research, and many options for treatment are available. The following review summarizes the current understanding of normal and abnormal sleep-related conditions and the available treatment options. All clinicians managing patients must recommend appropriate therapeutic interventions for abnormal sleep states. Clinicians' solid understanding of sleep physiology, abnormal sleep states, and treatments will greatly benefit patients regardless of their disease process. PMID:22778676

  12. Congenital abnormalities of the ovine paramesonephric ducts.

    PubMed

    Smith, K C; Long, S E; Parkinson, T J

    1995-01-01

    A 15 month survey of ovine reproductive tracts was undertaken in slaughterhouses in southwest England. A total of 33506 tracts were examined; 23536 from lambs and 9970 from adults. In total, 3.4% of tracts were pregnant and 3.3% exhibited abnormalities. Twenty cases of uterus unicornis, six of uterus didelphys and 11 of segmental aplasia were encountered, such that partial aplasia of the paramesonephric ducts accounted for 3.3% of all abnormalities. Although developmental abnormalities of the ovine female genital system are relatively uncommon, a substantial proportion of these can be accounted for by development defects of the paramesonephric ducts.

  13. [Radionuclide studies of congenital kidney abnormalities].

    PubMed

    Vlakhov, N

    1984-06-01

    Using the potentialities of isotope nephrograms as a screening test a total of 4746 patients suspected of renal abnormalities were examined. The author established pathological deviations in 561 cases (11.8%). During further verification using scintigraphy unsuspected congenital renal abnormalities (aplasia, hypoplasia, dystopia, double kidney, horseshoe kidney, solitary cyst and polycystic renal disease) were found in 46 patients (8.2%). The diagnosis was confirmed at subsequent venous x-ray urography. A conclusion has been made as to the role of comprehensive nephrographic-scintigraphic examination in the diagnosis of congenital renal abnormalities.

  14. Numerically abnormal chromosome constitutions in humans

    SciTech Connect

    1993-12-31

    Chapter 24, discusses numerically abnormal chromosome constitutions in humans. This involves abnormalities of human chromosome number, including polyploidy (when the number of sets of chromosomes increases) and aneuploidy (when the number of individual normal chromosomes changes). Chapter sections discuss the following chromosomal abnormalities: human triploids, imprinting and uniparental disomy, human tetraploids, hydatidiform moles, anomalies caused by chromosomal imbalance, 13 trisomy (D{sub 1} trisomy, Patau syndrome), 21 trisomy (Down syndrome), 18 trisomy syndrome (Edwards syndrome), other autosomal aneuploidy syndromes, and spontaneous abortions. The chapter concludes with remarks on the nonrandom participation of chromosomes in trisomy. 69 refs., 3 figs., 4 tabs.

  15. 32 CFR 169a.11 - Expansions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Expansions. 169a.11 Section 169a.11 National... PROGRAM PROCEDURES Procedures § 169a.11 Expansions. In cases where expansion of an in-house commercial activity is anticipated, a review of the entire commercial activity, including the proposed...

  16. 32 CFR 169a.11 - Expansions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 1 2013-07-01 2013-07-01 false Expansions. 169a.11 Section 169a.11 National... PROGRAM PROCEDURES Procedures § 169a.11 Expansions. In cases where expansion of an in-house commercial activity is anticipated, a review of the entire commercial activity, including the proposed...

  17. 32 CFR 169a.11 - Expansions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 1 2012-07-01 2012-07-01 false Expansions. 169a.11 Section 169a.11 National... PROGRAM PROCEDURES Procedures § 169a.11 Expansions. In cases where expansion of an in-house commercial activity is anticipated, a review of the entire commercial activity, including the proposed...

  18. 32 CFR 169a.11 - Expansions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 false Expansions. 169a.11 Section 169a.11 National... PROGRAM PROCEDURES Procedures § 169a.11 Expansions. In cases where expansion of an in-house commercial activity is anticipated, a review of the entire commercial activity, including the proposed...

  19. 32 CFR 169a.11 - Expansions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 1 2014-07-01 2014-07-01 false Expansions. 169a.11 Section 169a.11 National... PROGRAM PROCEDURES Procedures § 169a.11 Expansions. In cases where expansion of an in-house commercial activity is anticipated, a review of the entire commercial activity, including the proposed...

  20. Space nuclear system expansion joints

    NASA Technical Reports Server (NTRS)

    Whitaker, W. D.; Shimazki, T. T.

    1973-01-01

    The engineering, design, and fabrication status of the expansion joint unit (EJU) to be employed in the NaK primary coolant piping loop of the 5-kwe Reactor thermoelectric system are described. Four EJU's are needed in the NaK primary coolant piping loop. The four EJU's which will be identical, utilize bellows as the flexing member, are hermetically sealed, and provide double containment. The bellows are of a nested-formed design, and are to be constructed of 1-ply thickness of 0.010-in. Inconel 718. The EJU's provide a minimum piping load margin of safety of +0.22.

  1. Calculation of Turbulent Expansion Processes

    NASA Technical Reports Server (NTRS)

    Tollmien, Walter

    1945-01-01

    On the basis of certain formulas recently established by L. Prandtl for the turbulent interchange of momentum in stationary flows, various cases of "free turbulence" - that is, of flows without boundary walls - are treated in the present report. Prandtl puts the apparent shearing stress introduced by the turbulent momentum interchange. This present report deals first with the mixing of an air stream of uniform velocity with the adjacent still air, than with the expansion or diffusion of an air jet in the surrounding air space.

  2. Cosmic growth and expansion conjoined

    NASA Astrophysics Data System (ADS)

    Linder, Eric V.

    2017-01-01

    Cosmological measurements of both the expansion history and growth history have matured, and the two together provide an important test of general relativity. We consider their joint evolutionary track, showing that this has advantages in distinguishing cosmologies relative to considering them individually or at isolated redshifts. In particular, the joint comparison relaxes the shape degeneracy that makes fσ8(z) curves difficult to separate from the overall growth amplitude. The conjoined method further helps visualization of which combinations of redshift ranges provide the clearest discrimination. We examine standard dark energy cosmologies, modified gravity, and "stuttering" growth, each showing distinct signatures.

  3. Report to Congress on abnormal occurrences

    SciTech Connect

    Not Available

    1991-03-01

    Section 208 of the Energy Reorganization Act of 1974 identified an abnormal occurrence as an unscheduled incident or event that the Nuclear Regulatory Commission determines to be significant from the standpoint of public health or safety and requires a quarterly report of such events to be made to Congress. This report covers the period from October 1 through December 31, 1990. The report discusses five abnormal occurrences, none of which involved a nuclear power plant. Two involved significant overexposures to the hands of two radiographers, two involved medical therapy misadministrations, and one involved a medical diagnostic misadministration. No abnormal occurrences were reported by the Agreement States. The report also contains information that updates a previously reported abnormal occurrence. 8 refs.

  4. MRI Helps Assess Fetal Brain Abnormalities

    MedlinePlus

    ... decisions about their pregnancy," said lead author Paul Griffiths. He's a professor of radiology at the University ... the fetus may have a suspected brain abnormality," Griffiths said in a journal news release. In this ...

  5. Abnormal Position and Presentation of the Fetus

    MedlinePlus

    ... Interest (Quiz) Breast Cancer (Video) Overview of the Female Reproductive System (News) Study: Plenty of IV Fluids May Make Childbirth Safer, Easier (News) Zejula Approved for Certain Female Cancers Additional Content Medical News Abnormal Position and ...

  6. Abnormalities of lung function in hay fever.

    PubMed Central

    Morgan, E J; Hall, D R

    1976-01-01

    Twenty subjects with symptoms of hay fever were studied to see whether abnormalities could be detected in the function of small airways. The investigations included dynamic compliance at varying respiratory frequencies, closing capacity, residual volume, transfer factor, and maximal expiratory flow-volume curves. The tests were repeated in the winter when symptoms had resolved. Frequency dependence of compliance was found in eight subjects with symptoms (40%), closing capacities being abnormal in only two instances. Conventional pulmonary function tests, including expiratory flow rates at mid vital capacity, were within the predicted range of all subjects. When tests were repeated in the winter, frequency dependence of compliance was no longer present in subjects whose symptoms had resolved. The study suggests that reversible small airway abnormalities are present in a significant proportion of subjects with symptoms of hay fever and that such abnormalities are best detected by the measurement of dynamic compliance at varying respiratory frequencies. PMID:769243

  7. Medial medullary infarction: abnormal ocular motor findings.

    PubMed

    Kim, J Soo; Choi, K-D; Oh, S-Y; Park, S-H; Han, M-K; Yoon, B-W; Roh, J-K

    2005-10-25

    In 20 consecutive patients with isolated medial medullary infarction, abnormal ocular motor findings included nystagmus (n = 8), ocular contrapulsion (n = 5), and contralesional ocular tilt reaction (n = 2). The nystagmus was ipsilesional (n = 4), gaze-evoked (n = 5), upbeating (n = 4), and hemiseesaw (n = 1). The ocular motor abnormalities may be explained by involvements of the nucleus prepositus hypoglossi, medial longitudinal fasciculus or efferent fibers from the vestibular nuclei, climbing fibers, and cells of the paramedian tracts.

  8. Congenital abnormalities associated with extrahepatic portal hypertension.

    PubMed Central

    Odièvre, M; Pigé, G; Alagille, D

    1977-01-01

    Congenital abnormalities were present in 12 out of 30 (40%) children with extrahepatic portal hypertension of unknown cause, but in only 2 out of 17 (12%) children with extnahepatic portal hypertension secondary to umbilical vein catheterization or omphalitis. The most frequent abnormalities in this series and in published reports were atrial septal defect, malformation of the biliary tract, and anomalous inferior vena cava. These findings are consistent with the view that some cases with extrahepatic portal hypertension are congenital in origin. PMID:869567

  9. Congenital abnormalities associated with extrahepatic portal hypertension.

    PubMed

    Odièvre, M; Pigé, G; Alagille, D

    1977-05-01

    Congenital abnormalities were present in 12 out of 30 (40%) children with extrahepatic portal hypertension of unknown cause, but in only 2 out of 17 (12%) children with extnahepatic portal hypertension secondary to umbilical vein catheterization or omphalitis. The most frequent abnormalities in this series and in published reports were atrial septal defect, malformation of the biliary tract, and anomalous inferior vena cava. These findings are consistent with the view that some cases with extrahepatic portal hypertension are congenital in origin.

  10. Basilar artery migraine and reversible imaging abnormalities.

    PubMed

    Maytal, J; Libman, R B; Lustrin, E S

    1998-01-01

    We report a case of a basilar artery migraine in a 17-year-old boy with transient CT and MR abnormalities after each of two migraine episodes. A repeat MR study 6 months after the last event showed complete resolution of the lesion. Transient abnormalities on brain images similar to those shown in our case have been reported in patients with migraine and other neurologic conditions and are most likely related to cerebral vasogenic edema.

  11. High thermal expansion, sealing glass

    DOEpatents

    Brow, R.K.; Kovacic, L.

    1993-11-16

    A glass composition is described for hermetically sealing to high thermal expansion materials such as aluminum alloys, stainless steels, copper, and copper/beryllium alloys, which includes between about 10 and about 25 mole percent Na[sub 2]O, between about 10 and about 25 mole percent K[sub 2]O, between about 5 and about 15 mole percent Al[sub 2]O[sub 3], between about 35 and about 50 mole percent P[sub 2]O[sub 5] and between about 5 and about 15 mole percent of one of PbO, BaO, and mixtures thereof. The composition, which may also include between 0 and about 5 mole percent Fe[sub 2]O[sub 3] and between 0 and about 10 mole percent B[sub 2]O[sub 3], has a thermal expansion coefficient in a range of between about 160 and 210[times]10[sup [minus]7]/C and a dissolution rate in a range of between about 2[times]10[sup [minus]7] and 2[times]10[sup [minus]9]g/cm[sup 2]-min. This composition is suitable to hermetically seal to metallic electrical components which will be subjected to humid environments over an extended period of time.

  12. Imagination as expansion of experience.

    PubMed

    Zittoun, Tania; Cerchia, Frédéric

    2013-09-01

    This paper proposes a developmental view on imagination: from this perspective, imagination can be seen as triggered by some disrupting event, which generates a disjunction from the person's unfolding experience of the "real" world, and as unfolding as a loop, which eventually comes back to the actual experience. Examining recent and classical theorization of imagination in psychology, the paper opposes a deficitary view of imagination to an expansive notion of imagination. The paper explores Piaget, Vygotsky, Harris and Pelaprat & Cole consider: 1) What does provoke a "rupture" or disjunction? 2) What are the psychological processes involved in the imaginary loop? 3) What nourishes such processes? 4) What are the consequences of such imaginary loop, or what does it enable doing? The paper proposes to adopt an expansive view of imagination, as Vygotsky proposed-a perspective that has been under-explored empirically since his seminal work. To stimulate such sociocultural psychology of imagination, two empirical examples are provided, one showing how children make sense of metaphor in an experimental setting, the other showing a young person using a novel met at school as symbolic resource.

  13. High thermal expansion, sealing glass

    DOEpatents

    Brow, Richard K.; Kovacic, Larry

    1993-01-01

    A glass composition for hermetically sealing to high thermal expansion materials such as aluminum alloys, stainless steels, copper, and copper/beryllium alloys, which includes between about 10 and about 25 mole percent Na.sub.2 O, between about 10 and about 25 mole percent K.sub.2 O, between about 5 and about 15 mole percent Al.sub.2 O.sub.3, between about 35 and about 50 mole percent P.sub.2 O.sub.5 and between about 5 and about 15 mole percent of one of PbO, BaO, and mixtures thereof. The composition, which may also include between 0 and about 5 mole percent Fe.sub.2 O.sub.3 and between 0 and about 10 mole percent B.sub.2 O.sub.3, has a thermal expansion coefficient in a range of between about 160 and 210.times.10-7/.degree.C. and a dissolution rate in a range of between about 2.times.10.sup.- 7 and 2.times.10.sup.-9 g/cm.sup.2 -min. This composition is suitable to hermetically seal to metallic electrical components which will be subjected to humid environments over an extended period of time.

  14. Gyrification from constrained cortical expansion

    PubMed Central

    Tallinen, Tuomas; Chung, Jun Young; Biggins, John S.; Mahadevan, L.

    2014-01-01

    The exterior of the mammalian brain—the cerebral cortex—has a conserved layered structure whose thickness varies little across species. However, selection pressures over evolutionary time scales have led to cortices that have a large surface area to volume ratio in some organisms, with the result that the brain is strongly convoluted into sulci and gyri. Here we show that the gyrification can arise as a nonlinear consequence of a simple mechanical instability driven by tangential expansion of the gray matter constrained by the white matter. A physical mimic of the process using a layered swelling gel captures the essence of the mechanism, and numerical simulations of the brain treated as a soft solid lead to the formation of cusped sulci and smooth gyri similar to those in the brain. The resulting gyrification patterns are a function of relative cortical expansion and relative thickness (compared with brain size), and are consistent with observations of a wide range of brains, ranging from smooth to highly convoluted. Furthermore, this dependence on two simple geometric parameters that characterize the brain also allows us to qualitatively explain how variations in these parameters lead to anatomical anomalies in such situations as polymicrogyria, pachygyria, and lissencephalia. PMID:25136099

  15. Expansion of Physician Assistant Education.

    PubMed

    Cawley, James F; Eugene Jones, P; Miller, Anthony A; Orcutt, Venetia L

    2016-12-01

    Physician assistant (PA) educational programs were created in the 1960s to prepare a new type of health care practitioner. Physician assistant programs began as experiments in medical education, and later, they proved to be highly successful in preparing capable, flexible, and productive clinicians. The growth of PA educational programs in US medical education-stimulated by grants, public policy, and anticipated shortages of providers-has gone through 3 distinct phases. At present, such programs are in the midst of the third growth spurt that is expected to continue beyond 2020, as a large number of colleges and universities seek to sponsor PA programs and attain accreditation status. Characteristics of these new programs are described, and the implications of the current expansion of PA education are examined.

  16. Asymptotic expansions in nonlinear rotordynamics

    NASA Technical Reports Server (NTRS)

    Day, William B.

    1987-01-01

    This paper is an examination of special nonlinearities of the Jeffcott equations in rotordynamics. The immediate application of this analysis is directed toward understanding the excessive vibrations recorded in the LOX pump of the SSME during hot-firing ground testing. Deadband, side force, and rubbing are three possible sources of inducing nonlinearity in the Jeffcott equations. The present analysis initially reduces these problems to the same mathematical description. A special frequency, named the nonlinear natural frequency, is defined and used to develop the solutions of the nonlinear Jeffcott equations as singular asymptotic expansions. This nonlinear natural frequency, which is the ratio of the cross-stiffness and the damping, plays a major role in determining response frequencies.

  17. Ensuring reliability in expansion schemes.

    PubMed

    Kamal-Uddin, Abu Sayed; Williams, Donald Leigh

    2005-01-01

    Existing electricity power supplies must serve, or be adapted to serve, the expansion of hospital buildings. With the existing power supply assets of many hospitals being up to 20 years old, assessing the security and reliability of the power system must be given appropriate priority to avoid unplanned outages due to overloads and equipment failures. It is imperative that adequate contingency is planned for essential and non-essential electricity circuits. This article describes the methodology undertaken, and the subsequent recommendations that were made, when evaluating the security and reliability of electricity power supplies to a number of major London hospitals. The methodology described aligns with the latest issue of NHS Estates HTM 2011 'Primary Electrical Infrastructure Emergency Electrical Services Design Guidance' (to which ERA Technology has contributed).

  18. 42 CFR 37.54 - Notification of abnormal radiographic findings.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... shape or size, tuberculosis, lung cancer, or any other significant abnormal findings other than..., tuberculosis, cancer, complicated pneumoconiosis, and any other significant abnormal findings, NIOSH...

  19. 42 CFR 37.54 - Notification of abnormal radiographic findings.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ..., abnormality of cardiac shape or size, tuberculosis, lung cancer, or any other significant abnormal findings... shape or size, tuberculosis, cancer, complicated pneumoconiosis, and any other significant...

  20. Abnormal Magnetic Field Effects on Electrogenerated Chemiluminescence

    NASA Astrophysics Data System (ADS)

    Pan, Haiping; Shen, Yan; Wang, Hongfeng; He, Lei; Hu, Bin

    2015-03-01

    We report abnormal magnetic field effects on electrogenerated chemiluminescence (MFEECL) based on triplet emission from the Ru(bpy)3Cl2-TPrA electrochemical system: the appearance of MFEECL after magnetic field ceases. In early studies the normal MFEECL have been observed from electrochemical systems during the application of magnetic field. Here, the abnormal MFEECL suggest that the activated charge-transfer [Ru(bpy)33+ … TPrA•] complexes may become magnetized in magnetic field and experience a long magnetic relaxation after removing magnetic field. Our analysis indicates that the magnetic relaxation can gradually increase the density of charge-transfer complexes within reaction region due to decayed magnetic interactions, leading to a positive component in the abnormal MFEECL. On the other hand, the magnetic relaxation facilitates an inverse conversion from triplets to singlets within charge-transfer complexes. The inverse triplet --> singlet conversion reduces the density of triplet light-emitting states through charge-transfer complexes and gives rise to a negative component in the abnormal MFEECL. The combination of positive and negative components can essentially lead to a non-monotonic profile in the abnormal MFEECL after ceasing magnetic field. Nevertheless, our experimental studies may reveal un-usual magnetic behaviors with long magnetic relaxation from the activated charge-transfer [Ru(bpy)33+ … TPrA•] complexes in solution at room temperature.

  1. A critical role for sonic hedgehog signaling in the early expansion of the developing brain.

    PubMed

    Britto, Joanne; Tannahill, David; Keynes, Roger

    2002-02-01

    The mechanisms that coordinate the three-dimensional shape of the vertebrate brain during development are largely unknown. We have found that sonic hedgehog (Shh) is crucial in driving the rapid, extensive expansion of the early vesicles of the developing midbrain and forebrain. Transient displacement of the notochord from the midbrain floor plate resulted in abnormal folding and overall collapse of the vesicles, accompanied by reduced cell proliferation and increased cell death in the midbrain. Simultaneously, expression of Shh decreased locally in the notochord and floor plate, whereas overt patterning and differentiation proceeded normally. Normal midbrain expansion was restored by implantation of Shh-secreting cells in a dose-dependent manner; conversely, expansion was retarded following antagonism of the Shh signaling pathway by cyclopamine. Our results indicate that Shh signaling from the ventral midline is essential for regulating brain morphogenesis during early development.

  2. Pressurized electrolysis stack with thermal expansion capability

    DOEpatents

    Bourgeois, Richard Scott

    2015-07-14

    The present techniques provide systems and methods for mounting an electrolyzer stack in an outer shell so as to allow for differential thermal expansion of the electrolyzer stack and shell. Generally, an electrolyzer stack may be formed from a material with a high coefficient of thermal expansion, while the shell may be formed from a material having a lower coefficient of thermal expansion. The differences between the coefficients of thermal expansion may lead to damage to the electrolyzer stack as the shell may restrain the thermal expansion of the electrolyzer stack. To allow for the differences in thermal expansion, the electrolyzer stack may be mounted within the shell leaving a space between the electrolyzer stack and shell. The space between the electrolyzer stack and the shell may be filled with a non-conductive fluid to further equalize pressure inside and outside of the electrolyzer stack.

  3. XYY chromosome abnormality in sexual homicide perpetrators.

    PubMed

    Briken, Peer; Habermann, Niels; Berner, Wolfgang; Hill, Andreas

    2006-03-05

    In a retrospective investigation of the court reports about sexual homicide perpetrators chromosome analysis had been carried out in 13 of 166 (7.8%) men. Three men (1.8%) with XYY chromosome abnormality were found. This rate is much higher than that found in unselected samples of prisoners (0.7-0.9%) or in the general population (0.01%). The three men had shown prepubescent abnormalities, school problems, and had suffered from physical abuse. The chromosome analysis in all cases had been carried out in connection with the forensic psychiatric court report due to the sexual homicide. However, two men had earlier psychiatric referrals. All were diagnosed as sexual sadistic, showed a psychopathic syndrome or psychopathy according to the Psychopathy Checklist-Revised [Hare RD, 1991, The Hare Psychopathy Checklist-Revised, Toronto, Ontario, Canada: Multi-Health Systems]. Two were multiple murderers. Especially forensic psychiatrists should be vigilant of the possibility of XYY chromosome abnormalities in sexual offenders.

  4. Visual perceptual abnormalities: hallucinations and illusions.

    PubMed

    Norton, J W; Corbett, J J

    2000-01-01

    Visual perceptual abnormalities may be caused by diverse etiologies which span the fields of psychiatry and neurology. This article reviews the differential diagnosis of visual perceptual abnormalities from both a neurological and a psychiatric perspective. Psychiatric etiologies include mania, depression, substance dependence, and schizophrenia. Common neurological causes include migraine, epilepsy, delirium, dementia, tumor, and stroke. The phenomena of palinopsia, oscillopsia, dysmetropsia, and polyopia among others are also reviewed. A systematic approach to the many causes of illusions and hallucinations may help to achieve an accurate diagnosis, and a more focused evaluation and treatment plan for patients who develop visual perceptual abnormalities. This article provides the practicing neurologist with a practical understanding and approach to patients with these clinical symptoms.

  5. Abnormal Head Position in Infantile Nystagmus Syndrome

    PubMed Central

    Noval, Susana; González-Manrique, Mar; Rodríguez-Del Valle, José María; Rodríguez-Sánchez, José María

    2011-01-01

    Infantile nystagmus is an involuntary, bilateral, conjugate, and rhythmic oscillation of the eyes which is present at birth or develops within the first 6 months of life. It may be pendular or jerk-like and, its intensity usually increases in lateral gaze, decreasing with convergence. Up to 64% of all patients with nystagmus also present strabismus, and even more patients have an abnormal head position. The abnormal head positions are more often horizontal, but they may also be vertical or take the form of a tilt, even though the nystagmus itself is horizontal. The aim of this article is to review available information about the origin and treatment of the abnormal head position associated to nystagmus, and to describe our treatment strategies. PMID:24533187

  6. Parsing abnormal grain growth in specialty aluminas

    NASA Astrophysics Data System (ADS)

    Lawrence, Abigail Kremer

    Grain growth in alumina is strongly affected by the impurities present in the material. Certain impurity elements are known to have characteristic effects on abnormal grain growth in alumina. Specialty alumina powders contain multiple impurity species including MgO, CaO, SiO2, and Na 2O. In this work, sintered samples made from alumina powders containing various amounts of the impurities in question were characterized by their grain size and aspect ratio distributions. Multiple quantitative methods were used to characterize and classify samples with varying microstructures. The grain size distributions were used to partition the grain size population into subpopulations depending on the observed deviation from normal behavior. Using both grain size and aspect ratio a new visual representation for a microstructure was introduced called a morphology frequency map that gives a fingerprint for the material. The number of subpopulations within a sample and the shape of the distribution on the morphology map provided the basis for a classification scheme for different types of microstructures. Also using the two parameters a series of five metrics were calculated that describe the character of the abnormal grains in the sample, these were called abnormal character values. The abnormal character values describe the fraction of grains that are considered abnormal, the average magnitude of abnormality (including both grain size and aspect ratio), the average size, and variance in size. The final metric is the correlation between grain size and aspect ratio for the entire population of grains. The abnormal character values give a sense of how different from "normal" the sample is, given the assumption that a normal sample has a lognormal distribution of grain size and a Gaussian distribution of aspect ratios. In the second part of the work the quantified measures of abnormality were correlated with processing parameters such as composition and heat treatment conditions. A

  7. Schizophrenia and abnormal brain network hubs.

    PubMed

    Rubinov, Mikail; Bullmore, Ed

    2013-09-01

    Schizophrenia is a heterogeneous psychiatric disorder of unknown cause or characteristic pathology. Clinical neuroscientists increasingly postulate that schizophrenia is a disorder of brain network organization. In this article we discuss the conceptual framework of this dysconnection hypothesis, describe the predominant methodological paradigm for testing this hypothesis, and review recent evidence for disruption of central/hub brain regions, as a promising example of this hypothesis. We summarize studies of brain hubs in large-scale structural and functional brain networks and find strong evidence for network abnormalities of prefrontal hubs, and moderate evidence for network abnormalities of limbic, temporal, and parietal hubs. Future studies are needed to differentiate network dysfunction from previously observed gray- and white-matter abnormalities of these hubs, and to link endogenous network dysfunction phenotypes with perceptual, behavioral, and cognitive clinical phenotypes of schizophrenia.

  8. [Nutritional abnormalities in chronic obstructive pulmonary disease].

    PubMed

    Gea, Joaquim; Martínez-Llorens, Juana; Barreiro, Esther

    2014-07-22

    Nutritional abnormalities are associated with chronic obstructive pulmonary disease with a frequency ranging from 2 to 50%, depending on the geographical area and the study design. Diagnostic tools include anthropometry, bioelectrical impedance, dual energy radioabsortiometry and deuterium dilution, being the body mass and the lean mass indices the most frequently used parameters. While the most important consequences of nutritional abnormalities are muscle dysfunction and exercise limitation, factors implicated include an imbalance between caloric intake and consumption, and between anabolic and catabolic hormones, inflammation, tobacco smoking, poor physical activity, hypoxemia, some drugs and aging/comorbidities. The most important molecular mechanism for malnutrition associated with chronic obstructive pulmonary disease appears to be the mismatching between protein synthesis and breakdown. Among the therapeutic measures proposed for these nutritional abnormalities are improvements in lifestyle and nutritional support, although the use of anabolic drugs (such as secretagogues of the growth hormone) offers a new therapeutic strategy.

  9. Retinal abnormalities in β-thalassemia major

    PubMed Central

    Bhoiwala, Devang L.; Dunaief, Joshua L.

    2015-01-01

    Patients with beta (β)-thalassemia (β-TM: thalassemia major, β-TI: thalassemia intermedia) have a variety of complications that may affect all organs, including the eye. Ocular abnormalities include retinal pigment epithelium degeneration, angioid streaks, venous tortuosity, night blindness, visual field defects, decreased visual acuity, color vision abnormalities, and acute visual loss. Patients with β-TM are transfusion dependent and require iron chelation therapy (ICT) in order to survive. Retinal degeneration may result from either retinal iron accumulation from transfusion-induced iron overload or retinal toxicity induced by ICT. Some who were never treated with ICT exhibited retinopathy, and others receiving ICT had chelator-induced retinopathy. We will focus on retinal abnormalities present in individuals with β-TM viewed in light of new findings on the mechanisms and manifestations of retinal iron toxicity. PMID:26325202

  10. Abnormal Grain Growth Suppression in Aluminum Alloys

    NASA Technical Reports Server (NTRS)

    Hales, Stephen J. (Inventor); Claytor, Harold Dale (Inventor); Alexa, Joel A. (Inventor)

    2015-01-01

    The present invention provides a process for suppressing abnormal grain growth in friction stir welded aluminum alloys by inserting an intermediate annealing treatment ("IAT") after the welding step on the article. The IAT may be followed by a solution heat treatment (SHT) on the article under effectively high solution heat treatment conditions. In at least some embodiments, a deformation step is conducted on the article under effective spin-forming deformation conditions or under effective superplastic deformation conditions. The invention further provides a welded article having suppressed abnormal grain growth, prepared by the process above. Preferably the article is characterized with greater than about 90% reduction in area fraction abnormal grain growth in any friction-stir-welded nugget.

  11. Advances in understanding paternally transmitted Chromosomal Abnormalities

    SciTech Connect

    Marchetti, F; Sloter, E; Wyrobek, A J

    2001-03-01

    Multicolor FISH has been adapted for detecting the major types of chromosomal abnormalities in human sperm including aneuploidies for clinically-relevant chromosomes, chromosomal aberrations including breaks and rearrangements, and other numerical abnormalities. The various sperm FISH assays have been used to evaluate healthy men, men of advanced age, and men who have received mutagenic cancer therapy. The mouse has also been used as a model to investigate the mechanism of paternally transmitted genetic damage. Sperm FISH for the mouse has been used to detect chromosomally abnormal mouse sperm, while the PAINT/DAPI analysis of mouse zygotes has been used to evaluate the types of chromosomal defects that can be paternally transmitted to the embryo and their effects on embryonic development.

  12. Hydration and Thermal Expansion in Anatase Nanoparticles

    SciTech Connect

    Zhu, He; Li, Qiang; Ren, Yang; Fan, Longlong; Chen, Jun; Deng, Jinxia; Xing, Xianran

    2016-06-06

    A tunable thermal expansion is reported in nanosized anatase by taking advantage of surface hydration. The coefficient of thermal expansion of 4 nm TiO2 along a-axis is negative with a hydrated surface and is positive without a hydrated surface. High-energy synchrotron X-ray pair distribution function analysis combined with ab initio calculations on the specific hydrated surface are carried out to reveal the local structure distortion that is responsible for the unusual negative thermal expansion.

  13. Hydration and Thermal Expansion in Anatase Nanoparticles.

    PubMed

    Zhu, He; Li, Qiang; Ren, Yang; Fan, Longlong; Chen, Jun; Deng, Jinxia; Xing, Xianran

    2016-08-01

    A tunable thermal expansion is reported in nanosized anatase by taking advantage of surface hydration. The coefficient of thermal expansion of 4 nm TiO2 along a-axis is negative with a hydrated surface and is positive without a hydrated surface. High-energy synchrotron X-ray pair distribution function analysis combined with ab initio calculations on the specific hydrated surface are carried out to reveal the local structure distortion that is responsible for the unusual negative thermal expansion.

  14. Coalition formation in transmission expansion planning

    SciTech Connect

    Contreras, J.; Wu, F.F. |

    1999-08-01

    The study of a decentralized coalition formation scheme in a specific power systems transmission expansion scenario is the purpose of this paper. The authors define first who are the agents in the expansion game and provide a decentralized coalition scheme based on Bilateral Shapley values. Finally, they allocate the total costs of expansion amongst the agents, based on the coalition history, and they compare their method with a centralized scheme.

  15. Chromosome abnormalities in acute lymphoblastic leukemia

    SciTech Connect

    Rowley, J.D.

    1980-01-01

    Less information is available on the cytogenetic abnormalities in marrow cells of patients with acute lymphoblastic leukemia (ALL) than on abnormalities in acute nonlymphocytic leukemia (ANLL); nonetheless, some patterns of karyotypic change in ALL are evident. Even with banding, about 50% of patients appear to have a normal karyotype. The modal chromosome number tends to be higher in ALL than in ANLL. Every patient with B-cell ALL has had an abnormality of one chromosome No. 14 that involved the translocation of material to the end of the long arm. Among seven reported cases, the translocation was from 8q in three patients and 11q in one. Cells with a haploid or near-haploid (24 to 35) chromosome number have been reported in five patients with ALL and in four patients in a lymphoid blast crisis of chronic myelogeneous leukemia. The karyotype in the four ALL patients whose cells were analyzed with banding was remarkably consistent. All patients had the haploid number, usually with both sex chromosomes, plus an additional No. 10, 18, and 21. Evolution of the karyotype, which occurs in the leukemic cells of about 50% of patients, involves cells of patients who had an initially normal or an initially abnormal karyotype. The evidence regarding a correlation between the presence of an abnormal clone prior to treatment and response to treatment is contradictory at present. Some chromosome abnormalities, such as the presence of a Philadelphia (Ph/sup 1/) chromosome, a 14q+chromosome, or a haploid clone, are associated with a relatively short survival.

  16. Cranial strains and malocclusion VIII: palatal expansion.

    PubMed

    James, Gavin; Strokon, Dennis

    2009-01-01

    Current techniques for palatal expansion are reviewed. Pre-treatment asymmetry of the palate and maxillary arch is shown to be almost universal and is not randomly distributed. The use of a symmetrical expansion appliance does not necessarily result in a symmetrical arch. ALF appliances provide a means of achieving orthopedic, symmetrical expansion of the palate by using very light force. This is demonstrated in seven subjects. It is argued that rapid palatal expansion is an inappropriate, potentially iatrogenic procedure which no longer has a place in the orthodontic armamentarium.

  17. Temporal abnormalities in children with developmental dyscalculia.

    PubMed

    Vicario, Carmelo Mario; Rappo, Gaetano; Pepi, Annamaria; Pavan, Andrea; Martino, Davide

    2012-01-01

    Recent imaging studies have associated Developmental dyscalculia (DD) to structural and functional alterations corresponding Parietal and the Prefrontal cortex (PFC). Since these areas were shown also to be involved in timing abilities, we hypothesized that time processing is abnormal in DD. We compared time processing abilities between 10 children with pure DD (8 years old) and 11 age-matched healthy children. Results show that the DD group underestimated duration of a sub-second scale when asked to perform a time comparison task. The timing abnormality observed in our DD participants is consistent with evidence of a shared fronto-parietal neural network for representing time and quantity.

  18. Hemorheological abnormalities in human arterial hypertension

    NASA Astrophysics Data System (ADS)

    Lo Presti, Rosalia; Hopps, Eugenia; Caimi, Gregorio

    2014-05-01

    Blood rheology is impaired in hypertensive patients. The alteration involves blood and plasma viscosity, and the erythrocyte behaviour is often abnormal. The hemorheological pattern appears to be related to some pathophysiological mechanisms of hypertension and to organ damage, in particular left ventricular hypertrophy and myocardial ischemia. Abnormalities have been observed in erythrocyte membrane fluidity, explored by fluorescence spectroscopy and electron spin resonance. This may be relevant for red cell flow in microvessels and oxygen delivery to tissues. Although blood viscosity is not a direct target of antihypertensive therapy, the rheological properties of blood play a role in the pathophysiology of arterial hypertension and its vascular complications.

  19. Nonpathologizing trauma interventions in abnormal psychology courses.

    PubMed

    Hoover, Stephanie M; Luchner, Andrew F; Pickett, Rachel F

    2016-01-01

    Because abnormal psychology courses presuppose a focus on pathological human functioning, nonpathologizing interventions within these classes are particularly powerful and can reach survivors, bystanders, and perpetrators. Interventions are needed to improve the social response to trauma on college campuses. By applying psychodynamic and feminist multicultural theory, instructors can deliver nonpathologizing interventions about trauma and trauma response within these classes. We recommend class-based interventions with the following aims: (a) intentionally using nonpathologizing language, (b) normalizing trauma responses, (c) subjectively defining trauma, (d) challenging secondary victimization, and (e) questioning the delineation of abnormal and normal. The recommendations promote implications for instructor self-reflection, therapy interventions, and future research.

  20. Roentgenographic abnormalities in Rocky Mountain Spotted Fever.

    PubMed

    McCook, T A; Briley, C; Ravin, C E

    1982-02-01

    Rock Mountain spotted fever (RMSF) is a tick-borne rickettsial disease which produces a widespread vasculitis. A mortality of 7% to 13% has been reported in the United States which is due at least in part to delay in diagnosis and appropriate treatment. The classic features of this disease include a history of tick bite with the clinical presentation of skin rash and fever in association with thrombocytopenia. Few reports have emphasized the radiologic chest abnormalities in this disease or their relationship to thrombocytopenia. We review 70 cases of RMSF with abnormal roentgenographic features and their pathologic correlation.

  1. Normal and abnormal human vestibular ocular function

    NASA Technical Reports Server (NTRS)

    Peterka, R. J.; Black, F. O.

    1986-01-01

    The major motivation of this research is to understand the role the vestibular system plays in sensorimotor interactions which result in spatial disorientation and motion sickness. A second goal was to explore the range of abnormality as it is reflected in quantitative measures of vestibular reflex responses. The results of a study of vestibular reflex measurements in normal subjects and preliminary results in abnormal subjects are presented in this report. Statistical methods were used to define the range of normal responses, and determine age related changes in function.

  2. Magnetic Clouds: Global and local expansion

    NASA Astrophysics Data System (ADS)

    Gulisano, Adriana; Demoulin, Pascal; Soledad Nakwacki, Ms Maria; Dasso, Sergio; Emilia Ruiz, Maria

    Magnetic clouds (MCs) are magnetized objects forming flux ropes, which are expelled from the Sun and travel through the heliosphere, transporting important amounts of energy, mass, magnetic flux, and magnetic helicity from the Sun to the interplanetary medium. To know the detailed dynamical evolution of MCs is very useful to improve the knowledge of solar processes, for instance from linking a transient solar source with its interplanetary manifestation. During its travel, and mainly due to the decrease of the total (magnetic plus thermal) pressure in the surrounding solar wind, MCs are objects in expansion. However, the detailed magnetic structure and the dynamical evolution of MCs is still not fully known. Even the identification of their boundaries is an open question in some cases. In a previous work we have shown that from onepoint observations of the bulk velocity profile, it is possible to infer the 'local' expansion rate for a given MC, i.e., the expansion rate while the MC is observed by the spacecraft. By the another hand, and from the comparison of sizes for different MCs observed at different heliodistances, it is possible to quantify an 'average' expansion law (i.e., a global expansion). In this work, in order to study the variability of the 'local' expansion with respect to the 'average' expansion of MCs during their travel, we present results and a comparison between both approaches. We make a detailed study of one-point observations (magnetic and bulk velocity) using a set of MCs and we get the 'local' expansion rate for each studied event. We compare the obtained 'local' expansion rates with the 'average' expansion law, and also with the expansion rates for the stationary solar wind.

  3. Recurrent chromosome 6 abnormalities in malignant mesothelioma.

    PubMed

    Ribotta, M; Roseo, F; Salvio, M; Castagneto, B; Carbone, M; Procopio, A; Giordano, A; Mutti, L

    1998-04-01

    The long latency period between asbestos exposure and the onset of malignant mesothelioma (MM) suggests that a multistep tumorigenesis process occurs whilst the capability of asbestos fibres to interfere directly with chromosomes focuses on the critical role of the chromosomal abnormalities in this neoplasm. The aim of our study was to identify any recurrent chromosomal changes in ten primary MM cell cultures derived from pleural effusions of patients with MM from the same geographic area and environmental and/or occupational exposure to asbestos fibers. Cytogenetic analysis was performed in accordance with International System for Human Cytogenetic Nomenclature. Our results confirmed a great number of cytogenetic abnormalities in MM cells. Recurrent loss of the long arms of chromosome 6 (6q-) was the most frequent abnormality detected (four epithelial and two mixed subtypes) while, on the whole, abnormalities of chromosome 6 were found in nine out of ten cases whereas chromosome 6 was normal only in the case with fibromatous subtype. Monosomy 13 and 17 was found in five cases, monosomy 14 in four cases and 22 in three cases. Since deletion of 6q- was detected even in relatively undisturbed karyotype, we hypothesize a multistep carcinogenic process in which deletion of 6q- is an early event in the development and progression of malignant mesothelioma.

  4. Schizophrenogenic Parenting in Abnormal Psychology Textbooks.

    ERIC Educational Resources Information Center

    Wahl, Otto F.

    1989-01-01

    Considers the treatment of family causation of schizophrenia in undergraduate abnormal psychology textbooks. Reviews texts published only after 1986. Points out a number of implications for psychologists which arise from the inclusion in these texts of the idea that parents cause schizophrenia, not the least of which is the potential for…

  5. Teaching Abnormal Psychology in a Multimedia Classroom.

    ERIC Educational Resources Information Center

    Brewster, JoAnne

    1996-01-01

    Examines the techniques used in teaching an abnormal psychology class in a multimedia environment with two computers and a variety of audiovisual equipment. Students respond anonymously to various questions via keypads mounted on their desks, then immediately view and discuss summaries of their responses. (MJP)

  6. Dynamic Abnormal Grain Growth in Refractory Metals

    NASA Astrophysics Data System (ADS)

    Noell, Philip J.; Taleff, Eric M.

    2015-11-01

    High-temperature plastic deformation of the body-centered cubic (BCC) refractory metals Mo and Ta can initiate and propagate abnormal grains at significantly lower temperatures and faster rates than is possible by static annealing alone. This discovery reveals a new and potentially important aspect of abnormal grain growth (AGG) phenomena. The process of AGG during plastic deformation at elevated temperatures, termed dynamic abnormal grain growth (DAGG), was observed at homologous temperatures between 0.52 and 0.72 in both Mo and Ta sheet materials; these temperatures are much lower than those for previous observations of AGG in these materials during static annealing. DAGG was used to repeatedly grow single crystals several centimeters in length. Investigations to date have produced a basic understanding of the conditions that lead to DAGG and how DAGG is affected by microstructure in BCC refractory metals. The current state of understanding for DAGG is reviewed in this paper. Attention is given to the roles of temperature, plastic strain, boundary mobility and preexisting microstructure. DAGG is considered for its potential useful applications in solid-state crystal growth and its possibly detrimental role in creating undesired abnormal grains during thermomechanical processing.

  7. Abnormally high formation pressures, Potwar Plateau, Pakistan

    USGS Publications Warehouse

    Law, B.E.; Shah, S.H.A.; Malik, M.A.

    1998-01-01

    Abnormally high formation pressures in the Potwar Plateau of north-central Pakistan are major obstacles to oil and gas exploration. Severe drilling problems associated with high pressures have, in some cases, prevented adequate evaluation of reservoirs and significantly increased drilling costs. Previous investigations of abnormal pressure in the Potwar Plateau have only identified abnormal pressures in Neogene rocks. We have identified two distinct pressure regimes in this Himalayan foreland fold and thrust belt basin: one in Neogene rocks and another in pre-Neogene rocks. Pore pressures in Neogene rocks are as high as lithostatic and are interpreted to be due to tectonic compression and compaction disequilibrium associated with high rates of sedimentation. Pore pressure gradients in pre-Neogene rocks are generally less than those in Neogene rocks, commonly ranging from 0.5 to 0.7 psi/ft (11.3 to 15.8 kPa/m) and are most likely due to a combination of tectonic compression and hydrocarbon generation. The top of abnormally high pressure is highly variable and doesn't appear to be related to any specific lithologic seal. Consequently, attempts to predict the depth to the top of overpressure prior to drilling are precluded.

  8. Abnormal activated partial thromboplastin time and malignancy.

    PubMed

    Delicata, M; Hambley, H

    2011-08-01

    Malignancy often results in clotting abnormalities. The aetiology of haemostasis problems in cancer is complex, and is still not completely understood. We describe a case of a patient with malignant mesothelioma, who was found to have elevated activated partial thromboplastin time, due to lupus anticoagulant. We suggest that patients with malignancy should have their coagulation checked prior to any invasive procedures.

  9. First-Trimester Detection of Surface Abnormalities

    PubMed Central

    Rousian, Melek; Koning, Anton H. J.; Bonsel, Gouke J.; Eggink, Alex J.; Cornette, Jérôme M. J.; Schoonderwaldt, Ernst M.; Husen-Ebbinge, Margreet; Teunissen, Katinka K.; van der Spek, Peter J.; Steegers, Eric A. P.; Exalto, Niek

    2014-01-01

    The aim was to determine the diagnostic performance of 3-dimensional virtual reality ultrasound (3D_VR_US) and conventional 2- and 3-dimensional ultrasound (2D/3D_US) for first-trimester detection of structural abnormalities. Forty-eight first trimester cases (gold standard available, 22 normal, 26 abnormal) were evaluated offline using both techniques by 5 experienced, blinded sonographers. In each case, we analyzed whether each organ category was correctly indicated as normal or abnormal and whether the specific diagnosis was correctly made. Sensitivity in terms of normal or abnormal was comparable for both techniques (P = .24). The general sensitivity for specific diagnoses was 62.6% using 3D_VR_US and 52.2% using 2D/3D_US (P = .075). The 3D_VR_US more often correctly diagnosed skeleton/limb malformations (36.7% vs 10%; P = .013). Mean evaluation time in 3D_VR_US was 4:24 minutes and in 2D/3D_US 2:53 minutes (P < .001). General diagnostic performance of 3D_VR_US and 2D/3D_US apparently is comparable. Malformations of skeleton and limbs are more often detected using 3D_VR_US. Evaluation time is longer in 3D_VR_US. PMID:24440996

  10. Craniofacial abnormalities among patients with Edwards Syndrome

    PubMed Central

    Rosa, Rafael Fabiano M.; Rosa, Rosana Cardoso M.; Lorenzen, Marina Boff; Zen, Paulo Ricardo G.; Graziadio, Carla; Paskulin, Giorgio Adriano

    2013-01-01

    OBJECTIVE To determine the frequency and types of craniofacial abnormalities observed in patients with trisomy 18 or Edwards syndrome (ES). METHODS This descriptive and retrospective study of a case series included all patients diagnosed with ES in a Clinical Genetics Service of a reference hospital in Southern Brazil from 1975 to 2008. The results of the karyotypic analysis, along with clinical data, were collected from medical records. RESULTS: The sample consisted of 50 patients, of which 66% were female. The median age at first evaluation was 14 days. Regarding the karyotypes, full trisomy of chromosome 18 was the main alteration (90%). Mosaicism was observed in 10%. The main craniofacial abnormalities were: microretrognathia (76%), abnormalities of the ear helix/dysplastic ears (70%), prominent occiput (52%), posteriorly rotated (46%) and low set ears (44%), and short palpebral fissures/blepharophimosis (46%). Other uncommon - but relevant - abnormalities included: microtia (18%), orofacial clefts (12%), preauricular tags (10%), facial palsy (4%), encephalocele (4%), absence of external auditory canal (2%) and asymmetric face (2%). One patient had an initial suspicion of oculo-auriculo-vertebral spectrum (OAVS) or Goldenhar syndrome. CONCLUSIONS: Despite the literature description of a characteristic clinical presentation for ES, craniofacial alterations may be variable among these patients. The OAVS findings in this sample are noteworthy. The association of ES with OAVS has been reported once in the literature. PMID:24142310

  11. Abnormal Web Usage Control by Proxy Strategies.

    ERIC Educational Resources Information Center

    Yu, Hsiang-Fu; Tseng, Li-Ming

    2002-01-01

    Approaches to designing a proxy server with Web usage control and to making the proxy server effective on local area networks are proposed to prevent abnormal Web access and to prioritize Web usage. A system is implemented to demonstrate the approaches. The implementation reveals that the proposed approaches are effective, such that the abnormal…

  12. Engineering molecular crystals with abnormally weak cohesion.

    PubMed

    Maly, Kenneth E; Gagnon, Eric; Wuest, James D

    2011-05-14

    Adding astutely placed methyl groups to hexaphenylbenzene increases molecular weight but simultaneously weakens key C-H···π interactions, thereby leading to decreased enthalpies of sublimation and showing that materials with abnormally weak cohesion can be made by identifying and then obstructing interactions that help control association.

  13. Eye movement abnormalities in essential tremor

    PubMed Central

    Plinta, Klaudia; Krzak-Kubica, Agnieszka; Zajdel, Katarzyna; Falkiewicz, Marcel; Dylak, Jacek; Ober, Jan; Szczudlik, Andrzej; Rudzińska, Monika

    2016-01-01

    Abstract Essential tremor (ET) is the most prevalent movement disorder, characterized mainly by an action tremor of the arms. Only a few studies published as yet have assessed oculomotor abnormalities in ET and their results are unequivocal. The aim of this study was to assess the oculomotor abnormalities in ET patients compared with the control group and to find the relationship between oculomotor abnormalities and clinical features of ET patients. We studied 50 ET patients and 42 matched by age and gender healthy controls. Saccadometer Advanced (Ober Consulting, Poland) was used to investigate reflexive, pace-induced and cued saccades and conventional electrooculography for evaluation of smooth pursuit and fixation. The severity of the tremor was assessed by the Clinical Rating Scale for Tremor. Significant differences between ET patients and controls were found for the incidence of reflexive saccades dysmetria and deficit of smooth pursuit. Reflexive saccades dysmetria was more frequent in patients in the second and third phase of ET compared to the first phase. The reflexive saccades latency increase was correlated with severity of the tremor. In conclusion, oculomotor abnormalities were significantly more common in ET patients than in healthy subjects. The most common oculomotor disturbances in ET were reflexive saccades dysmetria and slowing of smooth pursuit. The frequency of reflexive saccades dysmetria increased with progression of ET. The reflexive saccades latency increase was related to the severity of tremor. PMID:28149393

  14. Psychology Faculty Perceptions of Abnormal Psychology Textbooks

    ERIC Educational Resources Information Center

    Rapport, Zachary

    2011-01-01

    The problem. The purpose of the current study was to investigate the perceptions and opinions of psychology professors regarding the accuracy and inclusiveness of abnormal psychology textbooks. It sought answers from psychology professors to the following questions: (1) What are the expectations of the psychology faculty at a private university of…

  15. Abnormal Saccadic Eye Movements in Autistic Children.

    ERIC Educational Resources Information Center

    Kemner, C.; Verbaten, M. N.; Cuperus, J. M.; Camfferman, G.; van Engeland, H.

    1998-01-01

    The saccadic eye movements, generated during a visual oddball task, were compared for 10 autistic children, 10 children with attention deficit hyperactivity disorder, 10 dyslexic children, and 10 typically developing children. Several abnormal patterns of saccades were found in the autistic group. (DB)

  16. Pathways to abnormal revenge and forgiveness.

    PubMed

    Barclay, Pat

    2013-02-01

    The target article’s important point is easily misunderstood to claim that all revenge is adaptive. Revenge and forgiveness can overstretch (or understretch) the bounds of utility due to misperceptions, minimization of costly errors, a breakdown within our evolved revenge systems, or natural genetic and developmental variation. Together, these factors can compound to produce highly abnormal instances of revenge and forgiveness.

  17. Meiotic chromosome abnormalities in human spermatogenesis.

    PubMed

    Martin, Renée H

    2006-08-01

    The last few years have witnessed an explosion in the information about chromosome abnormalities in human sperm and the meiotic events that predispose to these abnormalities. We have determined that all chromosomes are susceptible to nondisjunction, but chromosomes 21 and 22 and, especially, the sex chromosomes have an increased frequency of aneuploidy. Studies are just beginning on the effects of potential mutagens on the chromosomal constitution of human sperm. The effects of pesticides and cancer therapeutic agents have been reviewed. In the last decade, there has been a great impetus to study chromosome abnormalities in sperm from infertile men because the advent of intracytoplasmic sperm injection (ICSI) made it possible for these men to father pregnancies. A large number of studies have demonstrated that infertile men have an increased frequency of chromosomally abnormal sperm and children, even when they have a normal somatic karyotype. Meiotic studies on the pachytene stage of spermatogenesis have demonstrated that infertile men have impaired chromosome synapsis, a significantly decreased frequency of recombination, and an increased frequency of chromosomes completely lacking a recombination site. Such errors make these cells susceptible to meiotic arrest and the production of aneuploid gametes.

  18. Sensory Abnormalities in Autism: A Brief Report

    ERIC Educational Resources Information Center

    Klintwall Lars; Holm, Anette; Eriksson, Mats; Carlsson, Lotta Hoglund; Olsson, Martina Barnevik; Hedvall, Asa; Gillberg, Christopher; Fernell, Elisabeth

    2011-01-01

    Sensory abnormalities were assessed in a population-based group of 208 20-54-month-old children, diagnosed with autism spectrum disorder (ASD) and referred to a specialized habilitation centre for early intervention. The children were subgrouped based upon degree of autistic symptoms and cognitive level by a research team at the centre. Parents…

  19. [Y chromosome structural abnormalities and Turner's syndrome].

    PubMed

    Ravel, C; Siffroi, J-P

    2009-06-01

    Although specifically male, the human Y chromosome may be observed in female karyotypes, mostly in women with Turner syndrome stigmata. In women with isolated gonadal dysgenesis but otherwise normal stature, the testis determining factor or SRY gene may have been removed from the Y chromosome or may be mutated. In other women with Turner syndrome, the karyotype is usually abnormal and shows a frequent 45,X/46,XY mosaicism. In these cases, the phenotype depends on the ratio between Y positive and 45,X cell lines in the body. When in mosaicism, Y chromosomes are likely to carry structural abnormalities which explain mitotic instability, such as the existence of two centromeres. Dicentric Y isochromosomes for the short arm (idic[Yp]) or ring Y chromosomes (r[Y]) are the most frequent abnormal Y chromosomes found in infertile patients and in Turner syndrome in mosaic with 45,X cells. Although monocentric, deleted Y chromosomes for the long arm and those carrying microdeletions in the AZF region are also instable and are frequently associated with a 45,X cell line. Management of infertile patients carrying such abnormal Y chromosomes must take into account the risk and the consequences of a mosaicism in the offspring.

  20. Esophageal motility abnormalities in gastroesophageal reflux disease.

    PubMed

    Martinucci, Irene; de Bortoli, Nicola; Giacchino, Maria; Bodini, Giorgia; Marabotto, Elisa; Marchi, Santino; Savarino, Vincenzo; Savarino, Edoardo

    2014-05-06

    Esophageal motility abnormalities are among the main factors implicated in the pathogenesis of gastroesophageal reflux disease. The recent introduction in clinical and research practice of novel esophageal testing has markedly improved our understanding of the mechanisms contributing to the development of gastroesophageal reflux disease, allowing a better management of patients with this disorder. In this context, the present article intends to provide an overview of the current literature about esophageal motility dysfunctions in patients with gastroesophageal reflux disease. Esophageal manometry, by recording intraluminal pressure, represents the gold standard to diagnose esophageal motility abnormalities. In particular, using novel techniques, such as high resolution manometry with or without concurrent intraluminal impedance monitoring, transient lower esophageal sphincter (LES) relaxations, hypotensive LES, ineffective esophageal peristalsis and bolus transit abnormalities have been better defined and strongly implicated in gastroesophageal reflux disease development. Overall, recent findings suggest that esophageal motility abnormalities are increasingly prevalent with increasing severity of reflux disease, from non-erosive reflux disease to erosive reflux disease and Barrett's esophagus. Characterizing esophageal dysmotility among different subgroups of patients with reflux disease may represent a fundamental approach to properly diagnose these patients and, thus, to set up the best therapeutic management. Currently, surgery represents the only reliable way to restore the esophagogastric junction integrity and to reduce transient LES relaxations that are considered to be the predominant mechanism by which gastric contents can enter the esophagus. On that ground, more in depth future studies assessing the pathogenetic role of dysmotility in patients with reflux disease are warranted.

  1. Abnormal interhemispheric connectivity in male psychopathic offenders

    PubMed Central

    Hoppenbrouwers, Sylco S.; De Jesus, Danilo R.; Sun, Yinming; Stirpe, Tania; Hofman, Dennis; McMaster, Jeff; Hughes, Ginny; Daskalakis, Zafiris J.; Schutter, Dennis J.L.G.

    2014-01-01

    Background Psychopathic offenders inevitably violate interpersonal norms and frequently resort to aggressive and criminal behaviour. The affective and cognitive deficits underlying these behaviours have been linked to abnormalities in functional interhemispheric connectivity. However, direct neurophysiological evidence for dysfunctional connectivity in psychopathic offenders is lacking. Methods We used transcranial magnetic stimulation combined with electroencephalography to examine interhemispheric connectivity in the dorsolateral and motor cortex in a sample of psychopathic offenders and healthy controls. We also measured intracortical inhibition and facilitation over the left and right motor cortex to investigate the effects of local cortical processes on interhemispheric connectivity. Results We enrolled 17 psychopathic offenders and 14 controls in our study. Global abnormalities in right to left functional connectivity were observed in psychopathic offenders compared with controls. Furthermore, in contrast to controls, psychopathic offenders showed increased intracortical inhibition in the right, but not the left, hemisphere. Limitations The relatively small sample size limited the sensitivity to show that the abnormalities in interhemispheric connectivity were specifically related to the dorsolateral prefrontal cortex in psychopathic offenders. Conclusion To our knowledge, this study provides the first neurophysiological evidence for abnormal interhemispheric connectivity in psychopathic offenders and may further our understanding of the disruptive antisocial behaviour of these offenders. PMID:23937798

  2. Abnormal Selective Attention Normalizes P3 Amplitudes in PDD

    ERIC Educational Resources Information Center

    Hoeksma, Marco R.; Kemner, Chantal; Kenemans, J. Leon; van Engeland, Herman

    2006-01-01

    This paper studied whether abnormal P3 amplitudes in PDD are a corollary of abnormalities in ERP components related to selective attention in visual and auditory tasks. Furthermore, this study sought to clarify possible age differences in such abnormalities. Children with PDD showed smaller P3 amplitudes than controls, but no abnormalities in…

  3. Analysis of Performance Variation Using Query Expansion.

    ERIC Educational Resources Information Center

    Alemayehu, Nega

    2003-01-01

    Discussion of information retrieval performance evaluation focuses on a case study using a statistical repeated measures analysis of variance for testing the significance of factors, such as retrieval method and topic in retrieval performance variation. Analyses of the effect of query expansion on document ranking confirm that expansion affects…

  4. A reduced volumetric expansion factor plot

    NASA Technical Reports Server (NTRS)

    Hendricks, R. C.

    1979-01-01

    A reduced volumetric expansion factor plot was constructed for simple fluids which is suitable for engineering computations in heat transfer. Volumetric expansion factors were found useful in correlating heat transfer data over a wide range of operating conditions including liquids, gases and the near critical region.

  5. A reduced volumetric expansion factor plot

    NASA Technical Reports Server (NTRS)

    Hendricks, R. C.

    1979-01-01

    A reduced volumetric expansion factor plot has been constructed for simple fluids which is suitable for engineering computations in heat transfer. Volumetric expansion factors have been found useful in correlating heat transfer data over a wide range of operating conditions including liquids, gases and the near critical region.

  6. Unitary expansion of the time evolution operator

    SciTech Connect

    Zagury, N.; Aragao, A.; Casanova, J.; Solano, E.

    2010-10-15

    We propose an expansion of the unitary evolution operator, associated with a given Schroedinger equation, in terms of a finite product of explicit unitary operators. In this manner, this unitary expansion can be truncated at the desired level of approximation, as shown in the given examples.

  7. Multipole expansion method for supernova neutrino oscillations

    SciTech Connect

    Duan, Huaiyu; Shalgar, Shashank E-mail: shashankshalgar@unm.edu

    2014-10-01

    We demonstrate a multipole expansion method to calculate collective neutrino oscillations in supernovae using the neutrino bulb model. We show that it is much more efficient to solve multi-angle neutrino oscillations in multipole basis than in angle basis. The multipole expansion method also provides interesting insights into multi-angle calculations that were accomplished previously in angle basis.

  8. 45 CFR 800.104 - Phased expansion.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 3 2014-10-01 2014-10-01 false Phased expansion. 800.104 Section 800.104 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF PERSONNEL MANAGEMENT MULTI-STATE PLAN PROGRAM Multi-State Plan Program Issuer Requirements § 800.104 Phased expansion. (a) Phase-in. OPM...

  9. Expansion techniques for collisionless stellar dynamical simulations

    SciTech Connect

    Meiron, Yohai; Li, Baile; Holley-Bockelmann, Kelly; Spurzem, Rainer

    2014-09-10

    We present graphics processing unit (GPU) implementations of two fast force calculation methods based on series expansions of the Poisson equation. One method is the self-consistent field (SCF) method, which is a Fourier-like expansion of the density field in some basis set; the other method is the multipole expansion (MEX) method, which is a Taylor-like expansion of the Green's function. MEX, which has been advocated in the past, has not gained as much popularity as SCF. Both are particle-field methods and optimized for collisionless galactic dynamics, but while SCF is a 'pure' expansion, MEX is an expansion in just the angular part; thus, MEX is capable of capturing radial structure easily, while SCF needs a large number of radial terms. We show that despite the expansion bias, these methods are more accurate than direct techniques for the same number of particles. The performance of our GPU code, which we call ETICS, is profiled and compared to a CPU implementation. On the tested GPU hardware, a full force calculation for one million particles took ∼0.1 s (depending on expansion cutoff), making simulations with as many as 10{sup 8} particles fast for a comparatively small number of nodes.

  10. 45 CFR 800.104 - Phased expansion.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 3 2013-10-01 2013-10-01 false Phased expansion. 800.104 Section 800.104 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF PERSONNEL MANAGEMENT MULTI-STATE PLAN PROGRAM Multi-State Plan Program Issuer Requirements § 800.104 Phased expansion. (a) Phase-in. OPM...

  11. Finnish Higher Education Expansion and Regional Policy

    ERIC Educational Resources Information Center

    Saarivirta, Toni

    2010-01-01

    This paper concentrates on the expansion of Finnish higher education between the 1960s and 1970s, exposes its background in the light of the policy decisions that were made, compares the unique features of this expansion with those of certain other countries, discusses the impact of the controlled "top down" governance of higher…

  12. Earnings Returns to the British Education Expansion

    ERIC Educational Resources Information Center

    Devereux, Paul J.; Fan, Wen

    2011-01-01

    We study the effects of the large expansion in British educational attainment that took place for cohorts born between 1970 and 1975. Using the Quarterly Labour Force Survey, we find that the expansion caused men to increase education by about a year on average and gain about 8% higher wages; women obtained a slightly greater increase in education…

  13. The heavy quark expansion of QCD

    SciTech Connect

    Falk, A.F.

    1997-06-01

    These lectures contain an elementary introduction to heavy quark symmetry and the heavy quark expansion. Applications such as the expansion of heavy meson decay constants and the treatment of inclusive and exclusive semileptonic B decays are included. Heavy hadron production via nonperturbative fragmentation processes is also discussed. 54 refs., 7 figs.

  14. Expansive Learning as Production of Community

    ERIC Educational Resources Information Center

    Morck, Line Lerche

    2010-01-01

    This article contributes a framework for analyzing learning as an expansive process in which persons come to partly transcend marginalization. Expansive learning is a kind of learning that partly transcends marginalization through changed participation and recognition by others of participants in their changed communities. This article draws on…

  15. 76 FR 19746 - Approval for Subzone Expansion and Expansion of Manufacturing Authority; Foreign-Trade Subzone...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-08

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE Foreign-Trade Zones Board Approval for Subzone Expansion and Expansion of Manufacturing Authority; Foreign... Jefferson County Riverport Authority, grantee of Foreign-Trade Zone 29, has requested an expansion of...

  16. 76 FR 75870 - Approval for Subzone Expansion and Expansion of Manufacturing Authority; Foreign-Trade Subzone...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-05

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE Foreign-Trade Zones Board Approval for Subzone Expansion and Expansion of Manufacturing Authority; Foreign... Louisiana Port Commission, grantee of Foreign- Trade Zone 124, has requested an expansion of the subzone...

  17. Low-thermal expansion infrared glass ceramics

    NASA Astrophysics Data System (ADS)

    Lam, Philip

    2009-05-01

    L2 Tech, Inc. is in development of an innovative infrared-transparent glass ceramic material with low-thermal expansion (<0.5 ppm/°C) and high thermal-shock resistance to be used as windows and domes for high speed flight. The material is an inorganic, non-porous glass ceramic, characterized by crystalline phases of evenly distributed nano-crystals in a residual glass phase. The major crystalline phase is zirconium tungstate (ZrW2O8) which has Negative Thermal Expansion (NTE). The glass phase is the infrared-transparent germanate glass which has positive thermal expansion (PTE). Then glass ceramic material has a balanced thermal expansion of near zero. The crystal structure is cubic and the thermal expansion of the glass ceramic is isotropic or equal in all directions.

  18. Differential ventricular expansion in hydrocephalus.

    PubMed

    McAllister, J P; Chovan, P; Steiner, C P; Johnson, M J; Ayzman, I; Wood, A S; Tkach, J A; Hahn, J F; Luciano, M G

    1998-12-01

    In the large canine model of acquired obstructive hydrocephalus that we have developed recently, computer-assisted 3-dimensional morphometry has been performed on T1-weighted Spin Echo MRI images from adult dogs before and after the induction of hydrocephalus. To date, 7 hydrocephalic animals have been analyzed that survived 7-83 days (median = 54) after receiving injections of cyanoacrylate glue into the anterior fourth ventricle. Measurements were obtained from lateral, 3rd, and 4th ventricles. The volumes of the left and right lateral ventricles were symmetrical before and after induction. Mean lateral ventricle volume increased 424% from a baseline of 0.63 cc to a post-induction value of 3.30 cc (p < 0.01 with unpaired t-test). In contrast, the 3rd ventricle expanded 187% from a mean of 0.15 cc to 0.43 cc (p < 0.05). The combined volume of the lateral and 3rd ventricles increased 369% from a mean of 0.78 cc to 3.69 cc (p < 0.01). Evans' ratios, which are used routinely in the clinical setting, were also obtained from linear measurements of the lateral ventricle width divided by brain width at the level of the foramen of Monro. These values exhibited only a 94% increase from mean baseline ratios of 0.17 to post-induction ratios of 0.33 (p < 0.05). These findings indicate that in mechanically-induced obstructive hydrocephalus the relative expansion of the lateral ventricles is greater than that of the 3rd ventricle. In addition, volumetric measurements of the lateral and 3rd ventricles suggest that the extent of ventriculomegaly is 3-4 times greater than estimated by Evans' ratios.

  19. Morphokinetics of human blastocyst expansion in vitro.

    PubMed

    Huang, T T F; Chinn, K; Kosasa, T; Ahn, H J; Kessel, B

    2016-12-01

    Time-lapse imaging offers new tools to study dynamic processes of development such as blastocyst formation and expansion. This study quantitatively describes expansion in human blastocysts from donated oocytes. Measurements of hourly interval rate of changes in the blastocoel cross-sectional area revealed oscillatory pulses having 2-4 h periodicities. Two types of oscillations were distinguished. An E-Type ('expansion') had positive peak and positive or slightly negative trough interval rate of change values, and these characterized most of the expansion period. A C-type ('contraction') represented an infrequent but notable contraction of the blastocoel with loss of blastocoel fluid. These were reversible within 2-4 h in both groups and followed by further expansion. Therefore, oscillatory pulses are an intrinsic property of the trophectoderm. The zona seems to variably dampen the amplitude of these pulses. Expansion kinetics were compared between blastocysts with known positive (KID+) or negative (KID-) implantation outcomes. Regression analysis suggests that expansion may be relatively restricted in KID- embryos blastulating at relatively later times. These data extend observations in other mammalian systems and may provide information useful for clinical selection algorithms.

  20. Developmental pragmatics in normal and abnormal children.

    PubMed

    Bara, B G; Bosco, F M; Bucciarelli, M

    1999-07-01

    We propose a critical review of current theories of developmental pragmatics. The underlying assumption is that such a theory ought to account for both normal and abnormal development. From a clinical point of view, we are concerned with the effects of brain damage on the emergence of pragmatic competence. In particular, the paper deals with direct speech acts, indirect speech acts, irony, and deceit in children with head injury, closed head injury, hydrocephalus, focal brain damage, and autism. Since no single theory covers systematically the emergence of pragmatic capacity in normal children, it is not surprising that we have not found a systematic account of deficits in the communicative performance of brain injured children. In our view, the challenge for a pragmatic theory is the determination of the normal developmental pattern within which different pragmatic phenomena may find a precise role. Such a framework of normal behavior would then permit the systematic study of abnormal pragmatic development.

  1. Abnormal single or composite dissipative solitons generation

    NASA Astrophysics Data System (ADS)

    Zhong, Xianqiong; Liu, Dingyao; Cheng, Ke; Sheng, Jianan

    2016-12-01

    The evolution dynamics of the initial finite energy Airy pulses and Airy pulse pairs are numerically investigated in the cubic-quintic complex Ginzberg-Laudau equation governed dissipative system. Depending on different initial excitations and system parameters, abnormal double, triple, and quadruple composite dissipative solitons as well as single dissipative solitons can be observed. The composite dissipative solitons may consist of identical or different types of pulsating solitons. Moreover, the creeping solitons and the single ordinary pulsating solitons can even appear in the parameter regions where originally the other types of pulsating solitons exist. Besides, before evolving into each abnormal dissipative soliton, the initial finite energy Airy pulse or pulse pairs generally exhibit very interesting and unique early evolution behavior.

  2. [Abnormal hemoglobins in Negroid Ecuadorian populations].

    PubMed

    Jara, N O; Guevara Espinoza, A; Guderian, R H

    1989-02-01

    The prevalence of hemoglobinopathies was determined in the black race located in two distinct geographical areas in Ecuador; in the coastal province of Esmeraldas, particularly the Santiago basin (Rio Cayapas and Rio Onzoles) and in the province of Imbabura, particularly in the intermoutain valley, Valle de Chota. A total of 2038 blood samples were analyzed, 1734 in Esmeraldas and 304 in Inbabura, of which 23.2% (473 individuals) were found to be carriers of abnormal hemoglobins, 25.4% (441) in Esmeraldas and 10.5% (32) in Imbabura. The abnormal hemoglobins found in Esmeraldas were Hb AS (19.2%), Hb AC (5.0%), Hb SS (0.6%) and Hb SC (0.5%) while in Imbabura only Hb AS (9.5%) and Hb AC (0.9%) were found. The factors that could influence the difference in prevalence found in the two geographical areas are discussed.

  3. Chromosomal abnormalities in a psychiatric population

    SciTech Connect

    Lewis, K.E.; Lubetsky, M.J.; Wenger, S.L.; Steele, M.W.

    1995-02-27

    Over a 3.5 year period of time, 345 patients hospitalized for psychiatric problems were evaluated cytogenetically. The patient population included 76% males and 94% children with a mean age of 12 years. The criteria for testing was an undiagnosed etiology for mental retardation and/or autism. Cytogenetic studies identified 11, or 3%, with abnormal karyotypes, including 4 fragile X positive individuals (2 males, 2 females), and 8 with chromosomal aneuploidy, rearrangements, or deletions. While individuals with chromosomal abnormalities do not demonstrate specific behavioral, psychiatric, or developmental problems relative to other psychiatric patients, our results demonstrate the need for an increased awareness to order chromosomal analysis and fragile X testing in those individuals who have combinations of behavioral/psychiatric, learning, communication, or cognitive disturbance. 5 refs., 1 fig., 2 tabs.

  4. Gastric emptying abnormalities in progressive systemic sclerosis

    SciTech Connect

    Sridhar, K.; Magyar, L.; Lange, R.; McCallum, R.W.

    1985-05-01

    The authors studied gastric emptying (GE) in patients with peripheral manifestations of progressive systemic sclerosis (PSS) using a radionuclide method. 18 patients underwent esophageal manometry and a GE study using chicken liver labeled in vivo with Tc-99m sulfur colloid as a marker of solid emptying. GE was also measured in 13 normal volunteers. 4 PSS patients with normal esophageal motility also had normal GE. The GE of 14 PSS patients with abnormal esophageal motility was significantly (p < 0.05) delayed; with 67.4% retention of isotope after 2 hours compared to 49.8 in normals. The authors conclude that GE of solids is slow in approximately 2/3 of PSS patients with abnormal esophageal motility but is normal if the esophagus is uninvolved; Delayed GE may contribute to the severity of gastroesophageal reflux in PSS patients and the degree of dysphasgia; and Metoclopramide accelerates GE in PSS patients and should have a valuable therapeutic role.

  5. Giant negative thermal expansion in magnetic nanocrystals.

    PubMed

    Zheng, X G; Kubozono, H; Yamada, H; Kato, K; Ishiwata, Y; Xu, C N

    2008-12-01

    Most solids expand when they are heated, but a property known as negative thermal expansion has been observed in a number of materials, including the oxide ZrW2O8 (ref. 1) and the framework material ZnxCd1-x(CN)2 (refs 2,3). This unusual behaviour can be understood in terms of low-energy phonons, while the colossal values of both positive and negative thermal expansion recently observed in another framework material, Ag3[Co(CN)6], have been explained in terms of the geometric flexibility of its metal-cyanide-metal linkages. Thermal expansion can also be stopped in some magnetic transition metal alloys below their magnetic ordering temperature, a phenomenon known as the Invar effect, and the possibility of exploiting materials with tuneable positive or negative thermal expansion in industrial applications has led to intense interest in both the Invar effect and negative thermal expansion. Here we report the results of thermal expansion experiments on three magnetic nanocrystals-CuO, MnF2 and NiO-and find evidence for negative thermal expansion in both CuO and MnF2 below their magnetic ordering temperatures, but not in NiO. Larger particles of CuO and MnF2 also show prominent magnetostriction (that is, they change shape in response to an applied magnetic field), which results in significantly reduced thermal expansion below their magnetic ordering temperatures; this behaviour is not observed in NiO. We propose that the negative thermal expansion effect in CuO (which is four times larger than that observed in ZrW2O8) and MnF2 is a general property of nanoparticles in which there is strong coupling between magnetism and the crystal lattice.

  6. Varenicline and Abnormal Sleep Related Events

    PubMed Central

    Savage, Ruth L.; Zekarias, Alem; Caduff-Janosa, Pia

    2015-01-01

    Study Objectives: To assess adverse drug reaction reports of “abnormal sleep related events” associated with varenicline, a partial agonist to the α4β2 subtype of nicotinic acetylcholine receptors on neurones, indicated for smoking cessation. Design: Twenty-seven reports of “abnormal sleep related events” often associated with abnormal dreams, nightmares, or somnambulism, which are known to be associated with varenicline use, were identified in the World Health Organisation (WHO) Global Individual Case Safety Reports Database. Original anonymous reports were obtained from the four national pharmacovigilance centers that submitted these reports and assessed for reaction description and causality. Measurements and Results: These 27 reports include 10 of aggressive activity occurring during sleep and seven of other sleep related harmful or potentially harmful activities, such as apparently deliberate self-harm, moving a child or a car, or lighting a stove or a cigarette. Assessment of these 17 reports of aggression or other actual or potential harm showed that nine patients recovered or were recovering on varenicline withdrawal and there were no consistent alternative explanations. Thirteen patients experienced single events, and two had multiple events. Frequency was not stated for the remaining two patients. Conclusions: The descriptions of the reports of aggression during sleep with violent dreaming are similar to those of rapid eye movement sleep behavior disorder and also nonrapid eye movement (NREM) sleep parasomnias in some adults. Patients who experience somnambulism or dreams of a violent nature while taking varenicline should be advised to consult their health providers. Consideration should be given to clarifying the term sleep disorders in varenicline product information and including sleep related harmful and potentially harmful events. Citation: Savage RL, Zekarias A, Caduff-Janosa P. Varenicline and abnormal sleep related events. SLEEP 2015

  7. CT of trauma to the abnormal kidney

    SciTech Connect

    Rhyner, P.; Federle, M.P.; Jeffrey, R.B.

    1984-04-01

    Traumatic injuries to already abnormal kidneys are difficult to assess by excretory urography and clinical evaluation. Bleeding and urinary extravasation may accompany minor trauma; conversely, underlying tumors, perirenal hemorrhage, and extravasation may be missed on urography. Computed tomography (CT) was performed in eight cases including three neoplasms, one adult polycystic disease, one simple renal cyst, two hydronephrotic kidneys, and one horseshoe kidney. CT provided specific and clinically useful information in each case that was not apparent on excretory urography.

  8. Computed tomography of the abnormal pericardium

    SciTech Connect

    Silverman, P.M.; Harell, G.S.; Korobkin, M.

    1983-06-01

    Computed tomographic (CT) findings in 18 patients with documented pericardial disease are reported. The pericardium appears as a thin, curvilinear, 1- to 2-mm-thick density best seen anterior to the right ventricular part of the heart. Pericardial abnormalities detected by CT include effusions, thickening, calcification, and cystic and solid masses. Computed tomography is complimentary to echocardiography in its ability to more accurately characterize pericardial effusions, masses, and pericardial thickening.

  9. Binocular combination in abnormal binocular vision.

    PubMed

    Ding, Jian; Klein, Stanley A; Levi, Dennis M

    2013-02-08

    We investigated suprathreshold binocular combination in humans with abnormal binocular visual experience early in life. In the first experiment we presented the two eyes with equal but opposite phase shifted sine waves and measured the perceived phase of the cyclopean sine wave. Normal observers have balanced vision between the two eyes when the two eyes' images have equal contrast (i.e., both eyes contribute equally to the perceived image and perceived phase = 0°). However, in observers with strabismus and/or amblyopia, balanced vision requires a higher contrast image in the nondominant eye (NDE) than the dominant eye (DE). This asymmetry between the two eyes is larger than predicted from the contrast sensitivities or monocular perceived contrast of the two eyes and is dependent on contrast and spatial frequency: more asymmetric with higher contrast and/or spatial frequency. Our results also revealed a surprising NDE-to-DE enhancement in some of our abnormal observers. This enhancement is not evident in normal vision because it is normally masked by interocular suppression. However, in these abnormal observers the NDE-to-DE suppression was weak or absent. In the second experiment, we used the identical stimuli to measure the perceived contrast of a cyclopean grating by matching the binocular combined contrast to a standard contrast presented to the DE. These measures provide strong constraints for model fitting. We found asymmetric interocular interactions in binocular contrast perception, which was dependent on both contrast and spatial frequency in the same way as in phase perception. By introducing asymmetric parameters to the modified Ding-Sperling model including interocular contrast gain enhancement, we succeeded in accounting for both binocular combined phase and contrast simultaneously. Adding binocular contrast gain control to the modified Ding-Sperling model enabled us to predict the results of dichoptic and binocular contrast discrimination experiments

  10. Sensory abnormalities in autism. A brief report.

    PubMed

    Klintwall, Lars; Holm, Anette; Eriksson, Mats; Carlsson, Lotta Höglund; Olsson, Martina Barnevik; Hedvall, Asa; Gillberg, Christopher; Fernell, Elisabeth

    2011-01-01

    Sensory abnormalities were assessed in a population-based group of 208 20-54-month-old children, diagnosed with autism spectrum disorder (ASD) and referred to a specialized habilitation centre for early intervention. The children were subgrouped based upon degree of autistic symptoms and cognitive level by a research team at the centre. Parents were interviewed systematically about any abnormal sensory reactions in the child. In the whole group, pain and hearing were the most commonly affected modalities. Children in the most typical autism subgroup (nuclear autism with no learning disability) had the highest number of affected modalities. The children who were classified in an "autistic features" subgroup had the lowest number of affected modalities. There were no group differences in number of affected sensory modalities between groups of different cognitive levels or level of expressive speech. The findings provide support for the notion that sensory abnormality is very common in young children with autism. This symptom has been proposed for inclusion among the diagnostic criteria for ASD in the upcoming DSM-V.

  11. Abnormal parietal encephalomalacia associated with schizophrenia

    PubMed Central

    Pan, Fen; Wang, Jun-Yuan; Xu, Yi; Huang, Man-Li

    2017-01-01

    Abstract Rationale: It is widely believed that structural abnormalities of the brain contribute to the pathophysiology of schizophrenia. The parietal lobe is a central hub of multisensory integration, and abnormities in this region might account for the clinical features of schizophrenia. However, few cases of parietal encephalomalacia associated with schizophrenia have been described. Patient concerns and Diagnoses: In this paper, we present a case of a 25-year-old schizophrenia patient with abnormal parietal encephalomalacia. The patient had poor nutrition and frequently had upper respiratory infections during childhood and adolescence. She showed severe schizophrenic symptoms such as visual hallucinations for 2 years. After examining all her possible medical conditions, we found that the patient had a lesion consistent with the diagnosis of encephalomalacia in her right parietal lobe and slight brain atrophy. Interventions: The patient was prescribed olanzapine (10 mg per day). Outcomes: Her symptoms significantly improved after antipsychotic treatment and were still well controlled 1 year later. Lessons: This case suggested that parietal encephalomalacia, which might be caused by inflammatory and infectious conditions in early life and be aggravated by undernutrition, might be implicated in the etiology of schizophrenia. PMID:28272261

  12. Abnormal hippocampal shape in offenders with psychopathy.

    PubMed

    Boccardi, Marina; Ganzola, Rossana; Rossi, Roberta; Sabattoli, Francesca; Laakso, Mikko P; Repo-Tiihonen, Eila; Vaurio, Olli; Könönen, Mervi; Aronen, Hannu J; Thompson, Paul M; Frisoni, Giovanni B; Tiihonen, Jari

    2010-03-01

    Posterior hippocampal volumes correlate negatively with the severity of psychopathy, but local morphological features are unknown. The aim of this study was to investigate hippocampal morphology in habitually violent offenders having psychopathy. Manual tracings of hippocampi from magnetic resonance images of 26 offenders (age: 32.5 +/- 8.4), with different degrees of psychopathy (12 high, 14 medium psychopathy based on the Psychopathy Checklist Revised), and 25 healthy controls (age: 34.6 +/- 10.8) were used for statistical modelling of local changes with a surface-based radial distance mapping method. Both offenders and controls had similar hippocampal volume and asymmetry ratios. Local analysis showed that the high psychopathy group had a significant depression along the longitudinal hippocampal axis, on both the dorsal and ventral aspects, when compared with the healthy controls and the medium psychopathy group. The opposite comparison revealed abnormal enlargement of the lateral borders in both the right and left hippocampi of both high and medium psychopathy groups versus controls, throughout CA1, CA2-3 and the subicular regions. These enlargement and reduction effects survived statistical correction for multiple comparisons in the main contrast (26 offenders vs. 25 controls) and in most subgroup comparisons. A statistical check excluded a possible confounding effect from amphetamine and polysubstance abuse. These results indicate that habitually violent offenders exhibit a specific abnormal hippocampal morphology, in the absence of total gray matter volume changes, that may relate to different autonomic modulation and abnormal fear-conditioning.

  13. Abnormal Activity Detection Using Pyroelectric Infrared Sensors.

    PubMed

    Luo, Xiaomu; Tan, Huoyuan; Guan, Qiuju; Liu, Tong; Zhuo, Hankz Hankui; Shen, Baihua

    2016-06-03

    Healthy aging is one of the most important social issues. In this paper, we propose a method for abnormal activity detection without any manual labeling of the training samples. By leveraging the Field of View (FOV) modulation, the spatio-temporal characteristic of human activity is encoded into low-dimension data stream generated by the ceiling-mounted Pyroelectric Infrared (PIR) sensors. The similarity between normal training samples are measured based on Kullback-Leibler (KL) divergence of each pair of them. The natural clustering of normal activities is discovered through a self-tuning spectral clustering algorithm with unsupervised model selection on the eigenvectors of a modified similarity matrix. Hidden Markov Models (HMMs) are employed to model each cluster of normal activities and form feature vectors. One-Class Support Vector Machines (OSVMs) are used to profile the normal activities and detect abnormal activities. To validate the efficacy of our method, we conducted experiments in real indoor environments. The encouraging results show that our method is able to detect abnormal activities given only the normal training samples, which aims to avoid the laborious and inconsistent data labeling process.

  14. Abnormal dynamics of language in schizophrenia.

    PubMed

    Stephane, Massoud; Kuskowski, Michael; Gundel, Jeanette

    2014-05-30

    Language could be conceptualized as a dynamic system that includes multiple interactive levels (sub-lexical, lexical, sentence, and discourse) and components (phonology, semantics, and syntax). In schizophrenia, abnormalities are observed at all language elements (levels and components) but the dynamic between these elements remains unclear. We hypothesize that the dynamics between language elements in schizophrenia is abnormal and explore how this dynamic is altered. We, first, investigated language elements with comparable procedures in patients and healthy controls. Second, using measures of reaction time, we performed multiple linear regression analyses to evaluate the inter-relationships among language elements and the effect of group on these relationships. Patients significantly differed from controls with respect to sub-lexical/lexical, lexical/sentence, and sentence/discourse regression coefficients. The intercepts of the regression slopes increased in the same order above (from lower to higher levels) in patients but not in controls. Regression coefficients between syntax and both sentence level and discourse level semantics did not differentiate patients from controls. This study indicates that the dynamics between language elements is abnormal in schizophrenia. In patients, top-down flow of linguistic information might be reduced, and the relationship between phonology and semantics but not between syntax and semantics appears to be altered.

  15. Abnormal Activity Detection Using Pyroelectric Infrared Sensors

    PubMed Central

    Luo, Xiaomu; Tan, Huoyuan; Guan, Qiuju; Liu, Tong; Zhuo, Hankz Hankui; Shen, Baihua

    2016-01-01

    Healthy aging is one of the most important social issues. In this paper, we propose a method for abnormal activity detection without any manual labeling of the training samples. By leveraging the Field of View (FOV) modulation, the spatio-temporal characteristic of human activity is encoded into low-dimension data stream generated by the ceiling-mounted Pyroelectric Infrared (PIR) sensors. The similarity between normal training samples are measured based on Kullback-Leibler (KL) divergence of each pair of them. The natural clustering of normal activities is discovered through a self-tuning spectral clustering algorithm with unsupervised model selection on the eigenvectors of a modified similarity matrix. Hidden Markov Models (HMMs) are employed to model each cluster of normal activities and form feature vectors. One-Class Support Vector Machines (OSVMs) are used to profile the normal activities and detect abnormal activities. To validate the efficacy of our method, we conducted experiments in real indoor environments. The encouraging results show that our method is able to detect abnormal activities given only the normal training samples, which aims to avoid the laborious and inconsistent data labeling process. PMID:27271632

  16. Abnormal asymmetry of brain connectivity in schizophrenia.

    PubMed

    Ribolsi, Michele; Daskalakis, Zafiris J; Siracusano, Alberto; Koch, Giacomo

    2014-01-01

    Recently, a growing body of data has revealed that beyond a dysfunction of connectivity among different brain areas in schizophrenia patients (SCZ), there is also an abnormal asymmetry of functional connectivity compared with healthy subjects. The loss of the cerebral torque and the abnormalities of gyrification, with an increased or more complex cortical folding in the right hemisphere may provide an anatomical basis for such aberrant connectivity in SCZ. Furthermore, diffusion tensor imaging studies have shown a significant reduction of leftward asymmetry in some key white-matter tracts in SCZ. In this paper, we review the studies that investigated both structural brain asymmetry and asymmetry of functional connectivity in healthy subjects and SCZ. From an analysis of the existing literature on this topic, we can hypothesize an overall generally attenuated asymmetry of functional connectivity in SCZ compared to healthy controls. Such attenuated asymmetry increases with the duration of the disease and correlates with psychotic symptoms. Finally, we hypothesize that structural deficits across the corpus callosum may contribute to the abnormal asymmetry of intra-hemispheric connectivity in schizophrenia.

  17. Chemical induction of sperm abnormalities in mice.

    PubMed Central

    Wyrobek, A J; Bruce, W R

    1975-01-01

    The sperm of (C57BL X C3H)F1 mice were examined 1, 4, and 10 weeks after a subacute treatment with one of 25 chemicals at two or more dose levels. The fraction of sperm that were abnormal in shape was elevated above control values of 1.2-3.4% for methyl methanesulfonate, ethyl methanesulfonate, griseofulvin, benzo[a]pyrene, METEPA [tris(2-methyl-l-aziridinyl)phosphine oxide], THIO-TEPA [tris(l-aziridinyl)phosphine sulfide], mitomycin C, myleran, vinblastine sulphate, hydroxyurea, 3-methylcholanthrene, colchicine, actinomycin D, imuran, cyclophosphamide, 5-iododeoxyuridine, dichlorvos, aminopterin, and trimethylphosphate. Dimethylnitrosamine, urethane, DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane], 1,1-dimethylhydrazine, caffeine, and calcium cyclamate did not induce elevated levels of sperm abnormalities. The results suggest that sperm abnormalities might provide a rapid inexpensive mammalian screen for agents that lead to errors in the differentiation of spermatogenic stem cells in vivo and thus indicate agents which might prove to be mutagenic, teratogenic, or carcinogenic. Images PMID:1060122

  18. Hematopoietic Stem Cell Expansion and Gene Therapy

    PubMed Central

    Watts, Korashon Lynn; Adair, Jennifer; Kiem, Hans-Peter

    2012-01-01

    Hematopoietic stem cell (HSC) gene therapy remains a highly attractive treatment option for many disorders including hematologic conditions, immunodeficiencies including HIV/AIDS, and other genetic disorders like lysosomal storage diseases, among others. In this review, we discuss the successes, side effects, and limitations of current gene therapy protocols. In addition, we describe the opportunities presented by implementing ex vivo expansion of gene-modified HSCs, as well as summarize the most promising ex vivo expansion techniques currently available. We conclude by discussing how some of the current limitations of HSC gene therapy could be overcome by combining novel HSC expansion strategies with gene therapy. PMID:21999373

  19. Concentric ring flywheel without expansion separators

    DOEpatents

    Kuklo, Thomas C.

    1999-01-01

    A concentric ring flywheel wherein the adjacent rings are configured to eliminate the need for differential expansion separators between the adjacent rings. This is accomplished by forming a circumferential step on an outer surface of an inner concentric ring and forming a matching circumferential step on the inner surface of an adjacent outer concentric ring. During operation the circumferential steps allow the rings to differentially expand due to the difference in the radius of the rings without the formation of gaps therebetween, thereby eliminating the need for expansion separators to take up the gaps formed by differential expansion.

  20. Concentric ring flywheel without expansion separators

    DOEpatents

    Kuklo, T.C.

    1999-08-24

    A concentric ring flywheel wherein the adjacent rings are configured to eliminate the need for differential expansion separators between the adjacent rings. This is accomplished by forming a circumferential step on an outer surface of an inner concentric ring and forming a matching circumferential step on the inner surface of an adjacent outer concentric ring. During operation the circumferential steps allow the rings to differentially expand due to the difference in the radius of the rings without the formation of gaps therebetween, thereby eliminating the need for expansion separators to take up the gaps formed by differential expansion. 3 figs.

  1. Thermal expansion properties of composite materials

    NASA Technical Reports Server (NTRS)

    Johnson, R. R.; Kural, M. H.; Mackey, G. B.

    1981-01-01

    Thermal expansion data for several composite materials, including generic epoxy resins, various graphite, boron, and glass fibers, and unidirectional and woven fabric composites in an epoxy matrix, were compiled. A discussion of the design, material, environmental, and fabrication properties affecting thermal expansion behavior is presented. Test methods and their accuracy are discussed. Analytical approaches to predict laminate coefficients of thermal expansion (CTE) based on lamination theory and micromechanics are also included. A discussion is included of methods of tuning a laminate to obtain a near-zero CTE for space applications.

  2. Abnormalities occurring during female gametophyte development result in the diversity of abnormal embryo sacs and leads to abnormal fertilization in indica/japonica hybrids in rice.

    PubMed

    Zeng, Yu-Xiang; Hu, Chao-Yue; Lu, Yong-Gen; Li, Jin-Quan; Liu, Xiang-Dong

    2009-01-01

    Embryo sac abortion is one of the major reasons for sterility in indica/japonica hybrids in rice. To clarify the causal mechanism of embryo sac abortion, we studied the female gametophyte development in two indica/japonica hybrids via an eosin B staining procedure for embryo sac scanning using confocal laser scanning microscope. Different types of abnormalities occurred during megasporogenesis and megagametogenesis were demonstrated. The earliest abnormality was observed in the megasporocyte. A lot of the chalazal-most megaspores were degenerated before the mono-nucleate embryo sac stage. Disordered positioning of nucleus and abnormal nucellus tissue were characteristics of the abnormal female gametes from the mono-nucleate to four-nucleate embryo sac stages. The abnormalities that occurred from the early stage of the eight-nucleate embryo sac development to the mature embryo sac stage were characterized by smaller sizes and wrinkled antipodals. Asynchronous nuclear migration, abnormal positioning of nucleus, and degeneration of egg apparatus were also found at the eight-nucleate embryo sac stage. The abnormalities that occurred during female gametophyte development resulted in five major types of abnormal embryo sacs. These abnormal embryo sacs led to abnormal fertilization. Hand pollination using normal pollens on the spikelets during anthesis showed that normal pollens could not exclude the effect of abnormal embryo sac on seed setting.

  3. Improvement of Expansive Soils Using Chemical Stabilizers

    NASA Astrophysics Data System (ADS)

    Ikizler, S. B.; Senol, A.; Khosrowshahi, S. K.; Hatipoğlu, M.

    2014-12-01

    The aim of this study is to investigate the effect of two chemical stabilizers on the swelling potential of expansive soil. A high plasticity sodium bentonite was used as the expansive soil. The additive materials including fly ash (FA) and lime (L) were evaluated as potential stabilizers to decrease the swelling pressure of bentonite. Depending on the type of additive materials, they were blended with bentonite in different percentages to assess the optimum state and approch the maximum swell pressure reduction. According to the results of swell pressure test, both fly ash and lime reduce the swelling potential of bentonite but the maximum improvement occurs using bentonite-lime mixture while the swelling pressure reduction approaches to 49%. The results reveal a significant reduction of swelling potential of expansive soil using chemical stabilizers. Keywords: Expansive soil; swell pressure; chemical stabilization; fly ash; lime

  4. Adapted polynomial chaos expansion for failure detection

    SciTech Connect

    Paffrath, M. Wever, U.

    2007-09-10

    In this paper, we consider two methods of computation of failure probabilities by adapted polynomial chaos expansions. The performance of the two methods is demonstrated by a predator-prey model and a chemical reaction problem.

  5. Adapted polynomial chaos expansion for failure detection

    NASA Astrophysics Data System (ADS)

    Paffrath, M.; Wever, U.

    2007-09-01

    In this paper, we consider two methods of computation of failure probabilities by adapted polynomial chaos expansions. The performance of the two methods is demonstrated by a predator-prey model and a chemical reaction problem.

  6. Low expansion superalloy with improved toughness

    DOEpatents

    Smith, Darrell F.; Stein, Larry I.; Hwang, Il S.

    1995-01-01

    A high strength, low coefficient of thermal expansion superalloy exhibiting improved toughness over a broad temperature range down to about 4.degree. K. The composition is adapted for use with wrought superconducting sheathing.

  7. The thermal expansion behavior of unalloyed plutonium

    SciTech Connect

    Schonfeld, F.W.; Tate, R.E.

    1996-09-01

    Information and data concerning the thermal expansion characteristics of the solid and liquid phases of unalloyed plutonium have been collected from published and unpublished sources and evaluated, and are presented to provide increased availability in compact form.

  8. Collisional and collisionless expansion of Yukawa balls.

    PubMed

    Piel, Alexander; Goree, John A

    2013-12-01

    The expansion of Yukawa balls is studied by means of molecular dynamics simulations of collisionless and collisional situations. High computation speed was achieved by using the parallel computing power of graphics processing units. When the radius of the Yukawa ball is large compared to the shielding length, the expansion process starts with the blow-off of the outermost layer. A rarefactive wave subsequently propagates radially inward at the speed of longitudinal phonons. This mechanism is fundamentally different from Coulomb explosions, which employ a self-similar expansion of the entire system. In the collisionless limit, the outer layers carry away most of the available energy. The simulations are compared with analytical estimates. In the collisional case, the expansion process can be described by a nonlinear diffusion equation that is a special case of the porous medium equation.

  9. Thermal Expansion of AuIn2

    SciTech Connect

    Saw, C K; Siekhaus, W J

    2004-07-12

    The thermal expansion of AuIn{sub 2} gold is of great interest in soldering technology. Indium containing solders have been used to make gold wire interconnects at low soldering temperature and over time, AuIn{sub 2} is formed between the gold wire and the solder due to the high heat of formation and the high inter-metallic diffusion of indium. Hence, the thermal expansion of AuIn{sub 2} alloy in comparison with that of the gold wire and the indium-containing solder is critical in determining the integrity of the connection. We present the results of x-ray diffraction measurement of the coefficient of linear expansion of AuIn{sub 2} as well as the bulk expansion and density changes over the temperature range of 30 to 500 C.

  10. Low expansion superalloy with improved toughness

    DOEpatents

    Smith, D.F.; Stein, L.I.; Hwang, I.S.

    1995-06-20

    A high strength, low coefficient of thermal expansion superalloy exhibiting improved toughness over a broad temperature range down to about 4 K is disclosed. The composition is adapted for use with wrought superconducting sheathing.

  11. Motor Abnormalities in Premanifest Persons with Huntington’s Disease: The PREDICT-HD Study

    PubMed Central

    Biglan, Kevin M.; Ross, Christopher A.; Langbehn, Douglas R.; Aylward, Elizabeth H.; Stout, Julie C.; Queller, Sarah; Carlozzi, Noelle E.; Duff, Kevin; Beglinger, Leigh J.; Paulsen, Jane S.

    2011-01-01

    Background The PREDICT-HD study seeks to identify clinical and biological markers of Huntington’s disease in premanifest individuals who have undergone predictive genetic testing. Methods We compared baseline motor data between gene-expansion carriers (cases) and non gene-expansion carriers (controls) using T-tests and Chi-Square. Cases were categorized as near, mid or far from diagnosis using a CAG-based formula. Striatal volumes were calculated using volumetric MRI measurements. Multiple linear regression associated total motor score, motor domains and individual motor items with estimated diagnosis and striatal volumes. Results Elevated total motor scores at baseline were associated with higher genetic probability of disease diagnosis in the near future (partial R2 0.14, p<0.0001) and smaller striatal volumes (partial R2 0.15, p<0.0001). Nearly all motor domain scores showed greater abnormality with increasing proximity to diagnosis, although bradykinesia and chorea were most highly associated with diagnostic immediacy. Among individual motor items, worse scores on finger tapping, tandem gait, Luria, saccade initiation, and chorea show unique association with diagnosis probability. Conclusions Even in this premanifest population subtle motor abnormalities were associated with a higher probability of disease diagnosis and smaller striatal volumes. Longitudinal assessment will help inform whether motor items will be useful measures in preventive clinical trials. PMID:19562761

  12. 78 FR 73208 - Underwriters Laboratories, Inc.: Application for Expansion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-05

    ... Occupational Safety and Health Administration Underwriters Laboratories, Inc.: Application for Expansion AGENCY... announces the application of Underwriters Laboratories, Inc., for expansion of its recognition as a... Application for Expansion The Occupational Safety and Health Administration (OSHA) is providing notice...

  13. Down's Syndrome and Leukemia: Mechanism of Additional Chromosomal Abnormalities

    ERIC Educational Resources Information Center

    And Others; Goh, Kong-oo

    1978-01-01

    Chromosomal abnormalities, some appearing in a stepwise clonal evoluation, were found in five Down's syndrome patients (35 weeks to 12 years old), four with acute leukemia and one with abnormal regulation of leukopoiesis. (Author/SBH)

  14. Atlas of computed body tomography: normal and abnormal anatomy

    SciTech Connect

    Chiu, L.C.; Schapiro, R.L.

    1980-01-01

    This atlas contains comparative sections on normal and abnormal computed tomography of the neck, chest, abdomen, pelvis, upper and lower limbs, fascia, and peritoneum. Also included is a subject index to aid in the identification of abnormal scans. (DLS)

  15. Novel brain MRI abnormalities in Gitelman syndrome

    PubMed Central

    Norbash, Alexander; Vattoth, Surjith

    2015-01-01

    Gitelman syndrome is an autosomal recessive renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. The syndrome is caused by a defective thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubules of the kidneys. Gitelman syndrome could be confused with Bartter syndrome; the main differentiating feature is the presence of low urinary calcium excretion in the former. Descriptions of neuroradiological imaging findings associated with Gitelman syndrome are very scarce in the literature and include basal ganglia calcification, idiopathic intracranial hypertension and sclerochoroidal calcification. Cauda equina syndrome-like presentation has been reported, but without any corresponding imaging findings on lumbar spine MRI. We report a 13-year-old male with Gitelman syndrome who presented with altered mental status following a fall and scalp laceration and unremarkable brain CT, followed during hospitalization by somnolence and seizures. Metabolically the patient demonstrated hypokalemia and hypomagnesemia. MRI demonstrated features of encephalopathy including predominantly right-sided cerebral hemispheric signal abnormality and cytotoxic edema, with bilateral symmetric involvement of the thalami, midbrain tegmentum and tectum and cerebellar dentate nuclei. MRI after five months obtained during a later episode of encephalopathy showed resolution of the signal abnormalities with setting in of brain atrophy and also areas of newly developed cytotoxic edema in the left thalamus, bilateral dorsal midbrain and right greater than left dentate nuclei. The described abnormalities, either recurrent or in isolation, have not previously been published in patients with Gitelman syndrome. We believe that the findings are due to alteration of respiratory chain function secondary to the metabolic derangement and hence have a similar imaging appearance as encephalopathy related to mitochondrial cytopathy or

  16. Neurological abnormalities in young adults born preterm

    PubMed Central

    Allin, M; Rooney, M; Griffiths, T; Cuddy, M; Wyatt, J; Rifkin, L; Murray, R

    2006-01-01

    Objective Individuals born before 33 weeks' gestation (very preterm, VPT) have an increased likelihood of neurological abnormality, impaired cognitive function, and reduced academic performance in childhood. It is currently not known whether neurological signs detected in VPT children persist into adulthood or become attenuated by maturation of the CNS. Method We assessed 153 VPT individuals and 71 term‐born controls at 17–18 years old, using a comprehensive neurological examination. This examination divides neurological signs into primary and integrative domains, the former representing the localising signs of classical neurology, and the latter representing signs requiring integration between different neural networks or systems. Integrative signs are sub‐divided into three groups: sensory integration, motor confusion, and sequencing. The VPT individuals have been followed up since birth, and neonatal information is available on them, along with the results of neurological assessment at 4 and 8 years of age and neuropsychological assessment at 18 years of age. Results The total neurology score and primary and integrative scores were significantly increased in VPT young adults compared to term‐born controls. Within the integrative domain, sensory integration and motor confusion scores were significantly increased in the VPT group, but sequencing was not significantly different between the VPT and term groups. Integrative neurological abnormalities at 18 were strongly associated with reduced IQ but primary abnormalities were not. Conclusions Neurological signs are increased in VPT adults compared to term‐born controls, and are strongly associated with reduced neuropsychological function. PMID:16543529

  17. Structural Pituitary Abnormalities Associated With CHARGE Syndrome

    PubMed Central

    Gregory, Louise C.; Gevers, Evelien F.; Baker, Joanne; Kasia, Tessa; Chong, Kling; Josifova, Dragana J.; Caimari, Maria; Bilan, Frederic; McCabe, Mark J.

    2013-01-01

    Introduction: CHARGE syndrome is a multisystem disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypoplasia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients. Objective: The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in septo-optic dysplasia /hypopituitarism. Methods: We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with septo-optic dysplasia/hypopituitarism. Results: EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 that were novel and undetected in control cohorts or in the international database of CHARGE patients, but were also present in their unaffected mothers. No CHD7 variants were detected in the patients with septo-optic dysplasia/hypopituitarism without additional CHARGE features. Conclusion: We report a novel association between CHARGE syndrome and structural abnormalities of the pituitary gland in 2 patients with variations in CHD7 that are of unknown significance. However, CHD7 mutations are an uncommon cause of septo-optic dysplasia or hypopituitarism. Our data suggest the need for evaluation of pituitary function/anatomy in patients with CHARGE syndrome. PMID:23526466

  18. Hereditary sideroblastic anemia with associated platelet abnormalities.

    PubMed

    Soslau, G; Brodsky, I

    1989-12-01

    A 62 year old male (R.H.) presented with a mild anemia (Hb 11-12 gm%) and a history of multiple hemorrhagic episodes. The marrow had 40-50% sideroblasts. Marrow chromosomes were normal. His wife was hematologically normal, while one daughter, age 30 years, had a sideroblastic anemia (Hb 11-12 gm%) with 40-50% sideroblasts in the marrow. Her anemia was first noted at age 15 years. Administration of vitamin B6 did not correct the anemia in either the father or daughter. Platelet abnormalities inherited jointly with this disorder are described for the first time. Both R.H. and his daughter had prolonged bleeding times, with normal PTT, PT times, fVIII:C, fVIII:Ag levels, and vWF multimers, which may rule out a von Willebrand's disease. They have normal platelet numbers but abnormally low platelet adhesiveness and greatly depressed ADP, collagen, and epinephrine responsiveness. Response to ristocetin was in the low normal range, and aggregation with thrombin was normal. While desmopressin completely normalized R.H.'s bleeding time, none of these platelet parameters were improved. No differences in the SDS PAGE protein patterns of RH platelets could be detected in comparison to normal samples. His platelets took up and released serotonin (5HT) normally, and electron micrographs defined no morphological abnormalities. However, no ATP was released from platelets activated with collagen, and when followed by thrombin about fourfold greater ATP was released by control platelets as compared to RH platelets. The dense granule fraction derived from RH platelets contained about 20% the level of ATP, 40% the level of ADP, and 50% the level of 5HT detected in a normal sample. The results indicate that the bleeding disorder is related to a non-classical heritable storage pool defect. The connection between the inherited sideroblastic anemia and platelet defects is obscure.

  19. [Abnormal daytime drowsiness--attempt at typology].

    PubMed

    Meier-Ewert, K

    1991-11-01

    Abnormal drowsiness during the day is defined on the basis of three criteria: 1. subjective feeling of increased tiredness, 2. objective observation of attacks of falling asleep, 3. detection of premature falling asleep in the multiple sleep latency test. About 3 to 4% of the population of modern industrial countries complain of this symptom which very quickly leads to inability to work in numerous occupations (driving instructors, lorry drivers, airline pilots). In many cases, the symptoms can be eliminated by effective methods of treatment. Early diagnosis and therapy is hence an important task of physicians. Clinically suitable tools and methods of measurement for appraising the phenomena are at present: 1. the multiple sleep latency test (Richardson et al., 1978), 2. the multiple staying awake test (Mitler et al., 1982), 3. the vigilance test according to Quatember and Maly from the Vienna test system. In neurophysiological terms, an attempt is made to differentiate between: REM drowsiness, non-REM drowsiness, hypofunction of the arousal systems of the reticular formation, and hyperfunction and overstimulation of the arousal systems of the reticular formation (over-aroused tiredness). Approaches to a clinical typology of abnormal drowsiness are available from two points of departure: 1. Forms of permanent somnolence which are not alleviated but intensified by a brief restorative sleep and resemble the 'oversleeping syndrome' of the healthy individual. 2. Attacks of imperative falling asleep in narcoleptic patients. The characteristic of this form of abnormal drowsiness during the day is that in the interval between the attacks of falling asleep patients can take on any healthy person with regard to alertness, reaction capacity and ready wit. After a brief restorative sleep of less than 5 min., they immediately feel fresh, alert and fit again.

  20. Chromosome abnormalities in primary ovarian cancer

    SciTech Connect

    Yonescu, R.; Currie, J.; Griffin, C.A.

    1994-09-01

    Chromosome abnormalities that are specific and recurrent may occur in regions of the genome that are involved in the conversion of normal cells to those with tumorigenic potential. Ovarian cancer is the primary cause of death among patients with gynecological malignancies. We have performed cytogenetic analysis of 16 ovarian tumors from women age 28-82. Three tumors of low malignant potential and three granulosa cell tumors had normal karyotypes. To look for the presence of trisomy 12, which has been suggested to be a common aberration in this group of tumors, interphase fluorescence in situ hybridization was performed on direct preparations from three of these tumors using a probe for alpha satellite sequences of chromosome 12. In the 3 preparations, 92-98 percent of the cells contained two copies of chromosome 12, indicating that trisomy 12 is not a universal finding in low grade ovarian tumors. Endometrioid carcinoma of the ovary is histologically indistinguishable from endometial carcinoma of the uterus. We studied 10 endometrioid tumors to determine the degree of genetic similarity between these two carcinomas. Six out of ten endometrioid tumors showed a near-triploid modal number, and one presented with a tetraploid modal number. Eight of the ten contained structural chromosome abnormalities, of which the most frequent were 1p- (5 tumors), 19q+ (3 tumors), 6q- or ins(6) (4 tumors), 3q- or 3q+ (4 tumors). These cytogenetic results resemble those reported for papillary ovarian tumors and differ from those of endometrial carcinoma of the uterus. We conclude that despite the histologic similarities between the endometrioid and endometrial carcinomas, the genetic abnormalities in the genesis of these tumors differ significantly.

  1. Unusual and abnormal canine estrous cycles.

    PubMed

    Meyers-Wallen, V N

    2007-12-01

    Preovulatory serum progesterone concentrations are used to estimate the day of LH peak (day 0), not only to accurately time insemination and predict parturition, but to identify abnormal or unusual estrous cycles due to ovarian dysfunction. Early identification of these disorders is of therapeutic and economic importance. This review discusses anovulation, slow preovulatory progesterone rise, "split heat", insufficient luteal phase, and persistent estrus in the bitch. Some of these were temporary dysfunctions; with appropriate breeding management, pregnancy can be achieved. However, in other cases, these were signs of severe, permanent ovarian dysfunction associated with infertility, with potentially lethal sequelae.

  2. Cranial computed tomographic abnormalities in leptomeningeal metastasis

    SciTech Connect

    Lee, Y.Y.; Glass, J.P.; Geoffray, A.; Wallace, S.

    1984-11-01

    Sixty-four (57.6%) of 111 cancer patients with cerebrospinal fluid cytology positive for malignant cells had cranial computed tomographic (CT) scans within 2 weeks before or after a lumbar puncture. Twenty-two (34.3%) of the 64 had abnormal CT findings indicative of leptomeningeal metastasis. Thirteen (59.6%) of these 22 patients had associated parenchymal metastases. Recognition of leptomeningeal disease may alter the management of patients with parenchymal metastases. Communicating hydrocephalus in cancer patients should be considered to be related to leptomeningeal metastasis until proven otherwise.

  3. Negative thermal expansion materials: technological key for control of thermal expansion

    PubMed Central

    Takenaka, Koshi

    2012-01-01

    Most materials expand upon heating. However, although rare, some materials contract upon heating. Such negative thermal expansion (NTE) materials have enormous industrial merit because they can control the thermal expansion of materials. Recent progress in materials research enables us to obtain materials exhibiting negative coefficients of linear thermal expansion over −30 ppm K−1. Such giant NTE is opening a new phase of control of thermal expansion in composites. Specifically examining practical aspects, this review briefly summarizes materials and mechanisms of NTE as well as composites containing NTE materials, based mainly on activities of the last decade. PMID:27877465

  4. Thermal expansion and thermal expansion anisotropy of SiC polytypes

    NASA Technical Reports Server (NTRS)

    Li, Z.; Bradt, R. C.

    1987-01-01

    The principal axial coefficients of thermal expansion for the (3C), (4H), and (6H) polytypes of SiC are considered to identify the structural role of the stacking layer sequence as it affects the thermal expansion. A general equation based on the fractions of cubic and hexagonal layer stacking is developed that expresses the principal axial thermal expansion coefficients of all of the SiC polytypes. It is then applied to address the thermal expansion anisotropy of the noncubic SiC structures.

  5. Negative thermal expansion materials: technological key for control of thermal expansion.

    PubMed

    Takenaka, Koshi

    2012-02-01

    Most materials expand upon heating. However, although rare, some materials contract upon heating. Such negative thermal expansion (NTE) materials have enormous industrial merit because they can control the thermal expansion of materials. Recent progress in materials research enables us to obtain materials exhibiting negative coefficients of linear thermal expansion over -30 ppm K(-1). Such giant NTE is opening a new phase of control of thermal expansion in composites. Specifically examining practical aspects, this review briefly summarizes materials and mechanisms of NTE as well as composites containing NTE materials, based mainly on activities of the last decade.

  6. Abnormal Splicing of NEDD4 in Myotonic Dystrophy Type 2

    PubMed Central

    Screen, Mark; Jonson, Per Harald; Raheem, Olayinka; Palmio, Johanna; Laaksonen, Reijo; Lehtimäki, Terho; Sirito, Mario; Krahe, Ralf; Hackman, Peter; Udd, Bjarne

    2015-01-01

    Myotonic dystrophy type 2 (DM2) is a multisystemic disorder caused by a (CCTG)n repeat expansion in intron 1 of CNBP. Transcription of the repeats causes a toxic RNA gain of function involving their accumulation in ribonuclear foci. This leads to sequestration of splicing factors and alters pre-mRNA splicing in a range of downstream effector genes, which is thought to contribute to the diverse DM2 clinical features. Hyperlipidemia is frequent in DM2 patients, but the treatment is problematic because of an increased risk of statin-induced adverse reactions. Hypothesizing that shared pathways lead to the increased risk, we compared the skeletal muscle expression profiles of DM2 patients and controls with patients with hyperlipidemia on statin therapy. Neural precursor cell expressed, developmentally downregulated-4 (NEDD4), an ubiquitin ligase, was one of the dysregulated genes identified in DM2 patients and patients with statin-treated hyperlipidemia. In DM2 muscle, NEDD4 mRNA was abnormally spliced, leading to aberrant NEDD4 proteins. NEDD4 was down-regulated in persons taking statins, and simvastatin treatment of C2C12 cells suppressed NEDD4 transcription. Phosphatase and tensin homologue (PTEN), an established NEDD4 target, was increased and accumulated in highly atrophic DM2 muscle fibers. PTEN ubiquitination was reduced in DM2 myofibers, suggesting that the NEDD4-PTEN pathway is dysregulated in DM2 skeletal muscle. Thus, this pathway may contribute to the increased risk of statin-adverse reactions in patients with DM2. PMID:24907641

  7. Genetic abnormality of the visual pathways in a "white" tiger.

    PubMed

    Guillery, R W; Kaas, J H

    1973-06-22

    "White"tigers show an inherited reduction of pigment, produced by an autosomal recessive gene. The brain of one of these tigers shows an abnormality of the visual pathways similar to abnormalities that are associated with albinism in many other mammals. There is a close relationship between the reduced pigment formation, the pathway abnormality, and strabismus.

  8. Abnormal Behavior in Relation to Cage Size in Rhesus Monkeys

    ERIC Educational Resources Information Center

    Paulk, H. H.; And Others

    1977-01-01

    Examines the effects of cage size on stereotyped and normal locomotion and on other abnormal behaviors in singly caged animals, whether observed abnormal behaviors tend to co-occur, and if the development of an abnormal behavior repertoire leads to reduction in the number of normal behavior categories. (Author/RK)

  9. Lipid abnormalities in patients with Rheumatoid Arthritis

    PubMed Central

    Erum, Uzma; Ahsan, Tasnim; Khowaja, Danish

    2017-01-01

    Objective: To determine the frequency of dyslipidemia in patients with Rheumatoid Arthritis. Methods: This is a prospective, cross-sectional, observational study, conducted at the ‘Rheumatology Clinic’ of Jinnah Postgraduate Medical Center (JPMC), Karachi, from November 2013 to May 2014. A total of 200 patients of Rheumatoid Arthritis (RA), diagnosed according to the ACR/EULAR criteria 2010, were included in the study. Laboratory investigations including creatinine, ALT, CBC, TSH and fasting lipid profile (LDL, HDL, and Total cholesterol) were done for all patients. Results: Out of 200 patients, 23 (11.5%) were male and 177 (88.5%) were female. The mean age was 36.31±10.46 years and the mean duration of disease was 3.82±3.03 years. A total of 107 (53.5%) patients had dyslipidemia, and the commonest abnormality was a low HDL, seen in 83 (41.5 %) patients. Conclusion: Dyslipidemia was frequently observed in Rheumatoid Arthritis. This may be considered as a secondary impact of chronic inflammatory state, seen in RA. Lipid abnormalities should be sought at regular intervals, and corrective actions taken to mitigate increased cardiovascular disease risk. PMID:28367205

  10. Acquired and congenital coronary artery abnormalities.

    PubMed

    Young, Ming-Lon; McLeary, Michael; Chan, Kak-Chen

    2017-01-01

    Sudden unexpected cardiac deaths in approximately 20% of young athletes are due to acquired or congenital coronary artery abnormalities. Kawasaki disease is the leading cause for acquired coronary artery abnormalities, which can cause late coronary artery sequelae including aneurysms, stenosis, and thrombosis, leading to myocardial ischaemia and ventricular fibrillation. Patients with anomalous left coronary artery from the pulmonary artery can develop adequate collateral circulation from the right coronary artery in the newborn period, which remains asymptomatic only to manifest in adulthood with myocardial ischaemia, ventricular arrhythmias, and sudden death. Anomalous origin of coronary artery from the opposite sinus occurs in 0.7% of the young general population aged between 11 and 15 years. If the anomalous coronary artery courses between the pulmonary artery and the aorta, sudden cardiac death may occur during or shortly after vigorous exercise, especially in patients where the anomalous left coronary artery originates from the right sinus of Valsalva. Symptomatic patients with evidence of ischaemia should have surgical correction. No treatment is needed for asymptomatic patients with an anomalous right coronary artery from the left sinus of Valsalva. At present, there is no consensus regarding how to manage asymptomatic patients with anomalous left coronary artery from the right sinus of Valsalva and interarterial course. Myocardial bridging is commonly observed in cardiac catheterisation and it rarely causes exercise-induced coronary syndrome or cardiac death. In symptomatic patients, refractory or β-blocker treatment and surgical un-bridging may be considered.

  11. Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders.

    PubMed

    Calogero, A E; Giagulli, V A; Mongioì, L M; Triggiani, V; Radicioni, A F; Jannini, E A; Pasquali, D

    2017-03-03

    Klinefelter syndrome (KS) is one of the most common genetic causes of male infertility. This condition is associated with much comorbidity and with a lower life expectancy. The aim of this review is to explore more in depth cardiovascular and metabolic disorders associated to KS. KS patients have an increased risk of cerebrovascular disease (standardized mortality ratio, SMR, 2.2; 95% confidence interval, CI, 1.6-3.0), but it is not clear whether the cause of the death is of thrombotic or hemorrhagic nature. Cardiovascular congenital anomalies (SMR, 7.3; 95% CI, 2.4-17.1) and the development of thrombosis or leg ulcers (SMR, 7.9; 95% CI, 2.9-17.2) are also more frequent in these subjects. Moreover, cardiovascular abnormalities may be at least partially reversed by testosterone replacement therapy (TRT). KS patients have also an increased probability of endocrine and/or metabolic disease, especially obesity, metabolic syndrome and type 2 diabetes mellitus. The effects of TRT on these abnormalities are not entirely clear.

  12. Control of Abnormal Synchronization in Neurological Disorders

    PubMed Central

    Popovych, Oleksandr V.; Tass, Peter A.

    2014-01-01

    In the nervous system, synchronization processes play an important role, e.g., in the context of information processing and motor control. However, pathological, excessive synchronization may strongly impair brain function and is a hallmark of several neurological disorders. This focused review addresses the question of how an abnormal neuronal synchronization can specifically be counteracted by invasive and non-invasive brain stimulation as, for instance, by deep brain stimulation for the treatment of Parkinson’s disease, or by acoustic stimulation for the treatment of tinnitus. On the example of coordinated reset (CR) neuromodulation, we illustrate how insights into the dynamics of complex systems contribute to successful model-based approaches, which use methods from synergetics, non-linear dynamics, and statistical physics, for the development of novel therapies for normalization of brain function and synaptic connectivity. Based on the intrinsic multistability of the neuronal populations induced by spike timing-dependent plasticity (STDP), CR neuromodulation utilizes the mutual interdependence between synaptic connectivity and dynamics of the neuronal networks in order to restore more physiological patterns of connectivity via desynchronization of neuronal activity. The very goal is to shift the neuronal population by stimulation from an abnormally coupled and synchronized state to a desynchronized regime with normalized synaptic connectivity, which significantly outlasts the stimulation cessation, so that long-lasting therapeutic effects can be achieved. PMID:25566174

  13. Skeleton-Based Abnormal Gait Detection.

    PubMed

    Nguyen, Trong-Nguyen; Huynh, Huu-Hung; Meunier, Jean

    2016-10-26

    Human gait analysis plays an important role in musculoskeletal disorder diagnosis. Detecting anomalies in human walking, such as shuffling gait, stiff leg or unsteady gait, can be difficult if the prior knowledge of such a gait pattern is not available. We propose an approach for detecting abnormal human gait based on a normal gait model. Instead of employing the color image, silhouette, or spatio-temporal volume, our model is created based on human joint positions (skeleton) in time series. We decompose each sequence of normal gait images into gait cycles. Each human instant posture is represented by a feature vector which describes relationships between pairs of bone joints located in the lower body. Such vectors are then converted into codewords using a clustering technique. The normal human gait model is created based on multiple sequences of codewords corresponding to different gait cycles. In the detection stage, a gait cycle with normality likelihood below a threshold, which is determined automatically in the training step, is assumed as an anomaly. The experimental results on both marker-based mocap data and Kinect skeleton show that our method is very promising in distinguishing normal and abnormal gaits with an overall accuracy of 90.12%.

  14. Skeleton-Based Abnormal Gait Detection

    PubMed Central

    Nguyen, Trong-Nguyen; Huynh, Huu-Hung; Meunier, Jean

    2016-01-01

    Human gait analysis plays an important role in musculoskeletal disorder diagnosis. Detecting anomalies in human walking, such as shuffling gait, stiff leg or unsteady gait, can be difficult if the prior knowledge of such a gait pattern is not available. We propose an approach for detecting abnormal human gait based on a normal gait model. Instead of employing the color image, silhouette, or spatio-temporal volume, our model is created based on human joint positions (skeleton) in time series. We decompose each sequence of normal gait images into gait cycles. Each human instant posture is represented by a feature vector which describes relationships between pairs of bone joints located in the lower body. Such vectors are then converted into codewords using a clustering technique. The normal human gait model is created based on multiple sequences of codewords corresponding to different gait cycles. In the detection stage, a gait cycle with normality likelihood below a threshold, which is determined automatically in the training step, is assumed as an anomaly. The experimental results on both marker-based mocap data and Kinect skeleton show that our method is very promising in distinguishing normal and abnormal gaits with an overall accuracy of 90.12%. PMID:27792181

  15. Abnormal mandibular growth and the condylar cartilage.

    PubMed

    Pirttiniemi, Pertti; Peltomäki, Timo; Müller, Lukas; Luder, Hans U

    2009-02-01

    Deviations in the growth of the mandibular condyle can affect both the functional occlusion and the aesthetic appearance of the face. The reasons for these growth deviations are numerous and often entail complex sequences of malfunction at the cellular level. The aim of this review is to summarize recent progress in the understanding of pathological alterations occurring during childhood and adolescence that affect the temporomandibular joint (TMJ) and, hence, result in disorders of mandibular growth. Pathological conditions taken into account are subdivided into (1) congenital malformations with associated growth disorders, (2) primary growth disorders, and (3) acquired diseases or trauma with associated growth disorders. Among the congenital malformations, hemifacial microsomia (HFM) appears to be the principal syndrome entailing severe growth disturbances, whereas growth abnormalities occurring in conjunction with other craniofacial dysplasias seem far less prominent than could be anticipated based on their often disfiguring nature. Hemimandibular hyperplasia and elongation undoubtedly constitute the most obscure conditions that are associated with prominent, often unilateral, abnormalities of condylar, and mandibular growth. Finally, disturbances of mandibular growth as a result of juvenile idiopathic arthritis (JIA) and condylar fractures seem to be direct consequences of inflammatory and/or mechanical damage to the condylar cartilage.

  16. DNA methylation abnormalities in congenital heart disease.

    PubMed

    Serra-Juhé, Clara; Cuscó, Ivon; Homs, Aïda; Flores, Raquel; Torán, Núria; Pérez-Jurado, Luis A

    2015-01-01

    Congenital heart defects represent the most common malformation at birth, occurring also in ∼50% of individuals with Down syndrome. Congenital heart defects are thought to have multifactorial etiology, but the main causes are largely unknown. We have explored the global methylation profile of fetal heart DNA in comparison to blood DNA from control subjects: an absolute correlation with the type of tissue was detected. Pathway analysis revealed a significant enrichment of differential methylation at genes related to muscle contraction and cardiomyopathies in the developing heart DNA. We have also searched for abnormal methylation profiles on developing heart-tissue DNA of syndromic and non-syndromic congenital heart defects. On average, 3 regions with aberrant methylation were detected per sample and 18 regions were found differentially methylated between groups. Several epimutations were detected in candidate genes involved in growth regulation, apoptosis and folate pathway. A likely pathogenic hypermethylation of several intragenic sites at the MSX1 gene, involved in outflow tract morphogenesis, was found in a fetus with isolated heart malformation. In addition, hypermethylation of the GATA4 gene was present in fetuses with Down syndrome with or without congenital heart defects, as well as in fetuses with isolated heart malformations. Expression deregulation of the abnormally methylated genes was detected. Our data indicate that epigenetic alterations of relevant genes are present in developing heart DNA in fetuses with both isolated and syndromic heart malformations. These epimutations likely contribute to the pathogenesis of the malformation by cis-acting effects on gene expression.

  17. Abnormal appearances: inspection, display and the clinic.

    PubMed

    Featherstone, Katie; Atkinson, Paul

    2014-01-01

    We provide an examination of the field of dysmorphology, a clinical speciality that in its current form combines a long history of inspection and display with the identification and representation of associated underlying molecular changes. The recognition and description of abnormal appearances is thus increasingly accompanied by genetic and other molecular investigations. Our analysis draws on our long-term ethnographic engagement with a UK clinical genetics service and the work of two clinical genetics teams within a regional teaching hospital. We document the intersection of genetic science with clinical work to suggest that while molecular testing often identifies the genetic basis for unusual appearances and abnormal development, it does not fully supplant clinical apperception and interpretation. The two modes of knowledge--the clinical and the biomedical--co-exist in the work and the discourse of dysmorphology practice. The contemporary dysmorphology clinic thus encapsulates the epistemological systems of modern medicine, grounded in the clinical gaze and on the classificatory systems of classic nosology. Within such a system of clinical knowledge, the 'monstrous' does not escape the boundaries of knowledge. Monstrous appearances are accommodated and domesticated within the classificatory systems of normal medicine.

  18. Native fluorescence characterization of human liver abnormalities

    NASA Astrophysics Data System (ADS)

    Ganesan, Singaravelu; Madhuri, S.; Aruna, Prakasa R.; Suchitra, S.; Srinivasan, T. G.

    1999-05-01

    Fluorescence spectroscopy of intrinsic biomolecules has been extensively used in biology and medicine for the past several decades. In the present study, we report the native fluorescence characteristics of blood plasma from normal human subjects and patients with different liver abnormalities such as hepatitis, leptospirosis, jaundice, cirrhosis and liver cell failure. Native fluorescence spectra of blood plasma -- acetone extract were measured at 405 nm excitation. The average spectrum of normal blood plasma has a prominent emission peak around 464 nm whereas in the case of liver diseased subjects, the primary peak is red shifted with respect to normal. In addition, liver diseased cases show distinct secondary emission peak around 615 nm, which may be attributed to the presence of endogenous porphyrins. The red shift of the prominent emission peak with respect to normal is found to be maximum for hepatitis and minimum for cirrhosis whereas the secondary emission peak around 615 nm was found to be more prominent in the case of cirrhosis than the rest. The ratio parameter I465/I615 is found to be statistically significant (p less than 0.001) in discriminating liver abnormalities from normal.

  19. Chromosomal abnormalities associated with cyclopia and synophthalmia.

    PubMed Central

    Howard, R O

    1977-01-01

    At the present time, essentially all known facts concerning cyclopia are consistent with some chromosomal disease, including clinical features of the pregnancy (fetal wastage, prematurity, intrauterine growth retardation, maternal age factor, complications of pregnancy), the generalized developmental abnormalities, specific ocular dysgenesis, by the high incidence of chromosomal abnormality already demonstrated, and the possibility of error in those cases of cyclopia with normal chromosomes. Even if chromosomal aberrations represent only one group of several different etiologic factors leading to cyclopia, at the present time chromosomal errors would seem to be the most common cause of cyclopia now recognized. Further studies will establish or disprove a chromosomal error in those instances which are now considered to be the result of an environmental factor alone or those with apparent familial patterns of inheritance. This apparent diverse origin of cyclopia can be clarified if future cyclopic specimens are carefully investigated. The evaluation should include a careful gross and microscopic examination of all organs, including the eye, and chromosome banding studies of all organs, including the eye, and chromosome banding studies of at least two cyclopic tissues. Then the presence or absence of multiple causative factors can be better evaluated. Images FIGURE 2 A FIGURE 2 B FIGURE 1 A FIGURE 1 B FIGURE 1 C FIGURE 1 D FIGURE 1 E FIGURE 1 F FIGURE 3 A FIGURE 3 B FIGURE 4 A FIGURE 4 B FIGURE 4 C FIGURE 4 D FIGURE 5 FIGURE 6 FIGURE 7 A FIGURE 7 B PMID:418547

  20. Protruding labia minora: abnormal or just uncool?

    PubMed

    Michala, Lina; Koliantzaki, Sofia; Antsaklis, Aris

    2011-09-01

    There is a wide variety in the appearance of normal female external genitalia. Nevertheless a specific prototype is promoted by the media, leading to a false sense that all other appearances are abnormal. As adolescents become sexually aware at an earlier age, most of them are worried about the appearance of their genitalia, especially when labia minora protrude beyond labia majora. This is a prospective audit of adolescents presenting for assessment of their perceived abnormal genitalia. Sixteen girls aged 10.2 to 17.8 years presented between June 2009 and December 2010 to a specialist adolescent gynecology service. Their mean labial width was 36 mm (range: 20-55 mm). In six girls, the reason for attending the service was inequality of the size of labia ranging between 6 mm and 35 mm (mean of 20 mm). Among the remaining 10 girls, the concern had arisen through comparison with a prepubescent sibling (one case), change of genitalia during puberty (four cases), looking at internet pictures (four cases), and looking at an anatomy book (one case). Risks of Female Genital Cosmetic Surgery (FGCS) have not been adequately documented, especially with regards to sexual function and long-term patient satisfaction. External genitalia are likely to change during puberty and therefore, any genital operation in the absence of clear pathology should be deferred until adulthood. Even then, women should have clear expectations of what will be achieved with the operation in terms of appearance and function.

  1. Effects of restraint on expansion due to delayed ettringite formation

    SciTech Connect

    Bouzabata, Hassina; Multon, Stephane; Sellier, Alain; Houari, Hacene

    2012-07-15

    Delayed ettringite formation (DEF) is a chemical reaction that causes expansion in civil engineering structures. The safety level of such damaged structures has to be reassessed. To do this, the mechanical conditions acting on DEF expansions have to be analysed and, in particular, the variation of strength with expansion and the effect of restraint on the DEF expansion. This paper highlights several points: DEF expansion is isotropic in stress-free conditions, compressive stresses decrease DEF expansion in the direction subjected to restraint and lead to cracks parallel to the restraint, and expansion measured in the stress-free direction of restrained specimens is not modified. Thus restraint causes a decrease of the volumetric expansion and DEF expansion under restraint is anisotropic. Moreover, the paper examines the correlation between DEF expansion and concrete damage, providing data that can be used for the quantification of the effect of stresses on DEF induced expansion.

  2. Changes in intracranial pressure after calvarial expansion surgery in children with slit ventricle syndrome.

    PubMed

    Eide, P K; Helseth, E; Due-Tønnessen, B; Lundar, T

    2001-10-01

    The effect of calvarial expansion on symptom relief and intracranial pressure (ICP) in three children with slit ventricle syndrome (SVS) and intracranial hypertension despite a functioning ventricular shunt is reported. These children presented with a clinical picture of SVS, accompanied by slit-like ventricles on cranial computer tomography scan and intracranial hypertension. Calvarial expansion was performed by mans of an anterior approach in one case and a posterior approach (modified tiara plastic) in the other two cases. After calvarial expansion, symptoms of intracranial hypertension were abolished in one case and markedly reduced in two cases (observation period 25-36 months). Comparison of ICP before and after surgery was performed by means of new software (Sensometrics Pressure Analyser, version 1.2) that revealed a significant reduction in the number of abnormal ICP elevations after surgery. The results were not accompanied by changes in the size of the cerebral ventricles. This study demonstrates that in children with SVS and intracranial hypertension despite a functioning shunt, calvarial expansion may reduce ICP and produce long-lasting symptom relief. In these cases, we suggest that intracranial hypertension was caused by compromised intracranial volume.

  3. Structure and thermal expansion of the tungsten bronze Pb₂KNb₅O₁₅.

    PubMed

    Lin, Kun; Wu, Hui; Wang, Fangfang; Rong, Yangchun; Chen, Jun; Deng, Jinxia; Yu, Ranbo; Fang, Liang; Huang, Qingzhen; Xing, Xianran

    2014-05-21

    The structure and thermal expansion behavior of the tetragonal tungsten bronze oxide Pb2KNb5O15 were investigated by neutron powder diffraction and high-temperature X-ray diffraction. Below the Curie temperature, T(C) (orthorhombic phase, T(C) ≈ 460 °C), the cell parameters a and c increase with temperature, while b decreases. The thermal expansion coefficients are α(a) = 1.29 × 10(-5) °C(-1), α(b) = -1.56 × 10(-5) °C(-1), and α(c) = 1.62 × 10(-5) °C(-1). Temperature-dependent second harmonic generation (SHG), dielectric, and polarization-electrical field (P-E) hysteresis loop measurements were performed to study the symmetry and electric properties. We show that the distortion and cooperative rotation of NbO6 octahedrons are directly responsible for the negative thermal expansion coefficient along the polar b axis. It is suggested that Pb-O covalency, especially in the large and asymmetric pentagonal prisms, may be related to orthorhombic distortion and abnormal spontaneous polarization along the b axis. This study shows that tungsten bronze families are possible candidates for exploring negative thermal expansion materials.

  4. PABPN1 polyalanine tract deletion and long expansions modify its aggregation pattern and expression

    SciTech Connect

    Klein, Arnaud F.; Ebihara, Mitsuru; Alexander, Christine; Dicaire, Marie-Josee; Sasseville, A. Marie-Josee; Langelier, Yves; Rouleau, Guy A.; Brais, Bernard

    2008-05-01

    Expansions of a (GCN){sub 10}/polyalanine tract in the Poly(A) Binding Protein Nuclear 1 (PABPN1) cause autosomal dominant oculopharyngeal muscular dystrophy (OPMD). In OPMD muscles, as in models, PABPN1 accumulates in intranuclear inclusions (INIs) whereas in other diseases caused by similar polyalanine expansions, the mutated proteins have been shown to abnormally accumulate in the cytoplasm. This study presents the impact on the subcellular localization of PABPN1 produced by large expansions or deletion of its polyalanine tract. Large tracts of more than 24 alanines result in the nuclear accumulation of PABPN1 in SFRS2-positive functional speckles and a significant decline in cell survival. These large expansions do not cause INIs formation nor do they lead to cytoplasmic accumulation. Deletion of the polyalanine tract induces the formation of aggregates that are located on either side and cross the nuclear membrane, highlighting the possible role of the N-terminal polyalanine tract in PABPN1 nucleo-cytoplasmic transport. We also show that even though five other proteins with polyalanine tracts tend to aggregate when over-expressed they do not co-aggregate with PABPN1 INIs. This study presents the first experimental evidence that there may be a relative loss of function in OPMD by decreasing the availability of PABPN1 through an INI-independent mechanism.

  5. The $\\hbar$ Expansion in Quantum Field Theory

    SciTech Connect

    Brodsky, Stanley J.; Hoyer, Paul; /Southern Denmark U., CP3-Origins /Helsinki U. /Helsinki Inst. of Phys.

    2010-10-27

    We show how expansions in powers of Planck's constant {h_bar} = h = 2{pi} can give new insights into perturbative and nonperturbative properties of quantum field theories. Since {h_bar} is a fundamental parameter, exact Lorentz invariance and gauge invariance are maintained at each order of the expansion. The physics of the {h_bar} expansion depends on the scheme; i.e., different expansions are obtained depending on which quantities (momenta, couplings and masses) are assumed to be independent of {h_bar}. We show that if the coupling and mass parameters appearing in the Lagrangian density are taken to be independent of {h_bar}, then each loop in perturbation theory brings a factor of {h_bar}. In the case of quantum electrodynamics, this scheme implies that the classical charge e, as well as the fine structure constant are linear in {h_bar}. The connection between the number of loops and factors of {h_bar} is more subtle for bound states since the binding energies and bound-state momenta themselves scale with {h_bar}. The {h_bar} expansion allows one to identify equal-time relativistic bound states in QED and QCD which are of lowest order in {h_bar} and transform dynamically under Lorentz boosts. The possibility to use retarded propagators at the Born level gives valence-like wave-functions which implicitly describe the sea constituents of the bound states normally present in its Fock state representation.

  6. Preliminary thermal expansion screening data for tuffs

    SciTech Connect

    Lappin, A.R.

    1980-03-01

    A major variable in evaluating the potential of silicic tuffs for use in geologic disposal of heat-producing nuclear wastes is thermal expansion. Results of ambient-pressure linear expansion measurements on a group of tuffs that vary treatly in porosity and mineralogy are presente here. Thermal expansion of devitrified welded tuffs is generally linear with increasing temperature and independent of both porosity and heating rate. Mineralogic factors affecting behavior of these tuffs are limited to the presence or absence of cristobalite and altered biotite. The presence of cristobalite results in markedly nonlinear expansion above 200{sup 0}C. If biotite in biotite-hearing rocks alters even slightly to expandable clays, the behavior of these tuffs near the boiling point of water can be dominated by contraction of the expandable phase. Expansion of both high- and low-porosity tuffs containing hydrated silicic glass and/or expandable clays is complex. The behavior of these rocks appears to be completely dominated by dehydration of hydrous phases and, hence, should be critically dependent on fluid pressure. Valid extrapolation of the ambient-pressure results presented here to depths of interest for construction of a nuclear-waste repository will depend on a good understanding of the interaction of dehydration rates and fluid pressures, and of the effects of both micro- and macrofractures on the response of tuff masss.

  7. [Current gene study in etiological analysis of congenital craniofacial abnormalities].

    PubMed

    Feng, Yi-miao; Fang, Bing

    2007-04-01

    The cause of congenital craniofacial abnormalities are very complicated. Understanding of the gene mechanisms of abnormalities taking place are very important for prevention and therapy.DNA sequence analysis provides the fundaments of gene study of the congenital craniofacial abnormalities. Human genome project (HGP) paved the confirmation of candidate gene of the congenital craniofacial abnormalities.Transgenic animal models and gene knockout techniques are effective methods in study of gene function. This paper reviews current gene study in etiopathogenisis analysis of the congenital craniofacial abnormalities.

  8. [Forum on tissue expansion. Expansion of the scalp. Surgical techniques and clinical applications].

    PubMed

    Foyatier, J L; Delay, E; Comparin, J P; Latarjet, J; Masson, C L

    1993-02-01

    Repair of all forms of alopecia is one of the principal applications of scalp expansion. The authors have inserted 400 expansion prostheses, including 20 in the scalp. The surgical technique, choice of material and various types of flaps are described and illustrated by clinical cases of extensive alopecia.

  9. Hepatic perfusion abnormalities during CT angiography: Detection and interpretation

    SciTech Connect

    Freeny, P.C.; Marks, W.M.

    1986-06-01

    Twenty-seven perfusion abnormalities were detected in 17 of 50 patients who underwent computed tomographic angiography (CTA) of the liver. All but one of the perfusion abnormalities occurred in patients with primary or metastatic liver tumors. Perfusion abnormalities were lobar in nine cases, segmental in 11, and subsegmental in seven; 14 were hypoperfusion and 13 were hyperperfusion abnormalities. The causes for the abnormalities included nonperfusion of a replaced hepatic artery (n = 11), cirrhosis and nodular regeneration (n = 3), altered hepatic hemodynamics (e.g., siphoning, laminar flow) caused by tumor (n = 7), contrast media washout from a nonperfused vessel (n = 1), compression of adjacent hepatic parenchyma (n = 1), and unknown (n = 4). Differentiation of perfusion abnormalities from tumor usually can be made by comparing the morphology of the known tumor with the suspected perfusion abnormality, changes of each on delayed CTA scans, and review of initial angiograms and other imaging studies.

  10. Prenatal diagnosis of limb abnormalities: role of fetal ultrasonography

    PubMed Central

    Ermito, Santina; Dinatale, Angela; Carrara, Sabina; Cavaliere, Alessandro; Imbruglia, Laura; Recupero, Stefania

    2009-01-01

    Fetal ultrasonografy is the most important tool to provide prenatal diagnosis of fetal anomalies. The detection of limb abnormalities may be a complex problem if the correct diagnostic approch is not established. A careful description of the abnormality using the rigth nomenclature is the first step. Looking for other associated abnormalities is the threshold to suspect chromosomal abnormalities or single gene disorder. According to the patogenic point of view, limb abnormalities may be the result of malformation, deformation, or disruption. The prenatal diagnosis and the management of limb abnormalities involve a multidisciplinary team of ostetrician, radiologist/sonologist, clinical geneticist, neonatologist, and orthopedic surgeons to provide the parents with the information regarding etiology of the disorder, prognosis, option related to the pregnancy and recurrence risk for future pregnancies. The aim of this review is to describe the importance of detailed fetal ultrasonography in prenatal diagnosis of limb abnormalities. PMID:22439035

  11. Abnormal selective attention normalizes P3 amplitudes in PDD.

    PubMed

    Hoeksma, Marco R; Kemner, Chantal; Kenemans, J Leon; van Engeland, Herman

    2006-07-01

    This paper studied whether abnormal P3 amplitudes in PDD are a corollary of abnormalities in ERP components related to selective attention in visual and auditory tasks. Furthermore, this study sought to clarify possible age differences in such abnormalities. Children with PDD showed smaller P3 amplitudes than controls, but no abnormalities in selective attention. Adolescents with PDD showed abnormal selective attention, as reflected by larger auditory Processing Negativity (PN) and visual N2b, but no P3 abnormalities. Dipole localizations revealed that the locations of PN generators in subjects with PDD differed from controls. It was concluded that the abnormalities in selective attention in adolescents with PDD have a normalizing effect on P3, and possibly act as a compensatory process.

  12. Mitochondrial footprints of human expansions in Africa.

    PubMed Central

    Watson, E; Forster, P; Richards, M; Bandelt, H J

    1997-01-01

    mtDNA studies support an African origin for modern Eurasians, but expansion events within Africa have not previously been investigated. We have therefore analyzed 407 mtDNA control-region sequences from 13 African ethnic groups. A number of sequences (13%) were highly divergent and coalesced on the "mitochondrial Eve" in Africans. The remaining sequences also ultimately coalesced on this sequence but fell into four major clusters whose starlike phylogenies testify to demographic expansions. The oldest of these African expansions dates to approximately 60,000-80,000 years ago. Eurasian sequences are derived from essentially one sequence within this ancient cluster, even though a diverse mitochondrial pool was present in Africa at the time. PMID:9326335

  13. Graphite thermal expansion reference for high temperature

    NASA Technical Reports Server (NTRS)

    Gaal, P. S.

    1974-01-01

    The design requirements of the aerospace and high-temperature nuclear reactor industries necessitate reliable thermal expansion data for graphite and other carbonaceous materials. The feasibility of an acceptable reference for calibration of expansion measuring systems that operate in carbon-rich atmospheres at temperatures ranging to 2500 C is the prime subject of this work. Present-day graphite technology provides acceptable materials for stable, reproducible references, as reflected by some of the candidate materials. The repeatability for a single specimen in a given expansion measuring system was found to be plus or minus 1%, while the combined results of several tests made on a number of samples fell within a plus or minus 2.5% band.

  14. Far field expansion for anisotropic wave equations

    NASA Technical Reports Server (NTRS)

    Hariharan, S. I.; Hagstrom, Thomas

    1989-01-01

    A necessary ingredient for the numerical simulation of many time dependent phenomena in acoustics and aerodynamics is the imposition of accurate radiation conditions at artificial boundaries. The asymptotic analysis of propagating waves provides a rational approach to the development of such conditions. A far field asymptotic expansion of solutions of anisotropic wave equations is derived. This generalizes the well known Friedlander expansion for the standard wave operator. The expansion is used to derive a hierarchy of radiation conditions of increasing accuracy. Two numerical experiments are given to illustrate the utility of this approach. The first application is the study of unsteady vortical disturbances impinging on a flat plate; the second is the simulation of inviscid flow past an impulsively started cylinder.

  15. Ultraprecise measurement of thermal coefficients of expansion.

    PubMed

    Jacobs, S F; Bradford, J N; Berthold Iii, J W

    1970-11-01

    A novel method for determining thermal expansion coefficients has been devised. It is based on the dependence of Fabry-Perot resonances on the mirror separation. The expansion sample is formed into an etalon spacer, with highly reflecting endplates optically contacted to each end. The Fabry-Perot resonances are probed by variable radiofrequency sidebands derived from a frequency stabilized 633-nm He-Ne laser. A change in sample temperature DeltaT causes a change in interferometer length DeltaL, which shifts the resonance frequencies by Deltanu. Then alpha = (1/DeltaT)(DeltaL/L) = (1/DeltaT)(Deltanu/nu). alpha can be measured with precision limited ultimately by the stability of the stabilized laser (1:10(9) with presently available commercial lasers). alpha vs temperature has been measured for samples of Owens-Illinois Cer-Vit, Corning ULE silica, and Schott low expansion glass-ceramic.

  16. DNA Triplet Repeat Expansion and Mismatch Repair

    PubMed Central

    Iyer, Ravi R.; Pluciennik, Anna; Napierala, Marek; Wells, Robert D.

    2016-01-01

    DNA mismatch repair is a conserved antimutagenic pathway that maintains genomic stability through rectification of DNA replication errors and attenuation of chromosomal rearrangements. Paradoxically, mutagenic action of mismatch repair has been implicated as a cause of triplet repeat expansions that cause neurological diseases such as Huntington disease and myotonic dystrophy. This mutagenic process requires the mismatch recognition factor MutSβ and the MutLα (and/or possibly MutLγ) endonuclease, and is thought to be triggered by the transient formation of unusual DNA structures within the expanded triplet repeat element. This review summarizes the current knowledge of DNA mismatch repair involvement in triplet repeat expansion, which encompasses in vitro biochemical findings, cellular studies, and various in vivo transgenic animal model experiments. We present current mechanistic hypotheses regarding mismatch repair protein function in mediating triplet repeat expansions and discuss potential therapeutic approaches targeting the mismatch repair pathway. PMID:25580529

  17. Spectral likelihood expansions for Bayesian inference

    NASA Astrophysics Data System (ADS)

    Nagel, Joseph B.; Sudret, Bruno

    2016-03-01

    A spectral approach to Bayesian inference is presented. It pursues the emulation of the posterior probability density. The starting point is a series expansion of the likelihood function in terms of orthogonal polynomials. From this spectral likelihood expansion all statistical quantities of interest can be calculated semi-analytically. The posterior is formally represented as the product of a reference density and a linear combination of polynomial basis functions. Both the model evidence and the posterior moments are related to the expansion coefficients. This formulation avoids Markov chain Monte Carlo simulation and allows one to make use of linear least squares instead. The pros and cons of spectral Bayesian inference are discussed and demonstrated on the basis of simple applications from classical statistics and inverse modeling.

  18. Electron-beam induced electric-hydraulic expansion in a silica-shelled gallium microball-nanotube structure

    NASA Astrophysics Data System (ADS)

    Gao, Y. H.; Sun, M.; Su, J.; Zhi, C. Y.; Golberg, D.; Bando, Y.; Duan, X. F.

    2011-08-01

    Heteroshape-heteroscale structure of silica-shelled Ga microball-nanotube was fabricated. Under in situ electron-beam irradiation, an abnormally large and fast expansion of Ga was observed. Failed by a sole routine heating effect of electron-beam, the expansion was explained by an electric-hydraulic expansion effect taking into account a huge inner pressure induced by the repelling Coulomb force of positively charged Ga ions on the Ga microball surface. The ions were accumulated due to knocking-out of Ga electrons under irradiation and shielding effect of a silica shell which prevents the charge balance restoration. A circuit model is proposed to calculate the accumulation of Ga ions.

  19. CAG repeat expansions in bipolar and unipolar disorders

    SciTech Connect

    Oruc, L.; Verheyen, G.R.; Raeymaekers, P.; Van Broeckhoven, C.

    1997-03-01

    Family, twin, and adoption studies consistently have indicated that the familial aggregation of bipolar (BP) disorder and unipolar recurrent major depression (UPR) is accounted for largely by genetic factors. However, the mode of inheritance is complex. One of the possible explanations could be that a gene with variable penetrance and variable expression is involved. Recently there have been reports on a new class of genetic diseases caused by an abnormal trinucleotide-repeat expansion (TRE). In a number of genetic disorders, these dynamic mutations were proved to be the biological basis for the clinically observed phenomenon of anticipation. DNA consisting of repeated triplets of nucleotides becomes unstable and increases in size over generations within families, giving rise to an increased severity and/or an earlier onset of the disorder. It has been recognized for a long time that anticipation occurs in multiplex families transmitting mental illness. More recent studies also suggest that both BP disorder and UPR show features that are compatible with anticipation. Although the findings of anticipation in BP disorders and in UPR must be interpreted with caution because of the possible presence of numerous ascertainment biases, they support the hypothesis that pathological TREs are implicated in the transmission of these disorders. TRE combined with variable penetrance of expression could explain the complex transmission pattern observed in BP disorder. In view of this, the recent reports of an association between CAG-repeat length and BP disorder in a Belgian, Swedish, and British population are promising. 14 refs., 1 fig., 1 tab.

  20. Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1.

    PubMed

    Virtaneva, K; D'Amato, E; Miao, J; Koskiniemi, M; Norio, R; Avanzini, G; Franceschetti, S; Michelucci, R; Tassinari, C A; Omer, S; Pennacchio, L A; Myers, R M; Dieguez-Lucena, J L; Krahe, R; de la Chapelle, A; Lehesjoki, A E

    1997-04-01

    Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder that occurs with a low frequency in many populations but is more common in Finland and the Mediterranean region. It is characterized by stimulus-sensitive myoclonus and tonic-clonic seizures with onset at age 6-15 years, typical electroencephalographic abnormalities and a variable rate of progression between and within families. Following the initial mapping of the EPM1 gene to chromosome 21 (ref. 6) and the refinement of the critical region to a small interval, positional cloning identified the gene encoding cystatin B (CST6), a cysteine protease inhibitor, as the gene underlying EPM1 (ref. 10). Levels of messenger RNA encoded by CST6 were dramatically decreased in patients. A 3' splice site and a stop codon mutation were identified in three families, leaving most mutations uncharacterized. In this study, we report a novel type of disease-causing mutation, an unstable 15- to 18-mer minisatellite repeat expansion in the putative promoter region of the CST6 gene. The mutation accounts for the majority of EPM1 patients worldwide. Haplotype data are compatible with a single ancestral founder mutation. The length of the repeat array differs between chromosomes and families, but changes in repeat number seem to be comparatively rare events.

  1. Propagating Stress Waves During Epithelial Expansion

    NASA Astrophysics Data System (ADS)

    Banerjee, Shiladitya; Utuje, Kazage J. C.; Marchetti, M. Cristina

    2015-06-01

    Coordinated motion of cell monolayers during epithelial wound healing and tissue morphogenesis involves mechanical stress generation. Here we propose a model for the dynamics of epithelial expansion that couples mechanical deformations in the tissue to contractile activity and polarization in the cells. A new ingredient of our model is a feedback between local strain, polarization, and contractility that naturally yields a mechanism for viscoelasticity and effective inertia in the cell monolayer. Using a combination of analytical and numerical techniques, we demonstrate that our model quantitatively reproduces many experimental findings [Nat. Phys. 8, 628 (2012)], including the buildup of intercellular stresses, and the existence of traveling mechanical waves guiding the oscillatory monolayer expansion.

  2. Therapeutics development for triplet repeat expansion diseases.

    PubMed

    Di Prospero, Nicholas A; Fischbeck, Kenneth H

    2005-10-01

    The underlying genetic mutations for many inherited neurodegenerative disorders have been identified in recent years. One frequent type of mutation is trinucleotide repeat expansion. Depending on the location of the repeat expansion, the mutation might result in a loss of function of the disease gene, a toxic gain of function or both. Disease gene identification has led to the development of model systems for investigating disease mechanisms and evaluating treatments. Examination of experimental findings reveals similarities in disease mechanisms as well as possibilities for treatment.

  3. Simulation of Magnetic Field Guided Plasma Expansion

    NASA Astrophysics Data System (ADS)

    Ebersohn, Frans; Sheehan, J. P.; Gallimore, Alec; Shebalin, John

    2015-09-01

    Magnetic field guided expansion of a radio-frequency plasma was simulated with a quasi-one-dimensional particle-in-cell code. Two-dimensional effects were included in a one-dimensional particle-in-cell code by varying the cross-sectional area of the one dimensional domain and including forces due to the magnetic field. Acceleration of electrons by the magnetic field forces leads to the formation of potential structures which then accelerate the ions into a beam. Density changes due to the plasma expansion only weakly affect the ion acceleration. Rapidly diverging magnetic fields lead to more rapid acceleration and the electrons cool as they expand.

  4. 36 CFR 72.42 - Expansion and new development.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 36 Parks, Forests, and Public Property 1 2014-07-01 2014-07-01 false Expansion and new development..., Rehabilitation and Innovation § 72.42 Expansion and new development. (a) Expansion. Because the UPARR Program is targeted to distressed areas, every assurance should be made that if any expansion takes place,...

  5. 36 CFR 72.42 - Expansion and new development.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 36 Parks, Forests, and Public Property 1 2013-07-01 2013-07-01 false Expansion and new development..., Rehabilitation and Innovation § 72.42 Expansion and new development. (a) Expansion. Because the UPARR Program is targeted to distressed areas, every assurance should be made that if any expansion takes place,...

  6. 36 CFR 72.42 - Expansion and new development.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Expansion and new development..., Rehabilitation and Innovation § 72.42 Expansion and new development. (a) Expansion. Because the UPARR Program is targeted to distressed areas, every assurance should be made that if any expansion takes place,...

  7. 36 CFR 72.42 - Expansion and new development.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 1 2011-07-01 2011-07-01 false Expansion and new development..., Rehabilitation and Innovation § 72.42 Expansion and new development. (a) Expansion. Because the UPARR Program is targeted to distressed areas, every assurance should be made that if any expansion takes place,...

  8. 36 CFR 72.42 - Expansion and new development.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 36 Parks, Forests, and Public Property 1 2012-07-01 2012-07-01 false Expansion and new development..., Rehabilitation and Innovation § 72.42 Expansion and new development. (a) Expansion. Because the UPARR Program is targeted to distressed areas, every assurance should be made that if any expansion takes place,...

  9. Asymptotic expansions for the reciprocal of the gamma function

    NASA Astrophysics Data System (ADS)

    Withers, Christopher S.; Nadarajah, Saralees

    2014-05-01

    Asymptotic expansions are derived for the reciprocal of the gamma function. We show that the coefficients of the expansion are the same, up to a sign change, as the asymptotic expansions for the gamma function obtained by exponentiating the expansions of its logarithm due to Stirling and de Moivre. Expressions for the coefficients are given in terms of Bell polynomials.

  10. Kidney abnormalities in sickle cell disease.

    PubMed

    López Revuelta, K; Ricard Andrés, M P

    2011-01-01

    Patients with sickle cell disease exhibits numerous kidney structural and functional abnormalities, changes that are seen along the entire length of the nephron. Changes are most marked in patients with homozygous sickle cell anemia, but are also seen in those with compound heterozygous states and the sickle cell trait. The renal features of sickle cell disease include some of the most common reasons for referral to nephrologists, such as hematuria, proteinuria, tubular disturbances and chronic kidney disease. Therapy of these conditions requires specialized knowledge of their distinct pathogenic mechanisms. Spanish Haemathology and Hemotherapy Association has recently publicated their Clinical Practice Guidelines of SCD management. Renal chapter is reproduced in this article for Nefrología difussion.

  11. Cardiac abnormalities and sudden infant death syndrome.

    PubMed

    Sweeting, Joanna; Semsarian, Christopher

    2014-12-01

    Many factors have been implicated in SIDS cases including environmental influences such as sleeping arrangements and smoking. Most recently, cardiac abnormalities have been hypothesised to play a role in some cases, particularly the primary genetic arrhythmogenic disorders such as familial long QT syndrome (LQTS). Both post-mortem and clinical studies of SIDS cases have provided supporting evidence for the involvement of cardiac genetic disorders in SIDS. This review provides a summary of this evidence focussing particularly on the primary hypothesis related to underlying familial LQTS. In addition, the current literature relating to other cardiac genetic conditions such as Brugada syndrome (BrS) and structural heart diseases such as hypertrophic cardiomyopathy (HCM) is briefly presented. Finally, the implications of a possible cardiac genetic cause of SIDS is discussed with reference to the need for genetic testing in SIDS cases and subsequent clinical and genetic testing in family members.

  12. Liver abnormalities in drug and substance abusers.

    PubMed

    Pateria, Puraskar; de Boer, Bastiaan; MacQuillan, Gerry

    2013-08-01

    Drug and substance abuse remains a major medical problem. Alcohol use, abuse and dependence are highly prevalent conditions. Alcohol related liver disease can present as simple steatosis, steatohepatitis, alcoholic hepatitis or liver cirrhosis. Paracetamol hepatotoxicity secondary to accidental or deliberate overdose is another common problem. While the adverse cardiovascular, neurological, renal and psychiatric consequences of various illicit substance abuses are widely studied and publicized, less attention has been directed towards possible hepatotoxic effects. Illicit drug abuse can cause a range of liver abnormalities ranging from asymptomatic derangement of liver function tests to fulminant hepatic failure. This article reviews the epidemiology, risk factors, clinical manifestations, pathogenesis, investigations, management and prognostic factors of alcohol related liver disease and paracetamol hepatotoxicity as well as the current knowledge pertaining to hepatotoxicity of the more commonly used illicit substances including cannabis, amphetamine type stimulants, cocaine, khat chewing and complementary and alternate medicine.

  13. Computed tomography of the abnormal thymus

    SciTech Connect

    Baron, R.L.; Lee, J.K.T.; Sagel, S.S.; Levitt, R.G.

    1982-01-01

    Computed tomography (CT) should be the imaging method of choice following plain chest radiographs when a suspected thymic abnormality requires further evaluation. Based upon a six-year experience, including the evaluation of 25 patients with thymic pathology, CT was found useful in suggesting or excluding a diagnosis of thymoma and in distinguishing thymic hyperplasis from thymoma in patients with myasthenia gravis. The thickness of the thymic lobes determined by CT was found to be a more accurate indicator of infiltrative disease (thymic hyperplasia and lymphoma) than the width. CT was helpful in differentiating benign thymic cysts from solid tumors, and in defining the extent of a thymic neoplasms. On occasion, CT may suggest the specific histologic nature of a thymic lesion.

  14. Abnormal epidermal changes after argon laser treatment

    SciTech Connect

    Neumann, R.A.; Knobler, R.M.; Aberer, E.; Klein, W.; Kocsis, F.; Ott, E. )

    1991-02-01

    A 26-year-old woman with a congenital port-wine stain on the forehead was treated three times at 2-month intervals with an argon laser. Six months after the last treatment, moderate blanching and mild scaling confined to the treated area was observed. A biopsy specimen of the treated area revealed a significant decrease in ectatic vessels. However, epidermal changes similar to those of actinic keratosis with disorganized cell layers and marked cytologic abnormalities were seen. Analysis of peripheral blood lymphocytes for a defect in DNA repair was negative. Multiple, argon laser-induced photothermal effects may be responsible for the changes observed in our case and may lead to premalignant epidermal transformation.

  15. [Pulmonary arterial hypertension and BMP system abnormality].

    PubMed

    Otsuka, Fumio

    2008-11-01

    Genetic analysis has uncovered that familial and idiopathic pulmonary arterial hypertension (PAH) is linked to germline mutations in BMP type II receptor (BMPRII). PAH is characterized by enhanced remodeling of pulmonary arteries due to arterial smooth muscle cell proliferation. BMPRII mutations contribute to abnormal mitotic responses to BMP ligands in pulmonary artery smooth muscle cells. Unbalanced Smad signaling induced by BMP and TGFbeta is functionally involved in the pathogenesis of PAH. BMPRII mutations also increase the susceptibility of endothelial cell apoptosis. The combination of increased endothelial injury and impaired suppression of smooth muscle cell proliferation is critical for the cellular pathogenesis of PAH. However, the detailed molecular mechanism leading to severe vascular remodeling caused by BMPRII mutations has yet to be elucidated.

  16. [Ultrasonic diagnosis of congenital uterine abnormalities].

    PubMed

    Funk, A; Fendel, H

    1988-01-01

    1-2% of women has abnormal uterine development due to nonunification of the Müllerian ducts in the embryonal period. At the RWTH Aachen, in the department of gynaecology and obstetrics, between January and June 1987, we had searched systematically for maldevelopment of the uterus in 2299 echosonografies. In 13 cases we found maldevelopment of internal genital; 5 of these cases were diagnosed by an echosonografic routine-examination. The echografic criteria of the different grades of uterine malformations have been determined, systematized and discussed in relation to the symptoms. The most frequent malformations as uterus subseptus, uterus septus, uterus bicornis and uterus duplex are subject of a detailed discussion. This work demonstrates that echosonografic is a very efficient instrument to diagnose uterine malformations and gives us a very exact anatomic interpretation of malformations.

  17. Renal abnormalities in sickle cell disease.

    PubMed

    Ataga, K I; Orringer, E P

    2000-04-01

    Sickle cell anemia and the related hemoglobinopathies are associated with a large spectrum of renal abnormalities. The patients have impaired urinary concentrating ability, defects in urinary acidification and potassium excretion, and supranormal proximal tubular function. The latter is manifest by increased secretion of creatinine and by reabsorption of phosphorus and beta(2)-microglobulin. Young patients with sickle cell disease (SCD) have supranormal renal hemodynamics with elevations in both effective renal plasma flow (ERPF) and glomerular filtration rate (GFR). These parameters decrease with age as well as following the administration of prostaglandin inhibitors. Proteinuria, a common finding in adults with sickle cell disease, may progress to the nephrotic syndrome. Proteinuria, hypertension, and increasing anemia predict end-stage renal disease (ESRD). While ESRD can be managed by dialysis and/or renal transplantation, there may be an increased rate of complications in renal transplant recipients with SCD. Hematuria is seen in individuals with all of the SCDs as well as with sickle cell trait. In most cases the etiology of the hematuria turns out to be benign. However, there does appear to be an increased association between SCD and renal medullary carcinoma. Therefore, those SCD patients who present with hematuria should initially undergo a thorough evaluation in order to exclude this aggressive neoplasm. Papillary necrosis may occur due to medullary ischemia and infarction. Erythropoietin levels are usually lower than expected for their degree of anemia and decrease further as renal function deteriorates. An abnormal balance of renal prostaglandins may be responsible for some of the changes in sickle cell nephropathy. Acute renal failure is a component of the acute multiorgan failure syndrome (MOFS). Finally, progression of sickle cell nephropathy to ESRD may be slowed by adequate control of hypertension and proteinuria. However, the prevention of the

  18. Abnormal Fixational Eye Movements in Amblyopia

    PubMed Central

    Shaikh, Aasef G.; Otero-Millan, Jorge; Kumar, Priyanka; Ghasia, Fatema F.

    2016-01-01

    Purpose Fixational saccades shift the foveal image to counteract visual fading related to neural adaptation. Drifts are slow eye movements between two adjacent fixational saccades. We quantified fixational saccades and asked whether their changes could be attributed to pathologic drifts seen in amblyopia, one of the most common causes of blindness in childhood. Methods Thirty-six pediatric subjects with varying severity of amblyopia and eleven healthy age-matched controls held their gaze on a visual target. Eye movements were measured with high-resolution video-oculography during fellow eye-viewing and amblyopic eye-viewing conditions. Fixational saccades and drifts were analyzed in the amblyopic and fellow eye and compared with controls. Results We found an increase in the amplitude with decreased frequency of fixational saccades in children with amblyopia. These alterations in fixational eye movements correlated with the severity of their amblyopia. There was also an increase in eye position variance during drifts in amblyopes. There was no correlation between the eye position variance or the eye velocity during ocular drifts and the amplitude of subsequent fixational saccade. Our findings suggest that abnormalities in fixational saccades in amblyopia are independent of the ocular drift. Discussion This investigation of amblyopia in pediatric age group quantitatively characterizes the fixation instability. Impaired properties of fixational saccades could be the consequence of abnormal processing and reorganization of the visual system in amblyopia. Paucity in the visual feedback during amblyopic eye-viewing condition can attribute to the increased eye position variance and drift velocity. PMID:26930079

  19. Carotid Vascular Abnormalities in Primary Hyperparathyroidism

    PubMed Central

    Walker, M. D.; Fleischer, J.; Rundek, T.; McMahon, D. J.; Homma, S.; Sacco, R.; Silverberg, S. J.

    2009-01-01

    Context: Data on the presence, extent, and reversibility of cardiovascular disease in primary hyperparathyroidism (PHPT) are conflicting. Objective: This study evaluated carotid structure and function in PHPT patients compared with population-based controls. Design: This is a case-control study. Setting: The study was conducted in a university hospital metabolic bone disease unit. Participants: Forty-nine men and women with PHPT and 991 controls without PHPT were studied. Outcome Measures: We measured carotid intima-media thickness (IMT), carotid plaque presence and thickness, and carotid stiffness, strain, and distensibility. Results: IMT, carotid plaque thickness, carotid stiffness, and distensibility were abnormal in PHPT patients, and IMT was higher in patients than controls (0.959 vs. 0.907 mm, P < 0.0001). In PHPT, PTH levels, but not calcium concentration, predicted carotid stiffness (P = 0.04), strain (P = 0.06), and distensibility (P = 0.07). Patients with increased carotid stiffness had significantly higher PTH levels than did those with normal stiffness (141 ± 48 vs. 94.9 ± 44 pg/ml, P = 0.002), and odds of abnormal stiffness increased 1.91 (confidence interval = 1.09–3.35; P = 0.024) for every 10 pg/ml increase in PTH, adjusted for age, creatinine, and albumin-corrected calcium. Conclusions: Mild PHPT is associated with subclinical carotid vascular manifestations. IMT, a predictor of cardiovascular outcomes, is increased. Measures of carotid stiffness are associated with extent of PTH elevation, suggesting that those with more severe PHPT may have impaired vascular compliance and that PTH, rather than calcium, is the mediator. PMID:19755478

  20. Principles of Thermal Expansion in Feldspars

    NASA Astrophysics Data System (ADS)

    Hovis, Guy; Medford, Aaron; Conlon, Maricate; Tether, Allison; Romanoski, Anthony

    2010-05-01

    Following the recent thermal expansion work of Hovis et al. (1) on AlSi3 feldspars, we have investigated the thermal expansion of plagioclase, Ba-K, and Ca-K feldspar crystalline solutions. X-ray powder diffraction data were collected between room temperature and 925 °C on six natural plagioclase specimens ranging in composition from anorthite to oligoclase, the K-exchanged equivalents of these plagioclase specimens, and five synthetic Ba-K feldspars with compositions ranging from 25 to 99 mol % BaAl2Si2O8. The resulting thermal expansion coefficients (α) for volume have been combined with earlier results for end-member Na- and K-feldspars (2,3). Unlike AlSi3 feldspars, Al2Si2 feldspars, including anorthite and celsian from the present study plus Sr- and Pb-feldspar from other workers (4,5), show essentially constant and very limited thermal expansion, regardless of divalent cation size. In the context of structures where the Lowenstein rule (6) requires Al and Si to alternate among tetrahedra, the proximity of bridging Al-O-Si oxygen ions to divalent neighbors (ranging from 0 to 2) produces short Ca-O (or Ba-O) bonds (7,8) that apparently are the result of local charge-balance requirements (9). Gibbs et al. (10) suggest that short bonds such as these have a partially covalent character. This in turn stiffens the structure. Thus, for feldspar series with coupled substitution the change away from a purely divalent M-site occupant gives the substituting (less strongly bonded) monovalent cations increasingly greater influence on thermal expansion. Overall, then, thermal expansion in the feldspar system is well represented on a plot of α against room-temperature volume, where one sees a quadrilateral bounded by data for (A) AlSi3 feldspars whose expansion behavior is controlled largely by the size of the monovalent alkali-site occupant, (B) Al2Si2 feldspars whose expansion is uniformly limited by partially-covalent bonds between divalent M-site occupants and

  1. Cluster expansions for the correlated basis functions theory

    NASA Astrophysics Data System (ADS)

    Guardiola, R.

    1982-08-01

    Four kinds of cluster expansions for the calculation of non-diagonal matrix elements of the hamiltonian between correlated states have been derived. The derivation is based on a linearization mechanism for the standard cluster expansions in a configuration mixed state. Particularly simple formulae result for the multiplicative Factor-Aviles-Hartog-Tolhoek expansion and for the exponential form of the Gaudin-Gillespie-Ripka cluster expansion. The resulting expansions are directly usable in finite nuclei.

  2. Global Expansion and English Language Learning

    ERIC Educational Resources Information Center

    Andrade, Maureen Snow

    2016-01-01

    Demand for higher education is global. As institutions extend opportunities beyond their borders, English language proficiency must be considered. This chapter focuses on considerations related to global expansion, with an emphasis on the role of distance English language courses and the distinct considerations in their development.

  3. T-expansion - a short review

    SciTech Connect

    Karliner, M.

    1985-09-01

    The t-expansion is a nonperturbative calculational tool recently developed for Hamiltonian systems. A short review of the method is given. It is followed by a summary of applications to two dimensional spin systems and to four dimensional non-abelian lattice gauge theories. 5 refs., 3 figs.

  4. Impact of Computer Technology on Library Expansions.

    ERIC Educational Resources Information Center

    Fisher, Tom

    1995-01-01

    Describes the impact of information technology on the physical and functional organization of libraries and briefly discusses technical issues, including wiring and distribution, access to power sources, codes, lighting, and security. The Duke University Library and the Purcellville (VA) public library's renovation and expansion plans are…

  5. Territorial expansion and primary state formation

    PubMed Central

    Spencer, Charles S.

    2010-01-01

    A major research problem in anthropology is the origin of the state and its bureaucratic form of governance. Of particular importance for evaluating theories of state origins are cases of primary state formation, whereby a first-generation state evolves without contact with any preexisting states. A general model of this process, the territorial-expansion model, is presented and assessed with archaeological data from six areas where primary states emerged in antiquity: Mesoamerica, Peru, Egypt, Mesopotamia, the Indus Valley, and China. In each case, the evidence shows a close correspondence in time between the first appearance of state institutions and the earliest expansion of the state's political-economic control to regions lying more than a day's round-trip from the capital. Although additional research will add detail and clarity to the empirical record, the results to date are consistent with the territorial-expansion model, which argues that the success of such long-distance expansion not only demanded the bureaucratization of central authority but also helped provide the resources necessary to underwrite this administrative transformation. PMID:20385804

  6. Term Dependence: Truncating the Bahadur Lazarsfeld Expansion.

    ERIC Educational Resources Information Center

    Losee, Robert M., Jr.

    1994-01-01

    Studies the performance of probabilistic information retrieval systems using differing statistical dependence assumptions when estimating the probabilities inherent in the retrieval model. Experimental results using the Bahadur Lazarsfeld expansion on the Cystic Fibrosis database are discussed that suggest that incorporating term dependence…

  7. Power system expansion planning under uncertainty

    SciTech Connect

    Gorenstin, B.G.; Campodonico, N.M.; Costa, J.P.; Pereira, M.V.F. . Centro de Pesquisas de Energia Electrica)

    1993-02-01

    This paper describes a methodology for expansion planning of power systems under several uncertainty factors such as demand growth, fuel cost, delay in project completion, financial constraints etc. The solution approach is based on stochastic optimization techniques, decision analysis, and multiobjective tradeoff analysis. Case studies with the Brazilian system are presented and discussed.

  8. Accelerated dryland expansion under climate change

    NASA Astrophysics Data System (ADS)

    Huang, Jianping; Yu, Haipeng; Guan, Xiaodan; Wang, Guoyin; Guo, Ruixia

    2016-02-01

    Drylands are home to more than 38% of the total global population and are one of the most sensitive areas to climate change and human activities. Projecting the areal change in drylands is essential for taking early action to prevent the aggravation of global desertification. However, dryland expansion has been underestimated in the Fifth Coupled Model Intercomparison Project (CMIP5) simulations considering the past 58 years (1948-2005). Here, using historical data to bias-correct CMIP5 projections, we show an increase in dryland expansion rate resulting in the drylands covering half of the global land surface by the end of this century. Dryland area, projected under representative concentration pathways (RCPs) RCP8.5 and RCP4.5, will increase by 23% and 11%, respectively, relative to 1961-1990 baseline, equalling 56% and 50%, respectively, of total land surface. Such an expansion of drylands would lead to reduced carbon sequestration and enhanced regional warming, resulting in warming trends over the present drylands that are double those over humid regions. The increasing aridity, enhanced warming and rapidly growing human population will exacerbate the risk of land degradation and desertification in the near future in the drylands of developing countries, where 78% of dryland expansion and 50% of the population growth will occur under RCP8.5.

  9. Stakeholder Support for School Food Policy Expansions

    ERIC Educational Resources Information Center

    Pettigrew, Simone; Pescud, Melanie; Donovan, Robert J.

    2012-01-01

    The aim of this study was to assess the extent to which parents and school-based stakeholders (principals, teachers, canteen managers and Parents & Citizen Committee presidents) are supportive of potential expansions to a new school food policy. Eight additional policy components elicited in preliminary focus groups with parents and 19 additional…

  10. Expansive Visibilization to Stimulate EFL Teacher Reflection

    ERIC Educational Resources Information Center

    Ito, Ryu

    2012-01-01

    Despite the growing popularity of action research, bridging the gap between data collection and reflective data analysis still lacks a well-developed methodology. As a supplement to the traditional action research procedure for language teaching, I adopted a method called expansive visibilization (EV), which has the potential to be a reflective…

  11. Natural Gas Pipeline and System Expansions

    EIA Publications

    1997-01-01

    This special report examines recent expansions to the North American natural gas pipeline network and the nature and type of proposed pipeline projects announced or approved for construction during the next several years in the United States. It includes those projects in Canada and Mexico that tie in with U.S. markets or projects.

  12. Climate Science: Tropical Expansion by Ocean Swing

    SciTech Connect

    Lu, Jian

    2014-04-01

    The tropical belt has become wider over the past decades, but climate models fall short of capturing the full rate of the expansion. The latest analysis of the climate simulations suggests that a long-term swing of the Pacific Decadal Oscillation is the main missing cause.

  13. Ex vivo expansion of hematopoietic stem cells.

    PubMed

    Xie, JingJing; Zhang, ChengCheng

    2015-09-01

    Ex vivo expansion of hematopoietic stem cells (HSCs) would benefit clinical applications in several aspects, to improve patient survival, utilize cord blood stem cells for adult applications, and selectively propagate stem cell populations after genetic manipulation. In this review we summarize and discuss recent advances in the culture systems of mouse and human HSCs, which include stroma/HSC co-culture, continuous perfusion and fed-batch cultures, and those supplemented with extrinsic ligands, membrane transportable transcription factors, complement components, protein modification enzymes, metabolites, or small molecule chemicals. Some of the expansion systems have been tested in clinical trials. The optimal condition for ex vivo expansion of the primitive and functional human HSCs is still under development. An improved understanding of the mechanisms for HSC cell fate determination and the HSC culture characteristics will guide development of new strategies to overcome difficulties. In the future, development of a combination treatment regimen with agents that enhance self-renewal, block differentiation, and improve homing will be critical. Methods to enhance yields and lower cost during collection and processing should be employed. The employment of an efficient system for ex vivo expansion of HSCs will facilitate the further development of novel strategies for cell and gene therapies including genome editing.

  14. Territorial expansion and primary state formation.

    PubMed

    Spencer, Charles S

    2010-04-20

    A major research problem in anthropology is the origin of the state and its bureaucratic form of governance. Of particular importance for evaluating theories of state origins are cases of primary state formation, whereby a first-generation state evolves without contact with any preexisting states. A general model of this process, the territorial-expansion model, is presented and assessed with archaeological data from six areas where primary states emerged in antiquity: Mesoamerica, Peru, Egypt, Mesopotamia, the Indus Valley, and China. In each case, the evidence shows a close correspondence in time between the first appearance of state institutions and the earliest expansion of the state's political-economic control to regions lying more than a day's round-trip from the capital. Although additional research will add detail and clarity to the empirical record, the results to date are consistent with the territorial-expansion model, which argues that the success of such long-distance expansion not only demanded the bureaucratization of central authority but also helped provide the resources necessary to underwrite this administrative transformation.

  15. A Pedagogical Approach to the Magnus Expansion

    ERIC Educational Resources Information Center

    Blanes, S.; Casas, F.; Oteo, J. A.; Ros, J.

    2010-01-01

    Time-dependent perturbation theory as a tool to compute approximate solutions of the Schrodinger equation does not preserve unitarity. Here we present, in a simple way, how the "Magnus expansion" (also known as "exponential perturbation theory") provides such unitary approximate solutions. The purpose is to illustrate the importance and…

  16. Thermal expansion anomaly regulated by entropy.

    PubMed

    Liu, Zi-Kui; Wang, Yi; Shang, ShunLi

    2014-11-13

    Thermal expansion, defined as the temperature dependence of volume under constant pressure, is a common phenomenon in nature and originates from anharmonic lattice dynamics. However, it has been poorly understood how thermal expansion can show anomalies such as colossal positive, zero, or negative thermal expansion (CPTE, ZTE, or NTE), especially in quantitative terms. Here we show that changes in configurational entropy due to metastable micro(scopic)states can lead to quantitative prediction of these anomalies. We integrate the Maxwell relation, statistic mechanics, and first-principles calculations to demonstrate that when the entropy is increased by pressure, NTE occurs such as in Invar alloy (Fe3Pt, for example), silicon, ice, and water, and when the entropy is decreased dramatically by pressure, CPTE is expected such as in anti-Invar cerium, ice and water. Our findings provide a theoretic framework to understand and predict a broad range of anomalies in nature in addition to thermal expansion, which may include gigantic electrocaloric and electromechanical responses, anomalously reduced thermal conductivity, and spin distributions.

  17. Thermal Expansion Anomaly Regulated by Entropy

    PubMed Central

    Liu, Zi-Kui; Wang, Yi; Shang, ShunLi

    2014-01-01

    Thermal expansion, defined as the temperature dependence of volume under constant pressure, is a common phenomenon in nature and originates from anharmonic lattice dynamics. However, it has been poorly understood how thermal expansion can show anomalies such as colossal positive, zero, or negative thermal expansion (CPTE, ZTE, or NTE), especially in quantitative terms. Here we show that changes in configurational entropy due to metastable micro(scopic)states can lead to quantitative prediction of these anomalies. We integrate the Maxwell relation, statistic mechanics, and first-principles calculations to demonstrate that when the entropy is increased by pressure, NTE occurs such as in Invar alloy (Fe3Pt, for example), silicon, ice, and water, and when the entropy is decreased dramatically by pressure, CPTE is expected such as in anti-Invar cerium, ice and water. Our findings provide a theoretic framework to understand and predict a broad range of anomalies in nature in addition to thermal expansion, which may include gigantic electrocaloric and electromechanical responses, anomalously reduced thermal conductivity, and spin distributions. PMID:25391631

  18. Polytope expansion of Lie characters and applications

    SciTech Connect

    Walton, Mark A.

    2013-12-15

    The weight systems of finite-dimensional representations of complex, simple Lie algebras exhibit patterns beyond Weyl-group symmetry. These patterns occur because weight systems can be decomposed into lattice polytopes in a natural way. Since lattice polytopes are relatively simple, this decomposition is useful, in addition to being more economical than the decomposition into single weights. An expansion of characters into polytope sums follows from the polytope decomposition of weight systems. We study this polytope expansion here. A new, general formula is given for the polytope sums involved. The combinatorics of the polytope expansion are analyzed; we point out that they are reduced from those of the Weyl character formula (described by the Kostant partition function) in an optimal way. We also show that the weight multiplicities can be found easily from the polytope multiplicities, indicating explicitly the equivalence of the two descriptions. Finally, we demonstrate the utility of the polytope expansion by showing how polytope multiplicities can be used in the calculation of tensor product decompositions, and subalgebra branching rules.

  19. A Computational Approach to Competitive Range Expansions

    NASA Astrophysics Data System (ADS)

    Weber, Markus F.; Poxleitner, Gabriele; Hebisch, Elke; Frey, Erwin; Opitz, Madeleine

    2014-03-01

    Bacterial communities represent complex and dynamic ecological systems. Environmental conditions and microbial interactions determine whether a bacterial strain survives an expansion to new territory. In our work, we studied competitive range expansions in a model system of three Escherichia coli strains. In this system, a colicin producing strain competed with a colicin resistant, and with a colicin sensitive strain for new territory. Genetic engineering allowed us to tune the strains' growth rates and to study their expansion in distinct ecological scenarios (with either cyclic or hierarchical dominance). The control over growth rates also enabled us to construct and to validate a predictive computational model of the bacterial dynamics. The model rested on an agent-based, coarse-grained description of the expansion process and we conducted independent experiments on the growth of single-strain colonies for its parametrization. Furthermore, the model considered the long-range nature of the toxin interaction between strains. The integration of experimental analysis with computational modeling made it possible to quantify how the level of biodiversity depends on the interplay between bacterial growth rates, the initial composition of the inoculum, and the toxin range.

  20. Eigenfunction expansions for time dependent hamiltonians

    NASA Astrophysics Data System (ADS)

    Jauslin, H. R.; Guerin, S.; Deroussiaux, A.

    We describe a generalization of Floquet theory for non periodic time dependent Hamiltonians. It allows to express the time evolution in terms of an expansion in eigenfunctions of a generalized quasienergy operator. We discuss a conjecture on the extension of the adiabatic theorem to this type of systems, which gives a procedure for the physical preparation of Floquet states. *** DIRECT SUPPORT *** A3418380 00004

  1. Causes and consequences of magnetic cloud expansion

    NASA Astrophysics Data System (ADS)

    Démoulin, P.; Dasso, S.

    2009-05-01

    Context: A magnetic cloud (MC) is a magnetic flux rope in the solar wind (SW), which, at 1 AU, is observed ~2-5 days after its expulsion from the Sun. The associated solar eruption is observed as a coronal mass ejection (CME). Aims: Both the in situ observations of plasma velocity distribution and the increase in their size with solar distance demonstrate that MCs are strongly expanding structures. The aim of this work is to find the main causes of this expansion and to derive a model to explain the plasma velocity profiles typically observed inside MCs. Methods: We model the flux rope evolution as a series of force-free field states with two extreme limits: (a) ideal magneto-hydrodynamics (MHD) and (b) minimization of the magnetic energy with conserved magnetic helicity. We consider cylindrical flux ropes to reduce the problem to the integration of ordinary differential equations. This allows us to explore a wide variety of magnetic fields at a broad range of distances to the Sun. Results: We demonstrate that the rapid decrease in the total SW pressure with solar distance is the main driver of the flux-rope radial expansion. Other effects, such as the internal over-pressure, the radial distribution, and the amount of twist within the flux rope have a much weaker influence on the expansion. We demonstrate that any force-free flux rope will have a self-similar expansion if its total boundary pressure evolves as the inverse of its length to the fourth power. With the total pressure gradient observed in the SW, the radial expansion of flux ropes is close to self-similar with a nearly linear radial velocity profile across the flux rope, as observed. Moreover, we show that the expansion rate is proportional to the radius and to the global velocity away from the Sun. Conclusions: The simple and universal law found for the radial expansion of flux ropes in the SW predicts the typical size, magnetic structure, and radial velocity of MCs at various solar distances.

  2. Novel expansion techniques for skin grafts

    PubMed Central

    Kadam, Dinesh

    2016-01-01

    The quest for skin expansion is not restricted to cover a large area alone, but to produce acceptable uniform surfaces, robust engraftment to withstand mechanical shear and infection, with a minimal donor morbidity. Ease of the technique, shorter healing period and reproducible results are essential parameters to adopt novel techniques. Significant advances seen in four fronts of autologous grafting are: (1) Dermal–epidermal graft expansion techniques, (2) epidermal graft harvests technique, (3) melanocyte-rich basal cell therapy for vitiligo and (4) robust and faster autologous cell cultures. Meek's original concept that the sum of perimeter of smaller grafts is larger than the harvested graft, and smaller the graft size, the greater is the potential for regeneration is witnessed in newer modification. Further, as graft size becomes smaller or minced, these micrografts can survive on the wound bed exudate irrespective of their dermal orientation. Expansion produced by 4 mm × 4 mm sized Meek micrografts is 10-folds, similarly 0.8 mm × 0.8 mm size micrografts produce 100-fold expansion, which becomes 700-fold with pixel grafts of 0.3 mm × 0.3 mm size. Fractional skin harvest is another new technique with 700 μ size full thickness graft. These provide instant autologous non-cultured graft to cover extensive areas with similar quality of engraftment surface as split skin grafts. Newer tools for epidermal blister graft harvest quickly, with uniform size to produce 7-fold expansions with reproducible results. In addition, donor area heals faster with minimal scar. Melanocyte-rich cell suspension is utilised in vitiligo surgery tapping the potential of hair root melanocytes. Further advances in the cell culture to reduce the cultivation time and provide stronger epidermal sheets with dermal carrier are seen in trials. PMID:27274117

  3. 216-B-3 expansion ponds closure plan

    SciTech Connect

    Not Available

    1994-10-01

    This document describes the activities for clean closure under the Resource Conservation and Recovery Act of 1976 (RCRA) of the 216-B-3 Expansion Ponds. The 216-B-3 Expansion Ponds are operated by the US Department of Energy, Richland Operations Office (DOE-RL) and co-operated by Westinghouse Hanford Company (Westinghouse Hanford). The 216-B-3 Expansion Ponds consists of a series of three earthen, unlined, interconnected ponds that receive waste water from various 200 East Area operating facilities. The 3A, 3B, and 3C ponds are referred to as Expansion Ponds because they expanded the capability of the B Pond System. Waste water (primarily cooling water, steam condensate, and sanitary water) from various 200 East Area facilities is discharged to the Bypass pipe (Project X-009). Water discharged to the Bypass pipe flows directly into the 216-B-3C Pond. The ponds were operated in a cascade mode, where the Main Pond overflowed into the 3A Pond and the 3A Pond overflowed into the 3C Pond. The 3B Pond has not received waste water since May 1985; however, when in operation, the 3B Pond received overflow from the 3A Pond. In the past, waste water discharges to the Expansion Ponds had the potential to have contained mixed waste (radioactive waste and dangerous waste). The radioactive portion of mixed waste has been interpreted by the US Department of Energy (DOE) to be regulated under the Atomic Energy Act of 1954; the dangerous waste portion of mixed waste is regulated under RCRA.

  4. Thermal Expansion of Vacuum Plasma Sprayed Coatings

    NASA Technical Reports Server (NTRS)

    Raj, S V.; Palczer, A. R.

    2010-01-01

    Metallic Cu-8%Cr, Cu-26%Cr, Cu-8%Cr-1%Al, NiAl and NiCrAlY monolithic coatings were fabricated by vacuum plasma spray deposition processes for thermal expansion property measurements between 293 and 1223 K. The corrected thermal expansion, (DL/L(sub 0) varies with the absolute temperature, T, as (DL/L(sub 0) = A(T - 293)(sup 3) + BIT - 293)(sup 2) + C(T - 293) + D, where, A, B, C and D are thermal, regression constants. Excellent reproducibility was observed for all of the coatings except for data obtained on the Cu-8%Cr and Cu-26%Cr coatings in the first heat-up cycle, which deviated from those determined in the subsequent cycles. This deviation is attributed to the presence of residual stresses developed during the spraying of the coatings, which are relieved after the first heat-up cycle. In the cases of Cu-8%Cr and NiAl, the thermal expansion data were observed to be reproducible for three specimens. The linear expansion data for Cu-8% Cr and Cu-26%Cr agree extremely well with rule of mixture (ROM) predictions. Comparison of the data for the Cu-8%Cr coating with literature data for Cr and Cu revealed that the thermal expansion behavior of this alloy is determined by the Cu-rich matrix. The data for NiAl and NiCrAlY are in excellent agreement with published results irrespective of composition and the methods used for processing the materials. The implications of these results on coating GRCop-84 copper alloy combustor liners for reusable launch vehicles are discussed.

  5. Congenital and acquired orthopedic abnormalities in patients with myelomeningocele.

    PubMed

    Westcott, M A; Dynes, M C; Remer, E M; Donaldson, J S; Dias, L S

    1992-11-01

    This article presents a radiologic review of the spectrum of acquired and congenital orthopedic abnormalities found in patients with myelomeningocele. These abnormalities are caused predominantly by muscle imbalance, paralysis, and decreased sensation in the lower extremity. Iatrogenic injury, such as a postoperative tethered cord, may also cause bone abnormalities. Selected images were obtained from more than 800 children. Important entities presented include spinal curvatures such as kyphosis, scoliosis, and lordosis; subluxation and dislocation of the hip, coxa valga, contractures of the hip, and femoral torsion; knee deformities; rotational abnormalities of the lower extremity and external and internal torsion; ankle and foot abnormalities such as ankle valgus, calcaneus foot, congenital vertical talus (rocker-bottom deformity), and talipes equinovarus; and metaphyseal, diaphyseal, and physeal fractures. Familiarity with congenital abnormalities and an understanding of the pathogenesis of acquired disorders in patients with myelomeningocele are essential for proper radiologic interpretation and timely therapy.

  6. The time of onset of abnormal calcification in spondylometaepiphyseal dysplasia, short limb-abnormal calcification type.

    PubMed

    Tüysüz, Beyhan; Gazioğlu, Nurperi; Ungür, Savaş; Aji, Dolly Yafet; Türkmen, Seval

    2009-01-01

    A 1-month-old boy with shortness of extremities on prenatal US was referred to our department with a provisional diagnosis of achondroplasia. His height was normal but he had short extremities and platyspondyly, premature carpal epiphyses on both hands, and short tubular bones with irregular metaphyses on radiographs. Re-evaluation of the patient at the age of 1 year revealed very short height and premature calcification of the costal cartilages and epiphyses. Spondylometaepiphyseal dysplasia (SMED), short limb-abnormal calcification type was diagnosed. This condition is a very rare autosomal recessively inherited disorder, and most of the patients die in early childhood due to neurological involvement. At the age of 2 years and 5 months, a CT scan showed narrowing of the cervical spinal canal. One month later he died suddenly because of spinal cord injury. In conclusion early diagnosis is very important because the recurrence risk is high and patients may die due to early neurological complications. The time of onset of abnormal calcifications, a diagnostic finding of the disease, is at the age of around 1 year in most patients. When abnormal calcifications are not yet present, but radiological changes associated with SMED are present, this rare disease must be considered.

  7. Review of congenital inner ear abnormalities on CT temporal bone.

    PubMed

    Yiin, R S Z; Tang, P H; Tan, T Y

    2011-09-01

    The aetiology of profound hearing loss in children is complex and multifactorial. Congenital inner ear abnormality is a major cause of hearing loss in children. CT temporal bone imaging is the modality of choice in the investigation of hearing loss. Recognising the congenital abnormalities of the inner ear guides the clinician's management of the condition. This pictorial essay illustrates the congenital abnormalities of the inner ear on high resolution CT temporal bone images and correlation with developmental arrest during embryology.

  8. Abnormal Breathing Patterns Predict Extubation Failure in Neurocritically Ill Patients

    PubMed Central

    Punj, Pragya; Nattanmai, Premkumar; George, Pravin

    2017-01-01

    In neurologically injured patients, predictors for extubation success are not well defined. Abnormal breathing patterns may result from the underlying neurological injury. We present three patients with abnormal breathing patterns highlighting failure of successful extubation as a result of these neurologically driven breathing patterns. Recognizing abnormal breathing patterns may be predictive of extubation failure and thus need to be considered as part of extubation readiness. PMID:28348899

  9. Tunable thermal expansion in framework materials through redox intercalation

    NASA Astrophysics Data System (ADS)

    Chen, Jun; Gao, Qilong; Sanson, Andrea; Jiang, Xingxing; Huang, Qingzhen; Carnera, Alberto; Rodriguez, Clara Guglieri; Olivi, Luca; Wang, Lei; Hu, Lei; Lin, Kun; Ren, Yang; Lin, Zheshuai; Wang, Cong; Gu, Lin; Deng, Jinxia; Attfield, J. Paul; Xing, Xianran

    2017-02-01

    Thermal expansion properties of solids are of fundamental interest and control of thermal expansion is important for practical applications but can be difficult to achieve. Many framework-type materials show negative thermal expansion when internal cages are empty but positive thermal expansion when additional atoms or molecules fill internal voids present. Here we show that redox intercalation offers an effective method to control thermal expansion from positive to zero to negative by insertion of Li ions into the simple negative thermal expansion framework material ScF3, doped with 10% Fe to enable reduction. The small concentration of intercalated Li ions has a strong influence through steric hindrance of transverse fluoride ion vibrations, which directly controls the thermal expansion. Redox intercalation of guest ions is thus likely to be a general and effective method for controlling thermal expansion in the many known framework materials with phonon-driven negative thermal expansion.

  10. Tunable thermal expansion in framework materials through redox intercalation

    PubMed Central

    Chen, Jun; Gao, Qilong; Sanson, Andrea; Jiang, Xingxing; Huang, Qingzhen; Carnera, Alberto; Rodriguez, Clara Guglieri; Olivi, Luca; Wang, Lei; Hu, Lei; Lin, Kun; Ren, Yang; Lin, Zheshuai; Wang, Cong; Gu, Lin; Deng, Jinxia; Attfield, J. Paul; Xing, Xianran

    2017-01-01

    Thermal expansion properties of solids are of fundamental interest and control of thermal expansion is important for practical applications but can be difficult to achieve. Many framework-type materials show negative thermal expansion when internal cages are empty but positive thermal expansion when additional atoms or molecules fill internal voids present. Here we show that redox intercalation offers an effective method to control thermal expansion from positive to zero to negative by insertion of Li ions into the simple negative thermal expansion framework material ScF3, doped with 10% Fe to enable reduction. The small concentration of intercalated Li ions has a strong influence through steric hindrance of transverse fluoride ion vibrations, which directly controls the thermal expansion. Redox intercalation of guest ions is thus likely to be a general and effective method for controlling thermal expansion in the many known framework materials with phonon-driven negative thermal expansion. PMID:28181576

  11. Tunable thermal expansion in framework materials through redox intercalation.

    PubMed

    Chen, Jun; Gao, Qilong; Sanson, Andrea; Jiang, Xingxing; Huang, Qingzhen; Carnera, Alberto; Rodriguez, Clara Guglieri; Olivi, Luca; Wang, Lei; Hu, Lei; Lin, Kun; Ren, Yang; Lin, Zheshuai; Wang, Cong; Gu, Lin; Deng, Jinxia; Attfield, J Paul; Xing, Xianran

    2017-02-09

    Thermal expansion properties of solids are of fundamental interest and control of thermal expansion is important for practical applications but can be difficult to achieve. Many framework-type materials show negative thermal expansion when internal cages are empty but positive thermal expansion when additional atoms or molecules fill internal voids present. Here we show that redox intercalation offers an effective method to control thermal expansion from positive to zero to negative by insertion of Li ions into the simple negative thermal expansion framework material ScF3, doped with 10% Fe to enable reduction. The small concentration of intercalated Li ions has a strong influence through steric hindrance of transverse fluoride ion vibrations, which directly controls the thermal expansion. Redox intercalation of guest ions is thus likely to be a general and effective method for controlling thermal expansion in the many known framework materials with phonon-driven negative thermal expansion.

  12. [Thymic abnormalities in patients with myasthenia gravis].

    PubMed

    Utsugisawa, Kimiaki; Nagane, Yuriko

    2011-07-01

    Thymic abnormalities were first noticed at autopsies of patients with myasthenia gravis (MG) more than 100 years ago. The thymus is believed to play an important role in the pathogenesis of MG, an autoimmune disease mediated by antibodies against the acetylcholine receptor (AChR) of skeletal muscles. Production of these antibodies in B cells is T cell dependent. T cells potentially specific for AChR are probably generated in the thymus via nontolerogenic thymopoiesis by an aberrant function of thymic epithelial cells. However, generation of these AChR-specific T cells is not the cause of MG, because these cells are also found in healthy individuals. The pathogenetic step in MG involves the activation of these potentially AChR-specific T cells; this activation is the trigger to develop the disease and a therapeutic target. The intra-thymic activation of AChR-specific T cells is probably limited to particular types of MG patients: those with early-onset MG in whom the thymus exhibits lymphofollicular hyperplasia (TLFH) and a few patients in whom MG is associated with a thymoma. The majority of thymomas and atrophic thymuses of patients with late-onset MG, an increasingly common condition, do not exhibit this T cell-activation process. In this paper, we review the available literature on thymic changes (TLFH, thymoma, and atrophic thymus) and the relationship of these changes to the pathogenesis of MG.

  13. Coagulation abnormalities in the cirrhotic patient.

    PubMed

    Muciño-Bermejo, Jimena; Carrillo-Esper, Raúl; Uribe, Misael; Méndez-Sánchez, Nahum

    2013-01-01

    The clotting process is a dynamic array of multiple processes which can be described in four phases: platelet plug initiation and formation, clotting process propagation by the coagulation cascade, clotting termination by antithrombotic mechanisms and clot removal by fibrinolysis. The liver plays a central role in each of these phases of clotting process, as it synthesizes the majority of coagulation factors and proteins involved in fibrinolysis as well as thrombopoeitin, which is responsible for platelet production from megakaryocytes. Many pathological processes associated with cirrhosis, such as portal hypertension and endothelial dysfunction, as well as co-morbid conditions, may also alter the coagulation process. Consequently, patients with liver disease have a disturbed balance of procoagulant and anti-coagulant factors which deviates from the normal coagulation cascade. This situation poses an additional problem in the diagnostic and therapeutic approach to this group of patients, since traditional coagulation test may not be reliable for assessing bleeding or thrombotic risk and traditional transfusional strategies may not be applicable in cirrhotic patients. In this article, we review the pathophysiological bases of coagulation abnormalities, in cirrhotic patients, the diagnostic therapeutic strategies to be followed and its impact on the clinical outcome in the cirrhotic patient.

  14. Sleep abnormality in neuromyelitis optica spectrum disorder

    PubMed Central

    Song, Yijun; Pan, Liping; Fu, Ying; Sun, Na; Li, Yu-Jing; Cai, Hao; Su, Lei; Shen, Yi; Cui, Linyang

    2015-01-01

    Objectives: We investigated the sleep structure of patients with neuromyelitis optica spectrum disorder (NMOSD) and the association of abnormalities with brain lesions. Methods: This was a prospective cross-sectional study. Thirty-three patients with NMOSD and 20 matched healthy individuals were enrolled. Demographic and clinical characteristics of patients were collected. Questionnaires were used to assess quality of sleep, daytime sleepiness, fatigue, and depression. Nocturnal polysomnography was performed. Results: Compared with healthy controls, patients with NMOSD had decreases in sleep efficiency (7%; p = 0.0341), non-REM sleep N3 (12%; p < 0.0001), and arousal index (6; p = 0.0138). REM sleep increased by 4% (p = 0.0423). There were correlations between arousal index and REM% or Epworth Sleepiness Scale (r = −0.0145; p = 0.0386, respectively). Six patients with NMOSD (18%, 5 without infratentorial lesions and 1 with infratentorial lesions) had a hypopnea index >5, and all of those with sleep apnea had predominantly the peripheral type. The periodic leg movement (PLM) index was higher in patients with NMOSD than in healthy controls (20 vs 2, p = 0.0457). Surprisingly, 77% of the patients with PLM manifested infratentorial lesions. Conclusions: Sleep architecture was markedly disrupted in patients with NMOSD. Surveillance of nocturnal symptoms and adequate symptomatic control are expected to improve the quality of life of patients with NMOSD. PMID:25918736

  15. Drug-induced abnormalities of potassium metabolism.

    PubMed

    Kokot, Franciszek; Hyla-Klekot, Lidia

    2008-01-01

    Pharmacotherapy has progressed rapidly over the last 20 years with the result that general practioners more and more often use drugs which may influence potassium metabolism at the kidney or gastrointestinal level, or the transmembrane transport of potassium at the cellular level. Potassium abnormalities may result in life-theatening clinical conditions. Hypokalemia is most frequently caused by renal loss of this electrolyte (thiazide, thiazide-like and loop diuretics, glucocorticoids) and the gastrointestinal tract (laxatives, diarrhea, vomiting, external fistula), and may be the result of an increased intracellular potassium influx induced by sympathicomimetics used mostly by patients with asthma, or by insulin overdosage in diabetic subjects. The leading symptoms of hypokalemia are skeletal and smooth muscle weakness and cardiac arrhythmias. Hyperkalemia may be caused by acute or end-stage renal failure, impaired tubular excretion of potassium (blockers of the renin-angiotensin-aldosterone system, nonsteroidal anti-inflammatory drugs, cyclosporine, antifungal drugs, potassium sparing diuretics), acidemia, and severe cellular injury (tumor lysis syndrome). Hyperkalemia may be the cause of severe injury of both skeletal and smooth muscle cells. The specific treatment counteracting hyperkalemia is a bolus injection of calcium salts and, when necessary, hemodialysis.

  16. Surrogate Motherhood and Abortion for Fetal Abnormality.

    PubMed

    Walker, Ruth; van Zyl, Liezl

    2015-10-01

    A diagnosis of fetal abnormality presents parents with a difficult - even tragic - moral dilemma. Where this diagnosis is made in the context of surrogate motherhood there is an added difficulty, namely that it is not obvious who should be involved in making decisions about abortion, for the person who would normally have the right to decide - the pregnant woman - does not intend to raise the child. This raises the question: To what extent, if at all, should the intended parents be involved in decision-making? In commercial surrogacy it is thought that as part of the contractual agreement the intended parents acquire the right to make this decision. By contrast, in altruistic surrogacy the pregnant woman retains the right to make these decisions, but the intended parents are free to decide not to adopt the child. We argue that both these strategies are morally unsound, and that the problems encountered serve to highlight more fundamental defects within the commercial and altruistic models, as well as in the legal and institutional frameworks that support them. We argue in favour of the professional model, which acknowledges the rights and responsibilities of both parties and provides a legal and institutional framework that supports good decision-making. In particular, the professional model acknowledges the surrogate's right to decide whether to undergo an abortion, and the intended parents' obligation to accept legal custody of the child. While not solving all the problems that arise in surrogacy, the model provides a framework that supports good decision-making.

  17. Abnormal osmotic regulation in trpv4-/- mice

    PubMed Central

    Liedtke, Wolfgang; Friedman, Jeffrey M.

    2003-01-01

    Osmotic homeostasis is one of the most aggressively defended physiological parameters in vertebrates. However, the molecular mechanisms underlying osmotic regulation are poorly understood. The transient receptor potential channel, vanilloid subfamily (TRPV4), is an osmotically activated ion channel that is expressed in circumventricular organs in the mammalian CNS, which is an important site of osmotic sensing. We have generated trpv4-null mice and observed abnormalities of their osmotic regulation. trpv4-/- mice drank less water and became more hyperosmolar than did wild-type littermates, a finding that was seen with and without administration of hypertonic saline. In addition, plasma levels of antidiuretic hormone were significantly lower in trpv4-/- mice than in wild-type littermates after a hyperosmotic challenge. Continuous s.c. infusion of the antidiuretic hormone analogue, dDAVP, resulted in systemic hypotonicity in trpv4-/- mice, despite the fact that their renal water reabsorption capacity was normal. Thus, the response to both hyper- and hypoosmolar stimuli is impaired in trpv4-/- mice. After a hyperosmolar challenge, there was markedly reduced expression of c-FOS in the circumventricular organ, the organum vasculosum of the lamina terminalis, of trpv4-/- mice compared with wild-type mice. This finding suggests that there is an impairment of osmotic sensing in the CNS of trpv4-/- mice. These data indicate that TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS. PMID:14581612

  18. Thyroid abnormalities after therapeutic external radiation

    SciTech Connect

    Hancock, S.L.; McDougall, I.R.; Constine, L.S.

    1995-03-30

    The thyroid gland is the largest pure endocrine gland in the body and one of the organs most likely to produce clinically significant abnormalities after therapeutic external radiation. Radiation doses to the thyroid that exceed approximately 26 Gy frequently produce hypothyroidism, which may be clinically overt or subclinical, as manifested by increased serum thyrotropin and normal serum-free thyroxine concentrations. Pituitary or hypothalamic hypothyroidism may arise when the pituitary region receives doses exceeding 50 Gy with conventional, 1.8-2 Gy fractionation. Direct irradiation of the thyroid may increase the risk of Graves` disease or euthyroid Graves` ophthalmopathy. Silent thyroiditis, cystic degeneration, benign adenoma, and thyroid cancer have been observed after therapeutically relevant doses of external radiation. Direct or incidental thyroid irradiation increases the risk for well-differentiated, papillary, and follicular thyroid cancer from 15- to 53-fold. Thyroid cancer risk is highest following radiation at a young age, decreases with increasing age at treatment, and increases with follow-up duration. The potentially prolonged latent period between radiation exposure and the development of thyroid dysfunction, thyroid nodularity, and thyroid cancer means that individuals who have received neck or pituitary irradiation require careful, periodic clinical and laboratory evaluation to avoid excess morbidity. 39 refs.

  19. Abnormal hopping conduction in semiconducting polycrystalline graphene

    NASA Astrophysics Data System (ADS)

    Park, Jeongho; Mitchel, William C.; Elhamri, Said; Grazulis, Larry; Altfeder, Igor

    2013-07-01

    We report the observation of an abnormal carrier transport phenomenon in polycrystalline semiconducting graphene grown by solid carbon source molecular beam epitaxy. At the lowest temperatures in samples with small grain size, the conduction does not obey the two-dimensional Mott-type variable-range hopping (VRH) conduction often reported in semiconducting graphene. The hopping exponent p is found to deviate from the 1/3 value expected for Mott VRH with several samples exhibiting a p=2/5 dependence. We also show that the maximum energy difference between hopping sites is larger than the activation energy for nearest-neighbor hopping, violating the assumptions of the Mott model. The 2/5 dependence more closely agrees with the quasi-one-dimensional VRH model proposed by Fogler, Teber, and Shklovskii (FTS). In the FTS model, conduction occurs by tunneling between neighboring metallic wires. We suggest that metallic edge states and conductive grain boundaries play the role of the metallic wires in the FTS model.

  20. Salivary abnormalities in Prader-Willi Syndrome

    SciTech Connect

    Hart, S.; Poshva, C.

    1994-09-01

    Although abnormal saliva is a well documented finding in PWS, little is known about the saliva in these individuals. We have recently undertaken a study to characterize the salivary composition from PW patients and to see if there is any correlation with their underlying molecular diagnosis (deletion vs. disomy). We have collected whole saliva on 3 patients; 2 had normal high-resolution karyotype analysis (Cases 1 & 3) and 1 had a deletion of 15q11q13 (Case 3). For all parameters, Case 3`s values were notably different from those of his unaffected sibling. The salivary flow rates and concentrations for all 3 PW patients are similar and are significantly different from normal controls (mean {plus_minus} SE) (p<0.05). Although this data is from only 3 PW patients, it provides valuable information. First, decreased flow appears to be due to an effect of PWS and not medications since Cases 2 & 3 are not on any medications. Second, decreased flow appears to be present in younger as well as older individuals. Third, deviations from normal in the salivary composition are evident. It is possible that these alterations are concentration effects relative to a decrease in flow rate. We are currently obtaining saliva from more PW individuals to see if these alterations are present in all PW patients and whether they can be applied as a screening test.