Specific binding of Haemophilus influenzae to minor gangliosides of human respiratory epithelial cells.

PubMed Central

Fakih, M G; Murphy, T F; Pattoli, M A; Berenson, C S

1997-01-01

Gangliosides are sialylated glycosphingolipids that serve as receptors for various bacteria. To investigate endogenous gangliosides of human respiratory epithelial cells as potential receptors for Haemophilus influenzae, three strains, including nontypeable H. influenzae (NTHI) 1479, and isogenic fimbriated (f+) and nonfimbriated (f0) H. influenzae type b 770235, were 3H labeled and overlaid on two-dimensional thin-layer chromatography (TLC) plates containing either purified HEp-2 gangliosides or murine brain gangliosides. NTHI 1479 bound exclusively to two distinct minor ganglioside doublets, with mobilities near that of GM1. These minor gangliosides comprised only 14.2 and 9.4% of the total, respectively. NTHI 1479 also bound to a distinct ganglioside of human macrophages whose chromatographic mobilities closely resemble those of one of the NTHI-binding gangliosides of HEp-2 cells. H. influenzae type b 770235 f+ and f0 each bound to a different minor HEp-2 ganglioside doublet, with proportionately weaker affinity for a major ganglioside doublet. Remarkably, none of the three strains bound to any murine brain gangliosides. Moreover, when 80 to 90% of sialic acid residues were enzymatically removed from HEp-2 gangliosides, NTHI 1479 binding was proportionately impaired, compared with untreated controls. Our findings support a role for specific gangliosides of specific cells as receptors for H. influenzae strains. Our findings further demonstrate that individual minor gangliosides possess unique biological properties. PMID:9125549

Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis.

PubMed

Harlalka, Gaurav V; Lehman, Anna; Chioza, Barry; Baple, Emma L; Maroofian, Reza; Cross, Harold; Sreekantan-Nair, Ajith; Priestman, David A; Al-Turki, Saeed; McEntagart, Meriel E; Proukakis, Christos; Royle, Louise; Kozak, Radoslaw P; Bastaki, Laila; Patton, Michael; Wagner, Karin; Coblentz, Roselyn; Price, Joy; Mezei, Michelle; Schlade-Bartusiak, Kamilla; Platt, Frances M; Hurles, Matthew E; Crosby, Andrew H

2013-12-01

Glycosphingolipids are ubiquitous constituents of eukaryotic plasma membranes, and their sialylated derivatives, gangliosides, are the major class of glycoconjugates expressed by neurons. Deficiencies in their catabolic pathways give rise to a large and well-studied group of inherited disorders, the lysosomal storage diseases. Although many glycosphingolipid catabolic defects have been defined, only one proven inherited disease arising from a defect in ganglioside biosynthesis is known. This disease, because of defects in the first step of ganglioside biosynthesis (GM3 synthase), results in a severe epileptic disorder found at high frequency amongst the Old Order Amish. Here we investigated an unusual neurodegenerative phenotype, most commonly classified as a complex form of hereditary spastic paraplegia, present in families from Kuwait, Italy and the Old Order Amish. Our genetic studies identified mutations in B4GALNT1 (GM2 synthase), encoding the enzyme that catalyzes the second step in complex ganglioside biosynthesis, as the cause of this neurodegenerative phenotype. Biochemical profiling of glycosphingolipid biosynthesis confirmed a lack of GM2 in affected subjects in association with a predictable increase in levels of its precursor, GM3, a finding that will greatly facilitate diagnosis of this condition. With the description of two neurological human diseases involving defects in two sequentially acting enzymes in ganglioside biosynthesis, there is the real possibility that a previously unidentified family of ganglioside deficiency diseases exist. The study of patients and animal models of these disorders will pave the way for a greater understanding of the role gangliosides play in neuronal structure and function and provide insights into the development of effective treatment therapies.

Novel Ganglioside-mediated Entry of Botulinum Neurotoxin Serotype D into Neurons

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

Kroken, Abby R.; Karalewitz, Andrew P.-A.; Fu, Zhuji

2012-02-07

Botulinum Neurotoxins (BoNTs) are organized into seven serotypes, A-G. Although several BoNT serotypes enter neurons through synaptic vesicle cycling utilizing dual receptors (a ganglioside and a synaptic vesicle-associated protein), the entry pathway of BoNT/D is less well understood. Although BoNT/D entry is ganglioside-dependent, alignment and structural studies show that BoNT/D lacks key residues within a conserved ganglioside binding pocket that are present in BoNT serotypes A, B, E, F, and G, which indicate that BoNT/D-ganglioside interactions may be unique. In this study BoNT/D is shown to have a unique association with ganglioside relative to the other BoNT serotypes, utilizing amore » ganglioside binding loop (GBL, residues Tyr-1235-Ala-1245) within the receptor binding domain of BoNT/D (HCR/D) via b-series gangliosides, including GT1b, GD1b, and GD2. HCR/D bound gangliosides and entered neurons dependent upon the aromatic ring of Phe-1240 within the GBL. This is the first BoNT-ganglioside interaction that is mediated by a phenylalanine. In contrast, Trp-1238, located near the N terminus of the ganglioside binding loop, was mostly solvent-inaccessible and appeared to contribute to maintaining the loop structure. BoNT/D entry and intoxication were enhanced by membrane depolarization via synaptic vesicle cycling, where HCR/D colocalized with synaptophysin, a synaptic vesicle marker, but immunoprecipitation experiments did not detect direct association with synaptic vesicle protein 2. Thus, BoNT/D utilizes unique associations with gangliosides and synaptic vesicles to enter neurons, which may facilitate new neurotoxin therapies.« less

Ganglioside biochemistry.

PubMed

Kolter, Thomas

2012-01-01

Gangliosides are sialic acid-containing glycosphingolipids. They occur especially on the cellular surfaces of neuronal cells, where they form a complex pattern, but are also found in many other cell types. The paper provides a general overview on their structures, occurrence, and metabolism. Key functional, biochemical, and pathobiochemical aspects are summarized.

Ganglioside Biochemistry

PubMed Central

Kolter, Thomas

2012-01-01

Gangliosides are sialic acid-containing glycosphingolipids. They occur especially on the cellular surfaces of neuronal cells, where they form a complex pattern, but are also found in many other cell types. The paper provides a general overview on their structures, occurrence, and metabolism. Key functional, biochemical, and pathobiochemical aspects are summarized. PMID:25969757

New Insights on Non-Enzymatic Oxidation of Ganglioside GM1 Using Mass Spectrometry

NASA Astrophysics Data System (ADS)

Couto, Daniela; Melo, Tânia; Maciel, Elisabete; Campos, Ana; Alves, Eliana; Guedes, Sofia; Domingues, M. Rosário M.; Domingues, Pedro

2016-12-01

Gangliosides are acidic glycosphingolipids that are present in cell membranes and lipid raft domains, being particularly abundant in central nervous systems. They participate in modulating cell membrane properties, cell-cell recognition, cell regulation, and signaling. Disturbance in ganglioside metabolism has been correlated with the development of diseases, such as neurodegenerative diseases, and in inflammation. Both conditions are associated with an increased production of reactive oxidation species (ROS) that can induce changes in the structure of biomolecules, including lipids, leading to the loss or modification of their function. Oxidized phospholipids are usually involved in chronic diseases and inflammation. However, knowledge regarding oxidation of gangliosides is scarce. In order to evaluate the effect of ROS in gangliosides, an in vitro biomimetic model system was used to study the susceptibility of GM1 (Neu5Ac α2-3(Gal β1-3GalNAc β1-4)Gal β1-4Glc β1Cer) to undergo oxidative modifications. Oxidation of GM1 under Fenton reaction conditions was monitored using high resolution electrospray ionization-mass spectrometry (ESI-MS) and tandem mass spectrometry (ESI-MS/MS). Upon oxidation, GM1 underwent oxidative cleavages in the carbohydrate chain, leading to the formation of other gangliosides GM2 (GalNAcβ1-4Gal(Neu5Acα2-3)1-4Glcβ1Cer), GM3 (Neu5Acα2-3Galβ1-4Glcβ1Cer), asialo-GM1 (Gal β1-3GalNAc β1-4Gal β1-4Glc β1Cer), asialo-GM2 (GalNAc β1-4Gal β1-4Glc β1Cer), of the small glycolipids lactosylceramide (LacCer), glucosylceramide (GlcCer), and of ceramide (Cer). In addition, oxygenated GM1 and GM2 (as keto and hydroxy derivatives), glycans, oxidized glycans, and oxidized ceramides were also identified. Nonenzymatic oxidation of GM1 under oxidative stress contributes to the generation of other gangliosides that may participate in the imbalance of gangliosides metabolism in vivo, through uncontrolled enzymatic pathways and, consequently, play

Cancer vaccines: an update with special focus on ganglioside antigens.

PubMed

Bitton, Roberto J; Guthmann, Marcel D; Gabri, Mariano R; Carnero, Ariel J L; Alonso, Daniel F; Fainboim, Leonardo; Gomez, Daniel E

2002-01-01

Vaccine development is one of the most promising and exciting fields in cancer research; numerous approaches are being studied to developed effective cancer vaccines. The aim of this form of therapy is to teach the patient's immune system to recognize the antigens expressed in tumor cells, but not in normal tissue, to be able to destroy these abnormal cells leaving the normal cells intact. In other words, is an attempt to teach the immune system to recognize antigens that escaped the immunologic surveillance and are by it, therefore able to survive and, in time, disseminate. However each research group developing a cancer vaccine, uses a different technology, targeting different antigens, combining different carriers and adjuvants, and using different immunization schedules. Most of the vaccines are still experimental and not approved by the US or European Regulatory Agencies. In this work, we will offer an update in the knowledge in cancer immunology and all the anticancer vaccine approaches, with special emphasis in ganglioside based vaccines. It has been demonstrated that quantitative and qualitative changes occur in ganglioside expression during the oncogenic transformation. Malignant transformation appears to activate enzymes associated with ganglioside glycosylation, resulting in altered patterns of ganglioside expression in tumors. Direct evidence of the importance of gangliosides as potential targets for active immunotherapy has been suggested by the observation that human monoclonal antibodies against these glycolipids induce shrinkage of human cutaneous melanoma metastasis. Thus, the cellular over-expression and shedding of gangliosides into the interstitial space may play a central role in cell growth regulation, immune tolerance and tumor-angiogenesis, therefore representing a new target for anticancer therapy. Since 1993 researchers at the University of Buenos Aires and the University of Quilmes (Argentina), have taken part in a project carried out by

Botulinum neurotoxin serotype C associates with dual ganglioside receptors to facilitate cell entry.

PubMed

Karalewitz, Andrew P-A; Fu, Zhuji; Baldwin, Michael R; Kim, Jung-Ja P; Barbieri, Joseph T

2012-11-23

How botulinum neurotoxin serotype C (BoNT/C) enters neurons is unclear. BoNT/C utilizes dual gangliosides as host cell receptors. BoNT/C accesses gangliosides on the plasma membrane. Plasma membrane accessibility of the dual ganglioside receptors suggests synaptic vesicle exocytosis may not be necessary to expose BoNT/C receptors. Botulinum neurotoxins (BoNTs) cleave SNARE proteins in motor neurons that inhibits synaptic vesicle (SV) exocytosis, resulting in flaccid paralysis. There are seven BoNT serotypes (A-G). In current models, BoNTs initially bind gangliosides on resting neurons and upon SV exocytosis associate with the luminal domains of SV-associated proteins as a second receptor. The entry of BoNT/C is less clear. Characterizing the heavy chain receptor binding domain (HCR), BoNT/C was shown to utilize gangliosides as dual host receptors. Crystallographic and biochemical studies showed that the two ganglioside binding sites, termed GBP2 and Sia-1, were independent and utilized unique mechanisms to bind complex gangliosides. The GBP2 binding site recognized gangliosides that contained a sia5 sialic acid, whereas the Sia-1 binding site recognized gangliosides that contained a sia7 sialic acid and sugars within the backbone of the ganglioside. Utilizing gangliosides that uniquely recognized the GBP2 and Sia-1 binding sites, HCR/C entry into Neuro-2A cells required both functional ganglioside binding sites. HCR/C entered cells differently than the HCR of tetanus toxin, which also utilizes dual gangliosides as host receptors. A point-mutated HCR/C that lacked GBP2 binding potential retained the ability to bind and enter Neuro-2A cells. This showed that ganglioside binding at the Sia-1 site was accessible on the plasma membrane, suggesting that SV exocytosis may not be required to expose BoNT/C receptors. These studies highlight the utility of BoNT HCRs as probes to study the role of gangliosides in neurotransmission.

Approaches in the study of ganglioside metabolism

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

Tettamanti, G.; Ghidoni, R.; Sonnino, S.

1984-01-01

Ganglioside GM1, /sup 3/H-labeled in the sphingosine or terminal galactose moiety was injected into mice and its metabolic fate in the liver was followed. After administration of sphingosine-labeled GM1 all major liver gangliosides (GM3, GM2, GM1, GD1a-NeuAc, NeuG1) became radioactive, the radioactivity residing in all cases on the sphingosine moiety. The specific radioactivity was highest on GM1, followed by GM2, GM3 and GD1a-NeuAc, NeuG1. Several neutral glycosphingolipids and sphingomyelin were also formed. After administration of galactose-labelled GM1 the only radioactive gangliosides present in the liver were GM1 and GD1a-NeuAc, NeuG1, both carrying the radioactivity on the terminal galactose residue, withmore » no formation of labelled neutral glycosphingolipids. Subcellular studies gave clear evidence that GM1, after being taken up by the liver, was mainly degraded to GM2, GM3 and neutral glycosphingolipids at the level of lysosomes. A part of it was sialylated to more complex gangliosides and some of its metabolic by-products were used for the biosynthesis of other sphingolipid species, likely at the level of the Golgi apparatus. All this suggests that exogenous GM1 is introduced in the metabolic routes of endogenous gangliosides and of other sphingolipids, which are operating in the liver.« less

Protective Role of Endogenous Gangliosides for Lysosomal Pathology in a Cellular Model of Synucleinopathies

PubMed Central

Wei, Jianshe; Fujita, Masayo; Nakai, Masaaki; Waragai, Masaaki; Sekigawa, Akio; Sugama, Shuei; Takenouchi, Takato; Masliah, Eliezer; Hashimoto, Makoto

2009-01-01

Gangliosides may be involved in the pathogenesis of Parkinson’s disease and related disorders, although the precise mechanisms governing this involvement remain unknown. In this study, we determined whether changes in endogenous ganglioside levels affect lysosomal pathology in a cellular model of synucleinopathy. For this purpose, dementia with Lewy body-linked P123H β-synuclein (β-syn) neuroblastoma cells transfected with α-synuclein were used as a model system because these cells were characterized as having extensive formation of lysosomal inclusions bodies. Treatment of these cells with d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosyl ceramide synthase, resulted in various features of lysosomal pathology, including compromised lysosomal activity, enhanced lysosomal membrane permeabilization, and increased cytotoxicity. Consistent with these findings, expression levels of lysosomal membrane proteins, ATP13A2 and LAMP-2, were significantly decreased, and electron microscopy demonstrated alterations in the lysosomal membrane structures. Furthermore, the accumulation of both P123H β-syn and α-synuclein proteins was significant in PDMP-treated cells because of the suppressive effect of PDMP on the autophagy pathway. Finally, the detrimental effects of PDMP on lysosomal pathology were significantly ameliorated by the addition of gangliosides to the cultured cells. These data suggest that endogenous gangliosides may play protective roles against the lysosomal pathology of synucleinopathies. PMID:19349362

Direct evidence that ganglioside is an integral component of the thyrotropin receptor

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

Kielczynski, W.; Harrison, L.C.; Leedman, P.J.

1991-03-01

Gangliosides were extracted from purified human and porcine thyrotropin (TSH) receptors (TSH-R) and were detected by probing with an {sup 125}I-labeled sialic acid-specific lectin, Limax flavus agglutinin. Gangliosides copurified with human and porcine TSH-R migrated between monosialoganglioside GM1 and disialoganglioside GD1a. Ceramide glycanase digestion of the purified human TSH-R-associated glycolipid confirmed its ganglioside nature. It was resistant to Vibrio cholerae sialidase, which digest all gangliosides except GM1, but was sensitive to Arthrobacter ureafaciens sialidase, which digests all gangliosides including GM1. These findings indicate that the human TSH-R contains ganglioside that belongs to the galactosyl({beta}1{r arrow} 3)-N-acetylgalactosaminyl({beta}1{r arrow} 4)-(N-acetylneuraminyl({alpha}2{r arrow} 3))galactosyl({beta}1more » {r arrow} 4)glucosyl({beta}1 {r arrow} 1)ceramide (GM1) family. Its intimate association with receptor protein implies a key role for ganglioside in the structure and function of the TSH-R.« less

Rapid and sensitive MRM-based mass spectrometry approach for systematically exploring ganglioside-protein interactions.

PubMed

Tian, Ruijun; Jin, Jing; Taylor, Lorne; Larsen, Brett; Quaggin, Susan E; Pawson, Tony

2013-04-01

Gangliosides are ubiquitous components of cell membranes. Their interactions with bacterial toxins and membrane-associated proteins (e.g. receptor tyrosine kinases) have important roles in the regulation of multiple cellular functions. Currently, an effective approach for measuring ganglioside-protein interactions especially in a large-scale fashion is largely missing. To this end, we report a facile MS-based approach to explore gangliosides extracted from cells and measure their interactions with protein of interest globally. We optimized a two-step protocol for extracting total gangliosides from cells within 2 h. Easy-to-use magnetic beads conjugated with a protein of interest were used to capture interacting gangliosides. To measure ganglioside-protein interaction on a global scale, we applied a high-sensitive LC-MS system, containing hydrophilic interaction LC separation and multiple reaction monitoring-based MS for ganglioside detection. Sensitivity for ganglioside GM1 is below 100 pg, and the whole analysis can be done in 20 min with isocratic elution. To measure ganglioside interactions with soluble vascular endothelial growth factor receptor 1 (sFlt1), we extracted and readily detected 36 species of gangliosides from perivascular retinal pigment epithelium cells across eight different classes. Twenty-three ganglioside species have significant interactions with sFlt1 as compared with IgG control based on p value cutoff <0.05. These results show that the described method provides a rapid and high-sensitive approach for systematically measuring ganglioside-protein interactions. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Imaging mass spectrometry detection of gangliosides species in the mouse brain following transient focal cerebral ischemia and long-term recovery.

PubMed

Whitehead, Shawn N; Chan, Kenneth H N; Gangaraju, Sandhya; Slinn, Jacqueline; Li, Jianjun; Hou, Sheng T

2011-01-01

Gangliosides, a member of the glycosphingolipid family, are heterogeneously expressed in biological membranes and are particularly enriched within the central nervous system. Gangliosides consist of mono- or poly-sialylated oligosaccharide chains of variable lengths attached to a ceramide unit and are found to be intimately involved in brain disease development. The purpose of this study is to examine the spatial profile of ganglioside species using matrix-assisted laser desorption/ionization (MALDI) imaging (IMS) following middle cerebral artery occlusion (MCAO) reperfusion injury in the mouse. IMS is a powerful method to not only discriminate gangliosides by their oligosaccharide components, but also by their carbon length within their sphingosine base. Mice were subjected to a 30 min unilateral MCAO followed by long-term survival (up to 28 days of reperfusion). Brain sections were sprayed with the matrix 5-Chloro-2-mercaptobenzothiazole, scanned and analyzed for a series of ganglioside molecules using an Applied Biosystems 4800 MALDI TOF/TOF. Traditional histological and immunofluorescence techniques were performed to assess brain tissue damage and verification of the expression of gangliosides of interest. Results revealed a unique anatomical profile of GM1, GD1 and GT1b (d18:1, d20:1 as well as other members of the glycosphingolipid family). There was marked variability in the ratio of expression between ipsilateral and contralateral cortices for the various detected ganglioside species following MCAO-reperfusion injury. Most interestingly, MCAO resulted in the transient induction of both GM2 and GM3 signals within the ipsilateral hemisphere; at the border of the infarcted tissue. Taken together, the data suggest that brain region specific expression of gangliosides, particularly with respect to hydrocarbon length, may play a role in neuronal responses to injury.

The biologic role of ganglioside in neuronal differentiation--effects of GM1 ganglioside on human neuroblastoma SH-SY5Y cells.

PubMed Central

Lee, M. C.; Lee, W. S.; Park, C. S.; Juhng, S. W.

1994-01-01

Human neuroblastoma SH-SY5Y cell is a cloned cell line which has many attractive features for the study of neuronal proliferation and neurite outgrowth, because it has receptors for insulin, IGF-I and PDGF. Gangliosides are sialic acid containing glycosphingolipids which form an integral part of the plasma membrane of many mammalian cells. They inhibit cell growth mediated by tyrosine kinase receptors and ligand-stimulated tyrosine kinase activity, and autophosphorylation of EGF(epidermal growth factor) and PDGF receptors. The experiment was designed to study the effects of GM1 ganglioside on growth of human neuroblastoma SH-SY5Y cells stimulated with trophic factor in vitro. The cells were plated in Eagle's minimum essential medium without serum. The number and morphologic change of SH-SY5Y cells were evaluated in the serum free medium added GM1 ganglioside with insulin or PDGF. SH-SY5Y cells were maintained for six days in serum-free medium, and then cultured for over two weeks in serum-free medium containing either insulin or PDGF. The effect of insulin on cell proliferation developed earlier and was more potent than that of PDGF. These proliferative effects were inhibited by GM1 ganglioside, and the cells showed prominent neurites outgrowth. These findings suggest that GM1 ganglioside inhibits the cell proliferation mediated by tyrosine kinase receptors and directly induces neuritogenesis as one of the neurotrophic factors. PMID:7986393

The role of gangliosides in brain development and the potential benefits of perinatal supplementation.

PubMed

Ryan, Jennifer M; Rice, Gregory E; Mitchell, Murray D

2013-11-01

The maternal diet provides critical nutrients that can influence fetal and infant brain development and function. This review highlights the potential benefits of maternal dietary ganglioside supplementation on fetal and infant brain development. English-language systematic reviews, preclinical studies, and clinical studies were obtained through searches on PubMed. Reports were selected if they included benefits and harms of maternal ganglioside supplementation during pregnancy or ganglioside-supplemented formula after pregnancy. The potential benefits of ganglioside supplementation were explored by investigating the following: (1) their role in neural development, (2) their therapeutic use in neural injury and disease, (3) their presence in human breast milk, and (4) their use as a dietary supplement during or after pregnancy. Preclinical studies indicate that ganglioside supplementation at high doses (1% of total dietary intake) can significantly increase cognitive development and body weight when given prenatally. However, lower ganglioside supplementation doses have no beneficial cognitive effects, even when given throughout pregnancy and lactation. In human clinical trials, infants given formula supplemented with gangliosides showed increased cognitive development and an increase in ganglioside content. Ganglioside supplementation may promote brain development and function in offspring when administered at the optimum dosage. We propose that prenatal maternal dietary supplementation with gangliosides throughout pregnancy may promote greater long-term effects on brain development and function. Before this concept can be encouraged in preconception clinics, future research and clinical trials are needed to confirm the ability of dietary gangliosides to improve cognitive development, but available results already encourage this area of research. © 2013.

The effect of exogenous GM1 ganglioside on kindled-amygdaloid seizures.

PubMed

Albertson, T E; Walby, W F

1987-01-01

The effects of 12 daily doses of 30 mg/kg GM1 ganglioside i.p. on the acquisition of kindled-amygdaloid seizures in the rat was studied. No modification in the rate of kindling or the expression of the elicited seizures was noted during the acquisition phase. Further studies with additional fully amygdaloid kindled rats failed to show significant modification of suprathreshold or threshold elicited seizures after single 30-60 mg/kg i.p. doses of GM1 ganglioside. Despite previous studies which have shown antibodies to GM1 ganglioside to be convulsive, no anticonvulsant activity was demonstrated in this study with exogenous GM1 ganglioside using a battery of kindled-amygdaloid seizure tests in the rat.

Water response to ganglioside GM1 surface remodelling.

PubMed

Brocca, P; Rondelli, V; Mallamace, F; Di Bari, M T; Deriu, A; Lohstroh, W; Del Favero, E; Corti, M; Cantu', L

2017-01-01

Gangliosides are biological glycolipids participating in rafts, structural and functional domains of cell membranes. Their headgroups are able to assume different conformations when packed on the surface of an aggregate, more lying or standing. Switching between different conformations is possible, and is a collective event. Switching can be induced, in model systems, by concentration or temperature increase, then possibly involving ganglioside-water interaction. In the present paper, the effect of GM1 ganglioside headgroup conformation on the water structuring and interactions is addressed. Depolarized Rayleigh Scattering, Raman Scattering, Quasielastic Neutron Scattering and NMR measurements were performed on GM1 ganglioside solutions, focusing on solvent properties. All used techniques agree in evidencing differences in the structure and dynamics of solvent water on different time-and-length scales in the presence of either GM1 headgroup conformations. In general, all results indicate that both the structural properties of solvent water and its interactions with the sugar headgroups of GM1 respond to surface remodelling. The extent of this modification is much higher than expected and, interestingly, ganglioside headgroups seem to turn from cosmotropes to chaotropes upon collective rearrangement from the standing- to the lying-conformation. In a biological perspective, water structure modulation could be one of the physico-chemical elements contributing to the raft strategy, both for rafts formation and persistence and for their functional aspects. In particular, the interaction with approaching bodies could be favoured or inhibited or triggered by complex-sugar-sequence conformational switch. This article is part of a Special Issue entitled "Science for Life" Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazù and Dr. Federica Migliardo. Copyright © 2016 Elsevier B.V. All rights reserved.

Protective effect of gangliosides on DNA in human spermatozoa exposed to cryopreservation.

PubMed

Gavella, Mirjana; Lipovac, Vaskresenija; Garaj-Vrhovac, Verica; Gajski, Goran

2012-01-01

Gangliosides, the sialic acid-containing glycosphyngolipids, are amphiphilic compounds which in micellar form affect the properties and functions of a cellular membrane. The aim of this study was to test whether exogenous gangliosides supplied to cryopreservation media before freezing could protect sperm cells from cryopreservation-induced DNA damage assessed by Comet assay. Additionally, to investigate whether gangliosides were also able to reduce membrane integrity damage, malonaldialdehyde as a measure of lipid peroxidation and sperm-specific lactate dehydrogenase-C4 activity as an enzyme marker of sperm membrane leakage were determined. The monosialogangliosides (GM1) and trisialogangliosides (GT1b) were examined at a concentration of 100 μM, which was above their respective critical micellar concentrations. Exogenous gangliosides were not found to protect sperm membrane from lipid peroxidation. However, a freezing-/thawing-induced increase in Comet parameters was equally significantly prevented by the presence of both GM1 and GT1b (P < .05), indicating that the ceramide moiety, rather than the polar groups, is involved in the protective ability of gangliosides. The observed phenomena suggest that ganglioside micelles could modulate hydrophobic properties of the sperm membrane responsible for better tolerance to DNA fragmentation, thus protecting DNA integrity from cryopreservation-induced damage.

Structure of ganglioside with CAD blood group antigen activity

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

Gillard, B.K.; Blanchard, D.; Cartron, J.P.

1986-05-01

The novel erythrocyte ganglioside which carries the blood group Cad determinant has been isolated, and its structure has been determined. The ganglioside contained Glu:Gal:GalNAc:GlcNAc in a molar ratio of 1.00:1.94:0.93:0.95. The ganglioside binds Helix pomatia lectin and its chromatographic mobility is similar to G/sub D3/. After treatment with ..beta..-hexosaminidase (human placenta HexA) the product migrated with sialosylparagloboside (SPG), no longer binds Helix lectin, and binds a human anti-SPG antibody. Treatment of this material with neuraminidase (V. cholera) yielded a product with the mobility of paragloboside that bound monoclonal antibody 1B2. NMR analysis revealed that the terminal GalNAc is linked ..beta..1-4more » to Gal, and confirms the structure proposed previously: GalNAc..beta..1-4(NeuAc..cap alpha..2-3)Gal..beta..1-4GlcNAc..beta..1-3Gal..beta..1-4Glc-Cer. This structure is consistent with the previous demonstration that a compound with the same chromatographic mobility as the Cad ganglioside could be synthesized by enzymatic transfer of GalNAc to sialosylparagloboside.« less

Effects of Gangliosides on the Activity of the Plasma Membrane Ca2+-ATPase

PubMed Central

Jiang, Lei; Bechtel, Misty D.; Bean, Jennifer L.; Winefield, Robert; Williams, Todd D.; Zaidi, Asma; Michaelis, Elias K.; Michaelis, Mary L.

2014-01-01

Control of intracellular calcium concentrations ([Ca2+]i) is essential for neuronal function, and the plasma membrane Ca2+-ATPase (PMCA) is crucial for the maintenance of low [Ca2+]i. We previously reported on loss of PMCA activity in brain synaptic membranes during aging. Gangliosides are known to modulate Ca2+ homeostasis and signal transduction in neurons. In the present study, we observed age-related changes in the ganglioside composition of synaptic plasma membranes. This led us to hypothesize that alterations in ganglioside species might contribute to the age-associated loss of PMCA activity. To probe the relationship between changes in endogenous ganglioside content or composition and PMCA activity in membranes of cortical neurons, we induced depletion of gangliosides by treating neurons with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP). This caused a marked decrease in the activity of PMCA, which suggested a direct correlation between ganglioside content and PMCA activity. Neurons treated with neuraminidase exhibited an increase in GM1 content, a loss in poly-sialoganglioside content, and a decrease in PMCA activity that was greater than that produced by D-PDMP treatment. Thus, it appeared that poly-sialogangliosides had a stimulatory effect whereas mono-sialogangliosides had the opposite effect. Our observations add support to previous reports of PMCA regulation by gangliosides by demonstrating that manipulations of endogenous ganglioside content and species affect the activity of PMCA in neuronal membranes. Furthermore, our studies suggest that age-associated loss in PMCA activity may result in part from changes in the lipid environment of this Ca2+ transporter. PMID:24434060

Serum antibodies against gangliosides and Campylobacter jejuni lipopolysaccharides in Miller Fisher syndrome.

PubMed Central

Neisser, A; Bernheimer, H; Berger, T; Moran, A P; Schwerer, B

1997-01-01

Seven patients with Miller Fisher syndrome (MFS), six in the acute phase and one in the recovery phase, were investigated for serum antibodies against gangliosides and purified lipopolysaccharides (LPS) from different strains of Campylobacter jejuni, including the MFS-associated serotypes O:2 and O:23. Immunoglobulin G antibodies against gangliosides GT1a and GQ1b were found in five of six patients in the acute phase of disease. Three of these patients also displayed antibodies to ganglioside GD2, a finding not previously reported for MFS. All anti-GT1a- and anti-GQ1b-seropositive patients showed antibody binding to C. jejuni LPS, predominantly to O:2 and O:23 LPS. Antibody cross-reactivity between gangliosides GT1a and GQ1b and O:2 and O:23 LPS was demonstrated by adsorption studies. This cross-reactivity between gangliosides and C.jejuni LPS, which is obviously due to oligosaccharide homologies, may be an important pathogenetic factor in the development of MFS after C. jejuni infection. PMID:9317004

Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration.

PubMed

Boutry, Maxime; Branchu, Julien; Lustremant, Céline; Pujol, Claire; Pernelle, Julie; Matusiak, Raphaël; Seyer, Alexandre; Poirel, Marion; Chu-Van, Emeline; Pierga, Alexandre; Dobrenis, Kostantin; Puech, Jean-Philippe; Caillaud, Catherine; Durr, Alexandra; Brice, Alexis; Colsch, Benoit; Mochel, Fanny; El Hachimi, Khalid Hamid; Stevanin, Giovanni; Darios, Frédéric

2018-06-26

Lysosome membrane recycling occurs at the end of the autophagic pathway and requires proteins that are mostly encoded by genes mutated in neurodegenerative diseases. However, its implication in neuronal death is still unclear. Here, we show that spatacsin, which is required for lysosome recycling and whose loss of function leads to hereditary spastic paraplegia 11 (SPG11), promotes clearance of gangliosides from lysosomes in mouse and human SPG11 models. We demonstrate that spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes. Gangliosides contributed to the accumulation of autophagy markers in lysosomes and to neuronal death. In contrast, decreasing ganglioside synthesis prevented neurodegeneration and improved motor phenotype in a SPG11 zebrafish model. Our work reveals how inhibition of lysosome membrane recycling leads to the deleterious accumulation of gangliosides, linking lysosome recycling to neurodegeneration. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Imbalance in Fatty-Acid-Chain Length of Gangliosides Triggers Alzheimer Amyloid Deposition in the Precuneus

PubMed Central

Oikawa, Naoto; Matsubara, Teruhiko; Fukuda, Ryoto; Yasumori, Hanaki; Hatsuta, Hiroyuki; Murayama, Shigeo; Sato, Toshinori; Suzuki, Akemi; Yanagisawa, Katsuhiko

2015-01-01

Amyloid deposition, a crucial event of Alzheimer’s disease (AD), emerges in distinct brain regions. A key question is what triggers the assembly of the monomeric amyloid ß-protein (Aß) into fibrils in the regions. On the basis of our previous findings that gangliosides facilitate the initiation of Aß assembly at presynaptic neuritic terminals, we investigated how lipids, including gangliosides, cholesterol and sphingomyelin, extracted from synaptic plasma membranes (SPMs) isolated from autopsy brains were involved in the Aß assembly. We focused on two regions of the cerebral cortex; precuneus and calcarine cortex, one of the most vulnerable and one of the most resistant regions to amyloid deposition, respectively. Here, we show that lipids extracted from SPMs isolated from the amyloid-bearing precuneus, but neither the amyloid-free precuneus nor the calcarine cortex, markedly accelerate the Aß assembly in vitro. Through liquid chromatography-mass spectrometry of the lipids, we identified an increase in the ratio of the level of GD1b-ganglioside containing C20:0 fatty acid to that containing C18:0 as a cause of the enhanced Aß assembly in the precuneus. Our results suggest that the local glycolipid environment play a critical role in the initiation of Alzheimer amyloid deposition. PMID:25798597

The function of cancer-shed gangliosides in macrophage phenotype: involvement with angiogenesis.

PubMed

Chung, Tae-Wook; Choi, Hee-Jung; Park, Mi-Ju; Choi, Hee-Jin; Lee, Syng-Ook; Kim, Keuk-Jun; Kim, Cheorl-Ho; Hong, Changwan; Kim, Kyun-Ha; Joo, Myungsoo; Ha, Ki-Tae

2017-01-17

Tumor-derived gangliosides in the tumor microenvironment are involved in the malignant progression of cancer. However, the molecular mechanisms underlying the effects of gangliosides shed from tumors on macrophage phenotype remain unknown. Here, we showed that ganglioside GM1 highly induced the activity and expression of arginase-1 (Arg-1), a major M2 macrophage marker, compared to various gangliosides in bone marrow-derived macrophages (BMDM), peritoneal macrophages and Raw264.7 macrophage cells. We found that GM1 bound to macrophage mannose receptor (MMR/CD206) and common gamma chain (γc). In addition, GM1 increased Arg-1 expression through CD206 and γc-mediated activation of Janus kinase 3 (JAK3) and signal transducer and activator of transcription- 6 (STAT-6). Interestingly, GM1-stimulated macrophages secreted monocyte chemoattractant protein-1 (MCP-1/CCL2) through a CD206/γc/STAT6-mediated signaling pathway and induced angiogenesis. Moreover, the angiogenic effect of GM1-treated macrophages was diminished by RS102895, an MCP-1 receptor (CCR2) antagonist. From these results we suggest that tumor-shed ganglioside is a secretory factor regulating the phenotype of macrophages and consequently enhancing angiogenesis.

Detection of Sendai virus receptor, the ganglioside GDla, in target tissue (mouse lung)

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

Markwell, M.A.K.; Sato, E.

1986-05-01

Previously the authors had shown that the gangliosides GDla, GTlb, and GQlb derived from brain function as receptors for the paramyxovirus Sendai virus by their ability to induce infection when incubated with receptor-deficient cells. Analyses of MDBK, HeLa, and MDCK cells in culture demonstrated that these putative receptors were present in host cells in the quantities required for infection. The primary site of infection for Sendai virus in the whole animal is the respiratory tract, culminating in the lung. Therefore, the ganglioside content of this target organ was analyzed to determine the endogenous receptor population available to Sendai virus. Themore » total ganglioside fraction of lung was resolved into individual species by HPTLC. Gangliosides of the gangliotetraose series were identified by the specific binding of /sup 125/I-labeled tetanus and cholera toxins before and after exposure with sialidase. In this manner one of the major resorcinol-positive bands was identified as GDla. Evidence of the more complex ganglioside receptors for Sendai virus was also seen.« less

Synthesis of ganglioside epitopes for oligosaccharide specific immunoadsorption therapy of Guillian-Barré syndrome.

PubMed

Andersen, Søren M; Ling, Chang-Chun; Zhang, Ping; Townson, Kate; Willison, Hugh J; Bundle, David R

2004-04-21

Guillain-Barré syndrome is a postinfectious, autoimmune neuropathy resulting in neuromuscular paralysis. Auto-antibodies, often induced by bacterial infection, bind to human gangliosides possessing monosialoside and diasialoside epitopes and impair the function of nerve junctions, where these ganglioside structures are highly enriched. Truncated gangliosides representive of GD3, GQ1b and GM2 epitopes have been synthesized as methyl glycosides and as a glycosides of an eleven carbon tether. The synthetic oligosaccharide ligands are structural mimics of these highly complex ganglioside epitopes and via their ability to neutralize or remove auto-antibodies have the potential for therapy, either as soluble blocking ligands administered systemically, or as immuno-affinity ligands for use as extracorporeal immunoadsorbents.

Studies on the turnover and subcellular localization of membrane gangliosides in cultured neuroblastoma cells

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

Clarke, J.T.; Cook, H.W.; Spence, M.W.

1985-03-01

To compare the subcellular distribution of endogenously synthesized and exogenous gangliosides, cultured murine neuroblastoma cells (N1E-115) were incubated in suspension for 22 h in the presence of D-(1-/sup 3/H)galactose or (/sup 3/H)GM1 ganglioside, transferred to culture medium containing no radioisotope for periods of up to 72 hr, and then subjected to subcellular fractionation and analysis of lipid-sialic acid and radiolabeled ganglioside levels. The results indicated that GM2 and GM3 were the principal gangliosides in the cells with only traces of GM1 and small amounts of disialogangliosides present. About 50% of the endogenously synthesized radiolabelled ganglioside in the four major subcellularmore » membrane fractions studied was recovered from plasma membrane and only 10-15% from the crude mitochondrial membrane fraction. In contrast, 45% of the exogenous (/sup 3/H)GM1 taken up into the same subcellular membrane fractions was recovered from the crude mitochondrial fraction; less than 15% was localized in the plasma membrane fraction. The results are similar to those obtained from previously reported studies on membrane phospholipid turnover. They suggest that exogenous GM1 ganglioside, like exogenous phosphatidylcholine, does not intermix freely with any quantitatively major pool of endogenous membrane lipid.« less

The biological activity of botulinum neurotoxin type C is dependent upon novel types of ganglioside binding sites.

PubMed

Strotmeier, Jasmin; Gu, Shenyan; Jutzi, Stephan; Mahrhold, Stefan; Zhou, Jie; Pich, Andreas; Eichner, Timo; Bigalke, Hans; Rummel, Andreas; Jin, Rongsheng; Binz, Thomas

2011-07-01

The seven botulinum neurotoxins (BoNT) cause muscle paralysis by selectively cleaving core components of the vesicular fusion machinery. Their extraordinary activity primarily relies on highly specific entry into neurons. Data on BoNT/A, B, E, F and G suggest that entry follows a dual receptor interaction with complex gangliosides via an established ganglioside binding region and a synaptic vesicle protein. Here, we report high resolution crystal structures of the BoNT/C cell binding fragment alone and in complex with sialic acid. The WY-motif characteristic of the established ganglioside binding region was located on an exposed loop. Sialic acid was co-ordinated at a novel position neighbouring the binding pocket for synaptotagmin in BoNT/B and G and the sialic acid binding site in BoNT/D and TeNT respectively. Employing synaptosomes and immobilized gangliosides binding studies with BoNT/C mutants showed that the ganglioside binding WY-loop, the newly identified sialic acid-co-ordinating pocket and the area corresponding to the established ganglioside binding region of other BoNTs are involved in ganglioside interaction. Phrenic nerve hemidiaphragm activity tests employing ganglioside deficient mice furthermore evidenced that the biological activity of BoNT/C depends on ganglioside interaction with at least two binding sites. These data suggest a unique cell binding and entry mechanism for BoNT/C among clostridial neurotoxins. © 2011 Blackwell Publishing Ltd.

Partial synthesis of ganglioside and lysoganglioside lipoforms as internal standards for MS quantification.

PubMed

Gantner, Martin; Schwarzmann, Günter; Sandhoff, Konrad; Kolter, Thomas

2014-12-01

Within recent years, ganglioside patterns have been increasingly analyzed by MS. However, internal standards for calibration are only available for gangliosides GM1, GM2, and GM3. For this reason, we prepared homologous internal standards bearing nonnatural fatty acids of the major mammalian brain gangliosides GM1, GD1a, GD1b, GT1b, and GQ1b, and of the tumor-associated gangliosides GM2 and GD2. The fatty acid moieties were incorporated after selective chemical or enzymatic deacylation of bovine brain gangliosides. For modification of the sphingoid bases, we developed a new synthetic method based on olefin cross metathesis. This method was used for the preparation of a lyso-GM1 and a lyso-GM2 standard. The total yield of this method was 8.7% for the synthesis of d17:1-lyso-GM1 from d20:1/18:0-GM1 in four steps. The title compounds are currently used as calibration substances for MS quantification and are also suitable for functional studies. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

Cholera toxin binding affinity and specificity for gangliosides determined by surface plasmon resonance

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

Kuziemko, G.M.; Stroh, M.; Stevens, R.C.

1996-05-21

The present study determines the affinity of cholera toxin for the ganglioside series GM1, GM2, GM3, GD1A, GD1B, GT1B, asialo GM1, globotriosyl ceramide, and lactosyl ceramide using real time biospecific interaction analysis (surface plasmon resonance, SPR). SPR shows that cholera toxin preferably binds to gangliosides in the following sequence: GM1 > GM2 > GD1A > GM3 > GT1B > GD1B > asialo-GM1. The measured binding affinity of cholera toxin for the ganglioside sequence ranges from 4.61 {times} 10{sup {minus}12} M for GM1 to 1.88 {times} 10{sup {minus}10} M for asialo GM1. The picomolar values obtained by surface plasmon resonance aremore » similar to K{sub d} values determined with whole-cell binding assays. Both whole-cell assays ans SPR measurements on synthetic membranes are higher than free solution measurements by several orders of magnitude. This difference may be caused by the effects of avidity and charged lipid head-groups, which may play a major role in the binding between cholera toxin, the receptor, and the membrane surface. The primary difference between free solution binding studies and surface plasmon resonance studies is that the latter technique is performed on surfaces resembling the cell membrane. Surface plasmon resonance has the further advantage of measuring apparent kinetic association and dissociation rates in real time, providing direct information about binding events at the membrane surface. 34 refs., 8 figs., 2 tabs.« less

Effect of gangliosides in the autoimmune response induced by liposome-associated antigens.

PubMed

Correa, S G; Rivero, V E; Yranzo-Volonté, N; Romero-Piffiguer, M; Ferro, M E; Riera, C M

1993-01-01

A model of autoimmunity to rat male accessory glands (RAG) was recently developed by intraperitoneal administration of three doses of native RAG associated with liposomes. In this work we analysed the effects of gangliosides in the cellular response to RAG when they were intraperitoneally administrated prior to the second dose of liposome-associated RAG. Results show that the ganglioside treatment could modify an established DTH response. Also, gangliosides markedly reduced the number of Ia antigen-positive peritoneal exudated cells (PEC). However, they modified neither the processing of liposomes through PEC nor their viability. Moreover, we obtained cellular response by transferring PEC from immunized donors into naive receptors.

The Protective Effect of Gangliosides on Lead (Pb)-Induced Neurotoxicity Is Mediated by Autophagic Pathways.

PubMed

Meng, Hongtao; Wang, Lan; He, Junhong; Wang, Zhufeng

2016-03-25

Lead (Pb) is a ubiquitous environmental and industrial pollutant and can affect intelligence development and the learning ability and memory of children. Therefore, necessary measures should be taken to protect the central nervous system (CNS) from Pb toxicity. Gangliosides are sialic acid-containing glycosphingolipids that are constituents of mammalian cell membranes and are more abundantly expressed in the CNS. Studies have shown that gangliosides constitute a useful tool in the attempt to promote functional recovery of CNS and can reverse Pb-induced impairments of synaptic plasticity in rats. However, the detailed mechanisms have yet to be fully understood. In our present study, we tried to investigate the role of gangliosides in Pb-induced injury in hippocampus neurons and to further confirm the detailed mechanism. Our results show that Pb-induced injuries in the spatial reference memory were associated with a reduction of cell viability and cell apoptosis, and treatment with gangliosides markedly ameliorated the Pb-induced injury by inhibition of apoptosis action. Gangliosides further attenuated Pb-induced the abnormal autophagic process by regulation of mTOR pathways. In summary, our study establishes the efficacy of gangliosides as neuroprotective agents and provides a strong rationale for further studies on the underlying mechanisms of their neuroprotective functions.

AKT Axis, miR-21, and RECK Play Pivotal Roles in Dihydroartemisinin Killing Malignant Glioma Cells

PubMed Central

Shao, Ying-Ying; Zhang, Tao-Lan; Wu, Lan-Xiang; Zou, He-Cun; Li, Shuang; Huang, Jin; Zhou, Hong-Hao

2017-01-01

Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, is known to play important roles in inhibiting proliferation rate, inducing apoptosis, as well as hindering the metastasis and invasion of glioma cells, but the underlying mechanisms are still unclear so far. In this study, methyl thiazolyl tetrazolium (MTT), colony-forming, wound healing, invasion, and apoptosis assays were performed to investigate the effect of DHA on malignant glioma cells. Results showed that DHA induced apoptosis of malignant glioma cells through Protein Kinase B (AKT) axis, induced death of malignant glioma cells by downregulating miR-21, and inhibited the invasion of malignant glioma cells corresponding with up-regulation of the reversion-inducing-cysteine-rich protein with kazal motifs (RECK). These results revealed that AKT axis, miR-21, and RECK play pivotal roles in DHA killing malignant glioma cells, suggesting that DHA is a potential agent for treating glioma. PMID:28208619

Revealing the Raft Domain Organization in the Plasma Membrane by Single-Molecule Imaging of Fluorescent Ganglioside Analogs.

PubMed

Suzuki, Kenichi G N; Ando, Hiromune; Komura, Naoko; Konishi, Miku; Imamura, Akihiro; Ishida, Hideharu; Kiso, Makoto; Fujiwara, Takahiro K; Kusumi, Akihiro

2018-01-01

Gangliosides have been implicated in a variety of physiological processes, particularly in the formation and function of raft domains in the plasma membrane. However, the scarcity of suitable fluorescent ganglioside analogs had long prevented us from determining exactly how gangliosides perform their functions in the live-cell plasma membrane. With the development of new fluorescent ganglioside analogs, as described by Komura et al. (2017), this barrier has been broken. We can now address the dynamic behaviors of gangliosides in the live-cell plasma membrane, using fluorescence microscopy, particularly by single-fluorescent molecule imaging and tracking. Single-molecule tracking of fluorescent GM1 and GM3 revealed that these molecules are transiently and dynamically recruited to monomers (monomer-associated rafts) and homodimer rafts of the raftophilic GPI-anchored protein CD59 in quiescent cells, with exponential residency times of 12 and 40ms, respectively, in a manner dependent on raft-lipid interactions. Upon CD59 stimulation, which induces CD59-cluster signaling rafts, the fluorescent GM1 and GM3 analogs were recruited to the signaling rafts, with a lifetime of 48ms. These results represent the first direct evidence that GPI-anchored receptors and gangliosides interact in a cholesterol-dependent manner. Furthermore, they show that gangliosides continually move in and out of rafts that contain CD59 in an extremely dynamic manner, with much higher frequency than expected previously. Such studies would not have been possible without fluorescent ganglioside probes, which exhibit native-like behavior and single-molecule tracking. In this chapter, we review the methods for single-molecule tracking of fluorescent ganglioside analogs and the results obtained by applying these methods. © 2018 Elsevier Inc. All rights reserved.

Requirement of GM2 ganglioside activator for phospholipase D activation

PubMed Central

Nakamura, Shun-ichi; Akisue, Toshihiro; Jinnai, Hitoshi; Hitomi, Tomohiro; Sarkar, Sukumar; Miwa, Noriko; Okada, Taro; Yoshida, Kimihisa; Kuroda, Shun’ichi; Kikkawa, Ushio; Nishizuka, Yasutomi

1998-01-01

Sequence analysis of a heat-stable protein necessary for the activation of ADP ribosylation factor-dependent phospholipase D (PLD) reveals that this protein has a structure highly homologous to the previously known GM2 ganglioside activator whose deficiency results in the AB-variant of GM2 gangliosidosis. The heat-stable activator protein indeed has the capacity to enhance enzymatic conversion of GM2 to GM3 ganglioside that is catalyzed by β-hexosaminidase A. Inversely, GM2 ganglioside activator purified separately from tissues as described earlier [Conzelmann, E. & Sandhoff, K. (1987) Methods Enzymol. 138, 792–815] stimulates ADP ribosylation factor-dependent PLD in a dose-dependent manner. At higher concentrations of ammonium sulfate, the PLD activator protein apparently substitutes for protein kinase C and phosphatidylinositol 4,5-bisphosphate, both of which are known as effective stimulators of the PLD reaction. The mechanism of action of the heat-stable PLD activator protein remains unknown. PMID:9770472

Structural and mutational analyses of the receptor binding domain of botulinum D/C mosaic neurotoxin: Insight into the ganglioside binding mechanism

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

Nuemket, Nipawan; Tanaka, Yoshikazu; Faculty of Advanced Life Science, Hokkaido University, Sapporo 060-0810

2011-07-29

Highlights: {yields} We determined the crystal structure of the receptor binding domain of BoNT in complex with 3'-sialyllactose. {yields} An electron density derived from the 3'-sialyllactose was confirmed at the cleft in the C-terminal subdomain. {yields} Alanine site-directed mutagenesis showed that GBS and GBL are important for ganglioside binding. {yields} A cell binding mechanism, which involves cooperative contribution of two sites, was proposed. -- Abstract: Clostridium botulinum type D strain OFD05, which produces the D/C mosaic neurotoxin, was isolated from cattle killed by the recent botulism outbreak in Japan. The D/C mosaic neurotoxin is the most toxic of the botulinummore » neurotoxins (BoNT) characterized to date. Here, we determined the crystal structure of the receptor binding domain of BoNT from strain OFD05 in complex with 3'-sialyllactose at a resolution of 3.0 A. In the structure, an electron density derived from the 3'-sialyllactose was confirmed at the cleft in the C-terminal subdomain. Alanine site-directed mutagenesis showed the significant contribution of the residues surrounding the cleft to ganglioside recognition. In addition, a loop adjoining the cleft also plays an important role in ganglioside recognition. In contrast, little effect was observed when the residues located around the surface previously identified as the protein receptor binding site in other BoNTs were substituted. The results of cell binding analysis of the mutants were significantly correlated with the ganglioside binding properties. Based on these observations, a cell binding mechanism of BoNT from strain OFD05 is proposed, which involves cooperative contribution of two ganglioside binding sites.« less

Glycosylated SV2 and Gangliosides as Dual Receptors for Botulinum Neurotoxin Serotype F

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

Fu, Zhuji; Chen, Chen; Barbieri, Joseph T.

2010-02-22

Botulinum neurotoxin causes rapid flaccid paralysis through the inhibition of acetylcholine release at the neuromuscular junction. The seven BoNT serotypes (A-G) have been proposed to bind motor neurons via ganglioside-protein dual receptors. To date, the structure-function properties of BoNT/F host receptor interactions have not been resolved. Here, we report the crystal structures of the receptor binding domains (HCR) of BoNT/A and BoNT/F and the characterization of the dual receptors for BoNT/F. The overall polypeptide fold of HCR/A is essentially identical to the receptor binding domain of the BoNT/A holotoxin, and the structure of HCR/F is very similar to that ofmore » HCR/A, except for two regions implicated in neuronal binding. Solid phase array analysis identified two HCR/F binding glycans: ganglioside GD1a and oligosaccharides containing an N-acetyllactosamine core. Using affinity chromatography, HCR/F bound native synaptic vesicle glycoproteins as part of a protein complex. Deglycosylation of glycoproteins using {alpha}(1-3,4)-fucosidase, endo-{beta}-galactosidase, and PNGase F disrupted the interaction with HCR/F, while the binding of HCR/B to its cognate receptor, synaptotagmin I, was unaffected. These data indicate that the HCR/F binds synaptic vesicle glycoproteins through the keratan sulfate moiety of SV2. The interaction of HCR/F with gangliosides was also investigated. HCR/F bound specifically to gangliosides that contain {alpha}2,3-linked sialic acid on the terminal galactose of a neutral saccharide core (binding order GT1b = GD1a GM3; no binding to GD1b and GM1a). Mutations within the putative ganglioside binding pocket of HCR/F decreased binding to gangliosides, synaptic vesicle protein complexes, and primary rat hippocampal neurons. Thus, BoNT/F neuronal discrimination involves the recognition of ganglioside and protein (glycosylated SV2) carbohydrate moieties, providing a structural basis for the high affinity and specificity of BoNT/F for

Dissecting the Role of Anti-ganglioside Antibodies in Guillain-Barré Syndrome: an Animal Model Approach.

PubMed

Asthana, Pallavi; Vong, Joaquim Si Long; Kumar, Gajendra; Chang, Raymond Chuen-Chung; Zhang, Gang; Sheikh, Kazim A; Ma, Chi Him Eddie

2016-09-01

Guillain-Barré syndrome (GBS) is an autoimmune polyneuropathy disease affecting the peripheral nervous system (PNS). Most of the GBS patients experienced neurological symptoms such as paresthesia, weakness, pain, and areflexia. There are also combinations of non-neurological symptoms which include upper respiratory tract infection and diarrhea. One of the major causes of GBS is due largely to the autoantibodies against gangliosides located on the peripheral nerves. Gangliosides are sialic acid-bearing glycosphingolipids consisting of a ceramide lipid anchor with one or more sialic acids attached to a neutral sugar backbone. Molecular mimicry between the outer components of oligosaccharide of gangliosides on nerve membrane and lipo-oligosaccharide of microbes is thought to trigger the autoimmunity. Intra-peritoneal implantation of monoclonal ganglioside antibodies secreting hybridoma into animals induced peripheral neuropathy. Recent studies demonstrated that injection of synthesized anti-ganglioside antibodies raised by hybridoma cells into mice initiates immune response against peripheral nerves, and eventually failure in peripheral nerve regeneration. Accumulating evidences indicate that the conjugation of anti-ganglioside monoclonal antibodies to activating FcγRIII present on the circulating macrophages inhibits axonal regeneration. The activation of RhoA signaling pathways is also involved in neurite outgrowth inhibition. However, the link between these two molecular events remains unresolved and requires further investigation. Development of anti-ganglioside antagonists can serve as targeted therapy for the treatment of GBS and will open a new approach of drug development with maximum efficacy and specificity.

Dependence of the form factor of ganglioside micelles on a conformational change with temperature

NASA Astrophysics Data System (ADS)

Corti, Mario; Boretta, Marco; Cantù, Laura; Del Favero, Elena; Lesieur, Pierre

1996-09-01

The gangliosides GM2, GM1 and GD1b, biological amphiphiles with a double tail hydrophobic part and an oligosaccharide chain headgroup, form micelles in solution. Light scattering experiments have shown that ganglioside micelles which have gone through a temperature cycle have a smaller molecular mass and hydrodynamic radius than those which have been kept at room temperature. This fact has been interpreted with the hypothesis that, with temperature, the ganglioside molecules undergo a conformational change which affects their micellar properties appreciably. Careful small angle X-ray experiments, aimed to confirm the light scattering data and to evidence differences in the micellar internal structure are presented. Ganglioside micelles are quite inhomogeneous particles with respect to X-ray scattering, since there is a large contrast variation between the inner lipid part and the external hydrated sugar layer. Experimental form factors are fitted with a double-shell oblate-ellipsoid model.

Ganglioside inhibition of sup 125 I-plasmin binding to colorectal carcinoma cells

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

Liepkalns, V.A.; Burtin, M.C.; Correc, P.

1990-01-01

The pre-incubation of human colorectal carcinoma cells SW 1116 with 25 to 100 uM purified gangliosides resulted in 35-60% inhibition of specific {sup 125}I-plasmin binding to the cell surface. After 5 to 6 days in culture, tumor cells were pre-incubated at 4 degrees for 1 to 4 h followed by post-incubation with {sup 125}I-plasmin by techniques previously described. At 25 uM the capacity for inhibition of plasmin binding was GT1b greater than GQ1b greater than or equal to GD1a greater than GM1 less than or equal to GgOse 4Cer. Thus a terminal sialyl moiety appears to be necessary (p lessmore » than 0.05) although exogenous N-acetyl neuraminic acid was ineffective (p greater than 0.05), indicating a role for the lipid portion of the ganglioside. Other (glyco)lipids such as sphingosine, fucolipid H-1 and sulfatide were without significant effect. The inhibition could not be reversed by the presence of 10 mM Ca+2, EDTA, pre-treatment of the cell with carboxypeptidase or pretreatment of plasmin with neuraminidases. The inhibition was however reversed by post-incubation in control medium without exogenous ganglioside. Cell counts determined prior to, and after ganglioside incubation showed that the effect was not due to cell death or detachment from the culture surface. The dissociation constant for {sup 125}I-plasmin binding was 5.6 x 10(-8) M (700,000 sites/cell), but in the presence of trisialoganglioside (GT1b), Scatchard plots suggested diversification of binding sites with 280,000 sites/cell at Kd 2.6 x 10(-8) M and 820,000 sites/cell at Kd 2.1 x 10(-7) M. Another interpretation of the Scatchard plot in the presence of ganglioside was that the glycolipid imposed negative cooperativity on plasmin binding to the cell surface. These results suggest that certain gangliosides can affect tumor cell invasiveness by altering protease binding to the cell surface.« less

Sialic Acids in the Brain: Gangliosides and Polysialic Acid in Nervous System Development, Stability, Disease, and Regeneration

PubMed Central

Gerardy-Schahn, Rita; Hildebrandt, Herbert

2014-01-01

Every cell in nature carries a rich surface coat of glycans, its glycocalyx, which constitutes the cell's interface with its environment. In eukaryotes, the glycocalyx is composed of glycolipids, glycoproteins, and proteoglycans, the compositions of which vary among different tissues and cell types. Many of the linear and branched glycans on cell surface glycoproteins and glycolipids of vertebrates are terminated with sialic acids, nine-carbon sugars with a carboxylic acid, a glycerol side-chain, and an N-acyl group that, along with their display at the outmost end of cell surface glycans, provide for varied molecular interactions. Among their functions, sialic acids regulate cell-cell interactions, modulate the activities of their glycoprotein and glycolipid scaffolds as well as other cell surface molecules, and are receptors for pathogens and toxins. In the brain, two families of sialoglycans are of particular interest: gangliosides and polysialic acid. Gangliosides, sialylated glycosphingolipids, are the most abundant sialoglycans of nerve cells. Mouse genetic studies and human disorders of ganglioside metabolism implicate gangliosides in axon-myelin interactions, axon stability, axon regeneration, and the modulation of nerve cell excitability. Polysialic acid is a unique homopolymer that reaches >90 sialic acid residues attached to select glycoproteins, especially the neural cell adhesion molecule in the brain. Molecular, cellular, and genetic studies implicate polysialic acid in the control of cell-cell and cell-matrix interactions, intermolecular interactions at cell surfaces, and interactions with other molecules in the cellular environment. Polysialic acid is essential for appropriate brain development, and polymorphisms in the human genes responsible for polysialic acid biosynthesis are associated with psychiatric disorders including schizophrenia, autism, and bipolar disorder. Polysialic acid also appears to play a role in adult brain plasticity

Broad neutralization of calcium-permeable amyloid pore channels with a chimeric Alzheimer/Parkinson peptide targeting brain gangliosides.

PubMed

Di Scala, Coralie; Yahi, Nouara; Flores, Alessandra; Boutemeur, Sonia; Kourdougli, Nazim; Chahinian, Henri; Fantini, Jacques

2016-02-01

Growing evidence supports a role for brain gangliosides in the pathogenesis of neurodegenerative diseases including Alzheimer's and Parkinson's. Recently we deciphered the ganglioside-recognition code controlling specific ganglioside binding to Alzheimer's β-amyloid (Aβ1-42) peptide and Parkinson's disease-associated protein α-synuclein. Cracking this code allowed us to engineer a short chimeric Aβ/α-synuclein peptide that recognizes all brain gangliosides. Here we show that ganglioside-deprived neural cells do no longer sustain the formation of zinc-sensitive amyloid pore channels induced by either Aβ1-42 or α-synuclein, as assessed by single-cell Ca(2+) fluorescence microscopy. Thus, amyloid channel formation, now considered a key step in neurodegeneration, is a ganglioside-dependent process. Nanomolar concentrations of chimeric peptide competitively inhibited amyloid pore formation induced by Aβ1-42 or α-synuclein in cultured neural cells. Moreover, this peptide abrogated the intracellular calcium increases induced by Parkinson's-associated mutant forms of α-synuclein (A30P, E46K and A53T). The chimeric peptide also prevented the deleterious effects of Aβ1-42 on synaptic vesicle trafficking and decreased the Aβ1-42-induced impairment of spontaneous activity in rat hippocampal slices. Taken together, these data show that the chimeric peptide has broad anti-amyloid pore activity, suggesting that a common therapeutic strategy based on the prevention of amyloid-ganglioside interactions is a reachable goal for both Alzheimer's and Parkinson's diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of Ganglioside on Working Memory and the Default Mode Network in Individuals with Subjective Cognitive Impairment: A Randomized Controlled Trial.

PubMed

Jeon, Yujin; Kim, Binna; Kim, Jieun E; Kim, Bori R; Ban, Soonhyun; Jeong, Jee Hyang; Kwon, Oran; Rhie, Sandy Jeong; Ahn, Chang-Won; Kim, Jong-Hoon; Jung, Sung Ug; Park, Soo-Hyun; Lyoo, In Kyoon; Yoon, Sujung

2016-01-01

This randomized, double-blind, placebo-controlled trial examined whether the administration of ganglioside, an active ingredient of deer bone extract, can improve working memory performance by increasing gray matter volume and functional connectivity in the default mode network (DMN) in individuals with subjective cognitive impairment. Seventy-five individuals with subjective cognitive impairment were chosen to receive either ganglioside (330[Formula: see text][Formula: see text]g/day or 660[Formula: see text][Formula: see text]g/day) or a placebo for 8 weeks. Changes in working memory performance with treatment of either ganglioside or placebo were assessed as cognitive outcome measures. Using voxel-based morphometry and functional connectivity analyses, changes in gray matter volume and functional connectivity in the DMN were also assessed as brain outcome measures. Improvement in working memory performance was greater in the ganglioside group than in the placebo group. The ganglioside group, relative to the placebo group, showed greater increases in gray matter volume and functional connectivity in the DMN. A significant relationship between increased functional connectivity of the precuneus and improved working memory performance was observed in the ganglioside group. The current findings suggest that ganglioside has cognitive-enhancing effects in individuals with subjective cognitive impairment. Ganglioside-induced increases in gray matter volume and functional connectivity in the DMN may partly be responsible for the potential nootropic effects of ganglioside. The clinical trial was registered with ClinicalTrials.gov (identifier: NCT02379481).

AP-MALDI Mass Spectrometry Imaging of Gangliosides Using 2,6-Dihydroxyacetophenone

NASA Astrophysics Data System (ADS)

Jackson, Shelley N.; Muller, Ludovic; Roux, Aurelie; Oktem, Berk; Moskovets, Eugene; Doroshenko, Vladimir M.; Woods, Amina S.

2018-03-01

Matrix-assisted laser/desorption ionization (MALDI) mass spectrometry imaging (MSI) is widely used as a unique tool to record the distribution of a large range of biomolecules in tissues. 2,6-Dihydroxyacetophenone (DHA) matrix has been shown to provide efficient ionization of lipids, especially gangliosides. The major drawback for DHA as it applies to MS imaging is that it sublimes under vacuum (low pressure) at the extended time necessary to complete both high spatial and mass resolution MSI studies of whole organs. To overcome the problem of sublimation, we used an atmospheric pressure (AP)-MALDI source to obtain high spatial resolution images of lipids in the brain using a high mass resolution mass spectrometer. Additionally, the advantages of atmospheric pressure and DHA for imaging gangliosides are highlighted. The imaging of [M-H]- and [M-H2O-H]- mass peaks for GD1 gangliosides showed different distribution, most likely reflecting the different spatial distribution of GD1a and GD1b species in the brain. [Figure not available: see fulltext.

Hevin Plays a Pivotal Role in Corneal Wound Healing

PubMed Central

Chaurasia, Shyam S.; Perera, Promoda R.; Poh, Rebekah; Lim, Rayne R.; Wong, Tina T.; Mehta, Jodhbir S.

2013-01-01

administration of rhHevin. Thus, hevin plays a pivotal role in the corneal wound healing. PMID:24303054

Dietary lipids containing gangliosides reduce Giardia muris infection in vivo and survival of Giardia lamblia trophozoites in vitro.

PubMed

Suh, M; Belosevic, M; Clandinin, M T

2004-06-01

We examined whether a ganglioside supplemented diet affected the course of Giardia muris infection in mice and survival of Giardia lamblia trophozoites in vitro. Female CD-1 mice were fed 1 of 5 experimental diets: standard lab chow as a control diet; semi-synthetic diets containing 20% (w/w) triglyceride based on the fat composition of a conventional infant formula; triglyceride diet; triglyceride diet containing a low level of ganglioside (0.1% w/w); and triglyceride diet containing a high level of ganglioside (1.0% w/w of diet). After 2 weeks of feeding, mice were inoculated with G. muris by gastric intubation and fed the experimental diets during the course of the infection. Cysts released in the faeces and trophozoites present in the small intestine were enumerated at various times post-infection. The average cyst output and the number of trophozoites during the course of the infection in mice fed ganglioside-containing diet were found to be significantly lower (3-log10 reduction) compared to animals fed control diets. The results of in vitro growth studies indicated that gangliosides may be directly toxic to the parasites. Thus, gangliosides have a protective effect against G. muris infection in vivo and affect the survival of G. lamblia trophozoites in vitro.

GD3/proteosome vaccines induce consistent IgM antibodies against the ganglioside GD3.

PubMed

Livingston, P O; Calves, M J; Helling, F; Zollinger, W D; Blake, M S; Lowell, G H

1993-09-01

The gangliosides of melanoma and other tumours of neuroectodermal origin are suitable targets for immune intervention with tumour vaccines. The optimal vaccines in current use contain ganglioside plus bacillus Calmette-Guérin and induce considerable morbidity. We have screened a variety of new adjuvants in the mouse, and describe one antigen-delivery system, proteosomes, which is especially effective. Highly hydrophobic Neisserial outer membrane proteins (OMP) form multimolecular liposome-like vesicular structures termed proteosomes which can readily incorporate amphiphilic molecules such as GD3 ganglioside. The optimal GD3/proteosome vaccine formulation for induction of GD3 antibodies in the mouse is determined. Interestingly, the use of potent immunological adjuvants in addition to proteosomes augments the IgM and IgG antibody titres against OMP in these vaccines but GD3 antibody titres are unaffected. The application of proteosomes to enhance the immune response to GD3 extends the concept of the proteosome immunopotentiating system from lipopeptides to amphipathic carbohydrate epitopes such as cell-surface gangliosides. The demonstrated safety of meningococcal OMP in humans and the data in mice presented here suggest that proteosome vaccines have potential for augmenting the immunogenicity of amphipathic tumour antigens in humans.

On the minor gangliosides of erythrocyte membranes of Japanese cats.

PubMed

Ando, N; Yamakawa, T

1982-03-01

Seven ganglioside species were isolated and purified from erythrocyte membranes of Japanese cats by DEAE-Sephadex and Iatrobeads column chromatographies. The structures of these gangliosides were determined as Gmi(NeuGc), Gm3(NeuAc), GM3(NeuGc), GD3(NeuGc), GD3(NeuGc comes from NeuAc), GT3(NeuGc), and another GM3 containing a sialic acid of unidentified nature. The occurrence of GT3 suggested the probable presence of a biosynthetic pathway of GM3 leads to GD3 leads to GT3 in erythropoietic cells of Japanese cats. The presence of GD3 having one penultimate N-glycolylneuraminic acid and one terminal N-acetylneuraminic acid, GD3(NeuGc comes from NeuAc) would indicate that this GD3 acts as an intermediate in a possible pathway from GM3(NeuGc) to GD3(NeuGc). Thin layer chromatographic patterns of total erythrocyte membrane gangliosides were compared among Japanese cats (n = 3), lions (n = 3), a serval and a racoon dog. The three species of felid showed similar patterns to each other and contained N-glycolylneuraminic acid as the major sialic acid. On the other hand, erythrocytes of racoon dog, a member of canidae, contained neither GD3 nor GT3, but only GM3.

Altered Expression of Ganglioside Metabolizing Enzymes Results in GM3 Ganglioside Accumulation in Cerebellar Cells of a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis.

PubMed

Somogyi, Aleksandra; Petcherski, Anton; Beckert, Benedikt; Huebecker, Mylene; Priestman, David A; Banning, Antje; Cotman, Susan L; Platt, Frances M; Ruonala, Mika O; Tikkanen, Ritva

2018-02-22

Juvenile neuronal ceroid lipofuscinosis (JNCL) is caused by mutations in the CLN3 gene. Most JNCL patients exhibit a 1.02 kb genomic deletion removing exons 7 and 8 of this gene, which results in a truncated CLN3 protein carrying an aberrant C-terminus. A genetically accurate mouse model ( Cln3 Δex7/8 mice) for this deletion has been generated. Using cerebellar precursor cell lines generated from wildtype and Cln3 Δex7/8 mice, we have here analyzed the consequences of the CLN3 deletion on levels of cellular gangliosides, particularly GM3, GM2, GM1a and GD1a. The levels of GM1a and GD1a were found to be significantly reduced by both biochemical and cytochemical methods. However, quantitative high-performance liquid chromatography analysis revealed a highly significant increase in GM3, suggesting a metabolic blockade in the conversion of GM3 to more complex gangliosides. Quantitative real-time PCR analysis revealed a significant reduction in the transcripts of the interconverting enzymes, especially of β-1,4- N -acetyl-galactosaminyl transferase 1 (GM2 synthase), which is the enzyme converting GM3 to GM2. Thus, our data suggest that the complex a-series gangliosides are reduced in Cln3 Δex7/8 mouse cerebellar precursor cells due to impaired transcription of the genes responsible for their synthesis.

Membrane-lipid homeostasis in a prodromal rat model of Alzheimer's disease: Characteristic profiles in ganglioside distributions during aging detected using MALDI imaging mass spectrometry.

PubMed

Caughlin, Sarah; Maheshwari, Shikhar; Agca, Yuksel; Agca, Cansu; Harris, Aaron J; Jurcic, Kristina; Yeung, Ken K-C; Cechetto, David F; Whitehead, Shawn N

2018-06-01

Accumulation of simple gangliosides GM2 and GM3, and gangliosides with longer long-chain bases (d20:1) have been linked to toxicity and the pathogenesis of Alzheimer's disease (AD). Conversely, complex gangliosides, such as GM1, have been shown to be neuroprotective. Recent evidence using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) has demonstrated that a-series gangliosides are differentially altered during normal aging, yet it remains unclear how simple species are shifting relative to complex gangliosides in the prodromal stages of AD. Ganglioside profiles in wild-type (Wt) and transgenic APP21 Fischer rats were detected and quantified using MALDI-IMS at P0 (birth), 3, 12, and 20 months of age and each species quantified to allow for individual species comparisons. Tg APP21 rats were found to have a decreased level of complex gangliosides in a number of brain regions as compared to Wt rats and showed higher levels of simple gangliosides. A unique pattern of expression was observed in the white matter as compared to gray matter regions, with an age-dependent decrease in GD1 d18:1 species observed and significantly elevated levels of GM3 in Tg APP21 rats. These results are indicative of a pathological shift in ganglioside homeostasis during aging that is exacerbated in Tg APP21 rats. Ganglioside dysregulation may occur in the prodromal stages of neurodegenerative diseases like AD. Copyright © 2018 Elsevier B.V. All rights reserved.

Rapid Profiling of Bovine and Human Milk Gangliosides by Matrix-Assisted Laser Desorption/Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry

PubMed Central

Lee, Hyeyoung; An, Hyun Joo; Lerno, Larry A.; German, J. Bruce; Lebrilla, Carlito B.

2010-01-01

Gangliosides are anionic glycosphingolipids widely distributed in vertebrate tissues and fluids. Their structural and quantitative expression patterns depend on phylogeny and are distinct down to the species level. In milk, gangliosides are exclusively associated with the milk fat globule membrane. They may participate in diverse biological processes but more specifically to host-pathogen interactions. However, due to the molecular complexities, the analysis needs extensive sample preparation, chromatographic separation, and even chemical reaction, which makes the process very complex and time-consuming. Here, we describe a rapid profiling method for bovine and human milk gangliosides employing matrix-assisted desorption/ionization (MALDI) Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS). Prior to the analyses of biological samples, milk ganglioside standards GM3 and GD3 fractions were first analyzed in order to validate this method. High mass accuracy and high resolution obtained from MALDI FTICR MS allow for the confident assignment of chain length and degree of unsaturation of the ceramide. For the structural elucidation, tandem mass spectrometry (MS/MS), specifically as collision-induced dissociation (CID) and infrared multiphoton dissociation (IRMPD) were employed. Complex ganglioside mixtures from bovine and human milk were further analyzed with this method. The samples were prepared by two consecutive chloroform/methanol extraction and solid phase extraction. We observed a number of differences between bovine milk and human milk. The common gangliosides in bovine and human milk are NeuAc-NeuAc-Hex-Hex-Cer (GD3) and NeuAc-Hex-Hex-Cer (GM3); whereas, the ion intensities of ganglioside species are different between two milk samples. Kendrick mass defect plot yields grouping of ganglioside peaks according to their structural similarities. Gangliosides were further probed by tandem MS to confirm the compositional and structural assignments

Isolation and structure of a monomethylated ganglioside possessing neuritogenic activity from the ovary of the sea urchin Diadema setosum.

PubMed

Yamada, Koji; Tanabe, Kaoru; Miyamoto, Tomofumi; Kusumoto, Toshihide; Inagaki, Masanori; Higuchi, Ryuichi

2008-05-01

A new monomethylated ganglioside, DSG-A (3), was obtained, together with four known gangliosides, compounds (1, 2, 4, 5), from the lipid fraction of the chloroform/methanol extract of the ovary of the sea urchin Diadema setosum. The structures of the new ganglioside was determined on the basis of chemical and spectroscopic evidence to be 1-O-[9-O-methyl-(N-acetyl-alpha-D-neuraminosyl)-(2-->6)-beta-D-glucopyranosyl]-ceramide (3). The ceramide moiety of 3 was composed of C18-phytosphingosine base, and 2-hydroxy and nonhydroxylated fatty acid units. These gangliosides showed neuritogenic activity toward the rat pheochromocytoma cell line PC-12 in the presence of nerve growth factor, in which compound 3 showed the most potent activity.

Endosomal/Lysosomal Processing of Gangliosides Affects Neuronal Cholesterol Sequestration in Niemann-Pick Disease Type C

PubMed Central

Zhou, Sharon; Davidson, Cristin; McGlynn, Robert; Stephney, Gloria; Dobrenis, Kostantin; Vanier, Marie T.; Walkley, Steven U.

2011-01-01

Niemann-Pick disease type C (NPC) is a severe neurovisceral lysosomal storage disorder caused by defects in NPC1 or NPC2 proteins. Although numerous studies support the primacy of cholesterol storage, neurons of double-mutant mice lacking both NPC1 and an enzyme required for synthesis of all complex gangliosides (β1,4GalNAc transferase) have been reported to exhibit dramatically reduced cholesterol sequestration. Here we show that NPC2-deficient mice lacking this enzyme also exhibit reduced cholesterol, but that genetically restricting synthesis to only a-series gangliosides fully restores neuronal cholesterol storage to typical disease levels. Examining the subcellular locations of sequestered compounds in neurons lacking NPC1 or NPC2 by confocal microscopy revealed that cholesterol and the two principal storage gangliosides (GM2 and GM3) were not consistently co-localized within the same intracellular vesicles. To determine whether the lack of GM2 and GM3 co-localization was due to differences in synthetic versus degradative pathway expression, we generated mice lacking both NPC1 and lysosomal β-galactosidase, and therefore unable to generate GM2 and GM3 in lysosomes. Double mutants lacked both gangliosides, indicating that each is the product of endosomal/lysosomal processing. Unexpectedly, GM1 accumulation in double mutants increased compared to single mutants consistent with a direct role for NPC1 in ganglioside salvage. These studies provide further evidence that NPC1 and NPC2 proteins participate in endosomal/lysosomal processing of both sphingolipids and cholesterol. PMID:21708114

Altered Expression of Ganglioside Metabolizing Enzymes Results in GM3 Ganglioside Accumulation in Cerebellar Cells of a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis

PubMed Central

Somogyi, Aleksandra; Petcherski, Anton; Beckert, Benedikt; Huebecker, Mylene; Priestman, David A.; Banning, Antje; Cotman, Susan L.; Platt, Frances M.; Ruonala, Mika O.

2018-01-01

Juvenile neuronal ceroid lipofuscinosis (JNCL) is caused by mutations in the CLN3 gene. Most JNCL patients exhibit a 1.02 kb genomic deletion removing exons 7 and 8 of this gene, which results in a truncated CLN3 protein carrying an aberrant C-terminus. A genetically accurate mouse model (Cln3Δex7/8 mice) for this deletion has been generated. Using cerebellar precursor cell lines generated from wildtype and Cln3Δex7/8 mice, we have here analyzed the consequences of the CLN3 deletion on levels of cellular gangliosides, particularly GM3, GM2, GM1a and GD1a. The levels of GM1a and GD1a were found to be significantly reduced by both biochemical and cytochemical methods. However, quantitative high-performance liquid chromatography analysis revealed a highly significant increase in GM3, suggesting a metabolic blockade in the conversion of GM3 to more complex gangliosides. Quantitative real-time PCR analysis revealed a significant reduction in the transcripts of the interconverting enzymes, especially of β-1,4-N-acetyl-galactosaminyl transferase 1 (GM2 synthase), which is the enzyme converting GM3 to GM2. Thus, our data suggest that the complex a-series gangliosides are reduced in Cln3Δex7/8 mouse cerebellar precursor cells due to impaired transcription of the genes responsible for their synthesis. PMID:29470438

Early Supplementation of Phospholipids and Gangliosides Affects Brain and Cognitive Development in Neonatal Piglets123

PubMed Central

Liu, Hongnan; Radlowski, Emily C; Conrad, Matthew S; Li, Yao; Dilger, Ryan N; Johnson, Rodney W

2014-01-01

Background: Because human breast milk is a rich source of phospholipids and gangliosides and breastfed infants have improved learning compared with formula-fed infants, the importance of dietary phospholipids and gangliosides for brain development is of interest. Objective: We sought to determine the effects of phospholipids and gangliosides on brain and cognitive development. Methods: Male and female piglets from multiple litters were artificially reared and fed formula containing 0% (control), 0.8%, or 2.5% Lacprodan PL-20 (PL-20; Arla Foods Ingredients), a phospholipid/ganglioside supplement, from postnatal day (PD) 2 to PD28. Beginning on PD14, performance in a spatial T-maze task was assessed. At PD28, brain MRI data were acquired and piglets were killed to obtain hippocampal tissue for metabolic profiling. Results: Diet affected maze performance, with piglets that were fed 0.8% and 2.5% PL-20 making fewer errors than control piglets (80% vs. 75% correct on average; P < 0.05) and taking less time to make a choice (3 vs. 5 s/trial; P < 0.01). Mean brain weight was 5% higher for piglets fed 0.8% and 2.5% PL-20 (P < 0.05) than control piglets, and voxel-based morphometry revealed multiple brain areas with greater volumes and more gray and white matter in piglets fed 0.8% and 2.5% PL-20 than in control piglets. Metabolic profiling of hippocampal tissue revealed that multiple phosphatidylcholine-related metabolites were altered by diet. Conclusion: In summary, dietary phospholipids and gangliosides improved spatial learning and affected brain growth and composition in neonatal piglets. PMID:25411030

Botulinum neurotoxin serotype D attacks neurons via two carbohydrate-binding sites in a ganglioside-dependent manner.

PubMed

Strotmeier, Jasmin; Lee, Kwangkook; Völker, Anne K; Mahrhold, Stefan; Zong, Yinong; Zeiser, Johannes; Zhou, Jie; Pich, Andreas; Bigalke, Hans; Binz, Thomas; Rummel, Andreas; Jin, Rongsheng

2010-10-15

The extraordinarily high toxicity of botulinum neurotoxins primarily results from their specific binding and uptake into neurons. At motor neurons, the seven BoNT (botulinum neurotoxin) serotypes A-G inhibit acetylcholine release leading to flaccid paralysis. Uptake of BoNT/A, B, E, F and G requires a dual interaction with gangliosides and the synaptic vesicle proteins synaptotagmin or SV2 (synaptic vesicle glycoprotein 2), whereas little is known about the cell entry mechanisms of the serotypes C and D, which display the lowest amino acid sequence identity compared with the other five serotypes. In the present study we demonstrate that the neurotoxicity of BoNT/D depends on the presence of gangliosides by employing phrenic nerve hemidiaphragm preparations derived from mice expressing the gangliosides GM3, GM2, GM1 and GD1a, or only GM3 [a description of our use of ganglioside nomenclature is given in Svennerholm (1994) Prog. Brain Res. 101, XI-XIV]. High-resolution crystal structures of the 50 kDa cell-binding domain of BoNT/D alone and in complex with sialic acid, as well as biological analyses of single-site BoNT/D mutants identified two carbohydrate-binding sites. One site is located at a position previously identified in BoNT/A, B, E, F and G, but is lacking the conserved SXWY motif. The other site, co-ordinating one molecule of sialic acid, resembles the second ganglioside-binding pocket (the sialic-acid-binding site) of TeNT (tetanus neurotoxin).

Association to HeLa cells and surface behavior of exogenous gangliosides studied with a fluorescent derivative of GM1

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

Masserini, M.; Giuliani, A.; Palestini, P.

1990-01-23

Cultured HeLa cells were incubated with pyrene-GM1/{sup 3}H-radiolabeled GM1 ganglioside (1:4 M/M) mixtures for various times. The process of association of pyrene-GM1 with cells was qualitatively and quantitatively the same as that of {sup 3}H-GM1. The pyrene-GM1 and {sup 3}H-GM1 proportions in the various forms of association with cells were similar to that of the starting ganglioside mixture. After 2-h incubation, the association of ganglioside with cells was well established whereas almost no metabolic processing had occurred. During a 24-h incubation, pyrene- and {sup 3}H-GM1 underwent similar metabolic processing and gave rise to catabolic (GM2 and GM3) and anabolic (GDla)more » derivatives. Fluorescence spectroscopy experiments carried out with the excimer formation technique on subcellular fractions containing plasma membranes showed that exogenous ganglioside was, in part, associated with the cells in a micellar form removable by trypsin treatment, and in part inserted in a seemingly molecular dispersion. Addition of Ca{sup 2+} salts caused aggregation of the ganglioside, as indicated by the increase of the excimer:monomer fluorescence ratio. The phenomenon was Ca{sup 2+} concentration dependent (maximum at 10 mM), and subsequent addition of EDTA has no effect. The saccharide portion of exogenously incorporated pyrene-GM1 was available to interact with external ligands, as shown by its ability to bind cholera toxin whose addition reduced the collision rate among the ganglioside lipid moieties.« less

Ganglioside GT1b protects human spermatozoa from hydrogen peroxide-induced DNA and membrane damage.

PubMed

Gavella, Mirjana; Garaj-Vrhovac, Verica; Lipovac, Vaskresenija; Antica, Mariastefania; Gajski, Goran; Car, Nikica

2010-06-01

We have reported previously that various gangliosides, the sialic acid containing glycosphingolipids, provide protection against sperm injury caused by reactive oxygen species (ROS). In this study, we investigated the effect of treatment of human spermatozoa with ganglioside GT1b on hydrogen peroxide (H(2)O(2))-induced DNA fragmentation and plasma membrane damage. Single-cell gel electrophoresis (Comet assay) used in the assessment of sperm DNA integrity showed that in vitro supplemented GT1b (100 microm) significantly reduced DNA damage induced by H(2)O(2) (200 microm) (p < 0.05). Measurements of Annexin V binding in combination with the propidium iodide vital dye labelling demonstrated that the spermatozoa pre-treated with GT1b exhibited a significant increase (p < 0.05) in the percentage of live cells with intact membrane and decreased phosphatidylserine translocation after exposure to H(2)O(2). Flow cytometry using the intracellular ROS-sensitive fluorescence dichlorodihydrofluorescein diacetate dye employed to investigate the transport of the extracellularly supplied H(2)O(2) into the cell interior revealed that ganglioside GT1b completely inhibited the passage of H(2)O(2) through the sperm membrane. These results suggest that ganglioside GT1b may protect human spermatozoa from H(2)O(2)-induced damage by rendering sperm membrane more hydrophobic, thus inhibiting the diffusion of H(2)O(2) across the membrane.

Assignment by Negative-Ion Electrospray Tandem Mass Spectrometry of the Tetrasaccharide Backbones of Monosialylated Glycans Released from Bovine Brain Gangliosides

NASA Astrophysics Data System (ADS)

Chai, Wengang; Zhang, Yibing; Mauri, Laura; Ciampa, Maria G.; Mulloy, Barbara; Sonnino, Sandro; Feizi, Ten

2018-05-01

Gangliosides, as plasma membrane-associated sialylated glycolipids, are antigenic structures and they serve as ligands for adhesion proteins of pathogens, for toxins of bacteria, and for endogenous proteins of the host. The detectability by carbohydrate-binding proteins of glycan antigens and ligands on glycolipids can be influenced by the differing lipid moieties. To investigate glycan sequences of gangliosides as recognition structures, we have underway a program of work to develop a "gangliome" microarray consisting of isolated natural gangliosides and neoglycolipids (NGLs) derived from glycans released from them, and each linked to the same lipid molecule for arraying and comparative microarray binding analyses. Here, in the first phase of our studies, we describe a strategy for high-sensitivity assignment of the tetrasaccharide backbones and application to identification of eight of monosialylated glycans released from bovine brain gangliosides. This approach is based on negative-ion electrospray mass spectrometry with collision-induced dissociation (ESI-CID-MS/MS) of the desialylated glycans. Using this strategy, we have the data on backbone regions of four minor components among the monosialo-ganglioside-derived glycans; these are of the ganglio-, lacto-, and neolacto-series.

Nitrogen dioxide-induced alterations in ganglioside content and structure of pulmonary artery endothelial cell plasma membranes

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

Sekharam, M.; Patel, J.M.; Block, E.R.

1990-02-26

Nitrogen dioxide (NO{sub 2}), an environmental oxidant, is known to cause injury to the surface of pulmonary artery endothelial cells (PAEC). Because gangliosides are present in the outer leaflet of plasma membranes, the authors hypothesize that NO{sub 2} exposure may alter the ganglioside content and structure of PAEC plasma membranes. To test this, confluent porcine PAEC were exposed to 5 ppm NO{sub 2} containing 5% CO{sub 2} for 48 hours at 37 C in a CO{sub 2} incubator. Controls were exposed to air containing 5% Co{sub 2} under identical conditions. After exposure: (1) total lipids were extracted and ganglioside basesmore » were separated and estimated by fluorescamine, (2) the sialic acid content of intact cells was measured by the resorcinol method, and (3) freeze-fracture analysis of the intact cell plasma membrane was done by propane jet freezing and shadowing with platinum and carbon to form a replica. The ganglioside and sialic acid/{mu}g protein, respectively. In No{sub 2}-exposed cells, ganglioside content was reduced by 45% and sialic acid content was increased by 30%. Freeze-fracture analysis of the plasma membrane of control cells showed the presence of 160{+-}12 particles/cm area at 45000x. In contrast, the number of particles on the No{sub 2}-exposed plasma membrane was reduced to 68{+-}5 particles/cm at 45000x (p < 0.05). These results demonstrate that NO{sub 2} causes structural changes in the surface of PAEC plasma membranes, and these are temporally associated with a reduction in the number of gagliosides in these cells.« less

EG-03EXPRESSION OF PRMT5 CORRELATES WITH MALIGNANT GRADE IN GLIOMAS AND PLAYS A PIVOTAL ROLE IN TUMOR GROWTH

PubMed Central

Han, Xiaosi; Li, Rong; Zhang, Wenbin; Yang, Xiuhua; Fathallah-Shaykh, Hassan; Gillespie, Yancey; Nabors, Burt

2014-01-01

Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N′G-symmetric dimethylarginine residues on histones as well as other proteins. The modification play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.

Mice lacking major brain gangliosides develop parkinsonism.

PubMed

Wu, Gusheng; Lu, Zi-Hua; Kulkarni, Neil; Amin, Ruchi; Ledeen, Robert W

2011-09-01

Parkinson's disease (PD) is the second most prevalent late-onset neurodegenerative disorder that affects nearly 1% of the global population aged 65 and older. Whereas palliative treatments are in use, the goal of blocking progression of motor and cognitive disability remains unfulfilled. A better understanding of the basic pathophysiological mechanisms underlying PD would help to advance that goal. The present study provides evidence that brain ganglioside abnormality, in particular GM1, may be involved. This is based on use of the genetically altered mice with disrupted gene Galgt1 for GM2/GD2 synthase which depletes GM2/GD2 and all the gangliotetraose gangliosides that constitute the major molecular species of brain. These knockout mice show overt motor disability on aging and clear indications of motor impairment with appropriate testing at an earlier age. This disability was rectified by L-dopa administration. These mice show other characteristic symptoms of PD, including depletion of striatal dopamine (DA), loss of DA neurons of the substantia nigra pars compacta, and aggregation of alpha synuclein. These manifestations of parkinsonism were largely attenuated by administration of LIGA-20, a membrane permeable analog of GM1 that penetrates the blood brain barrier and enters living neurons. These results suggest that perturbation of intracellular mechanisms mediated by intracellular GM1 may be a contributing factor to PD.

Enhanced expression of unique gangliosides with GM2-determinant in human uterine cervical carcinoma-derived cell lines.

PubMed

Tanaka, Kyoko; Miyazawa, Masaki; Mikami, Mikio; Aoki, Daisuke; Kiguchi, Kazushige; Iwamori, Masao

2016-10-01

Monoclonal antibody YHD-06 generated by immunization with GM2 reacted with gangliosides with GM2-determinant, i.e., GM2, GalNAc-GM1b and GalNAc-GD1a, among which GalNAc-GD1a was characterized as an antigen of autoimmune peripheral neuropathies including Guillain-Barré syndrome. When glycolipids were examined by TLC-immunostaining with YHD-06 in seven human cervical carcinoma-derived cell lines, GM2 was found in all cell lines, amounting to 15.5 % to 57.5 % of total gangliosides. Whereas GalNAc-GD1a was present in three cell lines, amounting to 5.4-17.5 % of total gangliosides, and GalNAc-GM1b in four cell lines in amounts of less than 2 %. The elevated amounts of gangliosides with GM2 determinant were closely correlated with the relative intensities of gene expression of GalNAc transferase, this being characteristic of cervical carcinoma-derived cells. However, in tissues from patients with several histological types of cervical carcinomas, GM3 was ubiquitously expressed in amounts of more than 66 % of total gangliosides, GM2 was expressed in only five of 15 tissues, and both GalNAc-GM1b and GalNAc-GD1a were not even detected in trace amounts. Since GM1 was detected in all tissues in amounts of less than 0.06 μg/mg dried tissue, all cervical carcinoma tissues were revealed to exhibit GM2 synthesis, indicating that enhanced synthesis of gangliosides with GM2 determinant is a characteristic of cultivated cells in vitro. Similarly, although I(3)SO3-GalCer was not present in the squamous cell carcinoma (SCC) tissues, SCC-derived cells selectively expressed II(3)SO3-LacCer. Since enhanced synthesis of GM2 has been reported in SV-40 virus-transfected fibroblasts, papilloma virus might be involved in the expression of GM2 in cervical carcinoma-derived cells.

Intrinsic motivation: how can it play a pivotal role in changing clinician behaviour?

PubMed

Nantha, Yogarabindranath Swarna

2013-01-01

In the light of an increasing healthcare burden, this paper seeks to offer insight about how intrinsic motivation could play a pivotal role in improving the pre-existing healthcare service delivery systems by altering clinician behaviour. The paper argues the case for four salient dimensions worth exploring through the lens of intrinsic motivation--non-financial incentives, positive affective states, organizational culture and prescribing quality. This article reviews literature from both social sciences and health management practices to provide rationale on how intrinsic motivational approaches could optimize healthcare service delivery systems. The scrutiny of the body of evidence leads to the assertion that there is neglect in the initiatives to reinforce intrinsic motivation as a method to address the ailing morale of doctors. This seems to have exacerbated negative outcomes that include job dissatisfaction, compromise in the quality of care and poor patient-doctor relationships. Diminution in positive affective states amongst doctors, largely controlled by intrinsic motivation, led to strained doctor-patient communication and poor quality of care. Barriers in a healthcare organizational culture that restricts autonomy and empowerment seem to directly undermine job satisfaction. The article argues that it is crucial to shift away from the conventional tendencies promoting tangible rewards. A more holistic approach should be adopted by conducting formal research into intrinsic motivation and how it could aid the formulation of policies tailored to meet the current demands of the healthcare system.

Radiometric assay for ganglioside sialidase applied to the determination of the enzyme subcellular location in culture human fibroblasts

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

Chigorno, V.; Cardace, G.; Pitto, M.

1986-03-01

A radiometric method for the assay of ganglioside sialidase in cultured human fibroblasts was set up. As substrate, highly radioactive (1.28 Ci/mmol) ganglioside GD/sub 1a/ isotopically tritium-labeled at carbon C-3 of the long chain base was employed; the liberated, and TLC separated (/sup 3/H)GM/sub 1/ was determined by computer-assisted radiochromatoscanning. Under experimental conditions that provided a low and quite acceptable (4-5%) coefficient of variation, the detection limit of the method was 0.1 nmol of liberated GM/sub 1/, using as low as 10 ..mu..g of fibroblast homogenate as protein. The detection limit could be lowered to 0.02-0.03 nmol, adopting conditions that,more » however, carried a higher analytical error (coefficient of variation over 10%). The content of ganglioside sialidase in human fibroblasts cultured in 75-cm/sup 2/ plastic flasks was 5.8 -/+ 2.5 (SD) nmol liberated GM/sub 1/ h/sup -1/ mg protein/sup -1/. Subfractionation studies performed on fibroblast homogenate showed that the ganglioside sialidase was mainly associated with the light membrane subfraction that was rich in plasma and intracellular membranes. This subfraction displayed almost no sialidase activity on the artificial substrate 4-methylumbelliferyl-D-N-acetylneuraminic acid. A small but measurable ganglioside sialidase activity was also present in the lysosome-enriched subfraction, which contained a very high sialidase activity on the above artificial substrate.« less

UVB-irradiated keratinocytes induce melanoma-associated ganglioside GD3 synthase gene in melanocytes via secretion of tumor necrosis factor α and interleukin 6

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

Miyata, Maiko; Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065; Ichihara, Masatoshi

Highlights: • Melanocytes showed low ST8SIA1 and high B3GALT4 levels in contrast with melanomas. • Direct UVB irradiation of melanocytes did not induce ganglioside synthase genes. • Culture supernatants of UVB-irradiated keratinocytes induced ST8SIA1 in melanocytes. • TNFα and IL-6 secreted from keratinocytes enhanced ST8SIA1 expression in melanocytes. • Inflammatory cytokines induced melanoma-related ST8SIA1 in melanocytes. - Abstract: Although expression of gangliosides and their synthetic enzyme genes in malignant melanomas has been well studied, that in normal melanocytes has been scarcely analyzed. In particular, changes in expression levels of glycosyltransferase genes responsible for ganglioside synthesis during evolution of melanomas frommore » melanocytes are very important to understand roles of gangliosides in melanomas. Here, expression of glycosyltransferase genes related to the ganglioside synthesis was analyzed using RNAs from cultured melanocytes and melanoma cell lines. Quantitative RT-PCR revealed that melanomas expressed high levels of mRNA of GD3 synthase and GM2/GD2 synthase genes and low levels of GM1/GD1b synthase genes compared with melanocytes. As a representative exogenous stimulation, effects of ultraviolet B (UVB) on the expression levels of 3 major ganglioside synthase genes in melanocytes were analyzed. Although direct UVB irradiation of melanocytes caused no marked changes, culture supernatants of UVB-irradiated keratinocytes (HaCaT cells) induced definite up-regulation of GD3 synthase and GM2/GD2 synthase genes. Detailed examination of the supernatants revealed that inflammatory cytokines such as TNFα and IL-6 enhanced GD3 synthase gene expression. These results suggest that inflammatory cytokines secreted from UVB-irradiated keratinocytes induced melanoma-associated ganglioside synthase genes, proposing roles of skin microenvironment in the promotion of melanoma-like ganglioside profiles in melanocytes.« less

Ganglioside GM2 mediates migration of tumor cells by interacting with integrin and modulating the downstream signaling pathway.

PubMed

Kundu, Manjari; Mahata, Barun; Banerjee, Avisek; Chakraborty, Sohini; Debnath, Shibjyoti; Ray, Sougata Sinha; Ghosh, Zhumur; Biswas, Kaushik

2016-07-01

The definitive role of ganglioside GM2 in mediating tumor-induced growth and progression is still unknown. Here we report a novel role of ganglioside GM2 in mediating tumor cell migration and uncovered its mechanism. Data shows differential expression levels of GM2-synthase as well as GM2 in different human cancer cells. siRNA mediated knockdown of GM2-synthase in CCF52, A549 and SK-RC-26B cells resulted in significant inhibition of tumor cell migration as well as invasion in vitro without affecting cellular proliferation. Over-expression of GM2-synthase in low-GM2 expressing SK-RC-45 cells resulted in a consequent increase in migration thus confirming the potential role GM2 and its downstream partners play in tumor cell migration and motility. Further, treatment of SK-RC-45 cells with exogenous GM2 resulted in a dramatic increase in migratory and invasive capacity with no change in proliferative capacity, thereby confirming the role of GM2 in tumorigenesis specifically by mediating tumor migration and invasion. Gene expression profiling of GM2-synthase silenced cells revealed altered expression of several genes involved in cell migration primarily those controlling the integrin mediated signaling. GM2-synthase knockdown resulted in decreased phosphorylation of FAK, Src as well as Erk, while over-expression and/or exogenous GM2 treatment caused increased FAK and Erk phosphorylation respectively. Again, GM2 mediated invasion and Erk phosphorylation is blocked in integrin knockdown SK-RC-45 cells, thus confirming that GM2 mediated migration and phosphorylation of Erk is integrin dependent. Finally, confocal microscopy suggested co-localization while co-immunoprecipitation and surface plasmon resonance (SPR) confirmed direct interaction of membrane bound ganglioside, GM2 with the integrin receptor. Copyright © 2016 Elsevier B.V. All rights reserved.

Auditory brainstem responses of CBA/J mice with neonatal conductive hearing losses and treatment with GM1 ganglioside.

PubMed

Money, M K; Pippin, G W; Weaver, K E; Kirsch, J P; Webster, D B

1995-07-01

Exogenous administration of GM1 ganglioside to CBA/J mice with a neonatal conductive hearing loss ameliorates the atrophy of spiral ganglion neurons, ventral cochlear nucleus neurons, and ventral cochlear nucleus volume. The present investigation demonstrates the extent of a conductive loss caused by atresia and tests the hypothesis that GM1 ganglioside treatment will ameliorate the conductive hearing loss. Auditory brainstem responses were recorded from four groups of seven mice each: two groups received daily subcutaneous injections of saline (one group had normal hearing; the other had a conductive hearing loss); the other two groups received daily subcutaneous injections of GM1 ganglioside (one group had normal hearing; the other had a conductive hearing loss). In mice with a conductive loss, decreases in hearing sensitivity were greatest at high frequencies. The decreases were determined by comparing mean ABR thresholds of the conductive loss mice with those of normal hearing mice. The conductive hearing loss induced in the mice in this study was similar to that seen in humans with congenital aural atresias. GM1 ganglioside treatment had no significant effect on ABR wave I thresholds or latencies in either group.

Specific tritium labeling of gangliosides at the 3-position of sphingosines.

PubMed

Ghidoni, R; Sonnino, S; Masserini, M; Orlando, P; Tettamanti, G

1981-11-01

GM1 and GD1a gangliosides, treated with 2,3-dichloro-5,6-dicyano benzoquinone (DDQ) in the presence of Triton X-100 and in a toluene medium were specifically oxidized at the 3-position of sphingosine. The maximum reaction yield (65%) was obtained after 40 hours at 37 degrees C with the following molar ratio of reactants: ganglioside-Triton X-100-DDQ 1:70:125. The formation of the 3-keto derivatives of GM1 and GD1a was demonstrated by: a) the appearance of a sharp peak at 1700 cm-1 and of a broad band at 1250 cm-1 (typical of allylic ketones and of carbonyl groups, respectively) in the infra-red spectrum; b) the appearance of an absorption maximum at 230 nm, identical to that featured by 3-keto-cerebrosides, in the ultraviolet spectrum; c) the degradation of long chain bases during the process of release from gangliosides and derivatization for analysis by gas-liquid chromatography (expected for long chain bases carrying a keto group in the 3-position); and d) the quantitative transformation of 3-keto-GM1 and 3-keto-GD1a to GM1 and GD1a, respectively, upon NaBH4 reduction. Reduction of 3-keto-GM1 and 3-keto-GD1a with [3H]-NaBH4 produced 3H-labeled GM1 and GD1a. [3H]GM1 and [3H]GD1a maintained the same carbohydrate and fatty acid composition of the original GM1 and GD1a, and did not contain any saturated long chain bases. Direct proof that the label was at C-3 of long chain bases was given by reoxidation with DDQ, which completely removed the label, and by ozonolysis, after which label was retained on the oligosaccharide-containing fragment. More than 99% of incorporated radioactivity was carried by the long chain bases. The radiochemical purity of labeled gangliosides was greater than 95% and the specific radioactivity was 1.25 and 1.28 Ci/m mol for [3H]GM1 and [3H]GD1a, respectively.

Early growth and development impairments in patients with ganglioside GM3 synthase deficiency.

PubMed

Wang, H; Wang, A; Wang, D; Bright, A; Sency, V; Zhou, A; Xin, B

2016-05-01

Ganglioside GM3 synthase is a key enzyme involved in the biosynthesis of gangliosides. GM3 synthase deficiency (GSD) causes a complete absence of GM3 and all downstream biosynthetic derivatives. The individuals affected by this disorder manifest severe irritability, intractable seizures and profound intellectual disability. However, we have found that most newborns seem symptom-free for a period of time after birth. In order to further understand the onset of the disease, we investigated the early growth and development of patients with this condition through this study. We compared 37 affected individuals with their normal siblings and revealed that all children with GSD had relatively normal intrauterine growth and development, as their weight, length and head circumference were similar to their normal siblings at birth. However, the disease progresses quickly after birth and causes significant constitutional impairments of growth and development by 6 months of age. Neither breastfeeding nor gastrostomy tube placement made significant difference on growth and development as all groups of patients showed the similar pattern. We conclude that GSD causes significant postnatal growth and developmental impairments and the amount of gangliosides in breast milk and general nutritional intervention do not seem to alter these outcomes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ganglioside structure dictates signal transduction by cholera toxin and association with caveolae-like membrane domains in polarized epithelia.

PubMed

Wolf, A A; Jobling, M G; Wimer-Mackin, S; Ferguson-Maltzman, M; Madara, J L; Holmes, R K; Lencer, W I

1998-05-18

In polarized cells, signal transduction by cholera toxin (CT) requires apical endocytosis and retrograde transport into Golgi cisternae and perhaps ER (Lencer, W.I., C. Constable, S. Moe, M. Jobling, H.M. Webb, S. Ruston, J.L. Madara, T. Hirst, and R. Holmes. 1995. J. Cell Biol. 131:951-962). In this study, we tested whether CT's apical membrane receptor ganglioside GM1 acts specifically in toxin action. To do so, we used CT and the related Escherichia coli heat-labile type II enterotoxin LTIIb. CT and LTIIb distinguish between gangliosides GM1 and GD1a at the cell surface by virtue of their dissimilar receptor-binding B subunits. The enzymatically active A subunits, however, are homologous. While both toxins bound specifically to human intestinal T84 cells (Kd approximately 5 nM), only CT elicited a cAMP-dependent Cl- secretory response. LTIIb, however, was more potent than CT in eliciting a cAMP-dependent response from mouse Y1 adrenal cells (toxic dose 10 vs. 300 pg/well). In T84 cells, CT fractionated with caveolae-like detergent-insoluble membranes, but LTIIb did not. To investigate further the relationship between the specificity of ganglioside binding and partitioning into detergent-insoluble membranes and signal transduction, CT and LTIIb chimeric toxins were prepared. Analysis of these chimeric toxins confirmed that toxin-induced signal transduction depended critically on the specificity of ganglioside structure. The mechanism(s) by which ganglioside GM1 functions in signal transduction likely depends on coupling CT with caveolae or caveolae-related membrane domains.

Neuroglobin overexpression plays a pivotal role in neuroprotection through mitochondrial raft-like microdomains in neuroblastoma SK-N-BE2 cells.

PubMed

Garofalo, Tina; Ferri, Alberto; Sorice, Maurizio; Azmoon, Pardis; Grasso, Maria; Mattei, Vincenzo; Capozzi, Antonella; Manganelli, Valeria; Misasi, Roberta

2018-04-01

Since stressing conditions induce a relocalization of endogenous human neuroglobin (NGB) to mitochondria, this research is aimed to evaluate the protective role of NGB overexpression against neurotoxic stimuli, through mitochondrial lipid raft-associated complexes. To this purpose, we built a neuronal model of oxidative stress by the use of human dopaminergic neuroblastoma cells, SK-N-BE2, stably overexpressing NGB by transfection and treated with 1-methyl-4-phenylpyridinium ion (MPP+). We preliminary observed the redistribution of NGB to mitochondria following MPP+ treatment. The analysis of mitochondrial raft-like microdomains revealed that, following MPP+ treatment, NGB translocated to raft fractions (Triton X-100-insoluble), where it interacts with ganglioside GD3. Interestingly, the administration of agents capable of perturbating microdomain before MPP+ treatment, significantly affected viability in SK-N-BE2-NGB cells. The overexpression of NGB was able to abrogate the mitochondrial injuries on complex IV activity or mitochondrial morphology induced by MPP+ administration. The protective action of NGB on mitochondria only takes place if the mitochondrial lipid(s) rafts-like microdomains are intact, indeed NGB fails to protect complex IV activity when purified mitochondria were treated with the lipid rafts disruptor methyl-β-cyclodextrin. Thus, our unique in vitro model of stably transfected cells overexpressing endogenous NGB allowed us to suggest that the role in neuroprotection played by NGB is reliable only through interaction with mitochondrial lipid raft-associated complexes. Copyright © 2018 Elsevier Inc. All rights reserved.

Constituents of ophiuroidea. 1. Isolation and structure of three ganglioside molecular species from the brittle star Ophiocoma scolopendrina.

PubMed

Inagaki, M; Shibai, M; Isobe, R; Higuchi, R

2001-12-01

Three ganglioside molecular species, OSG-0 (1), OSG-1 (2), and OSG-2 (3) have been obtained from the polar lipid fraction of the chloroform/methanol extract of the brittle star Ophiocoma scolopendrina. The structures of these gangliosides have been determined on the basis of chemical and spectroscopic evidence as 1-O-[(N-glycolyl-alpha-D-neuraminosyl)-(2-->6)-beta-D-glucopyranosyl]-ceramide (1), 1-O-[8-O-sulfo-(N-acetyl-alpha-D-neuraminosyl)-(2-->6)-beta-D-glucopyranosyll-ceramide (2) and 1-O-[(N-glycolyl-alpha-D-neuraminosyl)-(2-->8)-(N-acetyl- and N-glycolyl-alpha-D-neuraminosyl)-(2-->6)-beta-D-glucopyranosyl]-ceramide (3). The ceramide moieties were composed of heterogeneous unsubstituted fatty acid, 2-hydroxy fatty acid and phytosphingosine units. Compounds 2 and 3 represent new ganglioside molecular species.

Synthesis and characterization of N-parinaroyl analogs of ganglioside GM3 and de-N-acetyl GM3. Interactions with the EGF receptor kinase

NASA Technical Reports Server (NTRS)

Song, W.; Welti, R.; Hafner-Strauss, S.; Rintoul, D. A.; Spooner, B. S. (Principal Investigator)

1993-01-01

A specific plasma membrane glycosphingolipid, known as ganglioside GM3, can regulate the intrinsic tyrosyl kinase activity of the epidermal growth factor (EGF) receptor; this modulation is not associated with alterations in hormone binding to the receptor. GM3 inhibits EGF receptor tyrosyl kinase activity in detergent micelles, in plasma membrane vesicles, and in whole cells. In addition, immunoaffinity-purified EGF receptor preparations contain ganglioside GM3 (Hanai et al. (1988) J. Biol. Chem. 263, 10915-10921), implying that the glycosphingolipid is intimately associated with the receptor kinase in cell membranes. Both the nature of this association and the molecular mechanism of kinase inhibition remain to be elucidated. In this report, we describe the synthesis of a fluorescent analog of ganglioside GM3, in which the native fatty acid was replaced with trans-parinaric acid. This glycosphingolipid inhibited the receptor kinase activity in a manner similar to that of the native ganglioside. A modified fluorescent glycosphingolipid, N-trans-parinaroyl de-N-acetyl ganglioside GM3, was also prepared. This analog, like the nonfluorescent de-N-acetyl ganglioside GM3, had no effect on receptor kinase activity. Results from tryptophan fluorescence quenching and steady-state anisotropy measurements in membranes containing these fluorescent probes and the human EGF receptor were consistent with the notion that GM3, but not de-N-acetyl GM3, interacts specifically with the receptor in intact membranes.

Reduction of the ganglioside binding activity of the tetanus toxin HC fragment destroys immunogenicity: implications for development of novel tetanus vaccines.

PubMed

Qazi, Omar; Sesardic, Dorothea; Tierney, Robert; Söderbäck, Zahra; Crane, Dennis; Bolgiano, Barbara; Fairweather, Neil

2006-08-01

In this study, the immunogenicities of the nontoxic H(C) fragment of tetanus toxin and derivatives lacking ganglioside binding activity were compared with that of tetanus toxoid after subcutaneous immunization of mice. Wild-type H(C) (H(C)WT) protein and tetanus toxoid both elicited strong antibody responses against toxoid and H(C) antigens and provided complete protection against toxin challenge. Mutants of H(C) containing deletions essential for ganglioside binding elicited lower responses than H(C)WT. H(C)M115, containing two amino acid substitutions within the ganglioside binding site, provided reduced protection against tetanus toxin challenge compared with H(C)WT, consistent with lower anti-H(C) and anti-toxoid antibody titers. Circular-dichroism spectroscopy and intrinsic fluorescence spectroscopy showed minimal structural perturbation in H(C)M115. We conclude that the presence of the ganglioside binding site within H(C) may be essential for induction of a fully protective anti-tetanus response comparable to that induced by tetanus toxoid by subcutaneous injection.

Reduction of the Ganglioside Binding Activity of the Tetanus Toxin HC Fragment Destroys Immunogenicity: Implications for Development of Novel Tetanus Vaccines

PubMed Central

Qazi, Omar; Sesardic, Dorothea; Tierney, Robert; Söderbäck, Zahra; Crane, Dennis; Bolgiano, Barbara; Fairweather, Neil

2006-01-01

In this study, the immunogenicities of the nontoxic HC fragment of tetanus toxin and derivatives lacking ganglioside binding activity were compared with that of tetanus toxoid after subcutaneous immunization of mice. Wild-type HC (HCWT) protein and tetanus toxoid both elicited strong antibody responses against toxoid and HC antigens and provided complete protection against toxin challenge. Mutants of HC containing deletions essential for ganglioside binding elicited lower responses than HCWT. HCM115, containing two amino acid substitutions within the ganglioside binding site, provided reduced protection against tetanus toxin challenge compared with HCWT, consistent with lower anti-HC and anti-toxoid antibody titers. Circular-dichroism spectroscopy and intrinsic fluorescence spectroscopy showed minimal structural perturbation in HCM115. We conclude that the presence of the ganglioside binding site within HC may be essential for induction of a fully protective anti-tetanus response comparable to that induced by tetanus toxoid by subcutaneous injection. PMID:16861677

GD3- and O-acetylated GD3-gangliosides in the GM2 synthase-deficient mouse brain and their immunohistochemical localization

PubMed Central

Matsuda, Junko; Vanier, Marie T.; Popa, Iuliana; Portoukalian, Jacques; Suzuki, Kunihiko

2006-01-01

Gangliosides in the brain of the knockout mouse deficient in the activity of β1,4 N-acetylgalactosaminyl transferase (β1,4 GalNAc-T)(GM2 synthase) consisted of nearly exclusively of GM3- and GD3-gangliosides as expected from the known substrate specificity of the enzyme and in confirmation of the initial reports from two laboratories that generated the mutant mouse experimentally. The total molar amount of gangliosides was approximately 30% higher in the mutant mouse brain than that in the wild-type brain. However, contrary to the initial reports, one-fourth of total GD3-ganglioside was O-acetylated. It reacted positively with an anti-O-acetylated GD3 monoclonal antibody and disappeared with a corresponding increase in GD3-ganglioside after mild alkaline treatment. The absence of O-acetylated GD3 in the initial reports can be explained by the saponification step included in their analytical procedures. Although quantitatively much less and identification tentative, we also detected GT3 and O-acetylated GT3. Anti-GD3 and anti-O-acetylated GD3 monoclonal antibodies gave positive reactions in the brain of mutant mouse as expected from the analytical results. Either antibody barely stained wild-type brain except for immunoreactivity of GD3 in the cerebellar Purkinje cells. The distributions of GD3 and O-acetylated GD3 in the brain of mutant mouse were similar but differential localization was noted in the cerebellar Purkinje cells and cerebral cortex. PMID:25792782

Multi-Pivot Quicksort: an Experiment with Single, Dual, Triple, Quad, and Penta-Pivot Quicksort Algorithms in Python

NASA Astrophysics Data System (ADS)

Budiman, M. A.; Zamzami, E. M.; Rachmawati, D.

2017-03-01

Dual-pivot quicksort, which was proposed by Yaroslavsky, has been experimentally proven to be more efficient than the classical single-pivot quicksort under the Java Virtual Machine [6]. Moreover, Kushagara, López-Ortiz, and Munro [4] has shown that triple-pivot quicksort runs 7-8% faster than dual-pivot quicksort in C, mutatis mutandis. In this research, we implement and experiment with single, dual, triple, quad, and penta-pivot quicksort algorithms in Python. Our experimental results are as follows. Firstly, the quicksort with single pivot is the slowest among the five variants. Secondly, at least until five (penta) pivots are being used, it is proven that the more pivots are used in a quicksort algorithm, the faster its performance becomes. Thirdly, the increase of speed resulted by adding more pivots tends to decrease gradually.

Preset pivotal tool holder

DOEpatents

Asmanes, Charles

1979-01-01

A tool fixture is provided for precise pre-alignment of a radiused edge cutting tool in a tool holder relative to a fixed reference pivot point established on said holder about which the tool holder may be selectively pivoted relative to the fixture base member to change the contact point of the tool cutting edge with a workpiece while maintaining the precise same tool cutting radius relative to the reference pivot point.

Pivoting-Head Wrench

NASA Technical Reports Server (NTRS)

Bradley, Glen L.

1993-01-01

Wrench ends pivot so it can be used to loosen or tighten nuts or bolts in confined spaces. One end equipped with open-end socket; other end, with double-hexagon socket. Heads pivot on pins. Pins fit tightly so heads do not flop; friction on pins sufficient to hold heads in positions until rotated intentionally.

Binding to Gangliosides Containing N-Acetylneuraminic Acid Is Sufficient To Mediate the Immunomodulatory Properties of the Nontoxic Mucosal Adjuvant LT-IIb(T13I) ▿

PubMed Central

Nawar, Hesham F.; Berenson, Charles S.; Hajishengallis, George; Takematsu, Hiromu; Mandell, Lorrie; Clare, Ragina L.; Connell, Terry D.

2010-01-01

By use of a mouse mucosal immunization model, LT-IIb(T13I), a nontoxic mutant type II heat-labile enterotoxin, was shown to have potent mucosal and systemic adjuvant properties. In contrast to LT-IIb, which binds strongly to ganglioside receptors decorated with either N-acetylneuraminic acid (NeuAc) or N-glycolylneuraminic acid (NeuGc), LT-IIb(T13I) binds NeuAc gangliosides much less well. Rather, LT-IIb(T13I) binds preferentially to NeuGc gangliosides. To determine if the adjuvant properties of LT-IIb(T13I) are altered in the absence of NeuGc ganglioside receptors, experiments were conducted using a Cmah-null mouse line which is deficient in the synthesis of NeuGc gangliosides. Several immunomodulatory properties of LT-IIb(T13I) were shown to be dependent on NeuGc gangliosides. LT-IIb(T13I) had reduced binding activity for NeuGc-deficient B cells and macrophages; binding to NeuGc-deficient T cells and dendritic cells (DC) was essentially undetectable. Treatment of Cmah-null macrophages with LT-IIb(T13I), however, upregulated the transcription of interleukin-4 (IL-4), IL-6, IL-17, and gamma interferon (IFN-γ), four cytokines important for promoting immune responses. The production of mucosal IgA and serum IgG against an immunizing antigen was augmented in NeuGc-deficient mice administered LT-IIb(T13I) as a mucosal adjuvant. Notably, NeuGc gangliosides are not expressed in humans. Still, treatment of human monocytes with LT-IIb(T13I) induced the secretion of IL-6, an inflammatory cytokine that mediates differential control of leukocyte activation. These results suggested that NeuAc gangliosides are sufficient to mediate the immunomodulatory properties of LT-IIb(T13I) in mice and in human cells. The nontoxic mutant enterotoxin LT-IIb(T13I), therefore, is potentially a new and safe human mucosal adjuvant. PMID:20392887

Micromechanisms with floating pivot

DOEpatents

Garcia, Ernest J.

2001-03-06

A new class of tilting micromechanical mechanisms have been developed. These new mechanisms use floating pivot structures to relieve some of the problems encountered in the use of solid flexible pivots.

Composite ganglioside autoantibodies and immune treatment response in MMN and MADSAM.

PubMed

Martinez-Thompson, Jennifer M; Snyder, Melissa R; Ettore, Michael; McKeon, Andrew; Pittock, Sean J; Roforth, Matthew M; Mandrekar, Jay; Mauermann, Michelle L; Taylor, Bruce V; Dyck, P James B; Windebank, Anthony J; Klein, Christopher J

2018-06-01

Multifocal motor neuropathy (MMN) is a motor only, asymmetric onset neuropathy that is relatively treatment-refractory compared with classic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy. We reviewed 35 patients seropositive for GM1 (monosialo-asialo [immunoglobulin M, IgM; immunoglobulin G, IgG]) and/or GD1b (disialo [IgG, IgM]) autoantibodies having MMN, classic CIDP, or MADSAM. Immune-treatment responsiveness and clinical course was compared with antibody negative disease controls. Seventy-nine percent of seropositives with an initial diagnosis of MMN were immunotherapy responsive compared with 46% of seronegatives (P = 0.045). Eight ganglioside antibody positive MMN patients of 19 (42%) developed sensory findings consistent with MADSAM compared with 3 of 41 (7%) seronegative MMN patients (P = 0.003). MMN and MADSAM patients with ganglioside antibody positivity had more sustained treatment responses (P = 0.03). Patients initially diagnosed with MMN seropositive for diverse GM1 autoantibodies appear more likely to have sustained treatment response and evolution to MADSAM. Muscle Nerve 57: 1000-1005, 2018. © 2017 Wiley Periodicals, Inc.

Accumulation of cholesterol and GM2 ganglioside in cells cultured in the presence of progesterone: an implication for the basic defect in Niemann-Pick disease type C.

PubMed

Sato, M; Akaboshi, S; Katsumoto, T; Taniguchi, M; Higaki, K; Tai, T; Sakuraba, H; Ohno, K

1998-01-01

Cultured fibroblasts from patients with Niemann-Pick disease type C (NP-C) are characterized by lysosomal accumulation of unesterified cholesterol and a defect in intracellular trafficking of cholesterol. We have found the accumulation of GM2 ganglioside in NP-C fibroblasts [Yano T, Taniguchi M, Akaboshi S, Vanier MT, Tai T, Sakuraba H, et al. Proc Japan Acad 1996;72B:214-219]. In this communication we show that several inhibitors known to inhibit intracellular cholesterol transport, progesterone, imipramine and KN-62, elicit accumulation of not only unesterified cholesterol but also GM2 ganglioside. This finding suggests that intracellular transport of cholesterol may be coupled with that of GM2 ganglioside. The accumulation of free cholesterol and GM2 ganglioside may be a clue for understanding the basic defect of NP-C. Recently NPC1 gene is found by the positional cloning. The mechanism of accumulating of GM2 ganglioside should be further investigated by studying of the functions of NPC1 gene.

Osteopontin plays a pivotal role in increasing severity of respiratory syncytial virus infection

PubMed Central

Sampayo-Escobar, Viviana; Green, Ryan; Cheung, Michael B.; Bedi, Raminder; Mohapatra, Subhra

2018-01-01

The molecular mechanisms underlying susceptibility to severe respiratory syncytial virus (RSV) infection remain poorly understood. Herein, we report on the role of osteopontin (OPN) in regulation of RSV infection in human epithelial cells and how interleukin-1 beta (IL-1β), a cytokine secreted soon after RSV infection, when persistently expressed can induce OPN expression leading to increased viral infection. We first compared OPN expression in two human epithelial cell lines: HEK-293 and HEp-2. In contrast to HEp-2, HEK-293 expresses low levels of pro-caspase-1 resulting in decreased IL-1β expression in response to RSV infection. We found a correlation between low IL-1β levels and a delay in induction of OPN expression in RSV-infected HEK-293 cells compared to HEp-2. This phenomenon could partially explain the high susceptibility of HEp-2 cells to RSV infection versus the moderate susceptibility of HEK-293 cells. Also, HEK-293 cells expressing low levels of pro-caspase-1 exhibit decreased IL-1β expression and delayed OPN expression in response to RSV infection. HEK-293 cells incubated with human rIL-1β showed a dose-dependent increase in OPN expression upon RSV infection. Also, incubation with rOPN increased RSV viral load. Moreover, HEp-2 cells or mice infected with a mucogenic RSV strain RSV-L19F showed elevated levels of OPN in contrast to mice infected with the laboratory RSV strain rA2. This correlated with elevated levels of OPN following infection with RSV-L19F compared to rA2. Together, these results demonstrate that increased OPN expression is regulated in part by IL-1β, and the interplay between IL-1β and OPN signaling may play a pivotal role in the spread of RSV infection. PMID:29677209

Therapeutic evaluation of GM2 gangliosidoses by ELISA using anti-GM2 ganglioside antibodies.

PubMed

Tsuji, Daisuke; Higashine, Yukari; Matsuoka, Kazuhiko; Sakuraba, Hitoshi; Itoh, Kohji

2007-03-01

GM2 gangliosidoses, including Tay-Sachs disease, Sandhoff disease and the AB variant, comprise deficiencies of beta-hexosaminidase isozymes and GM2 ganglioside activator protein associated with accumulation of GM2 ganglioside (GM2) in lysosomes and neurosomatic clinical manifestations. A simple assay system for intracellular quantification of GM2 is required to evaluate the therapeutic effects on GM2-gangliosidoses. We newly established a cell-ELISA system involving anti-GM2 monoclonal antibodies for measuring GM2 storage in fibroblasts from Tay-Sachs and Sandhoff disease patients. We succeeded in detecting the corrective effect of enzyme replacement on elimination of GM2 in the cells with this ELISA system. This simple and sensitive system should be useful as additional diagnosis tool as well as therapeutic evaluation of GM2 gangliosidoses.

GM2-ganglioside metabolism in hexosaminidase A deficiency states: determination in situ using labeled GM2 added to fibroblast cultures

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

Raghavan, S.S.; Krusell, A.; Krusell, J.

1985-11-01

To clarify the relationship between hexosaminidase A (HEX A) activity and GM2-ganglioside hydrolysis in atypical clinical situations of HEX A deficiency, we have developed a simple method to assess GM2-ganglioside metabolism in cultured fibroblasts utilizing GM2 labeled with tritium in the sphingosine portion of the molecule. The radioactive lipid is added to the media of cultured skin fibroblasts, and after 10 days the cells are thoroughly washed, then harvested, and their lipid composition analyzed by HPLC. The degree of hydrolysis of the ingested GM2 is determined by comparing the amount of radioactive counts recovered in undegraded substrate with total cellularmore » radioactivity. A deficiency in GM2-ganglioside hydrolysis was demonstrated in seven HEX A-deficient adults with neurological signs and in two healthy-appearing adolescents with older affected siblings. In each case, an analysis of endogenous monosialoganglioside composition revealed an increase in GM2-ganglioside, confirming the presence of a block in the metabolism of GM2. No defect in GM2-catabolism was found in four other healthy individuals with HEX A deficiency. This method of assay is especially helpful in the evaluation of atypical cases of HEX A deficiency for the definitive diagnosis of GM2-gangliosidosis.« less

Tetanus toxin interaction with human erythrocytes. II. Kinetic properties of toxin association and evidence for a ganglioside-toxin macromolecular complex formation.

PubMed

Lazarovici, P; Yavin, E

1985-01-25

The properties of tetanus toxin interaction with human erythrocytes supplemented with disialo- and trisialo-gangliosides have been investigated. Binding of toxin is linear with time for 1 h and is 3-4-fold higher at 37 degrees C than at 4 degrees C during incubation of long duration. It exhibits saturation at toxin concentrations between 0.1 and 1 microgram/ml; however, it is nonsaturable between 1 and up to 50 micrograms/ml. It is effectively prevented by free gangliosides and antibodies or by pretreatment with sialidase but is unaffected by a number of closely related ligands including toxoid and toxin fragments. NaCl (1 M) removes a great portion (86%) of cell-associated toxin while Triton X-100 extracts an additional fraction (30%) of the salt-resistant cell-bound toxin. The residual sequestred toxin after detergent extraction is sensitive to proteolytic degradation. The trypsin-stable fraction (1.5%) is biotoxic and may be indicative of internalization of toxin. A macromolecular complex of about 700 kDa containing toxin and gangliosides has been isolated and characterized by Sephacryl S-300 gel permeation chromatography, SDS-gel electrophoresis, immunoprecipitability and biotoxicity. This complex is obtained only in ganglioside-supplemented cells and not when free 3H-labeled GD1b is reacted with 125I-labeled toxin in solution in the absence of cells. The hydrophobicity properties acquired as a result of ganglioside-toxin interaction, presumably at the cell surface, suggest a conformational change of the toxin which may enable its penetration into the bilayer.

Determination of ganglioside composition and structure in human brain hemangioma by chip-based nanoelectrospray ionization tandem mass spectrometry.

PubMed

Schiopu, Catalin; Flangea, Corina; Capitan, Florina; Serb, Alina; Vukelić, Zeljka; Kalanj-Bognar, Svjetlana; Sisu, Eugen; Przybylski, Michael; Zamfir, Alina D

2009-12-01

We report here on a preliminary investigation of ganglioside composition and structure in human hemangioma, a benign tumor in the frontal cortex (HFC) in comparison to normal frontal cortex (NFC) tissue using for the first time advanced mass spectrometric methods based on fully automated chip-nanoelectrospray (nanoESI) high-capacity ion trap (HCT) and collision-induced dissociation (CID). The high ionization efficiency, sensitivity and reproducibility provided by the chip-nanoESI approach allowed for a reliable MS-based ganglioside comparative assay. Unlike NFC, ganglioside mixture extracted from HFC was found dominated by species of short glycan chains exhibiting lower overall sialic acid content. In HFC, only GT1 (d18:1/20:0), and GT3 (d18:1/25:1) polysialylated species were detected. Interestingly, none of these trisialylated forms was detected in NFC, suggesting that such components might selectively be associated with HFC. Unlike the case of previously investigated high malignancy gliosarcoma, in HFC one modified O-Ac-GD2 and one modified O-Ac-GM4 gangliosides were observed. This aspect suggests that these O-acetylated structures could be associated with cerebral tumors having reduced malignancy grade. Fragmentation analysis by CID in MS(2) mode using as precursors the ions corresponding to GT1 (d18:1/20:0) and GD1 (d18:1/20:0) provided data corroborating for the first time the presence of the common GT1a and GT1b isomers and the incidence of unusual GT1c and GT1d glycoforms in brain hemangioma tumor.

Analysis of cholera toxin-ganglioside interactions by flow cytometry.

PubMed

Lauer, Sabine; Goldstein, Byron; Nolan, Rhiannon L; Nolan, John P

2002-02-12

Cholera toxin entry into mammalian cells is mediated by binding of the pentameric B subunit (CTB) to ganglioside GM(1) in the cell membrane. We used flow cytometry to quantitatively measure in real time the interactions of fluorescently labeled pentameric cholera toxin B-subunit (FITC-CTB) with its ganglioside receptor on microsphere-supported phospholipid membranes. A model that describes the multiple steps of this mode of recognition was developed to guide our flow cytometric experiments and extract relevant equilibrium and kinetic rate constants. In contrast to previous studies, our approach takes into account receptor cross-linking, an important feature for multivalent interactions. From equilibrium measurements, we determined an equilibrium binding constant for a single subunit of FITC-CTB binding monovalently to GM(1) presented in bilayers of approximately 8 x 10(7) M(-1) while that for binding to soluble GM(1)-pentasaccharide was found to be approximately 4 x 10(6) M(-1). From kinetic measurements, we determined the rate constant for dissociation of a single site of FITC-CTB from microsphere-supported bilayers to be (3.21 +/- 0.03) x 10(-3) s(-1), and the rate of association of a site on FITC-CTB in solution to a GM(1) in the bilayer to be (2.8 +/- 0.4) x 10(4) M(-1) s(-1). These values yield a lower estimate for the equilibrium binding constant of approximately 1 x 10(7) M(-1). We determined the equilibrium surface cross-linking constant [(1.1 +/- 0.1) x 10(-12) cm(2)] and from this value and the value for the rate constant for dissociation derived a value of approximately 3.5 x 10(-15) cm(2) s(-1) for the forward rate constant for cross-linking. We also compared the interaction of the receptor binding B-subunit with that of the whole toxin (A- and B-subunits). Our results show that the whole toxin binds with approximately 100-fold higher avidity than the pentameric B-subunit alone which is most likely due to the additional interaction of the A(2)-subunit

Human monoclonal IgM with autoantibody activity against two gangliosides (GM1 and GD1b) in a patient with motor neuron syndrome.

PubMed

Jauberteau, M O; Gualde, N; Preud'Homme, J L; Rigaud, M; Gil, R; Vallat, J M; Baumann, N

1990-05-01

Small amounts of oligoclonal immunoglobulins were detected by Western blotting in the serum from a patient with motor neuron syndrome. The prominent one, a monoclonal IgM lambda, reacted strongly with the gangliosides GM1 and GD1b and more weakly with asialo GM1, as shown by immunoenzymatic staining of thin-layer chromatograms of gangliosides, ELISA on purified glycolipid coats and immunoadsorption with purified GM1. Affinity-chromatography with purified GM1 resulted in the purification of monoclonal IgM lambda. This purified IgM and its Fab fragments showed the same pattern of reactivity with gangliosides as that observed with whole serum. Such monoclonal IgM could be responsible for motor neuron diseases in some patients with overt or barely detectable monoclonal gammopathies.

PiVoT GPS Receiver

NASA Technical Reports Server (NTRS)

Wennersten, Miriam Dvorak; Banes, Anthony Vince; Boegner, Gregory J.; Dougherty, Lamar; Edwards, Bernard L.; Roman, Joseph; Bauer, Frank H. (Technical Monitor)

2001-01-01

NASA Goddard Space Flight Center has built an open architecture, 24 channel space flight GPS receiver. The CompactPCI PiVoT GPS receiver card is based on the Mitel/GEC Plessey Builder-2 board. PiVoT uses two Plessey 2021 correlators to allow tracking of up to 24 separate GPS SV's on unique channels. Its four front ends can support four independent antennas, making it a useful card for hosting GPS attitude determination algorithms. It has been built using space quality, radiation tolerant parts. The PiVoT card will track a weaker signal than the original Builder 2 board. It also hosts an improved clock oscillator. The PiVoT software is based on the original Plessey Builder 2 software ported to the Linux operating system. The software is POSIX complaint and can easily be converted to other POSIX operating systems. The software is open source to anyone with a licensing agreement with Plessey. Additional tasks can be added to the software to support GPS science experiments or attitude determination algorithms. The next generation PiVoT receiver will be a single radiation hardened CompactPCI card containing the microprocessor and the GPS receiver optimized for use above the GPS constellation. PiVoT was flown successfully on a balloon in July, 2001, for its first non-simulated flight.

IgM ganglioside GM1 antibodies in patients with autoimmune disease or neuropathy, and controls.

PubMed Central

Bansal, A S; Abdul-Karim, B; Malik, R A; Goulding, P; Pumphrey, R S; Boulton, A J; Holt, P L; Wilson, P B

1994-01-01

AIMS--To compare the titre of anti-ganglioside antibodies (AGA) to GM1 ganglioside in patients with central and peripheral neurological disease and pure motor and sensorimotor neuropathy, in patients with classic autoimmune diseases, and controls. METHODS--AGA to GM1 were measured using an enzyme linked immunosorbent assay (ELISA) technique, highly purified bovine GM1 ganglioside, and sequential dilution of control and test sera. Antibody titre was calculated using the optical density readings of three consecutive serum dilutions multiplied by the dilution factor. RESULTS--A considerable overlap was evident in the titre of AGA to GM1 in control and test sera. High antibody titres were most frequent in patients with multifocal motor neuropathy with conduction block (MMNCB). Low AGA titre were observed in several patient groups. Compared with the controls, the median titre of AGA to GM1 was significantly higher in patients with multiple sclerosis, rheumatoid arthritis, primary Sjögren's syndrome and systemic lupus erythematosus. In contrast, the median titre in patients with diabetic peripheral neuropathy, motor neurone disease, sensorimotor neuropathy and chronic inflammatory demyelinating polyneuropathy was no different from that in normal control subjects. CONCLUSIONS--Estimation of AGA to GM1 may be helpful in the diagnosis of MMNCB in patients with a pure motor neuropathy but in few other conditions. Low titre AGA to GM1 are evident in several autoimmune conditions. The pathogenetic importance of AGA to GM1 in patients with neuropathy is not clear. PMID:8027366

Parallel pivoting combined with parallel reduction

NASA Technical Reports Server (NTRS)

Alaghband, Gita

1987-01-01

Parallel algorithms for triangularization of large, sparse, and unsymmetric matrices are presented. The method combines the parallel reduction with a new parallel pivoting technique, control over generations of fill-ins and a check for numerical stability, all done in parallel with the work being distributed over the active processes. The parallel technique uses the compatibility relation between pivots to identify parallel pivot candidates and uses the Markowitz number of pivots to minimize fill-in. This technique is not a preordering of the sparse matrix and is applied dynamically as the decomposition proceeds.

High-throughput imaging method for direct assessment of GM1 ganglioside levels in mammalian cells.

PubMed

Acosta, Walter; Martin, Reid; Radin, David N; Cramer, Carole L

2016-03-01

GM1-gangliosidosis is an inherited autosomal recessive disorder caused by mutations in the gene GLB1, which encodes acid β-galactosidase (β-gal). The lack of activity in this lysosomal enzyme leads to accumulation of GM1 gangliosides (GM1) in cells. We have developed a high-content-imaging method to assess GM1 levels in fibroblasts that can be used to evaluate substrate reduction in treated GLB1(-/-) cells [1]. This assay allows fluorescent quantification in a multi-well system which generates unbiased and statistically significant data. Fluorescently labeled Cholera Toxin B subunit (CTXB), which specifically binds to GM1 gangliosides, was used to detect in situ GM1 levels in a fixed monolayer of fibroblasts. This sensitive, rapid, and inexpensive method facilitates in vitro drug screening in a format that allows a high number of replicates using low working volumes.

Human monoclonal IgM with autoantibody activity against two gangliosides (GM1 and GD1b) in a patient with motor neuron syndrome.

PubMed Central

Jauberteau, M O; Gualde, N; Preud'Homme, J L; Rigaud, M; Gil, R; Vallat, J M; Baumann, N

1990-01-01

Small amounts of oligoclonal immunoglobulins were detected by Western blotting in the serum from a patient with motor neuron syndrome. The prominent one, a monoclonal IgM lambda, reacted strongly with the gangliosides GM1 and GD1b and more weakly with asialo GM1, as shown by immunoenzymatic staining of thin-layer chromatograms of gangliosides, ELISA on purified glycolipid coats and immunoadsorption with purified GM1. Affinity-chromatography with purified GM1 resulted in the purification of monoclonal IgM lambda. This purified IgM and its Fab fragments showed the same pattern of reactivity with gangliosides as that observed with whole serum. Such monoclonal IgM could be responsible for motor neuron diseases in some patients with overt or barely detectable monoclonal gammopathies. Images Fig. 2 Fig. 3 PMID:2357844

Histochemical detection of GM1 ganglioside using cholera toxin-B subunit. Evaluation of critical factors optimal for in situ detection with special emphasis to acetone pre-extraction

PubMed Central

Petr, T.; Šmíd, V.; Šmídová, J.; Hůlková, H.; Jirkovská, M.; Elleder, M.; Muchová, L.; Vítek, L.; Šmíd, F.

2010-01-01

A comparison of histochemical detection of GM1 ganglioside in cryostat sections using cholera toxin B-subunit after fixation with 4% formaldehyde and dry acetone gave tissue-dependent results. In the liver no pre-treatment showed detectable differences related to GM1 reaction products, while studies in the brain showed the superiority of acetone pre-extraction (followed by formaldehyde), which yielded sharper images compared with the diffuse, blurred staining pattern associated with formaldehyde. Therefore, the aim of our study was to define the optimal conditions for the GM1 detection using cholera toxin B-subunit. Ganglioside extractability with acetone, the ever neglected topic, was tested comparing anhydrous acetone with acetone containing admixture of water. TLC analysis of acetone extractable GM1 ganglioside from liver sections did not exceed 2% of the total GM1 ganglioside content using anhydrous acetone at −20°C, and 4% at room temperature. The loss increased to 30.5% using 9:1 acetone/water. Similarly, photometric analysis of lipid sialic acid, extracted from dried liver homogenates with anhydrous acetone, showed the loss of gangliosides into acetone 3.0±0.3% only. The loss from dried brain homogenate was 9.5±1.1%. Thus, anhydrous conditions (dry tissue samples and anhydrous acetone) are crucial factors for optimal in situ ganglioside detection using acetone pre-treatment. This ensures effective physical fixation, especially in tissues rich in polar lipids (precipitation, prevention of in situ diffusion), and removal of cholesterol, which can act as a hydrophobic blocking barrier. PMID:20558344

Sialidase activities of cultured human fibroblasts and the metabolism of GM3 ganglioside

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

Usuki, S.; Lyu, S.C.; Sweeley, C.C.

1988-05-15

Free sialic acid has been found in the cell-conditioned medium of human foreskin fibroblasts. It is proposed that the accumulation of extracellular sialic acid may result from the hydrolysis of GM3 ganglioside on the cell surface of these fibroblasts. Sialidase activities with GM3 ganglioside and sialyllactitol as substrates were demonstrated in cell-conditioned medium, and the levels of their activities correlated positively with cell density. The GM3 sialidase activity at pH 4.5 was 4.1 and 38 pmol/h/ml of medium at sparse and confluent densities, respectively; the corresponding activities with sialyllactitol as the substrate were 12 and 75 pmol/h/ml of medium (pHmore » 4.5). The pH versus activity profiles with GM3 as the substrate suggested the presence of a second sialidase with an optimal activity at pH 6.5 in the conditioned medium of preconfluent cells. This activity was virtually absent in the medium of contact-inhibited cells and could not be assayed with sialyllactitol as the substrate. The turnover of cell surface GM3 was assessed by pulse labeling human foreskin fibroblasts with a radioactive precursor of sialic acid ((1-14C)N-acetylmannosamine) and a radioactive precursor of ceramide ((3,3-3H2)serine). During a chase period of 24 h turnover of the doubly labeled cellular GM3 was observed; there was a loss of about 35% of the 14C-labeled sialic acid without any measureable loss of 3H-labeled ceramide from GM3. We have speculated that the enzyme-catalyzed removal of sialic acid from the GM3 ganglioside on the extracellular aspect of the plasma membrane may be a necessary event involved in the modulation of cell growth.« less

High-throughput imaging method for direct assessment of GM1 ganglioside levels in mammalian cells

PubMed Central

Acosta, Walter; Martin, Reid; Radin, David N.; Cramer, Carole L.

2016-01-01

GM1-gangliosidosis is an inherited autosomal recessive disorder caused by mutations in the gene GLB1, which encodes acid β-galactosidase (β-gal). The lack of activity in this lysosomal enzyme leads to accumulation of GM1 gangliosides (GM1) in cells. We have developed a high-content-imaging method to assess GM1 levels in fibroblasts that can be used to evaluate substrate reduction in treated GLB1−/− cells [1]. This assay allows fluorescent quantification in a multi-well system which generates unbiased and statistically significant data. Fluorescently labeled Cholera Toxin B subunit (CTXB), which specifically binds to GM1 gangliosides, was used to detect in situ GM1 levels in a fixed monolayer of fibroblasts. This sensitive, rapid, and inexpensive method facilitates in vitro drug screening in a format that allows a high number of replicates using low working volumes. PMID:26958633

PiVoT GPS Receiver

NASA Technical Reports Server (NTRS)

Wennersten, Miriam; Banes, Vince; Boegner, Greg; Clagnett, Charles; Dougherty, Lamar; Edwards, Bernard; Roman, Joe; Bauer, Frank H. (Technical Monitor)

2001-01-01

NASA Goddard Space Flight Center has built an open architecture, 24 channel spaceflight Global Positioning System (GPS) receiver. The compact PCI PiVoT GPS receiver card is based on the Mitel/GEC Plessey Builder 2 board. PiVoT uses two Plessey 2021 correlators to allow tracking of up to 24 separate GPS SV's on unique channels. Its four front ends can support four independent antennas, making it a useful card for hosting GPS attitude determination algorithms. It has been built using space quality, radiation tolerant parts. The PiVoT card works at a lower signal to noise ratio than the original Builder 2 board. It also hosts an improved clock oscillator. The PiVoT software is based on the original Piessey Builder 2 software ported to the Linux operating system. The software is posix compliant and can be easily converted to other posix operating systems. The software is open source to anyone with a licensing agreement with Plessey. Additional tasks can be added to the software to support GPS science experiments or attitude determination algorithms. The next generation PiVoT receiver will be a single radiation hardened compact PCI card containing the microprocessor and the GPS receiver optimized for use above the GPS constellation.

Pivoting neuromuscular control and proprioception in females and males.

PubMed

Lee, Song Joo; Ren, Yupeng; Kang, Sang Hoon; Geiger, François; Zhang, Li-Qun

2015-04-01

Noncontact ACL injuries occur most commonly in pivoting sports and are much more frequent in females than in males. However, information on sex differences in proprioceptive acuity under weight-bearing and leg neuromuscular control in pivoting is scarce. The objective of this study was to investigate sex differences in pivoting neuromuscular control during strenuous stepping tasks and proprioceptive acuity under weight-bearing. 21 male and 22 female subjects were recruited to evaluate pivoting proprioceptive acuity under weight-bearing, and pivoting neuromuscular control (in terms of leg pivoting instability, stiffness, maximum internal and external pivoting angles, and entropy of time-to-peak EMG in lower limb muscles) during strenuous stepping tasks performed on a novel offaxis elliptical trainer. Compared to males, females had significantly lower proprioceptive acuity under weight-bearing in both internal and external pivoting directions, higher pivoting instability, larger maximum internal pivoting angle, lower leg pivoting stiffness, and higher entropy of time-to-peak EMG in the gastrocnemius muscles during strenuous stepping tasks with internal and external pivoting perturbations. Results of this study may help us better understand factors contributing to ACL injuries in females and males, develop training strategies to improve pivoting neuromuscular control and proprioceptive acuity, and potentially reduce ACL and lower-limb musculoskeletal injuries.

Gangliosides as a potential new class of stem cell markers: the case of GD1a in human bone marrow mesenchymal stem cells.

PubMed

Bergante, Sonia; Torretta, Enrica; Creo, Pasquale; Sessarego, Nadia; Papini, Nadia; Piccoli, Marco; Fania, Chiara; Cirillo, Federica; Conforti, Erika; Ghiroldi, Andrea; Tringali, Cristina; Venerando, Bruno; Ibatici, Adalberto; Gelfi, Cecilia; Tettamanti, Guido; Anastasia, Luigi

2014-03-01

Owing to their exposure on the cell surface and the possibility of being directly recognized with specific antibodies, glycosphingolipids have aroused great interest in the field of stem cell biology. In the search for specific markers of the differentiation of human bone marrow mesenchymal stem cells (hBMSCs) toward osteoblasts, we studied their glycosphingolipid pattern, with particular attention to gangliosides. After lipid extraction and fractionation, gangliosides, metabolically (3)H-labeled in the sphingosine moiety, were separated by high-performance TLC and chemically characterized by MALDI MS. Upon induction of osteogenic differentiation, a 3-fold increase of ganglioside GD1a was observed. Therefore, the hypothesis of GD1a involvement in hBMSCs commitment toward the osteogenic phenotype was tested by comparison of the osteogenic propensity of GD1a-highly expressing versus GD1a-low expressing hBMSCs and direct addition of GD1a in the differentiation medium. It was found that either the high expression of GD1a in hBMSCs or the addition of GD1a in the differentiation medium favored osteogenesis, providing a remarkable increase of alkaline phosphatase. It was also observed that ganglioside GD2, although detectable in hBMSCs by immunohistochemistry with an anti-GD2 antibody, could not be recognized by chemical analysis, likely reflecting a case, not uncommon, of molecular mimicry.

Identification of a Unique Ganglioside Binding Loop within Botulinum Neurotoxins C and D-SA

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

Karalewitz, Andrew P.-A.; Kroken, Abby R.; Fu, Zhuji

2010-09-22

The botulinum neurotoxins (BoNTs) are the most potent protein toxins for humans. There are seven serotypes of BoNTs (A-G) based on a lack of cross antiserum neutralization. BoNTs utilize gangliosides as components of the host receptors for binding and entry into neurons. Members of BoNT/C and BoNT/D serotypes include mosaic toxins that are organized in D/C and C/D toxins. One D/C mosaic toxin, BoNT/D-South Africa (BoNT/D-SA), was not fully neutralized by immunization with BoNT serotype C or D, which stimulated this study. Here the crystal structures of the receptor binding domains of BoNT/C, BoNT/D, and BoNT/D-SA are presented. Biochemical andmore » cell binding studies show that BoNT/C and BoNT/D-SA possess unique mechanisms for ganglioside binding. These studies provide new information about how the BoNTs can enter host cells as well as a basis for understanding the immunological diversity of these neurotoxins.« less

Gangliosides and Ceramides Change in a Mouse Model of Blast Induced Traumatic Brain Injury

PubMed Central

2013-01-01

Explosive detonations generate atmospheric pressure changes that produce nonpenetrating blast induced “mild” traumatic brain injury (bTBI). The structural basis for mild bTBI has been extremely controversial. The present study applies matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging to track the distribution of gangliosides in mouse brain tissue that were exposed to very low level of explosive detonations (2.5–5.5 psi peak overpressure). We observed major increases of the ganglioside GM2 in the hippocampus, thalamus, and hypothalamus after a single blast exposure. Moreover, these changes were accompanied by depletion of ceramides. No neurological or brain structural signs of injury could be inferred using standard light microscopic techniques. The first source of variability is generated by the Latency between blast and tissue sampling (peak intensity of the blast wave). These findings suggest that subtle molecular changes in intracellular membranes and plasmalemma compartments may be biomarkers for biological responses to mild bTBI. This is also the first report of a GM2 increase in the brains of mature mice from a nongenetic etiology. PMID:23590251

The total chemical synthesis of the monoglycosylated GM2 ganglioside activator using a novel cysteine surrogate.

PubMed

Sato, Kohei; Kitakaze, Keisuke; Nakamura, Takahiro; Naruse, Naoto; Aihara, Keisuke; Shigenaga, Akira; Inokuma, Tsubasa; Tsuji, Daisuke; Itoh, Kohji; Otaka, Akira

2015-06-21

We describe a novel peptide ligation/desulfurization strategy using a β-mercapto-N-glycosylated asparagine derivative. The newly developed procedure was successfully applied to the total chemical synthesis of the GM2 ganglioside activator protein bearing a monosaccharide on the native glycosylation site.

Aβ1-25-Derived Sphingolipid-Domain Tracer Peptide SBD Interacts with Membrane Ganglioside Clusters via a Coil-Helix-Coil Motif

PubMed Central

Wang, Yaofeng; Kraut, Rachel; Mu, Yuguang

2015-01-01

The Amyloid-β (Aβ)-derived, sphingolipid binding domain (SBD) peptide is a fluorescently tagged probe used to trace the diffusion behavior of sphingolipid-containing microdomains in cell membranes through binding to a constellation of glycosphingolipids, sphingomyelin, and cholesterol. However, the molecular details of the binding mechanism between SBD and plasma membrane domains remain unclear. Here, to investigate how the peptide recognizes the lipid surface at an atomically detailed level, SBD peptides in the environment of raft-like bilayers were examined in micro-seconds-long molecular dynamics simulations. We found that SBD adopted a coil-helix-coil structural motif, which binds to multiple GT1b gangliosides via salt bridges and CH–π interactions. Our simulation results demonstrate that the CH–π and electrostatic forces between SBD monomers and GT1b gangliosides clusters are the main driving forces in the binding process. The presence of the fluorescent dye and linker molecules do not change the binding mechanism of SBD probes with gangliosides, which involves the helix-turn-helix structural motif that was suggested to constitute a glycolipid binding domain common to some sphingolipid interacting proteins, including HIV gp120, prion, and Aβ. PMID:26540054

Standardized pivot shift test improves measurement accuracy.

PubMed

Hoshino, Yuichi; Araujo, Paulo; Ahlden, Mattias; Moore, Charity G; Kuroda, Ryosuke; Zaffagnini, Stefano; Karlsson, Jon; Fu, Freddie H; Musahl, Volker

2012-04-01

The variability of the pivot shift test techniques greatly interferes with achieving a quantitative and generally comparable measurement. The purpose of this study was to compare the variation of the quantitative pivot shift measurements with different surgeons' preferred techniques to a standardized technique. The hypothesis was that standardizing the pivot shift test would improve consistency in the quantitative evaluation when compared with surgeon-specific techniques. A whole lower body cadaveric specimen was prepared to have a low-grade pivot shift on one side and high-grade pivot shift on the other side. Twelve expert surgeons performed the pivot shift test using (1) their preferred technique and (2) a standardized technique. Electromagnetic tracking was utilized to measure anterior tibial translation and acceleration of the reduction during the pivot shift test. The variation of the measurement was compared between the surgeons' preferred technique and the standardized technique. The anterior tibial translation during pivot shift test was similar between using surgeons' preferred technique (left 24.0 ± 4.3 mm; right 15.5 ± 3.8 mm) and using standardized technique (left 25.1 ± 3.2 mm; right 15.6 ± 4.0 mm; n.s.). However, the variation in acceleration was significantly smaller with the standardized technique (left 3.0 ± 1.3 mm/s(2); right 2.5 ± 0.7 mm/s(2)) compared with the surgeons' preferred technique (left 4.3 ± 3.3 mm/s(2); right 3.4 ± 2.3 mm/s(2); both P < 0.01). Standardizing the pivot shift test maneuver provides a more consistent quantitative evaluation and may be helpful in designing future multicenter clinical outcome trials. Diagnostic study, Level I.

Construction of a hybrid β-hexosaminidase subunit capable of forming stable homodimers that hydrolyze GM2 ganglioside in vivo.

PubMed

Tropak, Michael B; Yonekawa, Sayuri; Karumuthil-Melethil, Subha; Thompson, Patrick; Wakarchuk, Warren; Gray, Steven J; Walia, Jagdeep S; Mark, Brian L; Mahuran, Don

2016-01-01

Tay-Sachs or Sandhoff disease result from mutations in either the evolutionarily related HEXA or HEXB genes encoding respectively, the α- or β-subunits of β-hexosaminidase A (HexA). Of the three Hex isozymes, only HexA can interact with its cofactor, the GM2 activator protein (GM2AP), and hydrolyze GM2 ganglioside. A major impediment to establishing gene or enzyme replacement therapy based on HexA is the need to synthesize both subunits. Thus, we combined the critical features of both α- and β-subunits into a single hybrid µ-subunit that contains the α-subunit active site, the stable β-subunit interface and unique areas in each subunit needed to interact with GM2AP. To facilitate intracellular analysis and the purification of the µ-homodimer (HexM), CRISPR-based genome editing was used to disrupt the HEXA and HEXB genes in a Human Embryonic Kidney 293 cell line stably expressing the µ-subunit. In association with GM2AP, HexM was shown to hydrolyze a fluorescent GM2 ganglioside derivative both in cellulo and in vitro. Gene transfer studies in both Tay-Sachs and Sandhoff mouse models demonstrated that HexM expression reduced brain GM2 ganglioside levels.

Construction of a hybrid β-hexosaminidase subunit capable of forming stable homodimers that hydrolyze GM2 ganglioside in vivo

PubMed Central

Tropak, Michael B; Yonekawa, Sayuri; Karumuthil-Melethil, Subha; Thompson, Patrick; Wakarchuk, Warren; Gray, Steven J; Walia, Jagdeep S; Mark, Brian L; Mahuran, Don

2016-01-01

Tay-Sachs or Sandhoff disease result from mutations in either the evolutionarily related HEXA or HEXB genes encoding respectively, the α- or β-subunits of β-hexosaminidase A (HexA). Of the three Hex isozymes, only HexA can interact with its cofactor, the GM2 activator protein (GM2AP), and hydrolyze GM2 ganglioside. A major impediment to establishing gene or enzyme replacement therapy based on HexA is the need to synthesize both subunits. Thus, we combined the critical features of both α- and β-subunits into a single hybrid µ-subunit that contains the α-subunit active site, the stable β-subunit interface and unique areas in each subunit needed to interact with GM2AP. To facilitate intracellular analysis and the purification of the µ-homodimer (HexM), CRISPR-based genome editing was used to disrupt the HEXA and HEXB genes in a Human Embryonic Kidney 293 cell line stably expressing the µ-subunit. In association with GM2AP, HexM was shown to hydrolyze a fluorescent GM2 ganglioside derivative both in cellulo and in vitro. Gene transfer studies in both Tay-Sachs and Sandhoff mouse models demonstrated that HexM expression reduced brain GM2 ganglioside levels. PMID:26966698

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice

PubMed Central

Saito, Mariko; Wu, Gusheng; Hui, Maria; Masiello, Kurt; Dobrenis, Kostantin; Ledeen, Robert W.; Saito, Mitsuo

2015-01-01

Our previous studies have shown accumulation of GM2 ganglioside during ethanol-induced neurodegeneration in the developing brain, and GM2 elevation has also been reported in other brain injuries and neurodegenerative diseases. Using GM2/GD2 synthase KO mice lacking GM2/GD2 and downstream gangliosides, the current study explored the significance of GM2 elevation in WT mice. Immunohistochemical studies indicated that ethanol-induced acute neurodegeneration in postnatal day 7 (P7) WT mice was associated with GM2 accumulation in the late endosomes/lysosomes of both phagocytic microglia and increased glial fibrillary acidic protein (GFAP)-positive astrocytes. However, in KO mice, although ethanol induced robust neurodegeneration and accumulation of GD3 and GM3 in the late endosomes/lysosomes of phagocytic microglia, it did not increase the number of GFAP-positive astrocytes, and the accumulation of GD3/GM3 in astrocytes was minimal. Not only ethanol, but also DMSO, induced GM2 elevation in activated microglia and astrocytes along with neurodegeneration in P7 WT mice, while lipopolysaccharide, which did not induce significant neurodegeneration, caused GM2 accumulation mainly in lysosomes of activated astrocytes. Thus, GM2 elevation is associated with activation of microglia and astrocytes in the injured developing brain, and GM2, GD2, or other downstream gangliosides may regulate astroglial responses in ethanol-induced neurodegeneration. PMID:26063460

Gangliosides as a potential new class of stem cell markers: the case of GD1a in human bone marrow mesenchymal stem cells[S

PubMed Central

Bergante, Sonia; Torretta, Enrica; Creo, Pasquale; Sessarego, Nadia; Papini, Nadia; Piccoli, Marco; Fania, Chiara; Cirillo, Federica; Conforti, Erika; Ghiroldi, Andrea; Tringali, Cristina; Venerando, Bruno; Ibatici, Adalberto; Gelfi, Cecilia; Tettamanti, Guido; Anastasia, Luigi

2014-01-01

Owing to their exposure on the cell surface and the possibility of being directly recognized with specific antibodies, glycosphingolipids have aroused great interest in the field of stem cell biology. In the search for specific markers of the differentiation of human bone marrow mesenchymal stem cells (hBMSCs) toward osteoblasts, we studied their glycosphingolipid pattern, with particular attention to gangliosides. After lipid extraction and fractionation, gangliosides, metabolically 3H-labeled in the sphingosine moiety, were separated by high-performance TLC and chemically characterized by MALDI MS. Upon induction of osteogenic differentiation, a 3-fold increase of ganglioside GD1a was observed. Therefore, the hypothesis of GD1a involvement in hBMSCs commitment toward the osteogenic phenotype was tested by comparison of the osteogenic propensity of GD1a-highly expressing versus GD1a-low expressing hBMSCs and direct addition of GD1a in the differentiation medium. It was found that either the high expression of GD1a in hBMSCs or the addition of GD1a in the differentiation medium favored osteogenesis, providing a remarkable increase of alkaline phosphatase. It was also observed that ganglioside GD2, although detectable in hBMSCs by immunohistochemistry with an anti-GD2 antibody, could not be recognized by chemical analysis, likely reflecting a case, not uncommon, of molecular mimicry. PMID:24449473

Physiological demands of elite team handball with special reference to playing position.

PubMed

Póvoas, Susana C A; Ascensão, António A M R; Magalhães, José; Seabra, André F; Krustrup, Peter; Soares, José M C; Rebelo, António N C

2014-02-01

This study aimed to analyze the physiological demands of match play for different playing positions in elite male team handball. Time motion (N = 30) and heart rate (HR; N = 70) data were recorded throughout 10 official matches. The mean distance covered by backcourt players (4.96 ± 0.64 km) was greater (p ≤ 0.02) than for wings and pivots (4.23 ± 0.52 and 3.91 ± 0.51 km, respectively). Backcourt players spent less time standing still and walking (∼76%) than wings and pivots (∼80%) (p ≤ 0.03), and wings spent more time sprinting than the other playing positions. Backcourt players (122.9 ± 17.0) and pivots (126.8 ± 33.0) performed more high-demanding actions per game than wings (54.6 ± 15.6) (p = 0.01). The time spent by pivots in high-intensity activities decreased from the first to the second half (4.1 ± 2.4 to 2.7 ± 0.9%; p ≤ 0.01), while backcourt players showed a decrease in high-demanding playing actions (p ≤ 0.05). Backcourt players and pivots had higher mean (84 ± 9 and 83 ± 9% vs. 79 ± 10%; p ≤ 0.03) and peak effective HR, and percentage of total time at intensities >80% maximal HR (HRmax) than wings. The fraction of total time spent at intensities >80% HRmax decreased for all outfield playing positions in the second half (from 39-76 to 30-46%). Competitive team handball involves position-specific differences in the physiological demands. Furthermore, exercise intensity decreases from the first to the second half for all outfield playing positions suggesting that these players experience neuromuscular fatigue. Training of elite handball players should comprise high-intensity position-specific exercises aiming at improving the ability to maintain a high exercise intensity throughout the game.

Phospatidylserine or ganglioside--which of anionic lipids determines the effect of cationic dextran on lipid membrane?

PubMed

Hąc-Wydro, Katarzyna; Wydro, Paweł; Cetnar, Andrzej; Włodarczyk, Grzegorz

2015-02-01

In this work the influence of cationic polymer, namely diethylaminoethyl DEAE-dextran on model lipid membranes was investigated. This polymer is of a wide application as a biomaterial and a drug carrier and its cytotoxicity toward various cancer cells was also confirmed. It was suggested that anticancer effect of cationic dextran is connected with the binding of the polymer to the negatively charged sialic acid residues overexpressed in cancer membrane. This fact encouraged us to perform the studies aimed at verifying whether the effect of cationic DEAE-dextran on membrane is determined only by the presence of the negatively charged lipid in the system or the kind of anionic lipid is also important. To reach this goal systematic investigations on the effect of dextran on various one-component lipid monolayers and multicomponent hepatoma cell model membranes differing in the level and the kind of anionic lipids (phosphatidylserine, sialic acid-containing ganglioside GM3 or their mixture) were done. As evidenced the results the effect of DEAE-dextran on the model system is determined by anionic lipid-polymer electrostatic interactions. However, the magnitude of the effect of cationic polymer is strongly dependent on the kind of anionic lipid in the model system. Namely, the packing and ordering of the mixtures containing ganglioside GM3 were more affected by DEAE-dextran than phosphatidylserine-containing monolayers. Although the experiments were done on model systems and therefore further studies are highly needed, the collected data may indicate that ganglioside may be important in the differentiation of the effect of cationic dextran on membranes. Copyright © 2014 Elsevier B.V. All rights reserved.

Oriented 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine/ganglioside membranes: a Fourier transform infrared attenuated total reflection spectroscopic study. Band assignments; orientational, hydrational, and phase behavior; and effects of Ca2+ binding.

PubMed

Müller, E; Giehl, A; Schwarzmann, G; Sandhoff, K; Blume, A

1996-09-01

Fourier transform infrared (FTIR) attenuated total reflection (ATR) spectroscopy was used to elucidate the hydration behavior and molecular order of phospholipid/ganglioside bilayers. We examined dry and hydrated films of the gangliosides GM1, deacetyl-GM1, lyso-GM1, deacetyllyso-GM1, and GM3 and oriented mixed films of these gangliosides with 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC) using polarized light. Analysis of the amide I frequencies reveals that the amide groups are involved in intermolecular interactions via hydrogen bonds of varying strengths. The tilt angle of the acyl chains of the lipids in mixed films was determined as a function of ganglioside structure. Deacetylation of the sialic acid in the headgroup has a stronger influence on the tilt angle than the removal of the ganglioside fatty acid. The phase behavior was examined by FTIR ATR spectroscopy and by differential scanning calorimetry (DSC) measurements on lipid suspensions. At the same molar concentration, lyso-gangliosides have less effect on changes of transition temperature compared to the double-chain analogs. Distinct differences in the amide band shapes were observed between mixtures with lyso-gangliosides and normal double-chain gangliosides. Determined from the dicroic ratio RATR, the orientation of the COO- group in all DMPC/ganglioside mixtures was found to be relatively fixed with respect to the membrane normal. In 4:1 mixtures of DMPC with GM1 and deacetyl-GM1, the binding of Ca2+ leads to a slight decrease in chain tilt in the gel phase, probably caused by a dehydration of the membrane-water interface. In mixtures of DMPC with GM3 and deacetyl-lyso-GM1, a slight increase in chain tilt is observed. The chain tilt in DMPC/lyso-GM1 mixtures is unchanged. Analysis of the COO- band reveals that Ca2+ does not bind to the carboxylate group of the sialic acid of GM1 and deacetyl-GM1, the mixtures in which a decrease in chain tilt was observed. Binding to the sialic acid was

TGF-β1 (Transforming Growth Factor-β1) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity.

PubMed

Salvarani, Nicolò; Maguy, Ange; De Simone, Stefano A; Miragoli, Michele; Jousset, Florian; Rohr, Stephan

2017-05-01

TGF-β 1 (transforming growth factor-β 1 ) importantly contributes to cardiac fibrosis by controlling differentiation, migration, and collagen secretion of cardiac myofibroblasts. It is still elusive, however, to which extent TGF-β 1 alters the electrophysiological phenotype of myofibroblasts and cardiomyocytes and whether it affects proarrhythmic myofibroblast-cardiomyocyte crosstalk observed in vitro. Patch-clamp recordings of cultured neonatal rat ventricular myofibroblasts revealed that TGF-β 1 , applied for 24 to 48 hours at clinically relevant concentrations (≤2.5 ng/mL), causes substantial membrane depolarization concomitant with a several-fold increase of transmembrane currents. Transcriptome analysis revealed TGF-β 1 -dependent changes in 29 of 63 ion channel/pump/connexin transcripts, indicating a pleiotropic effect on the electrical phenotype of myofibroblasts. Whereas not affecting cardiomyocyte membrane potentials and cardiomyocyte-cardiomyocyte gap junctional coupling, TGF-β 1 depolarized cardiomyocytes coupled to myofibroblasts by ≈20 mV and increased gap junctional coupling between myofibroblasts and cardiomyocytes >5-fold as reflected by elevated connexin 43 and consortin transcripts. TGF-β 1 -dependent cardiomyocyte depolarization resulted from electrotonic crosstalk with myofibroblasts as demonstrated by immediate normalization of cardiomyocyte electrophysiology after targeted disruption of coupled myofibroblasts and by cessation of ectopic activity of cardiomyocytes coupled to myofibroblasts during pharmacological gap junctional uncoupling. In cardiac fibrosis models exhibiting slow conduction and ectopic activity, block of TGF-β 1 signaling completely abolished both arrhythmogenic conditions. TGF-β 1 profoundly alters the electrophysiological phenotype of cardiac myofibroblasts. Apart from possibly contributing to the control of cell function in general, the changes proved to be pivotal for proarrhythmic myofibroblast

In cellulo examination of a beta-alpha hybrid construct of beta-hexosaminidase A subunits, reported to interact with the GM2 activator protein and hydrolyze GM2 ganglioside.

PubMed

Sinici, Incilay; Yonekawa, Sayuri; Tkachyova, Ilona; Gray, Steven J; Samulski, R Jude; Wakarchuk, Warren; Mark, Brian L; Mahuran, Don J

2013-01-01

The hydrolysis in lysosomes of GM2 ganglioside to GM3 ganglioside requires the correct synthesis, intracellular assembly and transport of three separate gene products; i.e., the alpha and beta subunits of heterodimeric beta-hexosaminidase A, E.C. # 3.2.1.52 (encoded by the HEXA and HEXB genes, respectively), and the GM2-activator protein (GM2AP, encoded by the GM2A gene). Mutations in any one of these genes can result in one of three neurodegenerative diseases collectively known as GM2 gangliosidosis (HEXA, Tay-Sachs disease, MIM # 272800; HEXB, Sandhoff disease, MIM # 268800; and GM2A, AB-variant form, MIM # 272750). Elements of both of the hexosaminidase A subunits are needed to productively interact with the GM2 ganglioside-GM2AP complex in the lysosome. Some of these elements have been predicted from the crystal structures of hexosaminidase and the activator. Recently a hybrid of the two subunits has been constructed and reported to be capable of forming homodimers that can perform this reaction in vivo, which could greatly simplify vector-mediated gene transfer approaches for Tay-Sachs or Sandhoff diseases. A cDNA encoding a hybrid hexosaminidase subunit capable of dimerizing and hydrolyzing GM2 ganglioside could be incorporated into a single vector, whereas packaging both subunits of hexosaminidase A into vectors, such as adeno-associated virus, would be impractical due to size constraints. In this report we examine the previously published hybrid construct (H1) and a new more extensive hybrid (H2), with our documented in cellulo (live cell- based) assay utilizing a fluorescent GM2 ganglioside derivative. Unfortunately when Tay-Sachs cells were transfected with either the H1 or H2 hybrid construct and then were fed the GM2 derivative, no significant increase in its turnover was detected. In vitro assays with the isolated H1 or H2 homodimers confirmed that neither was capable of human GM2AP-dependent hydrolysis of GM2 ganglioside.

In Cellulo Examination of a Beta-Alpha Hybrid Construct of Beta-Hexosaminidase A Subunits, Reported to Interact with the GM2 Activator Protein and Hydrolyze GM2 Ganglioside

PubMed Central

Sinici, Incilay; Yonekawa, Sayuri; Tkachyova, Ilona; Gray, Steven J.; Samulski, R. Jude; Wakarchuk, Warren; Mark, Brian L.; Mahuran, Don J.

2013-01-01

The hydrolysis in lysosomes of GM2 ganglioside to GM3 ganglioside requires the correct synthesis, intracellular assembly and transport of three separate gene products; i.e., the alpha and beta subunits of heterodimeric beta-hexosaminidase A, E.C. # 3.2.1.52 (encoded by the HEXA and HEXB genes, respectively), and the GM2-activator protein (GM2AP, encoded by the GM2A gene). Mutations in any one of these genes can result in one of three neurodegenerative diseases collectively known as GM2 gangliosidosis (HEXA, Tay-Sachs disease, MIM # 272800; HEXB, Sandhoff disease, MIM # 268800; and GM2A, AB-variant form, MIM # 272750). Elements of both of the hexosaminidase A subunits are needed to productively interact with the GM2 ganglioside-GM2AP complex in the lysosome. Some of these elements have been predicted from the crystal structures of hexosaminidase and the activator. Recently a hybrid of the two subunits has been constructed and reported to be capable of forming homodimers that can perform this reaction in vivo, which could greatly simplify vector-mediated gene transfer approaches for Tay-Sachs or Sandhoff diseases. A cDNA encoding a hybrid hexosaminidase subunit capable of dimerizing and hydrolyzing GM2 ganglioside could be incorporated into a single vector, whereas packaging both subunits of hexosaminidase A into vectors, such as adeno-associated virus, would be impractical due to size constraints. In this report we examine the previously published hybrid construct (H1) and a new more extensive hybrid (H2), with our documented in cellulo (live cell- based) assay utilizing a fluorescent GM2 ganglioside derivative. Unfortunately when Tay-Sachs cells were transfected with either the H1 or H2 hybrid construct and then were fed the GM2 derivative, no significant increase in its turnover was detected. In vitro assays with the isolated H1 or H2 homodimers confirmed that neither was capable of human GM2AP-dependent hydrolysis of GM2 ganglioside. PMID:23483939

Glucose-6-phosphate dehydrogenase plays a pivotal role in nitric oxide-involved defense against oxidative stress under salt stress in red kidney bean roots.

PubMed

Liu, Yinggao; Wu, Ruru; Wan, Qi; Xie, Gengqiang; Bi, Yurong

2007-03-01

The pivotal role of glucose-6-phosphate dehydrogenase (G-6-PDH)-mediated nitric oxide (NO) production in the tolerance to oxidative stress induced by 100 mM NaCl in red kidney bean (Phaseolus vulgaris) roots was investigated. The results show that the G-6-PDH activity was enhanced rapidly in the presence of NaCl and reached a maximum at 100 mM. Western blot analysis indicated that the increase of G-6-PDH activity in the red kidney bean roots under 100 mM NaCl was mainly due to the increased content of the G-6-PDH protein. NO production and nitrate reductase (NR) activity were also induced by 100 mM NaCl. The NO production was reduced by NaN(3) (an NR inhibitor), but not affected by N(omega)-nitro-L-arginine (L-NNA) (an NOS inhibitor). Application of 2.5 mM Na(3)PO(4), an inhibitor of G-6-PDH, blocked the increase of G-6-PDH and NR activity, as well as NO production in red kidney bean roots under 100 mM NaCl. The activities of antioxidant enzymes in red kidney bean roots increased in the presence of 100 mM NaCl or sodium nitroprusside (SNP), an NO donor. The increased activities of all antioxidant enzymes tested at 100 mM NaCl were completely inhibited by 2.5 mM Na(3)PO(4). Based on these results, we conclude that G-6-PDH plays a pivotal role in NR-dependent NO production, and in establishing tolerance of red kidney bean roots to salt stress.

Anti-ganglioside antibodies in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy in Chinese patients.

PubMed

Fan, Chenghe; Jin, Haiqiang; Hao, Hongjun; Gao, Feng; Sun, Yongan; Lu, Yuanyuan; Liu, Yuanyuan; Lv, Pu; Cui, Wei; Teng, Yuming; Huang, Yining

2017-04-01

In this study we investigated the relationships between anti-ganglioside antibodies and Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Samples from 48 Chinese patients diagnosed with GBS and 18 patients diagnosed with CIDP were retrospectively reviewed. In the GBS patients, 62.5% were classified as having acute inflammatory demyelinating polyneuropathy (AIDP), 27.1% were found to have acute motor axonal neuropathy (AMAN), and 10.4% were unclassified. Serum IgG anti-ganglioside antibodies were detected in 46.2% of the AMAN patients and in 6.7% of the AIDP patients (P < 0.05); 5.6% of the 18 CIDP patients were IgG antibody positive, and 27.8% were IgM antibody positive. Facial palsy and sensory impairment were significantly associated with IgM antibodies. These results suggest that IgG anti-GM1 antibodies are associated with AMAN, but not with AIDP, and that IgM antibodies against GM1, GM2, and GM3 are associated with facial nerve palsy. Muscle Nerve 55: 470-475, 2017. © 2016 Wiley Periodicals, Inc.

Development of an Immunoassay for Rapid Detection of Ganglioside GM1 Mimicry in Campylobacter jejuni Strains

PubMed Central

Prendergast, Martina M.; Kosunen, Timo U.; Moran, Anthony P.

2001-01-01

Mimicry of peripheral nerve gangliosides by Campylobacter jejuni lipopolysaccharides (LPSs) has been proposed to induce cross-reacting antiganglioside antibodies in Guillain-Barré syndrome (GBS). Because current methods for LPS characterization are labor-intensive and inhibit the screening of large numbers of strains, a rapid GM1 epitope screening assay was developed. Biomass from two agar plates of confluent growth yielded sufficient LPS using a novel phenol-water and ether extraction procedure. Extracts of LPS were reacted with cholera toxin (GM1 ligand), peanut agglutinin (Galβ1→3GalNAc ligand), and anti-GM1 antibodies. After the assay was validated, 12 of 59 (20%) C. jejuni serostrains, including four serotypes that have not previously been associated with GBS, reacted with two or more anti-GM1 ganglioside reagents. Subsequently, LPS extracts from 5 of 7 (71%) C. jejuni isolates and 2 of 3 (67%) C. jejuni culture collection strains bore GM1 structures. Overall, the assay system was reliable, efficient, and reproducible and may be adapted for large-scale epidemiological studies. PMID:11283076

Altered distribution of the gangliosides GM1 and GM2 in Alzheimer's disease.

PubMed

Pernber, Z; Blennow, K; Bogdanovic, N; Månsson, J-E; Blomqvist, M

2012-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder where β-amyloid tends to aggregate and form plaques. Lipid raft-associated ganglioside GM1 has been suggested to facilitate β-amyloid aggregation; furthermore, GM1 and GM2 are increased in lipid rafts isolated from cerebral cortex of AD cases. The distribution of GM1 and GM2 was studied by immunohistochemistry in the frontal and temporal cortex of AD cases. Frontotemporal dementia (FTD) was included as a contrast group. The distribution of GM1 and GM2 changes during the process of AD (n = 5) and FTD (n = 3) compared to controls (n = 5). Altered location of the GM1-positive small circular structures seems to be associated with myelin degradation. In the grey matter, the staining of GM1-positive plasma membranes might reflect neuronal loss in the AD/FTD tissue. The GM1-positive compact bundles were only visible in cells located in the AD frontal grey matter, possibly reflecting raft formation of GM1 and thus a pathological connection. Furthermore, our results suggest GM2 to be enriched within vesicles of pyramidal neurons of the AD/FTD brain. Our study supports the biochemical finding of ganglioside accumulation in cellular membranes of AD patients and shows a redistribution of these molecules. Copyright © 2012 S. Karger AG, Basel.

Stimulation of a Ca sup 2+ -dependent protein kinase by G sub M1 ganglioside in nerve growth factor-treated PC12 cells

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

Hilbush, B.S.; Levine, J.M.

1991-07-01

The authors have investigated the ability of exogenous gangliosides to modulate nerve growth factor (NGF) signal transduction in PC12 cells. The effects of exogenous ganglioside G{sub M1} on multiple protein kinase activities were assayed by analyzing site-specific serine phosphorylation of tyrosine hydroxylase (TyrOHase) by two-dimensional phosphopeptide mapping. In the presence of NGF, exogenous G{sub M1} increased {sup 32}P incorporation into TyrOHase phosphopeptide T2, a Ca{sup 2+}/calmodulin-dependent protein kinase substrate whose phosphorylation is not normally affected by NGF treatment. In the absence of NGF, G{sub M1} treatment had no significant effects on TyrOHase phosphorylation. The removal of extracellular Ca{sup 2+} ormore » blockade of dihydropyridine-sensitive Ca{sup 2+} channels prevented the G{sub M1}-induced increases in {sup 32}P incorporation into phosphopeptide T2. Exogenous G{sub M1} also potentiated K{sup +} depolarization-induced increases in the phosphorylation of TyrOHase. These results suggest that the stimulatory effects of exogenous G{sub M1} ganglioside on NGF actions may be due to its ability to potentiate a Ca{sup 2+}-dependent signaling pathway.« less

Simultaneous quantification of GM1 and GM2 gangliosides by isotope dilution tandem mass spectrometry.

PubMed

Gu, Jianghong; Tifft, Cynthia J; Soldin, Steven J

2008-04-01

Gangliosides (GGs) are considered as diagnostic biomarkers and therapeutic targets and agents. The goal of this study was to develop a tandem mass spectrometry (MS/MS) method for the simultaneous measurement of both GM1 and GM2 gangliosides in human cerebrospinal fluid (CSF) samples in order to be able to determine their concentrations in patients with Tay-Sachs and Sandhoff disease and assess whether drugs or transplantation affect their concentrations. An API-4000 tandem mass spectrometer equipped with TurboIonSpray source and Shimadzu HPLC system was employed to perform the analysis using isotope dilution with deuterium labeled internal standards. To a 1.5 mL conical plastic Eppendorf centrifuge tube, 40 microL of human CSF sample was added and mixed with 400 microL of internal standard solution for deproteinization. After centrifugation, 100 microL of supernatant was injected onto a C-18 column. After a 2.5 min wash, the switching valve was activated and the analytes were eluted from the column with a water/methanol gradient into the MS/MS system. Quantification by multiple reaction-monitoring (MRM) analysis was performed in the negative mode. The within-day coefficients of variation were <3% for GM1 and <2% for GM2 and the between-day coefficients of variation were <5% for both GM1 and GM2 at all concentrations tested. Accuracy ranged between 98% and 102% for both analytes. Good linearity was also obtained within the concentration range of 10-200 ng/mL (6.5-129.3 nmol/L) for GM1 and 5-100 ng/mL (3.6-72.3 nmol/L) for GM2 (r> or =0.995). A new simple, accurate, and fast isotope dilution tandem mass spectrometry method was developed for the simultaneous quantification of GM1 and GM2 gangliosides in a small amount of human CSF. Concentrations were measured in "normal" CSF and in CSF from patients with Tay-Sachs disease.

Inhibition of glutamate-induced intensification of free radical reactions by gangliosides: possible role in their protective effect in rat cerebellar granule cells and brain synaptosomes.

PubMed

Avrova, N F; Victorov, I V; Tyurin, V A; Zakharova, I O; Sokolova, T V; Andreeva, N A; Stelmaschuk, E V; Tyurina, Y Y; Gonchar, V S

1998-07-01

The neurotoxic effect of exposure of rat cerebellar granule cells to glutamate (100 microM) is to a large extent prevented by incubation of neurons not only with micromolar, but even with nanomolar concentrations of gangliosides GM1, GD1b, and GT1b. GM1 was also shown to decrease significantly the per cent of dead neurons in culture after induction of lipid peroxidation. Exposure to glutamate was found to cause a significant decrease of the activity of Na+, K+-ATP-ase in rat brain cortex synaptosomes, but superoxide dismutase, alpha-tocopherol, or 10-100 nM GM1 practically prevented its action. Other data showing the ability of gangliosides to inhibit the intensification of free radical reactions by glutamate (based on the estimation of methemoglobin formation, SH group content, etc.) have been obtained. The results suggest that gangliosides are able to decrease the glutamate-induced activation of free radical reactions in nerve cells. This effect appears to contribute to their protective action against glutamate neurotoxicity.

Identification of ganglioside GM2 activator playing a role in cancer cell migration through proteomic analysis of breast cancer secretomes.

PubMed

Shin, Jihye; Kim, Gamin; Lee, Jong Won; Lee, Ji Eun; Kim, Yoo Seok; Yu, Jong-Han; Lee, Seung-Taek; Ahn, Sei Hyun; Kim, Hoguen; Lee, Cheolju

2016-06-01

Cancer cell secretomes are considered a potential source for the discovery of cancer markers. In this study, the secretomes of four breast cancer (BC) cell lines (Hs578T, MCF-7, MDA-MB-231, and SK-BR-3) were profiled with liquid chromatography-tandem mass spectrometry analysis. A total of 1410 proteins were identified with less than 1% false discovery rate, of which approximately 55% (796 proteins) were predicted to be secreted from cells. To find BC-specific proteins among the secreted proteins, data of immunohistochemical staining compiled in the Human Protein Atlas were investigated by comparing the data of BC tissues with those of normal tissues. By applying various criteria, including higher expression level in BC tissues, higher predicted potential of secretion, and sufficient number of tandem mass spectra, 12 biomarker candidate proteins including ganglioside GM2 activator (GM2A) were selected for confirmation. Western blot analysis and ELISA for plasma samples of healthy controls and BC patients revealed elevation of GM2A in BC patients, especially those who were estrogen receptor-negative. Additionally, siRNA-mediated knockdown of GM2A in BC cells decreased migration in vitro, whereas the overexpression of GM2A led to an increase in cell migration. Although GM2A as a diagnostic and prognostic marker in BC should be carefully verified further, this study has established the potential role of GM2A in BC progression. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

A Conformational Change of C Fragment of Tetanus Neurotoxin Reduces Its Ganglioside-Binding Activity but Does Not Destroy Its Immunogenicity ▿

PubMed Central

Yu, Rui; Yi, Shaoqiong; Yu, Changming; Fang, Ting; Liu, Shuling; Yu, Ting; Song, Xiaohong; Fu, Ling; Hou, Lihua; Chen, Wei

2011-01-01

The C fragment of tetanus neurotoxin (TeNT-Hc) with different conformations was observed due to the four cysteine residues within it which could form different intramolecular disulfide bonds. In this study, we prepared and compared three types of monomeric TeNT-Hc with different conformational components: free sulfhydryls (50 kDa), bound sulfhydryls (44 kDa), and a mixture of the two conformational proteins (half 50 kDa and half 44 kDa). TeNT-Hc with bound sulfhydryls reduced its binding activity to ganglioside GT1b and neuronal PC-12 cells compared to what was seen for TeNT-Hc with free sulfhydryls. However, there was no significant difference among their immunogenicities in mice, including induction of antitetanus toxoid IgG titers, antibody types, and protective capacities against tetanus neurotoxin challenge. Our results showed that the conformational changes of TeNT-Hc resulting from disulfide bond formation reduced its ganglioside-binding activity but did not destroy its immunogenicity, and the protein still retained continuous B cell and T cell epitopes; that is, the presence of the ganglioside-binding site within TeNT-Hc may be not essential for the induction of a fully protective antitetanus response. TeNT-Hc with bound sulfhydryls may be developed into an ideal human vaccine with a lower potential for side effects. PMID:21813664

Gangliosides inhibit bee venom melittin cytotoxicity but not phospholipase A{sub 2}-induced degranulation in mast cells

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

Nishikawa, Hirofumi; Kitani, Seiichi, E-mail: drkitani@kaiyodai.ac.jp

Sting accident by honeybee causes severe pain, inflammation and allergic reaction through IgE-mediated anaphylaxis. In addition to this hypersensitivity, an anaphylactoid reaction occurs by toxic effects even in a non-allergic person via cytolysis followed by similar clinical manifestations. Auto-injectable epinephrine might be effective for bee stings, but cannot inhibit mast cell lysis and degranulation by venom toxins. We used connective tissue type canine mast cell line (CM-MC) for finding an effective measure that might inhibit bee venom toxicity. We evaluated degranulation and cytotoxicity by measurement of {beta}-hexosaminidase release and MTT assay. Melittin and crude bee venom induced the degranulation andmore » cytotoxicity, which were strongly inhibited by mono-sialoganglioside (G{sub M1}), di-sialoganglioside (G{sub D1a}) and tri-sialoganglioside (G{sub T1b}). In contrast, honeybee venom-derived phospholipase A{sub 2} induced the net degranulation directly without cytotoxicity, which was not inhibited by G{sub M1}, G{sub D1a} and G{sub T1b}. For analysis of distribution of G{alpha}{sub q} and G{alpha}{sub i} protein by western blotting, lipid rafts were isolated by using discontinuous sucrose gradient centrifuge. Melittin disrupted the localization of G{alpha}{sub q} and G{alpha}{sub i} at lipid raft, but gangliosides stabilized the rafts. As a result from this cell-based study, bee venom-induced anaphylactoid reaction can be explained with melittin cytotoxicity and phospholipase A{sub 2}-induced degranulation. Taken together, gangliosides inhibit the effect of melittin such as degranulation, cytotoxicity and lipid raft disruption but not phospholipase A{sub 2}-induced degranulation in mast cells. Our study shows a potential of gangliosides as a therapeutic tool for anaphylactoid reaction by honeybee sting.« less

Enhanced Autophagy Contributes to Protective Effects of GM1 Ganglioside Against Aβ1-42-Induced Neurotoxicity and Cognitive Deficits.

PubMed

Dai, Ruwei; Zhang, Shijie; Duan, Wenjun; Wei, Renrong; Chen, Huifang; Cai, Weibin; Yang, Lei; Wang, Qi

2017-08-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. The aggregation of Aβ peptides, Aβ1-42 in particular, is thought to be a fundamental pathogenic mechanism leading to the neuronal damage in AD. Recently, monosialoganglioside GM1 is reported to possess pivotal neuroprotection in neurodegenerative diseases. Previous studies have focused on the conformational dynamics and the biochemical interaction of the amyloid-peptide with the GM1 ganglioside, as well as the protective effect of GM1 on cognition. However, the phenomenon of autophagy with regard to neuronal dysfunction in AD is less investigated. In the present study, GM1 treatment were investigated in an AD mouse model and cultured PC12 dells to examine cognition-protective and neuroprotective effects of GM1. Furthermore, GM1 was found to induce autophagy via testing light chain 3 (LC3), Beclin1, neighbor of BRCA1 gene 1 protein and p62 (a substrate of LC3). Chloroquine, an inhibitor of lysosomal, was used to exclude the interference of lysosome, which could fuse with autophagosome and then clear it. In the presence of the inhibitor of autophagy (3-methyladenine; 3-MA), the protective effect of GM1 on PC12 cells in Aβ (1-42) induced toxic conditions was diminished. Interestingly, the expression of histone deacetylase 1 was increased in PC12 cells when treated with GM1, indicating that autophagy might be activated by GM1 through a pathway integrates protein acetylation. This study provides a novel insight into the protective role of GM1 against Aβ (1-42)-induced neurotoxicity via enhancing autophagy.

Evaluating a Pivot-Based Approach for Bilingual Lexicon Extraction

PubMed Central

Kim, Jae-Hoon; Kwon, Hong-Seok; Seo, Hyeong-Won

2015-01-01

A pivot-based approach for bilingual lexicon extraction is based on the similarity of context vectors represented by words in a pivot language like English. In this paper, in order to show validity and usability of the pivot-based approach, we evaluate the approach in company with two different methods for estimating context vectors: one estimates them from two parallel corpora based on word association between source words (resp., target words) and pivot words and the other estimates them from two parallel corpora based on word alignment tools for statistical machine translation. Empirical results on two language pairs (e.g., Korean-Spanish and Korean-French) have shown that the pivot-based approach is very promising for resource-poor languages and this approach observes its validity and usability. Furthermore, for words with low frequency, our method is also well performed. PMID:25983745

The Ganglioside GM-1 Inhibits Bupivacaine-Induced Neurotoxicity in Mouse Neuroblastoma Neuro2a Cells.

PubMed

Liang, Yujie; Ji, Jiemei; Lin, Yunan; He, Yajun; Liu, Jingchen

2016-08-01

Studies indicate that bupivacaine-induced neurotoxicity results from apoptosis. Gangliosides have been shown to promote neuronal repair and recovery of neurological function after spinal cord injury. Previously, we confirmed that in vivo administration of the ganglioside GM-1 attenuated bupivacaine-induced neurotoxicity in various animal models; however, the underlying mechanism remains unclear. Cells of the neuroblastoma line N2a (Neuro2a cells) were divided into three experimental groups: control, bupivacaine-treated, and bupivacaine-treated with GM-1 pretreatment. Cell viability and apoptosis were assessed through CCK-8 assays, Hoechst staining, and flow cytometry analysis of Annexin-V/propidium iodide double labeling. Real-time polymerase chain reaction and western blotting assessed the expression of caspase-3, caspase-8, and caspase-9. Bupivacaine-induced apoptosis worsened with increasing dose and exposure time. Bupivacaine induced increased expression of caspase-3 and caspase-9, but not caspase-8, indicating that the mitochondrial pathway but not the death receptor apoptosis pathway was activated. GM-1 pretreatment inhibited bupivacaine-induced apoptosis and the expression of caspase-3 and caspase-9 in a dose-dependent manner. Bupivacaine induced neurotoxicity by activating apoptosis via the mitochondrial pathway, and this was inhibited by GM-1 pretreatment. Copyright © 2016 John Wiley & Sons, Ltd.

Pivot methods for global optimization

NASA Astrophysics Data System (ADS)

Stanton, Aaron Fletcher

A new algorithm is presented for the location of the global minimum of a multiple minima problem. It begins with a series of randomly placed probes in phase space, and then uses an iterative redistribution of the worst probes into better regions of phase space until a chosen convergence criterion is fulfilled. The method quickly converges, does not require derivatives, and is resistant to becoming trapped in local minima. Comparison of this algorithm with others using a standard test suite demonstrates that the number of function calls has been decreased conservatively by a factor of about three with the same degrees of accuracy. Two major variations of the method are presented, differing primarily in the method of choosing the probes that act as the basis for the new probes. The first variation, termed the lowest energy pivot method, ranks all probes by their energy and keeps the best probes. The probes being discarded select from those being kept as the basis for the new cycle. In the second variation, the nearest neighbor pivot method, all probes are paired with their nearest neighbor. The member of each pair with the higher energy is relocated in the vicinity of its neighbor. Both methods are tested against a standard test suite of functions to determine their relative efficiency, and the nearest neighbor pivot method is found to be the more efficient. A series of Lennard-Jones clusters is optimized with the nearest neighbor method, and a scaling law is found for cpu time versus the number of particles in the system. The two methods are then compared more explicitly, and finally a study in the use of the pivot method for solving the Schroedinger equation is presented. The nearest neighbor method is found to be able to solve the ground state of the quantum harmonic oscillator from a pure random initialization of the wavefunction.

Synthesis of novel ganglioside GM4 analogues containing N-deacetylated and lactamized sialic acid: probes for searching new ligand structures for human L-selectin.

PubMed

Otsubo, N; Ishida, H; Kiso, M

2001-01-15

Novel ganglioside GM4 analogues, which contain N-deacetylated or lactamized sialic acid instead of usual N-acetylneuraminic acid, were synthesized in a highly efficient manner. (Methyl 4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-trifluoroacetamido-D-glycero-alpha-D-galacto-2-nonulopyranosylonate)-(2-->3)-4,6-di-O-acetyl-2-O-benzoyl-D-galactopyranosyl trichloroacetimidate was coupled with 2-(tetradecyl)hexadecanol to give the desired beta-glycoside in high yield. Successive O- and N-deacylation, and saponification of the methyl ester group afforded the N-deacetylated sialyl derivative that was converted by treatment with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in Me2SO into the lactamized sialic acid-containing ganglioside GM4 analogue.

Pivotal Response Training. What Works Clearinghouse Intervention Report

ERIC Educational Resources Information Center

What Works Clearinghouse, 2016

2016-01-01

This intervention report presents findings from a systematic review of "pivotal response training" conducted using the What Works Clearinghouse Procedures and Standards Handbook (version 3.0) and the Children and Students with an Autism Spectrum Disorder review protocol (version 3.0). "Pivotal response training"…

Compound floating pivot micromechanisms

DOEpatents

Garcia, Ernest J.

2001-04-24

A new class of tilting micromechanical mechanisms have been developed. These new mechanisms use compound floating pivot structures to attain far greater tilt angles than are practical using other micromechanical techniques. The new mechanisms are also capable of bi-directional tilt about multiple axes.

What does it take to have a high-grade pivot shift?

PubMed

Tanaka, M; Vyas, D; Moloney, G; Bedi, A; Pearle, A D; Musahl, V

2012-04-01

The pivot shift is the most specific clinical test to assess pathological knee joint rotatory laxity following ACL injury. This article attempts to describe the anatomic structures responsible for creating a high-grade pivot shift and their potential role in customizing ACL reconstruction. A review of the literature demonstrates that disruption of the secondary stabilizers of anterior translation of the lateral compartment including the lateral meniscus, anterolateral capsule, and IT band contributes to a high-grade pivot shift in the ACL-deficient knee. The morphology of the lateral tibial plateau, including increased posteroinferior tibial slope and small size, can also contribute to high-grade pivot shift. Factors that may decrease the grade of the pivot shift include medial compartment injury, MCL injury, patient guarding, and osteoarthritis. In conclusion, a high-grade pivot shift in the ACL-deficient knee is often associated with incompetence of the lateral soft tissue envelope. Rotatory laxity as assessed by the pivot shift may also be falsely underestimated by concomitant injuries. IV.

WASP (Write a Scientific Paper) using Excel - 2: Pivot tables.

PubMed

Grech, Victor

2018-02-01

Data analysis at the descriptive stage and the eventual presentation of results requires the tabulation and summarisation of data. This exercise should always precede inferential statistics. Pivot tables and pivot charts are one of Excel's most powerful and underutilised features, with tabulation functions that immensely facilitate descriptive statistics. Pivot tables permit users to dynamically summarise and cross-tabulate data, create tables in several dimensions, offer a range of summary statistics and can be modified interactively with instant outputs. Large and detailed datasets are thereby easily manipulated making pivot tables arguably the best way to explore, summarise and present data from many different angles. This second paper in the WASP series in Early Human Development provides pointers for pivot table manipulation in Excel™. Copyright © 2018 Elsevier B.V. All rights reserved.

Elevation of GM2 ganglioside during ethanol-induced apoptotic neurodegeneration in the developing mouse brain

PubMed Central

Saito, Mitsuo; Chakraborty, Goutam; Shah, Relish; Mao, Rui-Fen; Kumar, Asok; Yang, Dun-Sheng; Dobrenis, Kostantin; Saito, Mariko

2012-01-01

GM2 ganglioside in the brain increased during ethanol-induced acute apoptotic neurodegeneration in 7-day-old mice. A small but a significant increase observed 2 h after ethanol exposure was followed by a marked increase around 24 h. Subcellular fractionation of the brain 24 h after ethanol treatment indicated that GM2 increased in synaptic and non-synaptic mitochondrial fractions as well as in a lysosome-enriched fraction characteristic to the ethanol-exposed brain. Immunohistochemical staining of GM2 in the ethanol-treated brain showed strong punctate staining mainly in activated microglia, in which it partially overlapped with staining for LAMP1, a late endosomal/lysosomal marker. Also, there was weaker neuronal staining, which partially co-localized with complex IV, a mitochondrial marker, and was augmented in cleaved caspase-3-positive neurons. In contrast, the control brain showed only faint and diffuse GM2 staining in neurons. Incubation of isolated brain mitochondria with GM2 in vitro induced cytochrome c release in a manner similar to that of GD3 ganglioside. Because ethanol is known to trigger mitochondria-mediated apoptosis with cytochrome c release and caspase-3 activation in the 7-day–old mouse brain, the GM2 elevation in mitochondria may be relevant to neuroapoptosis. Subsequently, activated microglia accumulated GM2, indicating a close relationship between GM2 and ethanol-induced neurodegeneration. PMID:22372857

Bis(monoacylglycero)phosphate and ganglioside GM1 spontaneously form small homogeneous vesicles at specific concentrations

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

Chebukati, Janetricks N.; Goff, Philip C.; Frederick, Thomas E.

2010-04-09

The morphology and size of hydrated lipid dispersions of bis(monoacylglycero)phosphate (BMP) mixed with varying mole percentages of the ganglioside GM1 were investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Electron paramagnetic resonance (EPR) spectroscopy of these same mixtures, doped at 0.5 mol% with doxyl labeled lipids, was used to investigate acyl-chain packing. Results show that for 20-30% GM1, hydrated BMP:GM1 mixtures spontaneously form small spherical vesicles with diameters {approx}100 nm and a narrow size distribution profile. For other concentrations of GM1, hydrated dispersions with BMP have non-spherical shapes and heterogeneous size profiles, with average vesicle diameters >400more » nm. All samples were prepared at pH 5.5 to mimic the lumen acidity of the late endosome where BMP is an essential component of intraendosomal vesicle budding, lipid sorting and trafficking. These findings indicate that GM1 and BMP under a limited concentration range spontaneously form small vesicles of homogeneous size in an energy independent manner without the need of protein templating. Because BMP is essential for intraendosomal vesicle formation, these results imply that lipid-lipid interactions may play a critical role in the endosomal process of lipid sorting and trafficking.« less

Analysis of anti-ganglioside antibodies by a line immunoassay in patients with chronic-inflammatory demyelinating polyneuropathies (CIDP).

PubMed

Klehmet, Juliane; Märschenz, Stefanie; Ruprecht, Klemens; Wunderlich, Benjamin; Büttner, Thomas; Hiemann, Rico; Roggenbuck, Dirk; Meisel, Andreas

2018-05-24

Unlike for acute immune-mediated neuropathies (IN), anti-ganglioside autoantibody (aGAAb) testing has been recommended for only a minority of chronic IN yet. Thus, we used a multiplex semi-quantitative line immunoassay (LIA) to search for aGAAb in chronic-inflammatory demyelinating polyneuropathy (CIDP) and its clinical variants. Anti-GAAb to 11 gangliosides and sulfatide (SF) were investigated by LIA in 61 patients with IN (27 typical CIDP, 12 distal-acquired demyelinating polyneuropathy, 6 multifocal-acquired demyelinating sensory/motor polyneuropathy, 10 sensory CIDP, 1 focal CIDP and 5 multifocal-motoric neuropathy), 40 with other neuromuscular disorders (OND) (15 non-immune polyneuropathies, 25 myasthenia gravis), 29 with multiple sclerosis (MS) and 54 healthy controls (HC). In contrast to IgG, positive anti-GAAB IgM against at least one ganglioside/SF was found in 17/61 (27.9%) IN compared to 2/40 (5%) in OND, 2/29 MS (6.9%) and 4/54 (7.4%) in HC (p=0.001). There was a statistically higher prevalence of anti-sulfatide (aSF) IgM in IN compared to OND (p=0.008). Further, aGM1 IgM was more prevalent in IN compared to OND and HC (p=0.009) as well as GD1b in IN compared to HC (p<0.04). The prevalence of aGM1 IgM in CIDP was lower compared to in multifocal motor neuropathy (MMN) (12% vs. 60%, p=0.027). Patients showing aSF, aGM1 and aGM2 IgM were younger compared to aGAAb negatives (p<0.05). Patients with aSF IgM positivity presented more frequently typical CIDP and MMN phenotypes (p<0.05, respectively). The aGAAb LIA revealed an elevated frequency of at least one aGAAb IgM in CIDP/MMN patients. Anti-SF, aGM1 and aGM2 IgM were associated with younger age and anti-SF with IN phenotypes.

A new approach to the modification of cell membrane glycosphingolipids: Ganglioside composition of JTC-12 P3 cells altered by feeding with galactose as a sole carbohydrate source in protein- and lipid-free synthetic medium

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

Kawaguchi, Tatsuya; Takaoka, Toshiko; Yoshida, Eiko

1988-12-01

A significant difference in the glycosphingolipid composition of JTC-12 P3 cells established from monkey kidney tissue was observed when cells cultured in a protein- and lipid-free synthetic medium containing glucose (DM-160) as a sole carbohydrate source were transferred and cultured in the same medium containing galactose and pyruvic acid (DM-170) in place of glucose. In particular, the amounts of gangliosides GM3, GM2, and GD3 in the cells cultured in DM-170 were 5.3-, 17.8-, and more than 8-fold those in the cells cultured in DM-160, respectively, indicating that anabolism of gangliosides is greatly enhanced in cells cultured in the presence ofmore » galactose and pyruvic acid, as compared with cells cultured in the presence of glucose. In fact, after cultivation of cells in the medium with N-acetyl-D-({sup 14}C)mannosamine for 96 h, the radioactivity incorporated into the gangliosides of the cells in DM-170 was 10-fold that of the cells in DM-160. Among the gangliosides of the cells in DM-170, highly sialylated molecules such as GD3, GD1a, GD1b, and GT1b were preferentially labeled, indicating that the sialytransferases responsible for the synthesis of gangliosides are significantly more activated in cells cultured in DM-170 than in DM-160. These observations reveal that the glycosphingolipid composition of the plasma membrane can be modified epigenetically under well-defined conditions and provide important clues for clarifying the roles of glycosphingolipids associated with particular cell functions.« less

Anti-GM2 gangliosides IgM paraprotein induces neuromuscular block without neuromuscular damage.

PubMed

Santafé, Manel M; Sabaté, M Mar; Garcia, Neus; Ortiz, Nico; Lanuza, M Angel; Tomàs, Josep

2008-11-15

We analyzed the effect on the mouse neuromuscular synapses of a human monoclonal IgM, which binds specifically to gangliosides with the common epitope [GalNAc beta 1-4Gal(3-2 alpha NeuAc)beta 1-]. We focused on the role of the complement. Evoked neurotransmission was partially blocked by IgM both acutely (1 h) and chronically (10 days). Transmission electron microscopy shows important nerve terminal growth and retraction remodelling though axonal injury can be ruled out. Synapses did not show mouse C5b-9 immunofluorescence and were only immunolabelled when human complement was added. Therefore, the IgM-induced synaptic changes occur without complement-mediated membrane attack.

Influence of Ganglioside GM1 Concentration on Lipid Clustering and Membrane Properties and Curvature.

PubMed

Patel, Dhilon S; Park, Soohyung; Wu, Emilia L; Yeom, Min Sun; Widmalm, Göran; Klauda, Jeffery B; Im, Wonpil

2016-11-01

Gangliosides are a class of glycosphingolipids (GSLs) with amphiphilic character that are found at the outer leaflet of the cell membranes, where their ability to organize into special domains makes them vital cell membrane components. However, a molecular understanding of GSL-rich membranes in terms of their clustered organization, stability, and dynamics is still elusive. To gain molecular insight into the organization and dynamics of GSL-rich membranes, we performed all-atom molecular-dynamics simulations of bicomponent ganglioside GM1 in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) phospholipid bilayers with varying concentrations of GM1 (10%, 20%, and 30%). Overall, the simulations show very good agreement with available experimental data, including x-ray electron density profiles along the membrane normal, NMR carbohydrate proton-proton distances, and x-ray crystal structures. This validates the quality of our model systems for investigating GM1 clustering through an ordered-lipid-cluster analysis. The increase in GM1 concentration induces tighter lipid packing, driven mainly by inter-GM1 carbohydrate-carbohydrate interactions, leading to a greater preference for the positive curvature of GM1-containing membranes and larger cluster sizes of ordered-lipid clusters (with a composite of GM1 and POPC). These clusters tend to segregate and form a large percolated cluster at a 30% GM1 concentration at 293 K. At a higher temperature of 330 K, however, the segregation is not maintained. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Elevation of GM2 ganglioside during ethanol-induced apoptotic neurodegeneration in the developing mouse brain.

PubMed

Saito, Mitsuo; Chakraborty, Goutam; Shah, Relish; Mao, Rui-Fen; Kumar, Asok; Yang, Dun-Sheng; Dobrenis, Kostantin; Saito, Mariko

2012-05-01

GM2 ganglioside in the brain increased during ethanol-induced acute apoptotic neurodegeneration in 7-day-old mice. A small but a significant increase observed 2 h after ethanol exposure was followed by a marked increase around 24 h. Subcellular fractionation of the brain 24 h after ethanol treatment indicated that GM2 increased in synaptic and non-synaptic mitochondrial fractions as well as in a lysosome-enriched fraction characteristic to the ethanol-exposed brain. Immunohistochemical staining of GM2 in the ethanol-treated brain showed strong punctate staining mainly in activated microglia, in which it partially overlapped with staining for LAMP1, a late endosomal/lysosomal marker. Also, there was weaker neuronal staining, which partially co-localized with complex IV, a mitochondrial marker, and was augmented in cleaved caspase 3-positive neurons. In contrast, the control brain showed only faint and diffuse GM2 staining in neurons. Incubation of isolated brain mitochondria with GM2 in vitro induced cytochrome c release in a manner similar to that of GD3 ganglioside. Because ethanol is known to trigger mitochondria-mediated apoptosis with cytochrome c release and caspase 3 activation in the 7-day-old mouse brain, the GM2 elevation in mitochondria may be relevant to neuroapoptosis. Subsequently, activated microglia accumulated GM2, indicating a close relationship between GM2 and ethanol-induced neurodegeneration. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Nitrogen dioxide induced changes in level of free fatty acids, triglyceride, esterified fatty acid, ganglioside and lipase activity in the guinea pig brain

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

Farahani, H.; Hasan, M.

1992-02-01

The biochemical response to controlled inhalation of nitrogen dioxide (NO2) was studied in 18 male guinea pigs. Animals were exposed to 2.5, 5.0, and 10 ppm NO2 for 2h daily for 35 consecutive days, and the results compared with six control animals exposed to filtered air for 2h daily for same period. Five biochemical parameters, including triglyceride, free fatty acids, esterified fatty acid, ganglioside and lipase activity were measured immediately after the last day of exposure. At 2.5 ppm NO2 inhalation no significant changes occurred in any region of the central nervous system (CNS). While as the dose concentration wasmore » increased to 5 and 10 ppm nitrogen dioxide, significant dose-related alteration were observed in the levels of triglyceride, free fatty acid, esterified fatty acid, ganglioside and lipase activity in the different regions of the guinea pig CNS.« less

Guillain–Barré syndrome and anti-ganglioside antibodies: a clinician-scientist’s journey

PubMed Central

YUKI, Nobuhiro

2012-01-01

Guillain–Barré syndrome (GBS) is the most frequent cause of acute flaccid paralysis. Having seen my first GBS patient in 1989, I have since then dedicated my time in research towards understanding the pathogenesis of GBS. Along with several colleagues, we identified IgG autoantibodies against ganglioside GM1 in two patients with GBS subsequent to Campylobacter jejuni enteritis. We proceeded to demonstrate molecular mimicry between GM1 and bacterial lipo-oligosaccharide of C. jejuni isolated from a patient with GBS. Our group then established a disease model for GBS by sensitization with GM1 or GM1-like lipo-oligosaccharide. With this, a new paradigm that carbohydrate mimicry can cause autoimmune disorders was demonstrated, making GBS the first proof of molecular mimicry in autoimmune disease. Patients with Fisher syndrome, characterized by ophthalmoplegia and ataxia, can develop the disease after an infection by C. jejuni. We showed that the genetic polymorphism of C. jejuni sialyltransferase, an enzyme essential to the biosynthesis of ganglioside-like lipo-oligosaccharides determines whether patients develop GBS or Fisher syndrome. This introduces another paradigm that microbial genetic polymorphism can determine the clinical phenotype of human autoimmune diseases. Similarities between the clinical presentation of Fisher syndrome and Bickerstaff brainstem encephalitis have caused debate as to whether they are in fact the same disease. We demonstrated that IgG anti-GQ1b antibodies were common to both, suggesting that they are part of the same disease spectrum. We followed this work by clarifying the nosological relationship between the various clinical presentations within the anti-GQ1b antibody syndrome. In this review, I wanted to share my journey from being a clinician to a clinician-scientist in the hopes of inspiring younger clinicians to follow a similar path. PMID:22850724

Modified rib pivot lateral thoracotomy: a case series.

PubMed

Appelgrein, C; Hosgood, G

2018-01-01

To describe a modified rib pivot thoracotomy and its clinical application in client-owned dogs and cats. Case series of 24 dogs and 1 cat requiring a thoracotomy. A lateral thoracic incision over the required thoracic segment was made. The latissimus dorsi muscle was reflected dorsally. The predetermined rib was identified and the periosteum overlying the rib was elevated circumferentially, avoiding the intercostal neurovascular structures. Holes were pre-placed above and below the proposed osteotomy site. The rib was osteotomised and pivoted cranially. The pleura was incised and the required intrathoracic procedure was then performed. The thoracic cavity was closed by pre-placement of a suture through the pre-placed holes within the osteotomised rib. The pleura and intercostal musculature were closed, avoiding the intercostal neurovascular structures. The rib was re-apposed and the lateral approach was closed. The cases included were reviewed for both the rib pivoted as per the procedure required and postoperative complications. The study group comprised 8 Staffordshire Bull Terriers, 2 Poodles, 2 German Shepherd Dogs, 1 each of Basset Hound, Rhodesian Ridgeback, Golden Retriever, Australian Shepherd, Vizsla, Bull Mastiff, Schnauzer, Jack Russell Terrier, Bulldog, Deerhound, Labrador Retriever and Australian Terrier, and 1 cat. A modified rib pivot thoracotomy was performed for lung lobectomy (n = 11), oesophagectomy (7), subtotal pericardectomy (5), patent ductus arteriosus ligation (1) and thoracic duct ligation (1). Follow-up ranged from 2 to 40 weeks postoperatively. Postoperative complications included seroma formation in two dogs. A modified rib pivot thoracotomy should be considered as an alternative lateral thoracic approach with good exposure, minimal complications and low morbidity. © 2018 Australian Veterinary Association.

A SENSITIVE FLUORESCENCE-BASED ASSAY FOR MONITORING GM2 GANGLIOSIDE HYDROLYSIS IN LIVE PATIENT CELLS AND THEIR LYSATES

PubMed Central

Tropak, Michael B.; Bukovac, Scott W.; Rigat, Brigitte A.; Yonekawa, Sayuri; Wakarchuk, Warren; Mahuran, Don J.

2010-01-01

Enzyme enhancement therapy, utilizing small molecules as pharmacological chaperones, is anattractive approach for the treatment of lysosomal storage diseases that are associated with protein misfolding. However, pharmacological chaperones are alsoinhibitors of their target enzyme. Thus, a major concern with this approach is that, despite enhancing protein folding within, and intracellular transport of the functional mutant enzyme out of the endoplasmic reticulum, the chaperone will continue to inhibit the enzyme in the lysosome, preventing substrate clearance. Herewe demonstrate that the in vitro hydrolysis of a fluorescent derivative of lyso-GM2 ganglioside, like natural GM2 ganglioside, is specifically carried out by the β-hexosaminidase A isozyme, requires the GM2 activator protein as a co-factor, increases when the derivative is incorporated into anionic liposomes and follows similar Michaelis-Menten kinetics. This substrate can also be used to differentiate between lysates from normal and GM2 activator-deficient cells. When added to the growth medium of cells, the substrate is internalized and primarily incorporated into lysosomes. Utilizing adult Tay-Sachs fibroblasts that have been pre-treated with the pharmacological chaperone Pyrimethamine and subsequently loaded with this substrate, we demonstrate an increase in both the levels of mutant β-hexosaminidase A and substrate-hydrolysis as compared to mock treated cells. PMID:19917668

A sensitive fluorescence-based assay for monitoring GM2 ganglioside hydrolysis in live patient cells and their lysates.

PubMed

Tropak, Michael B; Bukovac, Scott W; Rigat, Brigitte A; Yonekawa, Sayuri; Wakarchuk, Warren; Mahuran, Don J

2010-03-01

Enzyme enhancement therapy, utilizing small molecules as pharmacological chaperones, is an attractive approach for the treatment of lysosomal storage diseases that are associated with protein misfolding. However, pharmacological chaperones are also inhibitors of their target enzyme. Thus, a major concern with this approach is that, despite enhancing protein folding within, and intracellular transport of the functional mutant enzyme out of the endoplasmic reticulum, the chaperone will continue to inhibit the enzyme in the lysosome, preventing substrate clearance. Here we demonstrate that the in vitro hydrolysis of a fluorescent derivative of lyso-GM2 ganglioside, like natural GM2 ganglioside, is specifically carried out by the beta-hexosaminidase A isozyme, requires the GM2 activator protein as a co-factor, increases when the derivative is incorporated into anionic liposomes and follows similar Michaelis-Menten kinetics. This substrate can also be used to differentiate between lysates from normal and GM2 activator-deficient cells. When added to the growth medium of cells, the substrate is internalized and primarily incorporated into lysosomes. Utilizing adult Tay-Sachs fibroblasts that have been pre-treated with the pharmacological chaperone Pyrimethamine and subsequently loaded with this substrate, we demonstrate an increase in both the levels of mutant beta-hexosaminidase A and substrate-hydrolysis as compared to mock-treated cells.

Understanding Rasch Measurement: Partial Credit Model and Pivot Anchoring.

ERIC Educational Resources Information Center

Bode, Rita K.

2001-01-01

Describes the Rasch measurement partial credit model, what it is, how it differs from other Rasch models, and when and how to use it. Also describes the calibration of instruments with increasingly complex items. Explains pivot anchoring and illustrates its use and describes the effect of pivot anchoring on step calibrations, item hierarchy, and…

Abasic pivot substitution harnesses target specificity of RNA interference

PubMed Central

Lee, Hye-Sook; Seok, Heeyoung; Lee, Dong Ha; Ham, Juyoung; Lee, Wooje; Youm, Emilia Moonkyung; Yoo, Jin Seon; Lee, Yong-Seung; Jang, Eun-Sook; Chi, Sung Wook

2015-01-01

Gene silencing via RNA interference inadvertently represses hundreds of off-target transcripts. Because small interfering RNAs (siRNAs) can function as microRNAs, avoiding miRNA-like off-target repression is a major challenge. Functional miRNA–target interactions are known to pre-require transitional nucleation, base pairs from position 2 to the pivot (position 6). Here, by substituting nucleotide in pivot with abasic spacers, which prevent base pairing and alleviate steric hindrance, we eliminate miRNA-like off-target repression while preserving on-target activity at ∼80–100%. Specifically, miR-124 containing dSpacer pivot substitution (6pi) loses seed-mediated transcriptome-wide target interactions, repression activity and biological function, whereas other conventional modifications are ineffective. Application of 6pi allows PCSK9 siRNA to efficiently lower plasma cholesterol concentration in vivo, and abolish potentially deleterious off-target phenotypes. The smallest spacer, C3, also shows the same improvement in target specificity. Abasic pivot substitution serves as a general means to harness the specificity of siRNA experiments and therapeutic applications. PMID:26679372

Failure Analysis on Tail Rotor Teeter Pivot Bolt on a Helicopter

NASA Astrophysics Data System (ADS)

Qiang, WANG; Zi-long, DONG

2018-03-01

Tail rotor teeter pivot bolt of a helicopter fractured when in one flight. Failure analysis on the bolt was finished in laboratory. Macroscopic observation of the tailor rotor teeter pivot bolt, macro and microscopic inspection on the fracture surface of the bolt was carried out. Chemical components and metallurgical structure was also carried out. Experiment results showed that fracture mode of the tail rotor teeter pivot bolt is fatigue fracture. Fatigue area is over 80% of the total fracture surface, obvious fatigue band characteristics can be found at the fracture face. According to the results were analyzed from the macroscopic and microcosmic aspects, fracture reasons of the tail rotor teeter pivot bolt were analyzed in detail

Anthropometric and physical performance characteristics of professional handball players: influence of playing position.

PubMed

Schwesig, René; Hermassi, Souhail; Fieseler, Georg; Irlenbusch, Lars; Noack, Frank; Delank, Karl-Stefan; Shephard, Roy J; Chelly, Mohamed-Souhaiel

2017-11-01

The aims of the study were to examine the anthropometric and physical performance characteristics of professional handball players classified by playing position. Twenty-one competitors (age: 25.2±5.1 years) were categorized as backs, pivots, wings or goalkeepers. Measures included anthropometrics (body height and mass), scores on the Yo-Yo Intermittent Recovery Test (total distance covered, TD), repeated-sprint ability (6 repetitions of 2x15-m shuttle sprints with recording of best time for a single trial, RSAbest) and performance on a complex handball test (HBKT) of throw slap (TS) and throw jump (TJ) with and without precision. The anthropometric data revealed a significantly lower body height for wings and pivots than for goalkeepers. Wings, pivots and goalkeepers were significantly shorter than backs, but had a similar BMI. The TD was greater for the wings (2.400 m) than for backs (1.832 m) and pivots (2.067m). Wings also achieved a better RSAbest (5.41 s) than backs (5.68 s) or pivots (5.82 s). Body height was significantly related to throw slap (TS) and jump (JT) (r=0.53, P<0.01; r=0.51, P<0.01 respectively). No significant difference (P=0.675; η2=0.009) was seen between JT with precision and JT without precision. Substantial differences of body build and physical performance between playing positions underline the importance of a careful assignment of such positions and the development of position-specific training for professional handball players by modifying both intermittent aerobic and anaerobic endurance components of training sessions.

A sustainable model for training teachers to use pivotal response training.

PubMed

Suhrheinrich, Jessica

2015-08-01

The increase in the rate of autism diagnoses has created a growing demand for teachers who are trained to use effective interventions. The train-the-trainer model, which involves training supervisors to train others, may be ideal for providing cost-effective training and ongoing support to teachers. Although research supports interventions, such as pivotal response training, as evidence-based, dissemination to school environments has been problematic. This study assessed the benefits of using the train-the-trainer model to disseminate pivotal response training to school settings. A multiple-baseline design was conducted across three training groups, each consisting of one school staff member (trainer), three special education teachers, and six students. Trainers conducted the teacher-training workshop with high adherence to training protocol and met mastery criteria in their ability to implement pivotal response training, assess implementation of pivotal response training, and provide feedback to teachers. Six of the nine teachers mastered all components of pivotal response training. The remaining three teachers implemented 89% of the pivotal response training components correctly. The majority of trainers and teachers maintained their abilities at follow-up. These results support the use of the train-the-trainer model as an effective method of disseminating evidence-based practices in school settings. © The Author(s) 2014.

Design and evaluation of a single-pivot supported centrifugal blood pump.

PubMed

Yoshino, M; Uemura, M; Takahashi, K; Watanabe, N; Hoshi, H; Ohuchi, K; Nakamura, M; Fujita, H; Sakamoto, T; Takatani, S

2001-09-01

In order to develop a centrifugal blood pump that meets the requirements of a long-term, implantable circulatory support device, in this study a single-pivot bearing supported centrifugal blood pump was designed to evaluate its basic performance. The single-pivot structure consisted of a ceramic ball male pivot mounted on the bottom surface of the impeller and a polyethylene female pivot incorporated in the bottom pump casing. The follower magnet mounted inside the impeller was magnetically coupled to the driver magnet mounted on the shaft of the direct current brushless motor. As the motor rotated, the impeller rotated supported entirely by a single-pivot bearing system. The static pump performance obtained in the mock circulatory loop revealed an acceptable performance as a left ventricular assist device in terms of flow and head pressure. The pump flow of 5 L/min against the head pressure of 100 mm Hg was obtained at rotational speeds of 2,000 to 2,200 rpm. The maximum pump flow was 9 L/min with 2,200 rpm. The maximum electrical-to-hydraulic power conversion efficiency was around 14% at pump flows of 4 to 5 L/min. The stability of the impeller was demonstrated at the pump rpm higher than 1,400 with a single-pivot bearing without an additional support at its top. The single-pivot supported centrifugal pump can provide adequate flow and pressure as a ventricular assist device, but its mechanical stability and hemolytic as well as thrombotic performances must be tested prior to clinical use.

Apprehending ganglioside diversity: a comprehensive methodological approach[S

PubMed Central

Masson, Elodie A. Y.; Sibille, Estelle; Martine, Lucy; Chaux-Picquet, Fanny; Bretillon, Lionel; Berdeaux, Olivier

2015-01-01

Gangliosides (GGs) make a wide family of glycosphingolipids ubiquitously expressed in mammalian tissues and particularly abundant in the brain and nervous system. They exhibit a huge diversity due to structural variations in both their oligosaccharidic chain and ceramide moiety, which represent a real analytical challenge. Since their discovery in the 1940s, methods have persistently improved until the emergence of LC/MS, which offers a high level of specificity and sensitivity and is suitable with high-throughput profiling studies. We describe here a comprehensive approach relying on various techniques and aiming at fully characterizing GGs in biological samples. First, total GG content was determined by a biochemical assay. Second, GG class composition was assessed by high-performance thin-layer chromatography followed by colorimetric revelation. Then, ceramide types of GG classes were identified, and their relative quantification was performed thanks to the development of a powerful and reliable LC/MS method. Finally, ceramides were structurally characterized, and minor and less common GG classes were identified using high-resolution MS. These methods were applied to the rat retina to provide an exhaustive description of its GG composition, giving the base for a better understanding of the precise roles of GGs in this tissue. PMID:26142958

Physical and physiological characteristics of male handball players: influence of playing position and competitive level.

PubMed

Haugen, Thomas A; Tønnessen, Espen; Seiler, Stephen

2016-01-01

The purpose of this study was to quantify differences in anthropometrical and physical characteristics according to playing position and competitive level in male elite handball. One hundred and seventy-six national team and 1st division players (age 23±4 years, body mass 89±11 kg, body height 188±5 cm) participated in the study. All participants were tested on throwing velocity, 20-meter sprint, countermovement jump, 3000-meter run, 1RM squat and bench press. Back players achieved higher throwing velocities compared to other positions. National team back players achieved higher velocities in set shots (9.4%, P<0.001, d=1.5) and jump shots (8.1%, P<0.001, d=1.5) than 1st division players. Wings sprinted faster than pivots (3.5%, P<0.001, d=1.2) and goalkeepers (5.4%, P<0.001, d=1.2). Wings jumped higher than pivots (13.0%, P<0.001, d=1.0) and goalkeepers (11.4%, P=0.003, d=0.9). National team back players ran faster than 1st division back players over 3000 meters (4.9%, P=0.011, d=0.7). Back players showed better relative strength in squat than pivots (12.1%, P=0.016, d=0.7). Wings had better relative strength in squat that pivots (17.4%, P=0.001, d=1.0) and goalkeepers (13.1%, P=0.016, d=0.8). Pivots were 8.9% stronger than wing players (P=0.044, d=0.7) in 1RM bench press. Varying on-court demands in handball are reflected by different physical and physiological characteristics across playing standard and positions. Physical conditioning of players should therefore be individualized and targeted to solve the position-dependent tasks during play.

Increased Expression of Simple Ganglioside Species GM2 and GM3 Detected by MALDI Imaging Mass Spectrometry in a Combined Rat Model of Aβ Toxicity and Stroke

PubMed Central

Caughlin, Sarah; Hepburn, Jeffrey D.; Park, Dae Hee; Jurcic, Kristina; Yeung, Ken K.-C.; Cechetto, David F.; Whitehead, Shawn N.

2015-01-01

The aging brain is often characterized by the presence of multiple comorbidities resulting in synergistic damaging effects in the brain as demonstrated through the interaction of Alzheimer’s disease (AD) and stroke. Gangliosides, a family of membrane lipids enriched in the central nervous system, may have a mechanistic role in mediating the brain’s response to injury as their expression is altered in a number of disease and injury states. Matrix-Assisted Laser Desorption Ionization (MALDI) Imaging Mass Spectrometry (IMS) was used to study the expression of A-series ganglioside species GD1a, GM1, GM2, and GM3 to determine alteration of their expression profiles in the presence of beta-amyloid (Aβ) toxicity in addition to ischemic injury. To model a stroke, rats received a unilateral striatal injection of endothelin-1 (ET-1) (stroke alone group). To model Aβ toxicity, rats received intracerebralventricular (icv) injections of the toxic 25-35 fragment of the Aβ peptide (Aβ alone group). To model the combination of Aβ toxicity with stroke, rats received both the unilateral ET-1 injection and the bilateral icv injections of Aβ₂₅₋₃₅ (combined Aβ/ET-1 group). By 3 d, a significant increase in the simple ganglioside species GM2 was observed in the ischemic brain region of rats who received a stroke (ET-1), with or without Aβ. By 21 d, GM2 levels only remained elevated in the combined Aβ/ET-1 group. GM3 levels however demonstrated a different pattern of expression. By 3 d GM3 was elevated in the ischemic brain region only in the combined Aβ/ET-1 group. By 21 d, GM3 was elevated in the ischemic brain region in both stroke alone and Aβ/ET-1 groups. Overall, results indicate that the accumulation of simple ganglioside species GM2 and GM3 may be indicative of a mechanism of interaction between AD and stroke. PMID:26086081

Increased Expression of Simple Ganglioside Species GM2 and GM3 Detected by MALDI Imaging Mass Spectrometry in a Combined Rat Model of Aβ Toxicity and Stroke.

PubMed

Caughlin, Sarah; Hepburn, Jeffrey D; Park, Dae Hee; Jurcic, Kristina; Yeung, Ken K-C; Cechetto, David F; Whitehead, Shawn N

2015-01-01

The aging brain is often characterized by the presence of multiple comorbidities resulting in synergistic damaging effects in the brain as demonstrated through the interaction of Alzheimer's disease (AD) and stroke. Gangliosides, a family of membrane lipids enriched in the central nervous system, may have a mechanistic role in mediating the brain's response to injury as their expression is altered in a number of disease and injury states. Matrix-Assisted Laser Desorption Ionization (MALDI) Imaging Mass Spectrometry (IMS) was used to study the expression of A-series ganglioside species GD1a, GM1, GM2, and GM3 to determine alteration of their expression profiles in the presence of beta-amyloid (Aβ) toxicity in addition to ischemic injury. To model a stroke, rats received a unilateral striatal injection of endothelin-1 (ET-1) (stroke alone group). To model Aβ toxicity, rats received intracerebralventricular (i.c.v.) injections of the toxic 25-35 fragment of the Aβ peptide (Aβ alone group). To model the combination of Aβ toxicity with stroke, rats received both the unilateral ET-1 injection and the bilateral icv injections of Aβ25-35 (combined Aβ/ET-1 group). By 3 d, a significant increase in the simple ganglioside species GM2 was observed in the ischemic brain region of rats who received a stroke (ET-1), with or without Aβ. By 21 d, GM2 levels only remained elevated in the combined Aβ/ET-1 group. GM3 levels however demonstrated a different pattern of expression. By 3 d GM3 was elevated in the ischemic brain region only in the combined Aβ/ET-1 group. By 21 d, GM3 was elevated in the ischemic brain region in both stroke alone and Aβ/ET-1 groups. Overall, results indicate that the accumulation of simple ganglioside species GM2 and GM3 may be indicative of a mechanism of interaction between AD and stroke.

Association of anti-gangliosides antibodies and anti-CMV antibodies in Guillain-Barré syndrome.

PubMed

Wang, Lijuan; Shao, Chunqing; Yang, Chunjiao; Kang, Xixiong; Zhang, Guojun

2017-05-01

Numerous types of infection were closely related to GBS, mainly including Campylobacter jejuni , Cytomegalovirus, which may lead to the production of anti-gangliosides antibodies (AGA) . Currently, although there are increased studies on the AGA and a few studies of anti-CMV antibodies in GBS, the association between them remains poorly documented. Therefore, our research aims to analyze the correlation of anti-CMV antibodies and AGA in GBS. A total of 29 patients with GBS were enrolled in this study. The CMV antibodies were tested by the electrochemiluminescence immunoassay "ECLIA" (Roche Diagnostics GmbH). The serum gangliosides were determined by The EUROLINE test kit. Of the 29 patients with GBS, 9 (31%) were AGA-seropositive, in which 22 were CMV-IgG positive in CSF at the same time, but all 29 samples were CMV-IgM negative in both serum and CSF. In the AGA-positive group, the rate of both serum and CSF positive was 87.5% (7/8), higher than 50% (7/14) of the negative group, although no statistical significance was found. In addition, we found that there was a trend of higher ratio of men, a younger age onset, less frequent preceding infection, a higher level of CSF proteins, and less frequent cranial nerve deficits, although the data did not reach a statistical significance. In spite of no statistical significance association was found between serum AGA and CMV-IgG in serum and CSF. However, we found that there was a trend of high positive rate of both serum and CSF-CMV-IgG in AGA-positive than the negative group. So we should further expand the sample size to analyze the association between AGA and CMV or other neurotropic virus antibodies in various diseases, to observe whether they could be serological marker of these diseases (especially GBS) or the underlying pathogenesis.

Liquid chromatography/electrospray ionisation-tandem mass spectrometry quantification of GM2 gangliosides in human peripheral cells and plasma.

PubMed

Fuller, Maria; Duplock, Stephen; Hein, Leanne K; Rigat, Brigitte A; Mahuran, Don J

2014-08-01

GM2 gangliosidosis is a group of inherited neurodegenerative disorders resulting primarily from the excessive accumulation of GM2 gangliosides (GM2) in neuronal cells. As biomarkers for categorising patients and monitoring the effectiveness of developing therapies are lacking for this group of disorders, we sought to develop methodology to quantify GM2 levels in more readily attainable patient samples such as plasma, leukocytes, and cultured skin fibroblasts. Following organic extraction, gangliosides were partitioned into the aqueous phase and isolated using C18 solid-phase extraction columns. Relative quantification of three species of GM2 was achieved using LC/ESI-MS/MS with d35GM1 18:1/18:0 as an internal standard. The assay was linear over the biological range, and all GM2 gangliosidosis patients were demarcated from controls by elevated GM2 in cultured skin fibroblast extracts. However, in leukocytes only some molecular species could be used for differentiation and in plasma only one was informative. A reduction in GM2 was easily detected in patient skin fibroblasts after a short treatment with media from normal cells enriched in secreted β-hexosaminidase. This method may show promise for measuring the effectiveness of experimental therapies for GM2 gangliosidosis by allowing quantification of a reduction in the primary storage burden. Copyright © 2014 Elsevier Inc. All rights reserved.

Promotion of neuritogenesis in mouse neuroblastoma cells by ganglioside GM3: Involvement of three signal pathways

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

Edwards, A.H.

1989-01-01

Ganglioside GM3 was extracted from human placentae and tested for neuritogenic properties towards the mouse neuroblastoma cell line Neuro-2A. GM3 (2.5 {mu}M) was found to inhibit cell growth when added exogenously to the cell culture. ({sup 3}H)Thymidine incorporation was inhibited by 49% within 6 hr. Neuritogenesis was evident within 24 hr evidenced by an increase in the number and length of neurites produced compared to control cells. An enzymatic assay for protein kinase C activity was employed to study effects of GM3 on the subcellular localization of the enzyme. Ganglioside GM3 was found to alter the subcellular localization of themore » phospholipid- and calcium-dependent protein kinase C. These results were confirmed using a binding assay employing the labeled phorbol ester ({sup 3}H)phorbol-12,13-dibutyrate. Finally, GM3-modulation of IP{sub 3} formation and cytosolic calcium in the Neuro-2A cells was investigated. GM3 did not alter the phosphoinositol metabolism as evidenced by IP{sub 3} formation in these cells. However, the addition of GM3 (16 {mu}M) to cells loaded with the photoprotein, aequorin, induced an increase in the intracellular calcium concentration within 2 min, which was sustained for 10 min. Removal of external calcium by chelation did not abrogate the response to GM3, indicating that calcium was being released from internal stores. The calcium influx was temporally correlated with the translocation of protein kinase C, providing a rationale whereby GM3 may induce the enzyme to translocate.« less

Neoglycolipid analogues of ganglioside G sub M1 as functional receptors of cholera toxin

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

Pacuszka, T.; Bradley, R.M.; Fishman, P.H.

1991-03-12

The authors synthesized several lipid analogues of ganglioside G{sub M1} by attaching its oligosaccharide moiety (G{sub M1}OS) to aminophospholipids, aliphatic amines, and cholesteryl hemisuccinate. They incubated G{sub M1}-deficient rat glioma C6 cells with each of the derivatives as well as native G{sub M1} and assayed the cells for their ability to bind and respond to cholera toxin. On the basis of the observed increase in binding of {sup 125}I-labeled cholera toxin, it was apparent that the cells took up and initially incorporated most of the derivatives into the plasma membrane. In the case of the aliphatic amine derivatives, the abilitymore » to generate new toxin binding sites was dependent on chain length; whereas the C{sub 10} derivative was ineffective, C{sub 12} and higher analogues were effective. Increased binding was dependent on both the concentration of the neoglycolipid in the medium and the time of exposure. Cells pretreated with the various derivatives accumulated cyclic AMP in response to cholera toxin, but there were differences in their effectiveness. The cholesterol and long-chain aliphatic amine derivatives were more effective than native G{sub M1}, whereas the phospholipid derivatives were less effective. The distance between G{sub M1}OS and the phospholipid also appeared to influence its functional activity. The results indicate that although G{sub M1}OS provides the recognition site for the binding of cholera toxin, the nature of the lipid moiety plays an important role in the action of the toxin.« less

PIVOT: platform for interactive analysis and visualization of transcriptomics data.

PubMed

Zhu, Qin; Fisher, Stephen A; Dueck, Hannah; Middleton, Sarah; Khaladkar, Mugdha; Kim, Junhyong

2018-01-05

Many R packages have been developed for transcriptome analysis but their use often requires familiarity with R and integrating results of different packages requires scripts to wrangle the datatypes. Furthermore, exploratory data analyses often generate multiple derived datasets such as data subsets or data transformations, which can be difficult to track. Here we present PIVOT, an R-based platform that wraps open source transcriptome analysis packages with a uniform user interface and graphical data management that allows non-programmers to interactively explore transcriptomics data. PIVOT supports more than 40 popular open source packages for transcriptome analysis and provides an extensive set of tools for statistical data manipulations. A graph-based visual interface is used to represent the links between derived datasets, allowing easy tracking of data versions. PIVOT further supports automatic report generation, publication-quality plots, and program/data state saving, such that all analysis can be saved, shared and reproduced. PIVOT will allow researchers with broad background to easily access sophisticated transcriptome analysis tools and interactively explore transcriptome datasets.

Mechanical design of deformation compensated flexural pivots structured for linear nanopositioning stages

DOEpatents

Shu, Deming; Kearney, Steven P.; Preissner, Curt A.

2015-02-17

A method and deformation compensated flexural pivots structured for precision linear nanopositioning stages are provided. A deformation-compensated flexural linear guiding mechanism includes a basic parallel mechanism including a U-shaped member and a pair of parallel bars linked to respective pairs of I-link bars and each of the I-bars coupled by a respective pair of flexural pivots. The basic parallel mechanism includes substantially evenly distributed flexural pivots minimizing center shift dynamic errors.

Pivot tables for mortality analysis, or who needs life tables anyway?

PubMed

Wesley, David; Cox, Hugh F

2007-01-01

Actuarial life-table analysis has long been used by life insurance medical directors for mortality abstraction from clinical studies. Ironically, today's life actuary instead uses pivot tables to analyze mortality. Pivot tables (a feature/function in MS Excel) collapse various dimensions of data that were previously arranged in an "experience study" format. Summary statistics such as actual deaths, actual and expected mortality (usually measured in dollars), and calculated results such as actual to expected ratios, are then displayed in a 2-dimensional grid. The same analytic process, excluding the dollar focus, can be used for clinical mortality studies. For raw survival data, especially large datasets, this combination of experience study data and pivot tables has clear advantages over life-table analysis in both accuracy and flexibility. Using the SEER breast cancer data, we compare the results of life-table analysis and pivot-table analysis.

In situ detection of GM1 and GM2 gangliosides using immunohistochemical and immunofluorescent techniques for auxiliary diagnosis of canine and feline gangliosidoses.

PubMed

Kohyama, Moeko; Yabuki, Akira; Ochiai, Kenji; Nakamoto, Yuya; Uchida, Kazuyuki; Hasegawa, Daisuke; Takahashi, Kimimasa; Kawaguchi, Hiroaki; Tsuboi, Masaya; Yamato, Osamu

2016-03-31

GM1 and GM2 gangliosidoses are progressive neurodegenerative lysosomal storage diseases resulting from the excessive accumulation of GM1 and GM2 gangliosides in the lysosomes, respectively. The diagnosis of gangliosidosis is carried out based on comprehensive findings using various types of specimens for histological, ultrastructural, biochemical and genetic analyses. Therefore, the partial absence or lack of specimens might have resulted in many undiagnosed cases. The aim of the present study was to establish immunohistochemical and immunofluorescent techniques for the auxiliary diagnosis of canine and feline gangliosidoses, using paraffin-embedded brain specimens stored for a long period. Using hematoxylin and eosin staining, cytoplasmic accumulation of pale to eosinophilic granular materials in swollen neurons was observed in animals previously diagnosed with GM1 or GM2 gangliosidosis. The immunohistochemical and immunofluorescent techniques developed in this study clearly demonstrated the accumulated material to be either GM1 or GM2 ganglioside. Immunohistochemical and immunofluorescent techniques using stored paraffin-embedded brain specimens are useful for the retrospective diagnosis of GM1 and GM2 gangliosidoses in dogs and cats.

The influence of applied internal and external rotation on the pivot shift phenomenon.

PubMed

Kopf, Sebastian; Musahl, Volker; Perka, Carsten; Kauert, Ralf; Hoburg, Arnd; Becker, Roland

2017-04-01

The pivot shift test is performed in different techniques and the rotation of the tibia seems to have a significant impact on the amount of the pivot shift phenomenon. It has been hypothesised that external rotation will increase the phenomenon due to less tension at the iliotibial band in knee extension. Twenty-four patients with unilateral anterior cruciate ligament insufficiency were included prospectively. The pivot shift test was performed bilaterally in internal and external tibial rotation under general anaesthesia. Knee motion was captured using a femoral and a tibial inertial sensor. The difference between positive and negative peak values in Euclidean norm of acceleration was calculated to evaluate the amount of the pivot shift phenomenon. The pivot shift phenomenon was significantly increased in patients with ACL insufficiency when the test was performed in external [mean 5.2 ms - 2 (95% CI 4.3-6.0)] compared to internal tibial rotation [mean 4.4 ms - 2 (95% CI 3.5-5.4)] (p = 0.002). In healthy, contralateral knees did not show any difference between external [mean 4.0 ms - 2 (95% CI 3.3-4.7)] and internal tibial rotation [mean 4.0 ms - 2 (95% CI 3.4-4.6)] (ns). The pivot shift phenomenon was increased with external rotation in ACL-insufficient knees, and therefore, one should perform the pivot shift test, rather, in external rotation to easily evoke the, sometimes difficult to detect, pivot shift phenomenon. I (diagnostic study).

Integration of Ganglioside GT1b Receptor into DPPE and DPPC Phospholipid Monolayers: An X-Ray Reflectivity and Grazing-Incidence Diffraction Study

PubMed Central

Miller, C. E.; Busath, D. D.; Strongin, B.; Majewski, J.

2008-01-01

Using synchrotron grazing-incidence x-ray diffraction (GIXD) and reflectivity, the in-plane and out-of-plane structures of mixed-ganglioside GT1b-phospholipid monolayers were investigated at the air-liquid interface and compared with monolayers of the pure components. The receptor GT1b is involved in the binding of lectins and toxins, including botulinum neurotoxin, to cell membranes. Monolayers composed of 20 mol % ganglioside GT1b, the phospholipid dipalmitoyl phosphatidylethanolamine (DPPE), and the phospholipid dipalmitoyl phosphatidylcholine (DPPC) were studied in the gel phase at 23°C and at surface pressures of 20 and 40 mN/m, and at pH 7.4 and 5. Under these conditions, the two components did not phase-separate, and no evidence of domain formation was observed. The x-ray scattering measurements revealed that GT1b was intercalated within the host DPPE/DPPC monolayers, and slightly expanded DPPE but condensed the DPPC matrix. The oligosaccharide headgroups extended normally from the monolayer surfaces into the subphase. This study demonstrated that these monolayers can serve as platforms for investigating toxin membrane binding and penetration. PMID:18599631

27. VIEW NORTHWEST FROM DECKING ON SOUTHEAST CORNER OF PIVOT ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

27. VIEW NORTHWEST FROM DECKING ON SOUTHEAST CORNER OF PIVOT PIER, DRIVE SYSTEM FOR SWING-SPAN INCLUDES: (from left to right) WEDGE DRIVE GEAR BOX, SHAFTS TO WEDGE DRIVE DRIVE, WEDGE DRIVE CRANK SHAFTS, ELECTRIC MOTOR, INTERNATIONAL HARVESTER GASOLINE ENGINE, CONTROL RODS FOR STARTING AND CHOKING ENGINE, PIVOT (bottom center), AND TRACK ON CONCRETE PIER - Tipers Bridge, Spanning Great Wicomico River at State Route 200, Kilmarnock, Lancaster County, VA

A photoreactive derivative of radiolabeled GM1 ganglioside: Preparation and use to establish the involvement of specific proteins in GM1 uptake by human fibroblasts in culture

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

Sonnino, S.; Chigorno, V.; Acquotti, D.

1989-01-10

A new procedure was used to synthesize a derivative of ganglioside GM1 containing a photoreactive nitrophenyl azide group at the end of the fatty acyl moiety, using deAc-deAcyl-GM1 obtained by deacetylation of the sialic acid and deacylation of the ceramide portion of GM1. This deAc-deAcyl-GM1 was first acylated at the long chain base amino group with 12-aminododecanoic acid, which has the amino group protected by a fluorenyl residue, and tritium labeled at the sialic acid amino group with ({sup 3}H)acetic anhydride of very high specific radioactivity. Cultured human fibroblasts were exposed to mixtures of radioactive photolabeled GM1 for different timesmore » and then illuminated and the radioactive protein patterns studied by SDS-PAGE. After 2 h of exposure, the photolabeled GM1 was stably associated to the cells and underwent almost no metabolic processing, behaving exactly as the underivatized natural GM1. Under these conditions very few proteins became radioactive. Thus, it is evident that the ganglioside binding to fibroblasts and insertion into the outer layer of the plasma membrane involve few individual proteins. When the incubation was prolonged to 24 h, photolabeled GM1 underwent extensive metabolic processing and gave origins to the corresponding ganglioside derivatives of GM2, GM3, and GD1a. Under these conditions many proteins became radioactive, a consequence of GM1 transfer from the surface to the interior or the cell and of the ready availability of interaction of GM1 and its metabolites.« less

Uptake of raft components into amyloid β-peptide aggregates and membrane damage.

PubMed

Sasahara, Kenji; Morigaki, Kenichi; Mori, Yasuko

2015-07-15

Amyloid aggregation and deposition of amyloid β-peptide (Aβ) are pathologic characteristics of Alzheimer's disease (AD). Recent reports have shown that the association of Aβ with membranes containing ganglioside GM1 (GM1) plays a pivotal role in amyloid deposition and the pathogenesis of AD. However, the molecular interactions responsible for membrane damage associated with Aβ deposition are not fully understood. In this study, we microscopically observed amyloid aggregation of Aβ in the presence of lipid vesicles and on a substrate-supported planar membrane containing raft components and GM1. The experimental system enabled us to observe lipid-associated aggregation of Aβ, uptake of the raft components into Aβ aggregates, and relevant membrane damage. The results indicate that uptake of raft components from the membrane into Aβ deposits induces macroscopic heterogeneity of the membrane structure. Copyright © 2015 Elsevier Inc. All rights reserved.

Damaging effects of Clostridium perfringens delta toxin on blood platelets and their relevance to ganglioside GM2.

PubMed

Jolivet-Reynaud, C; Launay, J M; Alouf, J E

1988-04-01

The lytic effect of Clostridium perfringens delta toxin was investigated on goat, human, rabbit, and guinea pig platelets. In contrast to erythrocytes from the latter three species, which are insensitive to the toxin, the platelets were equally lysed by the same amount of toxin. These results suggest the presence of GM2 or GM2-like ganglioside(s) as a specific recognition site of the toxin on platelet plasmic membrane as previously established for sensitive erythrocytes. Plasmic membrane damage of human platelets was evidenced by the release of entrapped alpha-[14C]aminoisobutyric acid used as a cytoplasmic marker. The specific binding of hemolytically active 125I-delta toxin by human and rabbit platelets was practically identical, dose dependent, and inhibitable by GM2. Labeled toxin was also bound by various subcellular organelles separated from rabbit platelets except the 5-hydroxytryptamine (5-HT)-containing dense bodies, suggesting the absence or inaccessibility of GM2 on the surface of the latter organelles. This result correlates with the low amounts of 5-[3H]HT liberated after platelet challenge with delta toxin whereas this mediator was massively liberated upon lysis by the sulfhydryl-activated toxin alveolysin. The levels of M and P forms of phenol sulfotransferase (PST), involved in 5-HT catabolism, were determined in human platelet lysates after challenge with delta toxin, alveolysin, and other disruptive treatments. The low PST-M activities detected after lysis by delta toxin suggest that this isoenzyme is very likely associated to dense bodies in contrast to PST-P which is cytoplasmic. Platelet lysis by the toxin allows easy separation of these organelles.

The Pivotal Role of Airway Smooth Muscle in Asthma Pathophysiology

PubMed Central

Ozier, Annaïg; Allard, Benoit; Bara, Imane; Girodet, Pierre-Olivier; Trian, Thomas; Marthan, Roger; Berger, Patrick

2011-01-01

Asthma is characterized by the association of airway hyperresponsiveness (AHR), inflammation, and remodelling. The aim of the present article is to review the pivotal role of airway smooth muscle (ASM) in the pathophysiology of asthma. ASM is the main effector of AHR. The mechanisms of AHR in asthma may involve a larger release of contractile mediators and/or a lower release of relaxant mediators, an improved ASM cell excitation/contraction coupling, and/or an alteration in the contraction/load coupling. Beyond its contractile function, ASM is also involved in bronchial inflammation and remodelling. Whereas ASM is a target of the inflammatory process, it can also display proinflammatory and immunomodulatory functions, through its synthetic properties and the expression of a wide range of cell surface molecules. ASM remodelling represents a key feature of asthmatic bronchial remodelling. ASM also plays a role in promoting complementary airway structural alterations, in particular by its synthetic function. PMID:22220184

Affinity-purified tetanus neurotoxin interaction with synaptic membranes: properties of a protease-sensitive receptor component

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

Lazarovici, P.; Yavin, E.

1986-11-04

The pharmacokinetic interaction of an affinity-purified /sup 125/I-labeled tetanotoxin fraction with guinea pig brain synaptosomal preparations was investigated. Binding of tetanotoxin was time- and temperature-dependent, was proportional to protein concentration, and was saturable at about 8 x 10/sup -9/ M as estimated by a solid-surface binding assay. Binding was optimal at pH 6.5 under low ionic strength buffer and was almost entirely blocked by gangliosides or antitoxin. In analogy to intact nerve cells, binding of toxin to membranes resulted in a tight association operationally defined as sequestration. Binding and sequestration were abolished after membrane pretreatment with sialidase. The enzyme couldmore » not dissociate the membrane-bound toxin formed at 4 or 37/sup 0/C under low ionic strength conditions, which is in part compatible with internalization as defined in nerve cell cultures. In the latter system the toxin could be removed at 4/sup 0/C but not at 37/sup 0/C. Binding was significantly reduced upon pretreatment of guinea pig brain membranes by a variety of hydrolytic enzymes. It is proposed that, in addition to a ganglioside, interaction of tetanotoxin with synaptic membranes is facilitated by a protein and may also require an appropriate lipid environment. These latter membrane constituents may play a pivotal role in the sequestration of the toxin.« less

Interaction of Clostridium perfringens delta toxin with erythrocyte and liposome membranes and relation with the specific binding to the ganglioside GM2.

PubMed

Jolivet-Reynaud, C; Hauttecoeur, B; Alouf, J E

1989-01-01

The specific interaction of the cytolytic Clostridium perfringens delta toxin with membrane GM2 was indicated by: (i) characterization of this glycolipid in the membrane of sheep and goat erythrocytes, which are lysed by the toxin, whereas GM2 was undetectable in insensitive rabbit erythrocytes, (ii) demonstration of 125I-toxin binding to GM2, by autoradiography, following incubation with thin-layer chromatograms containing separated neuroblastoma gangliosides, and (iii) toxin fixation by phospholipid-cholesterol unilamellar vesicles containing either sheep gangliosides or GM2. In order to investigate the intramembrane events leading to membrane disruption following toxin binding, the photoreactive probe 12(4-azido-2-nitrophenoxy)stearoyl 1-14C glucosamine, which inserts into the outer layer and labels integral membrane proteins, was used to establish whether delta toxin penetrates into target cell membrane. No toxin labeling was found, suggesting that toxin action takes place at the membrane surface. This contention is supported by the observation that despite toxin binding, GM2 liposomes did not release entrapped 14C-glucose. Treatment of toxin with carboxypeptidases, but not aminopeptidases, abolished both toxin binding capacity onto erythrocytes and its combination with antitoxin neutralizing antibodies, suggesting that the carboxy terminal end of the toxin is critical for binding to cell membrane.

Center Pivot Irrigated Agriculture, Libya

NASA Technical Reports Server (NTRS)

1981-01-01

A view of the Faregh Agricultural Station in the Great Calanscio Sand Sea, Libya (26.5N, 22.0E) about 300 miles southeast of Benghazi. A pattern of water wells have been drilled several miles apart to support a quarter mile center-pivot-swing-arm agricultural irrigation system. The crop grown is alfalfa which is eaten on location by flocks of sheep following the swing arm as it rotates. At maturity, the sheep are flown to market throughout Libya.

Droplet Kinetic Energy from Center-Pivot Sprinklers

USDA-ARS?s Scientific Manuscript database

The kinetic energy of discrete water drops impacting a bare soil surface is generally observed to lead to a drastic reduction in water infiltration rate due to soil surface seal formation. Under center-pivot sprinkler irrigation, kinetic energy transferred to the soil prior to crop canopy developmen...

Continuous wavelength tunable laser source with optimum positioning of pivot axis for grating

DOEpatents

Pushkarsky, Michael; Amone, David F.

2010-06-08

A laser source (10) for generating a continuously wavelength tunable light (12) includes a gain media (16), an optical output coupler (36F), a cavity collimator (38A), a diffraction grating (30), a grating beam (54), and a beam attacher (56). The diffraction grating (30) is spaced apart from the cavity collimator (38A) and the grating (30) cooperates with the optical output coupler (36F) to define an external cavity (32). The grating (30) includes a grating face surface (42A) that is in a grating plane (42B). The beam attacher (56) retains the grating beam (54) and allows the grating beam (54) and the grating (30) to effectively pivot about a pivot axis (33) that is located approximately at an intersection of a pivot plane (50) and the grating plane (42B). As provided herein, the diffraction grating (30) can be pivoted about the unique pivot axis (33) to move the diffraction grating (30) relative to the gain media (16) to continuously tune the lasing frequency of the external cavity (32) and the wavelength of the output light (12) so that the output light (12) is mode hop free.

Efficient Execution Methods of Pivoting for Bulk Extraction of Entity-Attribute-Value-Modeled Data

PubMed Central

Luo, Gang; Frey, Lewis J.

2017-01-01

Entity-attribute-value (EAV) tables are widely used to store data in electronic medical records and clinical study data management systems. Before they can be used by various analytical (e.g., data mining and machine learning) programs, EAV-modeled data usually must be transformed into conventional relational table format through pivot operations. This time-consuming and resource-intensive process is often performed repeatedly on a regular basis, e.g., to provide a daily refresh of the content in a clinical data warehouse. Thus, it would be beneficial to make pivot operations as efficient as possible. In this paper, we present three techniques for improving the efficiency of pivot operations: 1) filtering out EAV tuples related to unneeded clinical parameters early on; 2) supporting pivoting across multiple EAV tables; and 3) conducting multi-query optimization. We demonstrate the effectiveness of our techniques through implementation. We show that our optimized execution method of pivoting using these techniques significantly outperforms the current basic execution method of pivoting. Our techniques can be used to build a data extraction tool to simplify the specification of and improve the efficiency of extracting data from the EAV tables in electronic medical records and clinical study data management systems. PMID:25608318

Functional characterisation of ganglioside-induced differentiation-associated protein 1 as a glutathione transferase.

PubMed

Shield, Alison J; Murray, Tracy P; Board, Philip G

2006-09-08

Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene have been linked with Charcot-Marie-Tooth (CMT) disease. This protein, and its paralogue GDAP1L1, appear to be structurally related to the cytosolic glutathione S-transferases (GST) including an N-terminal thioredoxin fold domain with conserved active site residues. The specific function, of GDAP1 remains unknown. To further characterise their structure and function we purified recombinant human GDAP1 and GDAP1L1 proteins using bacterial expression and immobilised metal affinity chromatography. Like other cytosolic GSTs, GDAP1 protein has a dimeric structure. Although the full-length proteins were largely insoluble, the deletion of a proposed C-terminal transmembrane domain allowed the preparation of soluble protein. The purified proteins were assayed for glutathione-dependent activity against a library of 'prototypic' GST substrates. No evidence of glutathione-dependent activity or an ability to bind glutathione immobilised on agarose was found.

Current controversies in Niemann-Pick C1 disease: steroids or gangliosides; neurons or neurons and glia.

PubMed

Erickson, Robert P

2013-05-01

There has been a recent explosion in research on Niemann-Pick type C disease. Much of the work has used mouse models or cells in culture to elucidate the pathophysiological mechanisms resulting in the phenotype of the disease. This work has generated several contrasting views on the mechanism, which are labeled 'controversies' here. In this review, two of these controversies are explored. The first concerns which stored materials are causative in the disease: cholesterol, gangliosides and sphingolipids, or something else? The second concerns which cells in the body require Npc1 in order to function properly: somatic cells, neurons only, or neurons and glia? For the first controversy, a clear answer has emerged. More research will be needed in order to definitively solve the second controversy.

Remote pivot decoupler pylon: Wing/store flutter suppressor

NASA Technical Reports Server (NTRS)

Hassler, J. M., Jr. (Inventor)

1986-01-01

A device for suspending a store from an aerodynamic support surface, such an an aircraft wing, and more specifically, for improving upon singlet pivot decoupler pylons by reducing both frequency of active store, alignment, and alignment system space and power requirements. Two links suspend a lower pylon/rack section and releasable attached store from an upper pylon section mounted under the wing. The links allow the lower pylon section to rotate in pitch about a remote pivot point. A leaf spring connected between the lower section and electrical alignment system servomechanism provides pitch alignment of the lower section/store combination. The servomechanism utilizes an electric servomotor to drive the gear train and reversibly move the leaf spring, thereby maintaining the pitch attitude of the store within acceptable limits. The damper strokes when the lower section rotates to damp large oscillations of store.

As-CATH1-6, novel cathelicidins with potent antimicrobial and immunomodulatory properties from Alligator sinensis, play pivotal roles in host antimicrobial immune responses.

PubMed

Chen, Yan; Cai, Shasha; Qiao, Xue; Wu, Mali; Guo, Zhilai; Wang, Renping; Kuang, Yi-Qun; Yu, Haining; Wang, Yipeng

2017-08-10

Crocodilians are regarded as possessing a powerful immune system. However, the composition and action of the crocodilian immune system have remained unclear until now. Cathelicidins, the principal family of host defense peptides, play pivotal roles in vertebrate immune defense against microbial invasions. However, cathelicidins from crocodilians have not been extensively studied to date. In the present study, six novel cathelicidins (As-CATH1-6) were identified and characterized from the endangered Chinese alligator ( Alligator sinensis ). As-CATH1-6 exhibit no sequence similarity with any of the known cathelicidins. Structure analysis indicated that As-CATH1-3 adopt a random coil secondary conformation, whereas As-CATH4-6 were predicted to mainly adopt an amphipathic α-helix conformation. Among them, As-CATH4-6 exhibited potent, broad-spectrum and rapid antimicrobial activity by inducing the disruption of cell membrane integrity. They also exhibited strong ability to prevent the formation of bacterial biofilms and eradicate preformed biofilms. Furthermore, As-CATH4-6 exhibited potent anti-inflammatory activity by inhibiting the lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and pro-inflammatory cytokines in mouse peritoneal macrophages. They directly neutralized LPS toxicity and therefore inhibited the binding of LPS to the TLR4 receptor and the subsequent activation of inflammatory response pathways. In a peritonitis mice model, As-CATH2-6 provided effective protection against bacterial infection through enhanced immune cell recruitment. In the host Chinese alligator, As-CATH1-6 are mainly expressed in immune organs and epithelial tissues. Bacterial infection significantly enhances their expression, which implies an important role in host anti-infective response. Taken together, the diversity and multiple functions of As-CATH1-6 partially reveal the powerful immune system of the Chinese alligator. © 2017 The Author(s). Published by Portland

Lyso-GM2 ganglioside: a possible biomarker of Tay-Sachs disease and Sandhoff disease.

PubMed

Kodama, Takashi; Togawa, Tadayasu; Tsukimura, Takahiro; Kawashima, Ikuo; Matsuoka, Kazuhiko; Kitakaze, Keisuke; Tsuji, Daisuke; Itoh, Kohji; Ishida, Yo-Ichi; Suzuki, Minoru; Suzuki, Toshihiro; Sakuraba, Hitoshi

2011-01-01

To find a new biomarker of Tay-Sachs disease and Sandhoff disease. The lyso-GM2 ganglioside (lyso-GM2) levels in the brain and plasma in Sandhoff mice were measured by means of high performance liquid chromatography and the effect of a modified hexosaminidase (Hex) B exhibiting Hex A-like activity was examined. Then, the lyso-GM2 concentrations in human plasma samples were determined. The lyso-GM2 levels in the brain and plasma in Sandhoff mice were apparently increased compared with those in wild-type mice, and they decreased on intracerebroventricular administration of the modified Hex B. The lyso-GM2 levels in plasma of patients with Tay-Sachs disease and Sandhoff disease were increased, and the increase in lyso-GM2 was associated with a decrease in Hex A activity. Lyso-GM2 is expected to be a potential biomarker of Tay-Sachs disease and Sandhoff disease.

Plant responses, climate pivot points, and trade-offs in water-limited ecosystems

NASA Astrophysics Data System (ADS)

Munson, S. M.; Bunting, E.

2017-12-01

Ecosystem transitions and thresholds are conceptually well-defined and have become a framework to address vegetation response to climate change and land-use intensification, yet there are few approaches to define the environmental conditions which can lead to them. We demonstrate a novel climate pivot point approach using long-term monitoring data from a broad network of permanent plots, satellite imagery, and experimental treatments across the southwestern U.S. The climate pivot point identifies conditions that lead to decreased plant performance and serves as an early warning sign of increased vulnerability of crossing a threshold into an altered ecosystem state. Plant responses and climate pivot points aligned with the lifespan and structural characteristics of species, were modified by soil and landscape attributes of a site, and had non-linear dynamics in some cases. Species with strong increases in abundance when water was available were most susceptible to losses during water shortages, reinforcing plant energetic and physiological tradeoffs. Future research to uncover the heterogeneity of plant responses and climate pivot points at multiple scales can lead to greater understanding of shifts in ecosystem productivity and vulnerability to climate change.

Spot-Welding Gun With Pivoting Twin-Collet Assembly

NASA Technical Reports Server (NTRS)

Nguyen, Francis; Simpson, Gareth; Hoult, William S.

1996-01-01

Modified spot-welding gun includes pivoting twin-collet assembly that holds two spot-welding electrodes. Designed to weld highly conductive (30 percent gold) brazing-alloy foils to thin nickel alloy workpieces; also suitable for other spot-welding applications compatible with two-electrode configuration.

Stress optimization of leaf-spring crossed flexure pivots for an active Gurney flap mechanism

NASA Astrophysics Data System (ADS)

Freire Gómez, Jon; Booker, Julian D.; Mellor, Phil H.

2015-04-01

The EU's Green Rotorcraft programme is pursuing the development of a functional and airworthy Active Gurney Flap (AGF) for a full-scale helicopter rotor blade. Interest in the development of this `smart adaptive rotor blade' technology lies in its potential to provide a number of aerodynamic benefits, which would in turn translate into a reduction in fuel consumption and noise levels. The AGF mechanism selected employs leaf-spring crossed flexure pivots. These provide important advantages over bearings as they are not susceptible to seizing and do not require maintenance (i.e. lubrication or cleaning). A baseline design of this mechanism was successfully tested both in a fatigue rig and in a 2D wind tunnel environment at flight-representative deployment schedules. For full validation, a flight test would also be required. However, the severity of the in-flight loading conditions would likely compromise the mechanical integrity of the pivots' leaf-springs in their current form. This paper investigates the scope for stress reduction through three-dimensional shape optimization of the leaf-springs of a generic crossed flexure pivot. To this end, a procedure combining a linear strain energy formulation, a parametric leaf-spring profile definition and a series of optimization algorithms is employed. The resulting optimized leaf-springs are proven to be not only independent of the angular rotation at which the pivot operates, but also linearly scalable to leaf-springs of any length, minimum thickness and width. Validated using non-linear finite element analysis, the results show very significant stress reductions relative to pivots with constant cross section leaf-springs, of up to as much as 30% for the specific pivot configuration employed in the AGF mechanism. It is concluded that shape optimization offers great potential for reducing stress in crossed flexure pivots and, consequently, for extending their fatigue life and/or rotational range.

TmSR-C, scavenger receptor class C, plays a pivotal role in antifungal and antibacterial immunity in the coleopteran insect Tenebrio molitor.

PubMed

Kim, Soo Gon; Jo, Yong Hun; Seong, Jeong Hwan; Park, Ki Beom; Noh, Mi Young; Cho, Jun Ho; Ko, Hye Jin; Kim, Chang Eun; Tindwa, Hamisi; Patnaik, Bharat Bhusan; Bang, In Seok; Lee, Yong Seok; Han, Yeon Soo

2017-10-01

Scavenger receptors (SRs) constitute a family of membrane-bound receptors that bind to multiple ligands. The SR family of proteins is involved in removing cellular debris, oxidized low-density lipoproteins, and pathogens. Specifically, class C scavenger receptors (SR-C) have also been reported to be involved in phagocytosis of gram-positive and -negative bacteria in Drosophila and viruses in shrimp. However, reports are unavailable regarding the role of SR-C in antifungal immune mechanisms in insects. In this study, a full-length Tenebrio molitor SR-C (TmSR-C) sequence was obtained by 5'- and 3'-Rapid amplification of cDNA ends-polymerase chain reaction (RACE-PCR). The TmSR-C full-length cDNA comprised 1671 bp with 5'- and 3'-untranslated regions of 23- and 107-bp, respectively. TmSR-C encodes a putative protein of 556 amino acid residues that is constitutively expressed in all tissues of late instar larvae and 2-day-old adults, with the highest transcript levels observed in hemocytes of larvae and adults. TmSR-C mRNA showed a 2.5-fold and 3-fold increase at 24 and 6 h after infection with Candida albicans and β-glucan, respectively. Immunoassay with TmSR-C polyclonal antibody showed induction of the putative protein in the cytosols of hemocytes at 3 h after inoculation of C. albicans. RNA interference (RNAi)-based gene silencing and phagocytosis assays were used to understand the role of TmSR-C in antifungal immunity. Silencing of TmSR-C transcripts reduced the survivability of late instar larvae at 2 days post-inoculation of C. albicans, Escherichia coli, or Staphylococcus aureus. Furthermore, in TmSR-C-silenced larvae, there was a decline in the rate of microorganism phagocytosis. Taken together, results of this study suggest that TmSR-C plays a pivotal role in phagocytosing not only fungi but also gram-negative and -positive bacteria in T. molitor. Copyright © 2017. Published by Elsevier Ltd.

Classroom Pivotal Response Teaching for Children with Autism

ERIC Educational Resources Information Center

Stahmer, Aubyn C.; Suhrheinrich, Jessica; Reed, Sarah; Schreibman, Laura; Bolduc, Cynthia

2011-01-01

This practical manual and accompanying DVD-ROM present a research-supported behavioral intervention for children with autism that teachers can easily integrate into their existing classroom curriculum. Classroom Pivotal Response Teaching (CPRT) enhances children's motivation and participation in learning; increases the number of learning…

NEU3 inhibitory effect of naringin suppresses cancer cell growth by attenuation of EGFR signaling through GM3 ganglioside accumulation.

PubMed

Yoshinaga, Ayana; Kajiya, Natsuki; Oishi, Kazuki; Kamada, Yuko; Ikeda, Asami; Chigwechokha, Petros Kingstone; Kibe, Toshiro; Kishida, Michiko; Kishida, Shosei; Komatsu, Masaharu; Shiozaki, Kazuhiro

2016-07-05

Naringin, which is one of the flavonoids contained in citrus fruits, is well known to possess various healthy functions to humans. It has been reported that naringin suppresses cancer cell growth in vitro and in vivo, although the underlying mechanisms are not fully understood. Recently, the roles of glycoconjugates, such as gangliosides, in cancer cells have been focused because of their regulatory effects of malignant phenotypes. Here, to clarify the roles of naringin in the negative-regulation of cancer cell growth, the alteration of glycoconjugates induced by naringin exposure and its significance on cell signaling were investigated. Human cancer cells, HeLa and A549, were exposed to various concentrations of naringin. Naringin treatment induced the suppression of cell growth toward HeLa and A549 cells accompanied with an increase of apoptotic cells. In naringin-exposed cells, GM3 ganglioside was drastically increased compared to the GM3 content prior to the treatment. Furthermore, naringin inhibited NEU3 sialidase, a GM3 degrading glycosidase. Similarly, NEU3 inhibition activities were also detected by other flavanone, such as hesperidin and neohesperidin dihydrocalcone, but their aglycones showed less inhibitions. Naringin-treated cancer cells showed suppressed EGFR and ERK phosphorylation levels. These results suggest a novel mechanism of naringin in the suppression of cancer cell growth through the alteration of glycolipids. NEU3 inhibitory effect of naringin induced GM3 accumulation in HeLa and A549 cells, leading the attenuation of EGFR/ERK signaling accompanied with a decrease in cell growth. Copyright © 2016 Elsevier B.V. All rights reserved.

Lyso-GM2 Ganglioside: A Possible Biomarker of Tay-Sachs Disease and Sandhoff Disease

PubMed Central

Kodama, Takashi; Togawa, Tadayasu; Tsukimura, Takahiro; Kawashima, Ikuo; Matsuoka, Kazuhiko; Kitakaze, Keisuke; Tsuji, Daisuke; Itoh, Kohji; Ishida, Yo-ichi; Suzuki, Minoru; Suzuki, Toshihiro; Sakuraba, Hitoshi

2011-01-01

To find a new biomarker of Tay-Sachs disease and Sandhoff disease. The lyso-GM2 ganglioside (lyso-GM2) levels in the brain and plasma in Sandhoff mice were measured by means of high performance liquid chromatography and the effect of a modified hexosaminidase (Hex) B exhibiting Hex A-like activity was examined. Then, the lyso-GM2 concentrations in human plasma samples were determined. The lyso-GM2 levels in the brain and plasma in Sandhoff mice were apparently increased compared with those in wild-type mice, and they decreased on intracerebroventricular administration of the modified Hex B. The lyso-GM2 levels in plasma of patients with Tay-Sachs disease and Sandhoff disease were increased, and the increase in lyso-GM2 was associated with a decrease in Hex A activity. Lyso-GM2 is expected to be a potential biomarker of Tay-Sachs disease and Sandhoff disease. PMID:22205997

Operational Implications of Pivots of Maneuver,

DTIC Science & Technology

1991-09-05

Offensive from the Second World War , and Douglas MacArthur’s Inchon/Pusan Breakout operations will be examined to aid in the validation of the...different services together ;n a cohesive plan. Significant technological improvenentIS eare m a de du r IrI the Fi rst Worl d War , however i t was...AD-A240 322 ) Operational Implications of Pivots of Maneuver A Monograph by Major Paul C. Jussel Armor DTICS ~FIECTE D SEP 1 21991 D School of

What Strains the Anterior Cruciate Ligament During a Pivot Landing?

PubMed Central

Oh, Youkeun K.; Lipps, David B.; Ashton-Miller, James A.; Wojtys, Edward M.

2015-01-01

Background The relative contributions of an axial tibial torque and frontal plane moment to anterior cruciate ligament (ACL) strain during pivot landings are unknown. Hypothesis The peak normalized relative strain in the anteromedial (AM) bundle of the ACL is affected by the direction of the axial tibial torque but not by the direction of the frontal plane moment applied concurrently during a simulated jump landing. Study Design Controlled and descriptive laboratory studies. Methods Fifteen adult male knees with pretensioned knee muscle-tendon unit forces were loaded under a simulated pivot landing test. Compression, flexion moment, internal or external tibial torque, and knee varus or valgus moment were simultaneously applied to the distal tibia while recording the 3D knee loads and tibiofemoral kinematics. The AM-ACL relative strain was measured using a 3-mm differential variable reluctance transducer. The results were analyzed using nonparametric Wilcoxon signed–rank tests. A 3D dynamic biomechanical knee model was developed using ADAMS and validated to help interpret the experimental results. Results The mean (SD) peak AM-ACL relative strain was 192% greater (P <.001) under the internal tibial torque combined with a knee varus or valgus moment (7.0% [3.9%] and 7.0% [4.1%], respectively) than under external tibial torque with the same moments (2.4% [2.5%] and 2.4% [3.2%], respectively). The knee valgus moment augmented the AM-ACL strain due to the slope of the tibial plateau inducing mechanical coupling (ie, internal tibial rotation and knee valgus moment); this augmentation occurred before medial knee joint space opening. Conclusion An internal tibial torque combined with a knee valgus moment is the worst-case ACL loading condition. However, it is the internal tibial torque that primarily causes large ACL strain. Clinical Relevance Limiting the maximum coefficient of friction between the shoe and playing surface should limit the peak internal tibial torque

Activity-Dependent Calpain Activation Plays a Critical Role in Synaptic Facilitation and Post-Tetanic Potentiation

ERIC Educational Resources Information Center

Khoutorsky, Arkady; Spira, Micha E.

2009-01-01

Synaptic facilitation and post-tetanic potentiation (PTP) are believed to necessitate active regeneration of the release machinery and supply of synaptic vesicles to a ready-releasable site. The prevailing hypothesis assumes that synapsins play pivotal roles in these processes. Using a cholinergic synapse formed between cultured "Aplysia" neurons…

A Funds of Knowledge Approach to Examining Play Interests: Listening to Children's and Parents' Perspectives

ERIC Educational Resources Information Center

Chesworth, Liz

2016-01-01

Children's interests are widely recognised as pivotal to meaningful learning and play in the early years. However, less is known about how children's diverse interests may contribute to relationships and interactions within peer cultures. This article builds upon previous studies to argue that participation in sociocultural activity generates…

Development of confidence limits by pivotal functions for estimating software reliability

NASA Technical Reports Server (NTRS)

Dotson, Kelly J.

1987-01-01

The utility of pivotal functions is established for assessing software reliability. Based on the Moranda geometric de-eutrophication model of reliability growth, confidence limits for attained reliability and prediction limits for the time to the next failure are derived using a pivotal function approach. Asymptotic approximations to the confidence and prediction limits are considered and are shown to be inadequate in cases where only a few bugs are found in the software. Departures from the assumed exponentially distributed interfailure times in the model are also investigated. The effect of these departures is discussed relative to restricting the use of the Moranda model.

Investigation of delayed cracking in pivot steel box girders.

DOT National Transportation Integrated Search

1997-01-01

This report describes the results of an investigation to find the cause of the delayed cracking in the welds of the fracturecritical steel pivot box girders fabricated for the George P. Coleman Bridge. Through the use of different nondestructive meth...

Plant hormone cross-talk: the pivot of root growth.

PubMed

Pacifici, Elena; Polverari, Laura; Sabatini, Sabrina

2015-02-01

Root indeterminate growth and its outstanding ability to produce new tissues continuously make this organ a highly dynamic structure able to respond promptly to external environmental stimuli. Developmental processes therefore need to be finely tuned, and hormonal cross-talk plays a pivotal role in the regulation of root growth. In contrast to what happens in animals, plant development is a post-embryonic process. A pool of stem cells, placed in a niche at the apex of the meristem, is a source of self-renewing cells that provides cells for tissue formation. During the first days post-germination, the meristem reaches its final size as a result of a balance between cell division and cell differentiation. A complex network of interactions between hormonal pathways co-ordinates such developmental inputs. In recent years, by means of molecular and computational approaches, many efforts have been made aiming to define the molecular components of these networks. In this review, we focus our attention on the molecular mechanisms at the basis of hormone cross-talk during root meristem size determination. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis.

PubMed

Lemieux, M Joanne; Mark, Brian L; Cherney, Maia M; Withers, Stephen G; Mahuran, Don J; James, Michael N G

2006-06-16

Lysosomal beta-hexosaminidase A (Hex A) is essential for the degradation of GM2 gangliosides in the central and peripheral nervous system. Accumulation of GM2 leads to severely debilitating neurodegeneration associated with Tay-Sachs disease (TSD), Sandoff disease (SD) and AB variant. Here, we present the X-ray crystallographic structure of Hex A to 2.8 A resolution and the structure of Hex A in complex with NAG-thiazoline, (NGT) to 3.25 A resolution. NGT, a mechanism-based inhibitor, has been shown to act as a chemical chaperone that, to some extent, prevents misfolding of a Hex A mutant associated with adult onset Tay Sachs disease and, as a result, increases the residual activity of Hex A to a level above the critical threshold for disease. The crystal structure of Hex A reveals an alphabeta heterodimer, with each subunit having a functional active site. Only the alpha-subunit active site can hydrolyze GM2 gangliosides due to a flexible loop structure that is removed post-translationally from beta, and to the presence of alphaAsn423 and alphaArg424. The loop structure is involved in binding the GM2 activator protein, while alphaArg424 is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. The beta-subunit lacks these key residues and has betaAsp452 and betaLeu453 in their place; the beta-subunit therefore cleaves only neutral substrates efficiently. Mutations in the alpha-subunit, associated with TSD, and those in the beta-subunit, associated with SD are discussed. The effect of NGT binding in the active site of a mutant Hex A and its effect on protein function is discussed.

18. Detail view of central pivot pier, drive gear rack, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

18. Detail view of central pivot pier, drive gear rack, and stabilizing wheel, looking southwest - India Point Railroad Bridge, Spanning Seekonk River between Providence & East Providence, Providence, Providence County, RI

Detail of plate and gears on center pivot. From civilian ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Detail of plate and gears on center pivot. From civilian land. Looking north. - Naval Supply Annex Stockton, Daggett Road Bridge, Daggett Road traversing Burns Cut Off, Stockton, San Joaquin County, CA

Center pivot, showing substantial beams that support the trusses. Looking ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Center pivot, showing substantial beams that support the trusses. Looking north from civilian land. - Naval Supply Annex Stockton, Daggett Road Bridge, Daggett Road traversing Burns Cut Off, Stockton, San Joaquin County, CA

Analysis of Non-Pivotal Bioequivalence Studies Submitted in Abbreviated New Drug Submissions for Delayed-Release Drug Products.

PubMed

Kaur, Paramjeet; Jiang, Xiaojian; Stier, Ethan

2017-01-01

The US FDA's rule on "Requirements for Submission of Bioequivalence Data" requiring submission of all bioequivalence (BE) studies conducted on the same formulation of the drug product submitted for approval was published in Federal Register in January 2009. With the publication of this rule, we evaluated the impact of data from non-pivotal BE studies in assessing BE and identified the reasons for failed in vivo BE studies for generic oral delayed-release (DR) drug products only. We searched the Agency databases from January 2009 toDecember 2016 to identify Abbreviated New Drug Applications (ANDAs) submitted for DR drug products containing non-pivotal BE studies. Out of 202 ANDAs, 43 ANDAs contained 102 non-pivotal BE studies. Forty-nine non-pivotal BE studies were conducted on the to-be-marketed (TBM) formulation and 53 were conducted on formulations different from the TBM formulation. These experimental formulations primarily differed in the ratio of components of the enteric coating layer and/or amount (i.e., %w/w) of enteric coating layer. Of the 49 non-pivotal BE studies conducted on the TBM formulation, 41 failed to meet the BE acceptance criteria. The majority of failed non-pivotal BE studies on the TBM DR generic products had insufficient power, which was expected as these studies are exploratory in nature and not designed to have adequate power to pass the BE statistical criteria. In addition, among the failed non-pivotal BE studies on the TBM DR generic products, the most commonly failing pharmacokinetic parameter was Cmax. The data from these non-pivotal BE studies indicate that inadequate BE study design can lead to failure of the BE on the same formulation. Also, the non-pivotal BE studies on formulations different from the TBM formulation help us link the formulation design to the product performance in vivo. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue

Reliability of the anterior drawer test, the pivot shift test, and the Lachman test.

PubMed

Kim, S J; Kim, H K

1995-08-01

In 147 patients with arthroscopically proved chronic injuries of the anterior cruciate ligament, the anterior drawer test, the Lachman test, and the pivot shift test were done before operation under general or spinal anesthesia. Results of the anterior drawer test were positive in 79.6% of the patients, in 98.6% patients having the Lachman test, and in 89.8% of patients having the pivot shift test. In 19 cases (12.9%), arthroscopic examination showed reattachment of the proximally torn end of the anterior cruciate ligament to the posterior cruciate ligament. In these cases, results of the anterior drawer test were positive in 13 patients (68.4%), in 17 (89.5%) patients having the Lachman test, and in 12 patients (63.2%) having the pivot shift test. In 15 cases with a false negative pivot shift test, arthroscopy showed blockage of anterior subluxation of the lateral tibial condyle by a partially functioning portion of the anterior cruciate ligament, which was reattached to the posterior cruciate ligament in 7 cases. In 2 cases with a false negative Lachman test, there was firm reattachment of the torn end of the anterior cruciate ligament to the proximal portion of the posterior cruciate ligament combined with a bucket handle tear of the medial meniscus. The Lachman test was most sensitive in diagnosing chronic injuries of the anterior cruciate ligament. The pivot shift test was also sensitive but was influenced by many factors.

Ganglioside GM3 content in skeletal muscles is increased in type 2 but decreased in type 1 diabetes rat models: Implications of glycosphingolipid metabolism in pathophysiology of diabetes.

PubMed

Bozic, Josko; Markotic, Anita; Cikes-Culic, Vedrana; Novak, Anela; Borovac, Josip A; Vucemilovic, Hrvoje; Trgo, Gorana; Ticinovic Kurir, Tina

2018-02-01

Ganglioside GM3 is found in the plasma membrane, where its accumulation attenuates insulin receptor signaling. Considering the role of skeletal muscles in insulin-stimulated glucose uptake, the aim of the present study was to determine the expression of GM3 and its precursors in skeletal muscles of rat models of type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively). Diabetes was induced in male Sprague-Dawley rats by streptozotocin injection (55 mg/kg, i.p., for T1DM induction; 35 mg/kg, i.p., for T2DM induction), followed by feeding of rats with either a normal pellet diet (T1DM) or a high-fat diet (T2DM). Rats were killed 2 weeks after diabetes induction and samples of skeletal muscle were collected. Frozen quadriceps muscle sections were stained with a primary antibody against GM3 (Neu5Ac) and visualized using a secondary antibody coupled with Texas Red. The muscle content of ganglioside GM3 and its precursors was analyzed by high-performance thin-layer chromatography (HPTLC) followed by GM3 immunostaining. Muscle GM3 content was significantly higher in T2DM compared with control rats (P < 0.001). Furthermore, levels of the GM3 precursors ceramide, glucosylceramide, and lactosylceramide were significantly higher in T2DM compared with control rats (P < 0.05), whereas ceramide content was significantly lower in T1DM rats (P < 0.05). The intensity of the GM3 band on HPTLC was significantly higher in T2DM rats (P < 0.001) and significantly lower in T1DM rats (P < 0.05) compared with control. The expression patterns of GM3 ganglioside and its precursors in diabetic rats suggest that the role of glycosphingolipid metabolism may differ between T2DM and T1DM. © 2017 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Determination of kinetic energy applied by center pivot sprinklers

USDA-ARS?s Scientific Manuscript database

The kinetic energy of discrete drops impacting a bare soil surface is generally observed to lead to a drastic reduction in water infiltration rate due to soil surface seal formation. Under center pivot sprinkler irrigation, kinetic energy transferred to the soil prior to crop canopy development can...

Pivotal Teaching Moments in Technology-Intensive Secondary Geometry Classrooms

ERIC Educational Resources Information Center

Cayton, Charity; Hollebrands, Karen; Okumus, Samet; Boehm, Ethan

2017-01-01

This study investigates three teachers' uses of a dynamic geometry program (The Geometer's Sketchpad) in their high school geometry classes over a 2-year period. The researchers examine teachers' actions and questions during pivotal teaching moments to characterize mathematics instruction that utilizes technology. Findings support an association…

Anti-ganglioside antibodies in patients with systemic lupus erythematosus and neurological manifestations.

PubMed

Labrador-Horrillo, M; Martinez-Valle, F; Gallardo, E; Rojas-Garcia, R; Ordi-Ros, J; Vilardell, M

2012-05-01

Anti-ganglioside antibodies (AGA) have been associated with several peripheral neuropathies, such as Miller-Fisher syndrome, Guillain-Barré syndrome and multifocal motor neuropathy. They have also been studied in patients with systemic lupus erythematosus (SLE), focusing on neuropsychiatric manifestations and peripheral neuropathy, but the results are contradictory. To study the presence of AGA in a large cohort of patients with SLE and neuropsychiatric manifestations. Serum from 65 consecutive patients with SLE and neuropsychiatric manifestations, collected from 1985 to 2009, was tested for the presence of AGA antibodies (GM1, GM2, GM3, asialo-GM1 GD1a, GD1b, GD3, GT1b, GQ1b) using a standard enzyme-linked immunosorbent assay ELISA test (INCAT 1999) and thin layer chromatography (TLC). Positive results for asialo-GM1 (IgM) were found in 10 patients, 6 were positive for asialo-GM1 (IgM and IgG), and 4 were positive for other AGA such as GM1, GM2, GM3, GD1b, GT1b, GD3, (mainly IgM). Clinical and statistical studies showed no correlation between AGA and neuropsychiatric manifestations of SLE. Although some patients showed reactivity to AGA, these antibodies are not a useful marker of neuropsychiatric manifestations in SLE patients.

Clinical Outcome of Medial Pivot Compared With Press-Fit Condylar Sigma Cruciate-Retaining Mobile-Bearing Total Knee Arthroplasty.

PubMed

Kim, Young-Hoo; Park, Jang-Won; Kim, Jun-Shik

2017-10-01

The purpose of this study was to compare the long-term clinical results, radiographic results, range of knee motion, patient satisfaction, and the survival rate of Medial-Pivot posterior cruciate-substituting, knee prosthesis and a press-fit condylar (PFC) Sigma cruciate-retaining mobile-bearing knee prosthesis in the same patients. One hundred eighty-two patients received Medial-Pivot knee prosthesis in one knee and a PFC Sigma knee prosthesis in the contralateral knee. The minimum duration of follow-up was 11 years (range, 11-12.6 years). The knees with a Medial-Pivot knee prosthesis had significantly worse results than those with a PFC Sigma knee prosthesis at the final follow-up with regard to the mean postoperative Knee Society knee scores (90 compared with 95 points), Western Ontario and McMaster Universities Osteoarthritis Index score (25 compared with 18 points), and range of knee motion (117° compared with 128°). Patients were more satisfied with PFC Sigma knee prosthesis (93%) than with Medial-Pivot knee prosthesis (75%). Complication rates were significantly higher in the Medial-Pivot knee group (26%) than those in the PFC Sigma knee group (6.5%). Radiographic results and survival rates (99% compared with 99.5%) were similar between the 2 groups. Although the long-term fixation and survival rate of both Medial-Pivot and PFC Sigma prostheses were similar, we observed a worse knee score, worse range of knee motion, and patient satisfaction was less in the Medial-Pivot knee group than in the PFC Sigma knee group. Furthermore, complication rate was also higher in the Medial-Pivot knee group than the other group. Copyright © 2017 Elsevier Inc. All rights reserved.

European Marketing Authorizations Granted Based on a Single Pivotal Clinical Trial: The Rule or the Exception?

PubMed

Morant, Anne Vinther; Vestergaard, Henrik Tang

2018-07-01

A minimum of two positive, adequate, and well-controlled clinical trials has historically been the gold standard for providing substantial evidence to support regulatory approval of a new medicine. Nevertheless, the present analysis of European Marketing Authorizations granted between 2012 and 2016 showed that 45% of new active substances were approved based on a single pivotal clinical trial. For therapeutic areas such as oncology and cardiovascular diseases, approvals based on a single pivotal trial are the rule rather than the exception, whereas new medicines within the nervous system area were generally supported by two or more pivotal trials. While overall similar trends have been observed in the US, the recent US Food and Drug Administration approvals of nervous system medicines based on a single pivotal trial suggest that a case-by-case scientific evaluation of the totality of evidence is increasingly applied to facilitate faster access of new medicines to patients suffering from serious diseases. © 2017 American Society for Clinical Pharmacology and Therapeutics.

A pivotal role for galectin-1 in fetomaternal tolerance.

PubMed

Blois, Sandra M; Ilarregui, Juan M; Tometten, Mareike; Garcia, Mariana; Orsal, Arif S; Cordo-Russo, Rosalia; Toscano, Marta A; Bianco, Germán A; Kobelt, Peter; Handjiski, Bori; Tirado, Irene; Markert, Udo R; Klapp, Burghard F; Poirier, Francoise; Szekeres-Bartho, Julia; Rabinovich, Gabriel A; Arck, Petra C

2007-12-01

A successful pregnancy requires synchronized adaptation of maternal immune-endocrine mechanisms to the fetus. Here we show that galectin-1 (Gal-1), an immunoregulatory glycan-binding protein, has a pivotal role in conferring fetomaternal tolerance. Consistently with a marked decrease in Gal-1 expression during failing pregnancies, Gal-1-deficient (Lgals1-/-) mice showed higher rates of fetal loss compared to wild-type mice in allogeneic matings, whereas fetal survival was unaffected in syngeneic matings. Treatment with recombinant Gal-1 prevented fetal loss and restored tolerance through multiple mechanisms, including the induction of tolerogenic dendritic cells, which in turn promoted the expansion of interleukin-10 (IL-10)-secreting regulatory T cells in vivo. Accordingly, Gal-1's protective effects were abrogated in mice depleted of regulatory T cells or deficient in IL-10. In addition, we provide evidence for synergy between Gal-1 and progesterone in the maintenance of pregnancy. Thus, Gal-1 is a pivotal regulator of fetomaternal tolerance that has potential therapeutic implications in threatened pregnancies.

Estimation of optimal pivot point for remote center of motion alignment in surgery.

PubMed

Rosa, Benoît; Gruijthuijsen, Caspar; Van Cleynenbreugel, Ben; Sloten, Jos Vander; Reynaerts, Dominiek; Poorten, Emmanuel Vander

2015-02-01

The determination of an optimal pivot point ([Formula: see text]) is important for instrument manipulation in minimally invasive surgery. Such knowledge is of particular importance for robotic-assisted surgery where robots need to rotate precisely around a specific point in space in order to minimize trauma to the body wall while maintaining position control. Remote center of motion (RCM) mechanisms are commonly used, where the RCM point is manually and visually aligned. If not positioned appropriately, this misalignment might lead to intolerably high forces on the body wall with increased risk of postoperative complications or instrument damage. An automated method to align the RCM with the [Formula: see text] was developed and tested. Computer vision and a lightweight calibration procedure are used to estimate the optimal pivot point. One or two pre-calibrated cameras viewing the surgical scene are employed. The surgeon is asked to make short pivoting movements, applying as little torque as possible, with an instrument of choice passing through the insertion point while camera images are being recorded. The physical properties of an instrument rotating around a pivot point are exploited in a random sample consensus scheme to robustly estimate the ideal position of the RCM in the image planes. Triangulation is used to estimate the RCM position in 3D. Experiments were performed on a specially designed mockup to test the method. The position of the pivot point is estimated with an average error less than 1.85 mm using two webcams placed from approximately 30 cm to 1 m away from the scene. The entire procedure was completed in a few seconds. In automated method to estimate the ideal position of the RCM was shown to be reliable. The method can be implemented within a visual servoing approach to automatically place the RCM point, or the results can be displayed on a screen to provide guidance to the surgeon. Further work includes the development of an image

N-Dimensional LLL Reduction Algorithm with Pivoted Reflection

PubMed Central

Deng, Zhongliang; Zhu, Di

2018-01-01

The Lenstra-Lenstra-Lovász (LLL) lattice reduction algorithm and many of its variants have been widely used by cryptography, multiple-input-multiple-output (MIMO) communication systems and carrier phase positioning in global navigation satellite system (GNSS) to solve the integer least squares (ILS) problem. In this paper, we propose an n-dimensional LLL reduction algorithm (n-LLL), expanding the Lovász condition in LLL algorithm to n-dimensional space in order to obtain a further reduced basis. We also introduce pivoted Householder reflection into the algorithm to optimize the reduction time. For an m-order positive definite matrix, analysis shows that the n-LLL reduction algorithm will converge within finite steps and always produce better results than the original LLL reduction algorithm with n > 2. The simulations clearly prove that n-LLL is better than the original LLL in reducing the condition number of an ill-conditioned input matrix with 39% improvement on average for typical cases, which can significantly reduce the searching space for solving ILS problem. The simulation results also show that the pivoted reflection has significantly declined the number of swaps in the algorithm by 57%, making n-LLL a more practical reduction algorithm. PMID:29351224

The reactivities of human erythrocyte autoantibodies anti-Pr2, anti-Gd, Fl and Sa with gangliosides in a chromatogram binding assay.

PubMed Central

Uemura, K; Roelcke, D; Nagai, Y; Feizi, T

1984-01-01

The thin layer chromatogram binding assay was used to study the reaction of several natural-monoclonal autoantibodies which recognize sialic acid-dependent antigens of human erythrocytes. Immunostaining of gangliosides derived from human and bovine erythrocytes was achieved with four autoantibodies designated anti-Pr2, anti-Gd, Sa and Fl, each of which has a different haemagglutination pattern with untreated and proteinase-treated erythrocytes and with cells of I and i antigen types. From the chromatogram binding patterns of anti-Pr2 with gangliosides of the neolacto and the ganglio series, it is deduced that this antibody reacts best with N-acetylneuraminic acid when it is alpha 2-3- or alpha 2-6-linked to a terminal Gal(beta 1-4)Glc/GlcNAc GlcNAc sequence and to a lesser extent when it is alpha 2-3-linked to a terminal Gal(beta 1-3)GalNAc sequence or to an internal galactose and when it is alpha 2-8-linked to another, internal N-acetylneuraminic acid residue. The other three antibodies differ from anti-Pr2 in their lack of reaction with glycolipids of the ganglio series. They react with the NeuAc(alpha 2-3)Gal(beta 1-4)Glc/GlcNAc sequence as found in GM3 and in glycolipids of the neolacto series, but show a preference for the latter, longer sequences. Thus all four antibodies react with sialylated oligosaccharides containing i type (linear) and I type (branched) neolacto backbones. Fl antibody differs from the other three in its stronger reaction with branched neolacto sequences in accordance with its stronger agglutination of erythrocytes of I rather than i type. The four antibodies show a specificity for N-acetyl- rather than N-glycolyl-neuraminic acid. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. PMID:6204642

ELECTRIC FURNACES TILT AROUND A PIVOT UNDER THE SPOUT TO ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ELECTRIC FURNACES TILT AROUND A PIVOT UNDER THE SPOUT TO FILL BULL LADLES BELOW THE CHARGING DECK. THE REAR VIEW OF A POURING ELECTRIC FURNACE FROM THE CHARGING DECK IS SHOWN HERE. - Southern Ductile Casting Company, Melting, 2217 Carolina Avenue, Bessemer, Jefferson County, AL

Epidermal growth factor-induced mobilization of a ganglioside-specific sialidase (NEU3) to membrane ruffles

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

Yamaguchi, Kazunori; Hata, Keiko; Wada, Tadashi

2006-07-28

Human ganglioside-specific sialidase, NEU3, localized at cell membranes is thought to regulate various biological processes at cell surfaces. We here explored functional subcellular localization of the sialidase by immunofluorescence and found accumulation at leading edges of cell membranes in the presence of serum in culture. In response to EGF, the sialidase redistributed rapidly to ruffling cell membranes of squamous carcinoma A431 cells and co-localized with Rac-1. NEU3 overexpression enhanced Rac-1 activation and cell migration as compared with controls in HeLa cells as well as in A431 cells. Consistent with co-localization with Rac-1 by immunofluorescence, NEU3 was found to co-precipitate withmore » activated Rac bound to GST-PAK-1 fusion protein. NEU3 silencing by siRNA, in contrast, resulted in inhibition of Rac-1 activation. These results indicate that NEU3 is able to mobilize to membrane ruffles in response to growth stimuli and activate the Rac-1 signaling by co-localization with Rac-1, leading to increased cell motility.« less

Anti-GM2 ganglioside antibodies are a biomarker for acute canine polyradiculoneuritis

PubMed Central

Bianchi, Ezio; Dondi, Maurizio; Penderis, Jacques; Cappell, Joanna; Burgess, Karl; Matiasek, Kaspar; McGonigal, Rhona; Willison, Hugh J.

2016-01-01

Acute canine polyradiculoneuritis (ACP) is considered to be the canine equivalent of the human peripheral nerve disorder Guillain-Barré syndrome (GBS); an aetiological relationship, however, remains to be demonstrated. In GBS, anti-glycolipid antibodies (Abs) are considered as important disease mediators. To address the possibility of common Ab biomarkers, the sera of 25 ACP dogs, 19 non-neurological, and 15 epileptic control dogs were screened for IgG Abs to 10 glycolipids and their 1 : 1 heteromeric complexes using combinatorial glycoarrays. Anti-GM2 ganglioside Abs were detected in 14/25 ACP dogs, and anti-GA1 Abs in one further dog. All controls except for one were negative for anti-glycolipid Abs. In this cohort of cases and controls, the glycoarray screen reached a diagnostic sensitivity of 60% and a specificity of 97%; a lower sensitivity (32%) was reported using a conventional glycolipid ELISA. To address the possible pathogenic role for anti-GM2 Abs in ACP, we identified GM2 in canine sciatic nerve by both mass spectrometry and thin layer chromatography overlay. In immunohistological studies, GM2 was localized predominantly to the abaxonal Schwann cell membrane. The presence of anti-GM2 Abs in ACP suggests that it may share a similar pathophysiology with GBS, for which it could thus be considered a naturally occurring animal model. PMID:23521648

Molecular recognition and colorimetric detection of cholera toxin by poly(diacetylene) liposomes incorporating G{sub m1} ganglioside

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

Pan, J.J.; Charych, D.

1997-03-19

Molecular recognition sites on cell membranes serve as the main communication channels between the inside of a cell and its surroundings. Upon receptor binding, cellular messages such as ion channel opening or activation of enzymes are triggered. In this report, we demonstrate that artificial cell membranes made from conjugated lipid polymers (poly(diacetylene)) can, on a simple level, mimic membrane processes of molecular recognition and signal transduction. The ganglioside GM1 was incorporated into poly(diacetylene) liposomes. Molecular recognition of cholera toxin at the interface of the liposome resulted in a change of the membrane color due to conformational charges in the conjugatedmore » (ene-yne) polymer backbone. The `colored liposomes` might be used as simple colorimetric sensors for drug screening or as new tools to study membrane-membrane or membrane-receptor interactions. 21 refs., 3 figs.« less

Performance evaluation of a center pivot variable rate irrigation system

USDA-ARS?s Scientific Manuscript database

Variable Rate Irrigation (VRI) for center pivots offers potential to match specific application rates to non-uniform soil conditions along the length of the lateral. The benefit of such systems is influenced by the areal extent of these variations and the smallest scale to which the irrigation syste...

Examination of Studies Targeting Social Skills with Pivotal Response Treatment

ERIC Educational Resources Information Center

Bozkus Genc, Gulden; Vuran, Sezgin

2013-01-01

In early education, especially in effective teaching to children with autism spectrum disorders, the teaching methods which are applicable in natural settings like pivotal response treatment (PRT) are commonly used. It is one of the naturalistic intervention models aiming to facilitate the stimulant-response generalization, decrease the dependency…

New insights into muscle function during pivot feeding in seahorses.

PubMed

Van Wassenbergh, Sam; Dries, Billy; Herrel, Anthony

2014-01-01

Seahorses, pipefish and their syngnathiform relatives are considered unique amongst fishes in using elastic recoil of post-cranial tendons to pivot the head extremely quickly towards small crustacean prey. It is known that pipefish activate the epaxial muscles for a considerable time before striking, at which rotations of the head and the hyoid are temporarily prevented to allow energy storage in the epaxial tendons. Here, we studied the motor control of this system in seahorses using electromyographic recordings of the epaxial muscles and the sternohyoideus-hypaxial muscles with simultaneous high-speed video recordings of prey capture. In addition we present the results from a stimulation experiment including the muscle hypothesised to be responsible for the locking and triggering of pivot feeding in seahorses (m. adductor arcus palatini). Our data confirmed that the epaxial pre-activation pattern observed previously for pipefish also occurs in seahorses. Similar to the epaxials, the sternohyoideus-hypaxial muscle complex shows prolonged anticipatory activity. Although a considerable variation in displacements of the mouth via head rotation could be observed, it could not be demonstrated that seahorses have control over strike distance. In addition, we could not identify the source of the kinematic variability in the activation patterns of the associated muscles. Finally, the stimulation experiment supported the previously hypothesized role of the m. adductor arcus palatini as the trigger in this elastic recoil system. Our results show that pre-stressing of both the head elevators and the hyoid retractors is taking place. As pre-activation of the main muscles involved in pivot feeding has now been demonstrated for both seahorses and pipefish, this is probably a generalized trait of Syngnathidae.

New Insights into Muscle Function during Pivot Feeding in Seahorses

PubMed Central

Van Wassenbergh, Sam; Dries, Billy; Herrel, Anthony

2014-01-01

Seahorses, pipefish and their syngnathiform relatives are considered unique amongst fishes in using elastic recoil of post-cranial tendons to pivot the head extremely quickly towards small crustacean prey. It is known that pipefish activate the epaxial muscles for a considerable time before striking, at which rotations of the head and the hyoid are temporarily prevented to allow energy storage in the epaxial tendons. Here, we studied the motor control of this system in seahorses using electromyographic recordings of the epaxial muscles and the sternohyoideus-hypaxial muscles with simultaneous high-speed video recordings of prey capture. In addition we present the results from a stimulation experiment including the muscle hypothesised to be responsible for the locking and triggering of pivot feeding in seahorses (m. adductor arcus palatini). Our data confirmed that the epaxial pre-activation pattern observed previously for pipefish also occurs in seahorses. Similar to the epaxials, the sternohyoideus-hypaxial muscle complex shows prolonged anticipatory activity. Although a considerable variation in displacements of the mouth via head rotation could be observed, it could not be demonstrated that seahorses have control over strike distance. In addition, we could not identify the source of the kinematic variability in the activation patterns of the associated muscles. Finally, the stimulation experiment supported the previously hypothesized role of the m. adductor arcus palatini as the trigger in this elastic recoil system. Our results show that pre-stressing of both the head elevators and the hyoid retractors is taking place. As pre-activation of the main muscles involved in pivot feeding has now been demonstrated for both seahorses and pipefish, this is probably a generalized trait of Syngnathidae. PMID:25271759

US pivotal studies of irinotecan in colorectal carcinoma.

PubMed

Pitot, H C

1998-08-01

Phase I trials of irinotecan (CPT-11 [Camptosar]), conducted at Johns Hopkins and the University of Texas, San Antonio, demonstrated some activity in patients with refractory advanced cancer. Three pivotal phase II studies of irinotecan in advanced colorectal carcinoma were conducted at The University of Texas, San Antonio, Mayo/North Central Cancer Treatment Group (NCCTG), and the CPT-11 Study Group in a total of 304 patients. All patients had received prior fluorouracil (5-FU) chemotherapy, and over 90% had progressed while on treatment within the last 6 months. The initial starting dose of irinotecan ranged from 100 to 150 mg/m2. The overall response rate was 12.8% (95% confidence interval, 9.1% to 16.6%) with a 15% response rate at a recommended starting dose of 125 mg/m2. The response durations and overall median survivals were similar in the three studies. The principal toxicities included diarrhea, nausea, vomiting, and neutropenia. Severe diarrhea was limited by use of an intensive loperamide regimen and appropriate dose modification. The three pivotal studies of irinotecan in advanced colorectal carcinoma demonstrate consistent response rates and duration, with manageable toxicity. Future studies will focus on the use of irinotecan in chemotherapeutically naive colorectal carcinoma, the adjuvant treatment of colon carcinoma, combination chemotherapeutic regimens, and treatment of other malignant diseases.

Re-use of pilot data and interim analysis of pivotal data in MRMC studies: a simulation study

NASA Astrophysics Data System (ADS)

Chen, Weijie; Samuelson, Frank; Sahiner, Berkman; Petrick, Nicholas

2017-03-01

Novel medical imaging devices are often evaluated with multi-reader multi-case (MRMC) studies in which radiologists read images of patient cases for a specified clinical task (e.g., cancer detection). A pilot study is often used to measure the effect size and variance parameters that are necessary for sizing a pivotal study (including sizing readers, non-diseased and diseased cases). Due to the practical difficulty of collecting patient cases or recruiting clinical readers, some investigators attempt to include the pilot data as part of their pivotal study. In other situations, some investigators attempt to perform an interim analysis of their pivotal study data based upon which the sample sizes may be re-estimated. Re-use of the pilot data or interim analyses of the pivotal data may inflate the type I error of the pivotal study. In this work, we use the Roe and Metz model to simulate MRMC data under the null hypothesis (i.e., two devices have equal diagnostic performance) and investigate the type I error rate for several practical designs involving re-use of pilot data or interim analysis of pivotal data. Our preliminary simulation results indicate that, under the simulation conditions we investigated, the inflation of type I error is none or only marginal for some design strategies (e.g., re-use of patient data without re-using readers, and size re-estimation without using the effect-size estimated in the interim analysis). Upon further verifications, these are potentially useful design methods in that they may help make a study less burdensome and have a better chance to succeed without substantial loss of the statistical rigor.

Spatial ET field mapping using sensors mounted on a center pivot

USDA-ARS?s Scientific Manuscript database

Site-specific irrigation management is becoming more important for improving crop water use efficiency and reducing water wastage, especially as competition for quality water resources increases. Continuous geo-referenced canopy temperature measurements using sensors mounted on a center pivot irriga...

Pivotal Response Treatments for Autism: Communication, Social, and Academic Development

ERIC Educational Resources Information Center

Koegel, Robert L.; Kern Koegel, Lynn

2006-01-01

Recognized as one of the top state-of-the-art treatments for autism in the United States, the innovative Pivotal Response Treatment uses natural learning opportunities to target and modify key behaviors in children with autism, leading to widespread positive effects on communication, behavior, and social skills. The product of 20 years of…

Technical match characteristics and influence of body anthropometry on playing performance in male elite team handball.

PubMed

Michalsik, Lars Bojsen; Madsen, Klavs; Aagaard, Per

2015-02-01

Modern team handball match-play imposes substantial physical and technical demands on elite players. However, only limited knowledge seems to exist about the specific working requirements in elite team handball. Thus, the purpose of this study was to examine the physical demands imposed on male elite team handball players in relation to playing position and body anthropometry. Based on continuous video recording of individual players during elite team handball match-play (62 tournament games, ∼4 players per game), computerized technical match analysis was performed in male elite team handball players along with anthropometric measurements over a 6 season time span. Technical match activities were distributed in 6 major types of playing actions (shots, breakthroughs, fast breaks, tackles, technical errors, and defense errors) and further divided into various subcategories (e.g., hard or light tackles, type of shot, claspings, screenings, and blockings). Players showed 36.9 ± 13.1 (group mean ± SD) high-intense technical playing actions per match with a mean total effective playing time of 53.85 ± 5.87 minutes. In offense, each player performed 6.0 ± 5.2 fast breaks, received 34.5 ± 21.3 tackles in total, and performed in defense 3.7 ± 3.5 blockings, 3.9 ± 3.0 claspings, and 5.8 ± 3.6 hard tackles. Wing players (84.5 ± 5.8 kg, 184.9 ± 5.7 cm) were less heavy and smaller (p < 0.001) than backcourt players (94.7 ± 7.1 kg, 191.9 ± 5.4 cm) and pivots (99.4 ± 6.2 kg, 194.8 ± 3.6 cm). In conclusion, modern male elite team handball match-play is characterized by a high number of short-term, high-intense intermittent technical playing actions. Indications of technical fatigue were observed. Physical demands differed between playing positions with wing players performing more fast breaks and less physical confrontations with opponent players than backcourt players and pivots. Body anthropometry seemed to have an important influence on playing performance

Effectiveness of Community-Based Early Intervention Based on Pivotal Response Treatment

ERIC Educational Resources Information Center

Smith, Isabel M.; Flanagan, Helen E.; Garon, Nancy; Bryson, Susan E.

2015-01-01

Preschoolers (n = 118) with autism spectrum disorder (ASD) participated in this prospective effectiveness study of an early intervention program. Treatment entailed parent training and therapist-implemented components, incorporating Pivotal Response Treatment and Positive Behaviour Support. Standardized ability and behavioural measures were…

Ganglioside Composition in Beef, Chicken, Pork, and Fish Determined Using Liquid Chromatography-High-Resolution Mass Spectrometry.

PubMed

Fong, Bertram Y; Ma, Lin; Khor, Geok Lin; van der Does, Yvonne; Rowan, Angela; McJarrow, Paul; MacGibbon, Alastair K H

2016-08-17

Gangliosides (GA) are found in animal tissues and fluids, such as blood and milk. These sialo-glycosphingolipids have bioactivities in neural development, the gastrointestinal tract, and the immune system. In this study, a high-performance liquid chromatography-mass spectrometry (HPLC-MS) method was validated to characterize and quantitate the GA in beef, chicken, pork, and fish species (turbot, snapper, king salmon, and island mackerel). For the first time, we report the concentration of GM3, the dominant GA in these foods, as ranging from 0.35 to 1.1 mg/100 g and 0.70 to 5.86 mg/100 g of meat and fish, respectively. The minor GAs measured were GD3, GD1a, GD1b, and GT1b. Molecular species distribution revealed that the GA contained long- to very-long-chain acyl fatty acids attached to the ceramide moiety. Fish GA contained only N-acetylneuraminic acid (NeuAc) sialic acid, while beef, chicken, and pork contained GD1a/b species that incorporated both NeuAc and N-glycolylneuraminic acid (NeuGc) and hydroxylated fatty acids.

"Palmar pivot flap" for resurfacing palmar lateral defects of the fingers.

PubMed

Yam, Andrew; Peng, Yeong-Pin; Pho, Robert Wan-Heng

2008-12-01

Soft tissue defects on the lateral borders of the digits are difficult to reconstruct using local or local-regional flaps. We describe a "palmar pivot flap" to resurface an adjacent defect on the palmar-lateral aspect of the digit. The surgical technique is described. This flap is an axial pattern flap based on the subcutaneous transverse branches of the digital artery. The flap is pivoted up to 90 degrees on the neurovascular bundle in its base, into an adjacent defect. The flap can be raised from either the proximal or the middle phalangeal segments. It can cover defects sited from the level of the proximal interphalangeal joint up to the fingertip. The donor defect is limited to the same digit and is covered with a full-thickness skin graft. We have used this flap on 3 patients with defects at the middle phalangeal segment, the distal interphalangeal joint, and the fingertip. All healed primarily. One patient had a mild flexion contracture of the proximal interphalangeal joint, whereas the other 2 had no complications. The patients with distal interphalangeal joint and fingertip defects had excellent sensation in the flap (2-point discrimination of 5-6 mm). The palmar pivot flap is useful for resurfacing otherwise difficult defects on the lateral borders of the digits around and distal to the proximal interphalangeal joint, including those at the fingertip. It provides sensate, glabrous skin. The donor defect is on the same digit and is well hidden, producing an aesthetic and functional reconstruction.

Differences in biological maturation, anthropometry and physical performance between playing positions in youth team handball.

PubMed

Matthys, Stijn P J; Fransen, Job; Vaeyens, Roel; Lenoir, Matthieu; Philippaerts, Renaat

2013-01-01

It was the goal of this cross-sectional study to examine differences in maturity, anthropometry and physical performance between youth handball players across different playing positions (i.e. goalkeeper, back, pivot and wing). Multivariate analysis of covariance (MANCOVA), accounting for biological maturation, was used to assess positional differences in 472 male youth handball players from three age groups: U14, U15 and U16. Differences in age at peak height velocity were found in all age groups. Backs were significantly more mature than wings in U14 and U15 and than wings and pivots in U16. Furthermore, backs are overall taller, have a bigger arm span and perform best on tests for strength, agility and speed, especially in the U15 age group. Therefore, it can be concluded that youth players with the most advanced maturation status and the most favourable anthropometry and physical fitness scores, are consistently positioned in the back position. Players with a less advanced maturity status and an overall smaller stature are placed on the wing or pivot positions. In conclusion, it seems that anthropometrical and maturational characteristics are used by coaches to directly and/or indirectly select players for specific field positions. This strategy is risky since anthropometry and maturity status change over the years.

Anti-GM1 ganglioside antibodies modulate membrane-associated sphingomyelin metabolism by altering neutral sphingomyelinase activity.

PubMed

Ueda, Akihiro; Shima, Sayuri; Murate, Kenitiroh; Kikuchi, Kouichi; Nagao, Ryunosuke; Maeda, Toshiki; Muto, Eri; Niimi, Yoshiki; Mizutani, Yasuaki; Mutoh, Tatsuro

2018-06-01

Previous studies have shown that patients with Guillain-Barré syndrome express autoantibodies against ganglioside GM1 (GM1), although its pathogenic significance for the development of the disease remains to be elucidated. nSMase2 is the best characterized neutral sphingomyelinase (nSMase) found in neuronal cells. Activation of this enzyme leads to ceramide production, which is a known second messenger of the cell-death program in neuronal cells. We have explored the effects of anti-GM1 antibodies on sphingomyelin metabolism of PC12 cells stably transfected with human trk cDNA (PCtrk cells) by determining their effects on nSMase2 activity. The data we present here strongly suggest that anti-GM1 caused a significant change in sphingomyelin content of the membrane fraction in PCtrk cells. Both nSMase2 activity and the level of nSMase2 protein were significantly decreased by anti-GM1 treatment of PCtrk cells, while acidic SMase activities remained unchanged. Our results indicate, for the first time, that anti-GM1 may produce profound impacts on lipid metabolism in neuronal cell membranes. Copyright © 2018 Elsevier Inc. All rights reserved.

Anti-GM2 ganglioside antibodies are a biomarker for acute canine polyradiculoneuritis.

PubMed

Rupp, Angie; Galban-Horcajo, Francesc; Bianchi, Ezio; Dondi, Maurizio; Penderis, Jacques; Cappell, Joanna; Burgess, Karl; Matiasek, Kaspar; McGonigal, Rhona; Willison, Hugh J

2013-03-01

Acute canine polyradiculoneuritis (ACP) is considered to be the canine equivalent of the human peripheral nerve disorder Guillain-Barré syndrome (GBS); an aetiological relationship, however, remains to be demonstrated. In GBS, anti-glycolipid antibodies (Abs) are considered as important disease mediators. To address the possibility of common Ab biomarkers, the sera of 25 ACP dogs, 19 non-neurological, and 15 epileptic control dogs were screened for IgG Abs to 10 glycolipids and their 1 : 1 heteromeric complexes using combinatorial glycoarrays. Anti-GM2 ganglioside Abs were detected in 14/25 ACP dogs, and anti-GA1 Abs in one further dog. All controls except for one were negative for anti-glycolipid Abs. In this cohort of cases and controls, the glycoarray screen reached a diagnostic sensitivity of 60% and a specificity of 97%; a lower sensitivity (32%) was reported using a conventional glycolipid ELISA. To address the possible pathogenic role for anti-GM2 Abs in ACP, we identified GM2 in canine sciatic nerve by both mass spectrometry and thin layer chromatography overlay. In immunohistological studies, GM2 was localized predominantly to the abaxonal Schwann cell membrane. The presence of anti-GM2 Abs in ACP suggests that it may share a similar pathophysiology with GBS, for which it could thus be considered a naturally occurring animal model. © 2013 Peripheral Nerve Society.

Self-Balancing, Optical-Center-Pivot, Fast-Steering Mirror

NASA Technical Reports Server (NTRS)

Moore, James D.; Carson, Johnathan W.

2011-01-01

A complete, self-contained fast-steering- mirror (FSM) mechanism is reported consisting of a housing, a mirror and mirror-mounting cell, three PZT (piezoelectric) actuators, and a counterbalance mass. Basically, it is a comparatively stiff, two-axis (tip-tilt), self-balanced FSM. The present invention requires only three (or three pairs for flight redundancy) actuators. If a PZT actuator degrades, the inherent balance remains, and compensation for degraded stroke is made by simply increasing the voltage to the PZT. Prior designs typically do not pivot at the mirror optical center, creating unacceptable beam shear.

Droplet kinetic energy of moving spray-plate center-pivot irrigation sprinklers

USDA-ARS?s Scientific Manuscript database

The kinetic energy of discrete water drops impacting a bare soil surface generally leads to a drastic reduction in water infiltration rate due to formation of a seal on the soil surface. Under center-pivot sprinkler irrigation, kinetic energy transferred to the soil prior to crop canopy development ...

Plant responses, climate pivot points, and trade-offs in water-limited ecosystems

USGS Publications Warehouse

Munson, Seth M.

2013-01-01

Plant species in dryland ecosystems are limited by water availability and may be vulnerable to increases in aridity. Methods are needed to monitor and assess the rate of change in plant abundance and composition in relation to climate, understand the potential for degradation in dryland ecosystems, and forecast future changes in plant species assemblages. I employ nearly a century of vegetation monitoring data from three North American deserts to demonstrate an approach to determine plant species responses to climate and critical points over a range of climatic conditions at which plant species shift from increases to decreases in abundance (climate pivot points). I assess these metrics from a site to regional scale and highlight how these indicators of plant performance can be modified by the physical and biotic environment. For example, shrubs were more responsive to drought and high temperatures on shallow soils with limited capacity to store water and fine-textured soils with slow percolation rates, whereas perennial grasses were more responsive to precipitation in sparse shrublands than in relatively dense grasslands and shrublands, where competition for water is likely more intense. The responses and associated climate pivot points of plant species aligned with their lifespan and structural characteristics, and the relationship between responses and climate pivot points provides evidence of the trade-off between the capacity of a plant species to increase in abundance when water is available and its drought resistance.

Designs and adaptive analysis plans for pivotal clinical trials of therapeutics and companion diagnostics.

PubMed

Simon, Richard

2008-06-01

Developments in genomics and biotechnology provide unprecedented opportunities for the development of effective therapeutics and companion diagnostics for matching the right drug to the right patient. Effective co-development involves many new challenges with increased opportunity for success as well as delay and failure. Clinical trial designs and adaptive analysis plans for the prospective design of pivotal trials of new therapeutics and companion diagnostics are reviewed. Effective co-development requires careful prospective planning of the design and analysis strategy for pivotal clinical trials. Randomized clinical trials continue to be important for evaluating the effectiveness of new treatments, but the target populations for analysis should be prospectively specified based on the companion diagnostic. Post hoc analyses of traditionally designed randomized clinical trials are often deeply problematic. Clear separation is generally required of the data used for developing the diagnostic test, including their threshold of positivity, from the data used for evaluating treatment effectiveness in subsets determined by the test. Adaptive analysis can be used to provide flexibility to the analysis but the use of such methods requires careful planning and prospective definition in order to assure that the pivotal trial adequately limits the chance of erroneous conclusions.

Brief Report: Reduced Restricted and Repetitive Behaviors after Pivotal Response Treatment

ERIC Educational Resources Information Center

Ventola, Pamela E.; Yang, Daniel; Abdullahi, Sebiha M.; Paisley, Courtney A.; Braconnier, Megan L.; Sukhodolsky, Denis G.

2016-01-01

Children with ASD show high frequency of restricted and repetitive behaviors (RRBs); however, higher-order RRBs, such as restricted interests, have remained largely resistant to treatment. This study evaluated change in severity of RRBs following a 16-weeks open trial of Pivotal Response Treatment (PRT). Participants included 15 children with ASD…

Instance Analysis for the Error of Three-pivot Pressure Transducer Static Balancing Method for Hydraulic Turbine Runner

NASA Astrophysics Data System (ADS)

Weng, Hanli; Li, Youping

2017-04-01

The working principle, process device and test procedure of runner static balancing test method by weighting with three-pivot pressure transducers are introduced in this paper. Based on an actual instance of a V hydraulic turbine runner, the error and sensitivity of the three-pivot pressure transducer static balancing method are analysed. Suggestions about improving the accuracy and the application of the method are also proposed.

Origin and characteristics of high Shannon entropy at the pivot of locally stable rotors: insights from computational simulation.

PubMed

Ganesan, Anand N; Kuklik, Pawel; Gharaviri, Ali; Brooks, Anthony; Chapman, Darius; Lau, Dennis H; Roberts-Thomson, Kurt C; Sanders, Prashanthan

2014-01-01

Rotors are postulated to maintain cardiac fibrillation. Despite the importance of bipolar electrograms in clinical electrophysiology, few data exist on the properties of bipolar electrograms at rotor sites. The pivot of a spiral wave is characterized by relative uncertainty of wavefront propagation direction compared to the periphery. The bipolar electrograms used in electrophysiology recording encode information on both direction and timing of approaching wavefronts. To test the hypothesis that bipolar electrograms from the pivot of rotors have higher Shannon entropy (ShEn) than electrograms recorded at the periphery due to the spatial dynamics of spiral waves. We studied spiral wave propagation in 2-dimensional sheets constructed using a simple cell automaton (FitzHugh-Nagumo), atrial (Courtemanche-Ramirez-Nattel) and ventricular (Luo-Rudy) myocyte cell models and in a geometric model spiral wave. In each system, bipolar electrogram recordings were simulated, and Shannon entropy maps constructed as a measure of electrogram information content. ShEn was consistently highest in the pivoting region associated with the phase singularity of the spiral wave. This property was consistently preserved across; (i) variation of model system (ii) alterations in bipolar electrode spacing, (iii) alternative bipolar electrode orientation (iv) bipolar electrogram filtering and (v) in the presence of rotor meander. Directional activation plots demonstrated that the origin of high ShEn at the pivot was the directional diversity of wavefront propagation observed in this location. The pivot of the rotor is consistently associated with high Shannon entropy of bipolar electrograms despite differences in action potential model, bipolar electrode spacing, signal filtering and rotor meander. Maximum ShEn is co-located with the pivot for rotors observed in the bipolar electrogram recording mode, and may be an intrinsic property of spiral wave dynamic behaviour.

Origin and Characteristics of High Shannon Entropy at the Pivot of Locally Stable Rotors: Insights from Computational Simulation

PubMed Central

Gharaviri, Ali; Brooks, Anthony; Chapman, Darius; Lau, Dennis H.; Roberts-Thomson, Kurt C.; Sanders, Prashanthan

2014-01-01

Background Rotors are postulated to maintain cardiac fibrillation. Despite the importance of bipolar electrograms in clinical electrophysiology, few data exist on the properties of bipolar electrograms at rotor sites. The pivot of a spiral wave is characterized by relative uncertainty of wavefront propagation direction compared to the periphery. The bipolar electrograms used in electrophysiology recording encode information on both direction and timing of approaching wavefronts. Objective To test the hypothesis that bipolar electrograms from the pivot of rotors have higher Shannon entropy (ShEn) than electrograms recorded at the periphery due to the spatial dynamics of spiral waves. Methods and Results We studied spiral wave propagation in 2-dimensional sheets constructed using a simple cell automaton (FitzHugh-Nagumo), atrial (Courtemanche-Ramirez-Nattel) and ventricular (Luo-Rudy) myocyte cell models and in a geometric model spiral wave. In each system, bipolar electrogram recordings were simulated, and Shannon entropy maps constructed as a measure of electrogram information content. ShEn was consistently highest in the pivoting region associated with the phase singularity of the spiral wave. This property was consistently preserved across; (i) variation of model system (ii) alterations in bipolar electrode spacing, (iii) alternative bipolar electrode orientation (iv) bipolar electrogram filtering and (v) in the presence of rotor meander. Directional activation plots demonstrated that the origin of high ShEn at the pivot was the directional diversity of wavefront propagation observed in this location. Conclusions The pivot of the rotor is consistently associated with high Shannon entropy of bipolar electrograms despite differences in action potential model, bipolar electrode spacing, signal filtering and rotor meander. Maximum ShEn is co-located with the pivot for rotors observed in the bipolar electrogram recording mode, and may be an intrinsic property of

Cholesterol accelerates the binding of Alzheimer's β-amyloid peptide to ganglioside GM1 through a universal hydrogen-bond-dependent sterol tuning of glycolipid conformation

PubMed Central

Fantini, Jacques; Yahi, Nouara; Garmy, Nicolas

2013-01-01

Age-related alterations of membrane lipids in brain cell membranes together with high blood cholesterol are considered as major risk factors for Alzheimer's disease. Yet the molecular mechanisms by which these factors increase Alzheimer's risk are mostly unknown. In lipid raft domains of the plasma membrane, neurotoxic Alzheimer's beta-amyloid (Abeta) peptides interact with both cholesterol and ganglioside GM1. Recent data also suggested that cholesterol could stimulate the binding of Abeta to GM1 through conformational modulation of the ganglioside headgroup. Here we used a combination of physicochemical and molecular modeling approaches to decipher the mechanisms of cholesterol-assisted binding of Abeta to GM1. With the aim of decoupling the effect of cholesterol on GM1 from direct Abeta-cholesterol interactions, we designed a minimal peptide (Abeta5-16) containing the GM1-binding domain but lacking the amino acid residues involved in cholesterol recognition. Using the Langmuir technique, we showed that cholesterol (but not phosphatidylcholine or sphingomyelin) significantly accelerates the interaction of Abeta5-16 with GM1. Molecular dynamics simulations suggested that Abeta5-16 interacts with a cholesterol-stabilized dimer of GM1. The main structural effect of cholesterol is to establish a hydrogen-bond between its own OH group and the glycosidic-bond linking ceramide to the glycone part of GM1, thereby inducing a tilt in the glycolipid headgroup. This fine conformational tuning stabilizes the active conformation of the GM1 dimer whose headgroups, oriented in two opposite directions, form a chalice-shaped receptacle for Abeta. These data give new mechanistic insights into the stimulatory effect of cholesterol on Abeta/GM1 interactions. They also support the emerging concept that cholesterol is a universal modulator of protein-glycolipid interactions in the broader context of membrane recognition processes. PMID:23772214

Dynamic behavior of air lubricated pivoted-pad journal-bearing, rotor system. 2: Pivot consideration and pad mass

NASA Technical Reports Server (NTRS)

Nemeth, Z. N.

1972-01-01

Rotor bearing dynamic tests were conducted with tilting-pad journal bearings having three different pad masses and two different pivot geometries. The rotor was vertically mounted and supported by two three-pad tilting-pad gas journal bearings and a simple externally pressurized thrust bearing. The bearing pads were 5.1 cm (2.02 in.) in diameter and 2.8 cm (1.5 in.) long. The length to diameter ratio was 0.75. One pad was mounted on a flexible diaphragm. The bearing supply pressure ranged from 0 to 690 kilonewtons per square meter (0 to 100 psig), and speeds ranged to 38,500 rpm. Heavy mass pad tilting-pad assemblies produced three rotor-bearing resonances above the first two rotor critical speeds. Lower supply pressure eliminated the resonances. The resonances were oriented primarily in the direction normal to the diaphragm.

Moving spray-plate center-pivot sprinkler rating index for assessing runoff potential

USDA-ARS?s Scientific Manuscript database

Numerous moving spray-plate center-pivot sprinklers are commercially available providing a range of drop size distributions and wetted diameters. A means to quantitatively compare sprinkler choices in regards to maximizing infiltration and minimizing runoff is currently lacking. The objective of thi...

Method for forming precision clockplate with pivot pins

DOEpatents

Wild, Ronald L [Albuquerque, NM

2010-06-01

Methods are disclosed for producing a precision clockplate with rotational bearing surfaces (e.g. pivot pins). The methods comprise providing an electrically conductive blank, conventionally machining oversize features comprising bearing surfaces into the blank, optionally machining of a relief on non-bearing surfaces, providing wire accesses adjacent to bearing surfaces, threading the wire of an electrical discharge machine through the accesses and finishing the bearing surfaces by wire electrical discharge machining. The methods have been shown to produce bearing surfaces of comparable dimension and tolerances as those produced by micro-machining methods such as LIGA, at reduced cost and complexity.

Communication Avoiding Rank Revealing QR Factorization with Column Pivoting

DTIC Science & Technology

2013-05-03

person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number...ParLab affiliates National Instruments, Nokia , NVIDIA, Oracle, and Samsung, and sup- port from MathWorks. We also acknowledge the support of the US...bounds from equation (1.3). In practice the QR factorization with column pivoting often works well, and it is widely used even if it is known to fail , for

Long-term effect of rituximab in a case with late-onset Rasmussen´s encephalitis with anti-ganglioside IgGQ1b and anti-GAD antibodies positivity. Case Report.

PubMed

Timarova, Gabriela; Lisa, Iveta; Kukumberg, Peter

2016-07-01

Rasmussen's encephalitis is a rare autoimmune encephalitis usually involving one brain hemisphere, presenting with refractory epileptic seizures, and neurological and cognitive decline. Only 10% of cases start later in adolescence/adulthood. The only effective treatment for refractory seizures in childhood is hemispherectomy. For late-onset cases with mild neurological deficit the hemispherectomy is usually postponed because of its severe consequences. Immunotherapy shows some temporal effect for seizure control and slowing the brain atrophy, mainly in late onset Rasmussen's encephalitis. We report a patient with late onset Rasmussen´s encephalitis with anti-ganglioside IgGQ1b and anti-GAD antibodies positivity, who failed immunotherapy with cytostatics, immunoglobulins and steroids. Anti-ganglioside IgGQ1b antibodies are typically associated with a Miller-Fisher variant of Guillain-Barre syndrome and Bickerstaff's brainstem encephalitis. The association with Rasmussen´s encephalitis was not described before. Patient´s neurological deficit was mild and hemispherectomy was refused. The treatment with rituximab, an anti-CD20+ monoclonal antibody, led to 36-month control of seizures without any signs of progression of neurological deficit and MRI brain atrophy. Although the treatment is associated with long term B-cells depletion, patient doesn´t suffer from any clinically relevant infection. The biological treatment with monoclonal antibodies might be the way to stabilize patients with Rasmussen´s encephalitis, mainly late-onset, to prevent them from harmful and devastating hemispherectomy.

Membrane lipids regulate ganglioside GM2 catabolism and GM2 activator protein activity.

PubMed

Anheuser, Susi; Breiden, Bernadette; Schwarzmann, Günter; Sandhoff, Konrad

2015-09-01

Ganglioside GM2 is the major lysosomal storage compound of Tay-Sachs disease. It also accumulates in Niemann-Pick disease types A and B with primary storage of SM and with cholesterol in type C. Reconstitution of GM2 catabolism with β-hexosaminidase A and GM2 activator protein (GM2AP) at uncharged liposomal surfaces carrying GM2 as substrate generated only a physiologically irrelevant catabolic rate, even at pH 4.2. However, incorporation of anionic phospholipids into the GM2 carrying liposomes stimulated GM2 hydrolysis more than 10-fold, while the incorporation of plasma membrane stabilizing lipids (SM and cholesterol) generated a strong inhibition of GM2 hydrolysis, even in the presence of anionic phospholipids. Mobilization of membrane lipids by GM2AP was also inhibited in the presence of cholesterol or SM, as revealed by surface plasmon resonance studies. These lipids also reduced the interliposomal transfer rate of 2-NBD-GM1 by GM2AP, as observed in assays using Förster resonance energy transfer. Our data raise major concerns about the usage of recombinant His-tagged GM2AP compared with untagged protein. The former binds more strongly to anionic GM2-carrying liposomal surfaces, increases GM2 hydrolysis, and accelerates intermembrane transfer of 2-NBD-GM1, but does not mobilize membrane lipids. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

Membrane lipids regulate ganglioside GM2 catabolism and GM2 activator protein activity[S

PubMed Central

Anheuser, Susi; Breiden, Bernadette; Schwarzmann, Günter; Sandhoff, Konrad

2015-01-01

Ganglioside GM2 is the major lysosomal storage compound of Tay-Sachs disease. It also accumulates in Niemann-Pick disease types A and B with primary storage of SM and with cholesterol in type C. Reconstitution of GM2 catabolism with β-hexosaminidase A and GM2 activator protein (GM2AP) at uncharged liposomal surfaces carrying GM2 as substrate generated only a physiologically irrelevant catabolic rate, even at pH 4.2. However, incorporation of anionic phospholipids into the GM2 carrying liposomes stimulated GM2 hydrolysis more than 10-fold, while the incorporation of plasma membrane stabilizing lipids (SM and cholesterol) generated a strong inhibition of GM2 hydrolysis, even in the presence of anionic phospholipids. Mobilization of membrane lipids by GM2AP was also inhibited in the presence of cholesterol or SM, as revealed by surface plasmon resonance studies. These lipids also reduced the interliposomal transfer rate of 2-NBD-GM1 by GM2AP, as observed in assays using Förster resonance energy transfer. Our data raise major concerns about the usage of recombinant His-tagged GM2AP compared with untagged protein. The former binds more strongly to anionic GM2-carrying liposomal surfaces, increases GM2 hydrolysis, and accelerates intermembrane transfer of 2-NBD-GM1, but does not mobilize membrane lipids. PMID:26175473

[Shushu (ancient Chinese numerology) in Lingshu: Gudu (Miraculous Pivot: Bone-Length Measurement)].

PubMed

Zhuo, Lian-Shi

2010-10-01

Lingshu: Gudu (Miraculous Pivot: Bone-Length Measurement) is compared with literatures concerning the Shushu (ancient Chinese numerology) of the Qin Dynasty (221 B. C. - 206 B. C. ) and the Han Dynasty (206 B. C.-220 A. D.) in this article. And it is discovered that "the number of heaven and earth" in Yijing (The Book of Change) was implied in the bone-length measurement. The theory of Shushu is hidden in the sized of head, neck, chest, abdomen, back and 4 extremities according to the measurement. The meaning of establishment of bone-length measurement, which is found to have universality, laid in setting down the measurement of meridians. And it is the origin of the proportional measurement of locating acupoints. Checked with the theory of Shushu, errors in the description of bone-length measurement could also be found in Lingshu: Gudu (Miraculous Pivot: Bone-Length Measurement) of the present edition, which is helpful for the modern study on the measurement.

Lift-Off Performance in Flexure Pivot Pad and Hybrid Bearings

DTIC Science & Technology

2008-12-01

and Dawson, M. P., 1998, "Experience in the Use of Flexure Pivot Tilt Pad Bearings in Boiler Feed Water Pumps ," Proc. of the 15th International...freely. Test Procedure 1) Turn on the pump to buffer water to the test bearing. 2) Turn on air to the air seal that prevents water flowing... Pump Users Symposium, Turbomachinery Laboratory, College Station, Texas, pp. 77-84. [6] Rodriguez, L., 2004, “Experimental Frequency-Dependent

16 CFR Figure 6 to Part 1633 - Burner Assembly Showing Arms and Pivots (Shoulder Screws), in Relation to, Portable Frame...

Code of Federal Regulations, 2010 CFR

2010-01-01

... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Burner Assembly Showing Arms and Pivots (Shoulder Screws), in Relation to, Portable Frame Allowing Burner Height Adjustment 6 Figure 6 to Part 1633... and Pivots (Shoulder Screws), in Relation to, Portable Frame Allowing Burner Height Adjustment...

16 CFR Figure 6 to Part 1633 - Burner Assembly Showing Arms and Pivots (Shoulder Screws), in Relation to, Portable Frame...

Code of Federal Regulations, 2013 CFR

2013-01-01

... 16 Commercial Practices 2 2013-01-01 2013-01-01 false Burner Assembly Showing Arms and Pivots (Shoulder Screws), in Relation to, Portable Frame Allowing Burner Height Adjustment 6 Figure 6 to Part 1633... and Pivots (Shoulder Screws), in Relation to, Portable Frame Allowing Burner Height Adjustment...

16 CFR Figure 6 to Part 1633 - Burner Assembly Showing Arms and Pivots (Shoulder Screws), in Relation to, Portable Frame...

Code of Federal Regulations, 2014 CFR

2014-01-01

... 16 Commercial Practices 2 2014-01-01 2014-01-01 false Burner Assembly Showing Arms and Pivots (Shoulder Screws), in Relation to, Portable Frame Allowing Burner Height Adjustment 6 Figure 6 to Part 1633... and Pivots (Shoulder Screws), in Relation to, Portable Frame Allowing Burner Height Adjustment...

The PRT Pocket Guide: Pivotal Response Treatment for Autism Spectrum Disorders

ERIC Educational Resources Information Center

Koegel, Robert L.; Koegel, Lynn Kern

2012-01-01

What is Pivotal Response Treatment? What's the research behind it, what does it look like in practice, and what are some good examples of how to use it? Now one concise book gives professionals and parents all the basics of the widely used PRT--one of a select group of highly effective, evidence-based treatments for autism. great resource for…

Functional Neuroimaging of Speech Perception during a Pivotal Period in Language Acquisition

ERIC Educational Resources Information Center

Redcay, Elizabeth; Haist, Frank; Courchesne, Eric

2008-01-01

A pivotal period in the development of language occurs in the second year of life, when language comprehension undergoes rapid acceleration. However, the brain bases of these advances remain speculative as there is currently no functional magnetic resonance imaging (fMRI) data from healthy, typically developing toddlers at this age. We…

Participation of the elderly, women, and minorities in pivotal trials supporting 2011-2013 U.S. Food and Drug Administration approvals.

PubMed

Downing, Nicholas S; Shah, Nilay D; Neiman, Joseph H; Aminawung, Jenerius A; Krumholz, Harlan M; Ross, Joseph S

2016-04-14

Pivotal trials, the clinical studies that inform U.S. Food and Drug Administration (FDA) approval decisions, provide the foundational evidence supporting the safety and efficacy of novel therapeutics. We determined the representation of the elderly, women, and patients from racial and ethnic minorities in pivotal trials and whether the FDA is making subgroup efficacy analyses among these subpopulations available to the public. We conducted a cross-sectional study of novel therapeutics approved by the FDA between 2011 and 2013. Using publicly available FDA documents, we collected information on the demographic characteristics of pivotal trial participants (age ≥65 years, sex [male, female], race [white, black, Asian, other], and ethnicity [Hispanic, non-Hispanic]) and determined the availability of subgroup analyses by age, sex, race, and ethnicity. We identified 86 novel therapeutic that were approved by the FDA between 2011 and 2013 for 92 indications on the basis of 206 pivotal trials. The median age of pivotal trial patients was 53.1 years (interquartile range 40.6-60.6), and the mean proportion of patients ≥65 years of age was 28.9 % (95 % CI 23.5-34.4 %). Similar proportions of pivotal trial participants were male (mean 50.3 %, 95 % CI 45.3-55.2 %) and female (mean 49.7 %, 95 % CI 44.7-54.7 %). Most participants were white (mean 79.2 %, 95 % CI 75.9-82.6 %), while the mean proportion of black patients was 7.4 % (95 % CI 5.5-9.3 %), that of Asian patients was 7.4 % (95 % CI 5.2-9.7 %), and that of patients of other races was 5.9 % (95 % CI 4.4-7.5 %). Information about ethnicity was available for only 59.8 % of indications, and where such data were available, the mean proportion of Hispanic participants was 13.3 % (95 % CI 10.3-16.3 %). FDA reviewers performed and made available subgroup efficacy analyses by age, sex, and race for at least one of the pivotal trials used as the basis of approval for over 80 % of indications. Although women are equally

Knee braces can decrease tibial rotation during pivoting that occurs in high demanding activities.

PubMed

Giotis, Dimitrios; Tsiaras, Vasilios; Ristanis, Stavros; Zampeli, Franceska; Mitsionis, Grigoris; Stergiou, Nicholas; Georgoulis, Anastasios D

2011-08-01

The purpose of this study was to investigate whether knee braces could effectively decrease tibial rotation during high demanding activities. Using an in vivo three-dimensional kinematic analysis, 21 physically active, healthy, male subjects were evaluated. Each subject performed two tasks that were used extensively in the literature because they combine increased rotational and translational loads on the knee, (1) descending from a stair and subsequent pivoting and (2) landing from a platform and subsequent pivoting under three conditions: (A) wearing a prophylactic brace (braced), (B) wearing a patellofemoral brace (sleeved), and (C) unbraced condition. In the first task, tibial rotation during the pivoting phase was significantly decreased in the braced condition as compared to the sleeved condition (P = 0.019) and the non-braced condition (P = 0.002). In the second task, the same variable was significantly decreased in the braced condition as compared to the sleeved (P = 0.001) and the unbraced condition (P < 0.001). The sleeved condition also produced significantly decreased tibial rotation with respect to the unbraced condition (P = 0.021). Bracing decreased tibial rotation in activities where increased translational and rotational forces were applied. Because knee braces decreased tibial rotation, they can possibly be used with ACL-reconstructed and ACL-deficient patients to prevent such problems. Case-control study, Level III.

28. VIEW EAST FROM DECKING ON SOUTHWEST CORNER OF PIVOT ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

28. VIEW EAST FROM DECKING ON SOUTHWEST CORNER OF PIVOT PIER, DRIVE SYSTEM FOR SWING-SPAN INCLUDES: (from left to right) ELECTRIC LINE FROM SHORE (bottom left), TRACK AND RAIL ON CONCRETE PIER, ELECTRIC MOTOR, GASOLINE MOTOR, SHAFTS TO WEDGE DRIVE CRANKS, WEDGE DRIVE DRIVE SHAFT, WEDGE DRIVE GEAR BOX, AND (on right) GEARING FOR MANUAL WEDGE DRIVE ACCESSED THROUGH BRIDGE DECK - Tipers Bridge, Spanning Great Wicomico River at State Route 200, Kilmarnock, Lancaster County, VA

The effects of target distance on pivot hip, trunk, pelvis, and kicking leg kinematics in Taekwondo roundhouse kicks.

PubMed

Kim, Jae-Woong; Kwon, Moon-Seok; Yenuga, Sree Sushma; Kwon, Young-Hoooo

2010-06-01

The study purpose was to investigate the effects of target distance on pivot hip, trunk, pelvis, and kicking leg movements in Taekwondo roundhouse kick. Twelve male black-belt holders executed roundhouse kicks for three target distances (Normal, Short, and Long). Linear displacements of the pivot hip and orientation angles of the pelvis, trunk, right thigh, and right shank were obtained through a three-dimensional video motion analysis. Select displacements, distances, peak orientation angles, and angle ranges were compared among the conditions using one-way repeated measure ANOVA (p < 0.05). Several orientation angle variables (posterior tilt range, peak right-tilted position, peak right-rotated position, peak left-rotated position, and left rotation range of the pelvis; peak hyperextended position and peak right-flexed position of the trunk; peak flexed position, flexion range and peak internal-rotated position of the hip) as well as the linear displacements of the pivot hip and the reach significantly changed in response to different target distances. It was concluded that the adjustment to different target distances was mainly accomplished through the pivot hip displacements, hip flexion, and pelvis left rotation. Target distance mainly affected the reach control function of the pelvis and the linear balance function of the trunk.

Insights from a cross-disciplinary seminar: 10 pivotal papers for ecological restoration

Treesearch

Melissa V. Eitzel; Sibyl Diver; Hillary Sardiñas; Lauren M. Hallett; Jessica J. Olson; Adam Romero; Gustavo de L. T. Oliveira; Alex T. Schuknecht; Rob Tidmore; Katharine N. Suding

2011-01-01

Restoration ecology is a deepening and diversifying field with current research incorporating multiple disciplines and infusing long-standing ideas with fresh perspectives. We present a list of 10 recent pivotal papers exemplifying new directions in ecological restoration that were selected by students in a cross-disciplinary graduate seminar at the University of...

Automating variable rate irrigation management prescriptions for center pivots from field data maps

USDA-ARS?s Scientific Manuscript database

Variable rate irrigation (VRI) enables center pivot systems to match irrigation application to non-uniform field needs. This technology has potential to improve application and water-use efficiency while reducing environmental impacts from excess runoff and poor water quality. Proper management of V...

Center pivot mounted infrared sensors: Retrieval of ET and interface with satellite systems

USDA-ARS?s Scientific Manuscript database

Infrared sensors mounted aboard cener pivot irrigation systems can remotely sense the surface temperatures of the crops and soils, which provides important information on crop water status. This can be used for irrigation management and irrigation automation, which can increase crop water productivi...

A ’Multiple Pivoting’ Algorithm for Goal-Interval Programming Formulations.

DTIC Science & Technology

1980-03-01

jotso _P- ,- Research Report CCS 355 A "MULTIPLE PIVOTING" ALGORITHM FOR GOAL-INTERVAL PROGRAMMING FORMULATIONS by R. Armstrong* A. Charnes*W. Cook...J. Godfrey*** March 1980 *The University of Texas at Austin **York University, Downsview, Ontario, Canada ***Washington, DC This research was partly...areas. However, the main direction of goal programing research has been in formulating models instead of seeking procedures that would provide

Morphological Profiles of Playing Positions in Defense and Offense in Professional Men's Handball.

PubMed

Ante, Burger; Nikola, Foretić; Marijana Čavala

2015-07-01

The main scope of the study is concerned with the morphological profiles of playing positions in defense, offense and the combinations of these two phases of the game. Furthermore, study attempted to identify the difference between the morphological profiles of the individual playing positions. Entity sample of the study consist of the 148 players that participated in 45 matches of the World Men's Handball Championship which took place in Croatia in 2009. The study dealt with the differences between playing positions concerning basic morphological characteristics which are due to the selection based on roles and tasks that need to be carried out in each position. Moreover, morphological similarity of playing positions in offense and defense was noticed. It was determined that wing players play dominantly in the position of left back, external players in the position of right and center back whereas pivots participate in the positions of center, back and center forward positions in defense. Morphological profiles of playing positions in defense, offense and in the combination of these two phases of the game were determined. Identical positions on different sides in offense (left-right wing player, left-right back player) have shown that these positions are quite similar when it comes to morphological profile and playing position in defense. It can be concluded that some playing positions in offense are accompanied by the respective positions in defense. All positions are characterized by one or two morphological profiles.

Detail of middle panel at pivot pier and above the ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Detail of middle panel at pivot pier and above the two (2) center supports. The middle panel chords (not shown) were made strong enough to provide for the full bending moment with the span open and arms swinging. The middle posts support the operator's house. When closed, the bridge acts as two (2) separate simple spans, except a small amount of negative bending is accommodated due to a continuous condition. - Bridgeport Swing Span Bridge, Spanning Tennessee River, Bridgeport, Jackson County, AL

Characterizing droplet kinetic energy applied by moving spray-plate center pivot irrigation sprinklers

USDA-ARS?s Scientific Manuscript database

The kinetic energy of discrete drops impacting a bare soil surface is generally observed to lead to a drastic reduction in water infiltration rate due to soil surface seal formation. Under center pivot sprinkler irrigation, kinetic energy transferred to the soil prior to crop canopy development can...

Pivot design in bileaflet valves.

PubMed

Vallana, F; Rinaldi, S; Galletti, P M; Nguyen, A; Piwnica, A

1992-01-01

The design criteria leading to the development of a new bileaflet valve (Sorin Bicarbon) were derived from the analysis of functional requirements, the performance of existing prostheses, and the availability of an advanced carbon coating technology (Carbofilm). The hinge is the critical element affecting fluid dynamics, durability, and thrombus formation in bileaflet valves. A comparative study of three existing models led to a new hinge design that was based on coupling two spheric surfaces with different radii of curvature (leaflet pivot and hinge recess) and obtained by electroerosion into a Carbofilm-coated metallic housing. In this valve, the point of contact moves continuously by rolling, not sliding. This minimizes friction and wear and allows uninterrupted washing of the blood exposed surfaces even during diastole (a finding established in patients using transesophageal echocardiography). Tricuspid implantation without anticoagulation in 33 sheep did not lead to thrombotic events (follow-up, 40-400 days). In the first 36 clinical implants observed for 15 months (mitral position, size 29; two unrelated deaths), the mean diastolic gradient by echo Doppler was 4 +/- 1.25 mmHg; the functional area was 3.2 +/- 0.6 cm2. No leaflet fracture and no thrombotic or embolic complications were observed clinically using a standard anticoagulant regimen.

Critical current scaling and the pivot-point in Nb3Sn strands

NASA Astrophysics Data System (ADS)

Tsui, Y.; Hampshire, D. P.

2012-05-01

Detailed measurements are provided of the engineering critical current density (Jc) and the index of transition (n-value) of two different types of advanced ITER Nb3Sn superconducting strand for fusion applications. The samples consist of one internal-tin strand (OST) and two bronze-route strands (BEAS I and BEAS II—reacted using different heat treatments). Tests on different sections of these wires show that prior to applying strain, Jc is homogeneous to better than 2% along the length of each strand. Jc data have been characterized as a function of magnetic field (B ≤ 14.5 T), temperature (4.2 K ≤ T ≤ 12 K) and applied axial strain ( - 1% ≤ ɛA ≤ 0.8%). Strain-cycling tests demonstrate that the variable strain Jc data are reversible to better than 2% when the applied axial strain is in the range of - 1% ≤ ɛA ≤ 0.5%. The wires are damaged when the intrinsic strain (ɛI) is ɛI ≥ 0.55% and ɛI ≥ 0.23% for the OST and BEAS strands, respectively. The strain dependences of the normalized Jc for each type of strand are similar to those of prototype strands of similar design measured in 2005 and 2008 to about 2% which makes them candidate strands for a round-robin interlaboratory comparison. The Jc data are described by Durham, ITER and Josephson-junction parameterizations to an accuracy of about 4%. For all of these scaling laws, the percentage difference between the data and the parameterization is larger when Jc is small, caused by high B, T or |ɛI|. The n-values can be described by a modified power law of the form n=1+r{I}_{{c}}^{s}, where r and s are approximately constant and Ic is the critical current. It has long been known that pivot-points (or cross-overs) in Jc occur at high magnetic field and temperature. Changing the magnetic field or temperature from one side of the pivot-point to the other changes the highest Jc sample to the lowest Jc sample and vice versa. The pivot-point follows the B-T phase boundary associated with the upper

16 CFR Figure 6 to Part 1633 - Burner Assembly Showing Arms and Pivots (Shoulder Screws) in Relation to Portable Frame Allowing...

Code of Federal Regulations, 2011 CFR

2011-01-01

... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Burner Assembly Showing Arms and Pivots (Shoulder Screws) in Relation to Portable Frame Allowing Burner Height Adjustment 6 Figure 6 to Part 1633... and Pivots (Shoulder Screws) in Relation to Portable Frame Allowing Burner Height Adjustment ER15MR06...

16 CFR Figure 6 to Part 1633 - Burner Assembly Showing Arms and Pivots (Shoulder Screws) in Relation to, Portable Frame Allowing...

Code of Federal Regulations, 2012 CFR

2012-01-01

... 16 Commercial Practices 2 2012-01-01 2012-01-01 false Burner Assembly Showing Arms and Pivots (Shoulder Screws) in Relation to, Portable Frame Allowing Burner Height Adjustment 6 Figure 6 to Part 1633... and Pivots (Shoulder Screws) in Relation to, Portable Frame Allowing Burner Height Adjustment ER15MR06...

Closeup view under the track at the center/pivot pier showing ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close-up view under the track at the center/pivot pier showing the system of distributing girders which transfer all the load of the swing span, both dead, live load, wind, etc., onto the circular drum, thence to the rim bearing 40 20-inch diameter wheels. Note: The track timber ties supported on the bottom truss chord of the swing span truss. - Bridgeport Swing Span Bridge, Spanning Tennessee River, Bridgeport, Jackson County, AL

Advances in understanding the renin-angiotensin-aldosterone system (RAAS) in blood pressure control and recent pivotal trials of RAAS blockade in heart failure and diabetic nephropathy.

PubMed

Ghazi, Lama; Drawz, Paul

2017-01-01

The renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in the physiology of blood pressure control and the pathophysiology of hypertension (HTN) with effects on vascular tone, sodium retention, oxidative stress, fibrosis, sympathetic tone, and inflammation. Fortunately, RAAS blocking agents have been available to treat HTN since the 1970s and newer medications are being developed. In this review, we will (1) examine new anti-hypertensive medications affecting the RAAS, (2) evaluate recent studies that help provide a better understanding of which patients may be more likely to benefit from RAAS blockade, and (3) review three recent pivotal randomized trials that involve newer RAAS blocking agents and inform clinical practice.

A Generalized Pivotal Quantity Approach to Analytical Method Validation Based on Total Error.

PubMed

Yang, Harry; Zhang, Jianchun

2015-01-01

The primary purpose of method validation is to demonstrate that the method is fit for its intended use. Traditionally, an analytical method is deemed valid if its performance characteristics such as accuracy and precision are shown to meet prespecified acceptance criteria. However, these acceptance criteria are not directly related to the method's intended purpose, which is usually a gurantee that a high percentage of the test results of future samples will be close to their true values. Alternate "fit for purpose" acceptance criteria based on the concept of total error have been increasingly used. Such criteria allow for assessing method validity, taking into account the relationship between accuracy and precision. Although several statistical test methods have been proposed in literature to test the "fit for purpose" hypothesis, the majority of the methods are not designed to protect the risk of accepting unsuitable methods, thus having the potential to cause uncontrolled consumer's risk. In this paper, we propose a test method based on generalized pivotal quantity inference. Through simulation studies, the performance of the method is compared to five existing approaches. The results show that both the new method and the method based on β-content tolerance interval with a confidence level of 90%, hereafter referred to as the β-content (0.9) method, control Type I error and thus consumer's risk, while the other existing methods do not. It is further demonstrated that the generalized pivotal quantity method is less conservative than the β-content (0.9) method when the analytical methods are biased, whereas it is more conservative when the analytical methods are unbiased. Therefore, selection of either the generalized pivotal quantity or β-content (0.9) method for an analytical method validation depends on the accuracy of the analytical method. It is also shown that the generalized pivotal quantity method has better asymptotic properties than all of the current

Genetically engineered humanized anti-ganglioside GM2 antibody against multiple organ metastasis produced by GM2-expressing small-cell lung cancer cells.

PubMed

Yamada, Tadaaki; Bando, Hideaki; Takeuchi, Shinji; Kita, Kenji; Li, Qi; Wang, Wei; Akinaga, Shiro; Nishioka, Yasuhiko; Sone, Saburo; Yano, Seiji

2011-12-01

Small-cell lung cancer (SCLC) grows rapidly and metastasizes to multiple organs. We examined the antimetastatic effects of the humanized anti-ganglioside GM2 (GM2) antibodies, BIW-8962 and KM8927, compared with the chimeric antibody KM966, in a SCID mouse model of multiple organ metastases induced by GM2-expressing SCLC cells. BIW-8962 and KM8927 induced higher antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity than KM966 against the GM2-expressing SCLC cell line SBC-3 in vitro. These humanized antibodies inhibited the production of multiple organ metastases, increased the number of apoptotic cells, and prolonged the survival of the SCID mice. Histological analyses using clinical specimens showed that SCLC cells expressed GM2. These findings suggest that humanized anti-GM2 antibodies could be therapeutically useful for controlling multiple organ metastases of GM2-expressing SCLC. © 2011 Japanese Cancer Association.

Child Demographics Associated with Outcomes in a Community-Based Pivotal Response Training Program

ERIC Educational Resources Information Center

Baker-Ericzen, Mary J.; Stahmer, Aubyn C.; Burns, Amelia

2007-01-01

Although knowledge about the efficacy of treatments such as pivotal response training (PRT) for children with autism is increasing, studies of large-scale effectiveness for and transportability to diverse community populations are needed. The current study provides a large-scale preliminary assessment of (a) the effectiveness of a community-based…

Integration of wireless sensor networks into automatic irrigation scheduling of a center pivot

USDA-ARS?s Scientific Manuscript database

A six-span center pivot system was used as a platform for testing two wireless sensor networks (WSN) of infrared thermometers. The cropped field was a semi-circle, divided into six pie shaped sections of which three were irrigated manually and three were irrigated automatically based on the time tem...

Automated generation of massive image knowledge collections using Microsoft Live Labs Pivot to promote neuroimaging and translational research.

PubMed

Viangteeravat, Teeradache; Anyanwu, Matthew N; Ra Nagisetty, Venkateswara; Kuscu, Emin

2011-07-15

Massive datasets comprising high-resolution images, generated in neuro-imaging studies and in clinical imaging research, are increasingly challenging our ability to analyze, share, and filter such images in clinical and basic translational research. Pivot collection exploratory analysis provides each user the ability to fully interact with the massive amounts of visual data to fully facilitate sufficient sorting, flexibility and speed to fluidly access, explore or analyze the massive image data sets of high-resolution images and their associated meta information, such as neuro-imaging databases from the Allen Brain Atlas. It is used in clustering, filtering, data sharing and classifying of the visual data into various deep zoom levels and meta information categories to detect the underlying hidden pattern within the data set that has been used. We deployed prototype Pivot collections using the Linux CentOS running on the Apache web server. We also tested the prototype Pivot collections on other operating systems like Windows (the most common variants) and UNIX, etc. It is demonstrated that the approach yields very good results when compared with other approaches used by some researchers for generation, creation, and clustering of massive image collections such as the coronal and horizontal sections of the mouse brain from the Allen Brain Atlas. Pivot visual analytics was used to analyze a prototype of dataset Dab2 co-expressed genes from the Allen Brain Atlas. The metadata along with high-resolution images were automatically extracted using the Allen Brain Atlas API. It is then used to identify the hidden information based on the various categories and conditions applied by using options generated from automated collection. A metadata category like chromosome, as well as data for individual cases like sex, age, and plan attributes of a particular gene, is used to filter, sort and to determine if there exist other genes with a similar characteristics to Dab2. And

Automated generation of massive image knowledge collections using Microsoft Live Labs Pivot to promote neuroimaging and translational research

PubMed Central

2011-01-01

Background Massive datasets comprising high-resolution images, generated in neuro-imaging studies and in clinical imaging research, are increasingly challenging our ability to analyze, share, and filter such images in clinical and basic translational research. Pivot collection exploratory analysis provides each user the ability to fully interact with the massive amounts of visual data to fully facilitate sufficient sorting, flexibility and speed to fluidly access, explore or analyze the massive image data sets of high-resolution images and their associated meta information, such as neuro-imaging databases from the Allen Brain Atlas. It is used in clustering, filtering, data sharing and classifying of the visual data into various deep zoom levels and meta information categories to detect the underlying hidden pattern within the data set that has been used. Method We deployed prototype Pivot collections using the Linux CentOS running on the Apache web server. We also tested the prototype Pivot collections on other operating systems like Windows (the most common variants) and UNIX, etc. It is demonstrated that the approach yields very good results when compared with other approaches used by some researchers for generation, creation, and clustering of massive image collections such as the coronal and horizontal sections of the mouse brain from the Allen Brain Atlas. Results Pivot visual analytics was used to analyze a prototype of dataset Dab2 co-expressed genes from the Allen Brain Atlas. The metadata along with high-resolution images were automatically extracted using the Allen Brain Atlas API. It is then used to identify the hidden information based on the various categories and conditions applied by using options generated from automated collection. A metadata category like chromosome, as well as data for individual cases like sex, age, and plan attributes of a particular gene, is used to filter, sort and to determine if there exist other genes with a similar

An approach to evaluate capacitance, capacitive reactance and resistance of pivoted pads of a thrust bearing

NASA Astrophysics Data System (ADS)

Prashad, Har

1992-07-01

A theoretical approach is developed for determining the capacitance and active resistance between the interacting surfaces of pivoted pads and thrust collar, under different conditions of operation. It is shown that resistance and capacitive reactance of a thrust bearing decrease with the number of pads times the values of these parameters for an individual pad, and that capacitance increases with the number of pads times the capacitance of an individual pad. The analysis presented has a potential to diagnose the behavior of pivoted pad thrust bearings with the angle of tilt and the ratio of film thickness at the leading to trailing edge, by determining the variation of capacitance, resistance, and capacitive reactance.

Section 504 and Student Health Problems: The Pivotal Position of the School Nurse

ERIC Educational Resources Information Center

Zirkel, Perry A.; Granthom, Margarita Fernan; Lovato, Leanna

2012-01-01

News reports illustrate controversies between parents and schools in response to student health problems. Today's school nurse is in a pivotal position for the avoidance and resolution of disputes not only by increasing awareness of student health conditions but also by having a working knowledge of legal developments under Section 504 and its…

A space efficient flexible pivot selection approach to evaluate determinant and inverse of a matrix.

PubMed

Jafree, Hafsa Athar; Imtiaz, Muhammad; Inayatullah, Syed; Khan, Fozia Hanif; Nizami, Tajuddin

2014-01-01

This paper presents new simple approaches for evaluating determinant and inverse of a matrix. The choice of pivot selection has been kept arbitrary thus they reduce the error while solving an ill conditioned system. Computation of determinant of a matrix has been made more efficient by saving unnecessary data storage and also by reducing the order of the matrix at each iteration, while dictionary notation [1] has been incorporated for computing the matrix inverse thereby saving unnecessary calculations. These algorithms are highly class room oriented, easy to use and implemented by students. By taking the advantage of flexibility in pivot selection, one may easily avoid development of the fractions by most. Unlike the matrix inversion method [2] and [3], the presented algorithms obviate the use of permutations and inverse permutations.

Comparison of treatment effect sizes from pivotal and postapproval trials of novel therapeutics approved by the FDA based on surrogate markers of disease: a meta-epidemiological study.

PubMed

Wallach, Joshua D; Ciani, Oriana; Pease, Alison M; Gonsalves, Gregg S; Krumholz, Harlan M; Taylor, Rod S; Ross, Joseph S

2018-03-21

The U.S. Food and Drug Administration (FDA) often approves new drugs based on trials that use surrogate markers for endpoints, which involve certain trade-offs and may risk making erroneous inferences about the medical product's actual clinical effect. This study aims to compare the treatment effects among pivotal trials supporting FDA approval of novel therapeutics based on surrogate markers of disease with those observed among postapproval trials for the same indication. We searched Drugs@FDA and PubMed to identify published randomized superiority design pivotal trials for all novel drugs initially approved by the FDA between 2005 and 2012 based on surrogate markers as primary endpoints and published postapproval trials using the same surrogate markers or patient-relevant outcomes as endpoints. Summary ratio of odds ratios (RORs) and difference between standardized mean differences (dSMDs) were used to quantify the average difference in treatment effects between pivotal and matched postapproval trials. Between 2005 and 2012, the FDA approved 88 novel drugs for 90 indications based on one or multiple pivotal trials using surrogate markers of disease. Of these, 27 novel drugs for 27 indications were approved based on pivotal trials using surrogate markers as primary endpoints that could be matched to at least one postapproval trial, for a total of 43 matches. For nine (75.0%) of the 12 matches using the same non-continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than postapproval trials. On average, treatment effects were 50% higher (more beneficial) in the pivotal than the postapproval trials (ROR 1.5; 95% confidence interval CI 1.01-2.23). For 17 (54.8%) of the 31 matches using the same continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than the postapproval trials. On average, there was no difference in treatment effects between pivotal and postapproval trials (dSMDs 0.01; 95

Is the posterior cruciate ligament necessary for medial pivot knee prostheses with regard to postoperative kinematics?

PubMed

Fang, Chao-Hua; Chang, Chia-Ming; Lai, Yu-Shu; Chen, Wen-Chuan; Song, Da-Yong; McClean, Colin J; Kao, Hao-Yuan; Qu, Tie-Bing; Cheng, Cheng-Kung

2015-11-01

Excellent clinical and kinematical performance is commonly reported after medial pivot knee arthroplasty. However, there is conflicting evidence as to whether the posterior cruciate ligament should be retained. This study simulated how the posterior cruciate ligament, post-cam mechanism and medial tibial insert morphology may affect postoperative kinematics. After the computational intact knee model was validated according to the motion of a normal knee, four TKA models were built based on a medial pivot prosthesis; PS type, modified PS type, CR type with PCL retained and CR type with PCL sacrificed. Anteroposterior translation and axial rotation of femoral condyles on the tibia during 0°-135° knee flexion were analyzed. There was no significant difference in kinematics between the intact knee model and reported data for a normal knee. In all TKA models, normal motion was almost fully restored, except for the CR type with PCL sacrificed. Sacrificing the PCL produced paradoxical anterior femoral translation and tibial external rotation during full flexion. Either the posterior cruciate ligament or post-cam mechanism is necessary for medial pivot prostheses to regain normal kinematics after total knee arthroplasty. The morphology of medial tibial insert was also shown to produce a small but noticeable effect on knee kinematics. V.

Combined reconstruction of the anterior cruciate ligament associated with anterolateral tenodesis effectively controls the acceleration of the tibia during the pivot shift.

PubMed

Hardy, Alexandre; Casabianca, Laurent; Hardy, Edouard; Grimaud, Olivier; Meyer, Alain

2017-04-01

The pivot shift test is quantified subjectively during assessment of patients presenting with suspected Anterior Cruciate Ligament (ACL) tears and has a low interobserver reproducibility. The Kinematic Rapid Assessment (KiRA) is a triaxial accelerometer that makes it possible to non-invasively quantify tibial acceleration during the pivot shift test. Abolishing pivot shift is considered to be a key element in surgical reconstruction but is incomplete in 25-38% of patients. Patients were included prospectively. Inclusion criteria were patients requiring ACL reconstruction associated with at least one of the following factors corresponding to the patient who have a high risk of rupture either by their sports activity, a failure case, or the notion of important rotational laxity: the patient practiced a competitive pivot-contact sport, revision ACL reconstruction (besides STG (semitendinosus-gracilis graft) repair), subjective explosive rotational laxity, Segond fracture, and TELOS value of >10 mm. Standardized pre- and postoperative pivot shift tests were immediately performed under anesthesia in both knees. Forty-three patients were included. Mean preoperative variations in tibial acceleration in the healthy and injured knees were 1.2 ± 0.1 and 2.7 ± 0.3 m/s 2 , respectively, p < 0.01. A statistically significant decrease in immediate postoperative mean variations in acceleration in the injured knee occurred: 1.5 ± 0.3 m/s 2 , p < 0.01. There was no longer any statistical difference between postoperative contralateral healthy knees and operated knees (n.s). Combined ACL reconstruction associated with anterolateral tenodesis suppress acute pathologic tibial acceleration in the pivot shift. III.

GM1 ganglioside counteracts cholinergic and behavioral deficits induced in the rat by intracerebral injection of vincristine.

PubMed

Di Patre, P L; Abbamondi, A; Bartolini, L; Pepeu, G

1989-03-14

The intracerebroventricular injection of 0.5 mg of vincristine sulphate in adult male Wistar rats caused within 11 days the impairment of motor and reflexive behavior, evaluated by the elevated platform and hanging wire tests, a decrease in food consumption and loss of body weight, a 45% decrease in hippocampal choline acetyltransferase (ChAT) activity and a 35% decrease in the rate of high-affinity choline uptake (HACU) in the injected side. The latter effects are due to the death of neurons in the respective hemiseptum. Intrafimbrial injection of vincristine caused the same decrease in ChAT activity without behavioral alterations. Daily i.p. administration of GM1 ganglioside, beginning immediately after the vincristine injection, prevented dose dependently the decrease in ChAT activity and HACU rate. Prevention was complete with the 60 mg/kg dose. The same dose was equally active on ChAT activity when given s.c. but was inactive p.o. The ChAT decrease was also prevented when GM1 treatment began 5 days after vincristine. GM1 60 mg/kg i.p. also reduced the behavioral toxicity of vincristine. The possibility that GM1 might prevent vincristine toxicity by antagonizing its disruption of neurofilaments and axonal flow is discussed.

Design charts for arbitrarily pivoted, liquid-lubricated flat-sector-pad thrust bearing

NASA Technical Reports Server (NTRS)

Etsion, I.

1977-01-01

A flat, sector-shaped geometry for a liquid-lubricated thrust bearing is analyzed considering both the pitch and roll of the pad. Results are presented in design charts that enable a direct approach to the design of point- and line-pivoted, tilting pad bearings. A comparison is made with the Mitchell bearing approximation and it is found that this approximation always overestimates load capacity.

Pivots for Pointing: Visually-Monitored Pointing Has Higher Arm Elevations than Pointing Blindfolded

ERIC Educational Resources Information Center

Wnuczko, Marta; Kennedy, John M.

2011-01-01

Observers pointing to a target viewed directly may elevate their fingertip close to the line of sight. However, pointing blindfolded, after viewing the target, they may pivot lower, from the shoulder, aligning the arm with the target as if reaching to the target. Indeed, in Experiment 1 participants elevated their arms more in visually monitored…

Complement Factor H and Simian Virus 40 bind the GM1 ganglioside in distinct conformations.

PubMed

Blaum, Bärbel S; Frank, Martin; Walker, Ross C; Neu, Ursula; Stehle, Thilo

2016-05-01

Mammalian cell surfaces are decorated with a variety of glycan chains that orchestrate development and defense and are exploited by pathogens for cellular attachment and entry. While glycosidic linkages are, in principle, flexible, the conformational space that a given glycan can sample is subject to spatial and electrostatic restrictions imposed by its overall chemical structure. Here, we show how the glycan moiety of the GM1 ganglioside, a branched, monosialylated pentasaccharide that serves as a ligand for various proteins, undergoes differential conformational selection in its interactions with different lectins. Using STD NMR and X-ray crystallography, we found that the innate immune regulator complement Factor H (FH) binds a previously not reported GM1 conformation that is not compatible with the GM1-binding sites of other structurally characterized GM1-binding lectins such as the Simian Virus 40 (SV40) capsid. Molecular dynamics simulations of the free glycan in explicit solvent on the 10 μs timescale reveal that the FH-bound conformation nevertheless corresponds to a minimum in the Gibbs free energy plot. In contrast to the GM1 conformation recognized by SV40, the FH-bound GM1 conformation is associated with poor NOE restraints, explaining how it escaped(1)H-(1)H NOE-restrained modeling in the past and highlighting the necessity for ensemble representations of glycan structures. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Novel and successful free comments method for sensory characterization of chocolate ice cream: A comparative study between pivot profile and comment analysis.

PubMed

Fonseca, Fernando G A; Esmerino, Erick A; Filho, Elson R Tavares; Ferraz, Juliana P; da Cruz, Adriano G; Bolini, Helena M A

2016-05-01

Rapid sensory profiling methods have gained space in the sensory evaluation field. Techniques using direct analysis of the terms generated by consumers are considered easy to perform, without specific training requirements, thus improving knowledge about consumer perceptions on various products. This study aimed to determine the sensory profile of different commercial samples of chocolate ice cream, labeled as conventional and light or diet, using the "comment analysis" and "pivot profile" methods, based on consumers' perceptions. In the comment analysis task, consumers responded to 2 separate open questions describing the sensory attributes they liked or disliked in each sample. In the pivot profile method, samples were served in pairs (consisting of a coded sample and pivot), and consumers indicated the higher and lower intensity attributes in the target sample compared with the pivot. We observed that both methods were able to characterize the different chocolate ice cream samples using consumer perception, with high correlation results and configurational similarity (regression vector coefficient=0.917) between them. However, it is worth emphasizing that comment analysis is performed intuitively by consumers, whereas the pivot profile method showed high analytical and discriminative power even using consumers, proving to be a promising technique for routine application when classical descriptive methods cannot be used. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

The Pivot to Asia: Can It Serve as the Foundation for American Grand Strategy in the 21st Century

DTIC Science & Technology

in which the Obama Administration cannot make a definitive choice in favor of one of these schools of thought, it has opted for a policy of hedging...also discusses the problems that the Obama Administration has been forced to confront in other placese.g., Ukraine, Libya, Syria, etc.that have...complicated its efforts to keep its focus on the pivot strategy in the IAP region. He concludes with some lessons for strategists, derived from the Obama teams experience with the pivot.

Pivotal Response Treatment for Children with Autism: Core Principles and Applications for School Psychologists

ERIC Educational Resources Information Center

Renshaw, Tyler L.; Kuriakose, Sarah

2011-01-01

During the past 2 decades, pivotal response treatment (PRT) has emerged as an evidence-based methodology for intervening with the behavioral, communicative, social, and academic impairments of children with autism. Unlike other highly structured behavioral interventions for autism, PRT emphasizes principles over procedures and focuses on enhancing…

Early outcome of TKA with a medial pivot fixed-bearing prosthesis is worse than with a PFC mobile-bearing prosthesis.

PubMed

Kim, Young-Hoo; Yoon, Sung-Hwan; Kim, Jun-Shik

2009-02-01

Although the design features of the Medial Pivot fixed-bearing prosthesis reportedly improve kinematics compared with TKAs using fixed-bearings, clinical improvements have not been reported. We asked whether the clinical and radiographic outcomes, ranges of motion of the knee, patient satisfaction, and complication rates would be better in knees with a Medial Pivot fixed-bearing prosthesis than in those with a PFC Sigma mobile-bearing prosthesis. We compared the results of 92 patients who had a Medial Pivot fixed-bearing prosthesis implanted in one knee and a PFC Sigma mobile-bearing prosthesis implanted in the other. There were 85 women and seven men with a mean age of 69.5 years (range, 55-81 years). The minimum followup was 2 years (mean, 2.6 years; range, 2-3 years). The patients were assessed clinically and radiographically using the rating systems of the Hospital for Special Surgery and the Knee Society at 3 months, 1 year, and annually thereafter. Contrary to expectations, we found worse early clinical outcomes, smaller ranges of knee motion, less patient satisfaction, and a higher complication rate for the Medial Pivot fixed-bearing prosthesis than for the PFC Sigma mobile-bearing prosthesis. Level I, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Satisfactory results at 8 years mean follow-up after ADVANCE® medial-pivot total knee arthroplasty.

PubMed

Chinzei, Nobuaki; Ishida, Kazunari; Tsumura, Nobuhiro; Matsumoto, Tomoyuki; Kitagawa, Atsushi; Iguchi, Tetsuhiro; Nishida, Kotaro; Akisue, Toshihiro; Kuroda, Ryosuke; Kurosaka, Masahiro

2014-03-01

Although good overall results have been reported with TKA, certain problems and limitations remain, primarily due to postoperative differences in joint kinematics, when compared with the normal knee. ADVANCE® Medial-Pivot TKA involves replicating the medial pivoting behavior observed in normal knees. Here, we aimed to investigate the clinical and radiological results and complications of TKA using this implant, at mid-term follow-up. From January 2001 to March 2012, we retrospectively selected 76 patients (85 knees; mean age at operation, 70.2±8.1 years; range, 51-88 years) with a mean follow-up period of 93.1±14.3 months (range, 72-132 months). Indications for TKA included primary degenerative osteoarthritis (60 knees), rheumatoid arthritis (22 knees), osteonecrosis (two knees), and osteoarthritis following high tibial osteotomy (one knee). The clinical and radiographic results were evaluated. Kaplan-Meier survivorship analysis indicated a success rate of 98.3% (95% confidence interval, 96.6-99.9%). Comparison of pre- and postoperative knee extension angles and ranges of motion showed significant improvement postoperatively, in both the Knee Society Scores (KSS) and Knee Society Functional Scores (KSFS) (p<0.05). In one case, radiographic assessment indicated implant loosening due to infection; however, despite this complication, significant improvement of postoperative varus or valgus deformity angles were noted in all cases (p<0.05). Patients undergoing ADVANCE® Medial-Pivot TKA achieved excellent clinical and radiographic results without any implant-related failures at mid-term follow-up. Level IV. © 2013.

Neural Mechanisms of Improvements in Social Motivation after Pivotal Response Treatment: Two Case Studies

ERIC Educational Resources Information Center

Voos, Avery C.; Pelphrey, Kevin A.; Tirrell, Jonathan; Bolling, Danielle Z.; Vander Wyk, Brent; Kaiser, Martha D.; McPartland, James C.; Volkmar, Fred R.; Ventola, Pamela

2013-01-01

Pivotal response treatment (PRT) is an empirically validated behavioral treatment that has widespread positive effects on communication, behavior, and social skills in young children with autism spectrum disorder (ASD). For the first time, functional magnetic resonance imaging was used to identify the neural correlates of successful response to…

Advances in understanding the renin-angiotensin-aldosterone system (RAAS) in blood pressure control and recent pivotal trials of RAAS blockade in heart failure and diabetic nephropathy

PubMed Central

Ghazi, Lama; Drawz, Paul

2017-01-01

The renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in the physiology of blood pressure control and the pathophysiology of hypertension (HTN) with effects on vascular tone, sodium retention, oxidative stress, fibrosis, sympathetic tone, and inflammation. Fortunately, RAAS blocking agents have been available to treat HTN since the 1970s and newer medications are being developed. In this review, we will (1) examine new anti-hypertensive medications affecting the RAAS, (2) evaluate recent studies that help provide a better understanding of which patients may be more likely to benefit from RAAS blockade, and (3) review three recent pivotal randomized trials that involve newer RAAS blocking agents and inform clinical practice. PMID:28413612

P-glycoprotein binds to ezrin at amino acid residues 149-242 in the FERM domain and plays a key role in the multidrug resistance of human osteosarcoma.

PubMed

Brambilla, Daria; Zamboni, Silvia; Federici, Cristina; Lugini, Luana; Lozupone, Francesco; De Milito, Angelo; Cecchetti, Serena; Cianfriglia, Maurizio; Fais, Stefano

2012-06-15

Overexpression of the mdr1 gene encoding P-glycoprotein (Pgp) exerts a major role in reducing the effectiveness of cytotoxic therapy in osteosarcoma. The interaction between actin and Pgp has been shown to be instrumental in the establishment of multidrug resistance (MDR) in human tumor cells. The cytoskeleton linker ezrin exerts a pivotal role in maintaining the functional connection between actin and Pgp. We investigated the role of ezrin in a human multidrug-resistant osteosarcoma cell line overexpressing Pgp and compared it to its counterpart that overexpresses an ezrin deletion mutant. The results showed that Pgp binds at amino acid residues 149-242 of the N-terminal domain of ezrin. The interaction between ezrin and Pgp occurs in the plasma membrane of MDR cells, where they also co-localize with the ganglioside G(M1) located in lipid rafts. The overexpression of the ezrin deletion mutant entirely restored drug susceptibility of osteosarcoma cells, consistent with Pgp dislocation to cytoplasmic compartments and abrogation of G(M1) /Pgp co-localization at the plasma membrane. Our study provides evidence that ezrin exerts a key role in MDR of human osteosarcoma cells through a Pgp-ezrin-actin connection that is instrumental for the permanence of Pgp into plasma membrane lipid rafts. We also show for the first time that Pgp-binding site is localized to amino acid residues 149-242 of the ezrin Band 4.1, Ezrin/Radixin/Moesin (FERM) domain, thus proposing a specific target for future molecular therapy aimed at counteracting MDR in osteosarcoma patients. Copyright © 2011 UICC.

Some anthropologic characteristics of elite female handball players at different playing positions.

PubMed

Rogulj, Nenad; Srhoj, Vatromir; Nazor, Mirjana; Srhoj, Ljerka; Cavala, Marijana

2005-12-01

Differences in motor and psychologic variables according to playing positions were analyzed in a sample of 53 elite female handball players, members of junior and senior national team. Motor status included 8 variables for assessment of explosive strength of landing and throwing, agility, speed strength, movement frequency, and flexibility. Psychologic status was analyzed through 4 dimensions according to Eysenck: extroversion, psychotic behavior, neurotic behavior, and lie. The anthropologic features analyzed showed statistically significant differences. Considering motor abilities, differences were recorded in the variables for assessment of speed strength, agility and leg movement frequency, where wings predominated, whereas goalkeepers showed predominance in flexibility. In psychologic status, differences were present in the variable for assessment of extroversion, which was most pronounced in wings, whereas psychotic behavior was more expressed in those at pivot position. The differences were primarily consequential to the selection of players of a specific anthropologic profile for particular playing positions. The hypothesis of the impact of kinesiologic specificities of a particular playing position on the formation of the players' anthropologic profile should be scientifically tested. Study results may found application in training and contest practice, especially in forming anthropologic models for particular positions during the process of player selection.

A pivotal role of BEX1 in liver progenitor cell expansion in mice.

PubMed

Gu, Yuting; Wei, Weiting; Cheng, Yiji; Wan, Bing; Ding, Xinyuan; Wang, Hui; Zhang, Yanyun; Jin, Min

2018-06-15

The activation and expansion of bipotent liver progenitor cells (LPCs) are indispensable for liver regeneration after severe or chronic liver injury. However, the underlying molecular mechanisms regulating LPCs and LPC-mediated liver regeneration remain elusive. Hepatic brain-expressed X-linked 1 (BEX1) expression was evaluated using microarray screening, real-time polymerase chain reaction, immunoblotting and immunofluorescence. LPC activation and liver injury were studied following a choline-deficient, ethionine-supplemented (CDE) diet in wild-type (WT) and Bex1 -/- mice. Proliferation, apoptosis, colony formation and hepatic differentiation were examined in LPCs from WT and Bex1 -/- mice. Peroxisome proliferator-activated receptor gamma was detected in Bex1-deficient LPCs and mouse livers, and was silenced to analyse the expansion of LPCs from WT and Bex1 -/- mice. Hepatic BEX1 expression was increased during CDE diet-induced liver injury and was highly elevated primarily in LPCs. Bex1 -/- mice fed a CDE diet displayed impaired LPC expansion and liver regeneration. Bex1 deficiency inhibited LPC proliferation and enhanced LPC apoptosis in vitro. Additionally, Bex1 deficiency inhibited the colony formation of LPCs but had no effect on their hepatic differentiation. Mechanistically, BEX1 inhibited peroxisome proliferator-activated receptor gamma to promote LPC expansion. Our findings indicate that BEX1 plays a pivotal role in LPC activation and expansion during liver regeneration, potentially providing novel targets for liver regeneration and chronic liver disease therapies.

GM1 ganglioside in Parkinson's disease: Pilot study of effects on dopamine transporter binding.

PubMed

Schneider, Jay S; Cambi, Franca; Gollomp, Stephen M; Kuwabara, Hiroto; Brašić, James R; Leiby, Benjamin; Sendek, Stephanie; Wong, Dean F

2015-09-15

GM1 ganglioside has been suggested as a treatment for Parkinson's disease (PD), potentially having symptomatic and disease modifying effects. The current pilot imaging study was performed to examine effects of GM1 on dopamine transporter binding, as a surrogate measure of disease progression, studied longitudinally. Positron emission tomography (PET) imaging data were obtained from a subset of subjects enrolled in a delayed start clinical trial of GM1 in PD [1]: 15 Early-start (ES) subjects, 14 Delayed-start (DS) subjects, and 11 Comparison (standard-of-care) subjects. Treatment subjects were studied over a 2.5 year period while Comparison subjects were studied over 2 years. Dynamic PET scans were performed over 90 min following injection of [(11)C]methylphenidate. Regional values of binding potential (BPND) were analyzed for several striatal volumes of interest. Clinical results for this subset of subjects were similar to those previously reported for the larger study group. ES subjects showed early symptomatic improvement and slow symptom progression over the study period. DS and Comparison subjects were initially on the same symptom progression trajectory but diverged once DS subjects received GM1 treatment. Imaging results showed significant slowing of BPND loss in several striatal regions in GM1-treated subjects and in some cases, an increased BPND in some striatal regions was detected after GM1 use. Results of this pilot imaging study provide additional data to suggest a potential disease modifying effect of GM1 on PD. These results need to be confirmed in a larger number of subjects. Copyright © 2015 Elsevier B.V. All rights reserved.

Chronic hyperglicemia and nitric oxide bioavailability play a pivotal role in pro-atherogenic vascular modifications

PubMed Central

De Filippis, Elena Anna

2007-01-01

Diabetes is associated with accelerated atherosclerosis and macrovascular complications are a major cause of morbidity and mortality in this disease. Although our understanding of vascular pathology has lately greatly improved, the mechanism(s) underlying enhanced atherosclerosis in diabetes remain unclear. Endothelial cell dysfunction is emerging as a key component in the pathophysiology of cardiovascular abnormalities associated with diabetes. Although it has been established that endothelium plays a critical role in overall homeostasis of the vessels, vascular smooth muscle cells (vSMC) in the arterial intima have a relevant part in the development of atherosclerosis in diabetes. However, high glucose induced alterations in vSMC behaviour are not fully characterized. Several studies have reported that impaired nitric oxide (NO) synthesis and/or actions are often present in diabetes and endothelial dysfunction. Furthermore, although endothelial cells are by far the main site of vascular NO synthesis, vSMC do express nitric oxyde synthases (NOSs) and NO synthesis in vSMC might be important in vessel’s function. Although it is known that vSMC contribute to vascular pathology in diabetes by their change from a quiescent state to an activated proliferative and migratory phenotype (termed phenotypic modulation), whether this altered phenotypic modulation might also involve alterations in the nitrergic systems is still controversial. Our recent data indicate that, in vivo, chronic hyperglycemia might induce an increased number of vSMC proliferative clones which persist in culture and are associated with increased eNOS expression and activity. However, upregulation of eNOS and increased NO synthesis occur in the presence of a marked concomitant increase of O2− production. Since NO bioavailabilty might not be increased in high glucose stimulated vSMC, it is tempting to hypothesize that the proliferative phenotype observed in cells from diabetic rats is associated

Pivotal Response Treatment for Infants At-Risk for Autism Spectrum Disorders: A Pilot Study

ERIC Educational Resources Information Center

Steiner, Amanda Mossman; Gengoux, Grace W.; Klin, Ami; Chawarska, Katarzyna

2013-01-01

Presently there is limited research to suggest efficacious interventions for infants at-risk for autism. Pivotal response treatment (PRT) has empirical support for use with preschool children with autism, but there are no reports in the literature utilizing this approach with infants. In the current study, a developmental adaptation of PRT was…

Effects of an Off-Axis Pivoting Elliptical Training Program on Gait Function in Persons With Spastic Cerebral Palsy: A Preliminary Study.

PubMed

Tsai, Liang-Ching; Ren, Yupeng; Gaebler-Spira, Deborah J; Revivo, Gadi A; Zhang, Li-Qun

2017-07-01

This preliminary study examined the effects of off-axis elliptical training on reducing transverse-plane gait deviations and improving gait function in 8 individuals with cerebral palsy (CP) (15.5 ± 4.1 years) who completed an training program using a custom-made elliptical trainer that allows transverse-plane pivoting of the footplates during exercise. Lower-extremity off-axis control during elliptical exercise was evaluated by quantifying the root-mean-square and maximal angular displacement of the footplate pivoting angle. Lower-extremity pivoting strength was assessed. Gait function and balance were evaluated using 10-m walk test, 6-minute-walk test, and Pediatric Balance Scale. Toe-in angles during gait were quantified. Participants with CP demonstrated a significant decrease in the pivoting angle (root mean square and maximal angular displacement; effect size, 1.00-2.00) and increase in the lower-extremity pivoting strength (effect size = 0.91-1.09) after training. Reduced 10-m walk test time (11.9 ± 3.7 seconds vs. 10.8 ± 3.0 seconds; P = 0.004; effect size = 1.46), increased Pediatric Balance Scale score (43.6 ± 12.9 vs. 45.6 ± 10.8; P = 0.042; effect size = 0.79), and decreased toe-in angle (3.7 ± 10.5 degrees vs. 0.7 ± 11.7 degrees; P = 0.011; effect size = 1.22) were observed after training. We present an intervention to challenge lower-extremity off-axis control during a weight-bearing and functional activity for individuals with CP. Our preliminary findings suggest that this intervention was effective in enhancing off-axis control, gait function, and balance and reducing in-toeing gait in persons with CP.

On play and playing.

PubMed

Rudan, Dusko

2013-12-01

The paper offers a review of the development of the concept of play and playing. The true beginnings of the development of the theories of play are set as late as in the 19th century. It is difficult to define play as such; it may much more easily be defined through its antipode--work. In the beginning, play used to be connected with education; it was not before Freud's theory of psychoanalysis and Piaget's developmental psychology that the importance of play in a child's development began to be explained in more detail. The paper further tackles the role of play in the adult age. Detailed attention is paid to psychodynamic and psychoanalytic authors, in particular D. W. Winnicott and his understanding of playing in the intermediary (transitional) empirical or experiential space. In other words, playing occupies a space and time of its own. The neuroscientific concept of playing is also tackled, in the connection with development as well.

Circular buffer strips in center pivot irrigation for multiple benefits in the Southern Great Plains

USDA-ARS?s Scientific Manuscript database

The Ogallala Aquifer has converted the Southern Great Plains from a dust bowl to a highly productive agricultural region in the US. However, over exploitation of the aquifer is threatening sustainability of irrigated agriculture in the region. Partial pivots, where high water using conventional crop...

Acinetobacter baumannii universal stress protein A plays a pivotal role in stress response and is essential for pneumonia and sepsis pathogenesis.

PubMed

Elhosseiny, Noha M; Amin, Magdy A; Yassin, Aymen S; Attia, Ahmed S

2015-01-01

Acinetobacter baumannii is one of the most significant threats to global public health. This threat is compounded by the fact that A. baumannii is rapidly becoming resistant to all relevant antimicrobials. Identifying key microbial factors through which A. baumannii resists hostile host environment is paramount to the development of novel antimicrobials targeting infections caused by this emerging pathogen. An attractive target could be a molecule that plays a role in the pathogenesis and stress response of A. baumannii. Accordingly, the universal stress protein A (UspA) was chosen to be fully investigated in this study. A platform of A. baumannii constructs, expressing various levels of the uspA gene ranging from zero to thirteen folds of wild-type level, and a recombinant E. coli strain, were employed to investigate the role of UspA in vitro stress and in vivo pathogenesis. The UspA protein plays a significant role in protecting A. baumannii from H(2)O(2), low pH, and the respiratory toxin 2,4-DNP. A. baumannii UspA protein plays an essential role in two of the deadliest types of infection caused by A. baumannii; pneumonia and sepsis. This distinguishes A. baumannii UspA from its closely related homolog, the Staphylococcus aureus Usp2, as well as from the less similar Burkholderia glumae Usps. Heterologous and overexpression experiments suggest that UspA mediates its role via an indirect mechanism. Our study highlights the role of UspA as an important contributor to the A. baumannii stress and virulence machineries, and polishes it as a plausible target for new therapeutics. Copyright © 2014 Elsevier GmbH. All rights reserved.

Pivotal factors concerned in design of acupuncture clinical research: From two articles in JAMA.

PubMed

Wu, Jia-Ni; Qin, Zong-Shi; Liu, Zhi-Shun

2017-11-01

Two randomized controlled trials of acupuncture concerning polycystic ovary syndrome (PCOS) and stress urinary incontinence (SUI) were published simultaneously in the 24th issue, 2017 of The Journal of the American Medical Association (JAMA). A trial involving PCOS indicated that active acupuncture did not increase live birth compared with sham acupuncture; meanwhile, another trial referring to SUI showed that electroacupuncture resulted in less urine leakage compared with sham electroacupuncture. With an eye to the negative and positive results of acupuncture, three pivotal factors should be contemplated: (1) proper illness for acupuncture, that is, a problem need to be solved in current medical science, and acupuncture may really work for it; (2) proper pre-studied primary outcome, which is better be objective and repeatedly measurable to reveal the therapeutic effect of acupuncture truly and objectively; (3) proper sham control, which can blind the patients to the upmost extent with minimal biological effects. Through the publication of clinical trials of acupuncture in high-impact journals in recent years, researchers should have confidence in their clinical trials by pondering over these three pivotal factors.

Guilford Courthouse: A Pivotal Battle in the War for Independence. Teaching with Historic Places.

ERIC Educational Resources Information Center

Baker, Thomas E.

The backwoods county seat of Guilford Courthouse, North Carolina, was the site of a pivotal battle on March 15, 1781, in the Revolutionary War's decisive southern campaign. The engagement set the stage for the region's liberation from enemy occupation and impelled British general Lord Charles Cornwallis to take the ill-fated road that led him to…

A pivot mutation impedes reverse evolution across an adaptive landscape for drug resistance in Plasmodium vivax.

PubMed

Ogbunugafor, C Brandon; Hartl, Daniel

2016-01-25

The study of reverse evolution from resistant to susceptible phenotypes can reveal constraints on biological evolution, a topic for which evolutionary theory has relatively few general principles. The public health catastrophe of antimicrobial resistance in malaria has brought these constraints on evolution into a practical realm, with one proposed solution: withdrawing anti-malarial medication use in high resistance settings, built on the assumption that reverse evolution occurs readily enough that populations of pathogens may revert to their susceptible states. While past studies have suggested limits to reverse evolution, there have been few attempts to properly dissect its mechanistic constraints. Growth rates were determined from empirical data on the growth and resistance from a set of combinatorially complete set of mutants of a resistance protein (dihydrofolate reductase) in Plasmodium vivax, to construct reverse evolution trajectories. The fitness effects of individual mutations were calculated as a function of drug environment, revealing the magnitude of epistatic interactions between mutations and genetic backgrounds. Evolution across the landscape was simulated in two settings: starting from the population fixed for the quadruple mutant, and from a polymorphic population evenly distributed between double mutants. A single mutation of large effect (S117N) serves as a pivot point for evolution to high resistance regions of the landscape. Through epistatic interactions with other mutations, this pivot creates an epistatic ratchet against reverse evolution towards the wild type ancestor, even in environments where the wild type is the most fit of all genotypes. This pivot mutation underlies the directional bias in evolution across the landscape, where evolution towards the ancestor is precluded across all examined drug concentrations from various starting points in the landscape. The presence of pivot mutations can dictate dynamics of evolution across

Large Scale Dissemination and Community Implementation of Pivotal Response Treatment: Program Description and Preliminary Data

ERIC Educational Resources Information Center

Bryson, Susan E.; Koegel, Lynn K.; Koegel, Robert L.; Openden, Daniel; Smith, Isabel M.; Nefdt, Nicolette

2007-01-01

This paper describes a collaborative effort aimed at province-wide dissemination and implementation of pivotal response treatment (PRT) for young children with autism spectrum disorder (ASD) in Nova Scotia, Canada. Three critical components of the associated training model are described: (1) direct training of treatment teams (parents, one-to-one…

Triple-axis common-pivot arm wrist device for manipulative applications

NASA Technical Reports Server (NTRS)

Kersten, L.; Johnston, J. D.

1980-01-01

A concept in manipulator development to overcome the 'weak wrist syndrome', a triple-axis common-pivot arm wrist (TACPAW), is presented. It contains torque motors for actuation, tachometers for measuring rate, and resolvers for position measurements. Furthermore, it provides three degrees of freedom, i.e., pitch, yaw, and roll, in a single manipulator joint. The advantages of this development are increased strength, compactness, and simplification of controls. Designed to be compatible with the protoflight manipulator arm, the joints of TACPAW are back-driveable with + or - 45 deg rotation in pitch, + or - 45 deg in yaw and continuous roll in either direction while delivering 20.5 N-m (15 ft-lb) torque in each of the three movements.

Tropical grasslands: A pivotal place for a more multi-functional agriculture.

PubMed

Boval, Maryline; Angeon, Valérie; Rudel, Tom

2017-02-01

Tropical grasslands represent a pivotal arena for the sustainable intensification of agriculture in the coming decades. The abundant ecosystem services provided by the grasslands, coupled with the aversion to further forest destruction, makes sustainable intensification of tropical grasslands a high policy priority. In this article, we provide an inventory of agricultural initiatives that would contribute to the sustainable intensification of the tropical grassland agro-ecosystem, and we recommend a shift in the scientific priorities of animal scientists that would contribute to realization of a more agro-ecological and multi-functional agriculture in the world's tropical grasslands.

LU Factorization with Partial Pivoting for a Multi-CPU, Multi-GPU Shared Memory System

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

Kurzak, Jakub; Luszczek, Pitior; Faverge, Mathieu

2012-03-01

LU factorization with partial pivoting is a canonical numerical procedure and the main component of the High Performance LINPACK benchmark. This article presents an implementation of the algorithm for a hybrid, shared memory, system with standard CPU cores and GPU accelerators. Performance in excess of one TeraFLOPS is achieved using four AMD Magny Cours CPUs and four NVIDIA Fermi GPUs.

Selective Intracellular Delivery of Ganglioside GM3-Binding Peptide through Caveolae/Raft-Mediated Endocytosis.

PubMed

Matsubara, Teruhiko; Otani, Ryohei; Yamashita, Miki; Maeno, Haruka; Nodono, Hanae; Sato, Toshinori

2017-02-13

Glycosphingolipids are major components of the membrane raft, and several kinds of viruses and bacterial toxins are known to bind to glycosphingolipids in the membrane raft. Since the viral genes and pathogenic proteins that are taken into cells are directly delivered to their target organelles, caveolae/raft-mediated endocytosis represents a promising pathway for specific delivery. In the present study, we demonstrated the ability of an artificial pentadecapeptide, which binds to ganglioside GM3, to deliver protein into cells by caveolae/raft-mediated endocytosis. The cellular uptake of a biotinylated GM3-binding peptide (GM3BP)-avidin complex into HeLa cells was observed, and the cellular uptake of this complex was inhibited by an incubation with sialic acid or endocytic inhibitors such as methyl-ß-cyclodextrin, and also by an incubation at 4 °C. These results indicate that the GM3BP-avidin complex bind to GM3 in membrane raft, and are taken into cell through caveolae/raft-mediated endocytosis. The GM3BP-avidin complex was transported into cells and localized around the nucleus more slowly than a human immunodeficiency virus type 1 TAT peptide. Furthermore, the uptake of a green fluorescent protein (GFP) linked with GM3BP into HeLa cells was similar to that of the GM3BP-avidin complex, and the localization of the GM3BP-GFP fusion protein was markedly different with that of the TAT-GFP fusion protein. The uptake and trafficking of GM3BP were distinguished from conventional cell-penetrating peptides. GM3BP has potential as a novel peptide for the selective delivery of therapeutic proteins and materials into cells in addition to being a cell-penetrating peptide.

A new scheduling algorithm for parallel sparse LU factorization with static pivoting

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

Grigori, Laura; Li, Xiaoye S.

2002-08-20

In this paper we present a static scheduling algorithm for parallel sparse LU factorization with static pivoting. The algorithm is divided into mapping and scheduling phases, using the symmetric pruned graphs of L' and U to represent dependencies. The scheduling algorithm is designed for driving the parallel execution of the factorization on a distributed-memory architecture. Experimental results and comparisons with SuperLU{_}DIST are reported after applying this algorithm on real world application matrices on an IBM SP RS/6000 distributed memory machine.

Communication Efficient Gaussian Elimination with Partial Pivoting using a Shape Morphing Data Layout

DTIC Science & Technology

2013-02-21

support comes from ParLab affiliates National Instruments, Nokia, NVIDIA , Oracle and Samsung, as well as MathWorks. Research is also supported by DOE...affiliates National Instruments, Nokia, NVIDIA , Oracle and Samsung, as well as MathWorks. Research is also supported by DOE grants DE-SC0004938, DE-SC0005136...International Business Machines Company , 1966. [17] S. Toledo. Locality of reference in LU decomposition with partial pivoting. SIAM J. Matrix Anal. Appl., 18

Pivotal Ways of Improving Leadership and the Scholarship of Learning and Teaching in Higher Education

ERIC Educational Resources Information Center

Simon, Sue; Christie, Michael; Graham, Wayne A.; Call, Kairen

2014-01-01

This paper presents a new model of leadership that can improve the knowledge and skills needed by school leaders who undertake Masters of Business and Masters of Education. The model is called PIVOTAL which stands for Partnerships, Innovation and Vitality--Opportunities for Thriving Academic Leadership. The model is compared and contrasted with…

To what extent do joint attention, imitation, and object play behaviors in infancy predict later communication and intellectual functioning in ASD?

PubMed

Poon, Kenneth K; Watson, Linda R; Baranek, Grace T; Poe, Michele D

2012-06-01

The extent to which early social communication behaviors predict later communication and intellectual outcomes was investigated via retrospective video analysis. Joint attention, imitation, and complex object play behaviors were coded from edited home videos featuring scenes of 29 children with ASD at 9-12 and/or 15-18 months. A quantitative interval recording of behavior and a qualitative rating of the developmental level were applied. Social communication behaviors increased between 9-12 and 15-18 months. Their mean level during infancy, but not the rate of change, predicted both Vineland Communication scores and intellectual functioning at 3-7 years. The two methods of measurement yielded similar results. Thus, early social communicative behaviors may play pivotal roles in the development of subsequent communication and intellectual functioning.

Pivotal Response Treatment Parent Training for Autism: Findings from a 3-Month Follow-Up Evaluation

ERIC Educational Resources Information Center

Gengoux, Grace W.; Berquist, Kari L.; Salzman, Emma; Schapp, Salena; Phillips, Jennifer M.; Frazier, Thomas W.; Minjarez, Mendy B.; Hardan, Antonio Y.

2015-01-01

This study's objective was to assess maintenance of treatment effects 3 months after completion of a 12-week Pivotal Response Treatment (PRT) parent education group. Families who completed the active treatment (N = 23) were followed for an additional 12 weeks to measure changes in language and cognitive skills. Results indicated a significant…

Electrospray mass spectrometry of NeuAc oligomers associated with the C fragment of the tetanus toxin

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

Prieto, M C; Whittal, R M; Baldwin, M A

2005-04-03

The Clostridial neurotoxins, botulinum and tetanus, gain entry into neuronal cells by protein recognition involving cell specific binding sites. The sialic or N-acetylneuraminic acid (NeuAc) residues of gangliosides attached to the surface of motor neurons are the suspected recognition and interaction points with Clostridial neurotoxins, although not necessarily the only ones. We have used electrospray ionization mass spectrometry (ESIMS) to examine formation of complexes between the tetanus toxin C fragment, or targeting domain, and carbohydrates containing NeuAc groups to determine how NeuAc residues contribute to ganglioside binding. ESI-MS was used to rapidly and efficiently measure dissociation constants for a numbermore » of related NeuAc-containing carbohydrates and NeuAc oligomers, information that has helped identify the structural features of gangliosides that determine their binding to tetanus toxin. The strength of the interactions between the C fragment and (NeuAc){sub n}, are consistent with the topography of the targeting domain of tetanus toxin and the nature of its carbohydrate binding sites. The results suggest that the targeting domain of tetanus toxin contains two binding sites that can accommodate NeuAc (or a dimer). This study also shows that NeuAc must play an important role in ganglioside binding and molecular recognition, a process critical for normal cell function and one frequently exploited by toxins, bacteria and viruses to facilitate their entrance into cells.« less

Behavioral Cusps: A Person-Centered Concept for Establishing Pivotal Individual, Family, and Community Behaviors and Repertoires

ERIC Educational Resources Information Center

Smith, Garnett J.; McDougall, Dennis; Edelen-Smith, Patricia

2006-01-01

Cumulative-hierarchical learning (CHL) and behavior, a premise first introduced by Staats in 1975, describes how higher-level behavioral patterns and structures can emerge from interactions among a set of lower-level actions. Proponents of CHL emphasize the importance of pivotal response interventions, behavior repertoires, generative learning,…

The pivotal role of primary care in meeting the health needs of people recently released from prison.

PubMed

Kinner, Stuart A; Young, Jesse T; Carroll, Megan

2015-12-01

Australia's prison population is growing at a rate well in excess of population growth. Indigenous Australians are over-represented by a factor of 13. Prisoners are a profoundly marginalised group characterised by complex health and social needs. Despite improvements in health during incarceration, poor health outcomes after release are common, and the net effect of incarceration is usually health depleting. Given the need for effective care coordination, primary care plays a pivotal role in meeting the health needs of this population. In this paper we review what is known about patterns of primary care utilisation in ex-prisoners, identify evidence-based strategies for increasing access to primary care in ex-prisoners, and consider how such contact may shape subsequent health service outcomes. Primary care is a necessary but not sufficient condition for effective post-release support. Positive outcomes may depend more on the quality than the quantity of care received. Given massive over-representation of Indigenous people in Australia's prisons, and compelling evidence of preventable morbidity and mortality after release from prison, effective models of care for this population are an important component of closing the gap in Indigenous life expectancy. © The Royal Australian and New Zealand College of Psychiatrists 2015.

Tay-Sachs disease

MedlinePlus

GM2 gangliosidosis - Tay-Sachs; Lysosomal storage disease - Tay-Sachs disease ... called gangliosides. Without this protein, gangliosides, particularly ganglioside GM2, build up in cells, often nerve cells in ...

Training Teachers to Use Pivotal Response Training with Children with Autism: Coaching as a Critical Component

ERIC Educational Resources Information Center

Suhrheinrich, Jessica

2011-01-01

Although evidence-based practices (EBPs) for educating children with autism, such as pivotal response training (PRT), exist, teachers often lack adequate training to use these practices. The current investigation examined the efficacy of a 6-hour group workshop plus individual coaching for training 20 teachers to use PRT. Results indicate that the…

Evolution of the Ureteral Stent: The Pivotal Role of the Gibbons Ureteral Catheter.

PubMed

Donahue, Ryan P; Stamm, Andrew W; Gibbons, Robert P; Porter, Christopher R; Kobashi, Kathleen C; Corman, John M; Lee, Una J

2018-05-01

To review the pioneering contributions of Dr. Robert Gibbons of Virginia Mason Medical Center to the evolution and development of the modern ureteral stent. We reviewed Dr. Gibbons' extensive work through primary sources, including interviews, projector slides, radiology images, stent prototypes, his personal writings, and archived documents. In addition, we performed a review of historical texts and manuscripts describing important innovations in the development of the ureteral stent. In 1972, motivated by a desire to provide his patients with a long-term alternative to open nephrostomy and inspired by Drs. David Davis and Paul Zimskind, who in 1967 had described the use of indwelling ureteral silicone tubing, Dr. Gibbons began to experiment with modifications to improve upon existing stents. To address distal migration, Dr. Gibbons added "wings" that collapsed as the stent was advanced and expanded once in proper position to secure the stent in place. Barium was embedded into the proximal tip to facilitate radiographic visualization. A flange was added to the distal end, preventing proximal migration and minimizing trigonal irritation, and a tail was attached to aid in stent removal. The result was the original Gibbons stent, the first commercially available ureteral stent, and the establishment of Current Procedural Terminology code 52332, still used today. The ureteral stent is a fundamental component of urologic practice. In developing the Gibbons stent, Dr. Gibbons played a pivotal role in addressing the challenge of internal urinary diversion particularly for those who needed long-term management. Urologists and the patients they serve owe Dr. Gibbons and other surgeon-inventors a debt of gratitude for their innovative work. Copyright © 2018 Elsevier Inc. All rights reserved.

Simultaneous Measurements of Auto-Immune and Infectious Disease Specific Antibodies Using a High Throughput Multiplexing Tool

PubMed Central

Asati, Atul; Kachurina, Olga; Kachurin, Anatoly

2012-01-01

Considering importance of ganglioside antibodies as biomarkers in various immune-mediated neuropathies and neurological disorders, we developed a high throughput multiplexing tool for the assessment of gangliosides-specific antibodies based on Biolpex/Luminex platform. In this report, we demonstrate that the ganglioside high throughput multiplexing tool is robust, highly specific and demonstrating ∼100-fold higher concentration sensitivity for IgG detection than ELISA. In addition to the ganglioside-coated array, the high throughput multiplexing tool contains beads coated with influenza hemagglutinins derived from H1N1 A/Brisbane/59/07 and H1N1 A/California/07/09 strains. Influenza beads provided an added advantage of simultaneous detection of ganglioside- and influenza-specific antibodies, a capacity important for the assay of both infectious antigen-specific and autoimmune antibodies following vaccination or disease. Taken together, these results support the potential adoption of the ganglioside high throughput multiplexing tool for measuring ganglioside antibodies in various neuropathic and neurological disorders. PMID:22952605

Designing Out the Play: Accessibility and Playfulness in Inclusive Play.

PubMed

Holt, Raymond; Beckett, Angharad

2017-01-01

Play is an important part of child development, yet disabled children are often excluded from the opportunity to play, either due to lack of accessible toys and games, or social pressures. This paper presents a case study reflecting on the development of Button Bash: a switch accessible game intended to encourage inclusive play between disabled and non-disabled children. In particular, the paper focuses on how changes intended to make the game more accessible tended to make it less playful, and reflects on the relationship between playfulness and accessibility.

Transformational Leaders? The Pivotal Role That Supervisors Play in Safety Culture

ERIC Educational Resources Information Center

Bahn, Susanne

2013-01-01

The purpose of this paper is to investigate the impact frontline supervisors have on workplace safety culture and to argue for increased formal supervisory training. Two studies conducted in 2006-08 and 2011 are examined and compared in which 28 Managers and Occupational Health and Safety Managers in the construction industry in Western Australia…

Potent neutralization of botulinum neurotoxin/B by synergistic action of antibodies recognizing protein and ganglioside receptor binding domain.

PubMed

Chen, Changchun; Wang, Shuhui; Wang, Huajing; Mao, Xiaoyan; Zhang, Tiancheng; Ji, Guanghui; Shi, Xin; Xia, Tian; Lu, Weijia; Zhang, Dapeng; Dai, Jianxin; Guo, Yajun

2012-01-01

Botulinum neurotoxins (BoNTs), the causative agents for life-threatening human disease botulism, have been recognized as biological warfare agents. Monoclonal antibody (mAb) therapeutics hold considerable promise as BoNT therapeutics, but the potencies of mAbs against BoNTs are usually less than that of polyclonal antibodies (or oligoclonal antibodies). The confirmation of key epitopes with development of effective mAb is urgently needed. We selected 3 neutralizing mAbs which recognize different non-overlapping epitopes of BoNT/B from a panel of neutralizing antibodies against BoNT/B. By comparing the neutralizing effects among different combination groups, we found that 8E10, response to ganglioside receptor binding site, could synergy with 5G10 and 2F4, recognizing non-overlapping epitopes within Syt II binding sites. However, the combination of 5G10 with 2F4 blocking protein receptor binding sites did not achieve synergistical effects. Moreover, we found that the binding epitope of 8E10 was conserved among BoNT A, B, E, and F, which might cross-protect the challenge of different serotypes of BoNTs in vivo. The combination of two mAbs recognizing different receptors' binding domain in BoNTs has a synergistic effect. 8E10 is a potential universal partner for the synergistical combination with other mAb against protein receptor binding domain in BoNTs of other serotypes.

Inertial sensors to quantify the pivot shift test in the treatment of anterior cruciate ligament injury

PubMed Central

ZAFFAGNINI, STEFANO; LOPOMO, NICOLA; SIGNORELLI, CECILIA; MUCCIOLI, GIULIO MARIA MARCHEGGIANI; BONANZINGA, TOMMASO; GRASSI, ALBERTO; RAGGI, FEDERICO; VISANI, ANDREA; MARCACCI, MAURILIO

2014-01-01

The main purpose of this article was to describe in detail, from the perspective of the clinical end user, a previously presented non-invasive methodology, applied in the treatment of anterior cruciate ligament injury, in which inertial sensors are used to quantify the pivot shift test. The outcomes obtained and relative considerations were compared with findings emerging from a review of the relevant updated literature. The detailed description here provided covers the system, the parameters identified and the testing procedure; it also includes the technical specifications of the hardware, the features introduced in the updated version of the software and the application of the system in clinical practice. The comparison of the technical considerations and clinical results with the updated literature confirmed the system’s optimal ergonomics, good reproducibility and clinical reliability. The novel approach here analyzed has been shown to overcome the weaknesses of other available devices and systems. Therefore, since it can be considered a new paradigm in the quantification of pivot shift test, we can recommend its routine use in clinical practice. PMID:25606555

Altered lipid raft–associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus

PubMed Central

Jury, Elizabeth C.; Kabouridis, Panagiotis S.; Flores-Borja, Fabian; Mageed, Rizgar A.; Isenberg, David A.

2004-01-01

Systemic lupus erythematosus (SLE) is characterized by abnormalities in T lymphocyte receptor–mediated signal transduction pathways. Our previous studies have established that lymphocyte-specific protein tyrosine kinase (LCK) is reduced in T lymphocytes from patients with SLE and that this reduction is associated with disease activity and parallels an increase in LCK ubiquitination independent of T cell activation. This study investigated the expression of molecules that regulate LCK homeostasis, such as CD45, C-terminal Src kinase (CSK), and c-Cbl, in lipid raft domains from SLE T cells and investigated the localization of these proteins during T cell receptor (TCR) triggering. Our results indicate that the expression of raft-associated ganglioside, GM1, is increased in T cells from SLE patients and LCK may be differentially regulated due to an alteration in the association of CD45 with lipid raft domains. CD45 tyrosine phosphatase, which regulates LCK activity, was differentially expressed and its localization into lipid rafts was increased in T cells from patients with SLE. Furthermore, T cells allowed to “rest” in vitro showed a reversal of the changes in LCK, CD45, and GM1 expression. The results also revealed that alterations in the level of GM1 expression and lipid raft occupancy cannot be induced by serum factors from patients with SLE but indicated that cell-cell contact, activating aberrant proximal signaling pathways, may be important in influencing abnormalities in T cell signaling and, therefore, function in patients with SLE. PMID:15085197

Morphological, motor and situation-motor characteristics of elite female handball players according to playing performance and position.

PubMed

Cavala, Marijana; Katić, Ratko

2010-12-01

The aim of the study was to define biomotor characteristics that determine playing performance and position in female handball. A battery of 13 variables consisting of somatotype components (3 variables), basic motor abilities (5 variables) and specific motor abilities (5 variables) were applied in a sample of 52 elite female handball players. Differences in biomotor characteristics according to playing performance and position of female handball players were determined by use of the analysis of variance (ANOVA) and discriminative analysis. Study results showed the high-quality female handball players to predominantly differ from the less successful ones in the specific factor of throw strength and basic dash factor, followed by the specific abilities of movement without and with ball, basic coordination/agility and specific ability of ball manipulation, and a more pronounced mesomorphic component. Results also revealed the wing players to be superior in the speed of movement frequency (psychomotor speed), run (explosive strength) and speed of movement with ball as compared with players at other playing positions. Also, endomorphic component was less pronounced in players at the wing and back player positions as compared with goalkeeper and pivot positions, where endomorphic component was considerably more pronounced.

Understanding pivotal experiences in behavior change for the design of technologies for personal wellbeing.

PubMed

Bhattacharya, Arpita; Kolovson, Samantha; Sung, Yi-Chen; Eacker, Mike; Chen, Michael; Munson, Sean A; Kientz, Julie A

2018-03-01

Most health technologies are designed to support people who have already decided to work toward better health. Thus, there remains an opportunity to design technologies to help motivate people who have not yet decided to make a change. Understanding the experiences of people who have already started to make a health behavior change and how they made a pivotal decision can be useful in understanding how to design such tools. In this paper, we describe results from data collected in 2 phases. Phase 1 consisted of 127 surveys and 13 interviews with adults who have already accomplished behavior change(s). Phase 2 consisted of 117 surveys and 12 interviews with adults who have either already accomplished their behavior change(s) or are currently working toward them. We identified four factors that lead to pivotal experiences: (1) prolonged discontent and desire to change, (2) significant changes that increase fear or hope of future, (3) increased understanding of one's behavior and personal data, and (4) social accountability. We also describe a design space for designing technology-based interventions for encouraging people to decide to make a change to improve their health. Based on feedback from participants, we discuss opportunities for further exploration of the design space for people who are not yet motivated to change and for ethical considerations for this type of intervention. Copyright © 2018 Elsevier Inc. All rights reserved.

Pneumolysin plays a key role at the initial step of establishing pneumococcal nasal colonization.

PubMed

Hotomi, Muneki; Yuasa, Jun; Briles, David E; Yamanaka, Noboru

2016-09-01

Nasopharyngeal colonization by Streptococcus pneumoniae is an important initial step for the subsequent development of pneumococcal infections. Pneumococci have many virulence factors that play a role in colonization. Pneumolysin (PLY), a pivotal pneumococcal virulence factor for invasive disease, causes severe tissue damage and inflammation with disruption of epithelial tight junctions. In this study, we evaluated the role of PLY in nasal colonization of S. pneumoniae using a mouse colonization model. A reduction of numbers of PLY-deficient pneumococci recovered from nasal tissue, as well as nasal wash, was observed at days 1 and 2 post-intranasal challenges, but not later. The findings strongly support an important role for PLY in the initial establishment nasal colonization. PLY-dependent invasion of local nasal mucosa may be required to establish nasal colonization with S. pneumoniae. The data help provide a rationale to explain why an organism that exists as an asymptomatic colonizer has evolved virulence factors that enable it to occasionally invade and kill its hosts. Thus, the same pneumococcal virulence factor, PLY that can contribute to killing the host, may also play a role early in the establishment of nasopharynx carriage.

Impact of Pivotal Response Training Group Therapy on Stress and Empowerment in Parents of Children with Autism

ERIC Educational Resources Information Center

Minjarez, Mendy Boettcher; Mercier, Emma M.; Williams, Sharon E.; Hardan, Antonio Y.

2013-01-01

Parents of children with autism are increasingly being considered as primary agents of intervention for their children. The goal of this study was to evaluate whether participating in a pivotal response training (PRT) group therapy program for parents of children with autism influenced related aspects of parents' lives, namely, their levels of…

GD1a Overcomes Inhibition of Myelination by Fibronectin via Activation of Protein Kinase A: Implications for Multiple Sclerosis.

PubMed

Qin, Jing; Sikkema, Arend H; van der Bij, Kristine; de Jonge, Jenny C; Klappe, Karin; Nies, Vera; Jonker, Johan W; Kok, Jan Willem; Hoekstra, Dick; Baron, Wia

2017-10-11

Remyelination failure by oligodendrocytes contributes to the functional impairment that characterizes the demyelinating disease multiple sclerosis (MS). Since incomplete remyelination will irreversibly damage axonal connections, treatments effectively promoting remyelination are pivotal in halting disease progression. Our previous findings suggest that fibronectin aggregates, as an environmental factor, contribute to remyelination failure by perturbing oligodendrocyte progenitor cell (OPC) maturation. Here, we aim at elucidating whether exogenously added gangliosides (i.e., cell surface lipids with a potential to modulate signaling pathways) could counteract fibronectin-mediated inhibition of OPC maturation. Exclusive exposure of rat oligodendrocytes to GD1a, but not other gangliosides, overcomes aggregated fibronectin-induced inhibition of myelin membrane formation, in vitro , and OPC differentiation in fibronectin aggregate containing cuprizone-induced demyelinated lesions in male mice. GD1a exerts its effect on OPCs by inducing their proliferation and, at a late stage, by modulating OPC maturation. Kinase activity profiling revealed that GD1a activated a protein kinase A (PKA)-dependent signaling pathway and increased phosphorylation of the transcription factor cAMP response element-binding protein. Consistently, the effect of GD1a in restoring myelin membrane formation in the presence of fibronectin aggregates was abolished by the PKA inhibitor H89, whereas the effect of GD1a was mimicked by the PKA activator dibutyryl-cAMP. Together, GD1a overcomes the inhibiting effect of aggregated fibronectin on OPC maturation by activating a PKA-dependent signaling pathway. Given the persistent presence of fibronectin aggregates in MS lesions, ganglioside GD1a might act as a potential novel therapeutic tool to selectively modulate the detrimental signaling environment that precludes remyelination. SIGNIFICANCE STATEMENT As an environmental factor, aggregates of the

Snout allometry in seahorses: insights on optimisation of pivot feeding performance during ontogeny.

PubMed

Roos, Gert; Van Wassenbergh, Sam; Herrel, Anthony; Adriaens, Dominique; Aerts, Peter

2010-07-01

As juvenile life-history stages are subjected to strong selection, these stages often show levels of performance approaching those of adults, or show a disproportionately rapid increase of performance with age. Although testing performance capacity in aquatic suction feeders is often problematic, in pivot feeders such as seahorses models have been proposed to estimate whether snout length is optimal to minimise the time needed to reach the prey. Here, we investigate whether the same model can also explain the snout lengths in an ontogenetic series of seahorses, explore how pivot feeding kinematics change during ontogeny, and test whether juveniles show disproportionate levels of performance. Our analysis shows that the dimensions of the snout change during ontogeny from short and broad to long and narrow. Model calculations show that the snout lengths of newborn and juvenile seahorses are nearly optimal for minimising prey reach time. However, in juveniles the centre of head rotation in the earth-bound frame of reference is located near the posterior end of the head, whereas in adults it is shifted forward and is located approximately above the eye. Modelling shows that this forward shift in the centre of rotation has the advantage of decreasing the moment of inertia and the torque required to rotate the head, but has the disadvantage of slightly increasing the time needed to reach the prey. Thus, the snout lengths of juvenile seahorses appear to be close to optimal, suggesting that they reach levels of performance close to adult levels, which illustrates the pervasive nature of selection on performance in juveniles.

Antitumor activity and carrier properties of novel hemocyanins coupled to a mimotope of GD2 ganglioside.

PubMed

Palacios, Miriam; Tampe, Ricardo; Del Campo, Miguel; Zhong, Ta-Ying; López, Mercedes N; Salazar-Onfray, Flavio; Becker, María Inés

2018-04-25

Conjugation to carrier proteins is a way to improve the immunogenicity of peptides. Such is the case for peptides mimicking carbohydrate tumor-associated antigens in cancer vaccine development. The most used protein for this purpose is the keyhole limpet hemocyanin (KLH) from Megathura crenulata. Its limited bioavailability has prompted interest in finding new candidates; nevertheless, it is not known whether other hemocyanins might be equally efficient as carrier of carbohydrate peptide mimotopes to promotes anti-tumor responses. Here, we evaluated the carrier and antitumor activity of novel hemocyanins with documented immunogenicity obtained from Concholepas concholepas (CCH) and Fissurella latimarginata (FLH), coupled through sulfo-SMCC to P10, a mimetic peptide of GD2, the major ganglioside constituent of neuroectodermal tumors, and incorporating AddaVax as an adjuvant. The humoral immune responses of mice showed that CCH-P10 and FLH-P10 conjugates elicited specific IgM and IgG antibodies against P10 mimotope, similar to those obtained with KLH-P10, which was used as a positive control. The CCH-P10 and FLH-P10 antisera, exhibited cross-reactivity with murine and human melanoma cells, like anti-CCH and anti-FLH sera suggesting a cross-reaction of CCH and FLH glycosylations with carbohydrate epitopes on the tumor cell surfaces, similar to the KLH antisera. When mice were primed with each hemocyanin-P10 and challenged with melanoma cells, better antitumor effects were observed for FLH-P10 than for CCH-P10 and, as for KLH-P10, irrespective of conjugation. These data demonstrate that CCH and FLH are useful carriers of carbohydrate mimotopes; however, the best antitumor activity of FLH preparations, indicate that is a suitable candidate for further cancer vaccines research. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

The pivotal role of nurse managers, leaders and educators in enabling excellence in nursing care.

PubMed

McSherry, Robert; Pearce, Paddy; Grimwood, Karen; McSherry, Wilfred

2012-01-01

The aims of this paper are to present the findings from a discursive analysis of key issues associated with providing excellence in nursing care; and to provide an exemplar framework to support excellence in nursing care and describe the potential benefits when excellence in nursing care occurs. The challenge facing the nursing profession is in ensuring that the core principles of dignity, respect, compassion and person (people) centered care become central to all aspects of nursing practice. To regain the public and professional confidence in nursing, nurse leaders, managers and educators play a pivotal role in improving the image of nursing. Excellence in nursing care will only happen by ensuring that nurse managers, leaders and educators are able to respond to the complexity of reform and change by leading, managing, enabling, empowering, encouraging and resourcing staff to be innovative and entrepreneurial in practice. Creating healthcare environments that enable excellence in nursing care will not occur without the development of genuine shared working partnerships and collaborations between nurse managers, leaders and educators and their associated organizations. The importance of adopting an authentic sustainable leadership approach to facilitating and supporting frontline staff to innovate and change is imperative in restoring and evidencing that nurses do care and are excellent at what they do. By focusing attention on what resources are required to create a healthcare environment that enables compassion, safety and excellence in nursing care and what this means would be a reasonable start on the journey to excellence in nursing. © 2012 Blackwell Publishing Ltd.

Point of optimal kinematic error: improvement of the instantaneous helical pivot method for locating centers of rotation.

PubMed

De Rosario, Helios; Page, Alvaro; Mata, Vicente

2014-05-07

This paper proposes a variation of the instantaneous helical pivot technique for locating centers of rotation. The point of optimal kinematic error (POKE), which minimizes the velocity at the center of rotation, may be obtained by just adding a weighting factor equal to the square of angular velocity in Woltring׳s equation of the pivot of instantaneous helical axes (PIHA). Calculations are simplified with respect to the original method, since it is not necessary to make explicit calculations of the helical axis, and the effect of accidental errors is reduced. The improved performance of this method was validated by simulations based on a functional calibration task for the gleno-humeral joint center. Noisy data caused a systematic dislocation of the calculated center of rotation towards the center of the arm marker cluster. This error in PIHA could even exceed the effect of soft tissue artifacts associated to small and medium deformations, but it was successfully reduced by the POKE estimation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effect of structural modifications of ganglioside GM2 on intra-molecular carbohydrate-to-carbohydrate interaction and enzymatic susceptibility

PubMed Central

Li, Yu-Teh; Li, Su-Chen; Kiso, Makoto; Ishida, Hideharu; Mauri, Laura; Raimondi, Laura; Bernardi, Anna; Sonnino, Sandro

2008-01-01

Summary The effect of inter-molecular carbohydrate-to-carbohydrate interaction on basic cell biological processes has been well documented and appreciated. In contrast, very little is known about the intra-molecular carbohydrate-to-carbohydrate interaction. The presence of an interaction between the GalNAc and the Neu5Ac in GM2 detected by NMR spectroscopy represents a well-defined intra-molecular carbohydrate-to-carbohydrate interaction. This intriguing interaction is responsible for the GM2-epitope, GalNAcβ1Π4(Neu5Acα2Π3)Gal-, to exhibit a rigid and compact conformation. We hypothesized that this compact conformation may be the cause for both the GalNAc and the Neu5Ac in GM2 to be refractory to enzymatic hydrolysis and the GM2 activator protein is able to interact with the compact trisaccharide GM2-epitope, rendering the GalNAc and the Neu5Ac accessible to β-hexosaminidase A and sialidase. We have used a series of structurally modified GM2 to study the effect of modifications of sugar chains on the conformation and enzymatic susceptibility of this ganglioside. Our hypothesis was borne out by the fact that when the GalNAcβ1Π4Gal linkage in GM2 was converted to the GalNAcβ1Π6Gal, both the GalNAc and the Neu5Ac became susceptible to β-hexosaminidase A and sialidase, respectively, without GM2 activator protein. We hope our work will engender interest in identifying other intra-molecular carbohydrate-to-carbohydrate interactions in glycoconjugates. PMID:17967427

Effect of structural modifications of ganglioside GM2 on intra-molecular carbohydrate-to-carbohydrate interaction and enzymatic susceptibility.

PubMed

Li, Yu-Teh; Li, Su-Chen; Kiso, Makoto; Ishida, Hideharu; Mauri, Laura; Raimondi, Laura; Bernardi, Anna; Sonnino, Sandro

2008-03-01

The effect of inter-molecular carbohydrate-to-carbohydrate interaction on basic cell biological processes has been well documented and appreciated. In contrast, very little is known about the intra-molecular carbohydrate-to-carbohydrate interaction. The presence of an interaction between the GalNAc and the Neu5Ac in GM2 detected by NMR spectroscopy represents a well-defined intra-molecular carbohydrate-to-carbohydrate interaction. This intriguing interaction is responsible for the GM2-epitope, GalNAcbeta1-->4(Neu5Acalpha2-->3)Gal-, to exhibit a rigid and compact conformation. We hypothesized that this compact conformation may be the cause for both the GalNAc and the Neu5Ac in GM2 to be refractory to enzymatic hydrolysis and the GM2 activator protein is able to interact with the compact trisaccharide GM2-epitope, rendering the GalNAc and the Neu5Ac accessible to beta-hexosaminidase A and sialidase. We have used a series of structurally modified GM2 to study the effect of modifications of sugar chains on the conformation and enzymatic susceptibility of this ganglioside. Our hypothesis was borne out by the fact that when the GalNAcbeta1-->4Gal linkage in GM2 was converted to the GalNAcbeta1-->6Gal, both the GalNAc and the Neu5Ac became susceptible to beta-hexosaminidase A and sialidase, respectively, without GM2 activator protein. We hope our work will engender interest in identifying other intra-molecular carbohydrate-to-carbohydrate interactions in glycoconjugates.

NEU3 sialidase strictly modulates GM3 levels in skeletal myoblasts C2C12 thus favoring their differentiation and protecting them from apoptosis.

PubMed

Anastasia, Luigi; Papini, Nadia; Colazzo, Francesca; Palazzolo, Giacomo; Tringali, Cristina; Dileo, Loredana; Piccoli, Marco; Conforti, Erika; Sitzia, Clementina; Monti, Eugenio; Sampaolesi, Maurilio; Tettamanti, Guido; Venerando, Bruno

2008-12-26

Membrane-bound sialidase NEU3, often referred to as the "ganglioside sialidase," has a critical regulatory function on the sialoglycosphingolipid pattern of the cell membrane, with an anti-apoptotic function, especially in cancer cells. Although other sialidases have been shown to be involved in skeletal muscle differentiation, the role of NEU3 had yet to be disclosed. Herein we report that NEU3 plays a key role in skeletal muscle differentiation by strictly modulating the ganglioside content of adjacent cells, with special regard to GM3. Induced down-regulation of NEU3 in murine C2C12 myoblasts, even when partial, totally inhibits their capability to differentiate by increasing the GM3 level above a critical point, which causes epidermal growth factor receptor inhibition (and ultimately its down-regulation) and an higher responsiveness of myoblasts to the apoptotic stimuli.

Development of computer tablet software for clinical quantification of lateral knee compartment translation during the pivot shift test.

PubMed

Muller, Bart; Hofbauer, Marcus; Rahnemai-Azar, Amir Ata; Wolf, Megan; Araki, Daisuke; Hoshino, Yuichi; Araujo, Paulo; Debski, Richard E; Irrgang, James J; Fu, Freddie H; Musahl, Volker

2016-01-01

The pivot shift test is a commonly used clinical examination by orthopedic surgeons to evaluate knee function following injury. However, the test can only be graded subjectively by the examiner. Therefore, the purpose of this study is to develop software for a computer tablet to quantify anterior translation of the lateral knee compartment during the pivot shift test. Based on the simple image analysis method, software for a computer tablet was developed with the following primary design constraint - the software should be easy to use in a clinical setting and it should not slow down an outpatient visit. Translation of the lateral compartment of the intact knee was 2.0 ± 0.2 mm and for the anterior cruciate ligament-deficient knee was 8.9 ± 0.9 mm (p < 0.001). Intra-tester (ICC range = 0.913 to 0.999) and inter-tester (ICC = 0.949) reliability were excellent for the repeatability assessments. Overall, the average percent error of measuring simulated translation of the lateral knee compartment with the tablet parallel to the monitor increased from 2.8% at 50 cm distance to 7.7% at 200 cm. Deviation from the parallel position of the tablet did not have a significant effect until a tablet angle of 45°. Average percent error during anterior translation of the lateral knee compartment of 6mm was 2.2% compared to 6.2% for 2 mm of translation. The software provides reliable, objective, and quantitative data on translation of the lateral knee compartment during the pivot shift test and meets the design constraints posed by the clinical setting.

The Core Subunit of A Chromatin-Remodeling Complex, ZmCHB101, Plays Essential Roles in Maize Growth and Development.

PubMed

Yu, Xiaoming; Jiang, Lili; Wu, Rui; Meng, Xinchao; Zhang, Ai; Li, Ning; Xia, Qiong; Qi, Xin; Pang, Jinsong; Xu, Zheng-Yi; Liu, Bao

2016-12-05

ATP-dependent chromatin remodeling complexes play essential roles in the regulation of diverse biological processes by formulating a DNA template that is accessible to the general transcription apparatus. Although the function of chromatin remodelers in plant development has been studied in A. thaliana, how it affects growth and development of major crops (e.g., maize) remains uninvestigated. Combining genetic, genomic and bioinformatic analyses, we show here that the maize core subunit of chromatin remodeling complex, ZmCHB101, plays essential roles in growth and development of maize at both vegetative and reproductive stages. Independent ZmCHB101 RNA interference plant lines displayed abaxially curling leaf phenotype due to increase of bulliform cell numbers, and showed impaired development of tassel and cob. RNA-seq-based transcriptome profiling revealed that ZmCHB101 dictated transcriptional reprogramming of a significant set of genes involved in plant development, photosynthesis, metabolic regulation, stress response and gene expressional regulation. Intriguingly, we found that ZmCHB101 was required for maintaining normal nucleosome density and 45 S rDNA compaction. Our findings suggest that the SWI3 protein, ZmCHB101, plays pivotal roles in maize normal growth and development via regulation of chromatin structure.

New design of care: Assessment of an interdisciplinary orthopaedic clinic with a pivot nurse in the province of Quebec.

PubMed

Poder, Thomas G; Bellemare, Christian; Bédard, Suzanne K; He, Jie; Lemieux, Renald

2010-01-01

New designs of care in orthopaedic clinics are needed to cope with the shortage of orthopaedic surgeons and the lengthening of waiting times. To assess the effectiveness of an interdisciplinary orthopaedic clinic with a pivot nurse in the Canadian province of Quebec with regard to accessibility, quality of care, efficacy and efficiency of the clinic, and patient's quality of life. Two strategies were developed: (1) a selected cohort of new patients attending an orthopaedic service from February to September 2008 were entered into a database recording patient details, source of referral, diagnosis, satisfaction, and quality of life (36-Item Short Form Health Survey version 2). In this setting, 2 sets of questionnaires were administered to the patients: the first one during the first visit and the second one, 2 months later. A total of 243 patients from the case control were compared with 89 patients of the case study, where an interdisciplinary orthopaedic clinic with a pivot nurse has been developed; (2) costs per patient were calculated using the staff timesheets provided by the two orthopaedic clinics. The results showed a significant reduction in the waiting-list duration (accessibility) in the case study clinic owing to a strong decrease in the inappropriate consultations with the orthopaedic consultant. The quality of care remained high, and the target surgeries for total hip and knee replacement were reached, despite a strong shortage of orthopaedic doctors. Interdisciplinary orthopaedic clinic with a pivot nurse is a new approach in the province of Quebec and first results are encouraging.

Dichromatic State Sum Models for Four-Manifolds from Pivotal Functors

NASA Astrophysics Data System (ADS)

Bärenz, Manuel; Barrett, John

2017-11-01

A family of invariants of smooth, oriented four-dimensional manifolds is defined via handle decompositions and the Kirby calculus of framed link diagrams. The invariants are parametrised by a pivotal functor from a spherical fusion category into a ribbon fusion category. A state sum formula for the invariant is constructed via the chain-mail procedure, so a large class of topological state sum models can be expressed as link invariants. Most prominently, the Crane-Yetter state sum over an arbitrary ribbon fusion category is recovered, including the nonmodular case. It is shown that the Crane-Yetter invariant for nonmodular categories is stronger than signature and Euler invariant. A special case is the four-dimensional untwisted Dijkgraaf-Witten model. Derivations of state space dimensions of TQFTs arising from the state sum model agree with recent calculations of ground state degeneracies in Walker-Wang models. Relations to different approaches to quantum gravity such as Cartan geometry and teleparallel gravity are also discussed.

Dichromatic State Sum Models for Four-Manifolds from Pivotal Functors

NASA Astrophysics Data System (ADS)

Bärenz, Manuel; Barrett, John

2018-06-01

A family of invariants of smooth, oriented four-dimensional manifolds is defined via handle decompositions and the Kirby calculus of framed link diagrams. The invariants are parametrised by a pivotal functor from a spherical fusion category into a ribbon fusion category. A state sum formula for the invariant is constructed via the chain-mail procedure, so a large class of topological state sum models can be expressed as link invariants. Most prominently, the Crane-Yetter state sum over an arbitrary ribbon fusion category is recovered, including the nonmodular case. It is shown that the Crane-Yetter invariant for nonmodular categories is stronger than signature and Euler invariant. A special case is the four-dimensional untwisted Dijkgraaf-Witten model. Derivations of state space dimensions of TQFTs arising from the state sum model agree with recent calculations of ground state degeneracies in Walker-Wang models. Relations to different approaches to quantum gravity such as Cartan geometry and teleparallel gravity are also discussed.

Soil water balance calculation using a two source energy balance model and wireless sensor arrays aboard a center pivot

USDA-ARS?s Scientific Manuscript database

Recent developments in wireless sensor technology and remote sensing algorithms, coupled with increased use of center pivot irrigation systems, have removed several long-standing barriers to adoption of remote sensing for real-time irrigation management. One remote sensing-based algorithm is a two s...

The Influenza A Virus PB2, PA, NP, and M Segments Play a Pivotal Role during Genome Packaging

PubMed Central

Gao, Qinshan; Chou, Yi-Ying; Doğanay, Sultan; Vafabakhsh, Reza; Ha, Taekjip

2012-01-01

The genomes of influenza A viruses consist of eight negative-strand RNA segments. Recent studies suggest that influenza viruses are able to specifically package their segmented genomes into the progeny virions. Segment-specific packaging signals of influenza virus RNAs (vRNAs) are located in the 5′ and 3′ noncoding regions, as well as in the terminal regions, of the open reading frames. How these packaging signals function during genome packaging remains unclear. Previously, we generated a 7-segmented virus in which the hemagglutinin (HA) and neuraminidase (NA) segments of the influenza A/Puerto Rico/8/34 virus were replaced by a chimeric influenza C virus hemagglutinin/esterase/fusion (HEF) segment carrying the HA packaging sequences. The robust growth of the HEF virus suggested that the NA segment is not required for the packaging of other segments. In this study, in order to determine the roles of the other seven segments during influenza A virus genome assembly, we continued to use this HEF virus as a tool and analyzed the effects of replacing the packaging sequences of other segments with those of the NA segment. Our results showed that deleting the packaging signals of the PB1, HA, or NS segment had no effect on the growth of the HEF virus, while growth was greatly impaired when the packaging sequence of the PB2, PA, nucleoprotein (NP), or matrix (M) segment was removed. These results indicate that the PB2, PA, NP, and M segments play a more important role than the remaining four vRNAs during the genome-packaging process. PMID:22532680

ER stress and subsequent activated calpain play a pivotal role in skeletal muscle wasting after severe burn injury

PubMed Central

Shen, Chuanan; Li, Dawei; Wang, Xiaoteng

2017-01-01

Severe burns are typically followed by hypermetabolism characterized by significant muscle wasting, which causes considerable morbidity and mortality. The aim of the present study was to explore the underlying mechanisms of skeletal muscle damage/wasting post-burn. Rats were randomized to the sham, sham+4-phenylbutyrate (4-PBA, a pharmacological chaperone promoting endoplasmic reticulum (ER) folding/trafficking, commonly considered as an inhibitor of ER), burn (30% total body surface area), and burn+4-PBA groups; and sacrificed at 1, 4, 7, 14 days after the burn injury. Tibial anterior muscle was harvested for transmission electron microscopy, calcium imaging, gene expression and protein analysis of ER stress / ubiquitin-proteasome system / autophagy, and calpain activity measurement. The results showed that ER stress markers were increased in the burn group compared with the sham group, especially at post-burn days 4 and 7, which might consequently elevate cytoplasmic calcium concentration, promote calpain production as well as activation, and cause skeletal muscle damage/wasting of TA muscle after severe burn injury. Interestingly, treatment with 4-PBA prevented burn-induced ER swelling and altered protein expression of ER stress markers and calcium release, attenuating calpain activation and skeletal muscle damage/wasting after severe burn injury. Atrogin-1 and LC3-II/LC3-I ratio were also increased in the burn group compared with the sham group, while MuRF-1 remained unchanged; 4-PBA decreased atrogin-1 in the burn group. Taken together, these findings suggested that severe burn injury induces ER stress, which in turns causes calpain activation. ER stress and subsequent activated calpain play a critical role in skeletal muscle damage/wasting in burned rats. PMID:29028830

Phase I Study of Anti-GM2 Ganglioside Monoclonal Antibody BIW-8962 as Monotherapy in Patients with Previously Treated Multiple Myeloma.

PubMed

Baz, Rachid C; Zonder, Jeffrey A; Gasparetto, Cristina; Reu, Frederic J; Strout, Vincent

2016-01-01

BIW-8962 is a monoclonal antibody to GM2 ganglioside that shows preclinical activity towards multiple myeloma (MM) cell lines and in animal models bearing MM xenografts. The objective of this study was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of BIW-8962 in patients with heavily pretreated MM. Patients ( n  = 23) received escalating doses of BIW-8962 (0.03-3 mg/kg) intravenously every 2 weeks in phase Ia. The highest anticipated dose (10 mg/kg) was not tested and the study was discontinued without proceeding to phases Ib and II. The MTD of BIW-8962 was not established and BIW-8962 was relatively well tolerated. No pattern of consistent toxicity could be inferred from treatment-related AEs grade ≥3 and only two dose-limiting toxicities were recorded (atrial thrombosis + cardiomyopathy and chest pain, respectively). In the efficacy evaluable population ( n  = 22), no patient had a response (complete or partial) and 16 (72.7%) had a best response of stable disease, which was generally not durable. BIW-8962 did not show evidence of clinical activity. The study was therefore stopped and further development of BIW-8962 in MM was halted. This work was funded by Kyowa Kirin Pharmaceutical Development, Inc. ClinicalTrials.gov identifier, NCT00775502.

Cumulative Evidence and Consensus of Pivotal Response Treatment as a Naturalistic Developmental Behavior Intervention for Young Children with Autism

ERIC Educational Resources Information Center

Lyons, Gregory L.

2017-01-01

In contrast to Early Intensive Behavioral Intervention (EIBI), there are far fewer meta-analyses evaluating Naturalistic Developmental Behavioral Interventions (NDBIs) (Schreibman et al., 2015). Indeed, Pivotal Response Treatment (PRT)--a prominent NDBI--lacks meta-analytic studies. In the context of developing a line of research on the…

Thigh Muscle Activity, Knee Motion, and Impact Force During Side-Step Pivoting in Agility-Trained Female Basketball Players

PubMed Central

Wilderman, Danielle R; Ross, Scott E; Padua, Darin A

2009-01-01

Context: Improving neuromuscular control of hamstrings muscles might have implications for decreasing anterior cruciate ligament injuries in females. Objective: To examine the effects of a 6-week agility training program on quadriceps and hamstrings muscle activation, knee flexion angles, and peak vertical ground reaction force. Design: Prospective, randomized clinical research trial. Setting: Sports medicine research laboratory. Patients or Other Participants: Thirty female intramural basketball players with no history of knee injury (age  =  21.07 ± 2.82 years, height  =  171.27 ± 4.66 cm, mass  =  66.36 ± 7.41 kg). Intervention(s): Participants were assigned to an agility training group or a control group that did not participate in agility training. Participants in the agility training group trained 4 times per week for 6 weeks. Main Outcome Measure(s): We used surface electromyography to assess muscle activation for the rectus femoris, vastus medialis oblique, medial hamstrings, and lateral hamstrings for 50 milliseconds before initial ground contact and while the foot was in contact with the ground during a side-step pivot maneuver. Knee flexion angles (at initial ground contact, maximum knee flexion, knee flexion displacement) and peak vertical ground reaction force also were assessed during this maneuver. Results: Participants in the training group increased medial hamstrings activation during ground contact after the 6-week agility training program. Both groups decreased their vastus medialis oblique muscle activation during ground contact. Knee flexion angles and peak vertical ground reaction force did not change for either group. Conclusions: Agility training improved medial hamstrings activity in female intramural basketball players during a side-step pivot maneuver. Agility training that improves hamstrings activity might have implications for reducing anterior cruciate ligament sprain injury associated with side-step pivots. PMID

Estimating Temperature Retrieval Accuracy Associated With Thermal Band Spatial Resolution Requirements for Center Pivot Irrigation Monitoring and Management

NASA Technical Reports Server (NTRS)

Ryan, Robert E.; Irons, James; Spruce, Joseph P.; Underwood, Lauren W.; Pagnutti, Mary

2006-01-01

This study explores the use of synthetic thermal center pivot irrigation scenes to estimate temperature retrieval accuracy for thermal remote sensed data, such as data acquired from current and proposed Landsat-like thermal systems. Center pivot irrigation is a common practice in the western United States and in other parts of the world where water resources are scarce. Wide-area ET (evapotranspiration) estimates and reliable water management decisions depend on accurate temperature information retrieval from remotely sensed data. Spatial resolution, sensor noise, and the temperature step between a field and its surrounding area impose limits on the ability to retrieve temperature information. Spatial resolution is an interrelationship between GSD (ground sample distance) and a measure of image sharpness, such as edge response or edge slope. Edge response and edge slope are intuitive, and direct measures of spatial resolution are easier to visualize and estimate than the more common Modulation Transfer Function or Point Spread Function. For these reasons, recent data specifications, such as those for the LDCM (Landsat Data Continuity Mission), have used GSD and edge response to specify spatial resolution. For this study, we have defined a 400-800 m diameter center pivot irrigation area with a large 25 K temperature step associated with a 300 K well-watered field surrounded by an infinite 325 K dry area. In this context, we defined the benchmark problem as an easily modeled, highly common stressing case. By parametrically varying GSD (30-240 m) and edge slope, we determined the number of pixels and field area fraction that meet a given temperature accuracy estimate for 400-m, 600-m, and 800-m diameter field sizes. Results of this project will help assess the utility of proposed specifications for the LDCM and other future thermal remote sensing missions and for water resource management.

Return to play after anterior cruciate ligament reconstruction in major league baseball athletes.

PubMed

Fabricant, Peter D; Chin, Christopher S; Conte, Stan; Coleman, Struan H; Pearle, Andrew D; Dines, Joshua S

2015-05-01

The purpose of the study was to (1) investigate the rate of return to play among Major League Baseball (MLB) athletes after anterior cruciate ligament reconstruction (ACLR), (2) determine the impact of ACL injury on ability to perform baseball-specific planting and pivoting tasks (batting and stealing bases), and (3) to explore the effect of the injured side on these metrics. ACL injury data from 1999 to 2012 were compiled, along with player performance statistics recorded for players with at least 30 games before ACL injury. Predictor variables included side of injury and outcome variables focused on batting average, stolen bases, and number of times caught stealing before injury and after surgery. Twenty-three of 26 (88%) players were able to return to at least 30 games after ACLR, although they experienced a decline of 21.2% in number of games played (P = .004). Those who had a ACLR for a rear batting leg injury averaged a 12.3% decline in batting average, whereas those who had ACLR for a lead leg injury had a 6.4% increase in batting average (P = .04). Side of injury was not predictive of stolen base metrics. The overall rate of return to play among MLB position players after ACLR was 88%, although there was a 21.2% decline in the number of games played postoperatively. Injury to the rear batting leg resulted in a lower returning batting average compared with an injury to the lead batting leg. Side of injury had no effect on stolen bases or on the number of times a player was caught stealing. Level IV, therapeutic case series. Copyright © 2015 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Core Transmembrane Domain 6 Plays a Pivotal Role in the Transport Cycle of the Sodium/Proline Symporter PutP*

PubMed Central

Bracher, Susanne; Schmidt, Claudia C.; Dittmer, Sophie I.; Jung, Heinrich

2016-01-01

Crystal structures of transporters with a LeuT-type structural fold assign core transmembrane domain 6 (TM6′) a central role in substrate binding and translocation. Here, the function of TM6′ in the sodium/proline symporter PutP, a member of the solute/sodium symporter family, was investigated. A complete scan of TM6′ identified eight amino acids as particularly important for PutP function. Of these residues, Tyr-248, His-253, and Arg-257 impact sodium binding, whereas Arg-257 and Ala-260 may participate in interactions leading to closure of the inner gate. Furthermore, the previous suggestion of an involvement of Trp-244, Tyr-248, and Pro-252 in proline binding is further supported. In addition, substitution of Gly-245, Gly-247, and Gly-250 affects the amount of PutP in the membrane. A Cys accessibility analysis suggests an involvement of the inner half of TM6′ in the formation of a hydrophilic pathway that is open to the inside in the absence of ligands and closed in the presence of sodium and proline. In conclusion, the results demonstrate that TM6′ plays a central role in substrate binding and release on the inner side of the membrane also in PutP and extend the knowledge on functionally relevant amino acids in transporters with a LeuT-type structural fold. PMID:27793991

Problematic game play: the diagnostic value of playing motives, passion, and playing time in men.

PubMed

Kneer, Julia; Rieger, Diana

2015-04-30

Internet gaming disorder is currently listed in the DSM-not in order to diagnose such a disorder but to encourage research to investigate this phenomenon. Even whether it is still questionable if Internet Gaming Disorder exists and can be judged as a form of addiction, problematic game play is already very well researched to cause problems in daily life. Approaches trying to predict problematic tendencies in digital game play have mainly focused on playing time as a diagnostic criterion. However, motives to engage in digital game play and obsessive passion for game play have also been found to predict problematic game play but have not yet been investigated together. The present study aims at (1) analyzing if obsessive passion can be distinguished from problematic game play as separate concepts, and (2) testing motives of game play, passion, and playing time for their predictive values for problematic tendencies. We found (N = 99 males, Age: M = 22.80, SD = 3.81) that obsessive passion can be conceptually separated from problematic game play. In addition, the results suggest that compared to solely playing time immersion as playing motive and obsessive passion have added predictive value for problematic game play. The implications focus on broadening the criteria in order to diagnose problematic playing.

Problematic Game Play: The Diagnostic Value of Playing Motives, Passion, and Playing Time in Men

PubMed Central

Kneer, Julia; Rieger, Diana

2015-01-01

Internet gaming disorder is currently listed in the DSM—not in order to diagnose such a disorder but to encourage research to investigate this phenomenon. Even whether it is still questionable if Internet Gaming Disorder exists and can be judged as a form of addiction, problematic game play is already very well researched to cause problems in daily life. Approaches trying to predict problematic tendencies in digital game play have mainly focused on playing time as a diagnostic criterion. However, motives to engage in digital game play and obsessive passion for game play have also been found to predict problematic game play but have not yet been investigated together. The present study aims at (1) analyzing if obsessive passion can be distinguished from problematic game play as separate concepts, and (2) testing motives of game play, passion, and playing time for their predictive values for problematic tendencies. We found (N = 99 males, Age: M = 22.80, SD = 3.81) that obsessive passion can be conceptually separated from problematic game play. In addition, the results suggest that compared to solely playing time immersion as playing motive and obsessive passion have added predictive value for problematic game play. The implications focus on broadening the criteria in order to diagnose problematic playing. PMID:25942516

Play to learn, teach by play.

PubMed

Palagi, Elisabetta; Stanyon, Roscoe; Demuru, Elisa

2015-01-01

The synthesis provided by Kline in the target article is noteworthy, but ignores the inseparable role of play in the evolution of learning and teaching in both humans and other animals. Play is distinguished and advantaged by its positive feedback reinforcement through pleasure. Play, especially between adults and infants, is probably the platform from which human learning and teaching evolved.

Antiganglioside antibodies in Guillain-Barré syndrome after a recent cytomegalovirus infection

PubMed Central

Khalili-Shirazi, A.; Gregson, N.; Gray, I.; Rees, J.; Winer, J.; Hughes, R.

1999-01-01

OBJECTIVE—To study the association between anti-ganglioside antibody responses and Guillan-Barré syndrome (GBS) after a recent cytomegalovirus (CMV) infection.
METHODS—Enzyme linked immunosorbant assay (ELISA) was undertaken on serum samples from 14 patients with GBS with recent cytomegalovirus (CMV) infection (CMV+GBS) and 12 without (CMV-GBS), 17 patients with other neurological diseases (OND), 11 patients with a recent CMV infection but without neurological involvement, 11 patients with recent Epstein-Barr virus (EBV) infection but without neurological involvement, and 20 normal control (NC) subjects.
RESULTS—IgM antibodies were found at 1:100 serum dilution to gangliosides GM2 (six of 14 patients), GM1 (four of 14), GD1a (three of 14) and GD1b (two of 14) in the serum samples of the CMV+GBS patients, but not in those of any of the CMV-GBS patients. IgM antibodies were also found to gangliosides GM1, GD1a, and GD1b in one of 11 OND patients, to ganglioside GM1 in one of 11 non- neurological CMV patients, and to ganglioside GD1b in one of 20NC subjects. Some patients with EBV infection had IgM antibodies to gangliosides GM1 (five of 11), GM2 (three of 11), and GD1a (two of 11). However, the antibodies to ganglioside GM2 had a low titre, none being positive at 1:200 dilution, whereas five of the CMV+GBS serum samples remained positive at this dilution.
CONCLUSION—Antibodies to ganglioside GM2 are often associated with GBS after CMV infection, but their relevance is not known. It is unlikely that CMV infection and anti-ganglioside GM2 antibodies are solely responsible and an additional factor is required to elicit GBS.

 PMID:10084538

Antiganglioside antibodies in Guillain-Barré syndrome after a recent cytomegalovirus infection.

PubMed

Khalili-Shirazi, A; Gregson, N; Gray, I; Rees, J; Winer, J; Hughes, R

1999-03-01

To study the association between anti-ganglioside antibody responses and Guillan-Barré syndrome (GBS) after a recent cytomegalovirus (CMV) infection. Enzyme linked immunosorbant assay (ELISA) was undertaken on serum samples from 14 patients with GBS with recent cytomegalovirus (CMV) infection (CMV+GBS) and 12 without (CMV-GBS), 17 patients with other neurological diseases (OND), 11 patients with a recent CMV infection but without neurological involvement, 11 patients with recent Epstein-Barr virus (EBV) infection but without neurological involvement, and 20 normal control (NC) subjects. IgM antibodies were found at 1:100 serum dilution to gangliosides GM2 (six of 14 patients), GM1 (four of 14), GD1a (three of 14) and GD1b (two of 14) in the serum samples of the CMV+GBS patients, but not in those of any of the CMV-GBS patients. IgM antibodies were also found to gangliosides GM1, GD1a, and GD1b in one of 11 OND patients, to ganglioside GM1 in one of 11 non- neurological CMV patients, and to ganglioside GD1b in one of 20 NC subjects. Some patients with EBV infection had IgM antibodies to gangliosides GM1 (five of 11), GM2 (three of 11), and GD1a (two of 11). However, the antibodies to ganglioside GM2 had a low titre, none being positive at 1:200 dilution, whereas five of the CMV+GBS serum samples remained positive at this dilution. Antibodies to ganglioside GM2 are often associated with GBS after CMV infection, but their relevance is not known. It is unlikely that CMV infection and anti-ganglioside GM2 antibodies are solely responsible and an additional factor is required to elicit GBS.

Intermediate Filaments Play a Pivotal Role in Regulating Cell Architecture and Function.

PubMed

Lowery, Jason; Kuczmarski, Edward R; Herrmann, Harald; Goldman, Robert D

2015-07-10

Intermediate filaments (IFs) are composed of one or more members of a large family of cytoskeletal proteins, whose expression is cell- and tissue type-specific. Their importance in regulating the physiological properties of cells is becoming widely recognized in functions ranging from cell motility to signal transduction. IF proteins assemble into nanoscale biopolymers with unique strain-hardening properties that are related to their roles in regulating the mechanical integrity of cells. Furthermore, mutations in the genes encoding IF proteins cause a wide range of human diseases. Due to the number of different types of IF proteins, we have limited this short review to cover structure and function topics mainly related to the simpler homopolymeric IF networks composed of vimentin, and specifically for diseases, the related muscle-specific desmin IF networks. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Intermediate Filaments Play a Pivotal Role in Regulating Cell Architecture and Function*

PubMed Central

Lowery, Jason; Kuczmarski, Edward R.; Herrmann, Harald; Goldman, Robert D.

2015-01-01

Intermediate filaments (IFs) are composed of one or more members of a large family of cytoskeletal proteins, whose expression is cell- and tissue type-specific. Their importance in regulating the physiological properties of cells is becoming widely recognized in functions ranging from cell motility to signal transduction. IF proteins assemble into nanoscale biopolymers with unique strain-hardening properties that are related to their roles in regulating the mechanical integrity of cells. Furthermore, mutations in the genes encoding IF proteins cause a wide range of human diseases. Due to the number of different types of IF proteins, we have limited this short review to cover structure and function topics mainly related to the simpler homopolymeric IF networks composed of vimentin, and specifically for diseases, the related muscle-specific desmin IF networks. PMID:25957409

Causes of death from the randomized CoreValve US Pivotal High-Risk Trial.

PubMed

Gaudiani, Vincent; Deeb, G Michael; Popma, Jeffrey J; Adams, David H; Gleason, Thomas G; Conte, John V; Zorn, George L; Hermiller, James B; Chetcuti, Stan; Mumtaz, Mubashir; Yakubov, Steven J; Kleiman, Neal S; Huang, Jian; Reardon, Michael J

2017-06-01

Explore causes and timing of death from the CoreValve US Pivotal High-Risk Trial. An independent clinical events committee adjudicated causes of death, followed by post hoc hierarchical classification. Baseline characteristics, early outcomes, and causes of death were evaluated for 3 time periods (selected based on threshold of surgical 30-day mortality and on the differences in the continuous hazard between the 2 groups): early (0-30 days), recovery (31-120 days), and late (121-365 days). Differences in the rate of death were evident only during the recovery period (31-120 days), whereas 15 patients undergoing transcatheter aortic valve replacement (TAVR) (4.0%) and 27 surgical aortic valve replacement (SAVR) patients (7.9%) died (P = .025). This mortality difference was largely driven by higher rates of technical failure, surgical complications, and lack of recovery following surgery. From 0 to 30 days, the causes of death were more technical failures in the TAVR group and lack of recovery in the SAVR group. Mortality in the late period (121-365 days) in both arms was most commonly ascribed to other circumstances, comprising death from medical complications from comorbid disease. Mortality at 1 year in the CoreValve US Pivotal High-Risk Trial favored TAVR over SAVR. The major contributor was that more SAVR patients died during the recovery period (31-121 days), likely affected by the overall influence of physical stress associated with surgery. Similar rates of technical failure and complications were observed between the 2 groups. This suggests that early TAVR results can improve with technical refinements and that high-risk surgical patients will benefit from reducing complications. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Quantitative approach to control spinning stability of the impeller in the pivot bearing-supported centrifugal pump.

PubMed

Takami, Y; Makinouchi, K; Otsuka, G; Nosé, Y

1997-12-01

The Gyro C1E3 pump has been developed as a completely sealless centrifugal pump driven by a magnetic coupling system for long-term usage. The Gyro C1E3 pump is a pivot bearing-supported pump in which the impeller is supported with the top and bottom pivot bearings. In the Gyro C1E3 pump, the impeller spinning is affected by the force balance between the floating force (Ff[N]) of the hydrodynamic effect and the magnetic thrust force (Tf[N]). The authors quantitatively investigated the floating force of the impeller in vitro to determine the magnetic coupling distance (MCD[mm]) that would result in stable impeller spinning. In vitro tests were performed using a loop filled with 37% glycerin solution to obtain the relationship between the MCD and floating speed (Rf, rotational speed when the impeller starts floating [rpm]) and the relationship between the MCD and Tf. From the obtained relationships, we calculated Ff and determined the relationship between the Ff and the rotational speed (R). Furthermore, we determined the relationship between d (minimum required MCD [mm]) and R from the results of determining the relationship of the MCD and Tf and of the Ff and R. The following relationships were obtained: Rf = 6.24 x 10(4) x MCD-1.35; Tf = 5.27 x 10(3) x MCD-2.29; Ff = 4.71 x 10(-6) x RPM1.69; and d = 9.02 x RPM-0.85 where RPM is the rotational speed. It was demonstrated that the floating force of the impeller is a function only of the rotational speed in the pivot bearing-supported Gyro C1E3 pump. The floating force is estimated to be 10 N to 40 N at rotational speeds of 1,500 rpm to 3,000 rpm at which the Gyro pump may be used in most clinical situations. It would be possible to control the impeller position of the Gyro pump automatically at the stable spinning condition by controlling the adequate magnetic coupling distance based upon its relationship with the rotational speed which was obtained in this study.

Effect of ACL Transection on Internal Tibial Rotation in an in Vitro Simulated Pivot Landing

PubMed Central

Oh, Youkeun K.; Kreinbrink, Jennifer L.; Ashton-Miller, James A.; Wojtys, Edward M.

2011-01-01

Background: The amount of resistance provided by the ACL (anterior cruciate ligament) to axial tibial rotation remains controversial. The goal of this study was to test the primary hypotheses that ACL transection would not significantly affect tibial rotation under the large impulsive loads associated with a simulated pivot landing but would increase anterior tibial translation. Methods: Twelve cadaveric knees (mean age of donors [and standard deviation] at the time of death, 65.0 ± 10.5 years) were mounted in a custom testing apparatus to simulate a single-leg pivot landing. A compound impulsive load was applied to the distal part of the tibia with compression (∼800 N), flexion moment (∼40 N-m), and axial tibial torque (∼17 N-m) in the presence of five trans-knee muscle forces. A differential variable reluctance transducer mounted on the anteromedial aspect of the ACL measured relative strain. With the knee initially in 15° of flexion, and after five combined compression and flexion moment (baseline) loading trials, six trials were conducted with the addition of either internal or external tibial torque (internal or external loading), and then six baseline trials were performed. The ACL was then sectioned, six baseline trials were repeated, and then six trials of either the internal or the external loading condition, whichever had initially resulted in the larger relative ACL strain, were carried out. Tibiofemoral kinematics were measured optoelectronically. The results were analyzed with a nonparametric Wilcoxon signed-rank test. Results: Following ACL transection, the increase in the normalized internal tibial rotation was significant but small (0.7°/N-m ± 0.3°/N-m to 0.8°/N-m ± 0.3°/N-m, p = 0.012), while anterior tibial translation increased significantly (3.8 ± 2.9 to 7.0 ± 2.9 mm, p = 0.017). Conclusions: ACL transection leads to a small increase in internal tibial rotation, equivalent to a 13% decrease in the dynamic rotational resistance

Section 504 and student health problems: the pivotal position of the school nurse.

PubMed

Zirkel, Perry A; Granthom, Margarita Fernan; Lovato, Leanna

2012-12-01

News reports illustrate controversies between parents and schools in response to student health problems. Today's school nurse is in a pivotal position for the avoidance and resolution of disputes not only by increasing awareness of student health conditions but also by having a working knowledge of legal developments under Section 504 and its sister statute-the Americans with Disabilities Act (ADA). The ADA amendments of 2008 have extended the standards for eligibility and expanded questions about school districts' obligations under Section 504 and the ADA. This article provides a comprehensive synthesis of recent case law and related legal developments under this pair of federal statutes, culminating in practical implications and professional recommendations for school nurses.

HTML5 PivotViewer: high-throughput visualization and querying of image data on the web.

PubMed

Taylor, Stephen; Noble, Roger

2014-09-15

Visualization and analysis of large numbers of biological images has generated a bottle neck in research. We present HTML5 PivotViewer, a novel, open source, platform-independent viewer making use of the latest web technologies that allows seamless access to images and associated metadata for each image. This provides a powerful method to allow end users to mine their data. Documentation, examples and links to the software are available from http://www.cbrg.ox.ac.uk/data/pivotviewer/. The software is licensed under GPLv2. © The Author 2014. Published by Oxford University Press.

PDGFRα plays a crucial role in connective tissue remodeling.

PubMed

Horikawa, Shinjiro; Ishii, Yoko; Hamashima, Takeru; Yamamoto, Seiji; Mori, Hisashi; Fujimori, Toshihiko; Shen, Jie; Inoue, Ran; Nishizono, Hirofumi; Itoh, Hiroshi; Majima, Masataka; Abraham, David; Miyawaki, Toshio; Sasahara, Masakiyo

2015-12-07

Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor-α (PDGFRα) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (α-KO mouse), and the role of PDGFRα was examined in the subcutaneously implanted sponge matrices. PDGFRα expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in α-KO mice. Neovascularized areas were largely suppressed in the α-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in α-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the α-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRα-dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRα may be a relevant target to regulate connective tissue remodeling.

PDGFRα plays a crucial role in connective tissue remodeling

PubMed Central

Horikawa, Shinjiro; Ishii, Yoko; Hamashima, Takeru; Yamamoto, Seiji; Mori, Hisashi; Fujimori, Toshihiko; Shen, Jie; Inoue, Ran; Nishizono, Hirofumi; Itoh, Hiroshi; Majima, Masataka; Abraham, David; Miyawaki, Toshio; Sasahara, Masakiyo

2015-01-01

Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor-α (PDGFRα) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (α-KO mouse), and the role of PDGFRα was examined in the subcutaneously implanted sponge matrices. PDGFRα expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in α-KO mice. Neovascularized areas were largely suppressed in the α-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in α-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the α-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRα-dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRα may be a relevant target to regulate connective tissue remodeling. PMID:26639755

Collaborative School Innovation Project as a Pivot for Teachers' Professional Development: The Case of Acharnes' Second Chance School in Greece

ERIC Educational Resources Information Center

Katsarou, Eleni; Tsafos, Vassilis

2008-01-01

A collaborative school innovation project is explored as a pivot for the professional development of the teachers involved. The Second Chance School (SCS) of Acharnes in Greece constitutes such a collaborative innovative project, regarding the underlying theory of multiliteracies, its decentralised character, respect for student individuality, and…

Play & Play Grounds. A Report.

ERIC Educational Resources Information Center

Stone, Jeannette Galambos

Using camera and tape recorder, a photographer and an early childhood specialist explored as a team the universe of children's outdoor play, seeking worthy and innovative ideas and stressing urban playground problems and solutions. The resulting photographs and text focus on (1) the characteristics of play, (2) the nature of playgrounds, and (3)…

Playing My Heart Out: Original Play as Adventure.

ERIC Educational Resources Information Center

Donaldson, O. Fred

1999-01-01

"Original" play denotes play that is pre-cultural--before conceptualizations and learned responses. Four anecdotes about play with an infant with Down's syndrome, a child with leukemia, a lioness, and a dying woman illustrate the connections between beings and between the ordinary and the sacred during trusting, fearless, playful encounters. (SV)

Child's Play: Revisiting Play in Early Childhood Settings.

ERIC Educational Resources Information Center

Dau, Elizabeth, Ed.; Jones, Elizabeth, Ed.

Noting that play is an essential aspect of learning for young children, this book presents a collection of articles on children's play in Australia. Part 1, "Play, Development, and Learning," contains the following chapters: (1) "The Role of Play in Development and Learning" (Ann Glover); (2) "Stop, Look, and Listen:…

Childhood-Onset Multifocal Motor Neuropathy With Immunoglobulin M Antibodies to Gangliosides GM1 and GM2: A Case Report and Review of the Literature.

PubMed

Ishigaki, Hidetoshi; Hiraide, Takuya; Miyagi, Yoshifumi; Hayashi, Taiju; Matsubayashi, Tomoko; Shimoda, Ayumi; Kusunoki, Susumu; Fukuda, Tokiko

2016-09-01

Multifocal motor neuropathy is a rare immune-mediated neuropathy characterized by progressive asymmetric weakness and atrophy without sensory abnormalities. Although disease onset is usually in adulthood, a few childhood-onset cases have been reported. Here, we report the case of an 8-year-old boy with multifocal motor neuropathy who presented with a slowly progressive left and distal upper limb weakness without sensory loss. The initial high-dose intravenous immunoglobulin treatment significantly improved left upper limb muscle weakness. Continued monthly intravenous immunoglobulin treatment gradually improved muscle strength for several months initially. While the muscle strength decreased slightly after 8 months of therapy, it was better than that before intravenous immunoglobulin treatment. One year and eight months after the initiation of treatment, serum testing for IgM antibodies to gangliosides, GM1 and GM2, was negative. This is the first pediatric report of the serum IgM autoantibodies positive to GM1 and GM2. The clinical course is similar to that of partial intravenous immunoglobulin responders among patients with adulthood-onset multifocal motor neuropathy. Since the symptoms plateaued after the initial intravenous immunoglobulin therapy, prognosis appears to be determined by the patient's initial response to intravenous immunoglobulin treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

Play as Regulation: Promoting Self-Regulation through Play

ERIC Educational Resources Information Center

Foley, Gilbert M.

2017-01-01

The nature of play and an overview of the stages of play in the first 5 years of childhood are discussed. The core features of sensorimotor, functional, and symbolic play are identified. Vignettes describing how play serves a regulatory function punctuate each section. A conceptual framework for the construct of regulation is presented and…

New Play.

ERIC Educational Resources Information Center

Lersten, Kenneth C.

There have been many theories and hypotheses about play, one of which is the equation of play with "transcendence." Play may have the ingredients to allow us to transcend and, for a moment, remythologize life. There have been recent authors who have given play the status of theology, indicating that play contains elements also found in religion.…

Pivot/Remote: a distributed database for remote data entry in multi-center clinical trials.

PubMed

Higgins, S B; Jiang, K; Plummer, W D; Edens, T R; Stroud, M J; Swindell, B B; Wheeler, A P; Bernard, G R

1995-01-01

1. INTRODUCTION. Data collection is a critical component of multi-center clinical trials. Clinical trials conducted in intensive care units (ICU) are even more difficult because the acute nature of illnesses in ICU settings requires that masses of data be collected in a short time. More than a thousand data points are routinely collected for each study patient. The majority of clinical trials are still "paper-based," even if a remote data entry (RDE) system is utilized. The typical RDE system consists of a computer housed in the CC office and connected by modem to a centralized data coordinating center (DCC). Study data must first be recorded on a paper case report form (CRF), transcribed into the RDE system, and transmitted to the DCC. This approach requires additional monitoring since both the paper CRF and study database must be verified. The paper-based RDE system cannot take full advantage of automatic data checking routines. Much of the effort (and expense) of a clinical trial is ensuring that study data matches the original patient data. 2. METHODS. We have developed an RDE system, Pivot/Remote, that eliminates the need for paper-based CRFs. It creates an innovative, distributed database. The database resides partially at the study clinical centers (CC) and at the DCC. Pivot/Remote is descended from technology introduced with Pivot [1]. Study data is collected at the bedside with laptop computers. A graphical user interface (GUI) allows the display of electronic CRFs that closely mimic the normal paper-based forms. Data entry time is the same as for paper CRFs. Pull-down menus, displaying the possible responses, simplify the process of entering data. Edit checks are performed on most data items. For example, entered dates must conform to some temporal logic imposed by the study. Data must conform to some acceptable range of values. Calculations, such as computing the subject's age or the APACHE II score, are automatically made as the data is entered. Data

Pi (Spleen)-deficiency syndrome in tumor microenvironment is the pivotal pathogenesis of colorectal cancer immune escape.

PubMed

Sun, Xue-Gang; Lin, Xiao-Chang; Diao, Jian-Xin; Yu, Zhi-Ling; Li, Kun

2016-10-01

Cancer immunoediting consists of three sequential phases: elimination, equilibrium, and escape. For colorectal adenoma-carcinoma sequence, the adenoma dysplastic progression may represent an equilibrium phase and the cancer stage as escape phase. Immune system eliminates transformed enterocytes by destroying them at first, sculpts them at the same time and selects the variants subsequently that are no longer recognized and insensitive to immune effectors, and finally induces immunosuppressive state within the tumor microenvironment that facilitates immune escape and tumor outgrowth. Immunosuppression and inflammation are the two crucial features of Pi (Spleen)-deficiency. Classic quotations, immune evidence and clinical observations suggest that Spleen (but not other organs) deficiency is the key pathogenesis of colorectal cancer (CRC) microenvironment. Weakness of old age, immunosuppressive cytokines from chronic inflammation, tumor-derived immunosuppressive factors and surrendered immune cells-regulatory T cells, myeloid-derived suppressor cells and tumor associated macrophages (TAMs) constitutes CRC microenvironment of Pi-deficiency. Furthermore, excess in superficiality, such as phlegm stagnation, blood stasis and toxin accumulation are induced by chronic inflammation on the basis of asthenia in origin, an immunosuppressive state. Great masters of Chinese medicine emphasize that strengthen Pi is the chief therapeutic principle for CRC which receives good therapeutic effects. So, Pi-deficiency based syndrome is the pivotal pathogenesis of tumor microenvironment. The immunosuppressive microenvironment facilitates immune escape which play an important role in the transition from adenoma to adenocarcinoma. There are some signs that strengthen Pi based treatment has potential capacity to ameliorate tumor environment. It might be a novel starting point to explore the mechanism of strengthen Pi based therapy in the prevention and treatment of CRC through regulation of

Function-sparing tibialis anterior pivoted muscle flap for reconstruction of post-burn and post-traumatic middle-third leg defects with exposed tibia

PubMed Central

Megahed, M.A.

2011-01-01

Summary Reconstruction of the middle third of the leg is a challenging procedure. The tibialis anterior muscle flap can be useful in reconstruction of the middle third of the leg with exposed tibia. The aim of this work was to evaluate the efficacy of tibialis anterior pivoted muscle flap for reconstruction of the middle third of the leg with functional preservation. This study, performed in the Plastic, Reconstructive and Burn Unit, Menoufiya University Hospital, Egypt, included 16 patients (13 males and 3 females) during the period February 2007/May 2010: seven post-burn and nine post-traumatic patients with post-burn middle-third leg defects with exposed tibia. Their ages ranged from 14 to 67 years. A function-sparing lateral split tibialis anterior pivoted muscle flap was used in all the patients. Follow-up ranged from six months to two years. Partial flap loss occurred in one patient (6.25%), there was no post-operative haematoma or infection, and only one case of wound dehiscence (6.25%), managed by secondary suture. No donor site morbidity or any significant functional impairment was observed, and the subjective aesthetic results were satisfactory. Lateral split tibialis anterior pivoted muscle flap is a useful, simple technique, allowing rapid, durable and reliable coverage of middle-third leg defects without significant impairment of function and without sacrificing major nerves or vessels in the foot, and without any donor site morbidity. PMID:22262962

Fucosylation and protein glycosylation create functional receptors for cholera toxin

PubMed Central

Wands, Amberlyn M; Fujita, Akiko; McCombs, Janet E; Cervin, Jakob; Dedic, Benjamin; Rodriguez, Andrea C; Nischan, Nicole; Bond, Michelle R; Mettlen, Marcel; Trudgian, David C; Lemoff, Andrew; Quiding-Järbrink, Marianne; Gustavsson, Bengt; Steentoft, Catharina; Clausen, Henrik; Mirzaei, Hamid; Teneberg, Susann; Yrlid, Ulf; Kohler, Jennifer J

2015-01-01

Cholera toxin (CT) enters and intoxicates host cells after binding cell surface receptors using its B subunit (CTB). The ganglioside (glycolipid) GM1 is thought to be the sole CT receptor; however, the mechanism by which CTB binding to GM1 mediates internalization of CT remains enigmatic. Here we report that CTB binds cell surface glycoproteins. Relative contributions of gangliosides and glycoproteins to CTB binding depend on cell type, and CTB binds primarily to glycoproteins in colonic epithelial cell lines. Using a metabolically incorporated photocrosslinking sugar, we identified one CTB-binding glycoprotein and demonstrated that the glycan portion of the molecule, not the protein, provides the CTB interaction motif. We further show that fucosylated structures promote CTB entry into a colonic epithelial cell line and subsequent host cell intoxication. CTB-binding fucosylated glycoproteins are present in normal human intestinal epithelia and could play a role in cholera. DOI: http://dx.doi.org/10.7554/eLife.09545.001 PMID:26512888

Dynamic evaluation of pivot-shift kinematics in physeal-sparing pediatric anterior cruciate ligament reconstruction techniques.

PubMed

Sena, Mark; Chen, James; Dellamaggioria, Ryan; Coughlin, Dezba G; Lotz, Jeffrey C; Feeley, Brian T

2013-04-01

Conventional transphyseal anterior cruciate ligament (ACL) reconstruction techniques in skeletally immature patients have been questioned because of potential physeal injuries. Consequently, multiple alternative reconstruction options have been described to restore stability while sparing the physes in the skeletally immature patient. All pediatric reconstruction techniques will restore knee stability to intact levels, and the knee stability index (KSI) will discriminate stability patterns between reconstruction techniques. Controlled laboratory study. A novel mechanical pivot-shift device (MPSD) that consistently applies dynamic loads to cadaveric knees was used to study the effect of different physeal-sparing ACL reconstruction techniques on knee stability. Six adult cadaveric fresh-frozen knees were used. All knees were tested with 3 physeal-sparing reconstruction techniques: all epiphyseal (AE), transtibial over the top (TT), and iliotibial band (ITB). The MPSD was used to consistently perform a simulated pivot-shift maneuver. Tibial anterior displacement (AD), internal rotation (IR), posterior translational velocity (PTV), and external rotational velocity (ERV) were recorded using an Optotrak navigation system. The KSI (score range, 0-100; 0 = intact knee) was quantified using a regression analysis of AD, IR, PTV, and ERV. Repeated-measures analysis of variance and logistic regression were used for comparison of kinematics and derivation of KSI coefficients, respectively. ACL deficiency resulted in an increase of 20% to 115% in all primary stability measures tested compared with the ACL-intact state. All reconstructions resulted in a decrease in ADmax and IRmax as well as PTVmax and ERVmax to within intact ranges, indicating that all reconstructions do improve stability compared with the ACL-deficient state. The ITB reconstruction overconstrained AD and IR by 38% and 52%, respectively. The mean (±SD) KSI for the ACL-deficient state was 61.7 ± 22.2 (range, 47

Play Therapy

PubMed Central

Kool, Ritesh

2010-01-01

Play therapy represents a unique form of treatment that is not only geared toward young children, but is translated into a language children can comprehend and utilize—the language of play. For the referring provider or practitioner, questions may remain regarding the nature, course, and efficacy of play therapy. This article reviews the theoretical underpinnings of play therapy, some practical considerations, and finally a summary of the current state of research in regard to play therapy. The authors present the practicing psychiatrist with a road map for referring a patient to play therapy or initiating it in appropriate cases. PMID:21103141

GM1 ganglioside reduces the motor incoordination and loss of righting reflex caused by acute ethanol in C57BL/6J mice

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

Wallis, C.; Rezazadeh, S.M.; Forster, M.J.

1992-02-26

Ethanol produces its intoxicating effects by modifying neuronal membranes. Gangliosides stabilize neuronal membranes and promote their recovery from a variety of insults. In this experiment, the efficacy of GM1(i.p.) to reverse ethanol intoxication was evaluated in male mice trained to run on a constantly accelerating rotorod. When mice were tested 15-min following saline or ethanol GM1 pre-treatment reduced rotorod performance by 15% but was ineffective in modifying the ethanol-impaired performance. However, when mice were tested at 15, 35, 55, 75, and 95 min intervals following ethanol, GM1 pre-treatments dose-dependently reduced the efficacy and duration of ethanol in producing motor incoordination.more » Further, GM1 given prior to ethanol significantly prolonged the time to onset of the loss of righting reflex from 1.4 to 1.9 min, and reduced the duration of the righting-reflex loss from 94 to 77 min. This GM1 effect was seen at 24 h, but not at 48 or 72 h after its administration. The blood ethanol concentration at awakening was significantly higher in 24h GM1-treated animals than in controls suggesting that the GM1 effect was not due to an alteration in ethanol clearance. These findings support the hypothesis that GM1 promotes recovery from ethanol intoxication via a neuroprotective mechanism.« less

Increasing Opportunities for Question-Asking in School-Aged Children with Autism Spectrum Disorder: Effectiveness of Staff Training in Pivotal Response Treatment

ERIC Educational Resources Information Center

Verschuur, Rianne; Huskens, Bibi; Verhoeven, Ludo; Didden, Robert

2017-01-01

Deficits in question-asking are common in children with autism spectrum disorder (ASD). Furthermore, their opportunities to self-initiate questions are often hindered by directive behavior of their conversation partners. This study assessed the effectiveness of staff training in pivotal response treatment (PRT) on staff member-created…

Pretend play.

PubMed

Weisberg, Deena Skolnick

2015-01-01

Pretend play is a form of playful behavior that involves nonliteral action. Although on the surface this activity appears to be merely for fun, recent research has discovered that children's pretend play has connections to important cognitive and social skills, such as symbolic thinking, theory of mind, and counterfactual reasoning. The current article first defines pretend play and then reviews the arguments and evidence for these three connections. Pretend play has a nonliteral correspondence to reality, hence pretending may provide children with practice with navigating symbolic relationships, which may strengthen their language skills. Pretend play and theory of mind reasoning share a focus on others' mental states in order to correctly interpret their behavior, hence pretending and theory of mind may be mutually supportive in development. Pretend play and counterfactual reasoning both involve representing nonreal states of affairs, hence pretending may facilitate children's counterfactual abilities. These connections make pretend play an important phenomenon in cognitive science: Studying children's pretend play can provide insight into these other abilities and their developmental trajectories, and thereby into human cognitive architecture and its development. © 2015 John Wiley & Sons, Ltd.

Loss model for off-design performance analysis of radial turbines with pivoting-vane, variable-area stators

NASA Technical Reports Server (NTRS)

Meitner, P. L.; Glassman, A. J.

1980-01-01

An off-design performance loss model is developed for variable-area (pivoted vane) radial turbines. The variation in stator loss with stator area is determined by a viscous loss model while the variation in rotor loss due to stator area variation (for no stator end-clearance gap) is determined through analytical matching of experimental data. An incidence loss model is also based on matching of the experimental data. A stator vane end-clearance leakage model is developed and sample calculations are made to show the predicted effects of stator vane end-clearance leakage on performance.

Possible role of autoantibodies in the pathophysiology of GM2 gangliosidoses

PubMed Central

Yamaguchi, Akira; Katsuyama, Kayoko; Nagahama, Kiyotaka; Takai, Toshiyuki; Aoki, Ichiro; Yamanaka, Shoji

2004-01-01

Mice containing a disruption of the Hexb gene have provided a useful model system for the study of the human lysosomal storage disorder known as Sandhoff disease (SD). Hexb–/– mice rapidly develop a progressive neurologic disease of ganglioside GM2 and GA2 storage. Our study revealed that the disease states in this model are associated with the appearance of antiganglioside autoantibodies. Both elevation of serum antiganglioside autoantibodies and IgG deposition to CNS neurons were found in the advanced stages of the disease in Hexb–/– mice; serum transfer from these mice showed IgG binding to neurons. To determine the role of these autoantibodies, the Fc receptor γ gene (FcRγ) was additionally disrupted in Hexb–/– mice, as it plays a key role in immune complex–mediated autoimmune diseases. Clinical symptoms were improved and life spans were extended in the Hexb–/–FcRγ–/– mice; the number of apoptotic cells was also decreased. The level of ganglioside accumulation, however, did not change. IgG deposition was also confirmed in the brain of an autopsied SD patient. Taken together, these findings suggest that the production of autoantibodies plays an important role in the pathogenesis of neuropathy in SD and therefore provides a target for novel therapies. PMID:14722612

Word Play: Scaffolding Language Development through Child-Directed Play

ERIC Educational Resources Information Center

Wasik, Barbara A.; Jacobi-Vessels, Jill L.

2017-01-01

Play is an important activity in young children's lives. It is how children explore their world and build knowledge. Although free play, which is play that is totally child directed, contributes to children's learning, self-regulation and motivation, adults' participation in children's play is critical in their development, especially their…

The influence of somatotype components and personality traits on the playing position and the quality of top Croatian female cadet handball players.

PubMed

Cavala, Marijana; Trninić, Viktorija; Jasić, Dajana; Tomljanović, Mario

2013-05-01

The research was conducted with the aim to establish the structure and the differences of morphological features and personality traits between different age groups of female cadet handball players grouped by their playing quality and playing positions. Further on, the research was done on 70 handball players aged 15, 31 on average, who were grouped according to their positions on goalkeepers, outside players, wings and pivots. Furthermore, according to the quality of playing, they were divided in two quality groups of players, those from the wider cadet national team, thus characterised as top female players in Croatia, and those who had never been invited into the cadet national team and thus can be referred to as low-quality, i.e. average female handball players. The structure of predictor variables has indicated the existence of general morphological factor assessing the players' constitution and two personality features factors - neuroticism and extraversion. The variance analysis showed no statistically significant differences of somatotype variables with relation to quality and playing position. By observing basic personality traits, a statistically significant difference was confirmed only in introversion-extraversion with a lower score in goalkeepers than in other positions, which indicates a higher level of introversion in this playing position. Such result was expected since this particular position abounds in specific tasks and demands in the game in relation to all other playing positions. Further on, it has been concluded that the selection of players must not be based only on the stated physical and psychological characteristics, but on relevant anthropological complexes determining performance and sport achievement.

Play Therapy

PubMed Central

Lawver, Timothy; Blankenship, Kelly

2008-01-01

Play therapy is a treatment modality in which the therapist engages in play with the child. Its use has been documented in a variety of settings and with a variety of diagnoses. Treating within the context of play brings the therapist and the therapy to the level of the child. By way of an introduction to this approach, a case is presented of a six-year-old boy with oppositional defiant disorder. The presentation focuses on the events and interactions of a typical session with an established patient. The primary issues of the session are aggression, self worth, and self efficacy. These themes manifest themselves through the content of the child’s play and narration of his actions. The therapist then reflects these back to the child while gently encouraging the child toward more positive play. Though the example is one of nondirective play therapy, a wide range of variation exists under the heading of play therapy. PMID:19724720

A personal history of the human exploration initiative with commentary on the pivotal role for life support research

NASA Technical Reports Server (NTRS)

Mendell, Wendell

1990-01-01

The author relates the history of the human exploration initiative from a personal perspective from the 1961 J. F. Kennedy initiative to land a man on the moon up to 1986 when a memo was circulated from NASA Headquarters to its employees which stated as a major goal the expansion of the human presence beyond Earth into the solar system. The pivotal role of life support research is woven into this personalized history.

HTML5 PivotViewer: high-throughput visualization and querying of image data on the web

PubMed Central

Taylor, Stephen; Noble, Roger

2014-01-01

Motivation: Visualization and analysis of large numbers of biological images has generated a bottle neck in research. We present HTML5 PivotViewer, a novel, open source, platform-independent viewer making use of the latest web technologies that allows seamless access to images and associated metadata for each image. This provides a powerful method to allow end users to mine their data. Availability and implementation: Documentation, examples and links to the software are available from http://www.cbrg.ox.ac.uk/data/pivotviewer/. The software is licensed under GPLv2. Contact:  stephen.taylor@imm.ox.ac.uk and roger@coritsu.com PMID:24849578

Performance of gas-lubricated nonconforming pivoted-pad journal bearings and a flexibly mounted spiral-groove thrust bearing

NASA Technical Reports Server (NTRS)

Ream, L. W.

1973-01-01

A test program was conducted to determine the performance characteristics of gas-lubricated nonconforming pivoted-pad journal bearings and a spiral-groove thrust bearing designed for the Brayton cycle rotating unit (BRU). Hydrostatic, hybrid (simultaneously hydrostatic and hydrodynamic), and hydrodynamic tests were conducted in argon gas at ambient pressure and temperature ranges representative of hydrostatic operation up to the 10.5-kWe BRU power-generating level. Performance of the gas lubricated bearings is presented, including hydrostatic gas flow rates, bearing clearances, bearing temperatures, and transient performance.

Development of an automated method to detect sitting pivot transfer phases using biomechanical variables: toward a standardized method

PubMed Central

2012-01-01

Background Sitting pivot transfer (SPT) is one of the most important, but at the same time strenuous at the upper extremity, functional task for spinal cord injured individuals. In order to better teach this task to those individuals and to improve performance, a better biomechanical understanding during the different SPT phases is a prerequisite. However, no consensus has yet been reached on how to depict the different phases of the SPT. The definition of the phases of the SPT, along with the events characterizing these phases, will facilitate the interpretation of biomechanical outcome measures related to the performance of SPTs as well as strengthen the evidence generated across studies. Methods Thirty-five individuals with a spinal cord injury performed two SPTs between seats of similar height using their usual SPT technique. Kinematics and kinetics were recorded using an instrumented transfer assessment system. Based on kinetic and kinematic measurements, a relative threshold-based algorithm was developed to identify four distinct phases: pre-lift, upper arm loading, lift-pivot and post-lift phases. To determine the stability of the algorithm between the two SPTs, Student t-tests for dependent samples were performed on the absolute duration of each phase. Results The mean total duration of the SPT was 2.00 ± 0.49 s. The mean duration of the pre-lift, upper arm loading, lift-pivot and post-lift phases were 0.74 ± 0.29 s, 0.28 ± 0.13 s, 0.72 ± 0.24 s, 0.27 ± 0.14 s whereas their relative contributions represented approximately 35%, 15%, 35% and 15% of the overall SPT cycle, respectively. No significant differences were found between the trials (p = 0.480-0.891). Conclusion The relative threshold-based algorithm used to automatically detect the four distinct phases of the SPT, is rapid, accurate and repeatable. A quantitative and thorough description of the precise phases of the SPT is prerequisite to better interpret biomechanical findings and measure task

The influence of age, playing position, anthropometry and fitness on career attainment outcomes in rugby league.

PubMed

Till, Kevin; Cobley, Steve; Morley, David; O'hara, John; Chapman, Chris; Cooke, Carlton

2016-01-01

This study evaluated the influence of annual-age category, relative age, playing position, anthropometry and fitness on the career attainment outcomes of junior rugby league players originally selected for a talent identification and development (TID) programme. Junior rugby league players (N = 580) were grouped retrospectively according to their career attainment level (i.e., amateur, academy and professional). Anthropometric (height, sitting height, body mass, sum of four skinfolds), maturational (age at peak height velocity; PHV) and fitness (power, speed, change of direction speed, estimated[Formula: see text]) characteristics were assessed at the Under 13s, 14s and 15s annual-age categories. Relative age (Q2 = 8.5% vs. Q4 = 25.5%) and playing position (Pivots = 19.5% vs. Props = 5.8%) influenced the percentage of players attaining professional status. Anthropometry and fitness had a significant effect on career attainment at the Under 14 (P = 0.002, η(2) = 0.16) and 15 (P = 0.01, η(2) = 0.12) annual-age categories. Findings at the Under 14s showed future professional players were significantly later maturing compared to academy and amateur players. Findings suggest that relative age, playing position, anthropometry and fitness can influence the career attainment of junior rugby league players. TID programmes within rugby league, and other related team sports, should be aware and acknowledge the factors influencing long-term career attainment, and not delimit development opportunities during early adolescence.

Off-design performance loss model for radial turbines with pivoting, variable-area stators

NASA Technical Reports Server (NTRS)

Meitner, P. L.; Glassman, A. J.

1980-01-01

An off-design performance loss model was developed for variable stator (pivoted vane), radial turbines through analytical modeling and experimental data analysis. Stator loss is determined by a viscous loss model; stator vane end-clearance leakage effects are determined by a clearance flow model. Rotor loss coefficient were obtained by analyzing the experimental data from a turbine rotor previously tested with six stators having throat areas from 20 to 144 percent of design area and were correlated with stator-to-rotor throat area ratio. An incidence loss model was selected to obtain best agreement with experimental results. Predicted turbine performance is compared with experimental results for the design rotor as well as with results for extended and cutback versions of the rotor. Sample calculations were made to show the effects of stator vane end-clearance leakage.

Play Therapy: Facilitative Use of Child's Play in Elementary School Counseling.

ERIC Educational Resources Information Center

Landreth, Garry L.

1987-01-01

Reviews five major developments in play therapy: psychoanalysis, release therapy, relationship therapy, nondirective therapy, and play therapy in school settings. Suggests ways school counselors can use play therapy. Describes play therapy facilities, location selection, and play materials. Lists objectives of play therapy and how teachers can aid…

Transforming Play: An Analysis of First-, Third-, and Fifth-Graders' Play.

ERIC Educational Resources Information Center

Bagley, Donna M.; Chaille, Christine

1996-01-01

Compared children's play with transformational objects (vehicles that change to robots) to play with representational objects (cars and figures). Found that those playing with transformers engaged in more parallel play and manipulative activity, while those with representational objects displayed more social play and more symbolic play. Found no…

Aldehyde Dehydrogenase Plays a Pivotal Role in the Maintenance of Stallion Sperm Motility.

PubMed

Gibb, Zamira; Lambourne, Sarah R; Curry, Benjamin J; Hall, Sally E; Aitken, Robert J

2016-06-01

Although stallion spermatozoa produce significant quantities of reactive oxygen species, a lag between 4-hydroxynonenal (4HNE) adduction and the loss of motility in stallion spermatozoa suggests the presence of a robust aldehyde detoxification mechanism. Because there is a paucity of studies characterizing the role of aldehyde dehydrogenase (ALDH) in sperm functionality, the aim of this study was to ascertain the relationship between 4HNE production and motility and ALDH expression by stallion spermatozoa. PCR analysis revealed the presence of the ALDH1A3, ALDH1B1, and ALDH2 isoforms in these cells. Strong correlations (P < 0.001) were found between ALDH expression and various motility parameters of stallion spermatozoa including the percentage of progressive (r = 0.79) and rapidly motile (r = 0.79) spermatozoa, whereas repeated measurements over 24 h revealed highly significant correlations among progressive motility loss, 4HNE accumulation, and ALDH expression (P ≤ 0.001). ALDH inhibition resulted in a spontaneous increase in 4HNE levels in viable cells (21.1 ± 5.8% vs. 42.6 ± 5.2%; P ≤ 0.05) and a corresponding decrease in total motility (41.7 ± 6.2% vs. 6.4 ± 2.6%; P ≤ 0.001) and progressive motility (17.0 ± 4.1% vs. 0.7 ± 0.4%; P ≤ 0.001) of stallion spermatozoa over 24 h. Similarly, inhibition of ALDH in 4HNE-challenged spermatozoa significantly reduced total motility over 4 h (35.4 ± 9.7% vs. 15.3 ± 5.1%, respectively; P ≤ 0.05). This study contributes valuable information about the role of the ALDH enzymes in the maintenance of stallion sperm functionality, with potential diagnostic and in vitro applications for assisted reproductive technologies. © 2016 by the Society for the Study of Reproduction, Inc.

Mechanisms of Chemoresistance in Breast Cancer Cells

DTIC Science & Technology

2008-02-01

which blocks ganglioside biosynthesis at the juncture of ceramide synthase, or Vibrio cholerae neuraminidase, which cleaves cell surface gangliosides...MCF-7-AdrR and MCF-7-AdrR/GCS antisense cells were rinsed, harvested in PBS, and lysed in a PBS buffer containing 10% glycerol, 1% Triton X-100, 1.0...analysis of gangliosides. Cells harvested in PBS were homogenized in 6 mL chloroform/methanol (1:1, v/v); the mixture remained overnight at room

Pivotal issues on relativistic electrons in ITER

NASA Astrophysics Data System (ADS)

Boozer, Allen H.

2018-03-01

The transfer of the plasma current from thermal to relativistic electrons is a threat to ITER achieving its mission. This danger is significantly greater in the nuclear than in the non-nuclear phase of ITER operations. Two issues are pivotal. The first is the extent and duration of magnetic surface breaking in conjunction with the thermal quenches. The second is the exponential sensitivity of the current transfer to three quantities: (1) the poloidal flux change required to e-fold the number of relativistic electrons, (2) the time τa after the beginning of the thermal quench before the accelerating electric field exceeds the Connor-Hastie field for runaway, and (3) the duration of the period τ_op in which magnetic surfaces remain open. Adequate knowledge does not exist to devise a reliable strategy for the protection of ITER. Uncertainties are sufficiently large that a transfer of neither a negligible nor the full plasma current to relativistic electrons can be ruled out during the non-nuclear phase of ITER. Tritium decay can provide a sufficiently strong seed for a dangerous relativistic-electron current even if τa and τ_op are sufficiently long to avoid relativistic electrons during non-nuclear operations. The breakup of magnetic surfaces that is associated with thermal quenches occurs on a time scale associated with fast magnetic reconnection, which means reconnection at an Alfvénic rather than a resistive rate. Alfvénic reconnection is well beyond the capabilities of existing computational tools for tokamaks, but its effects can be studied using its property of conserving magnetic helicity. Although the dangers to ITER from relativistic electrons have been known for twenty years, the critical issues have not been defined with sufficient precision to formulate an effective research program. Studies are particularly needed on plasma behavior in existing tokamaks during thermal quenches, behavior which could be clarified using methods developed here.

Pretending to Play or Playing to Pretend: The Case of Autism.

PubMed

Kasari, Connie; Chang, Ya-Chih; Patterson, Stephanie

2013-01-01

An article by Angeline S. Lillard and others published in the January 2013 issue of Psychological Bulletin about the impact of pretend play on child development raised a number of issues about play studies and child psychology. They claimed that, contrary to current theories on the subject, the evidence of many studies does not support causal explanations of play's relationship to most childhood development. In this article, authors Kasari, Chang, and Patterson review these arguments about play and devlopment in relation to children with autism-children who show specific deficits in pretend play. They argue that the study of these children provides a unique opportunity to consider which elements in play are important and how play skills are associated with different periods of child development. They conclude that, because pretend play requires intervention for the majority of children with autism, improving pretense in these children may shed more light on the causal impact of pretense on later developing skills in children. Key words: child development and pretend play; children with autism; funtional play; intervention in play; symbol play.

The carbon balance pivot point of southwestern U.S. semiarid ecosystems: Insights from the 21st century drought

NASA Astrophysics Data System (ADS)

Scott, Russell L.; Biederman, Joel A.; Hamerlynck, Erik P.; Barron-Gafford, Greg A.

2015-12-01

Global-scale studies indicate that semiarid regions strongly regulate the terrestrial carbon sink. However, we lack understanding of how climatic shifts, such as decadal drought, impact carbon sequestration across the wide range of structural diversity in semiarid ecosystems. Therefore, we used eddy covariance measurements to quantify how net ecosystem production of carbon dioxide (NEP) differed with relative grass and woody plant abundance over the last decade of drought in four Southwest U.S. ecosystems. We identified a precipitation "pivot point" in the carbon balance for each ecosystem where annual NEP switched from negative to positive. Ecosystems with grass had pivot points closer to the drought period precipitation than the predrought average, making them more likely to be carbon sinks (and a grass-free shrubland, a carbon source) during the current drought. One reason for this is that the grassland located closest to the shrubland supported higher leaf area and photosynthesis at the same water availability. Higher leaf area was associated with a greater proportion of evapotranspiration being transpiration (T/ET), and therefore with higher ecosystem water use efficiency (gross ecosystem photosynthesis/ET). Our findings strongly show that water availability is a primary driver of both gross and net semiarid productivity and illustrate that structural differences may contribute to the speed at which ecosystem carbon cycling adjusts to climatic shifts.

Towards Play Pedagogy: Supporting Teacher Play Practices with a Teacher Guide about Socio-Dramatic and Imaginative Play

ERIC Educational Resources Information Center

Loizou, Eleni

2017-01-01

Drawing on the work of Vygotsky on scaffolding play and research on teacher intervention and mature forms of play, we have developed a teacher guide about play which frames children's role and scenario development and provides a teacher play intervention schema. The research question explored in this study is "How does a teacher guide,…

Playing it cool: Characterizing social play, bout termination, and candidate play signals of juvenile and infant Tibetan macaques (Macaca thibetana).

PubMed

Wright, Kaitlin R; Mayhew, Jessica A; Sheeran, Lori K; Funkhouser, Jake A; Wagner, Ronald S; Sun, Li-Xing; Li, Jin-Hua

2018-07-18

Play behaviors and signals during playful interactions with juvenile conspecifics are important for both the social and cognitive development of young animals. The social organization of a species can also influence juvenile social play. We examined the relationships among play behaviors, candidate play signals, and play bout termination in Tibetan macaques (Macaca thibetana) during juvenile and infant social play to characterize the species play style. As Tibetan macaques are despotic and live in groups with strict linear dominance hierarchies and infrequent reconciliation, we predicted that play would be at risk of misinterpretation by both the individuals engaged in the play bout and by those watching, possibly leading to injury of the players. Animals living in such societies might need to frequently and clearly signal playful intent to play partners and other group members to avoid aggressive outcomes. We gathered video data on 21 individually-identified juvenile and infant macaques (one month to five years of age) from the Valley of the Wild Monkeys, Mt. Huangshan, China. We used all-occurrence sampling to record play behaviors and candidate play signals based on an ethogram. We predicted that play groups would use multiple candidate play signals in a variety of contexts and in association with the number of audience members in proximity to the players and play bout length. In the 283 playful interactions we scored, juvenile and infant macaques used multiple body and facial candidate play signals. Our data showed that juvenile and infant Tibetan macaques use a versatile repertoire of play behaviors and signals to sustain play.

The role of play themes in non-directive play therapy.

PubMed

Ryan, Virginia; Edge, Andrew

2012-07-01

Describing the processes underlying play therapy is important for evidence based practice in child therapy. Employing play themes to describe children's play session contents is in widespread use by practitioners, but an adequate classification of these themes for non-directive play therapy practice has not yet been established. This article sets out to fill this gap by first describing how themes can be distinguished and distilled from the contents of play therapy contents. Second, a classification of main themes and sub-themes with exemplars to illustrate these concepts which is compatible with non-directive play therapy practice is set out. Finally a pilot project with experienced play therapists to test this classification in practice is suggested, along with the research questions that will need to be investigated in the shorter and longer terms.

The Effect of Pivotal Response Treatment in Children with Autism Spectrum Disorders: A Non-Randomized Study with a Blinded Outcome Measure

ERIC Educational Resources Information Center

Duifhuis, E. A.; den Boer, J. C.; Doornbos, A.; Buitelaar, J. K.; Oosterling, I. J.; Klip, H.

2017-01-01

Purpose of this quasi-experimental trial was to investigate the effect of Pivotal response treatment (PRT) versus treatment as usual (TAU) on autism symptoms. Children with autism spectrum disorder (ASD), aged 3-8 years, received either PRT (n = 11) or TAU (n = 13). Primary outcome measure was the total score on the Autism Diagnostic Observation…

Heat-labile Enterotoxins as Adjuvants or Anti-Inflammatory Agents

PubMed Central

Liang, Shuang; Hajishengallis, George

2010-01-01

Escherichia coli and Vibrio cholerae produce structurally related AB5-type heat-labile enterotoxins which are classified into two major types. The Type I subfamily includes cholera toxin and E. coli LT-I, whereas the Type II subfamily comprises LT-IIa and LT-IIb. In addition to their roles in microbial pathogenesis, the enterotoxins are widely and intensively studied for their exceptionally strong adjuvant and immunomodulatory activities, which are not necessarily dependent upon their abilities to elevate intracellular cAMP levels. Despite general structural similarities, these molecules, in intact or derivative form, display notable differences in their interactions with gangliosides or Toll-like receptors. This divergence results in differential immune response outcomes, the underlying mechanisms of which remain largely uncharacterized. Whereas the study of these molecules has been pivotal in understanding basic mechanisms of immune regulation, a formidable challenge is to dissociate toxicity from useful properties that can be exploited in vaccine development or for the treatment of autoimmune inflammatory diseases. PMID:20461887

Heat-labile enterotoxins as adjuvants or anti-inflammatory agents.

PubMed

Liang, Shuang; Hajishengallis, George

2010-01-01

Escherichia coli and Vibrio cholerae produce structurally related AB5-type heat-labile enterotoxins, which are classified into two major types. The Type I subfamily includes cholera toxin and E. coli LT-I, whereas the Type II subfamily comprises LT-IIa and LT-IIb. In addition to their roles in microbial pathogenesis, the enterotoxins are widely and intensively studied for their exceptionally strong adjuvant and immunomodulatory activities, which are not necessarily dependent upon their abilities to elevate intracellular cAMP levels. Despite general structural similarities, these molecules, in intact or derivative form, display notable differences in their interactions with gangliosides or Toll-like receptors. This divergence results in differential immune response outcomes, the underlying mechanisms of which remain largely uncharacterized. Whereas the study of these molecules has been pivotal in understanding basic mechanisms of immune regulation, a formidable challenge is to dissociate toxicity from useful properties that can be exploited in vaccine development or for the treatment of autoimmune inflammatory diseases.

N-butyldeoxynojirimycin treatment restores the innate fear response and improves learning in mucopolysaccharidosis IIIA mice.

PubMed

Kaidonis, Xenia; Byers, Sharon; Ranieri, Enzo; Sharp, Peter; Fletcher, Janice; Derrick-Roberts, Ainslie

2016-06-01

Mucopolysaccharidosis IIIA is a heritable neurodegenerative disorder resulting from the dysfunction of the lysosomal hydrolase sulphamidase. This leads to the primary accumulation of the complex carbohydrate heparan sulphate in a wide range of tissues and the secondary neuronal storage of gangliosides GM2 and GM3 in the brain. GM2 storage is associated with CNS deterioration in the GM2 gangliosidosis group of lysosomal storage disorders and may also contribute to MPS CNS disease. N-butyldeoxynojirimycin, an inhibitor of ceramide glucosyltransferase activity and therefore of ganglioside synthesis, was administered to MPS IIIA mice both prior to maximal GM2 and GM3 accumulation (early treatment) and after the maximum level of ganglioside had accumulated in the brain (late treatment) to determine if behaviour was altered by ganglioside level. Ceramide glucosyltransferase activity was decreased in both treatment groups; however, brain ganglioside levels were only decreased in the late treatment group. Learning in the water cross maze was improved in both groups and the innate fear response was also restored in both groups. A reduction in the expression of inflammatory gene Ccl3 was observed in the early treatment group, while IL1β expression was reduced in both treatment groups. Thus, it appears that NB-DNJ elicits a transient decrease in brain ganglioside levels, some modulation of inflammatory cytokines and a functional improvement in behaviour that can be elicited both before and after overt neurological changes manifest. NB-DNJ improves learning and restores the innate fear response in MPS IIIA mice by decreasing ceramide glucosyltransferase activity and transiently reducing ganglioside storage and/or modulating inflammatory signals. Copyright © 2016 Elsevier Inc. All rights reserved.

Imagination, Playfulness, and Creativity in Children's Play with Different Toys

ERIC Educational Resources Information Center

Mo????ller, Signe?? Juhl?

2015-01-01

Based on a four-month experimental study of preschool children's play with creative-construction and social-fantasy toys, the author examines the in?uence of both types of toys on the play of preschool children. Her comparative analysis considers the impact of transformative play on the development of imagination during play activities and…

Play

NASA Astrophysics Data System (ADS)

Harteveld, Casper

Designing a game with a serious purpose involves considering the worlds of Reality and Meaning yet it is undeniably impossible to create a game without a third world, one that is specifically concerned with what makes a game a game: the play elements. This third world, the world of people like designers and artists, and disciplines as computer science and game design, I call the world of Play and this level is devoted to it. The level starts off with some of the misperceptions people have of play. Unlike some may think, we play all the time, even when we grow old—this was also very noticeable in designing the game Levee Patroller as the team exhibited very playful behavior at many occasions. From there, I go into the aspects that characterize this world. The first concerns the goal of the game. This relates to the objectives people have to achieve within the game. This is constituted by the second aspect: the gameplay. Taking actions and facing challenges is subsequently constituted by a gameworld, which concerns the third aspect. And all of it is not possible without the fourth and final aspect, the type of technology that creates and facilitates the game. The four aspects together make up a “game concept” and from this world such a concept can be judged on the basis of three closely interrelated criteria: engagement, immersion, and fun.

Risk of anterior cruciate ligament fatigue failure is increased by limited internal femoral rotation during in vitro repeated pivot landings.

PubMed

Beaulieu, Mélanie L; Wojtys, Edward M; Ashton-Miller, James A

2015-09-01

A reduced range of hip internal rotation is associated with increased peak anterior cruciate ligament (ACL) strain and risk for injury. It is unknown, however, whether limiting the available range of internal femoral rotation increases the susceptibility of the ACL to fatigue failure. Risk of ACL failure is significantly greater in female knee specimens with a limited range of internal femoral rotation, smaller femoral-ACL attachment angle, and smaller tibial eminence volume during repeated in vitro simulated single-leg pivot landings. Controlled laboratory study. A custom-built testing apparatus was used to simulate repeated single-leg pivot landings with a 4×-body weight impulsive load that induces knee compression, knee flexion, and internal tibial torque in 32 paired human knee specimens from 8 male and 8 female donors. These test loads were applied to each pair of specimens, in one knee with limited internal femoral rotation and in the contralateral knee with femoral rotation resisted by 2 springs to simulate the active hip rotator muscles' resistance to stretch. The landings were repeated until ACL failure occurred or until a minimum of 100 trials were executed. The angle at which the ACL originates from the femur and the tibial eminence volume were measured on magnetic resonance images. The final Cox regression model (P = .024) revealed that range of internal femoral rotation and sex of donor were significant factors in determining risk of ACL fatigue failure. The specimens with limited range of internal femoral rotation had a failure risk 17.1 times higher than did the specimens with free rotation (P = .016). The female knee specimens had a risk of ACL failure 26.9 times higher than the male specimens (P = .055). Limiting the range of internal femoral rotation during repetitive pivot landings increases the risk of an ACL fatigue failure in comparison with free rotation in a cadaveric model. Screening for restricted internal rotation at the hip in ACL

Giving raw data a chance to talk: a demonstration of exploratory visual analytics with a pediatric research database using Microsoft Live Labs Pivot to promote cohort discovery, research, and quality assessment.

PubMed

Viangteeravat, Teeradache; Nagisetty, Naga Satya V Rao

2014-01-01

Secondary use of large and open data sets provides researchers with an opportunity to address high-impact questions that would otherwise be prohibitively expensive and time consuming to study. Despite the availability of data, generating hypotheses from huge data sets is often challenging, and the lack of complex analysis of data might lead to weak hypotheses. To overcome these issues and to assist researchers in building hypotheses from raw data, we are working on a visual and analytical platform called PRD Pivot. PRD Pivot is a de-identified pediatric research database designed to make secondary use of rich data sources, such as the electronic health record (EHR). The development of visual analytics using Microsoft Live Labs Pivot makes the process of data elaboration, information gathering, knowledge generation, and complex information exploration transparent to tool users and provides researchers with the ability to sort and filter by various criteria, which can lead to strong, novel hypotheses.

Giving Raw Data a Chance to Talk: A Demonstration of Exploratory Visual Analytics with a Pediatric Research Database Using Microsoft Live Labs Pivot to Promote Cohort Discovery, Research, and Quality Assessment

PubMed Central

Viangteeravat, Teeradache; Nagisetty, Naga Satya V. Rao

2014-01-01

Secondary use of large and open data sets provides researchers with an opportunity to address high-impact questions that would otherwise be prohibitively expensive and time consuming to study. Despite the availability of data, generating hypotheses from huge data sets is often challenging, and the lack of complex analysis of data might lead to weak hypotheses. To overcome these issues and to assist researchers in building hypotheses from raw data, we are working on a visual and analytical platform called PRD Pivot. PRD Pivot is a de-identified pediatric research database designed to make secondary use of rich data sources, such as the electronic health record (EHR). The development of visual analytics using Microsoft Live Labs Pivot makes the process of data elaboration, information gathering, knowledge generation, and complex information exploration transparent to tool users and provides researchers with the ability to sort and filter by various criteria, which can lead to strong, novel hypotheses. PMID:24808811

Play and Non-Play Tutoring in Pre-School Children: Is It Play or Tutoring Which Matters?

ERIC Educational Resources Information Center

Smith, P. K.; Syddall, Susan

1978-01-01

Previous studies on fantasy play tutoring are reviewed and research reported on the effect of the adult-child contact in this situation. Matched samples of preschoolers received either play or skills tutoring with equivalent tutor verbal contact. In these circumstances, differential advantages to the play-tutored children were few. (SJL)

Technical activity profile and influence of body anthropometry on playing performance in female elite team handball.

PubMed

Michalsik, Lars B; Aagaard, Per; Madsen, Klavs

2015-04-01

To determine the physical demands placed on female elite team handball (TH) players in relation to playing position and body anthropometry, female elite TH primarily field players were monitored during match-play using video recording and subsequent computerized technical match analysis during 5 regular tournament match seasons. Technical match activities were distributed in 6 major types of playing actions (shots, breakthroughs, fast breaks, technical errors, defensive errors, and tackles) and further divided into various subcategories (e.g., type of shot, hard or light tackles, claspings, screenings, and blockings). Furthermore, anthropometric measurements were performed. Each player had 28.3 ± 11.0 (group means ± SD) high-intense playing actions per match with a total effective playing time of 50.70 ± 5.83 minutes. On average, each player made 2.8 ± 2.6 fast breaks, gave 7.9 ± 14.4 screenings, received 14.6 ± 9.2 tackles in total, and performed 7.7 ± 3.7 shots while in offense, along with 3.5 ± 3.8 blockings, 1.9 ± 2.7 claspings, and 6.2 ± 3.8 hard tackles in defense. Mean body height, body mass, and age in the Danish Premier Female Team Handball League were 175.4 ± 6.1 cm, 69.5 ± 6.5 kg, and 25.4 ± 3.7 years, respectively. Wing players were lighter (63.5 ± 4.8 kg, p < 0.001) and smaller (169.3 ± 4.9 cm, p < 0.001) than backcourt players (BP) (70.6 ± 5.3 kg, 177.0 ± 5.4 cm) and pivots (PV) (72.5 ± 4.9 kg, 177.7 ± 4.9 cm). In conclusion, the present match observations revealed that female elite TH players during competitive games intermittently perform a high number of short-term, high-intense technical playing actions making modern female elite TH a physically demanding team sport. No sign of technical fatigue were observed, since the amount of intense technical playing actions remained unchanged in the second half. Marked positional differences in the physical demands were demonstrated, with wing players performing more fast breaks and less

Play and Mate Preference: Testing the Signal Theory of Adult Playfulness

ERIC Educational Resources Information Center

Chick, Garry; Yarnal, Careen; Purrington, Andrew

2012-01-01

The overwhelming majority of play research concerns juveniles. However, a full understanding of the phenomenon requires knowledge of play and playfulness across the life spans of those animals, including humans, who play in adulthood. The authors investigate a theory of play based on Darwin's concept of sexual selection that may account for the…

Playful biometrics: controversial technology through the lens of play.

PubMed

Ellerbrok, Ariane

2011-01-01

This article considers the role of play in the context of technological emergence and expansion, particularly as it relates to recently emerging surveillance technologies. As a case study, I consider the trajectory of automated face recognition—a biometric technology of numerous applications, from its more controversial manifestations under the rubric of national security to a clearly emerging orientation toward play. This shift toward “playful” biometrics—or from a technology traditionally coded as “hard” to one now increasingly coded as “soft”—is critical insofar as it renders problematic the traditional modes of critique that have, up until this point, challenged the expansion of biometric systems into increasingly ubiquitous realms of everyday life. In response to this dynamic, I propose theorizing the expansion of face recognition specifically in relation to “play,” a step that allows us to broaden the critical space around newly emerging playful biometrics, as well as playful surveillance more generally. In addition, play may also have relevance for theorizing other forms of controversial technology, particularly given its potential role in processes of obfuscation, normalization, and marginalization.

Pivotal response treatment prompts a functional rewiring of the brain among individuals with autism spectrum disorder.

PubMed

Venkataraman, Archana; Yang, Daniel Y-J; Dvornek, Nicha; Staib, Lawrence H; Duncan, James S; Pelphrey, Kevin A; Ventola, Pamela

2016-09-28

Behavioral interventions for autism have gained prominence in recent years; however, the neural-systems-level targets of these interventions remain poorly understood. We use a novel Bayesian framework to extract network-based differences before and after a 16-week pivotal response treatment (PRT) regimen. Our results suggest that the functional changes induced by PRT localize to the posterior cingulate and are marked by a shift in connectivity from the orbitofrontal cortex to the occipital-temporal cortex. Our results illuminate a potential PRT-induced learning mechanism, whereby the neural circuits involved during social perception shift from sensory and attentional systems to higher-level object and face processing areas.

Pivotal Response Treatment Prompts a Functional Rewiring of the Brain amongst Individuals with Autism Spectrum Disorder

PubMed Central

Venkataraman, Archana; Yang, Daniel Y.-J.; Dvornek, Nicha; Staib, Lawrence H.; Duncan, James S.; Pelphrey, Kevin A.; Ventola, Pamela

2016-01-01

Behavioral interventions for autism have gained prominence in recent years; however, the neural-systems-level targets of these interventions remain poorly understood. We use a novel Bayesian framework to extract network-based differences before and after a 16-week Pivotal Response Treatment (PRT) regimen. Our results suggest that functional changes induced by PRT localize to the posterior cingulate and are marked by a shift in connectivity from the orbitofrontal cortex to the occipital temporal cortex. Our results illuminate a potential PRT-induced learning mechanism, whereby the neural circuits involved during social perception shift from sensory and attentional systems to higher-level object and face processing areas. PMID:27532879

Target of rapamycin (TOR) plays a critical role in triacylglycerol accumulation in microalgae.

PubMed

Imamura, Sousuke; Kawase, Yasuko; Kobayashi, Ikki; Sone, Toshiyuki; Era, Atsuko; Miyagishima, Shin-Ya; Shimojima, Mie; Ohta, Hiroyuki; Tanaka, Kan

2015-10-01

Most microalgae produce triacylglycerol (TAG) under stress conditions such as nitrogen depletion, but the underlying molecular mechanism remains unclear. In this study, we focused on the role of target of rapamycin (TOR) in TAG accumulation. TOR is a serine/threonine protein kinase that is highly conserved and plays pivotal roles in nitrogen and other signaling pathways in eukaryotes. We previously constructed a rapamycin-susceptible Cyanidioschyzon merolae, a unicellular red alga, by expressing yeast FKBP12 protein to evaluate the results of TOR inhibition (Imamura et al. in Biochem Biophys Res Commun 439:264-269, 2013). By using this strain, we here report that rapamycin-induced TOR inhibition results in accumulation of cytoplasmic lipid droplets containing TAG. Transcripts for TAG synthesis-related genes, such as glycerol-3-phosphate acyltransferase and acyl-CoA:diacylglycerol acyltransferase (DGAT), were increased by rapamycin treatment. We also found that fatty acid synthase-dependent de novo fatty acid synthesis was required for the accumulation of lipid droplets. Induction of TAG and up-regulation of DGAT gene expression by rapamycin were similarly observed in the unicellular green alga, Chlamydomonas reinhardtii. These results suggest the general involvement of TOR signaling in TAG accumulation in divergent microalgae.

Metallothionein plays a prominent role in the prevention of diabetic nephropathy by sulforaphane via up-regulation of Nrf2

PubMed Central

Wu, Hao; Kong, Lili; Cheng, Yanli; Zhang, Zhiguo; Wang, Yangwei; Lou, Manyu; Tan, Yi; Chen, Xiangmei; Miao, Lining; Cai, Lu

2015-01-01

Sulforaphane (SFN) prevents diabetic nephropathy (DN) in type 1 diabetes via up-regulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, it has not been addressed whether SFN also prevents DN from type 2 diabetes or which Nrf2 downstream gene(s) play(s) the key role in SFN renal protection. Here we investigated whether Nrf2 is required for SFN protection against type 2 diabetes-induced DN and whether metallothionein (MT) is an Nrf2 downstream antioxidant using Nrf2 knockout (Nrf2-null) mice. In addition, MT knockout mice were used to further verify if MT is indispensable for SFN protection against DN. Diabetes-increased albuminuria, renal fibrosis, and inflammation were significantly prevented by SFN, and Nrf2 and MT expression was increased. However, SFN renal protection was completely lost in Nrf2-null diabetic mice, confirming the pivotal role of Nrf2 in SFN protection from type 2 diabetes-induced DN. Moreover, SFN failed to up-regulate MT in the absence of Nrf2, suggesting that MT is an Nrf2 downstream antioxidant. MT deletion resulted in a partial, but significant attenuation of SFN renal protection from type 2 diabetes, demonstrating a partial requirement for MT for SFN renal protection. Therefore, the present study demonstrates for the first time that as an Nrf2 downstream antioxidant, MT plays an important, though partial, role in mediating SFN renal protection from type 2 diabetes. PMID:26415026

Metallothionein plays a prominent role in the prevention of diabetic nephropathy by sulforaphane via up-regulation of Nrf2.

PubMed

Wu, Hao; Kong, Lili; Cheng, Yanli; Zhang, Zhiguo; Wang, Yangwei; Luo, Manyu; Tan, Yi; Chen, Xiangmei; Miao, Lining; Cai, Lu

2015-12-01

Sulforaphane (SFN) prevents diabetic nephropathy (DN) in type 1 diabetes via up-regulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, it has not been addressed whether SFN also prevents DN from type 2 diabetes or which Nrf2 downstream gene(s) play(s) the key role in SFN renal protection. Here we investigated whether Nrf2 is required for SFN protection against type 2 diabetes-induced DN and whether metallothionein (MT) is an Nrf2 downstream antioxidant using Nrf2 knockout (Nrf2-null) mice. In addition, MT knockout mice were used to further verify if MT is indispensable for SFN protection against DN. Diabetes-increased albuminuria, renal fibrosis, and inflammation were significantly prevented by SFN, and Nrf2 and MT expression was increased. However, SFN renal protection was completely lost in Nrf2-null diabetic mice, confirming the pivotal role of Nrf2 in SFN protection from type 2 diabetes-induced DN. Moreover, SFN failed to up-regulate MT in the absence of Nrf2, suggesting that MT is an Nrf2 downstream antioxidant. MT deletion resulted in a partial, but significant attenuation of SFN renal protection from type 2 diabetes, demonstrating a partial requirement for MT for SFN renal protection. Therefore, the present study demonstrates for the first time that as an Nrf2 downstream antioxidant, MT plays an important, though partial, role in mediating SFN renal protection from type 2 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

Quantitative comparison of the pivot shift test results before and after anterior cruciate ligament reconstruction by using the three-dimensional electromagnetic measurement system.

PubMed

Nagai, Kanto; Hoshino, Yuichi; Nishizawa, Yuichiro; Araki, Daisuke; Matsushita, Takehiko; Matsumoto, Tomoyuki; Takayama, Koji; Nagamune, Kouki; Kurosaka, Masahiro; Kuroda, Ryosuke

2015-10-01

Tibial acceleration during the pivot shift test is a potential quantitative parameter to evaluate rotational laxity of anterior cruciate ligament (ACL) insufficiency. However, clinical application of this measurement has not been fully examined. This study aimed to measure and compare tibial acceleration before and after ACL reconstruction (ACLR) in ACL-injured patients. We hypothesized tibial acceleration would be reduced by ACLR and tibial acceleration would be consistent in the same knee at different time points. Seventy ACL-injured patients who underwent ACLR were enrolled. Tibial acceleration during the pivot shift test was measured using an electromagnetic measurement system before ALCR and at the second-look arthroscopy 1 year post-operatively. Tibial acceleration was compared to clinical grading and between ACL-injured/ACL-reconstructed and contralateral knees. Pre-operative tibial acceleration was increased stepwise with the increase in clinical grading (P < 0.01). Tibial acceleration in ACL-injured knee (1.9 ± 1.2 m/s(2)) was larger than that in the contralateral knee (0.8 ± 0.3 m/s(2), P < 0.01), and reduced to 0.9 ± 0.3 m/s(2) post-operatively (P < 0.01). There was no difference between ACL-reconstructed and contralateral knee (n.s.). Tibial acceleration in contralateral knees was consistent pre- and post-operatively (n.s.). Tibial acceleration measurement demonstrated increased rotational laxity in ACL-injured knees and its reduction by ALCR. Additionally, consistent measurements were obtained in ACL-intact knees at different time points. Therefore, tibial acceleration during the pivot shift test could provide quantitative evaluation of rotational stability before and after ACL reconstruction. III.

Exploring Play/Playfulness and Learning in the Adult and Higher Education Classroom

ERIC Educational Resources Information Center

Tanis, David J.

2012-01-01

Play and playfulness and their role in learning are researched extensively in early childhood education. However, as the child matures into an adult, play and playfulness are given less attention in the teaching and learning process. In adult education, there is very little research about play/playfulness and its significance for learning. Despite…

The glycolipid GM1 reshapes asymmetric biomembranes and giant vesicles by curvature generation.

PubMed

Dasgupta, Raktim; Miettinen, Markus S; Fricke, Nico; Lipowsky, Reinhard; Dimova, Rumiana

2018-05-29

The ganglioside GM1 is present in neuronal membranes at elevated concentrations with an asymmetric spatial distribution. It is known to generate curvature and can be expected to strongly influence the neuron morphology. To elucidate these effects, we prepared giant vesicles with GM1 predominantly present in one leaflet of the membrane, mimicking the asymmetric GM1 distribution in neuronal membranes. Based on pulling inward and outward tubes, we developed a technique that allowed the direct measurement of the membrane spontaneous curvature. Using vesicle electroporation and fluorescence intensity analysis, we were able to quantify the GM1 asymmetry across the membrane and to subsequently estimate the local curvature generated by the molecule in the bilayer. Molecular-dynamics simulations confirm the experimentally determined dependence of the membrane spontaneous curvature as a function of GM1 asymmetry. GM1 plays a crucial role in connection with receptor proteins. Our results on curvature generation of GM1 point to an additional important role of this ganglioside, namely in shaping neuronal membranes. Copyright © 2018 the Author(s). Published by PNAS.

Isotopic labeling of milk disialogangliosides (GD3).

PubMed

Reis, Mariza Gomes; Bibiloni, Rodrigo; McJarrow, Paul; MacGibbon, Alastair; Fong, Bertram; Bassett, Shalome; Roy, Nicole; Dos Reis, Marlon Martins

2016-10-01

The most abundant ganglioside group in both human milk and bovine milk during the first postnatal week is ganglioside GD3. This group of disialogangliosides forms up to 80% of the total ganglioside content of colostrum. Although dietary gangliosides have shown biological activity such as improvement of cognitive development, gastrointestinal health, and immune function, there is still a gap in our understanding of the molecular mechanisms governing its uptake and the metabolic processes affecting its bioavailability. The use of isotopically labeled ganglioside to track the bioavailability, absorption, distribution, and metabolism of gangliosides may provide key information to bridge this gap. However, isotope labeled GD3 is not commercially available and its preparation has not been described. We report for the first time the preparation of labeled GD3 with stable isotopes. Using alkaline hydrolysis, we were able to selectively remove both acetyl groups from the tetrasaccharide portion of GD3 without promoting significant hydrolysis of the ceramide portion of the molecule to generate N-deacetyl-GD3 (Neu5α2-8Neu5-GD3). The N-deacetyl-GD3 was then chemoselectively re-acetylated in aqueous medium using deuterated acetic anhydride in the presence of Triton X 100 to produce 2 H 6 -GD3 {GD3[(Neu5Ac-11- 2 H 3 )-(Neu5Ac-11- 2 H 3 )]}. This method provided 2 H 6 -GD3 with approximately 60% yield. This compound was characterized by proton nuclear magnetic resonance ( 1 H NMR) and liquid chromatography mass spectrometry (LC-MS). The oral absorption of the 2 H 6 -GD3 was demonstrated using a Sprague-Dawley weaning rats. Our results indicate that some ingested labeled milk gangliosides are absorbed and transported into the bloodstream without modification. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Frog brain uridine diphosphate galactose–N-acetylgalactosaminyl-N-acetylneuraminylgalactosylglucosylceramide galactosyltransferase

PubMed Central

Yip, Morris C. M.; Dain, Joel A.

1970-01-01

1. The enzyme that catalyses the transfer of galactose from UDP-galactose to N-acetylgalactosaminyl-(1→4)-N-acetylneuraminyl-(2→3)-galactosyl-(1→4)-glucosylceramide (GM2) was found mainly in the heavy- and light-microsomal fractions of the adult frog brain. 2. The subcellular distribution of the enzyme, UDP-galactose–GM2 galactosyltransferase, parallels that of gangliosides in adult frog brain. 3. The enzymic activity was first detected at late gastrulation (Shumway stage 11½) and increased until the completion of the operculum (Shumway stage 25) and then decreased in the tadpoles. 4. In adult frog brain, the enzyme exhibited a pH optimum of 7.2–7.3 in both cacodylate and tris buffers. The enzyme required 10mm-Mn2+ for maximal activity and the Km for Mn2+ was determined as 2.2mm. The half-maximal velocity was obtained at a GM2 concentration of 0.18mm. Inhibition of the enzymic reaction was found when the GM2 concentration was greater than 1.38mm. 5. The enzymic activity was also inhibited by the products in the pathway of ganglioside synthesis, i.e. either by a mixture of gangliosides or by individual ganglioside components. The most active inhibitor was disialoganglioside. The degree of inhibition is a function of the individual ganglioside concentration. 6. A product-inhibition mechanism for the regulation of ganglioside biosynthesis is discussed. PMID:5484669

Pivots for pointing: visually-monitored pointing has higher arm elevations than pointing blindfolded.

PubMed

Wnuczko, Marta; Kennedy, John M

2011-10-01

Observers pointing to a target viewed directly may elevate their fingertip close to the line of sight. However, pointing blindfolded, after viewing the target, they may pivot lower, from the shoulder, aligning the arm with the target as if reaching to the target. Indeed, in Experiment 1 participants elevated their arms more in visually monitored than blindfolded pointing. In Experiment 2, pointing to a visible target they elevated a short pointer more than a long one, raising its tip to the line of sight. In Experiment 3, the Experimenter aligned the participant's arm with the target. Participants judged they were pointing below a visually monitored target. In Experiment 4, participants viewing another person pointing, eyes-open or eyes-closed, judged the target was aligned with the pointing arm. In Experiment 5, participants viewed their arm and the target via a mirror and posed their arm so that it was aligned with the target. Arm elevation was higher in pointing directly.

[Play therapy--psychotherapy with play as the medium: II. New developments].

PubMed

von Gontard, Alexander; Lehmkuhl, Gerd

2003-02-01

A wide array of new forms and combinations of play therapy have been developed. The aim of the second part of this paper is to present an overview of these newer approaches, including: focussed therapies for specific disorders; behavioural approaches like the Cognitive-Behavioral Play Therapy and the Parent-Child Interaction Therapy; various combinations with family therapy; and therapies especially for preschool children like Filial Therapy, Developmental Play Therapy and Thera-play. Following a phase of experiments and combinations, the empirical evaluation of many play-therapy forms is needed. Especially questions of the differential indication of specific play-therapies and their effectiveness in the therapeutical practice need to be studied.

Analysing playing using the note-time playing path.

PubMed

de Graaff, Deborah L E; Schubert, Emery

2011-03-01

This article introduces a new method of data analysis that represents the playing of written music as a graph. The method, inspired by Miklaszewski, charts low-level note timings from a sound recording of a single-line instrument using high-precision audio-to-MIDI conversion software. Note onset times of pitch sequences are then plotted against the score-predicted timings to produce a Note-Time Playing Path (NTPP). The score-predicted onset time of each sequentially performed note (horizontal axis) unfolds in performed time down the page (vertical axis). NTPPs provide a visualisation that shows (1) tempo variations, (2) repetitive practice behaviours, (3) segmenting of material, (4) precise note time positions, and (5) time spent on playing or not playing. The NTPP can provide significant new insights into behaviour and cognition of music performance and may also be used to complement established traditional approaches such as think-alouds, interviews, and video coding.

Playing It Safe: Risk Management for Games Play.

ERIC Educational Resources Information Center

Halliday, Nancy

1996-01-01

Considering the players, the game, and the environment in which games are played can make games play at camp safer, more successful, and more enjoyable. Presents factors concerning the players, the game, roughhousing, excessive competitiveness, the environment, space, boundaries, weather, time, and overall game objectives that need to be…

Dynamic profile of a prototype pivoted proof-mass actuator. [damping the vibration of large space structures

NASA Technical Reports Server (NTRS)

Miller, D. W.

1981-01-01

A prototype of a linear inertial reaction actuation (damper) device employing a flexure-pivoted reaction (proof) mass is discussed. The mass is driven by an electromechanic motor using a dc electromagnetic field and an ac electromagnetic drive. During the damping process, the actuator dissipates structural kinetic energy as heat through electromagnetic damping. A model of the inertial, stiffness and damping properties is presented along with the characteristic differential equations describing the coupled response of the actuator and structure. The equations, employing the dynamic coefficients, are oriented in the form of a feedback control network in which distributed sensors are used to dictate actuator response leading to a specified amount of structural excitation or damping.

Return to Play and Player Performance After Anterior Cruciate Ligament Injury in Elite Australian Rules Football Players

PubMed Central

Liptak, Matthew G.; Angel, Kevin R.

2017-01-01

Background: Australian Rules football is a highly aerobic and anaerobic game that at times requires players to perform cutting or pivoting maneuvers, potentially exposing them to anterior cruciate ligament (ACL) injury. At present, there are limited data available addressing the impact of ACL injury on return to play and preinjury form after ACL reconstruction. Purpose: To determine the prevalence of ACL injury and the incidence of further ACL injury, and to consider player return to play and return to preinjury form after ACL reconstruction. It was hypothesized that elite-level Australian Football League (AFL) players do not return to preinjury form until, at minimum, 2 years after returning to play. Study Design: Case series; Level of evidence, 4. Methods: A retrospective analysis was undertaken on a cohort of elite AFL players who injured their ACL between 1990 and 2000. Return to play after ACL reconstruction was determined by the mean number of ball disposals, or release of the ball by the hand or foot, at 1, 2, and 3 years after return to play and compared with preinjury form. Associations between player and injury characteristics, method of reconstruction, and outcomes (return to play, preinjury form, and further ACL injury) were examined. Results: During the included seasons, a total of 2723 AFL players were listed. Of these, 131 (4.8%) sustained an ACL injury, with 115 players eligible for inclusion. Of 115 players, 26% did not return to elite competition, while 28% of those who did return experienced further ACL injury. The adjusted mean number of disposals (± standard error of the mean) was significantly lower at 1 year (12.21 ± 0.63; P = .003), 2 years (12.09 ± 0.65; P = .008), and 3 years (11.78 ± 0.77; P = .01) after return to play compared with preinjury (14.23 ± 0.67). On average, players did not return to preinjury form by 3 years (P < .01). Players aged 30 years or older were less likely to return to play compared with younger players (P

Distinct Immunoglobulin Class and Immunoglobulin G Subclass Patterns against Ganglioside GQ1b in Miller Fisher Syndrome following Different Types of Infection

PubMed Central

Schwerer, Beatrix; Neisser, Andrea; Bernheimer, Hanno

1999-01-01

We studied serum antibodies against gangliosides GQ1b and GM1 in 13 patients with Miller Fisher syndrome (MFS) and in 18 patients with Guillain-Barré syndrome (GBS) with cranial nerve involvement. Anti-GQ1b titers were elevated in all patients with MFS cases (immunoglobulin G [IgG] > IgA, IgM), and in 8 of the 18 with GBS. Lower frequencies of increased anti-GM1 titers were observed in MFS patients (3 of 13), as well as in GBS patients (5 of 18). During the course of MFS, anti-GQ1b titers of all Ig classes decreased within 3 weeks after onset. By contrast, anti-GM1 titers (mainly IgM) transiently increased during the course of MFS in five of six patients, suggesting a nonspecific secondary immune response. In patients with MFS following respiratory infections, IgG was the major anti-GQ1b Ig class (six of six patients) and IgG3 was the major subclass (five of six). In contrast, four of five patients with MFS following gastrointestinal infections showed predominance of anti-GQ1b IgA or IgM over IgG and predominance of the IgG2 subclass; anti-GQ1b IgG (IgG3) prevailed in one patient only. These distinct Ig patterns strongly suggest that different infections may trigger different mechanisms of anti-GQ1b production, such as via T-cell-dependent as opposed to T-cell-independent pathways. Thus, the origin of antibodies against GQ1b in MFS may be determined by the type of infectious agent that precipitates the disease. PMID:10225903

Localization patterns of the ganglioside GM1 in human sperm are indicative of male fertility and independent of traditional semen measures

PubMed Central

Cardona, Cristina; Neri, Queenie V.; Simpson, Alana J.; Moody, Melissa A.; Ostermeier, G. Charles; Seaman, Eric K.; Paniza, Theodore; Rosenwaks, Zev; Palermo, Gianpiero D.

2017-01-01

Semen analysis lacks a functional component and best identifies extreme cases of infertility. The ganglioside GM1 is known to have functional roles during capacitation and acrosome exocytosis. Here, we assessed whether GM1 localization patterns (Cap‐Score™) correspond with male fertility in different settings: Study 1 involved couples pursuing assisted reproduction in a tertiary care fertility clinic, while Study 2 involved men with known fertility versus those questioning their fertility at a local urology center. In Study 1, we examined various thresholds versus clinical history for 42 patients; 13 had Cap‐Scores ≥39.5%, with 12 of these (92.3%) achieving clinical pregnancy by natural conception or ≤3 intrauterine insemination cycles. Of the 29 patients scoring <39.5%, only six (20.7%) attained clinical pregnancy by natural conception or ≤3 intrauterine insemination cycles. In Study 2, Cap‐Scores were obtained from 76 fertile men (Cohort 1, pregnant partner or recent father) and compared to 122 men seeking fertility assessment (Cohort 2). Cap‐Score values were normally distributed in Cohort 1, with 13.2% having Cap‐Scores more than one standard deviation below the mean (35.3 ± 7.7%). Significantly, more men in Cohort 2 had Cap‐Scores greater than one standard deviation below the normal mean (33.6%; p = 0.001). Minimal/no relationship was found between Cap‐Score and sperm concentration, morphology, or motility. Together, these data demonstrate that Cap‐Score provides novel, clinically relevant insights into sperm function and male fertility that complement traditional semen analysis. Furthermore, the data provide normal reference ranges for fertile men that can help clinicians counsel couples toward the most appropriate fertility treatment. PMID:28418610

Play Therapy: A Review

ERIC Educational Resources Information Center

Porter, Maggie L.; Hernandez-Reif, Maria; Jessee, Peggy

2009-01-01

This article discusses the current issues in play therapy and its implications for play therapists. A brief history of play therapy is provided along with the current play therapy approaches and techniques. This article also touches on current issues or problems that play therapists may face, such as interpreting children's play, implementing…

Histidine biosynthesis plays a crucial role in metal homeostasis and virulence of Aspergillus fumigatus

PubMed Central

Dietl, Anna-Maria; Amich, Jorge; Leal, Sixto; Beckmann, Nicola; Binder, Ulrike; Beilhack, Andreas; Pearlman, Eric; Haas, Hubertus

2016-01-01

Abstract Aspergillus fumigatus is the most prevalent airborne fungal pathogen causing invasive fungal infections in immunosuppressed individuals. The histidine biosynthetic pathway is found in bacteria, archaebacteria, lower eukaryotes, and plants, but is absent in mammals. Here we demonstrate that deletion of the gene encoding imidazoleglycerol-phosphate dehydratase (HisB) in A. fumigatus causes (i) histidine auxotrophy, (ii) decreased resistance to both starvation and excess of various heavy metals, including iron, copper and zinc, which play a pivotal role in antimicrobial host defense, (iii) attenuation of pathogenicity in 4 virulence models: murine pulmonary infection, murine systemic infection, murine corneal infection, and wax moth larvae. In agreement with the in vivo importance of histidine biosynthesis, the HisB inhibitor 3-amino-1,2,4-triazole reduced the virulence of the A. fumigatus wild type and histidine supplementation partially rescued virulence of the histidine-auxotrophic mutant in the wax moth model. Taken together, this study reveals limited histidine availability in diverse A. fumigatus host niches, a crucial role for histidine in metal homeostasis, and the histidine biosynthetic pathway as being an attractive target for development of novel antifungal therapy approaches. PMID:26854126

Histidine biosynthesis plays a crucial role in metal homeostasis and virulence of Aspergillus fumigatus.

PubMed

Dietl, Anna-Maria; Amich, Jorge; Leal, Sixto; Beckmann, Nicola; Binder, Ulrike; Beilhack, Andreas; Pearlman, Eric; Haas, Hubertus

2016-05-18

Aspergillus fumigatus is the most prevalent airborne fungal pathogen causing invasive fungal infections in immunosuppressed individuals. The histidine biosynthetic pathway is found in bacteria, archaebacteria, lower eukaryotes, and plants, but is absent in mammals. Here we demonstrate that deletion of the gene encoding imidazoleglycerol-phosphate dehydratase (HisB) in A. fumigatus causes (i) histidine auxotrophy, (ii) decreased resistance to both starvation and excess of various heavy metals, including iron, copper and zinc, which play a pivotal role in antimicrobial host defense, (iii) attenuation of pathogenicity in 4 virulence models: murine pulmonary infection, murine systemic infection, murine corneal infection, and wax moth larvae. In agreement with the in vivo importance of histidine biosynthesis, the HisB inhibitor 3-amino-1,2,4-triazole reduced the virulence of the A. fumigatus wild type and histidine supplementation partially rescued virulence of the histidine-auxotrophic mutant in the wax moth model. Taken together, this study reveals limited histidine availability in diverse A. fumigatus host niches, a crucial role for histidine in metal homeostasis, and the histidine biosynthetic pathway as being an attractive target for development of novel antifungal therapy approaches.

Well Played: The Origins and Future of Playfulness

ERIC Educational Resources Information Center

Gordon, Gwen

2014-01-01

In this article, the author synthesizes research from several disciplines to shed light on play's central role in healthy development. Gordon builds on research in attachment theory that correlates secure attachment in infancy with adult well-being to demonstrate how playfulness might be a lifelong outcome of secure attachment and a primary…

Risk of Anterior Cruciate Ligament Fatigue Failure Is Increased by Limited Internal Femoral Rotation During In Vitro Repeated Pivot Landings

PubMed Central

Beaulieu, Mélanie L.; Wojtys, Edward M.; Ashton-Miller, James A.

2015-01-01

Background A reduced range of hip internal rotation is associated with increased peak anterior cruciate ligament (ACL) strain and risk for injury. It is unknown, however, whether limiting the available range of internal femoral rotation increases the susceptibility of the ACL to fatigue failure. Hypothesis Risk of ACL failure is significantly greater in female knee specimens with a limited range of internal femoral rotation, smaller femoral-ACL attachment angle, and smaller tibial eminence volume during repeated in vitro simulated single-leg pivot landings. Study Design Controlled laboratory study. Methods A custom-built testing apparatus was used to simulate repeated single-leg pivot landings with a 4×-body weight impulsive load that induces knee compression, knee flexion, and internal tibial torque in 32 paired human knee specimens from 8 male and 8 female donors. These test loads were applied to each pair of specimens, in one knee with limited internal femoral rotation and in the contralateral knee with femoral rotation resisted by 2 springs to simulate the active hip rotator muscles’ resistance to stretch. The landings were repeated until ACL failure occurred or until a minimum of 100 trials were executed. The angle at which the ACL originates from the femur and the tibial eminence volume were measured on magnetic resonance images. Results The final Cox regression model (P = .024) revealed that range of internal femoral rotation and sex of donor were significant factors in determining risk of ACL fatigue failure. The specimens with limited range of internal femoral rotation had a failure risk 17.1 times higher than did the specimens with free rotation (P = .016). The female knee specimens had a risk of ACL failure 26.9 times higher than the male specimens (P = .055). Conclusion Limiting the range of internal femoral rotation during repetitive pivot landings increases the risk of an ACL fatigue failure in comparison with free rotation in a cadaveric model

Lateral femoral notch depth is not associated with increased rotatory instability in ACL-injured knees: a quantitative pivot shift analysis.

PubMed

Kanakamedala, Ajay C; Burnham, Jeremy M; Pfeiffer, Thomas R; Herbst, Elmar; Kowalczuk, Marcin; Popchak, Adam; Irrgang, James; Fu, Freddie H; Musahl, Volker

2018-05-01

A deep lateral femoral notch (LFN) on lateral radiographs is indicative of ACL injury. Prior studies have suggested that a deep LFN may also be a sign of persistent rotatory instability and a concomitant lateral meniscus tear. Therefore, the purpose of this study was to evaluate the relationship between LFN depth and both quantitative measures of rotatory knee instability and the incidence of lateral meniscus tears. It was hypothesized that greater LFN depth would be correlated with increased rotatory instability, quantified by lateral compartment translation and tibial acceleration during a quantitative pivot shift test, and incidence of lateral meniscus tears. ACL-injured patients enrolled in a prospective ACL registry from 2014 to 2016 were analyzed. To limit confounders, patients were only included if they had primary ACL tears, no concurrent ligamentous or bony injuries requiring operative treatment, and no previous knee injuries or surgeries to either knee. Eighty-four patients were included in the final analysis. A standardized quantitative pivot shift test was performed pre-operatively under anesthesia in both knees, and rotatory instability, specifically lateral compartment translation and tibial acceleration, was quantified using tablet image analysis software and accelerometer sensors. Standard lateral radiographs and sagittal magnetic resonance images (MRI) of the injured knee were evaluated for LFN depth. There were no significant correlations between LFN depth on either imaging modality and ipsilateral lateral compartment translation or tibial acceleration during a quantitative pivot shift test or side-to-side differences in these measurements. Patients with lateral meniscus tears were found to have significantly greater LFN depths than those without on conventional radiograph and MRI (1.0 vs. 0.6 mm, p < 0.05; 1.2 vs. 0.8 mm, p < 0.05, respectively). There was no correlation between lateral femoral notch depth on conventional radiographs or

Pivotal role of PGE2 and IL-10 in the cross-regulation of dendritic cell-derived inflammatory mediators.

PubMed

Harizi, Hedi; Gualde, Norbert

2006-08-01

Exposure to pathogens induces antigen-presenting cells (APC) such as macrophages and dendritic cells (DC) to produce various endogenous mediators, including arachidonic acid (AA)-derived eicosanoids, cytokines, and nitric oxide (NO). Many secreted products of activated APC can act by themselves in an autocrine manner and modulate their function. Moreover, the cross-interaction between endogenous bioactive molecules regulates the function of professional APC with important consequences for their ability to activate and sustain immune and inflammatory responses, and to regulate immune homeostasis. Although neglected for many years when compared to their role in cardiovascular homeostasis, cancer and inflammation, the importance of eicosanoids in immunology is becoming more defined. The role of prostaglandin (PG) E2 (PGE2), one of the best known and most well studied eicosanoids, is of particular interest. It modulates the activities of professional DC by acting on their differentiation, maturation and their ability to secrete cytokines. Uniquely among haematopoietic cytokines, interleukin-10 (IL-10) is a pleiotropic molecule that displays both immunostimulatory and immunoregulatory activities. IL-10 has attached much attention because of its anti-inflammatory properties. It modulates expression of cytokines, soluble mediators and cell surface molecules by cells of myeloid origin, particularly macrophages and DC. We previously reported that PGE2 is a potent inducer of IL-10 in bone marrow-derived DC (BM-DC), and PGE2-induced IL-10 is a key regulator of the BM-DC pro-inflammatory phenotype. BM-DC may be considered as an important model to study complex interactions between endogenous mediators, and autocrine IL-10 plays a pivotal role in the crossregulation of AA-derived lipid mediators, cytokines, and NO, with critical effects on immune and inflammatory responses.

Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.

PubMed

Nordström, Viola; Willershäuser, Monja; Herzer, Silke; Rozman, Jan; von Bohlen Und Halbach, Oliver; Meldner, Sascha; Rothermel, Ulrike; Kaden, Sylvia; Roth, Fabian C; Waldeck, Clemens; Gretz, Norbert; de Angelis, Martin Hrabě; Draguhn, Andreas; Klingenspor, Martin; Gröne, Hermann-Josef; Jennemann, Richard

2013-01-01

Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase). As a major mechanism of central nervous system (CNS) metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR) in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos) in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg) display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV)-mediated Ugcg delivery to the arcuate nucleus (Arc) significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis.

Play: early and eternal.

PubMed Central

Mears, C E; Harlow, H F

1975-01-01

A systematic 12-week investigation of development of play behavior was conducted with eight socially reared rhesus monkey infants. A new, basic and primary play form termed self-motion play or peragration was identified and examined. This behavior follows a human model which includes a wide range of pleasurable activities involving motion of the body through space, e.g., rocking, swinging, running, leaping, and water or snow skiing. It can be argued that self-motion play is the initial primate play form and because of its persistence constitutes a reinforcing agent for maintaining many complex patterns and even pastimes. Monkey self-motion play in the present study was divided into five separate patterns in order to compare the relative importance of social and individual peragration play, the role of apparatus and the overall developmental relationships between the different individual and social self-motion play patterns. The data showed that from 90 to 180 days of age self-motion play was independent of other forms of play, that individual self-motion play appeared earlier and with significantly greater increases in frequency than did social self-motion play, and that apparatus was a necessary component for significant increases in social self-motion play. Other findings were that self-motion play existed independent of locomotion and, though initiated by exploration, was separate from it. Therapeutic implications of self-motion play were discussed. Images PMID:1057178

Inefficiency in GM2 ganglioside elimination by human lysosomal beta-hexosaminidase beta-subunit gene transfer to fibroblastic cell line derived from Sandhoff disease model mice.

PubMed

Itakura, Tomohiro; Kuroki, Aya; Ishibashi, Yasuhiro; Tsuji, Daisuke; Kawashita, Eri; Higashine, Yukari; Sakuraba, Hitoshi; Yamanaka, Shoji; Itoh, Kohji

2006-08-01

Sandhoff disease (SD) is an autosomal recessive GM2 gangliosidosis caused by the defect of lysosomal beta-hexosaminidase (Hex) beta-subunit gene associated with neurosomatic manifestations. Therapeutic effects of Hex subunit gene transduction have been examined on Sandhoff disease model mice (SD mice) produced by the allelic disruption of Hexb gene encoding the murine beta-subunit. We demonstrate here that elimination of GM2 ganglioside (GM2) accumulated in the fibroblastic cell line derived from SD mice (FSD) did not occur when the HEXB gene only was transfected. In contrast, a significant increase in the HexB (betabeta homodimer) activity toward neutral substrates, including GA2 (asialo-GM2) and oligosaccharides carrying the terminal N-acetylglucosamine residues at their non-reducing ends (GlcNAc-oligosaccharides) was observed. Immunoblotting with anti-human HexA (alphabeta heterodimer) serum after native polyacrylamide gel electrophoresis (Native-PAGE) revealed that the human HEXB gene product could hardly form the chimeric HexA through associating with the murine alpha-subunit. However, co-introduction of the HEXA encoding the human alpha-subunit and HEXB genes caused significant corrective effect on the GM2 degradation by producing the human HexA. These results indicate that the recombinant human HexA could interspeciesly associate with the murine GM2 activator protein to degrade GM2 accumulated in the FSD cells. Thus, therapeutic effects of the recombinant human HexA isozyme but not human HEXB gene product could be evaluated by using the SD mice.

Science as Play

ERIC Educational Resources Information Center

Raymo, Chester

1973-01-01

Analyzes the nature and characteristics of the scientific endeavor to compare with that of children's play. Describes science as a form of religious sacred play which creates a world of make-believe that one may enter if one chooses to play. (CC)

Glycolipids as indicators of tumorigenesis.

PubMed

Morré, D J; Kloppel, T M; Merritt, W D; Keenan, T W

1978-01-01

Hyperplastic liver nodules and hepatocellular carcinomas were induced in rats by oral administration of the carcinogen N-2-fluorenylacetamide. Neoplastic tissue was compared with control, fetal, neonatal, and precancerous liver tissues. The development of the tumors was slow, such that temporal changes in the biochemical and morphologic development of carcinogenesis could be identified. Ganglioside sialic acid levels were elevated in all but the most poorly differentiated tumors. Experiments to monitor individual enzymes suggested that the alterations in glycolipid composition were a direct effect of alterations in biosynthetic activities. The pattern during tumorigenesis was the inverse of that during normal development. Also, ganglioside patterns showed a progressive simplification from hyperplastic nodules to well-differentiated hepatomas and through two grades of poorly differentiated hepatomas. An increase in the activity of the branchpoint enzyme of ganglioside biosynthesis preceded both a decrease in the branchpoint enzyme of the disialoganglioside pathway and a marked increase in the galactosyltranferase of GM1 formation. The results indicate that ganglioside deletions are the end result of a cascade of events in the tumorigenic transformation. The onset of ganglioside deletions but not of the cascade per se may correlate with the onset of malignancy. Glycolipid levels are elevated early in certain surrounding tissues especially in the blood. In rats bearing transplantable hepatomas, serum levels of lipid-bound sialic acid were elevated 2.5-fold. Similar results were obtained with sera of mice bearing transplantable mammary carcinomas and of cancer patients. These findings provide new emphasis for gangliosides in both cancer detection and as regulatory signals for growth and multiplication of cells.

Web GIS in practice IX: a demonstration of geospatial visual analytics using Microsoft Live Labs Pivot technology and WHO mortality data

PubMed Central

2011-01-01

The goal of visual analytics is to facilitate the discourse between the user and the data by providing dynamic displays and versatile visual interaction opportunities with the data that can support analytical reasoning and the exploration of data from multiple user-customisable aspects. This paper introduces geospatial visual analytics, a specialised subtype of visual analytics, and provides pointers to a number of learning resources about the subject, as well as some examples of human health, surveillance, emergency management and epidemiology-related geospatial visual analytics applications and examples of free software tools that readers can experiment with, such as Google Public Data Explorer. The authors also present a practical demonstration of geospatial visual analytics using partial data for 35 countries from a publicly available World Health Organization (WHO) mortality dataset and Microsoft Live Labs Pivot technology, a free, general purpose visual analytics tool that offers a fresh way to visually browse and arrange massive amounts of data and images online and also supports geographic and temporal classifications of datasets featuring geospatial and temporal components. Interested readers can download a Zip archive (included with the manuscript as an additional file) containing all files, modules and library functions used to deploy the WHO mortality data Pivot collection described in this paper. PMID:21410968

Web GIS in practice IX: a demonstration of geospatial visual analytics using Microsoft Live Labs Pivot technology and WHO mortality data.

PubMed

Kamel Boulos, Maged N; Viangteeravat, Teeradache; Anyanwu, Matthew N; Ra Nagisetty, Venkateswara; Kuscu, Emin

2011-03-16

The goal of visual analytics is to facilitate the discourse between the user and the data by providing dynamic displays and versatile visual interaction opportunities with the data that can support analytical reasoning and the exploration of data from multiple user-customisable aspects. This paper introduces geospatial visual analytics, a specialised subtype of visual analytics, and provides pointers to a number of learning resources about the subject, as well as some examples of human health, surveillance, emergency management and epidemiology-related geospatial visual analytics applications and examples of free software tools that readers can experiment with, such as Google Public Data Explorer. The authors also present a practical demonstration of geospatial visual analytics using partial data for 35 countries from a publicly available World Health Organization (WHO) mortality dataset and Microsoft Live Labs Pivot technology, a free, general purpose visual analytics tool that offers a fresh way to visually browse and arrange massive amounts of data and images online and also supports geographic and temporal classifications of datasets featuring geospatial and temporal components. Interested readers can download a Zip archive (included with the manuscript as an additional file) containing all files, modules and library functions used to deploy the WHO mortality data Pivot collection described in this paper.

Novel insights into the lipidome of glioblastoma cells based on a combined PLSR and DD-HDS computational analysis

NASA Astrophysics Data System (ADS)

Lespinats, S.; Meyer-Bäse, Anke; He, Huan; Marshall, Alan G.; Conrad, Charles A.; Emmett, Mark R.

2009-05-01

Partial Least Square Regression (PLSR) and Data-Driven High Dimensional Scaling (DD-HDS) are employed for the prediction and the visualization of changes in polar lipid expression induced by different combinations of wild-type (wt) p53 gene therapy and SN38 chemotherapy of U87 MG glioblastoma cells. A very detailed analysis of the gangliosides reveals that certain gangliosides of GM3 or GD1-type have unique properties not shared by the others. In summary, this preliminary work shows that data mining techniques are able to determine the modulation of gangliosides by different treatment combinations.

Game playing.

PubMed

Rosin, Christopher D

2014-03-01

Game playing has been a core domain of artificial intelligence research since the beginnings of the field. Game playing provides clearly defined arenas within which computational approaches can be readily compared to human expertise through head-to-head competition and other benchmarks. Game playing research has identified several simple core algorithms that provide successful foundations, with development focused on the challenges of defeating human experts in specific games. Key developments include minimax search in chess, machine learning from self-play in backgammon, and Monte Carlo tree search in Go. These approaches have generalized successfully to additional games. While computers have surpassed human expertise in a wide variety of games, open challenges remain and research focuses on identifying and developing new successful algorithmic foundations. WIREs Cogn Sci 2014, 5:193-205. doi: 10.1002/wcs.1278 CONFLICT OF INTEREST: The author has declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. © 2014 John Wiley & Sons, Ltd.

Mother-Infant and Extra-Dyadic Interactions with a New Social Partner: Developmental Trajectories of Early Social Abilities during Play.

PubMed

Fadda, Roberta; Lucarelli, Loredana

2017-01-01

Mother-infant interactions during feeding and play are pivotal experiences in the development of infants' early social abilities (Stern, 1985, 1995; Biringen, 2000). Stern indicated distinctive characteristics of mother-infant interactions, respectively, during feeding and play, suggesting to evaluate both to better describe the complexity of such early affective and social experiences (Stern, 1996). Moreover, during the first years of life, infants acquire cognitive and social skills that allow them to interact with new social partners in extra-dyadic interactions. However, the relations between mother-child interactions and infants' social skills in extra-dyadic interactions are still unknown. We investigated longitudinally the relations between mother-child interactions during feeding and play and child's pre-verbal communicative abilities in extra-dyadic interactions during play. 20 dyads were evaluated at T 1 (infants aged between 9-22 months) and 6 months later, at T 2 . The interdyadic differences in mother-infant interactions during feeding and play were evaluated, respectively, with the "Feeding Scale" (Chatoor et al., 1997) and with the "Play Scale" (Chatoor, 2006) and the socio-communicative abilities of children with a new social partner during play were evaluated with the "Early Social Communication Scales" (Mundy et al., 2003). We distinguished the dyads into two categories: dyads with functional interactions (high dyadic reciprocity, low dyadic conflict) and dyads with dysfunctional interactions (lower dyadic reciprocity, higher dyadic conflict). At T 1 , infants belonging to dyads with dysfunctional interactions were significantly lower in "Initiating Joint Attention" and in "Responding to Joint Attention" in interaction with a new social partner compared to the infants belonging to dyads with functional interactions. At T 2 , infants belonging to dyads with dysfunctional interactions were significantly lower in "Initiating Social Interactions" with

Two-Character Plays for Student Actors: A Collection of 15 One-Act Plays.

ERIC Educational Resources Information Center

Mauro, Robert

Designed for workshop or classroom use, this collection of short plays for two actors is a source of material for auditions and readings and a valuable training tool for acting classes. The collection contains plays for men only, plays for women only, plays for men and women, plays with a wide variety of roles, plays of comedy and serious drama,…

Alibis for Adult Play

PubMed Central

2017-01-01

The social meanings of play sit at odds with norms of responsible and productive adult conduct. To be “caught” playing as an adult therefore risks embarrassment. Still, many designers want to create enjoyable, nonembarrassing play experiences for adults. To address this need, this article reads instances of spontaneous adult play through the lens of Erving Goffman’s theory of the interaction order to unpack conditions and strategies for nonembarrassing adult play. It identifies established frames, segregated audiences, scripts supporting smooth performance, managing audience awareness, role distancing, and, particularly, alibis for play: Adults routinely provide alternative, adult-appropriate motives to account for their play, such as child care, professional duties, creative expression, or health. Once legitimized, the norms and rules of play themselves then provide an alibi for behavior that would risk being embarrassing outside play. PMID:29706842

Hungry for Life: How the arcuate nucleus and neuropeptide Y may play a critical role in mediating the benefits of calorie restriction

PubMed Central

Minor, Robin K.; Chang, Joy W.; de Cabo, Rafael

2009-01-01

Laboratory studies consistently demonstrate extended lifespan in animals on calorie restriction (CR), where total caloric intake is reduced by 10–40% but adequate nutrition is otherwise maintained. CR has been further shown to delay the onset and severity of chronic diseases associated with aging such as cancer, and to extend the functional health span of important functions including cognition. Less understood are the underlying mechanisms through which CR might act to induce such alterations. One theory postulates that CR’s beneficial effects are intimately tied to the neuroendocrine response to low energy availability, of which the arcuate nucleus in the hypothalamus plays a pivotal role. Neuropeptide Y (NPY), a neurotransmitter in the front line of the arcuate response to low energy availability, is the primary hunger signal affected by CR and therefore may be a critical mechanism for lifespan extension. PMID:19041366

Hungry for life: How the arcuate nucleus and neuropeptide Y may play a critical role in mediating the benefits of calorie restriction.

PubMed

Minor, Robin K; Chang, Joy W; de Cabo, Rafael

2009-02-05

Laboratory studies consistently demonstrate extended lifespan in animals on calorie restriction (CR), where total caloric intake is reduced by 10-40% but adequate nutrition is otherwise maintained. CR has been further shown to delay the onset and severity of chronic diseases associated with aging such as cancer, and to extend the functional health span of important faculties like cognition. Less understood are the underlying mechanisms through which CR might act to induce such alterations. One theory postulates that CR's beneficial effects are intimately tied to the neuroendocrine response to low energy availability, of which the arcuate nucleus in the hypothalamus plays a pivotal role. Neuropeptide Y (NPY), a neurotransmitter in the front line of the arcuate response to low energy availability, is the primary hunger signal affected by CR and therefore may be a critical mechanism for lifespan extension.

Forms of vitality play and symbolic play during the third year of life.

PubMed

Español, Silvia; Bordoni, Mariana; Martínez, Mauricio; Camarasa, Rosario; Carretero, Soledad

2015-08-01

This article focuses on the development of forms of vitality play, a recently described type of play, and links it to the development of symbolic play, one of the most studied types of play in developmental psychology. Two adult-infant dyads were videotaped longitudinally during in-house free play meetings every 15 days during the third year of life. Convergence technique was applied in order to accelerate the longitudinal study. A total of 17h 48min were registered in 28 sessions. An observational code with categories of forms of vitality play (a non-figurative play frame in which child and adult play together with the dynamics of their own movements and sounds in a repetition-variation form), symbolic play, and categories of combined patterns of both types of play was applied. The rate of each play was calculated for different age periods. Forms of vitality play is present at a constant rate during the third year of life. Symbolic play flourishes during this period. Combined play patterns are not the most frequent but are present from the beginning to the end of the third year. We suggest that FoVP favours intimate and intersubjective experiences essential to the understanding and the development of the interpersonal world; that it can be thought of as a good runway for the development of symbolic play; and that it prepares the child to participate in the temporal arts that belong to his culture. Copyright © 2015 Elsevier Inc. All rights reserved.

Training in Fantasy Play.

ERIC Educational Resources Information Center

Smith, Peter K.

1983-01-01

Outcomes of fantasy play training were compared with those of nonfantasy/skills training in English nursery classes and play groups. Children receiving fantasy play training engaged in cooperative play more than did those receiving skills training, played more often in larger subgroups, and were more physically active. Most effects were present at…

Picture me playing: increasing pretend play dialogue of children with autism spectrum disorders.

PubMed

Murdock, Linda C; Hobbs, Jan Q

2011-07-01

This study examined the effectiveness of the Picture Me Playing intervention for increasing the play dialogue of preschool children with ASD during pretend play opportunities with typical peers. Picture Me Playing is a pictorially enhanced, script based intervention targeting character role play through a narrative vignette. A single-treatment counterbalanced design was utilized to contrast the performance of intervention and comparison groups, followed by within-subject analysis. Results indicated significant increases in play dialogue represented by both scripted and novel utterances. Results generalized to an unscripted play opportunity with novel toys.

Playing Shakespeare.

ERIC Educational Resources Information Center

Bashian, Kathleen Ryniker

1993-01-01

Describes a yearlong project at 12 Catholic middle schools in the Diocese of Arlington, Virginia, to incorporate the plays of William Shakespeare into the curriculum. Teachers attended university lectures and directed students in performances of the plays. Concludes that Shakespeare can be understood and enjoyed by middle school students. (BCY)

Virtual Playgrounds? Assessing the Playfulness of Massively Multiplayer Online Role-Playing Games

ERIC Educational Resources Information Center

Graham, Kerrie Lewis

2010-01-01

Millions of children and adults devote much of their leisure time to playing massively multiplayer online role-playing games (MMORPGs). Most observers commonly categorize computer games as a play activity, but this article asks whether MMORPGs contain activities that might not be play. The author examines the phenomenon of online gaming and…

Base excitation testing system using spring elements to pivotally mount wind turbine blades

DOEpatents

Cotrell, Jason; Hughes, Scott; Butterfield, Sandy; Lambert, Scott

2013-12-10

A system (1100) for fatigue testing wind turbine blades (1102) through forced or resonant excitation of the base (1104) of a blade (1102). The system (1100) includes a test stand (1112) and a restoring spring assembly (1120) mounted on the test stand (1112). The restoring spring assembly (1120) includes a primary spring element (1124) that extends outward from the test stand (1112) to a blade mounting plate (1130) configured to receive a base (1104) of blade (1102). During fatigue testing, a supported base (1104) of a blad (1102) may be pivotally mounted to the test stand (1112) via the restoring spring assembly (1120). The system (1100) may include an excitation input assembly (1140) that is interconnected with the blade mouting plate (1130) to selectively apply flapwise, edgewise, and/or pitch excitation forces. The restoring spring assemply (1120) may include at least one tuning spring member (1127) positioned adjacent to the primary spring element (1124) used to tune the spring constant or stiffness of the primary spring element (1124) in one of the excitation directions.

Playful Teaching Workshop Sampler. Classroom Play Ideas for Early Childhood Educators.

ERIC Educational Resources Information Center

Battista, Donna

Based on Piaget's theory "children learn best by doing," play offers a natural way of learning for young children. The "Playful Teaching" Workshop Sampler offers teachers several different movement activities for incorporation into academic classroom curricula. The play ideas were presented at national and regional teaching workshops. The…

Play and Adversity: How the Playful Mammalian Brain Withstands Threats and Anxieties

ERIC Educational Resources Information Center

Siviy, Stephen M.

2010-01-01

Most mammals play, but they do so in a dangerous world. The dynamic relationship between the stresses created by their world and the activity of play helps to explain the evolution of play in mammals, as the author demonstrates in evidence garnered from experiments that introduce elements of fear to rats at play. The author describes the resulting…

The Influence of Play Material on Discourse during Play.

ERIC Educational Resources Information Center

Burroughs, Elizabeth I.; Murray, Sharon E.

1992-01-01

Evaluation of the conversational behavior of 36 children (ages 48-59 months) playing in dyads with 3 different materials (modeling dough, a farm set, and animal puppets) found that each toy elicited the same amount of talking, though there were differences in discourse structure attributable to play materials. (DB)

Detecting Protein-Glycolipid Interactions Using Glycomicelles and CaR-ESI-MS

NASA Astrophysics Data System (ADS)

Han, Ling; Kitova, Elena N.; Klassen, John S.

2016-11-01

This study reports on the use of the catch-and-release electrospray ionization mass spectrometry (CaR-ESI-MS) assay, combined with glycomicelles, as a method for detecting specific interactions between water-soluble proteins and glycolipids (GLs) in aqueous solution. The B subunit homopentamers of cholera toxin (CTB5) and Shiga toxin type 1 B (Stx1B5) and the gangliosides GM1, GM2, GM3, GD1a, GD1b, GT1b, and GD2 served as model systems for this study. The CTB5 exhibits broad specificity for gangliosides and binds to GM1, GM2, GM3, GD1a, GD1b, and GT1b; Stx1B5 does not recognize gangliosides. The CaR-ESI-MS assay was used to analyze solutions of CTB5 or Stx1B5 and individual gangliosides (GM1, GM2, GM3, GD1a, GD1b, GT1b, and GD2) or mixtures thereof. The high affinity interaction of CTB5 with GM1 was successfully detected. However, the apparent affinity, as determined from the mass spectra, is significantly lower than that of the corresponding pentasaccharide or when GM1 is presented in model membranes such as nanodiscs. Interactions between CTB5 and the low affinity gangliosides GD1a, GD1b, and GT1b, as well as GD2, which served as a negative control, were detected; no binding of CTB5 to GM2 or GM3 was observed. The CaR-ESI-MS results obtained for Stx1B5 reveal that nonspecific protein-ganglioside binding can occur during the ESI process, although the extent of binding varies between gangliosides. Consequently, interactions detected for CTB5 with GD1a, GD1b, and GT1b are likely nonspecific in origin. Taken together, these results reveal that the CaR-ESI-MS/glycomicelle approach for detecting protein-GL interactions is prone to false positives and false negatives and must be used with caution.

Crystal Structure of the Botulinum Neurotoxin Type G Binding Domain: Insight into Cell Surface Binding

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

Stenmark, Pål; Dong, Min; Dupuy, Jérôme

2011-11-02

Botulinum neurotoxins (BoNTs) typically bind the neuronal cell surface via dual interactions with both protein receptors and gangliosides. We present here the 1.9-{angstrom} X-ray structure of the BoNT serotype G (BoNT/G) receptor binding domain (residues 868-1297) and a detailed view of protein receptor and ganglioside binding regions. The ganglioside binding motif (SxWY) has a conserved structure compared to the corresponding regions in BoNT serotype A and BoNT serotype B (BoNT/B), but several features of interactions with the hydrophilic face of the ganglioside are absent at the opposite side of the motif in the BoNT/G ganglioside binding cleft. This may significantlymore » reduce the affinity between BoNT/G and gangliosides. BoNT/G and BoNT/B share the protein receptor synaptotagmin (Syt) I/II. The Syt binding site has a conserved hydrophobic plateau located centrally in the proposed protein receptor binding interface (Tyr1189, Phe1202, Ala1204, Pro1205, and Phe1212). Interestingly, only 5 of 14 residues that are important for binding between Syt-II and BoNT/B are conserved in BoNT/G, suggesting that the means by which BoNT/G and BoNT/B bind Syt diverges more than previously appreciated. Indeed, substitution of Syt-II Phe47 and Phe55 with alanine residues had little effect on the binding of BoNT/G, but strongly reduced the binding of BoNT/B. Furthermore, an extended solvent-exposed hydrophobic loop, located between the Syt binding site and the ganglioside binding cleft, may serve as a third membrane association and binding element to contribute to high-affinity binding to the neuronal membrane. While BoNT/G and BoNT/B are homologous to each other and both utilize Syt-I/Syt-II as their protein receptor, the precise means by which these two toxin serotypes bind to Syt appears surprisingly divergent.« less

Crystal structure of the botulinum neurotoxin type G binding domain: insight into cell surface binding.

PubMed

Stenmark, Pål; Dong, Min; Dupuy, Jérôme; Chapman, Edwin R; Stevens, Raymond C

2010-04-16

Botulinum neurotoxins (BoNTs) typically bind the neuronal cell surface via dual interactions with both protein receptors and gangliosides. We present here the 1.9-A X-ray structure of the BoNT serotype G (BoNT/G) receptor binding domain (residues 868-1297) and a detailed view of protein receptor and ganglioside binding regions. The ganglioside binding motif (SxWY) has a conserved structure compared to the corresponding regions in BoNT serotype A and BoNT serotype B (BoNT/B), but several features of interactions with the hydrophilic face of the ganglioside are absent at the opposite side of the motif in the BoNT/G ganglioside binding cleft. This may significantly reduce the affinity between BoNT/G and gangliosides. BoNT/G and BoNT/B share the protein receptor synaptotagmin (Syt) I/II. The Syt binding site has a conserved hydrophobic plateau located centrally in the proposed protein receptor binding interface (Tyr1189, Phe1202, Ala1204, Pro1205, and Phe1212). Interestingly, only 5 of 14 residues that are important for binding between Syt-II and BoNT/B are conserved in BoNT/G, suggesting that the means by which BoNT/G and BoNT/B bind Syt diverges more than previously appreciated. Indeed, substitution of Syt-II Phe47 and Phe55 with alanine residues had little effect on the binding of BoNT/G, but strongly reduced the binding of BoNT/B. Furthermore, an extended solvent-exposed hydrophobic loop, located between the Syt binding site and the ganglioside binding cleft, may serve as a third membrane association and binding element to contribute to high-affinity binding to the neuronal membrane. While BoNT/G and BoNT/B are homologous to each other and both utilize Syt-I/Syt-II as their protein receptor, the precise means by which these two toxin serotypes bind to Syt appears surprisingly divergent. Copyright (c) 2010. Published by Elsevier Ltd.

Shadow Play

ERIC Educational Resources Information Center

Trundle, Kathy Cabe; Hilson, Margilee P.

2012-01-01

A bunny rabbit playfully hops across the wall. Then hands realign and fingers shift to make a hawk soar toward the ceiling. Most children have enjoyed the delightful experience of playing with shadow puppets. The authors build on this natural curiosity to help students link shadows to complex astronomical concepts such as seasons. The…

Time perspective as a predictor of massive multiplayer online role-playing game playing.

PubMed

Lukavska, Katerina

2012-01-01

This article focuses on the relationship between the time perspective (TP) personality trait and massive multiplayer online role-playing game (MMORPG) playing. We investigate the question of frequency of playing. The TP was measured with Zimbardo's TP Inventory (ZTPI), which includes five factors-past negative, past positive, present hedonistic, present fatalistic, and future. The study used data from 154 MMORPG players. We demonstrated that TP partially explained differences within a group of players with respect to the frequency of playing. Significant positive correlations were found between present factors and the amount of time spent playing MMORPGs, and significant negative correlation was found between the future factor and the time spent playing MMORPGs. Our study also revealed the influence of future-present balance on playing time. Players who scored lower in future-present balance variables (their present score was relatively high compared with their future score) reported higher values in playing time. In contrast to referential studies on TP and drug abuse and gambling, present fatalistic TP was demonstrated to be a stronger predictor of extensive playing than present hedonistic TP, which opened the question of motivation for playing. The advantage of our study compared with other personality-based studies lies in the fact that TP is a stable but malleable personality trait with a direct link to playing behavior. Therefore, TP is a promising conceptual resource for excessive playing therapy.

Multi-oxide active layer deposition using Applied Materials Pivot array coater for high-mobility metal oxide TFT

NASA Astrophysics Data System (ADS)

Park, Hyun Chan; Scheer, Evelyn; Witting, Karin; Hanika, Markus; Bender, Marcus; Hsu, Hao Chien; Yim, Dong Kil

2015-11-01

By controlling a thin indium tin oxide (ITO), indium zinc oxide interface layer between gate insulator and indium gallium zinc oxide (IGZO), the thin-film transistor (TFT) performance can reach higher mobility as conventional IGZO as well as superior stability. For large-area display application, Applied Materials static PVD array coater (Applied Materials GmbH & Co. KG, Alzenau, Germany) using rotary targets has been developed to enable uniform thin layer deposition in display industry. Unique magnet motion parameter optimization in Pivot sputtering coater is shown to provide very uniform thin ITO layer to reach TFT performance with high mobility, not only on small scale, but also on Gen8.5 (2500 × 2200 mm glass size) production system.

CXCR6 plays a critical role in angiotensin II-induced renal injury and fibrosis.

PubMed

Xia, Yunfeng; Jin, Xiaogao; Yan, Jingyin; Entman, Mark L; Wang, Yanlin

2014-07-01

Recent studies have shown that angiotensin II (Ang II) plays a critical role in the pathogenesis and progression of hypertensive kidney disease. However, the signaling mechanisms are poorly understood. In this study, we investigated the role of CXCR6 in Ang II-induced renal injury and fibrosis. Wild-type and CXCR6-green fluorescent protein (GFP) knockin mice were treated with Ang II via subcutaneous osmotic minipumps at 1500 ng/kg per minute after unilateral nephrectomy for ≤ 4 weeks. Wild-type and CXCR6-GFP knockin mice had virtually identical blood pressure at baseline. Ang II treatment led to an increase in blood pressure that was similar between wild-type and CXCR6-GFP knockin mice. CXCR6-GFP knockin mice were protected from Ang II-induced renal dysfunction, proteinuria, and fibrosis. CXCR6-GFP knockin mice accumulated fewer bone marrow-derived fibroblasts and myofibroblasts and produced less extracellular matrix protein in the kidneys after Ang II treatment. Furthermore, CXCR6-GFP knockin mice exhibited fewer F4/80(+) macrophages and CD3(+) T cells and expressed less proinflammatory cytokines in the kidneys after Ang II treatment. Finally, wild-type mice engrafted with CXCR6(-/-) bone marrow cells displayed fewer bone marrow-derived fibroblasts, macrophages, and T cells in the kidney after Ang II treatment when compared with wild-type mice engrafted with CXCR6(+/+) bone marrow cells. Our results indicate that CXCR6 plays a pivotal role in the development of Ang II-induced renal injury and fibrosis through regulation of macrophage and T-cell infiltration and bone marrow-derived fibroblast accumulation. © 2014 American Heart Association, Inc.

CXCR6 Plays a Critical Role in Angiotensin II-induced Renal Injury and Fibrosis

PubMed Central

Xia, Yunfeng; Jin, Xiaogao; Yan, Jingyin; Entman, Mark L.; Wang, Yanlin

2014-01-01

Objective Recent studies have shown that angiotensin II (Ang II) plays a critical role in the pathogenesis and progression of hypertensive kidney disease. However, the signaling mechanisms are poorly understood. In this study, we investigated the role of CXCR6 in Ang II-induced renal injury and fibrosis. Approach and Results Wild-type and CXCR6-GFP knockin mice were treated with Ang II via subcutaneous osmotic minipumps at 1500 ng/kg/min after unilateral nephrectomy for up to 4 weeks. WT and CXCR6-GFP knockin mice had virtually identical blood pressure at baseline. Ang II treatment led to an increase in blood pressure that was similar between WT and CXCR6-GFP knockin mice. CXCR6-GFP knockin mice were protected from Ang II-induced renal dysfunction, proteinuria, and fibrosis. CXCR6-GFP knockin mice accumulated fewer bone marrow-derived fibroblasts and myofibroblasts and produced less extracellular matrix protein in the kidneys following Ang II treatment. Furthermore, CXCR6-GFP knockin mice exhibited fewer F4/80+ macrophages and CD3+ T cells and expressed less proinflammatory cytokines in the kidneys after Ang II treatment. Finally, wild-type mice engrafted with CXCR6−/− bone marrow cells displayed fewer bone marrow-derived fibroblasts, macrophages, and T cells in the kidney after Ang II treatment compared with wild-type mice engrafted with CXCR6+/+ bone marrow cells. Conclusions Our results indicate that CXCR6 plays a pivotal role in the development of Ang II-induced renal injury and fibrosis through regulation of macrophage and T cell infiltration and bone marrow-derived fibroblast accumulation. PMID:24855055

Speed of Adoption of Immune Checkpoint Inhibitors of Programmed Cell Death 1 Protein and Comparison of Patient Ages in Clinical Practice vs Pivotal Clinical Trials.

PubMed

O'Connor, Jeremy M; Fessele, Kristen L; Steiner, Jean; Seidl-Rathkopf, Kathi; Carson, Kenneth R; Nussbaum, Nathan C; Yin, Emily S; Adelson, Kerin B; Presley, Carolyn J; Chiang, Anne C; Ross, Joseph S; Abernethy, Amy P; Gross, Cary P

2018-05-10

The US Food and Drug Administration (FDA) is increasing its pace of approvals for novel cancer therapeutics, including for immune checkpoint inhibitors of programmed cell death 1 protein (anti-PD-1 agents). However, little is known about how quickly anti-PD-1 agents reach eligible patients in practice or whether such patients differ from those studied in clinical trials that lead to FDA approval (pivotal clinical trials). To assess the speed with which anti-PD-1 agents reached eligible patients in practice and to compare the ages of patients treated in clinical practice with the ages of those treated in pivotal clinical trials. This retrospective cohort study, performed from January 1, 2011, through August 31, 2016, included patients from the Flatiron Health Network who were eligible for anti-PD-1 treatment of selected cancer types, which included melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Cumulative proportions of eligible patients receiving anti-PD-1 treatment and their age distributions. The study identified 3089 patients who were eligible for anti-PD-1 treatment (median age, 66 [interquartile range, 56-75] years for patients with melanoma, 66 [interquartile range, 58-72] years for patients with RCC, and 67 [interquartile range, 59-74] years for patients with NSCLC; 1742 male [56.4%] and 1347 [43.6%] female; 2066 [66.9%] white). Of these patients, 2123 (68.7%) received anti-PD-1 treatment, including 439 eligible patients with melanoma (79.1%), 1417 eligible patients with NSCLC (65.6%), and 267 eligible patients with RCC (71.2%). Within 4 months after FDA approval, greater than 60% of eligible patients in each cohort had received anti-PD-1 treatment. Overall, similar proportions of older and younger patients received anti-PD-1 treatment during the first 9 months after FDA approval. However, there were significant differences in age between clinical trial participants and patients receiving anti-PD-1 treatment in clinical

Alteration of Electrostatic Surface Potential Enhances Affinity and Tumor Killing Properties of Anti-ganglioside GD2 Monoclonal Antibody hu3F8.

PubMed

Zhao, Qi; Ahmed, Mahiuddin; Guo, Hong-fen; Cheung, Irene Y; Cheung, Nai-Kong V

2015-05-22

Ganglioside GD2 is highly expressed on neuroectodermal tumors and an attractive therapeutic target for antibodies that have already shown some clinical efficacy. To further improve the current antibodies, which have modest affinity, we sought to improve affinity by using a combined method of random mutagenesis and in silico assisted design to affinity-mature the anti-GD2 monoclonal antibody hu3F8. Using yeast display, mutants in the Fv with enhanced binding over the parental clone were FACS-sorted and cloned. In silico modeling identified the minimal key interacting residues involved in the important charged interactions with the sialic acid groups of GD2. Two mutations, D32H (L-CDR1) and E1K (L-FR1) altered the electrostatic surface potential of the antigen binding site, allowing for an increase in positive charge to enhance the interaction with the negatively charged GD2-pentasaccharide headgroup. Purified scFv and IgG mutant forms were then tested for antigen specificity by ELISA, for tissue specificity by immunohistochemistry, for affinity by BIACORE, for antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity in vitro, and for anti-tumor efficacy in xenografted humanized mice. The nearly 7-fold improvement in affinity of hu3F8 with a single D32H (L-CDR1) mutation translated into a ∼12-fold improvement in NK92MI-transfected CD16-mediated ADCC, a 6-fold improvement in CD32-mediated ADCC, and a 2.5-fold improvement in complement-mediated cytotoxicity while maintaining restricted normal tissue cross-reactivity and achieving substantial improvement in tumor ablation in vivo. Despite increasing GD2 affinity, the double mutation D32H (L-CDR1) and E1K (L-FR1) did not further improve anti-tumor efficacy. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Play and optimal welfare: Does play indicate the presence of positive affective states?

PubMed

Ahloy-Dallaire, Jamie; Espinosa, Julia; Mason, Georgia

2017-11-16

Play is commonly used to assess affective states in both humans and non-human animals. Play appears to be most common when animals are well-fed and not under any direct threats to fitness. Could play and playfulness therefore indicate pre-existing positive emotions, and thence optimal animal welfare? We examine this question by surveying the internal and external conditions that promote or suppress play in a variety of species, starting with humans. We find that negative affective states and poor welfare usually do suppress play (although there are notable exceptions where the opposite occurs). Furthermore, research in children suggests that beyond the frequency or total duration of play, poor welfare may additionally be reflected in qualitative aspects of this heterogeneous behaviour (e.g. display of solitary over social play; and the 'fragmentation' of play bouts) that are often overlooked in animals. There are surprisingly few studies of play in subjects with pre-existing optimal welfare or in unambiguously highly positive affective states, making it currently impossible to determine whether play can distinguish optimal or good welfare from merely neutral welfare. This therefore represents an important and exciting area for future research. Copyright © 2017 Elsevier B.V. All rights reserved.