Versatile platform for nanotechnology based on circular permutations of chaperonin protein

NASA Technical Reports Server (NTRS)

McMillan, R. Andrew (Inventor); Kagawa, Hiromi (Inventor); Paavola, Chad D. (Inventor); Chan, Suzanne L. (Inventor); Li, Yi-Fen (Inventor); Trent, Jonathan D. (Inventor)

2010-01-01

The present invention provides chaperonin polypeptides which are modified to include N-terminal and C-terminal ends that are relocated from the central pore region to various different positions in the polypeptide which are located on the exterior of the folded modified chaperonin polypeptide. In the modified chaperonin polypeptide, the naturally-occurring N-terminal and C-terminal ends are joined together directly or with an intervening linker peptide sequence. The relocated N-terminal or C-terminal ends can be covalently joined to, or bound with another molecule such as a nucleic acid molecule, a lipid, a carbohydrate, a second polypeptide, or a nanoparticle. The modified chaperonin polypeptides can assemble into double-ringed chaperonin structures. Further, the chaperonin structures can organize into higher order structures such as nanofilaments or nanoarrays which can be used to produce nanodevices and nanocoatings.

Ordered nanoparticle arrays formed on engineered chaperonin protein templates

NASA Technical Reports Server (NTRS)

McMillan, R. Andrew; Paavola, Chad D.; Howard, Jeanie; Chan, Suzanne L.; Zaluzec, Nestor J.; Trent, Jonathan D.

2002-01-01

Traditional methods for fabricating nanoscale arrays are usually based on lithographic techniques. Alternative new approaches rely on the use of nanoscale templates made of synthetic or biological materials. Some proteins, for example, have been used to form ordered two-dimensional arrays. Here, we fabricated nanoscale ordered arrays of metal and semiconductor quantum dots by binding preformed nanoparticles onto crystalline protein templates made from genetically engineered hollow double-ring structures called chaperonins. Using structural information as a guide, a thermostable recombinant chaperonin subunit was modified to assemble into chaperonins with either 3 nm or 9 nm apical pores surrounded by chemically reactive thiols. These engineered chaperonins were crystallized into two-dimensional templates up to 20 microm in diameter. The periodic solvent-exposed thiols within these crystalline templates were used to size-selectively bind and organize either gold (1.4, 5 or 10nm) or CdSe-ZnS semiconductor (4.5 nm) quantum dots into arrays. The order within the arrays was defined by the lattice of the underlying protein crystal. By combining the self-assembling properties of chaperonins with mutations guided by structural modelling, we demonstrate that quantum dots can be manipulated using modified chaperonins and organized into arrays for use in next-generation electronic and photonic devices.

Silver syndrome variant of hereditary spastic paraplegia: A locus to 4p and allelism with SPG4.

PubMed

Orlacchio, A; Patrono, C; Gaudiello, F; Rocchi, C; Moschella, V; Floris, R; Bernardi, G; Kawarai, T

2008-05-20

To perform a clinical and genetic study of two large Italian families (RM-36 and RM-51) showing the cardinal clinical features of Silver syndrome (SS), a rare dominantly inherited form of hereditary spastic paraplegia (HSP) complicated by amyotrophy of the small hand muscles. Clinical assessment including neurophysiologic, neuropsychological, and neuroimaging evaluations. Genetic studies included linkage and sequence analyses. Using a genome-wide survey in the RM-36 family, a novel locus (SPG38) has been identified and mapped within the 13.1-cM region on chromosome 4p16-p15 between markers D4S432 and D4S1599. The RM-51 family was linked to the SPG4 locus at 2p21-p24 and sequence analysis of SPG4 showed a novel frameshift mutation p.Asp321GlyfsX6. Clinical examination of the affected members carrying the mutation showed high frequency of additional clinical features including decreased vibration sense, pes cavus, temporal lobe epilepsy, and cognitive impairment. This study demonstrates evidence of a novel locus SPG38 for Silver syndrome (SS) and suggests that genetic defects in SPG4 might lead to broad clinical features overlapped with those of SS.

Homocarnosinosis: A historical update and findings in the SPG11 gene.

PubMed

Sjaastad, O; Blau, N; Rydning, S L; Peters, V; Rødningen, O; Stray-Pedersen, A; Krossnes, B; Tallaksen, C; Koht, J

2018-05-06

A family with homocarnosinosis was reported in the literature in 1976. Three affected siblings had spastic paraplegia, retinitis pigmentosa, mental retardation, and cerebrospinal fluid (CSF) homocarnosine concentrations 20 times higher than in controls. Based on the clinical findings and new genetic techniques, we have been able to establish a precise genetic diagnosis. The medical records were re-evaluated, and genetic analyses were performed post-mortem in this original family. SNP array-based whole genome homozygosity mapping and Sanger sequencing of the SPG11 gene were performed. Seven additional Norwegian SPG11 patients and their disease-causing variants and clinical findings were evaluated. Homocarnosine levels in CSF were measured in four of these seven patients. A homozygous pathogenic splice-site variant in the SPG11 gene, c.2316 + 1G>A, was found. The clinical findings in the original family correlate with the heterogeneous SPG11 phenotype. The same variant was found in seven other Norwegian SPG11 patients, unrelated to the original family, either as homozygous or compound heterozygous constellation. Normal homocarnosine levels were found in the CSF of all unrelated SPG11 patients. A re-evaluation of the clinical symptoms and findings in the original family correlates with the SPG11 phenotype. The increased levels of homocarnosine do not seem to be a biomarker for SPG11 in our patients. Homocarnosinosis is still a biochemical aberration with unknown clinical significance. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

SPG11 Presenting with Tremor

PubMed Central

Schneider, Susanne A.; Mummery, Catherine J.; Mehrabian, Mohadeseh; Houlden, Henry; Bain, Peter G.

2012-01-01

Background Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurological diseases, which typically present with progressive lower extremity weakness and spasticity causing progressive walking difficulties. Complicating neurological or extraneurological features may be present. Case Report We describe a 19-year-old male who was referred because of an action tremor of the hands; he later developed walking difficulties. Callosal atrophy was present on his cerebral magnetic resonance imaging scan, prompting genetic testing for SPG11, which revealed homozygous mutations. Discussion The clinical features, differential diagnosis and management of SPG11, the most common form of autosomal recessive complicated HSP with a thin corpus callosum are discussed. PMID:23439843

The Molecular Basis of Hyperthermophily: The Role of HSP60/Chaperonins In Vivo

NASA Technical Reports Server (NTRS)

Kagawa, Hiromi

2002-01-01

In this study, we aim to understand how S. shibatae copes with high temperatures. In particular, we investigated the role of the 60 kDa heat shock protein (HSP60 or chaperonin) with the hypothesis that chaperonin stabilizes the cell membrane under stressful conditions. To prove the hypothesis, this year two questions were addressed: (1) Is the chaperonin localized in the cytoplasm or on the cell membrane? (2) Does the chaperonin show affinity to lipid in vivo? In addition to those, we intensively studied newly discovered chaperonin-related protein, gamma, to understand how it influenced the function of the other components of chaperonin and how their combined activities contributed to hyperthermophily.

Arabidopsis thaliana type I and II chaperonins

PubMed Central

Hill, Janet E.; Hemmingsen, Sean M.

2001-01-01

An examination of the Arabidopsis thaliana genome sequence led to the identification of 29 predicted genes with the potential to encode members of the chaperonin family of chaperones (CPN60 and CCT), their associated cochaperonins, and the cytoplasmic chaperonin cofactor prefoldin. These comprise the first complete set of plant chaperonin protein sequences and indicate that the CPN family is more diverse than previously described. In addition to surprising sequence diversity within CPN subclasses, the genomic data also suggest the existence of previously undescribed family members, including a 10-kDa chloroplast cochaperonin. Consideration of the sequence data described in this review prompts questions about the complexities of plant CPN systems and the evolutionary relationships and functions of the component proteins, most of which have not been studied experimentally. PMID:11599560

Arabidopsis thaliana type I and II chaperonins.

PubMed

Hill, J E; Hemmingsen, S M

2001-07-01

An examination of the Arabidopsis thaliana genome sequence led to the identification of 29 predicted genes with the potential to encode members of the chaperonin family of chaperones (CPN60 and CCT), their associated cochaperonins, and the cytoplasmic chaperonin cofactor prefoldin. These comprise the first complete set of plant chaperonin protein sequences and indicate that the CPN family is more diverse than previously described. In addition to surprising sequence diversity within CPN subclasses, the genomic data also suggest the existence of previously undescribed family members, including a 10-kDa chloroplast cochaperonin. Consideration of the sequence data described in this review prompts questions about the complexities of plant CPN systems and the evolutionary relationships and functions of the component proteins, most of which have not been studied experimentally.

Prefoldin, a chaperone that delivers unfolded proteins to cytosolic chaperonin.

PubMed

Vainberg, I E; Lewis, S A; Rommelaere, H; Ampe, C; Vandekerckhove, J; Klein, H L; Cowan, N J

1998-05-29

We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin. Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it. Deletion of the gene encoding a prefoldin subunit in S. cerevisiae results in a phenotype similar to those found when c-cpn is mutated, namely impaired functions of the actin and tubulin-based cytoskeleton. Consistent with prefoldin having a general role in chaperonin-mediated folding, we identify homologs in archaea, which have a class II chaperonin but contain neither actin nor tubulin. We show that by directing target proteins to chaperonin, prefoldin promotes folding in an environment in which there are many competing pathways for nonnative proteins.

Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients’ neurons

PubMed Central

Havlicek, Steven; Kohl, Zacharias; Mishra, Himanshu K.; Prots, Iryna; Eberhardt, Esther; Denguir, Naime; Wend, Holger; Plötz, Sonja; Boyer, Leah; Marchetto, Maria C.N.; Aigner, Stefan; Sticht, Heinrich; Groemer, Teja W.; Hehr, Ute; Lampert, Angelika; Schlötzer-Schrehardt, Ursula; Winkler, Jürgen; Gage, Fred H.; Winner, Beate

2014-01-01

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of motorneuron diseases characterized by progressive spasticity and paresis of the lower limbs. Mutations in Spastic Gait 4 (SPG4), encoding spastin, are the most frequent cause of HSP. To understand how mutations in SPG4 affect human neurons, we generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of two patients carrying a c.1684C>T nonsense mutation and from two controls. These SPG4 and control hiPSCs were able to differentiate into neurons and glia at comparable efficiency. All known spastin isoforms were reduced in SPG4 neuronal cells. The complexity of SPG4 neurites was decreased, which was paralleled by an imbalance of axonal transport with less retrograde movement. Prominent neurite swellings with disrupted microtubules were present in SPG4 neurons at an ultrastructural level. While some of these swellings contain acetylated and detyrosinated tubulin, these tubulin modifications were unchanged in total cell lysates of SPG4 neurons. Upregulation of another microtubule-severing protein, p60 katanin, may partially compensate for microtubuli dynamics in SPG4 neurons. Overexpression of the M1 or M87 spastin isoforms restored neurite length, branching, numbers of primary neurites and reduced swellings in SPG4 neuronal cells. We conclude that neurite complexity and maintenance in HSP patient-derived neurons are critically sensitive to spastin gene dosage. Our data show that elevation of single spastin isoform levels is sufficient to restore neurite complexity and reduce neurite swellings in patient cells. Furthermore, our human model offers an ideal platform for pharmacological screenings with the goal to restore physiological spastin levels in SPG4 patients. PMID:24381312

ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

PubMed

Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio

2016-01-01

-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

ALS5/SPG11/ KIAA1840 mutations cause autosomal recessive axonal Charcot–Marie–Tooth disease

PubMed Central

Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L.; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H.; Barsottini, Orlando G. P.; Kawarai, Toshitaka

2016-01-01

TYMP genes. An additional locus for autosomal recessive Charcot–Marie–Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/ KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/ KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot–Marie–Tooth disease. 10.1093/brain/awv320_video_abstractawv320_video_abstract PMID:26556829

Facilitated release of substrate protein from prefoldin by chaperonin.

PubMed

Zako, Tamotsu; Iizuka, Ryo; Okochi, Mina; Nomura, Tomoko; Ueno, Taro; Tadakuma, Hisashi; Yohda, Masafumi; Funatsu, Takashi

2005-07-04

Prefoldin is a chaperone that captures a protein-folding intermediate and transfers it to the group II chaperonin for correct folding. However, kinetics of interactions between prefoldin and substrate proteins have not been investigated. In this study, dissociation constants and dissociation rate constants of unfolded proteins with prefoldin were firstly measured using fluorescence microscopy. Our results suggest that binding and release of prefoldin from hyperthermophilic archaea with substrate proteins were in a dynamic equilibrium. Interestingly, the release of substrate proteins from prefoldin was facilitated when chaperonin was present, supporting a handoff mechanism of substrate proteins from prefoldin to the chaperonin.

40 CFR 13.26 - Payment of compromised claims.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Payment of compromised claims. 13.26 Section 13.26 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL CLAIMS COLLECTION... will be required to execute a confess-judgment agreement which accelerates payment of the balance due...

New metabolic pathway for degradation of 2-nitrobenzoate by Arthrobacter sp. SPG

PubMed Central

Arora, Pankaj K.; Sharma, Ashutosh

2015-01-01

Arthrobacter sp. SPG utilized 2-nitrobenzoate as its sole source of carbon and energy and degraded it with accumulation of stoichiometric amounts of nitrite ions. Salicylate and catechol were detected as metabolites of the 2-nitrobenzoate degradation using high performance liquid chromatography and gas chromatography–mass spectrometry. Enzyme activities for 2-nitrobenzoate-2-monooxygenase, salicylate hydroxylase, and catechol-1,2-dioxygenase were detected in the crude extracts of the 2-nitrobenzoate-induced cells of strain SPG. The 2-nitrobenzoate-monooxygenase activity resulted in formation of salicylate and nitrite from 2-nitrobenzoate, whereas salicylate hydroxylase catalyzed the conversion of salicylate to catechol. The ring-cleaving enzyme, catechol-1,2-dioxygenase cleaved catechol to cis,cis-muconic acid. Cells of strain SPG were able to degrade 2-nitrobenzoate in sterile as well as non-sterile soil microcosms. The results of microcosm studies showed that strain SPG degraded more than 90% of 2-nitrobenzoate within 10–12 days. This study clearly shows that Arthrobacter sp. SPG degraded 2-nitrobenzoate via a new pathway with formation of salicylate and catechol as metabolites. Arthrobacter sp. SPG may be used for bioremediation of 2-nitrobenzoate-contaminated sites due to its ability to degrade 2-nitrobenzoate in soil. PMID:26082768

Coexistence of group I and group II chaperonins in the archaeon Methanosarcina mazei.

PubMed

Klunker, Daniel; Haas, Bernd; Hirtreiter, Angela; Figueiredo, Luis; Naylor, Dean J; Pfeifer, Günter; Müller, Volker; Deppenmeier, Uwe; Gottschalk, Gerhard; Hartl, F Ulrich; Hayer-Hartl, Manajit

2003-08-29

Two distantly related classes of cylindrical chaperonin complexes assist in the folding of newly synthesized and stress-denatured proteins in an ATP-dependent manner. Group I chaperonins are thought to be restricted to the cytosol of bacteria and to mitochondria and chloroplasts, whereas the group II chaperonins are found in the archaeal and eukaryotic cytosol. Here we show that members of the archaeal genus Methanosarcina co-express both the complete group I (GroEL/GroES) and group II (thermosome/prefoldin) chaperonin systems in their cytosol. These mesophilic archaea have acquired between 20 and 35% of their genes by lateral gene transfer from bacteria. In Methanosarcina mazei Gö1, both chaperonins are similarly abundant and are moderately induced under heat stress. The M. mazei GroEL/GroES proteins have the structural features of their bacterial counterparts. The thermosome contains three paralogous subunits, alpha, beta, and gamma, which assemble preferentially at a molar ratio of 2:1:1. As shown in vitro, the assembly reaction is dependent on ATP/Mg2+ or ADP/Mg2+ and the regulatory role of the beta subunit. The co-existence of both chaperonin systems in the same cellular compartment suggests the Methanosarcina species as useful model systems in studying the differential substrate specificity of the group I and II chaperonins and in elucidating how newly synthesized proteins are sorted from the ribosome to the proper chaperonin for folding.

SPG3A-linked hereditary spastic paraplegia associated with cerebral glucose hypometabolism.

PubMed

Terada, Tatsuhiro; Kono, Satoshi; Ouchi, Yasuomi; Yoshida, Kenichi; Hamaya, Yasushi; Kanaoka, Shigeru; Miyajima, Hiroaki

2013-04-01

SPG3A-linked hereditary spastic paraplegia (HSP) is a rare autosomal dominant motor disorder caused by a mutation in the SPG3A gene, and is characterized by progressive motor weakness and spasticity in the lower limbs, without any other neurological abnormalities. SPG3A-linked HSP caused by a R239C mutation has been reported to present a pure phenotype confined to impairment of the corticospinal tract. However, there is still a debate about the etiology of this motor deficit with regard to whether it is peripheral or central. We herein report two patients who were heterozygous for a R239C mutation in the SPG3A gene. Two middle-aged Japanese sisters had been suffering from a pure phenotype of HSP since their childhood. Both patients had a significant decrease in glucose metabolism in the frontal cortex medially and dorsolaterally in a [(18)F]-fluorodeoxyglucose (FDG) positron emission photography (PET) study and low scores on the Frontal Assessment Battery. A real-time PCR analysis in normal subjects showed the frontal cortex to be the major location where SPG3A mRNA is expressed. The present finding that the frontal glucose hypometabolism was associated with frontal cognitive impairment indicates that widespread neuropathology associated with mutations in the SPG3A gene may be present more centrally than previously assumed.

Novel chaperonins are prevalent in the virioplankton and demonstrate links to viral biology and ecology

PubMed Central

Marine, Rachel L; Nasko, Daniel J; Wray, Jeffrey; Polson, Shawn W; Wommack, K Eric

2017-01-01

Chaperonins are protein-folding machinery found in all cellular life. Chaperonin genes have been documented within a few viruses, yet, surprisingly, analysis of metagenome sequence data indicated that chaperonin-carrying viruses are common and geographically widespread in marine ecosystems. Also unexpected was the discovery of viral chaperonin sequences related to thermosome proteins of archaea, indicating the presence of virioplankton populations infecting marine archaeal hosts. Virioplankton large subunit chaperonin sequences (GroELs) were divergent from bacterial sequences, indicating that viruses have carried this gene over long evolutionary time. Analysis of viral metagenome contigs indicated that: the order of large and small subunit genes was linked to the phylogeny of GroEL; both lytic and temperate phages may carry group I chaperonin genes; and viruses carrying a GroEL gene likely have large double-stranded DNA (dsDNA) genomes (>70 kb). Given these connections, it is likely that chaperonins are critical to the biology and ecology of virioplankton populations that carry these genes. Moreover, these discoveries raise the intriguing possibility that viral chaperonins may more broadly alter the structure and function of viral and cellular proteins in infected host cells. PMID:28731469

Novel chaperonins are prevalent in the virioplankton and demonstrate links to viral biology and ecology.

PubMed

Marine, Rachel L; Nasko, Daniel J; Wray, Jeffrey; Polson, Shawn W; Wommack, K Eric

2017-11-01

Chaperonins are protein-folding machinery found in all cellular life. Chaperonin genes have been documented within a few viruses, yet, surprisingly, analysis of metagenome sequence data indicated that chaperonin-carrying viruses are common and geographically widespread in marine ecosystems. Also unexpected was the discovery of viral chaperonin sequences related to thermosome proteins of archaea, indicating the presence of virioplankton populations infecting marine archaeal hosts. Virioplankton large subunit chaperonin sequences (GroELs) were divergent from bacterial sequences, indicating that viruses have carried this gene over long evolutionary time. Analysis of viral metagenome contigs indicated that: the order of large and small subunit genes was linked to the phylogeny of GroEL; both lytic and temperate phages may carry group I chaperonin genes; and viruses carrying a GroEL gene likely have large double-stranded DNA (dsDNA) genomes (>70 kb). Given these connections, it is likely that chaperonins are critical to the biology and ecology of virioplankton populations that carry these genes. Moreover, these discoveries raise the intriguing possibility that viral chaperonins may more broadly alter the structure and function of viral and cellular proteins in infected host cells.

Group II chaperonins: new TRiC(k)s and turns of a protein folding machine.

PubMed

Gutsche, I; Essen, L O; Baumeister, W

1999-10-22

In the past decade, the eubacterial group I chaperonin GroEL became the paradigm of a protein folding machine. More recently, electron microscopy and X-ray crystallography offered insights into the structure of the thermosome, the archetype of the group II chaperonins which also comprise the chaperonin from the eukaryotic cytosol TRiC. Some structural differences from GroEL were revealed, namely the existence of a built-in lid provided by the helical protrusions of the apical domains instead of a GroES-like co-chaperonin. These structural studies provide a framework for understanding the differences in the mode of action between the group II and the group I chaperonins. In vitro analyses of the folding of non-native substrates coupled to ATP binding and hydrolysis are progressing towards establishing a functional cycle for group II chaperonins. A protein complex called GimC/prefoldin has recently been found to cooperate with TRiC in vivo, and its characterization is under way. Copyright 1999 Academic Press.

Thermal inactivation and chaperonin-mediated renaturation of mitochondrial aspartate aminotransferase.

PubMed Central

Lawton, J M; Doonan, S

1998-01-01

Mitochondrial aspartate aminotransferase is inactivated irreversibly on heating. The inactivated protein aggregates, but aggregation is prevented by the presence of the chaperonin 60 from Escherichia coli (GroEL). The chaperonin increases the rate of thermal inactivation in the temperature range 55-65 degrees C but not at lower temperatures. It has previously been shown [Twomey and Doonan (1997) Biochim. Biophys. Acta 1342, 37-44] that the enzyme switches to a modified, but catalytically active, conformation at approx. 55-60 degrees C and the present results show that this conformation is recognized by and binds to GroEL. The thermally inactivated protein can be released from GroEL in an active form by the addition of chaperonin 10 from E. coli (GroES)/ATP, showing that inactivation is not the result of irreversible chemical changes. These results suggest that the irreversibility of thermal inactivation is due to the formation of an altered conformation with a high kinetic barrier to refolding rather than to any covalent changes. In the absence of chaperonin the unfolded molecules aggregate but this is a consequence, rather than the cause, of irreversible inactivation. PMID:9693123

Localization of prefoldin interaction sites in the hyperthermophilic group II chaperonin and correlations between binding rate and protein transfer rate.

PubMed

Zako, Tamotsu; Murase, Yosuke; Iizuka, Ryo; Yoshida, Takao; Kanzaki, Taro; Ide, Naoki; Maeda, Mizuo; Funatsu, Takashi; Yohda, Masafumi

2006-11-17

Prefoldin is a molecular chaperone that captures a protein-folding intermediate and transfers it to a group II chaperonin for correct folding. The manner by which prefoldin interacts with a group II chaperonin is poorly understood. Here, we have examined the prefoldin interaction site in the archaeal group II chaperonin, comparing the interaction of two Thermococcus chaperonins and their mutants with Pyrococcus prefoldin by surface plasmon resonance. We show that the mutations of Lys250 and Lys256 of Thermococcus alpha chaperonin residues to Glu residues increase the affinity to Pyrococcus prefoldin to the level of Thermococcus beta chaperonin and Pyrococcus chaperonin, indicating that their Glu250 and Glu256 residues of the helical protrusion region are responsible for relatively stronger binding to Pyrococcus prefoldin than Thermococcus alpha chaperonin. Since the putative chaperonin binding sites in the distal ends of Pyrococcus prefoldin are rich in basic residues, electrostatic interaction seems to be important for their interaction. The substrate protein transfer rate from prefoldin correlates well with its affinity for chaperonin.

Mechanism of nucleotide sensing in group II chaperonins.

PubMed

Pereira, Jose H; Ralston, Corie Y; Douglas, Nicholai R; Kumar, Ramya; Lopez, Tom; McAndrew, Ryan P; Knee, Kelly M; King, Jonathan A; Frydman, Judith; Adams, Paul D

2012-02-01

Group II chaperonins mediate protein folding in an ATP-dependent manner in eukaryotes and archaea. The binding of ATP and subsequent hydrolysis promotes the closure of the multi-subunit rings where protein folding occurs. The mechanism by which local changes in the nucleotide-binding site are communicated between individual subunits is unknown. The crystal structure of the archaeal chaperonin from Methanococcus maripaludis in several nucleotides bound states reveals the local conformational changes associated with ATP hydrolysis. Residue Lys-161, which is extremely conserved among group II chaperonins, forms interactions with the γ-phosphate of ATP but shows a different orientation in the presence of ADP. The loss of the ATP γ-phosphate interaction with Lys-161 in the ADP state promotes a significant rearrangement of a loop consisting of residues 160-169. We propose that Lys-161 functions as an ATP sensor and that 160-169 constitutes a nucleotide-sensing loop (NSL) that monitors the presence of the γ-phosphate. Functional analysis using NSL mutants shows a significant decrease in ATPase activity, suggesting that the NSL is involved in timing of the protein folding cycle.

Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy

PubMed Central

Magen, Daniella; Georgopoulos, Costa; Bross, Peter; Ang, Debbie; Segev, Yardena; Goldsher, Dorit; Nemirovski, Alexandra; Shahar, Eli; Ravid, Sarit; Luder, Anthony; Heno, Bayan; Gershoni-Baruch, Ruth; Skorecki, Karl; Mandel, Hanna

2008-01-01

Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration. PMID:18571143

Functionality and Evolutionary History of the Chaperonins in Thermophilic Archaea. A Bioinformatical Perspective

NASA Technical Reports Server (NTRS)

Karlin, Samuel

2004-01-01

We used bioinformatics methods to study phylogenetic relations and differentiation patterns of the archaeal chaperonin 60 kDa heat-shock protein (HSP60) genes in support of the study of differential expression patterns of the three chaperonin genes encoded in Sulfolobus shibatae.

Chaperonin GroEL Reassembly: An Effect of Protein Ligands and Solvent Composition

PubMed Central

Ryabova, Nataliya; Marchenkov, Victor; Kotova, Nina; Semisotnov, Gennady

2014-01-01

Chaperonin GroEL is a complex oligomeric heat shock protein (Hsp60) assisting the correct folding and assembly of other proteins in the cell. An intriguing question is how GroEL folds itself. According to the literature, GroEL reassembly is dependent on chaperonin ligands and solvent composition. Here we demonstrate dependence of GroEL reassembly efficiency on concentrations of the essential factors (Mg2+, ADP, ATP, GroES, ammonium sulfate, NaCl and glycerol). Besides, kinetics of GroEL oligomerization in various conditions was monitored by the light scattering technique and proved to be two-exponential, which suggested accumulation of a certain oligomeric intermediate. This intermediate was resolved as a heptamer by nondenaturing blue electrophoresis of GroEL monomers during their assembly in the presence of both Mg-ATP and co-chaperonin GroES. Presumably, this intermediate heptamer plays a key role in formation of the GroEL tetradecameric particle. The role of co-chaperonin GroES (Hsp10) in GroEL assembly is also discussed. PMID:24970225

Mutations in the KIAA0196 Gene at the SPG8 Locus Cause Hereditary Spastic Paraplegia

PubMed Central

Valdmanis, Paul N.; Meijer, Inge A.; Reynolds, Annie; Lei, Adrienne; MacLeod, Patrick; Schlesinger, David; Zatz, Mayana; Reid, Evan; Dion, Patrick A.; Drapeau, Pierre; Rouleau, Guy A.

2007-01-01

Hereditary spastic paraplegia (HSP) is a progressive upper-motor neurodegenerative disease. The eighth HSP locus, SPG8, is on chromosome 8p24.13. The three families previously linked to the SPG8 locus present with relatively severe, pure spastic paraplegia. We have identified three mutations in the KIAA0196 gene in six families that map to the SPG8 locus. One mutation, V626F, segregated in three large North American families with European ancestry and in one British family. An L619F mutation was found in a Brazilian family. The third mutation, N471D, was identified in a smaller family of European origin and lies in a spectrin domain. None of these mutations were identified in 500 control individuals. Both the L619 and V626 residues are strictly conserved across species and likely have a notable effect on the structure of the protein product strumpellin. Rescue studies with human mRNA injected in zebrafish treated with morpholino oligonucleotides to knock down the endogenous protein showed that mutations at these two residues impaired the normal function of the KIAA0196 gene. However, the function of the 1,159-aa strumpellin protein is relatively unknown. The identification and characterization of the KIAA0196 gene will enable further insight into the pathogenesis of HSP. PMID:17160902

Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms.

PubMed

Fink, John K

2013-09-01

Hereditary spastic paraplegia (HSP) is a syndrome designation describing inherited disorders in which lower extremity weakness and spasticity are the predominant symptoms. There are more than 50 genetic types of HSP. HSP affects individuals of diverse ethnic groups with prevalence estimates ranging from 1.2 to 9.6 per 100,000. Symptoms may begin at any age. Gait impairment that begins after childhood usually worsens very slowly over many years. Gait impairment that begins in infancy and early childhood may not worsen significantly. Postmortem studies consistently identify degeneration of corticospinal tract axons (maximal in the thoracic spinal cord) and degeneration of fasciculus gracilis fibers (maximal in the cervico-medullary region). HSP syndromes thus appear to involve motor-sensory axon degeneration affecting predominantly (but not exclusively) the distal ends of long central nervous system (CNS) axons. In general, proteins encoded by HSP genes have diverse functions including (1) axon transport (e.g. SPG30/KIF1A, SPG10/KIF5A and possibly SPG4/Spastin); (2) endoplasmic reticulum morphology (e.g. SPG3A/Atlastin, SPG4/Spastin, SPG12/reticulon 2, and SPG31/REEP1, all of which interact); (3) mitochondrial function (e.g. SPG13/chaperonin 60/heat-shock protein 60, SPG7/paraplegin; and mitochondrial ATP6); (4) myelin formation (e.g. SPG2/Proteolipid protein and SPG42/Connexin 47); (5) protein folding and ER-stress response (SPG6/NIPA1, SPG8/K1AA0196 (Strumpellin), SGP17/BSCL2 (Seipin), "mutilating sensory neuropathy with spastic paraplegia" owing to CcT5 mutation and presumably SPG18/ERLIN2); (6) corticospinal tract and other neurodevelopment (e.g. SPG1/L1 cell adhesion molecule and SPG22/thyroid transporter MCT8); (7) fatty acid and phospholipid metabolism (e.g. SPG28/DDHD1, SPG35/FA2H, SPG39/NTE, SPG54/DDHD2, and SPG56/CYP2U1); and (8) endosome membrane trafficking and vesicle formation (e.g. SPG47/AP4B1, SPG48/KIAA0415, SPG50/AP4M1, SPG51/AP4E, SPG52/AP4S1, and

Chaperonin of Group I: Oligomeric Spectrum and Biochemical and Biological Implications.

PubMed

Vilasi, Silvia; Bulone, Donatella; Caruso Bavisotto, Celeste; Campanella, Claudia; Marino Gammazza, Antonella; San Biagio, Pier L; Cappello, Francesco; Conway de Macario, Everly; Macario, Alberto J L

2017-01-01

Chaperonins play various physiological roles and can also be pathogenic. Elucidation of their structure, e.g., oligomeric status and post-translational modifications (PTM), is necessary to understand their functions and mechanisms of action in health and disease. Group I chaperonins form tetradecamers with two stacked heptameric rings. The tetradecamer is considered the typical functional complex for folding of client polypeptides. However, other forms such as the monomer and oligomers with smaller number of subunits than the classical tetradecamer, also occur in cells. The properties and functions of the monomer and oligomers, and their roles in chaperonin-associated diseases are still incompletely understood. Chaperonin I in eukaryotes occurs in various locations, not just the mitochondrion, which is its canonical place of residence and function. Eukaryotic Chaperonin I, namely Hsp60 (designated HSP60 or HSPD1 in humans) has, indeed, been found in the cytosol; the plasma-cell membrane; on the outer surface of cells; in the intercellular space; in biological liquids such as lymph, blood, and cerebrospinal fluid; and in secretions, for instance saliva and urine. Hsp60 has also been found in cell-derived vesicles such as exosomes. The functions of Hsp60 in all these non-canonical locales are still poorly characterized and one of the questions not yet answered is in what form, i.e., monomer or oligomer, is the chaperonin present in these non-canonical locations. In view of the steady increase in interest on chaperonopathies over the last several years, we have studied human HSP60 to determine its role in various diseases, its locations in cells and tissues and migrations in the body, and its post-translational modifications that might have an impact on its location and function. We also carried out experiments to characterize the oligomeric status of extramitochondrial of HSP60 in solution. Here, we provide an overview of our results, focusing on the oligomeric

Biochemical and Genetic Analysis of the Chlamydia GroEL Chaperonins

PubMed Central

Illingworth, Melissa; Hooppaw, Anna J.; Ruan, Lu

2017-01-01

ABSTRACT Chaperonins are essential for cellular growth under normal and stressful conditions and consequently represent one of the most conserved and ancient protein classes. The paradigm Escherichia coli chaperonin, EcGroEL, and its cochaperonin, EcGroES, assist in the folding of proteins via an ATP-dependent mechanism. In addition to the presence of groEL and groES homologs, groEL paralogs are found in many bacteria, including pathogens, and have evolved poorly understood species-specific functions. Chlamydia spp., which are obligate intracellular bacteria, have reduced genomes that nonetheless contain three groEL genes, Chlamydia groEL (ChgroEL), ChgroEL2, and ChgroEL3. We hypothesized that ChGroEL is the bona fide chaperonin and that the paralogs perform novel Chlamydia-specific functions. To test our hypothesis, we investigated the biochemical properties of ChGroEL and its cochaperonin, ChGroES, and queried the in vivo essentiality of the three ChgroEL genes through targeted mutagenesis in Chlamydia trachomatis. ChGroEL hydrolyzed ATP at a rate 25% of that of EcGroEL and bound with high affinity to ChGroES, and the ChGroEL-ChGroES complex could refold malate dehydrogenase (MDH). The chlamydial ChGroEL was selective for its cognate cochaperonin, ChGroES, while EcGroEL could function with both EcGroES and ChGroES. A P35T ChGroES mutant (ChGroESP35T) reduced ChGroEL-ChGroES interactions and MDH folding activities but was tolerated by EcGroEL. Both ChGroEL-ChGroES and EcGroEL-ChGroESP35T could complement an EcGroEL-EcGroES mutant. Finally, we successfully inactivated both paralogs but not ChgroEL, leading to minor growth defects in cell culture that were not exacerbated by heat stress. Collectively, our results support novel functions for the paralogs and solidify ChGroEL as a bona fide chaperonin that is biochemically distinct from EcGroEL. IMPORTANCE Chlamydia is an important cause of human diseases, including pneumonia, sexually transmitted infections, and

Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms

PubMed Central

Fink, John K.

2014-01-01

Hereditary spastic paraplegia (HSP) is a syndrome designation describing inherited disorders in which lower extremity weakness and spasticity are the predominant symptoms. There are more than 50 genetic types of HSP. HSP affects individuals diverse ethnic groups with prevalence estimates ranging from 1.2 to 9.6 per 100,000 [39, 70, 77, 154, 185]. Symptoms may begin at any age. Gait impairment that begins after childhood usually worsens very slowly over many years. Gait impairment that begins in infancy and early childhood may not worsen significantly. Post mortem studies consistently identify degeneration of corticospinal tract axons (maximal in the thoracic spinal cord) and degeneration of fasciculus gracilis fibers (maximal in the cervico-medullary region). HSP syndromes thus appear to involve motor-sensory axon degeneration affecting predominantly (but not exclusively) the distal ends of long central nervous system (CNS) axons. In general, proteins encoded by HSP genes have diverse functions including axon transport (e.g. SPG30/KIF1A, SPG10/KIF5A and possibly SPG4/Spastin); endoplasmic reticulum morphology (e.g. SPG3A/Atlastin, SPG4/Spastin, SPG12/reticulon 2, and SPG31/REEP1, all of which interact); mitochondrial function (e.g. SPG13/chaperonin 60/heat shock protein 60, SPG7/paraplegin; and mitochondrial ATP6; 4) myelin formation (e.g. SPG2/Proteolipid protein and SPG42/Connexin 47); 5) protein folding and ER-stress response (SPG6/NIPA1, SPG8/K1AA0196 (Strumpellin), SGP17/BSCL2 (Seipin) [113-115], “mutilating sensory neuropathy with spastic paraplegia” due to CcT5 mutation and presumably SPG18/ERLIN2); 6) corticospinal tract and other neurodevelopment (e.g. SPG1/L1 cell adhesion molecule and SPG22/thyroid transporter MCT8); 7) fatty acid and phospholipid metabolism (e.g. SPG28/DDHD1, SPG35/FA2H, SPG39/NTE, SPG54/DDHD2, and SPG56/CYP2U1); and 8) endosome membrane trafficking and vesicle formation (e.g. SPG47/AP4B1, SPG48/KIAA0415, SPG50/AP4M1, SPG51/AP4E

Two cofactors and cytoplasmic chaperonin are required for the folding of alpha- and beta-tubulin.

PubMed Central

Gao, Y; Vainberg, I E; Chow, R L; Cowan, N J

1993-01-01

Though the chaperonins that mediate folding in prokaryotes, mitochondria, and chloroplasts have been relatively well characterized, the folding of proteins in the eukaryotic cytosol is much less well understood. We recently identified a cytoplasmic chaperonin as an 800-kDa multisubunit toroid which forms a binary complex with unfolded actin; the correctly folded polypeptide is released upon incubation with Mg-ATP (Y. Gao, J. O. Thomas, R. L. Chow, G.-H. Lee, and N. J. Cowan, Cell 69:1043-1050, 1992). Here we show that the same chaperonin also forms a binary complex with unfolded alpha- or beta-tubulin; however, there is no detectable release of the correctly folded product, irrespective of the concentration of added Mg-ATP and Mg-GTP or the presence of added carrier tubulin heterodimers with which newly folded alpha- or beta-tubulin polypeptides might exchange. Rather, two additional protein cofactors are required for the generation of properly folded alpha- or beta-tubulin, which is then competent for exchange into preexisting alpha/beta-tubulin heterodimers. We show that actin and tubulins compete efficiently with one another for association with cytoplasmic chaperonin complexes. These data imply that actin and alpha- and beta-tubulin interact with the same site(s) on chaperonin complexes. Images PMID:8096061

Improved surgical procedure using intraoperative navigation for the implantation of the SPG microstimulator in patients with chronic cluster headache.

PubMed

Kohlmeier, Carsten; Behrens, Peter; Böger, Andreas; Ramachandran, Brinda; Caparso, Anthony; Schulze, Dirk; Stude, Philipp; Heiland, Max; Assaf, Alexandre T

2017-12-01

The ATI SPG microstimulator is designed to be fixed on the posterior maxilla, with the integrated lead extending into the pterygopalatine fossa to electrically stimulate the sphenopalatine ganglion (SPG) as a treatment for cluster headache. Preoperative surgical planning to ensure the placement of the microstimulator in close proximity (within 5 mm) to the SPG is critical for treatment efficacy. The aim of this study was to improve the surgical procedure by navigating the initial dissection prior to implantation using a passive optical navigation system and to match the post-operative CBCT images with the preoperative treatment plan to verify the accuracy of the intraoperative placement of the microstimulator. Custom methods and software were used that result in a 3D rotatable digitally reconstructed fluoroscopic image illustrating the patient-specific placement with the ATI SPG microstimulator. Those software tools were preoperatively integrated with the planning software of the navigation system to be used intraoperatively for navigated placement. Intraoperatively, the SPG microstimulator was implanted by completing the initial dissection with CT navigation, while the final position of the stimulator was verified by 3D CBCT. Those reconstructed images were then immediately matched with the preoperative CT scans with the digitally inserted SPG microstimulator. This method allowed for visual comparison of both CT scans and verified correct positioning of the SPG microstimulator. Twenty-four surgeries were performed using this new method of CT navigated assistance during SPG microstimulator implantation. Those results were compared to results of 21 patients previously implanted without the assistance of CT navigation. Using CT navigation during the initial dissection, an average distance reduction of 1.2 mm between the target point and electrode tip of the SPG microstimulator was achieved. Using the navigation software for navigated implantation and matching the

Chaperonin-mediated Protein Folding

PubMed Central

Horwich, Arthur L.

2013-01-01

We have been studying chaperonins these past twenty years through an initial discovery of an action in protein folding, analysis of structure, and elucidation of mechanism. Some of the highlights of these studies were presented recently upon sharing the honor of the 2013 Herbert Tabor Award with my early collaborator, Ulrich Hartl, at the annual meeting of the American Society for Biochemistry and Molecular Biology in Boston. Here, some of the major findings are recounted, particularly recognizing my collaborators, describing how I met them and how our great times together propelled our thinking and experiments. PMID:23803606

In silico engineering of aggregation-prone recombinant proteins for substrate recognition by the chaperonin GroEL.

PubMed

Kumar, Vipul; Punetha, Ankita; Sundar, Durai; Chaudhuri, Tapan K

2012-01-01

Molecular chaperones appear to have been evolved to facilitate protein folding in the cell through entrapment of folding intermediates on the interior of a large cavity formed between GroEL and its co-chaperonin GroES. They bind newly synthesized or non-native polypeptides through hydrophobic interactions and prevent their aggregation. Some proteins do not interact with GroEL, hence even though they are aggregation prone, cannot be assisted by GroEL for their folding. In this study, we have attempted to engineer these non-substrate proteins to convert them as the substrate for GroEL, without compromising on their function. We have used a computational biology approach to generate mutants of the selected proteins by selectively mutating residues in the hydrophobic patch, similar to GroES mobile loop region that are responsible for interaction with GroEL, and compared with the wild counterparts for calculation of their instability and aggregation propensities. The energies of the newly designed mutants were computed through molecular dynamics simulations. We observed increased aggregation propensity of some of the mutants formed after replacing charged amino acid residues with hydrophobic ones in the well defined hydrophobic patch, raising the possibility of their binding ability to GroEL. The newly generated mutants may provide potential substrates for Chaperonin GroEL, which can be experimentally generated and tested for their tendency of aggregation, interactions with GroEL and the possibility of chaperone-assisted folding to produce functional proteins.

On the role of the chaperonin CCT in the just-in-time assembly process of APC/CCdc20.

PubMed

Dekker, Carien

2010-02-05

The just-in-time hypothesis relates to the assembly of large multi-protein complexes and their regulation of activation in the cell. Here I postulate that chaperonins may contribute to the timely assembly and activation of such complexes. For the case of anaphase promoting complex/cyclosome(Cdc20) assembly by the eukaryotic chaperonin chaperonin containing Tcp1 it is shown that just-in-time synthesis and chaperone-assisted folding can synergise to generate a highly regulated assembly process of a protein complex that is vital for cell cycle progression. Once dependency has been established transcriptional regulation and chaperonin-dependency may have co-evolved to safeguard the timely activation of important multi-protein complexes. 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Structure and function of archaeal prefoldin, a co-chaperone of group II chaperonin.

PubMed

Ohtaki, Akashi; Noguchi, Keiichi; Yohda, Masafumi

2010-01-01

Molecular chaperones are key cellular components involved in the maintenance of protein homeostasis and other unrelated functions. Prefoldin is a chaperone that acts as a co-factor of group II chaperonins in eukaryotes and archaea. It assists proper folding of protein by capturing nonnative proteins and delivering it to the group II chaperonin. Eukaryotic prefoldin is a multiple subunit complex composed of six different polypeptide chains. Archaeal prefoldin, on the other hand, is a heterohexameric complex composed of two alpha and four beta subunits, and forms a double beta barrel assembly with six long coiled coils protruding from it like a jellyfish with six tentacles. Based on the structural information of the archaeal prefoldin, substrate recognition and prefoldin-chaperonin binding mechanisms have been investigated. In this paper, we review a series of studies on the molecular mechanisms of archaeal PFD function. Particular emphasis will be placed on the molecular structures revealed by X-ray crystallography and molecular dynamics induced by binding to nonnative protein substrates.

Cellular Chaperonin CCTγ Contributes to Rabies Virus Replication during Infection

PubMed Central

Zhang, Jinyang; Wu, Xiaopeng; Zan, Jie; Wu, Yongping; Ye, Chengjin; Ruan, Xizhen

2013-01-01

Rabies, as the oldest known infectious disease, remains a serious threat to public health worldwide. The eukaryotic cytosolic chaperonin TRiC/CCT complex facilitates the folding of proteins through ATP hydrolysis. Here, we investigated the expression, cellular localization, and function of neuronal CCTγ during neurotropic rabies virus (RABV) infection using mouse N2a cells as a model. Following RABV infection, 24 altered proteins were identified by using two-dimensional electrophoresis and mass spectrometry, including 20 upregulated proteins and 4 downregulated proteins. In mouse N2a cells infected with RABV or cotransfected with RABV genes encoding nucleoprotein (N) and phosphoprotein (P), confocal microscopy demonstrated that upregulated cellular CCTγ was colocalized with viral proteins N and P, which formed a hollow cricoid inclusion within the region around the nucleus. These inclusions, which correspond to Negri bodies (NBs), did not form in mouse N2a cells only expressing the viral protein N or P. Knockdown of CCTγ by lentivirus-mediated RNA interference led to significant inhibition of RABV replication. These results demonstrate that the complex consisting of viral proteins N and P recruits CCTγ to NBs and identify the chaperonin CCTγ as a host factor that facilitates intracellular RABV replication. This work illustrates how viruses can utilize cellular chaperonins and compartmentalization for their own benefit. PMID:23637400

Contribution of the C-Terminal Region of a Group II Chaperonin to its Interaction with Prefoldin and Substrate Transfer.

PubMed

Zako, Tamotsu; Sahlan, Muhamad; Fujii, Sayaka; Yamamoto, Yohei Y; Tai, Phan The; Sakai, Kotaro; Maeda, Mizuo; Yohda, Masafumi

2016-06-05

Prefoldin is a molecular chaperone that captures an unfolded protein substrate and transfers it to a group II chaperonin. Previous studies have shown that the interaction sites for prefoldin are located in the helical protrusions of group II chaperonins. However, it does not exclude the possibility of the existence of other interaction sites. In this study, we constructed C-terminal truncation mutants of a group II chaperonin and examined the effects of these mutations on the chaperone's function and interaction with prefoldin. Whereas the mutants with up to 6 aa truncation from the C-terminus retained more than 90% chaperone activities for protecting citrate synthase from thermal aggregation and refolding of green fluorescent protein and isopropylmalate dehydrogenase, the truncation mutants showed decreased affinities for prefoldin. Consequently, the truncation mutants showed reduced transfer efficiency of the denatured substrate protein from prefoldin and subsequent chaperonin-dependent refolding. The results clearly show that the C-terminal region of group II chaperonins contributes to their interactions with prefoldin, the transfer of the substrate protein from prefoldin and its refolding. Copyright © 2016 Elsevier Ltd. All rights reserved.

Circular Permutation of a Chaperonin Protein: Biophysics and Application to Nanotechnology

NASA Technical Reports Server (NTRS)

Paavola, Chad; Chan, Suzanne; Li, Yi-Fen; McMillan, R. Andrew; Trent, Jonathan

2004-01-01

We have designed five circular permutants of a chaperonin protein derived from the hyperthermophilic organism Sulfolobus shibatae. These permuted proteins were expressed in E. coli and are well-folded. Furthermore, all the permutants assemble into 18-mer double rings of the same form as the wild-type protein. We characterized the thermodynamics of folding for each permutant by both guanidine denaturation and differential scanning calorimetry. We also examined the assembly of chaperonin rings into higher order structures that may be used as nanoscale templates. The results show that circular permutation can be used to tune the thermodynamic properties of a protein template as well as facilitating the fusion of peptides, binding proteins or enzymes onto nanostructured templates.

NIPA1 Gene Mutations Cause Autosomal Dominant Hereditary Spastic Paraplegia (SPG6)

PubMed Central

Rainier, Shirley; Chai, Jing-Hua; Tokarz, Debra; Nicholls, Robert D.; Fink, John K.

2003-01-01

The hereditary spastic paraplegias (HSPs) are genetically heterogeneous disorders characterized by progressive lower-extremity weakness and spasticity. The molecular pathogenesis is poorly understood. We report discovery of a dominant negative mutation in the NIPA1 gene in a kindred with autosomal dominant HSP (ADHSP), linked to chromosome 15q11-q13 (SPG6 locus); and precisely the same mutation in an unrelated kindred with ADHSP that was too small for meaningful linkage analysis. NIPA1 is highly expressed in neuronal tissues and encodes a putative membrane transporter or receptor. Identification of the NIPA1 function and ligand will aid an understanding of axonal neurodegeneration in HSP and may have important therapeutic implications. PMID:14508710

Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12

PubMed Central

Landouré, Guida; Zhu, Peng-Peng; Lourenço, Charles M.; Johnson, Janel O.; Toro, Camilo; Bricceno, Katherine V.; Rinaldi, Carlo; Meilleur, Katherine G.; Sangaré, Modibo; Diallo, Oumarou; Pierson, Tyler M.; Ishiura, Hiroyuki; Tsuji, Shoji; Hein, Nichole; Fink, John K.; Stoll, Marion; Nicholson, Garth; Gonzalez, Michael; Speziani, Fiorella; Dürr, Alexandra; Stevanin, Giovanni; Biesecker, Leslie G.; Accardi, John; Landis, Dennis M. D.; Gahl, William A.; Traynor, Bryan J.; Marques, Wilson; Züchner, Stephan; Blackstone, Craig; Fischbeck, Kenneth H.; Burnett, Barrington G.

2013-01-01

We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly-conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain. PMID:23857908

Probing the kinetic stabilities of Friedreich's ataxia clinical variants using a solid phase GroEL chaperonin capture platform.

PubMed

Correia, Ana R; Naik, Subhashchandra; Fisher, Mark T; Gomes, Cláudio M

2014-10-20

Numerous human diseases are caused by protein folding defects where the protein may become more susceptible to degradation or aggregation. Aberrant protein folding can affect the kinetic stability of the proteins even if these proteins appear to be soluble in vivo. Experimental discrimination between functional properly folded and misfolded nonfunctional conformers is not always straightforward at near physiological conditions. The differences in the kinetic behavior of two initially folded frataxin clinical variants were examined using a high affinity chaperonin kinetic trap approach at 25 °C. The kinetically stable wild type frataxin (FXN) shows no visible partitioning onto the chaperonin. In contrast, the clinical variants FXN-p.Asp122Tyr and FXN-p.Ile154Phe kinetically populate partial folded forms that tightly bind the GroEL chaperonin platform. The initially soluble FXN-p.Ile154Phe variant partitions onto GroEL more rapidly and is more kinetically liable. These differences in kinetic stability were confirmed using differential scanning fluorimetry. The kinetic and aggregation stability differences of these variants may lead to the distinct functional impairments described in Friedreich's ataxia, the neurodegenerative disease associated to frataxin functional deficiency. This chaperonin platform approach may be useful for identifying small molecule stabilizers since stabilizing ligands to frataxin variants should lead to a concomitant decrease in chaperonin binding.

Pyrococcus prefoldin stabilizes protein-folding intermediates and transfers them to chaperonins for correct folding.

PubMed

Okochi, Mina; Yoshida, Takao; Maruyama, Tadashi; Kawarabayasi, Yutaka; Kikuchi, Hisashi; Yohda, Masafumi

2002-03-08

A molecular chaperone prefoldin/GimC from the hyperthermophilic archaeum Pyrococcus horikoshii OT3 was characterized. Pyrococcus prefoldin protected porcine heart citrate synthase from thermal aggregation whereas each subunit alone afforded little protection. It also arrested the spontaneous refolding of acid-denatured green fluorescent protein and then transferred it not only to a group II chaperonin from the hyperthermophilic archaeum Thermococcus sp. strain KS-1, but also to a group I chaperonin from the thermophilic bacterium Thermus thermophilus HB8 for subsequent ATP dependent refolding.

Novel Compound Heterozygous Spatacsin Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia.

PubMed

Fraidakis, Matthew J; Brunetti, Maura; Blackstone, Craig; Filippi, Massimo; Chiò, Adriano

2016-01-01

SPG11 belongs to the autosomal recessive hereditary spastic paraplegias (HSP) and presents during childhood or puberty with a complex clinical phenotype encompassing learning difficulties, ataxia, peripheral neuropathy, amyotrophy, and mental retardation. We hereby present the case of a 30-year-old female patient with complex autosomal recessive HSP with thinning of the corpus callosum (TCC) and dementia that was compound heterozygous with two novel mutations in the SPG11 gene. Sequence analysis of the SPG11 gene revealed two novel mutations in a compound heterozygous state in the index patient (c.2431C>T/p.Gln811Ter and c.6755_6756insT/p.Glu2252Aspfs*88). MRI showed abnormal TCC, white matter (WM) hyperintensities periventricularly, and the 'ears of the lynx' sign. Diffusion tensor imaging showed a mild-to-moderate decrease in fractional anisotropy and an increase in mean diffusivity in WM compared to age-matched controls, while magnetic resonance spectroscopy showed abnormal findings in affected WM with a decrease in N-acetyl-aspartate in WM regions of interest. This is the first SPG11 kindred from the Greek population to be reported in the medical literature. © 2016 S. Karger AG, Basel.

13 CFR 108.1710 - SBA authority to collect or compromise its claims.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false SBA authority to collect or compromise its claims. 108.1710 Section 108.1710 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION NEW MARKETS VENTURE CAPITAL (âNMVCâ) PROGRAM SBA Financial Assistance for NMVC Companies (Leverage...

Prefoldin, a jellyfish-like molecular chaperone: functional cooperation with a group II chaperonin and beyond.

PubMed

Sahlan, Muhamad; Zako, Tamotsu; Yohda, Masafumi

2018-04-01

Prefoldin is a hexameric molecular chaperone found in the cytosol of archaea and eukaryotes. Its hexameric complex is built from two related classes of subunits and has the appearance of a jellyfish: its body consists of a double beta-barrel assembly with six long tentacle-like coiled coils protruding from it. Using the tentacles, prefoldin captures an unfolded protein substrate and transfers it to a group II chaperonin. The prefoldin-group II chaperonin system is thought to be important for the folding of newly synthesized proteins and for their maintenance, or proteostasis, in the cytosol. Based on structural information of archaeal prefoldins, the mechanisms of substrate recognition and prefoldin-chaperonin cooperation have been investigated. In contrast, the role and mechanism of eukaryotic PFDs remain unknown. Recent studies have shown that prefoldin plays an important role in proteostasis and is involved in various diseases. In this paper, we review a series of studies on the molecular mechanisms of archaeal prefoldins and introduce recent findings about eukaryotic prefoldin.

Draft Genome Sequence of Arthrobacter sp. Strain SPG23, a Hydrocarbon-Degrading and Plant Growth-Promoting Soil Bacterium.

PubMed

Gkorezis, Panagiotis; Bottos, Eric M; Van Hamme, Jonathan D; Thijs, Sofie; Rineau, Francois; Franzetti, Andrea; Balseiro-Romero, Maria; Weyens, Nele; Vangronsveld, Jaco

2015-12-23

We report here the 4.7-Mb draft genome of Arthrobacter sp. SPG23, a hydrocarbonoclastic Gram-positive bacterium belonging to the Actinobacteria, isolated from diesel-contaminated soil at the Ford Motor Company site in Genk, Belgium. Strain SPG23 is a potent plant growth promoter useful for diesel fuel remediation applications based on plant-bacterium associations. Copyright © 2015 Gkorezis et al.

Mechanism of the eukaryotic chaperonin: protein folding in the chamber of secrets

PubMed Central

Spiess, Christoph; Meyer, Anne S.; Reissmann, Stefanie; Frydman, Judith

2010-01-01

Chaperonins are key components of the cellular chaperone machinery. These large, cylindrical complexes contain a central cavity that binds to unfolded polypeptides and sequesters them from the cellular environment. Substrate folding then occurs in this central cavity in an ATP-dependent manner. The eukaryotic chaperonin TCP-1 ring complex (TRiC, also called CCT) is indispensable for cell survival because the folding of an essential subset of cytosolic proteins requires TRiC, and this function cannot be substituted by other chaperones. This specificity indicates that TRiC has evolved structural and mechanistic features that distinguish it from other chaperones. Although knowledge of this unique complex is in its infancy, we review recent advances that open the way to understanding the secrets of its folding chamber. PMID:15519848

Probing the interaction mechanisms between transmembrane peptides and the chaperonin GroEL with fluorescence anisotropy

NASA Astrophysics Data System (ADS)

Wang, Xiaoqiang; Chen, Han; Lu, Xinwei; Chi, Haixia; Li, Shixin; Huang, Fang

2018-04-01

Proper translocation, membrane insertion and folding are crucial biophysical steps in the biogenesis of functional transmembrane peptides/proteins (TMPs). ATP-dependent chaperonins are able to regulate each of these processes, but the underlying mechanisms remain unclear. In this work, interaction between the bacterial chaperonin GroEL and a synthetic fluorescent transmembrane peptide was investigated by fluorescence anisotropy. Binding of the peptide with GroEL resulted in increased fluorescence anisotropy and intensity. The dissociation constant and binding stoichiometry, as assessed by titration of the peptide with GroEL, were estimated to be 0.6 ± 0.2 μM and 2.96 ± 0.35, respectively. Complementary study with the single-ring version of GroEL confirmed the high-affinity peptide binding, and indicates that the two GroEL rings may function alternatively in binding the peptides. The co-chaperonin GroES was found to be effective at releasing the peptides initially bound to GroEL with the help of ATP. Moreover, our observation with the single-ring GroEL mutant demonstrated that during the encapsulation of GroEL by GroES, the bound peptides may either be confined in the cage thus formed, or escape outside. Competitive binding experiments indicated that the peptides studied interact with GroEL through the paired helices H and I on its apical domain. Our spectroscopic studies revealed some basic mechanisms of interaction between transmembrane peptides and GroEL, which would be instrumental for deciphering the chaperonin-mediated TMP biogenesis.

MtGimC, a novel archaeal chaperone related to the eukaryotic chaperonin cofactor GimC/prefoldin.

PubMed

Leroux, M R; Fändrich, M; Klunker, D; Siegers, K; Lupas, A N; Brown, J R; Schiebel, E; Dobson, C M; Hartl, F U

1999-12-01

Group II chaperonins in the eukaryotic and archaeal cytosol assist in protein folding independently of the GroES-like cofactors of eubacterial group I chaperonins. Recently, the eukaryotic chaperonin was shown to cooperate with the hetero-oligomeric protein complex GimC (prefoldin) in folding actin and tubulins. Here we report the characterization of the first archaeal homologue of GimC, from Methanobacterium thermoautotrophicum. MtGimC is a hexamer of 87 kDa, consisting of two alpha and four beta subunits of high alpha-helical content that are predicted to contain extended coiled coils and represent two evolutionarily conserved classes of Gim subunits. Reconstitution experiments with MtGimC suggest that two subunits of the alpha class (archaeal Gimalpha and eukaryotic Gim2 and 5) form a dimer onto which four subunits of the beta class (archaeal Gimbeta and eukaryotic Gim1, 3, 4 and 6) assemble. MtGimalpha and beta can form hetero-complexes with yeast Gim subunits and MtGimbeta partially complements yeast strains lacking Gim1 and 4. MtGimC is a molecular chaperone capable of stabilizing a range of non-native proteins and releasing them for subsequent chaperonin-assisted folding. In light of the absence of Hsp70 chaperones in many archaea, GimC may fulfil an ATP-independent, Hsp70-like function in archaeal de novo protein folding.

MtGimC, a novel archaeal chaperone related to the eukaryotic chaperonin cofactor GimC/prefoldin.

PubMed Central

Leroux, M R; Fändrich, M; Klunker, D; Siegers, K; Lupas, A N; Brown, J R; Schiebel, E; Dobson, C M; Hartl, F U

1999-01-01

Group II chaperonins in the eukaryotic and archaeal cytosol assist in protein folding independently of the GroES-like cofactors of eubacterial group I chaperonins. Recently, the eukaryotic chaperonin was shown to cooperate with the hetero-oligomeric protein complex GimC (prefoldin) in folding actin and tubulins. Here we report the characterization of the first archaeal homologue of GimC, from Methanobacterium thermoautotrophicum. MtGimC is a hexamer of 87 kDa, consisting of two alpha and four beta subunits of high alpha-helical content that are predicted to contain extended coiled coils and represent two evolutionarily conserved classes of Gim subunits. Reconstitution experiments with MtGimC suggest that two subunits of the alpha class (archaeal Gimalpha and eukaryotic Gim2 and 5) form a dimer onto which four subunits of the beta class (archaeal Gimbeta and eukaryotic Gim1, 3, 4 and 6) assemble. MtGimalpha and beta can form hetero-complexes with yeast Gim subunits and MtGimbeta partially complements yeast strains lacking Gim1 and 4. MtGimC is a molecular chaperone capable of stabilizing a range of non-native proteins and releasing them for subsequent chaperonin-assisted folding. In light of the absence of Hsp70 chaperones in many archaea, GimC may fulfil an ATP-independent, Hsp70-like function in archaeal de novo protein folding. PMID:10581246

A Versatile Platform for Nanotechnology Based on Circular Permutation of a Chaperonin Protein

NASA Technical Reports Server (NTRS)

Paavola, Chad; McMillan, Andrew; Trent, Jonathan; Chan, Suzanne; Mazzarella, Kellen; Li, Yi-Fen

2004-01-01

A number of protein complexes have been developed as nanoscale templates. These templates can be functionalized using the peptide sequences that bind inorganic materials. However, it is difficult to integrate peptides into a specific position within a protein template. Integrating intact proteins with desirable binding or catalytic activities is an even greater challenge. We present a general method for modifying protein templates using circular permutation so that additional peptide sequence can be added in a wide variety of specific locations. Circular permutation is a reordering of the polypeptide chain such that the original termini are joined and new termini are created elsewhere in the protein. New sequence can be joined to the protein termini without perturbing the protein structure and with minimal limitation on the size and conformation of the added sequence. We have used this approach to modify a chaperonin protein template, placing termini at five different locations distributed across the surface of the protein complex. These permutants are competent to form the double-ring structures typical of chaperonin proteins. The permuted double-rings also form the same assemblies as the unmodified protein. We fused a fluorescent protein to two representative permutants and demonstrated that it assumes its active structure and does not interfere with assembly of chaperonin double-rings.

Evaluation of Time-Temperature Integrators (TTIs) with Microorganism-Entrapped Microbeads Produced Using Homogenization and SPG Membrane Emulsification Techniques.

PubMed

Rahman, A T M Mijanur; Lee, Seung Ju; Jung, Seung Won

2015-12-28

A comparative study was conducted to evaluate precision and accuracy in controlling the temperature dependence of encapsulated microbial time-temperature integrators (TTIs) developed using two different emulsification techniques. Weissela cibaria CIFP 009 cells, immobilized within 2% Na-alginate gel microbeads using homogenization (5,000, 7,000, and 10,000 rpm) and Shirasu porous glass (SPG) membrane technologies (10 μm), were applied to microbial TTIs. The prepared micobeads were characterized with respect to their size, size distribution, shape and morphology, entrapment efficiency, and bead production yield. Additionally, fermentation process parameters including growth rate were investigated. The TTI responses (changes in pH and titratable acidity (TA)) were evaluated as a function of temperature (20°C, 25°C, and 30°C). In comparison with conventional methods, SPG membrane technology was able not only to produce highly uniform, small-sized beads with the narrowest size distribution, but also the bead production yield was found to be nearly 3.0 to 4.5 times higher. However, among the TTIs produced using the homogenization technique, poor linearity (R(2)) in terms of TA was observed for the 5,000 and 7,000 rpm treatments. Consequently, microbeads produced by the SPG membrane and by homogenization at 10,000 rpm were selected for adjusting the temperature dependence. The Ea values of TTIs containing 0.5, 1.0, and 1.5 g microbeads, prepared by SPG membrane and conventional methods, were estimated to be 86.0, 83.5, and 76.6 kJ/mol, and 85.5, 73.5, and 62.2 kJ/mol, respectively. Therefore, microbial TTIs developed using SPG membrane technology are much more efficient in controlling temperature dependence.

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan.

PubMed

Elsayed, Liena E O; Mohammed, Inaam N; Hamed, Ahlam A A; Elseed, Maha A; Johnson, Adam; Mairey, Mathilde; Mohamed, Hassab Elrasoul S A; Idris, Mohamed N; Salih, Mustafa A M; El-Sadig, Sarah M; Koko, Mahmoud E; Mohamed, Ashraf Y O; Raymond, Laure; Coutelier, Marie; Darios, Frédéric; Siddig, Rayan A; Ahmed, Ahmed K M A; Babai, Arwa M A; Malik, Hiba M O; Omer, Zulfa M B M; Mohamed, Eman O E; Eltahir, Hanan B; Magboul, Nasr Aldin A; Bushara, Elfatih E; Elnour, Abdelrahman; Rahim, Salah M Abdel; Alattaya, Abdelmoneim; Elbashir, Mustafa I; Ibrahim, Muntaser E; Durr, Alexandra; Audhya, Anjon; Brice, Alexis; Ahmed, Ammar E; Stevanin, Giovanni

2016-01-01

Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSP-related genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C>T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C>T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

PubMed Central

Elsayed, Liena E O; Mohammed, Inaam N; Hamed, Ahlam A A; Elseed, Maha A; Johnson, Adam; Mairey, Mathilde; Mohamed, Hassab Elrasoul S A; Idris, Mohamed N; Salih, Mustafa A M; El-sadig, Sarah M; Koko, Mahmoud E; Mohamed, Ashraf Y O; Raymond, Laure; Coutelier, Marie; Darios, Frédéric; Siddig, Rayan A; Ahmed, Ahmed K M A; Babai, Arwa M A; Malik, Hiba M O; Omer, Zulfa M B M; Mohamed, Eman O E; Eltahir, Hanan B; Magboul, Nasr Aldin A; Bushara, Elfatih E; Elnour, Abdelrahman; Rahim, Salah M Abdel; Alattaya, Abdelmoneim; Elbashir, Mustafa I; Ibrahim, Muntaser E; Durr, Alexandra; Audhya, Anjon; Brice, Alexis; Ahmed, Ammar E; Stevanin, Giovanni

2017-01-01

Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSP-related genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C>T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C>T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance. PMID:27601211

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

PubMed Central

Estrada-Cuzcano, Alejandro; Martin, Shaun; Chamova, Teodora; Synofzik, Matthis; Timmann, Dagmar; Holemans, Tine; Andreeva, Albena; Reichbauer, Jennifer; De Rycke, Riet; Chang, Dae-In; van Veen, Sarah; Samuel, Jean; Schöls, Ludger; Pöppel, Thorsten; Mollerup Sørensen, Danny; Asselbergh, Bob; Klein, Christine; Zuchner, Stephan; Jordanova, Albena; Vangheluwe, Peter; Tournev, Ivailo; Schüle, Rebecca

2017-01-01

Abstract Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower

Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness.

PubMed

Abdeen, Sanofar; Salim, Nilshad; Mammadova, Najiba; Summers, Corey M; Goldsmith-Pestana, Karen; McMahon-Pratt, Diane; Schultz, Peter G; Horwich, Arthur L; Chapman, Eli; Johnson, Steven M

2016-11-01

Trypanosoma brucei are protozoan parasites that cause African sleeping sickness in humans (also known as Human African Trypanosomiasis-HAT). Without treatment, T. brucei infections are fatal. There is an urgent need for new therapeutic strategies as current drugs are toxic, have complex treatment regimens, and are becoming less effective owing to rising antibiotic resistance in parasites. We hypothesize that targeting the HSP60/10 chaperonin systems in T. brucei is a viable anti-trypanosomal strategy as parasites rely on these stress response elements for their development and survival. We recently discovered several hundred inhibitors of the prototypical HSP60/10 chaperonin system from Escherichia coli, termed GroEL/ES. One of the most potent GroEL/ES inhibitors we discovered was compound 1. While examining the PubChem database, we found that a related analog, 2e-p, exhibited cytotoxicity to Leishmania major promastigotes, which are trypanosomatids highly related to Trypanosoma brucei. Through initial counter-screening, we found that compounds 1 and 2e-p were also cytotoxic to Trypanosoma brucei parasites (EC 50 =7.9 and 3.1μM, respectively). These encouraging initial results prompted us to develop a library of inhibitor analogs and examine their anti-parasitic potential in vitro. Of the 49 new chaperonin inhibitors developed, 39% exhibit greater cytotoxicity to T. brucei parasites than parent compound 1. While many analogs exhibit moderate cytotoxicity to human liver and kidney cells, we identified molecular substructures to pursue for further medicinal chemistry optimization to increase the therapeutic windows of this novel class of chaperonin-targeting anti-parasitic candidates. An intriguing finding from this study is that suramin, the first-line drug for treating early stage T. brucei infections, is also a potent inhibitor of GroEL/ES and HSP60/10 chaperonin systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

Late-onset spastic paraplegia: Aberrant SPG11 transcripts generated by a novel splice site donor mutation.

PubMed

Kawarai, Toshitaka; Miyamoto, Ryosuke; Mori, Atsuko; Oki, Ryosuke; Tsukamoto-Miyashiro, Ai; Matsui, Naoko; Miyazaki, Yoshimichi; Orlacchio, Antonio; Izumi, Yuishin; Nishida, Yoshihiko; Kaji, Ryuji

2015-12-15

We identified a novel homozygous mutation in the splice site donor (SSD) of intron 30 (c.5866+1G>A) in consanguineous Japanese SPG11 siblings showing late-onset spastic paraplegia using the whole-exome sequencing. Phenotypic variability was observed, including age-at-onset, dysarthria and pes cavus. Coding DNA sequencing revealed that the mutation affected the recognition of the constitutive SSD of intron 30, splicing upstream onto a nearby cryptic SSD in exon 30. The use of constitutive splice sites of intron 29 was confirmed by sequencing. The mutant transcripts are mostly subject to degradation by the nonsense-mediated mRNA decay system. SPG11 transcripts, escaping from the nonsense-mediated mRNA decay pathway, would generate a truncated protein (p.Tyr1900Phefs5X) containing the first 1899 amino acids and followed by 4 aberrant amino acids. This study showed a successful clinical application of whole-exome sequencing in spastic paraplegia and demonstrated a further evidence of allelic heterogeneity in SPG11. The confirmation of aberrant transcript by splice site mutation is a prerequisite for a more precise molecular diagnosis. Copyright © 2015 Elsevier B.V. All rights reserved.

Differential conformational modulations of MreB folding upon interactions with GroEL/ES and TRiC chaperonin components

PubMed Central

Moparthi, Satish Babu; Carlsson, Uno; Vincentelli, Renaud; Jonsson, Bengt-Harald; Hammarström, Per; Wenger, Jérôme

2016-01-01

Here, we study and compare the mechanisms of action of the GroEL/GroES and the TRiC chaperonin systems on MreB client protein variants extracted from E. coli. MreB is a homologue to actin in prokaryotes. Single-molecule fluorescence correlation spectroscopy (FCS) and time-resolved fluorescence polarization anisotropy report the binding interaction of folding MreB with GroEL, GroES and TRiC. Fluorescence resonance energy transfer (FRET) measurements on MreB variants quantified molecular distance changes occurring during conformational rearrangements within folding MreB bound to chaperonins. We observed that the MreB structure is rearranged by a binding-induced expansion mechanism in TRiC, GroEL and GroES. These results are quantitatively comparable to the structural rearrangements found during the interaction of β-actin with GroEL and TRiC, indicating that the mechanism of chaperonins is conserved during evolution. The chaperonin-bound MreB is also significantly compacted after addition of AMP-PNP for both the GroEL/ES and TRiC systems. Most importantly, our results showed that GroES may act as an unfoldase by inducing a dramatic initial expansion of MreB (even more than for GroEL) implicating a role for MreB folding, allowing us to suggest a delivery mechanism for GroES to GroEL in prokaryotes. PMID:27328749

Analysis of miRNA expression profiles in melatonin-exposed GC-1 spg cell line.

PubMed

Zhu, Xiaoling; Chen, Shuxiong; Jiang, Yanwen; Xu, Ying; Zhao, Yun; Chen, Lu; Li, Chunjin; Zhou, Xu

2018-02-05

Melatonin is an endocrine neurohormone secreted by pinealocytes in the pineal gland. It exerts diverse physiological effects, such as circadian rhythm regulator and antioxidant. However, the functional importance of melatonin in spermatogenesis regulation remains unclear. The objectives of this study are to: (1) detect melatonin affection on miRNA expression profiles in GC-1 spg cells by miRNA deep sequencing (DeepSeq) and (2) define melatonin affected miRNA-mRNA interactions and associated biological processes using bioinformatics analysis. GC-1 spg cells were cultured with melatonin (10 -7 M) for 24h. DeepSeq data were validated using quantitative real-time reverse transcription polymerase chain reaction analysis (qRT-PCR). A total of 176 miRNA expressions were found to be significantly different between two groups (fold change of >2 or <0.5 and FDR<0.05). Among these expressions, 171 were up-regulated, and 5 were down-regulated. Ontology analysis of biological processes of these targets indicated a variety of biological functions. Pathway analysis indicated that the predicted targets were involved in cancers, apoptosis and signaling pathways, such as VEGF, TNF, Ras and Notch. Results implicated that melatonin could regulate the expression of miRNA to perform its physiological effects in GC-1 spg cells. These results should be useful to investigate the biological function of miRNAs regulated by melatonin in spermatogenesis and testicular germ cell tumor. Copyright © 2017 Elsevier B.V. All rights reserved.

Eukaryotic chaperonin containing T-complex polypeptide 1 interacts with filamentous actin and reduces the initial rate of actin polymerization in vitro

PubMed Central

Grantham, Julie; Ruddock, Lloyd W.; Roobol, Anne; Carden, Martin J.

2002-01-01

We have previously observed that subunits of the chaperonin required for actin production (type-II chaperonin containing T-complex polypeptide 1 [CCT]) localize at sites of microfilament assembly. In this article we extend this observation by showing that substantially substoichiometric CCT reduces the initial rate of pyrene-labeled actin polymerization in vitro where eubacterial chaperonin GroEL had no such effect. CCT subunits bound selectively to F-actin in cosedimentation assays, and CCT reduced elongation rates from both purified actin filament “seeds” and the short and stabilized, minus-end blocked filaments in erythrocyte membrane cytoskeletons. These observations suggest CCT might remain involved in biogenesis of the actin cytoskeleton, by acting at filament (+) ends, beyond its already well-established role in producing new actin monomers. PMID:12482199

Intracellular localization of a group II chaperonin indicates a membrane-related function

NASA Technical Reports Server (NTRS)

Trent, Jonathan D.; Kagawa, Hiromi K.; Paavola, Chad D.; McMillan, R. Andrew; Howard, Jeanie; Jahnke, Linda; Lavin, Colleen; Embaye, Tsegereda; Henze, Christopher E.

2003-01-01

Chaperonins are protein complexes that are believed to function as part of a protein folding system in the cytoplasm of the cell. We observed, however, that the group II chaperonins known as rosettasomes in the hyperthermophilic archaeon Sulfolobus shibatae, are not cytoplasmic but membrane associated. This association was observed in cultures grown at 60 degrees C and 76 degrees C or heat-shocked at 85 degrees C by using immunofluorescence microscopy and in thick sections of rapidly frozen cells grown at 76 degrees C by using immunogold electron microscopy. We observed that increased abundance of rosettasomes after heat shock correlated with decreased membrane permeability at lethal temperature (92 degrees C). This change in permeability was not seen in cells heat-shocked in the presence of the amino acid analogue azetidine 2-carboxylic acid, indicating functional protein synthesis influences permeability. Azetidine experiments also indicated that observed heat-induced changes in lipid composition in S. shibatae could not account for changes in membrane permeability. Rosettasomes purified from cultures grown at 60 degrees C and 76 degrees C or heat-shocked at 85 degrees C bind to liposomes made from either the bipolar tetraether lipids of Sulfolobus or a variety of artificial lipid mixtures. The presence of rosettasomes did not significantly change the transition temperature of liposomes, as indicated by differential scanning calorimetry, or the proton permeability of liposomes, as indicated by pyranine fluorescence. We propose that these group II chaperonins function as a structural element in the natural membrane based on their intracellular location, the correlation between their functional abundance and membrane permeability, and their potential distribution on the membrane surface.

The eukaryote chaperonin CCT is a cold shock protein in Saccharomyces cerevisiae

PubMed Central

Somer, Lilach; Shmulman, Oshrit; Dror, Tali; Hashmueli, Sharon; Kashi, Yechezkel

2002-01-01

The eukaryotic Hsp60 cytoplasmic chaperonin CCT (chaperonin containing the T-complex polypeptide–1) is essential for growth in budding yeast, and mutations in individual CCT subunits have been shown to affect assembly of tubulin and actin. The present research focused mainly on the expression of the CCT subunits, CCTα and CCTβ, in yeast (Saccharomyces cerevisiae). Previous studies showed that, unlike most other chaperones, CCT in yeast does not undergo induction following heat shock. In this study, messenger ribonucleic acid (mRNA) and protein levels of CCT subunits following exposure to low temperatures, were examined. The Northern blot analysis indicated a 3- to 4-fold increase in mRNA levels of CCTα and CCTβ genes after cold shock at 4°C. Interestingly, Western blot analysis showed that cold shock induces an increase in the CCTα protein, which is expressed at 10°C, but not at 4°C. Transfer of 4°C cold-shocked cells to 10°C induced a 5-fold increase in the CCTα protein level. By means of fluorescent immunostaining and confocal microscopy, we found CCTα to be localized in the cortex and the cell cytoplasm of S. cerevisiae. Localization of CCTα was not affected at low temperatures. Co-localization of CCT and filaments of actin and tubulin was not observed by microscopy. The induction pattern of the CCTα protein suggests that expression of the chaperonin may be primarily important during the recovery from low temperatures and the transition to growth at higher temperatures, as found for other Hsps during the recovery phase from heat shock. PMID:11892987

Modulating the Effects of the Bacterial Chaperonin GroEL on Fibrillogenic Polypeptides through Modification of Domain Hinge Architecture.

PubMed

Fukui, Naoya; Araki, Kiho; Hongo, Kunihiro; Mizobata, Tomohiro; Kawata, Yasushi

2016-11-25

The isolated apical domain of the Escherichia coli GroEL subunit displays the ability to suppress the irreversible fibrillation of numerous amyloid-forming polypeptides. In previous experiments, we have shown that mutating Gly-192 (located at hinge II that connects the apical domain and the intermediate domain) to a tryptophan results in an inactive chaperonin whose apical domain is disoriented. In this study, we have utilized this disruptive effect of Gly-192 mutation to our advantage, by substituting this residue with amino acid residues of varying van der Waals volumes with the intent to modulate the affinity of GroEL toward fibrillogenic peptides. The affinities of GroEL toward fibrillogenic polypeptides such as Aβ(1-40) (amyloid-β(1-40)) peptide and α-synuclein increased in accordance to the larger van der Waals volume of the substituent amino acid side chain in the G192X mutants. When we compared the effects of wild-type GroEL and selected GroEL G192X mutants on α-synuclein fibril formation, we found that the effects of the chaperonin on α-synuclein fibrillation were different; the wild-type chaperonin caused changes in both the initial lag phase and the rate of fibril extension, whereas the effects of the G192X mutants were more specific toward the nucleus-forming lag phase. The chaperonins also displayed differential effects on α-synuclein fibril morphology, suggesting that through mutation of Gly-192, we may induce changes to the intermolecular affinities between GroEL and α-synuclein, leading to more efficient fibril suppression, and in specific cases, modulation of fibril morphology. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Local energetic frustration affects the dependence of green fluorescent protein folding on the chaperonin GroEL.

PubMed

Bandyopadhyay, Boudhayan; Goldenzweig, Adi; Unger, Tamar; Adato, Orit; Fleishman, Sarel J; Unger, Ron; Horovitz, Amnon

2017-12-15

The GroE chaperonin system in Escherichia coli comprises GroEL and GroES and facilitates ATP-dependent protein folding in vivo and in vitro Proteins with very similar sequences and structures can differ in their dependence on GroEL for efficient folding. One potential but unverified source for GroEL dependence is frustration, wherein not all interactions in the native state are optimized energetically, thereby potentiating slow folding and misfolding. Here, we chose enhanced green fluorescent protein as a model system and subjected it to random mutagenesis, followed by screening for variants whose in vivo folding displays increased or decreased GroEL dependence. We confirmed the altered GroEL dependence of these variants with in vitro folding assays. Strikingly, mutations at positions predicted to be highly frustrated were found to correlate with decreased GroEL dependence. Conversely, mutations at positions with low frustration were found to correlate with increased GroEL dependence. Further support for this finding was obtained by showing that folding of an enhanced green fluorescent protein variant designed computationally to have reduced frustration is indeed less GroEL-dependent. Our results indicate that changes in local frustration also affect partitioning in vivo between spontaneous and chaperonin-mediated folding. Hence, the design of minimally frustrated sequences can reduce chaperonin dependence and improve protein expression levels. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Distinct Stabilities of the Structurally Homologous Heptameric Co-Chaperonins GroES and gp31

NASA Astrophysics Data System (ADS)

Dyachenko, Andrey; Tamara, Sem; Heck, Albert J. R.

2018-05-01

The GroES heptamer is the molecular co-chaperonin that partners with the tetradecamer chaperonin GroEL, which assists in the folding of various nonnative polypeptide chains in Escherichia coli. Gp31 is a structural and functional analogue of GroES encoded by the bacteriophage T4, becoming highly expressed in T4-infected E. coli, taking over the role of GroES, favoring the folding of bacteriophage proteins. Despite being slightly larger, gp31 is quite homologous to GroES in terms of its tertiary and quaternary structure, as well as in its function and mode of interaction with the chaperonin GroEL. Here, we performed a side-by-side comparison of GroES and gp31 heptamer complexes by (ion mobility) tandem mass spectrometry. Surprisingly, we observed quite distinct fragmentation mechanisms for the GroES and gp31 heptamers, whereby GroES displays a unique and unusual bimodal charge distribution in its released monomers. Not only the gas-phase dissociation but also the gas-phase unfolding of GroES and gp31 were found to be very distinct. We rationalize these observations with the similar discrepancies we observed in the thermal unfolding characteristics and surface contacts within GroES and gp31 in the solution. From our data, we propose a model that explains the observed simultaneous dissociation pathways of GroES and the differences between GroES and gp31 gas-phase dissociation and unfolding. We conclude that, although GroES and gp31 exhibit high homology in tertiary and quaternary structure, they are quite distinct in their solution and gas-phase (un)folding characteristics and stability. [Figure not available: see fulltext.

Preparation and characterization of polyclonal antibodies against human chaperonin 10

PubMed Central

Somodevilla-Torres, Maria J.; Hillyard, Narelle C.; Morton, Halle; Alewood, Dianne; Halliday, Judy A.; Alewood, Paul F.; Vesey, David A.; Walsh, Michael D.; Cavanagh, Alice C.

2000-01-01

Abstract Early pregnancy factor (EPF) has been identified as an extracellular homologue of chaperonin 10 (Cpn10), a heat shock protein that functions within the cell as a molecular chaperone. Here, we report the production of polyclonal antibodies directed against several different regions of the human Cpn10 molecule and their application to specific protein quantitation and localization techniques. These antibodies will be valuable tools in further studies to elucidate the mechanisms underlying the differential spatial and temporal localization of EPF and Cpn10 and in studies to elucidate structure and function. PMID:10701835

Multigeneration family with dominant SPG30 hereditary spastic paraplegia.

PubMed

Roda, Ricardo H; Schindler, Alice B; Blackstone, Craig

2017-11-01

Autosomal recessive KIF1A missense mutations cause hereditary spastic paraplegia (HSP) type SPG30, while recessive truncations lead to sensory and autonomic neuropathy (HSN2C) and many de novo missense mutations are associated with cognitive impairment. Here, we describe family members across three generations with pure HSP. A heterozygous p.Ser69Leu KIF1A mutation segregates with those afflicted. The same variant was previously reported in a Finnish father and son with pure HSP as well as four members of a Sicilian kindred with more intrafamilial phenotypic variability. This further validates the pathogenicity of the p.Ser69Leu mutation and suggests that it may represent a mutation hot spot.

The chaperonin CCT promotes the formation of fibrillar aggregates of γ-tubulin.

PubMed

Pouchucq, Luis; Lobos-Ruiz, Pablo; Araya, Gissela; Valpuesta, José María; Monasterio, Octavio

2018-04-01

The type II chaperonin CCT is involved in the prevention of the pathogenesis of numerous human misfolding disorders, as it sequesters misfolded proteins, blocks their aggregation and helps them to achieve their native state. In addition, it has been reported that CCT can prevent the toxicity of non-client amyloidogenic proteins by the induction of non-toxic aggregates, leading to new insight in chaperonin function as an aggregate remodeling factor. Here we add experimental evidence to this alternative mechanism by which CCT actively promotes the formation of conformationally different aggregates of γ-tubulin, a non-amyloidogenic CCT client protein, which are mediated by specific CCT-γ-tubulin interactions. The in vitro-induced aggregates were in some cases long fiber polymers, which compete with the amorphous aggregates. Direct injection of unfolded purified γ-tubulin into single-cell zebra fish embryos allowed us to relate this in vitro activity with the in vivo formation of intracellular aggregates. Injection of a CCT-binding deficient γ-tubulin mutant dramatically diminished the size of the intracellular aggregates, increasing the toxicity of the misfolded protein. These results point to CCT having a role in the remodeling of aggregates, constituting one of its many functions in cellular proteostasis. Copyright © 2018. Published by Elsevier B.V.

Chaperonin GroEL-GroES Functions as both Alternating and Non-Alternating Engines.

PubMed

Yamamoto, Daisuke; Ando, Toshio

2016-07-31

A double ring-shaped GroEL consisting of 14 ATPase subunits assists protein folding, together with co-chaperonin GroES. The dynamic GroEL-GroES interaction is actively involved in the chaperonin reaction. Therefore, revealing this dynamic interaction is a key to understanding the operation principle of GroEL. Nevertheless, how this interaction proceeds in the reaction cycle has long been controversial. Here, we directly imaged GroEL-GroES interaction in the presence of disulfide-reduced α-lactalbumin as a substrate protein using high-speed atomic force microscopy. This real-time imaging revealed the occurrence of primary, symmetric GroEL:GroES2 and secondary, asymmetric GroEL:GroES1 complexes. Remarkably, the reaction was observed to often branch into main and side pathways. In the main pathway, alternate binding and release of GroES occurs at the two rings, indicating tight cooperation between the two rings. In the side pathway, however, this cooperation is disrupted, resulting in the interruption of alternating rhythm. From various properties observed for both pathways, we provide mechanistic insight into the alternate and non-alternate operations of the two-engine system. Copyright © 2016 Elsevier Ltd. All rights reserved.

Asymmetry in the function and dynamics of the cytosolic group II chaperonin CCT/TRiC.

PubMed

Yamamoto, Yohei Y; Uno, Yuko; Sha, Eiryo; Ikegami, Kentaro; Ishii, Noriyuki; Dohmae, Naoshi; Sekiguchi, Hiroshi; Sasaki, Yuji C; Yohda, Masafumi

2017-01-01

The eukaryotic group II chaperonin, the chaperonin-containing t-complex polypeptide 1 (CCT), plays an important role in cytosolic proteostasis. It has been estimated that as much as 10% of cytosolic proteins interact with CCT during their folding process. CCT is composed of 8 different paralogous subunits. Due to its complicated structure, molecular and biochemical investigations of CCT have been difficult. In this study, we constructed an expression system for CCT from a thermophilic fungus, Chaetomium thermophilum (CtCCT), by using E. coli as a host. As expected, we obtained recombinant CtCCT with a relatively high yield, and it exhibited fairly high thermal stability. We showed the advantages of the overproduction system by characterizing CtCCT variants containing ATPase-deficient subunits. For diffracted X-ray tracking experiment, we removed all surface exposed cysteine residues, and added cysteine residues at the tip of helical protrusions of selected two subunits. Gold nanocrystals were attached onto CtCCTs via gold-thiol bonds and applied for the analysis by diffracted X-ray tracking. Irrespective of the locations of cysteines, it was shown that ATP binding induces tilting motion followed by rotational motion in the CtCCT molecule, like the archaeal group II chaperonins. When gold nanocrystals were attached onto two subunits in the high ATPase activity hemisphere, the CtCCT complex exhibited a fairly rapid response to the motion. In contrast, the response of CtCCT, which had gold nanocrystals attached to the low-activity hemisphere, was slow. These results clearly support the possibility that ATP-dependent conformational change starts with the high-affinity hemisphere and progresses to the low-affinity hemisphere.

Asymmetry in the function and dynamics of the cytosolic group II chaperonin CCT/TRiC

PubMed Central

Yamamoto, Yohei Y.; Uno, Yuko; Sha, Eiryo; Ikegami, Kentaro; Ishii, Noriyuki; Dohmae, Naoshi; Sekiguchi, Hiroshi; Sasaki, Yuji C.

2017-01-01

The eukaryotic group II chaperonin, the chaperonin-containing t-complex polypeptide 1 (CCT), plays an important role in cytosolic proteostasis. It has been estimated that as much as 10% of cytosolic proteins interact with CCT during their folding process. CCT is composed of 8 different paralogous subunits. Due to its complicated structure, molecular and biochemical investigations of CCT have been difficult. In this study, we constructed an expression system for CCT from a thermophilic fungus, Chaetomium thermophilum (CtCCT), by using E. coli as a host. As expected, we obtained recombinant CtCCT with a relatively high yield, and it exhibited fairly high thermal stability. We showed the advantages of the overproduction system by characterizing CtCCT variants containing ATPase-deficient subunits. For diffracted X-ray tracking experiment, we removed all surface exposed cysteine residues, and added cysteine residues at the tip of helical protrusions of selected two subunits. Gold nanocrystals were attached onto CtCCTs via gold-thiol bonds and applied for the analysis by diffracted X-ray tracking. Irrespective of the locations of cysteines, it was shown that ATP binding induces tilting motion followed by rotational motion in the CtCCT molecule, like the archaeal group II chaperonins. When gold nanocrystals were attached onto two subunits in the high ATPase activity hemisphere, the CtCCT complex exhibited a fairly rapid response to the motion. In contrast, the response of CtCCT, which had gold nanocrystals attached to the low-activity hemisphere, was slow. These results clearly support the possibility that ATP-dependent conformational change starts with the high-affinity hemisphere and progresses to the low-affinity hemisphere. PMID:28463997

Structure of eukaryotic prefoldin and of its complexes with unfolded actin and the cytosolic chaperonin CCT

PubMed Central

Martín-Benito, Jaime; Boskovic, Jasminka; Gómez-Puertas, Paulino; Carrascosa, José L.; Simons, C.Torrey; Lewis, Sally A.; Bartolini, Francesca; Cowan, Nicholas J.; Valpuesta, José M.

2002-01-01

The biogenesis of the cytoskeletal proteins actin and tubulin involves interaction of nascent chains of each of the two proteins with the oligomeric protein prefoldin (PFD) and their subsequent transfer to the cytosolic chaperonin CCT (chaperonin containing TCP-1). Here we show by electron microscopy that eukaryotic PFD, which has a similar structure to its archaeal counterpart, interacts with unfolded actin along the tips of its projecting arms. In its PFD-bound state, actin seems to acquire a conformation similar to that adopted when it is bound to CCT. Three-dimensional reconstruction of the CCT:PFD complex based on cryoelectron microscopy reveals that PFD binds to each of the CCT rings in a unique conformation through two specific CCT subunits that are placed in a 1,4 arrangement. This defines the phasing of the CCT rings and suggests a handoff mechanism for PFD. PMID:12456645

[Effect of Membrane Wettability on Membrane Fouling and Chemical Durability of SPG Membranes].

PubMed

Zhang, Jing; Xiao, Tai-min; Zhang, Jing; Cao, Li-ya; Du, Ya-wei; Liu, Chun; Zhang, Lei

2015-05-01

Shirasu porous glass (SPG) membranes have been applied for microbubble aeration in aerobic wastewater treatment. In the present study, both hydrophilic and hydrophobic SPG membranes were used in a microbubble-aerated biofilm reactor with online chemical cleaning, and their membrane fouling and chemical durability were determined to be strongly dependent on the membrane wettability. The fouling layer formed on the surface of both membranes was confirmed to be mainly organic fouling, and the hydrophobic membrane showed a relatively stronger resistance to the organic fouling. The severe chemical corrosion of the hydrophilic membrane was observed due to exposure to the alkaline sodium hypochlorite solution used for chemical cleaning, which resulted in significant increases in the median pore diameter and the porosity. On the other hand, the pore structure of the hydrophobic membrane changed slightly when exposed to the alkaline sodium hypochlorite solution, suggesting its strong alkali-resistance due to the non-wetting surface. However, the surface hydrophobic groups of hydrophobic membrane could be oxidized by sodium hypochlorite solution, resulting in more wettable membrane surface. The hydrophobic membrane also showed better performance in the respects of oxygen transfer, contaminant removal and energy-saving. Therefore, the hydrophobic membrane seemed more appropriate to be applied for microbubble aeration in aerobic wastewater treatment process.

RandSpg: An open-source program for generating atomistic crystal structures with specific spacegroups

NASA Astrophysics Data System (ADS)

Avery, Patrick; Zurek, Eva

2017-04-01

A new algorithm, RANDSPG, that can be used to generate trial crystal structures with specific space groups and compositions is described. The program has been designed for systems where the atoms are independent of one another, and it is therefore primarily suited towards inorganic systems. The structures that are generated adhere to user-defined constraints such as: the lattice shape and size, stoichiometry, set of space groups to be generated, and factors that influence the minimum interatomic separations. In addition, the user can optionally specify if the most general Wyckoff position is to be occupied or constrain select atoms to specific Wyckoff positions. Extensive testing indicates that the algorithm is efficient and reliable. The library is lightweight, portable, dependency-free and is published under a license recognized by the Open Source Initiative. A web interface for the algorithm is publicly accessible at http://xtalopt.openmolecules.net/randSpg/randSpg.html. RANDSPG has also been interfaced with the XTALOPT evolutionary algorithm for crystal structure prediction, and it is illustrated that the use of symmetric lattices in the first generation of randomly created individuals decreases the number of structures that need to be optimized to find the global energy minimum.

Spectrum of X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): Clincal review with six additional families

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

Schrander-Stumpel, C.; Hoeweler, C.; Jones, M.

X-linked hydrocephalus (HSAS) (MIM{sup *}307000), MASA syndrome (MIM {sup *}303350), and complicated spastic paraplegia (SPG1) (MIM {sup *}3129000) are closely related. Soon after delineation, SPG1 was incorporated into the spectrum of MASA syndrome. HSAS and MASA syndrome show great clinical overlap; DNA linkage analysis places the loci at Xq28. In an increasing number of families with MASA syndrome or HSAS, mutations in L1CAM, a gene located at Xq28, have been reported. In order to further delineate the clinical spectrum, we studied 6 families with male patients presenting with MASA syndrome, HSAS, or a mixed phenotype. We summarized data from previousmore » reports and compared them with our data. Clinical variability appears to be great, even within families. Problems in genetic counseling and prenatal diagnosis, the possible overlap with X-linked corpus callosum agenesis and FG syndrome, and the different forms of X-linked complicated spastic paraplegia are discussed. Since adducted thumbs and spastic paraplegia are found in 90% of the patients, the condition may be present in males with nonspecific mental retardation. We propose to abandon the designation MASA syndrome and use the term HSAS/MASA spectrum, incorporating SPG1. 79 refs., 6 figs., 2 tabs.« less

Effect of interactions with the chaperonin cavity on protein folding and misfolding†

PubMed Central

Sirur, Anshul; Knott, Michael; Best, Robert B.

2015-01-01

Recent experimental and computational results have suggested that attractive interactions between a chaperonin and an enclosed substrate can have an important effect on the protein folding rate: it appears that folding may even be slower inside the cavity than under unconfined conditions, in contrast to what we would expect from excluded volume effects on the unfolded state. Here we examine systematically the dependence of the protein stability and folding rate on the strength of such attractive interactions between the chaperonin and substrate, by using molecular simulations of model protein systems in an idealised attractive cavity. Interestingly, we find a maximum in stability, and a rate which indeed slows down at high attraction strengths. We have developed a simple phenomenological model which can explain the variations in folding rate and stability due to differing effects on the free energies of the unfolded state, folded state, and transition state; changes in the diffusion coefficient along the folding coordinate are relatively small, at least for our simplified model. In order to investigate a possible role for these attractive interactions in folding, we have studied a recently developed model for misfolding in multidomain proteins. We find that, while encapsulation in repulsive cavities greatly increases the fraction of misfolded protein, sufficiently strong attractive protein-cavity interactions can strongly reduce the fraction of proteins reaching misfolded traps. PMID:24077053

SPG20 Protein Spartin Is Recruited to Midbodies by ESCRT-III Protein Ist1 and Participates in Cytokinesis

PubMed Central

Renvoisé, Benoît; Parker, Rell L.; Yang, Dong; Bakowska, Joanna C.; Hurley, James H.

2010-01-01

Hereditary spastic paraplegias (HSPs, SPG1-46) are inherited neurological disorders characterized by lower extremity spastic weakness. Loss-of-function SPG20 gene mutations cause an autosomal recessive HSP known as Troyer syndrome. The SPG20 protein spartin localizes to lipid droplets and endosomes, and it interacts with tail interacting protein 47 (TIP47) as well as the ubiquitin E3 ligases atrophin-1-interacting protein (AIP)4 and AIP5. Spartin harbors a domain contained within microtubule-interacting and trafficking molecules (MIT) at its N-terminus, and most proteins with MIT domains interact with specific ESCRT-III proteins. Using yeast two-hybrid and in vitro surface plasmon resonance assays, we demonstrate that the spartin MIT domain binds with micromolar affinity to the endosomal sorting complex required for transport (ESCRT)-III protein increased sodium tolerance (Ist)1 but not to ESCRT-III proteins charged multivesicular body proteins 1–7. Spartin colocalizes with Ist1 at the midbody, and depletion of Ist1 in cells by small interfering RNA significantly decreases the number of cells where spartin is present at midbodies. Depletion of spartin does not affect Ist1 localization to midbodies but markedly impairs cytokinesis. A structure-based amino acid substitution in the spartin MIT domain (F24D) blocks the spartin–Ist1 interaction. Spartin F24D does not localize to the midbody and acts in a dominant-negative manner to impair cytokinesis. These data suggest that Ist1 interaction is important for spartin recruitment to the midbody and that spartin participates in cytokinesis. PMID:20719964

Protein modeling and molecular dynamics simulation of the two novel surfactant proteins SP-G and SP-H.

PubMed

Rausch, Felix; Schicht, Martin; Bräuer, Lars; Paulsen, Friedrich; Brandt, Wolfgang

2014-11-01

Surfactant proteins are well known from the human lung where they are responsible for the stability and flexibility of the pulmonary surfactant system. They are able to influence the surface tension of the gas-liquid interface specifically by directly interacting with single lipids. This work describes the generation of reliable protein structure models to support the experimental characterization of two novel putative surfactant proteins called SP-G and SP-H. The obtained protein models were complemented by predicted posttranslational modifications and placed in a lipid model system mimicking the pulmonary surface. Molecular dynamics simulations of these protein-lipid systems showed the stability of the protein models and the formation of interactions between protein surface and lipid head groups on an atomic scale. Thereby, interaction interface and strength seem to be dependent on orientation and posttranslational modification of the protein. The here presented modeling was fundamental for experimental localization studies and the simulations showed that SP-G and SP-H are theoretically able to interact with lipid systems and thus are members of the surfactant protein family.

Interaction of the SPG21 protein ACP33/maspardin with the aldehyde dehydrogenase ALDH16A1

PubMed Central

2017-01-01

Mast syndrome (SPG21) is an autosomal-recessive complicated form of hereditary spastic paraplegia characterized by dementia, thin corpus callosum, white matter abnormalities, and cerebellar and extrapyramidal signs in addition to spastic paraparesis. A nucleotide insertion resulting in premature truncation of the SPG21 gene product acidic cluster protein 33 (ACP33)/maspardin underlies this disorder, likely causing loss of protein function. However, little is known about the function of maspardin. Here, we report that maspardin localizes prominently to cytoplasm as well as to membranes, possibly at trans-Golgi network/late endosomal compartments. Immunoprecipitation of maspardin with identification of coprecipitating proteins by mass spectrometry revealed the aldehyde dehydrogenase ALDH16A1 as an interacting protein. This interaction was confirmed using overexpressed proteins as well as by fusion protein pull down experiments, and these proteins colocalized in cells. Further studies of the function of ALDH16A1 and the role of the maspardin–ALDH16A1 interaction in neuronal cells may clarify the cellular pathogenesis of Mast syndrome. PMID:19184135

Streptococcus iniae, a Human and Animal Pathogen: Specific Identification by the Chaperonin 60 Gene Identification Method

PubMed Central

Goh, Swee Han; Driedger, David; Gillett, Sandra; Low, Donald E.; Hemmingsen, Sean M.; Amos, Mayben; Chan, David; Lovgren, Marguerite; Willey, Barbara M.; Shaw, Carol; Smith, John A.

1998-01-01

It was recently reported that Streptococcus iniae, a bacterial pathogen of aquatic animals, can cause serious disease in humans. Using the chaperonin 60 (Cpn60) gene identification method with reverse checkerboard hybridization and chemiluminescent detection, we identified correctly each of 12 S. iniae samples among 34 aerobic gram-positive isolates from animal and clinical human sources. PMID:9650992

Biochemical Characterization of Mutants in Chaperonin Proteins CCT4 and CCT5 Associated with Hereditary Sensory Neuropathy*

PubMed Central

Sergeeva, Oksana A.; Tran, Meme T.; Haase-Pettingell, Cameron; King, Jonathan A.

2014-01-01

Hereditary sensory neuropathies are a class of disorders marked by degeneration of the nerve fibers in the sensory periphery neurons. Recently, two mutations were identified in the subunits of the eukaryotic cytosolic chaperonin TRiC, a protein machine responsible for folding actin and tubulin in the cell. C450Y CCT4 was identified in a stock of Sprague-Dawley rats, whereas H147R CCT5 was found in a human Moroccan family. As with many genetically identified mutations associated with neuropathies, the underlying molecular basis of the mutants was not defined. We investigated the biochemical properties of these mutants using an expression system in Escherichia coli that produces homo-oligomeric rings of CCT4 and CCT5. Full-length versions of both mutant protein chains were expressed in E. coli at levels approaching that of the WT chains. Sucrose gradient centrifugation revealed chaperonin-sized complexes of both WT and mutant chaperonins, but with reduced recovery of C450Y CCT4 soluble subunits. Electron microscopy of negatively stained samples of C450Y CCT4 revealed few ring-shaped species, whereas WT CCT4, H147R CCT5, and WT CCT5 revealed similar ring structures. CCT5 complexes were assayed for their ability to suppress aggregation of and refold the model substrate γd-crystallin, suppress aggregation of mutant huntingtin, and refold the physiological substrate β-actin in vitro. H147R CCT5 was not as efficient in chaperoning these substrates as WT CCT5. The subtle effects of these mutations are consistent with the homozygous disease phenotype, in which most functions are carried out during development and adulthood, but some selective function is lost or reduced. PMID:25124038

From chaperonins to Rubisco assembly and metabolic repair.

PubMed

Hayer-Hartl, Manajit

2017-12-01

Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) mediates the fixation of atmospheric CO 2 in photosynthesis by catalyzing the carboxylation of the 5-carbon sugar ribulose-1,5-bisphosphate (RuBP). Despite its pivotal role, Rubisco is an inefficient enzyme and thus has been a key target for bioengineering. However, efforts to increase crop yields by Rubisco engineering remain unsuccessful, due in part to the complex machinery of molecular chaperones required for Rubisco biogenesis and metabolic repair. While the large subunit of Rubisco generally requires the chaperonin system for folding, the evolution of the hexadecameric Rubisco from its dimeric precursor resulted in the dependence on an array of additional factors required for assembly. Moreover, Rubisco function can be inhibited by a range of sugar-phosphate ligands. Metabolic repair of Rubisco depends on remodeling by the ATP-dependent Rubisco activase and hydrolysis of inhibitors by specific phosphatases. This review highlights our work toward understanding the structure and mechanism of these auxiliary machineries. © 2017 The Protein Society.

The zebrafish spiel-ohne-grenzen (spg) gene encodes the POU domain protein Pou2 related to mammalian Oct4 and is essential for formation of the midbrain and hindbrain, and for pre-gastrula morphogenesis.

PubMed

Burgess, Shawn; Reim, Gerlinde; Chen, Wenbiao; Hopkins, Nancy; Brand, Michael

2002-02-01

In early embryonic development, the brain is divided into three main regions along the anteroposterior axis: the forebrain, midbrain and hindbrain. Through retroviral insertional mutagenesis and chemical mutagenesis experiments in zebrafish, we have isolated mutations that cause abnormal hindbrain organization and a failure of the midbrain-hindbrain boundary (MHB) to form, a region that acts as an organizer for the adjacent brain regions. The mutations fail to complement the spiel-ohne-grenzen (spg) mutation, which causes a similar phenotype, but for which the affected gene is unknown. We show through genetic mapping, cloning of the proviral insertion site and allele sequencing that spg mutations disrupt pou2, a gene encoding the Pou2 transcription factor. Based on chromosomal synteny, phylogenetic sequence comparison, and expression and functional data, we suggest that pou2 is the zebrafish ortholog of mouse Oct3/Oct4 and human POU5F1. For the mammalian genes, a function in brain development has so far not been described. In the absence of functional pou2, expression of markers for the midbrain, MHB and the hindbrain primordium (pax2.1, wnt1, krox20) are severely reduced, correlating with the neuroectoderm-specific expression phase of pou2. Injection of pou2 mRNA restores these defects in spg mutant embryos, but does not activate these markers ectopically, demonstrating a permissive role for pou2. Injections of pou2-morpholinos phenocopy the spg phenotype at low concentration, further proving that spg encodes pou2. Two observations suggest that pou2 has an additional earlier function: higher pou2-morpholino concentrations specifically cause a pre-gastrula arrest of cell division and morphogenesis, and expression of pou2 mRNA itself is reduced in spg-homozygous embryos at this stage. These experiments suggest two roles for pou2. Initially, Pou2 functions during early proliferation and morphogenesis of the blastomeres, similar to Oct3/4 in mammals during formation

The chaperonin CCT inhibits assembly of α-synuclein amyloid fibrils by a specific, conformation-dependent interaction

PubMed Central

Sot, Begoña; Rubio-Muñoz, Alejandra; Leal-Quintero, Ahudrey; Martínez-Sabando, Javier; Marcilla, Miguel; Roodveldt, Cintia; Valpuesta, José M.

2017-01-01

The eukaryotic chaperonin CCT (chaperonin containing TCP-1) uses cavities built into its double-ring structure to encapsulate and to assist folding of a large subset of proteins. CCT can inhibit amyloid fibre assembly and toxicity of the polyQ extended mutant of huntingtin, the protein responsible for Huntington’s disease. This raises the possibility that CCT modulates other amyloidopathies, a still-unaddressed question. We show here that CCT inhibits amyloid fibre assembly of α-synuclein A53T, one of the mutants responsible for Parkinson’s disease. We evaluated fibrillation blockade in α-synuclein A53T deletion mutants and CCT interactions of full-length A53T in distinct oligomeric states to define an inhibition mechanism specific for α-synuclein. CCT interferes with fibre assembly by interaction of its CCTζ and CCTγ subunits with the A53T central hydrophobic region (NAC). This interaction is specific to NAC conformation, as it is produced once soluble α-synuclein A53T oligomers form and blocks the reaction before fibres begin to grow. Finally, we show that this association inhibits α-synuclein A53T oligomer toxicity in neuroblastoma cells. In summary, our results and those for huntingtin suggest that CCT is a general modulator of amyloidogenesis via a specific mechanism. PMID:28102321

Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3.

PubMed

Klebe, Stephan; Azzedine, Hamid; Durr, Alexandra; Bastien, Patrick; Bouslam, Naima; Elleuch, Nizar; Forlani, Sylvie; Charon, Celine; Koenig, Michel; Melki, Judith; Brice, Alexis; Stevanin, Giovanni

2006-06-01

The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive spasticity in the lower limbs. Twenty-nine different loci (SPG) have been mapped so far, and 11 responsible genes have been identified. Clinically, one distinguishes between pure and complex HSP forms which are variably associated with numerous combinations of neurological and extra-neurological signs. Less is known about autosomal recessive forms (ARHSP) since the mapped loci have been identified often in single families and account for only a small percentage of patients. We report a new ARHSP locus (SPG30) on chromosome 2q37.3 in a consanguineous family with seven unaffected and four affected members of Algerian origin living in Eastern France with a significant multipoint lod score of 3.8. Ten other families from France (n = 4), Tunisia (n = 2), Algeria (n = 3) and the Czech Republic (n = 1) were not linked to the newly identified locus thus demonstrating further genetic heterogeneity. The phenotype of the linked family consists of spastic paraparesis and peripheral neuropathy associated with slight cerebellar signs confirmed by cerebellar atrophy on one CT scan.

Varied effects of Pyrococcus furiosus prefoldin and P. furiosus chaperonin on the refolding reactions of substrate proteins.

PubMed

Hongo, Kunihiro; Itai, Hiroshi; Mizobata, Tomohiro; Kawata, Yasushi

2012-04-01

Prefoldin is a molecular chaperone found in the archaeal and eukaryotic cytosol. Prefoldin can stabilize tentatively nascent polypeptide chains or non-native forms of mainly cytoskeletal proteins, which are subsequently delivered to group II chaperonin to accomplish their precise folding. However, the detailed mechanism is not well known, especially with regard to endogenous substrate proteins. Here, we report the effects of Pyrococcus furiosus prefoldin (PfuPFD) on the refolding reactions of Pyrococcus furiosus citrate synthase (PfuCS) and Aequorea enhanced green fluorescence protein (GFPuv) in the presence or absence of Pyrococcus furiosus chaperonin (PfuCPN). We confirmed that both PfuPFD and PfuCPN interacted with PfuCS and GFPuv refolding intermediates. However, the interactions between chaperone and substrate were different for each case, as was the final effect on the refolding reaction. Effects on the refolding reaction varied from passive effects such as ATP-dependent binding and release (PfuCPN towards GFPuv) and binding which leads to folding arrest (PfuPFD towards GFPuv), to active effects such as net increase in thermal stability (PfuCPN towards PfuCS) to an active improvement in refolding yield (PfuPFD towards PfuCS). We postulate that differences in molecular interactions between substrate and chaperone lead to these differences in chaperoning effects.

Construction and characterization of the hetero-oligomer of the group II chaperonin from the hyperthermophilic archaeon, Thermococcus sp. strain KS-1.

PubMed

Sahlan, Muhamad; Kanzaki, Taro; Yohda, Masafumi

2009-05-01

The hyperthermophilic archaeon Thermococcus sp. strain KS-1 (T. KS-1) expresses two different chaperonin subunits, alpha and beta, for the folding of its proteins. The composition of the subunits in the hexadecameric double ring changes with temperature. The content of the beta subunit significantly increases according to the increase in temperature. The homo-oligomer of the beta subunit, Cpn beta, is more thermostable than that of the alpha subunit, Cpn alpha. Since Cpn alpha and Cpn beta also have different protein folding activities and interactions with prefoldin, the hetero-oligomer is thought to exhibit different characteristics according to the content of subunits. The hetero-oligomer of the T. KS-1 chaperonin has not been studied, however, because the alpha and beta subunits form hetero-oligomers of varying compositions when they are expressed simultaneously. In this study, we characterized the T. KS-1 chaperonin hetero-oligomer, Cpn alphabeta, containing both alpha and beta in the alternate order, which was constructed by the expression of alpha and beta subunits in a coordinated fashion and protease digestion. Cpn alphabeta protected citrate synthase from thermal aggregation, promoted the folding of acid-denatured GFP in an ATP-dependent manner, and exhibited an ATP-dependent conformational change. The yield of refolded GFP generated by Cpn alphabeta was almost equivalent to that generated by Cpn beta but lower than that generated by Cpn alpha. In contrast, Cpn alphabeta exhibited almost the same level of thermal stability as Cpn alpha, which was lower than that of Cpn beta. The affinity of Cpn alphabeta to prefoldin was found to be between those of Cpn alpha and Cpn beta, as expected.

13 CFR 107.1710 - SBA authority to collect or compromise its claims.

Code of Federal Regulations, 2010 CFR

2010-01-01

... SMALL BUSINESS INVESTMENT COMPANIES SBA Financial Assistance for Licensees (Leverage) Miscellaneous... consideration as it deems reasonable, collect or compromise all claims relating to Preferred or Participating...

The chaperonin CCTα is required for efficient transcription and replication of rabies virus.

PubMed

Zhang, Jinyang; Ye, Chengjin; Ruan, Xizhen; Zan, Jie; Xu, Yunbin; Liao, Min; Zhou, Jiyong

2014-10-01

Negri bodies (NBs) are formed in the cytoplasm of rabies virus (RABV)-infected cells and are accompanied by a number of host factors to NBs, in which replication and transcription occur. Here, it was found that chaperonin containing TCP-1 subunit alpha (CCTα) relocalizes to NBs in RABV-infected cells, and that cotransfection of nucleo- and phospho-proteins of RABV is sufficient to recruit CCTα to the NBs' structure. Inhibition of CCTα expression by specific short hairpin RNA knockdown inhibited the replication and transcription of RABV. Therefore, this study showed that the host factor CCTα is associated with RABV infection and is very likely required for efficient virus transcription and replication. © 2014 The Societies and Wiley Publishing Asia Pty Ltd.

Purification and characterization of the GroESLx chaperonins from the symbiotic X-bacteria in Amoeba proteus.

PubMed

Jung, G H; Ahn, T I

2001-12-01

GroELx and GroESx proteins of symbiotic X-bacteria from Amoeba proteus were overproduced in Escherichia coli transformed with pAJX91 and pUXGPRM, respectively, and their chaperonin functions were assayed. We utilized sigma(70)-dependent specific promoters of groEx in the expression vectors and grew recombinant cells at 37 degrees C to minimize coexpression of host groE of E. coli. For purifying the proteins, we applied the principle of heat stability for GroELx and pI difference for GroESx to minimize copurification with the hosts GroEL and GroES, respectively. After ultracentrifugation in a sucrose density gradient, the yield and purity of GroELx were 56 and 89%, respectively. The yield and purity of GroESx after anion-exchange chromatography were 62 and 91%, respectively. Purified GroELx had an ATPase activity of 53.2 nmol Pi released/min/mg protein at 37 degrees C. The GroESx protein inhibited ATPase activity of GroELx to 60% of the control at a ratio of 1 for GroESx-7mer/GroELx-14mer. GroESLx helped refolding of urea-unfolded rhodanese up to 80% of the native activity at 37 degrees C. By chemical cross-linking analysis, oligomeric properties of GroESx and GroELx were confirmed as GroESx(7) and GroELx(14) in two stacks of GroELx(7). In this study, we developed a method for the purification of GroESLx and demonstrated that their chaperonin function is homologous to GroESL of E. coli. Copyright 2001 Elsevier Science.

In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11

PubMed Central

Varga, Rita-Eva; Khundadze, Mukhran; Damme, Markus; Nietzsche, Sandor; Hoffmann, Birgit; Stauber, Tobias; Koch, Nicole; Hennings, J. Christopher; Franzka, Patricia; Huebner, Antje K.; Kessels, Michael M.; Biskup, Christoph; Jentsch, Thomas J.; Qualmann, Britta; Braulke, Thomas; Kurth, Ingo; Beetz, Christian; Hübner, Christian A.

2015-01-01

Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice. PMID:26284655

In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11.

PubMed

Varga, Rita-Eva; Khundadze, Mukhran; Damme, Markus; Nietzsche, Sandor; Hoffmann, Birgit; Stauber, Tobias; Koch, Nicole; Hennings, J Christopher; Franzka, Patricia; Huebner, Antje K; Kessels, Michael M; Biskup, Christoph; Jentsch, Thomas J; Qualmann, Britta; Braulke, Thomas; Kurth, Ingo; Beetz, Christian; Hübner, Christian A

2015-08-01

Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice.

Autoimmune Regulator (AIRE) Is Expressed in Spermatogenic Cells, and It Altered the Expression of Several Nucleic-Acid-Binding and Cytoskeletal Proteins in Germ Cell 1 Spermatogonial (GC1-spg) Cells.

PubMed

Radhakrishnan, Karthika; Bhagya, Kongattu P; Kumar, Anil Tr; Devi, Anandavalli N; Sengottaiyan, Jeeva; Kumar, Pradeep G

2016-08-01

Autoimmune regulator (AIRE) is a gene associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE is expressed heavily in the thymic epithelial cells and is involved in maintaining self-tolerance through regulating the expression of tissue-specific antigens. The testes are the most predominant extrathymic location where a heavy expression of AIRE is reported. Homozygous Aire-deficient male mice were infertile, possibly due to impaired spermatogenesis, deregulated germ cell apoptosis, or autoimmunity. We report that AIRE is expressed in the testes of neonatal, adolescent, and adult mice. AIRE expression was detected in glial cell derived neurotrophic factor receptor alpha (GFRα)(+) (spermatogonia), GFRα(-)/synaptonemal complex protein (SCP3)(+) (meiotic), and GFRα(-)/Phosphoglycerate kinase 2 (PGK2)(+) (postmeiotic) germ cells in mouse testes. GC1-spg, a germ-cell-derived cell line, did not express AIRE. Retinoic acid induced AIRE expression in GC1-spg cells. Ectopic expression of AIRE in GC1-spg cells using label-free LC-MS/MS identified a total of 371 proteins that were differentially expressed. 100 proteins were up-regulated, and 271 proteins were down-regulated. Data are available via ProteomeXchange with identifier PXD002511. Functional analysis of the differentially expressed proteins showed increased levels of various nucleic-acid-binding proteins and transcription factors and a decreased level of various cytoskeletal and structural proteins in the AIRE overexpressing cells as compared with the empty vector-transfected controls. The transcripts of a select set of the up-regulated proteins were also elevated. However, there was no corresponding decrease in the mRNA levels of the down-regulated set of proteins. Molecular function network analysis indicated that AIRE influenced gene expression in GC1-spg cells by acting at multiple levels, including transcription, translation, RNA processing, protein transport, protein

Arabidopsis chloroplast chaperonin 10 is a calmodulin-binding protein

NASA Technical Reports Server (NTRS)

Yang, T.; Poovaiah, B. W.

2000-01-01

Calcium regulates diverse cellular activities in plants through the action of calmodulin (CaM). By using (35)S-labeled CaM to screen an Arabidopsis seedling cDNA expression library, a cDNA designated as AtCh-CPN10 (Arabidopsis thaliana chloroplast chaperonin 10) was cloned. Chloroplast CPN10, a nuclear-encoded protein, is a functional homolog of E. coli GroES. It is believed that CPN60 and CPN10 are involved in the assembly of Rubisco, a key enzyme involved in the photosynthetic pathway. Northern analysis revealed that AtCh-CPN10 is highly expressed in green tissues. The recombinant AtCh-CPN10 binds to CaM in a calcium-dependent manner. Deletion mutants revealed that there is only one CaM-binding site in the last 31 amino acids of the AtCh-CPN10 at the C-terminal end. The CaM-binding region in AtCh-CPN10 has higher homology to other chloroplast CPN10s in comparison to GroES and mitochondrial CPN10s, suggesting that CaM may only bind to chloroplast CPN10s. Furthermore, the results also suggest that the calcium/CaM messenger system is involved in regulating Rubisco assembly in the chloroplast, thereby influencing photosynthesis. Copyright 2000 Academic Press.

Identification of in vivo substrates of the yeast mitochondrial chaperonins reveals overlapping but non-identical requirement for hsp60 and hsp10.

PubMed Central

Dubaquié, Y; Looser, R; Fünfschilling, U; Jenö, P; Rospert, S

1998-01-01

The mechanism of chaperonin-assisted protein folding has been mostly analyzed in vitro using non-homologous substrate proteins. In order to understand the relative importance of hsp60 and hsp10 in the living cell, homologous substrate proteins need to be identified and analyzed. We have devised a novel screen to test the folding of a large variety of homologous substrates in the mitochondrial matrix in the absence or presence of functional hsp60 or hsp10. The identified substrates have an Mr of 15-90 kDa and fall into three groups: (i) proteins that require both hsp60 and hsp10 for correct folding; (ii) proteins that completely fail to fold after inactivation of hsp60 but are unaffected by the inactivation of hsp10; and (iii) newly imported hsp60 itself, which is more severely affected by inactivation of hsp10 than by inactivation of pre-existing hsp60. The majority of the identified substrates are group I proteins. For these, the lack of hsp60 function has a more pronounced effect than inactivation of hsp10. We suggest that homologous substrate proteins have differential chaperonin requirements, indicating that hsp60 and hsp10 do not always act as a single functional unit in vivo. PMID:9774331

40 CFR 13.25 - Standards for compromise.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 13.25 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL CLAIMS COLLECTION STANDARDS... consider, among other factors, the following: (1) Individual debtors. (i) Age and health of the debtor; (ii... substantial doubt concerning the Government's ability to prove its case in court for the full amount of the...

Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48)

PubMed Central

Hirst, Jennifer; Madeo, Marianna; Smets, Katrien; Edgar, James R.; Schols, Ludger; Li, Jun; Yarrow, Anna; Deconinck, Tine; Baets, Jonathan; Van Aken, Elisabeth; De Bleecker, Jan; Datiles, Manuel B.; Roda, Ricardo H.; Liepert, Joachim; Züchner, Stephan; Mariotti, Caterina; De Jonghe, Peter; Blackstone, Craig

2016-01-01

Objective: Biallelic mutations in the AP5Z1 gene encoding the AP-5 ζ subunit have been described in a small number of patients with hereditary spastic paraplegia (HSP) (SPG48); we sought to define genotype–phenotype correlations in patients with homozygous or compound heterozygous sequence variants predicted to be deleterious. Methods: We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic mutations in AP5Z1. Results: In 4 of the 6 patients, there was complete loss of AP-5 ζ protein. Clinical features encompassed not only prominent spastic paraparesis but also sensory and motor neuropathy, ataxia, dystonia, myoclonus, and parkinsonism. Skin fibroblasts from affected patients tested positive for periodic acid Schiff and autofluorescent storage material, while electron microscopic analysis demonstrated lamellar storage material consistent with abnormal storage of lysosomal material. Conclusions: Our findings expand the spectrum of AP5Z1-associated neurodegenerative disorders and point to clinical and pathophysiologic overlap between autosomal recessive forms of HSP and lysosomal storage disorders. PMID:27606357

Does low self-esteem predict health compromising behaviours among adolescents?

PubMed

Mcgee, R; Williams, S

2000-10-01

It is often believed that low self-esteem is associated with such health-compromising behaviours in adolescence as substance use, early sexual activity, eating problems and suicidal ideation. Surprisingly, there is little longitudinal research addressing this issue. This longitudinal study examines the predictive association between both global and academic self-esteem from ages 9 to 13 years, and a variety of health compromising behaviours at age 15, in a large sample of young New Zealanders. Levels of global self-esteem significantly predicted adolescent report of problem eating, suicidal ideation, and multiple health compromising behaviours. Earlier levels of self-esteem were unrelated to later substance use and early sexual activity. The findings are discussed in terms of their implications for efforts to raise self-esteem among young people. Copyright 2000 The Association for Professionals in Services for Adolescents.

Arsenite promotes centrosome abnormalities under a p53 compromised status induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

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

Liao, W.-T.; Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

2010-02-15

Epidemiological evidence indicated that residents, especially cigarette smokers, in arseniasis areas had significantly higher lung cancer risk than those living in non-arseniasis areas. Thus an interaction between arsenite and cigarette smoking in lung carcinogenesis was suspected. In the present study, we investigated the interactions of a tobacco-specific carcinogen 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (nicotine-derived nitrosamine ketone, NNK) and arsenite on lung cell transformation. BEAS-2B, an immortalized human lung epithelial cell line, was selected to test the centrosomal abnormalities and colony formation by NNK and arsenite. We found that NNK, alone, could enhance BEAS-2B cell growth at 1-5 muM. Under NNK exposure, arsenite wasmore » able to increase centrosomal abnormality as compared with NNK or arsenite treatment alone. NNK treatment could also reduce arsenite-induced G2/M cell cycle arrest and apoptosis, these cellular effects were found to be correlated with p53 dysfunction. Increased anchorage-independent growth (colony formation) of BEAS-2B cells cotreated with NNK and arsenite was also observed in soft agar. Our present investigation demonstrated that NNK could provide a p53 compromised status. Arsenite would act specifically on this p53 compromised status to induce centrosomal abnormality and colony formation. These findings provided strong evidence on the carcinogenic promotional role of arsenite under tobacco-specific carcinogen co-exposure.« less

Compromises.

ERIC Educational Resources Information Center

Sizer, Theodore R.

1984-01-01

Taking as examples the issues of improving students'"high order thinking skills" and arriving at more equitable teacher salaries and school budgets, the author discusses the need for compromise solutions to widespread problems. (JBM)

Molecular characterization of the group II chaperonin from the hyperthermophilic archaeum Pyrococcus horikoshii OT3.

PubMed

Okochi, Mina; Matsuzaki, Hiroki; Nomura, Tomoko; Ishii, Noriyuki; Yohda, Masafumi

2005-04-01

The group II chaperonin from the hyperthermophilic archaeum Pyrococcus horikoshii OT3 (PhCPN) and its functional cooperation with the cognate prefoldin were investigated. PhCPN existed as a homo-oligomer in a double-ring structure, which protected the citrate synthase of a porcine heart from thermal aggregation at 45 degrees C, and did the same on the isopropylmalate dehydrogenase (IPMDH) of a thermophilic bacterium, Thermus thermophilus HB8, at 90 degrees C. PhCPN also enhanced the refolding of green fluorescent protein (GFP), which had been unfolded by low pH, in an ATP-dependent manner. Unexpectedly, functional cooperation between PhCPN and Pyrococcus prefoldin (PhPFD) in the refolding of GFP was not observed. Instead, cooperation between PhCPN and PhPFD was observed in the refolding of IPMDH unfolded with guanidine hydrochloride. Although PhCPN alone was not effective in the refolding of IPMDH, the refolding efficiency was enhanced by the cooperation of PhCPN with PhPFD.

Genetic expansion of chaperonin-containing TCP-1 (CCT/TRiC) complex subunits yields testis-specific isoforms required for spermatogenesis in planarian flatworms.

PubMed

Counts, Jenna T; Hester, Tasha M; Rouhana, Labib

2017-12-01

Chaperonin-containing Tail-less complex polypeptide 1 (CCT) is a highly conserved, hetero-oligomeric complex that ensures proper folding of actin, tubulin, and regulators of mitosis. Eight subunits (CCT1-8) make up this complex, and every subunit has a homolog expressed in the testes and somatic tissue of the planarian flatworm Schmidtea mediterranea. Gene duplications of four subunits in the genomes of S. mediterranea and other planarian flatworms created paralogs to CCT1, CCT3, CCT4, and CCT8 that are expressed exclusively in the testes. Functional analyses revealed that each CCT subunit expressed in the S. mediterranea soma is essential for homeostatic integrity and survival, whereas sperm elongation defects were observed upon knockdown of each individual testis-specific paralog (Smed-cct1B; Smed-cct3B; Smed-cct4A; and Smed-cct8B), regardless of potential redundancy with paralogs expressed in both testes and soma (Smed-cct1A; Smed-cct3A; Smed-cct4B; and Smed-cct8A). Yet, no detriment was observed in the number of adult somatic stem cells (neoblasts) that maintain differentiated tissue in planarians. Thus, expression of all eight CCT subunits is required to execute the essential functions of the CCT complex. Furthermore, expression of the somatic paralogs in planarian testes is not sufficient to complete spermatogenesis when testis-specific paralogs are knocked down, suggesting that the evolution of chaperonin subunits may drive changes in the development of sperm structure and that correct CCT subunit stoichiometry is crucial for spermiogenesis. © 2017 Wiley Periodicals, Inc.

45 CFR 30.22 - Bases for compromise.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 45 Public Welfare 1 2011-10-01 2011-10-01 false Bases for compromise. 30.22 Section 30.22 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION CLAIMS COLLECTION Debt Compromise § 30.22 Bases for compromise. (a) Compromise. The Secretary may compromise a debt if the full amount...

45 CFR 30.22 - Bases for compromise.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 45 Public Welfare 1 2012-10-01 2012-10-01 false Bases for compromise. 30.22 Section 30.22 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION CLAIMS COLLECTION Debt Compromise § 30.22 Bases for compromise. (a) Compromise. The Secretary may compromise a debt if the full amount...

45 CFR 30.22 - Bases for compromise.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 45 Public Welfare 1 2013-10-01 2013-10-01 false Bases for compromise. 30.22 Section 30.22 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION CLAIMS COLLECTION Debt Compromise § 30.22 Bases for compromise. (a) Compromise. The Secretary may compromise a debt if the full amount...

45 CFR 30.22 - Bases for compromise.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Bases for compromise. 30.22 Section 30.22 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION CLAIMS COLLECTION Debt Compromise § 30.22 Bases for compromise. (a) Compromise. The Secretary may compromise a debt if the full amount...

48 CFR 432.616 - Compromise actions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Compromise actions. 432.616 Section 432.616 Federal Acquisition Regulations System DEPARTMENT OF AGRICULTURE GENERAL CONTRACTING REQUIREMENTS CONTRACT FINANCING Contract Debts 432.616 Compromise actions. Compromise of a debt...

38 CFR 1.931 - Bases for compromise.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Bases for compromise. 1.931 Section 1.931 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS GENERAL PROVISIONS Standards for Compromise of Claims § 1.931 Bases for compromise. (a) VA may compromise a debt if...

38 CFR 1.931 - Bases for compromise.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Bases for compromise. 1.931 Section 1.931 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS GENERAL PROVISIONS Standards for Compromise of Claims § 1.931 Bases for compromise. (a) VA may compromise a debt if...

38 CFR 1.931 - Bases for compromise.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Bases for compromise. 1.931 Section 1.931 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS GENERAL PROVISIONS Standards for Compromise of Claims § 1.931 Bases for compromise. (a) VA may compromise a debt if...

38 CFR 1.931 - Bases for compromise.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Bases for compromise. 1.931 Section 1.931 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS GENERAL PROVISIONS Standards for Compromise of Claims § 1.931 Bases for compromise. (a) VA may compromise a debt if...

10 CFR 1015.302 - Bases for compromise.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 4 2011-01-01 2011-01-01 false Bases for compromise. 1015.302 Section 1015.302 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) COLLECTION OF CLAIMS OWED THE UNITED STATES Standards for the Compromise of Claims § 1015.302 Bases for compromise. (a) DOE may compromise a debt if the Government cannot...

10 CFR 1015.302 - Bases for compromise.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 4 2012-01-01 2012-01-01 false Bases for compromise. 1015.302 Section 1015.302 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) COLLECTION OF CLAIMS OWED THE UNITED STATES Standards for the Compromise of Claims § 1015.302 Bases for compromise. (a) DOE may compromise a debt if the Government cannot...

10 CFR 1015.302 - Bases for compromise.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 4 2013-01-01 2013-01-01 false Bases for compromise. 1015.302 Section 1015.302 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) COLLECTION OF CLAIMS OWED THE UNITED STATES Standards for the Compromise of Claims § 1015.302 Bases for compromise. (a) DOE may compromise a debt if the Government cannot...

10 CFR 1015.302 - Bases for compromise.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Bases for compromise. 1015.302 Section 1015.302 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) COLLECTION OF CLAIMS OWED THE UNITED STATES Standards for the Compromise of Claims § 1015.302 Bases for compromise. (a) DOE may compromise a debt if the Government cannot...

In Vivo Function of the Chaperonin TRiC in α-Actin Folding during Sarcomere Assembly.

PubMed

Berger, Joachim; Berger, Silke; Li, Mei; Jacoby, Arie S; Arner, Anders; Bavi, Navid; Stewart, Alastair G; Currie, Peter D

2018-01-09

The TCP-1 ring complex (TRiC) is a multi-subunit group II chaperonin that assists nascent or misfolded proteins to attain their native conformation in an ATP-dependent manner. Functional studies in yeast have suggested that TRiC is an essential and generalized component of the protein-folding machinery of eukaryotic cells. However, TRiC's involvement in specific cellular processes within multicellular organisms is largely unknown because little validation of TRiC function exists in animals. Our in vivo analysis reveals a surprisingly specific role of TRiC in the biogenesis of skeletal muscle α-actin during sarcomere assembly in myofibers. TRiC acts at the sarcomere's Z-disk, where it is required for efficient assembly of actin thin filaments. Binding of ATP specifically by the TRiC subunit Cct5 is required for efficient actin folding in vivo. Furthermore, mutant α-actin isoforms that result in nemaline myopathy in patients obtain their pathogenic conformation via this function of TRiC. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

45 CFR 79.46 - Compromise or settlement.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Compromise or settlement. 79.46 Section 79.46 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROGRAM FRAUD CIVIL REMEDIES § 79.46 Compromise or settlement. (a) Parties may make offers of compromise or settlement at any...

31 CFR 902.2 - Bases for compromise.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Bases for compromise. 902.2 Section 902.2 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FEDERAL CLAIMS... CLAIMS § 902.2 Bases for compromise. (a) Agencies may compromise a debt if the Government cannot collect...

31 CFR 902.2 - Bases for compromise.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Bases for compromise. 902.2 Section 902.2 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FEDERAL CLAIMS... CLAIMS § 902.2 Bases for compromise. (a) Agencies may compromise a debt if the Government cannot collect...

31 CFR 902.2 - Bases for compromise.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Bases for compromise. 902.2 Section 902.2 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FEDERAL CLAIMS... CLAIMS § 902.2 Bases for compromise. (a) Agencies may compromise a debt if the Government cannot collect...

31 CFR 902.2 - Bases for compromise.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Bases for compromise. 902.2 Section 902.2 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FEDERAL CLAIMS... CLAIMS § 902.2 Bases for compromise. (a) Agencies may compromise a debt if the Government cannot collect...

24 CFR 17.73 - Standards for compromise of claims.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Standards for compromise of claims... General Provisions § 17.73 Standards for compromise of claims. (a) Compromise offer. An offer to...) Documentary evidence of compromise. No compromise of a claim shall be final or binding on the Department...

Career Compromises: Framings and Their Implications.

ERIC Educational Resources Information Center

Gati, Itamar; Houminer, Daphna; Aviram, Tamar

1998-01-01

Career compromise was investigated in three framings (alternatives, aspect importance, within-aspect preference). Young adults and school counselors rated hypothetical stories. Results of four studies with different designs (Average N=106) supported the hypothesis. The alternatives framing was associated with greater compromise and decision…

26 CFR 301.7122-1 - Compromises.

Code of Federal Regulations, 2013 CFR

2013-04-01

... when they provide for payment of compromised amounts in one or more equal or unequal installments. (4... achieved, collection of the full liability would cause the taxpayer economic hardship within the meaning of... policy or equity considerations identified by the taxpayer provide a sufficient basis for compromising...

26 CFR 301.7122-1 - Compromises.

Code of Federal Regulations, 2012 CFR

2012-04-01

... when they provide for payment of compromised amounts in one or more equal or unequal installments. (4... achieved, collection of the full liability would cause the taxpayer economic hardship within the meaning of... policy or equity considerations identified by the taxpayer provide a sufficient basis for compromising...

Chaperonin GroE-facilitated refolding of disulfide-bonded and reduced Taka-amylase A from Aspergillus oryzae.

PubMed

Kawata, Y; Hongo, K; Mizobata, T; Nagai, J

1998-12-01

The refolding characteristics of Taka-amylase A (TAA) from Aspergillus oryzae in the presence of the chaperonin GroE were studied in terms of activity and fluorescence. Disulfide-bonded (intact) TAA and non-disulfide-bonded (reduced) TAA were unfolded in guanidine hydrochloride and refolded by dilution into buffer containing GroE. The intermediates of both intact and reduced enzymes were trapped by GroEL in the absence of nucleotide. Upon addition of nucleotides such as ATP, ADP, CTP or UTP, the intermediates were released from GroEL and recovery of activity was detected. In both cases, the refolding yields in the presence of GroEL and ATP were higher than spontaneous recoveries. Fluorescence studies of intrinsic tryptophan and a hydrophobic probe, 8-anilinonaphthalene-1-sulfonate, suggested that the intermediates trapped by GroEL assumed conformations with different hydrophobic properties. The presence of protein disulfide isomerase or reduced and oxidized forms of glutathione in addition to GroE greatly enhanced the refolding reaction of reduced TAA. These findings suggest that GroE has an ability to recognize folding intermediates of TAA protein and facilitate refolding, regardless of the existence or absence of disulfide bonds in the protein.

Thermodynamic characterization of the interaction between prefoldin and group II chaperonin.

PubMed

Sahlan, Muhamad; Zako, Tamotsu; Tai, Phan The; Ohtaki, Akashi; Noguchi, Keiichi; Maeda, Mizuo; Miyatake, Hideyuki; Dohmae, Naoshi; Yohda, Masafumi

2010-06-18

Prefoldin (PFD) is a hexameric chaperone that captures a protein substrate and transfers it to a group II chaperonin (CPN) to complete protein folding. We have studied the interaction between PFD and CPN using those from a hyperthermophilic archaeon, Thermococcus strain KS-1 (T. KS-1). In this study, we determined the crystal structure of the T. KS-1 PFDbeta2 subunit and characterized the interactions between T. KS-1 CPNs (CPNalpha and CPNbeta) and T. KS-1 PFDs (PFDalpha1-beta1 and PFDalpha2-beta2). As predicted from its amino acid sequence, the PFDbeta2 subunit conforms to a structure similar to those of the PFDbeta1 subunit and the Pyrococcus horikoshii OT3 PFDbeta subunit, with the exception of the tip of its coiled-coil domain, which is thought to be the CPN interaction site. The interactions between T. KS-1 CPNs and PFDs (CPNalpha and PFDalpha1-beta1; CPNalpha and PFDalpha2-beta2; CPNbeta and PFDalpha1-beta1; and CPNbeta and PFDalpha2-beta2) were analyzed using the Biacore T100 system at various temperatures ranging from 20 to 45 degrees C. The affinities between PFDs and CPNs increased with an increase in temperature. The thermodynamic parameters calculated from association constants showed that the interaction between PFD and CPN is entropy driven. Among the four combinations of PFD-CPN interactions, the entropy difference in binding between CPNbeta and PFDalpha2-beta2 was the largest, and affinity significantly increased at higher temperatures. Considering that expression of PFDalpha2-beta2 and CPNbeta subunit is induced upon heat shock, our results suggest that PFDalpha1-beta1 is a general PFD for T. KS-1 CPNs, whereas PFDalpha2-beta2 is specific for CPNbeta. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

49 CFR 1503.425 - Compromise orders.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Assessment of Civil Penalties by TSA § 1503.425 Compromise orders. (a) Issuance. At any time before the... Violation, may agree to dispose of the case by the issuance of a compromise order by TSA. (b) Contents. A... that the person agrees to pay the civil penalty specified. (4) A statement that TSA makes no finding of...

Repetitive Protein Unfolding by the trans Ring of the GroEL-GroES Chaperonin Complex Stimulates Folding*

PubMed Central

Lin, Zong; Puchalla, Jason; Shoup, Daniel; Rye, Hays S.

2013-01-01

A key constraint on the growth of most organisms is the slow and inefficient folding of many essential proteins. To deal with this problem, several diverse families of protein folding machines, known collectively as molecular chaperones, developed early in evolutionary history. The functional role and operational steps of these remarkably complex nanomachines remain subjects of active debate. Here we present evidence that, for the GroEL-GroES chaperonin system, the non-native substrate protein enters the folding cycle on the trans ring of the double-ring GroEL-ATP-GroES complex rather than the ADP-bound complex. The properties of this ATP complex are designed to ensure that non-native substrate protein binds first, followed by ATP and finally GroES. This binding order ensures efficient occupancy of the open GroEL ring and allows for disruption of misfolded structures through two phases of multiaxis unfolding. In this model, repeated cycles of partial unfolding, followed by confinement within the GroEL-GroES chamber, provide the most effective overall mechanism for facilitating the folding of the most stringently dependent GroEL substrate proteins. PMID:24022487

Chaperonin TRiC/CCT Modulates the Folding and Activity of Leukemogenic Fusion Oncoprotein AML1-ETO.

PubMed

Roh, Soung-Hun; Kasembeli, Moses; Galaz-Montoya, Jesús G; Trnka, Mike; Lau, Wilson Chun-Yu; Burlingame, Alma; Chiu, Wah; Tweardy, David J

2016-02-26

AML1-ETO is the most common fusion oncoprotein causing acute myeloid leukemia (AML), a disease with a 5-year survival rate of only 24%. AML1-ETO functions as a rogue transcription factor, altering the expression of genes critical for myeloid cell development and differentiation. Currently, there are no specific therapies for AML1-ETO-positive AML. While known for decades to be the translational product of a chimeric gene created by the stable chromosome translocation t(8;21)(q22;q22), it is not known how AML1-ETO achieves its native and functional conformation or whether this process can be targeted for therapeutic benefit. Here, we show that the biosynthesis and folding of the AML1-ETO protein is facilitated by interaction with the essential eukaryotic chaperonin TRiC (or CCT). We demonstrate that a folding intermediate of AML1-ETO binds to TRiC directly, mainly through its β-strand rich, DNA-binding domain (AML-(1-175)), with the assistance of HSP70. Our results suggest that TRiC contributes to AML1-ETO proteostasis through specific interactions between the oncoprotein's DNA-binding domain, which may be targeted for therapeutic benefit. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

20 CFR 255.18 - Compromise of overpayments.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false Compromise of overpayments. 255.18 Section 255.18 Employees' Benefits RAILROAD RETIREMENT BOARD REGULATIONS UNDER THE RAILROAD RETIREMENT ACT... standards which the Board applies in exercising its authority under 31 U.S.C. 3711 to compromise an...

45 CFR 30.25 - Further review of compromise offers.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Further review of compromise offers. 30.25 Section 30.25 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION CLAIMS COLLECTION Debt Compromise § 30.25 Further review of compromise offers. If the Secretary is uncertain whether to...

Acute gastrointestinal compromise in neonates with congenital diaphragmatic hernia prior to repair.

PubMed

Fox, Catherine; Stewart, Michael; King, Sebastian K; Patel, Neil

2016-12-01

Congenital diaphragmatic hernia (CDH) affects 1 in 3000 live births. Modern management strategies include delayed repair of the diaphragm to permit pre-operative optimization of cardiorespiratory status. We describe a cohort of neonates in whom early emergency operative intervention was required for potentially fatal intestinal compromise. A retrospective review was performed of all neonatal CDH patients managed at a tertiary center in an 8-year period (2005-2012). A total of 126 CDH patients were managed during the 8-year period. Five neonates (male - 1; gestation 37+4-39+7; birth weight 2.9-3.7kg; left CDH - 5) required emergency operative intervention for presumed gastrointestinal compromise. All five neonates demonstrated systemic hypotension despite inotropic support, raised serum lactate (>2mmol/L), and abnormal radiographic findings. Operative intervention occurred within 3days of birth (1-3days). Findings included gastric volvulus, jejunal volvulus, and perforated caecum. All patients underwent primary diaphragmatic repair without a patch. Temporary ileostomy was required in 1 patient. All patients remain alive. Gastrointestinal compromise is a rare, but potentially catastrophic, complication of CDH. Emergency operative intervention may be required in a select cohort of patients. Early deterioration following birth should alert clinicians to the possibility of significant intestinal pathology. Level IV case series with no comparison group. Copyright © 2016 Elsevier Inc. All rights reserved.

Signalling networks and dynamics of allosteric transitions in bacterial chaperonin GroEL: implications for iterative annealing of misfolded proteins.

PubMed

Thirumalai, D; Hyeon, Changbong

2018-06-19

Signal transmission at the molecular level in many biological complexes occurs through allosteric transitions. Allostery describes the responses of a complex to binding of ligands at sites that are spatially well separated from the binding region. We describe the structural perturbation method, based on phonon propagation in solids, which can be used to determine the signal-transmitting allostery wiring diagram (AWD) in large but finite-sized biological complexes. Application to the bacterial chaperonin GroEL-GroES complex shows that the AWD determined from structures also drives the allosteric transitions dynamically. From both a structural and dynamical perspective these transitions are largely determined by formation and rupture of salt-bridges. The molecular description of allostery in GroEL provides insights into its function, which is quantitatively described by the iterative annealing mechanism. Remarkably, in this complex molecular machine, a deep connection is established between the structures, reaction cycle during which GroEL undergoes a sequence of allosteric transitions, and function, in a self-consistent manner.This article is part of a discussion meeting issue 'Allostery and molecular machines'. © 2018 The Author(s).

Analysis of Atlanta Compromise School Desegregation Plan.

ERIC Educational Resources Information Center

Research Atlanta, Inc., GA.

On February 22, 1973, attorneys for the National Association for the Advancement of Colored People and the Atlanta Board of Education filed a compromise desegregation plan with the U.S. District Court for the Northern District of Georgia. If the Court approves, this compromise will constitute the final desegregation plan for the Atlanta Public…

Intensity of mobile phone use and health compromising behaviours--how is information and communication technology connected to health-related lifestyle in adolescence?

PubMed

Leena, Koivusilta; Tomi, Lintonen; Arja, R Rimpelä

2005-02-01

The association of mobile phone use with health compromising behaviours (smoking, snuffing, alcohol) was studied in a survey comprising a representative sample of 14-16-year-olds (N=3485) in 2001. Mobile phone was used by 89% of respondents and by 13% for at least 1h daily. The intensity of use was positively associated with health compromising behaviours. The associations remained, although somewhat reduced, after including weekly spending money in the models. This study concludes that, at least in the present developmental level of communication technologies, intensive mobile phone use seems to be part of the same health-related lifestyle as health compromising behaviours.

Leishmania donovani chaperonin 10 regulates parasite internalization and intracellular survival in human macrophages.

PubMed

Colineau, Lucie; Clos, Joachim; Moon, Kyung-Mee; Foster, Leonard J; Reiner, Neil E

2017-06-01

Protozoa of the genus Leishmania infect macrophages in their mammalian hosts causing a spectrum of diseases known as the leishmaniases. The search for leishmania effectors that support macrophage infection is a focus of significant interest. One such candidate is leishmania chaperonin 10 (CPN10) which is secreted in exosomes and may have immunosuppressive properties. Here, we report for the first time that leishmania CPN10 localizes to the cytosol of infected macrophages. Next, we generated two genetically modified strains of Leishmania donovani (Ld): one strain overexpressing CPN10 (CPN10+++) and the second, a CPN10 single allele knockdown (CPN10+/-), as the null mutant was lethal. When compared with the wild-type (WT) parental strain, CPN10+/- Ld showed higher infection rates and parasite loads in human macrophages after 24 h of infection. Conversely, CPN10+++ Ld was associated with lower initial infection rates. This unexpected apparent gain-of-function for the knockdown could have been explained either by enhanced parasite internalization or by enhanced intracellular survival. Paradoxically, we found that CPN10+/- leishmania were more readily internalized than WT Ld, but also displayed significantly impaired intracellular survival. This suggests that leishmania CPN10 negatively regulates the rate of parasite uptake by macrophages while being required for intracellular survival. Finally, quantitative proteomics identified an array of leishmania proteins whose expression was positively regulated by CPN10. In contrast, many macrophage proteins involved in innate immunity were negatively regulated by CPN10. Taken together, these findings identify leishmania CPN10 as a novel effector with broad based effects on macrophage cell regulation and parasite survival.

45 CFR 1177.12 - Compromise, suspension and termination.

Code of Federal Regulations, 2010 CFR

2010-10-01

... THE ARTS AND THE HUMANITIES NATIONAL ENDOWMENT FOR THE HUMANITIES CLAIMS COLLECTION § 1177.12 Compromise, suspension and termination. (a) The Chairperson of the National Endowment for the Humanities or... available to the public. (b) The Chairperson of the National Endowment for the Humanities may compromise...

45 CFR 1177.12 - Compromise, suspension and termination.

Code of Federal Regulations, 2011 CFR

2011-10-01

... THE ARTS AND THE HUMANITIES NATIONAL ENDOWMENT FOR THE HUMANITIES CLAIMS COLLECTION § 1177.12 Compromise, suspension and termination. (a) The Chairperson of the National Endowment for the Humanities or... available to the public. (b) The Chairperson of the National Endowment for the Humanities may compromise...

15 CFR 904.106 - Compromise of civil penalty.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 15 Commerce and Foreign Trade 3 2013-01-01 2013-01-01 false Compromise of civil penalty. 904.106...) NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE GENERAL REGULATIONS CIVIL PROCEDURES Civil Penalties § 904.106 Compromise of civil penalty. (a) NOAA, in its sole discretion, may...

Outcomes of Soft Tissue Reconstruction for Traumatic Lower Extremity Fractures with Compromised Vascularity.

PubMed

Badash, Ido; Burtt, Karen E; Leland, Hyuma A; Gould, Daniel J; Rounds, Alexis D; Azadgoli, Beina; Patel, Ketan M; Carey, Joseph N

2017-10-01

Traumatic lower extremity fractures with compromised arterial flow are limb-threatening injuries. A retrospective review of 158 lower extremities with traumatic fractures, including 26 extremities with arterial injuries, was performed to determine the effects of vascular compromise on flap survival, successful limb salvage and complication rates. Patients with arterial injuries had a larger average flap surface area (255.1 vs 144.6 cm2, P = 0.02) and a greater number of operations (4.7 vs 3.8, P = 0.01) than patients without vascular compromise. Patients presenting with vascular injury were also more likely to require fasciotomy [odds ratio (OR): 6.5, confidence interval (CI): 2.3-18.2] and to have a nerve deficit (OR: 16.6, CI: 3.9-70.0), fracture of the distal third of the leg (OR: 2.9, CI: 1.15-7.1) and intracranial hemorrhage (OR: 3.84, CI: 1.1-12.9). After soft tissue reconstruction, patients with arterial injuries had a higher rate of amputation (OR: 8.5, CI: 1.3-53.6) and flap failure requiring a return to the operating room (OR: 4.5, CI: 1.5-13.2). Arterial injury did not correlate with infection or overall complication rate. In conclusion, arterial injuries resulted in significant complications for patients with lower extremity fractures requiring flap coverage, although limb salvage was still effective in most cases.

5 CFR 1312.30 - Loss or possible compromise.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 3 2014-01-01 2014-01-01 false Loss or possible compromise. 1312.30 Section 1312.30 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES CLASSIFICATION... Classified Information § 1312.30 Loss or possible compromise. Any person who has knowledge of the loss or...

5 CFR 1312.30 - Loss or possible compromise.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 3 2012-01-01 2012-01-01 false Loss or possible compromise. 1312.30 Section 1312.30 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES CLASSIFICATION... Classified Information § 1312.30 Loss or possible compromise. Any person who has knowledge of the loss or...

5 CFR 1312.30 - Loss or possible compromise.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 3 2013-01-01 2013-01-01 false Loss or possible compromise. 1312.30 Section 1312.30 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES CLASSIFICATION... Classified Information § 1312.30 Loss or possible compromise. Any person who has knowledge of the loss or...

5 CFR 1312.30 - Loss or possible compromise.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Loss or possible compromise. 1312.30 Section 1312.30 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES CLASSIFICATION... Classified Information § 1312.30 Loss or possible compromise. Any person who has knowledge of the loss or...

5 CFR 1312.30 - Loss or possible compromise.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Loss or possible compromise. 1312.30 Section 1312.30 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES CLASSIFICATION... Classified Information § 1312.30 Loss or possible compromise. Any person who has knowledge of the loss or...

41 CFR 105-55.020 - Bases for compromise.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 41 Public Contracts and Property Management 3 2012-01-01 2012-01-01 false Bases for compromise. 105-55.020 Section 105-55.020 Public Contracts and Property Management Federal Property Management... Administration 55-COLLECTION OF CLAIMS OWED THE UNITED STATES § 105-55.020 Bases for compromise. (a) The General...

41 CFR 105-55.020 - Bases for compromise.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 41 Public Contracts and Property Management 3 2011-01-01 2011-01-01 false Bases for compromise. 105-55.020 Section 105-55.020 Public Contracts and Property Management Federal Property Management... Administration 55-COLLECTION OF CLAIMS OWED THE UNITED STATES § 105-55.020 Bases for compromise. (a) The General...

41 CFR 105-55.020 - Bases for compromise.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 41 Public Contracts and Property Management 3 2013-07-01 2013-07-01 false Bases for compromise. 105-55.020 Section 105-55.020 Public Contracts and Property Management Federal Property Management... Administration 55-COLLECTION OF CLAIMS OWED THE UNITED STATES § 105-55.020 Bases for compromise. (a) The General...

41 CFR 105-55.020 - Bases for compromise.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Bases for compromise. 105-55.020 Section 105-55.020 Public Contracts and Property Management Federal Property Management... Administration 55-COLLECTION OF CLAIMS OWED THE UNITED STATES § 105-55.020 Bases for compromise. (a) The General...

19 CFR 161.5 - Compromise of Government claims.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 2 2013-04-01 2013-04-01 false Compromise of Government claims. 161.5 Section 161.5 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF.... 1617), in compromise of a Government claim arising under the Customs laws and the terms upon which it...

19 CFR 161.5 - Compromise of Government claims.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 2 2011-04-01 2011-04-01 false Compromise of Government claims. 161.5 Section 161.5 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF.... 1617), in compromise of a Government claim arising under the Customs laws and the terms upon which it...

19 CFR 161.5 - Compromise of Government claims.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 2 2010-04-01 2010-04-01 false Compromise of Government claims. 161.5 Section 161.5 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF.... 1617), in compromise of a Government claim arising under the Customs laws and the terms upon which it...

19 CFR 161.5 - Compromise of Government claims.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 2 2012-04-01 2012-04-01 false Compromise of Government claims. 161.5 Section 161.5 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF.... 1617), in compromise of a Government claim arising under the Customs laws and the terms upon which it...

15 CFR 904.106 - Compromise of civil penalty.

Code of Federal Regulations, 2014 CFR

2014-01-01

... PROCEDURES Civil Penalties § 904.106 Compromise of civil penalty. (a) NOAA, in its sole discretion, may... NOAA under this section may be exercised either upon the initiative of NOAA or in response to a request... compromise authority of NOAA under this section nor NOAA's exercise thereof at any time changes the date upon...

15 CFR 904.106 - Compromise of civil penalty.

Code of Federal Regulations, 2012 CFR

2012-01-01

... PROCEDURES Civil Penalties § 904.106 Compromise of civil penalty. (a) NOAA, in its sole discretion, may... NOAA under this section may be exercised either upon the initiative of NOAA or in response to a request... compromise authority of NOAA under this section nor NOAA's exercise thereof at any time changes the date upon...

15 CFR 904.106 - Compromise of civil penalty.

Code of Federal Regulations, 2011 CFR

2011-01-01

... PROCEDURES Civil Penalties § 904.106 Compromise of civil penalty. (a) NOAA, in its sole discretion, may... NOAA under this section may be exercised either upon the initiative of NOAA or in response to a request... compromise authority of NOAA under this section nor NOAA's exercise thereof at any time changes the date upon...

15 CFR 904.106 - Compromise of civil penalty.

Code of Federal Regulations, 2010 CFR

2010-01-01

... PROCEDURES Civil Penalties § 904.106 Compromise of civil penalty. (a) NOAA, in its sole discretion, may... NOAA under this section may be exercised either upon the initiative of NOAA or in response to a request... compromise authority of NOAA under this section nor NOAA's exercise thereof at any time changes the date upon...

Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations.

PubMed

Paisán-Ruiz, Coro; Guevara, Rocio; Federoff, Monica; Hanagasi, Hasmet; Sina, Fardaz; Elahi, Elahe; Schneider, Susanne A; Schwingenschuh, Petra; Bajaj, Nin; Emre, Murat; Singleton, Andrew B; Hardy, John; Bhatia, Kailash P; Brandner, Sebastian; Lees, Andrew J; Houlden, Henry

2010-09-15

Seven autosomal recessive genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson's disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. Neurodegeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The genetic heterogeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido-pyramidal syndrome. © 2010 Movement Disorder Society.

Early-Onset L-dopa-Responsive Parkinsonism with Pyramidal Signs Due to ATP13A2, PLA2G6, FBXO7 and Spatacsin Mutations

PubMed Central

Paisán-Ruiz, Coro; Guevara, Rocio; Federoff, Monica; Hanagasi, Hasmet; Sina, Fardaz; Elahi, Elahe; Schneider, Susanne A.; Schwingenschuh, Petra; Bajaj, Nin; Emre, Murat; Singleton, Andrew B.; Hardy, John; Bhatia, Kailash P.; Brandner, Sebastian; Lees, Andrew J.; Houlden, Henry

2018-01-01

Seven autosomal recessive genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson’s disease including supranu-clear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. Neurodegeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The genetic heterogeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido-pyramidal syndrome. 3 2010 Movement Disorder Society PMID:20669327

19 CFR 161.5 - Compromise of Government claims.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 19 Customs Duties 2 2014-04-01 2014-04-01 false Compromise of Government claims. 161.5 Section 161... Government claims. (a) Offer. An offer made pursuant to section 617, Tariff Act of 1930, as amended (19 U.S.C. 1617), in compromise of a Government claim arising under the Customs laws and the terms upon which it...

Combating QR-Code-Based Compromised Accounts in Mobile Social Networks.

PubMed

Guo, Dong; Cao, Jian; Wang, Xiaoqi; Fu, Qiang; Li, Qiang

2016-09-20

Cyber Physical Social Sensing makes mobile social networks (MSNs) popular with users. However, such attacks are rampant as malicious URLs are spread covertly through quick response (QR) codes to control compromised accounts in MSNs to propagate malicious messages. Currently, there are generally two types of methods to identify compromised accounts in MSNs: one type is to analyze the potential threats on wireless access points and the potential threats on handheld devices' operation systems so as to stop compromised accounts from spreading malicious messages; the other type is to apply the method of detecting compromised accounts in online social networks to MSNs. The above types of methods above focus neither on the problems of MSNs themselves nor on the interaction of sensors' messages, which leads to the restrictiveness of platforms and the simplification of methods. In order to stop the spreading of compromised accounts in MSNs effectively, the attacks have to be traced to their sources first. Through sensors, users exchange information in MSNs and acquire information by scanning QR codes. Therefore, analyzing the traces of sensor-related information helps to identify the compromised accounts in MSNs. This paper analyzes the diversity of information sending modes of compromised accounts and normal accounts, analyzes the regularity of GPS (Global Positioning System)-based location information, and introduces the concepts of entropy and conditional entropy so as to construct an entropy-based model based on machine learning strategies. To achieve the goal, about 500,000 accounts of Sina Weibo and about 100 million corresponding messages are collected. Through the validation, the accuracy rate of the model is proved to be as high as 87.6%, and the false positive rate is only 3.7%. Meanwhile, the comparative experiments of the feature sets prove that sensor-based location information can be applied to detect the compromised accounts in MSNs.

Combating QR-Code-Based Compromised Accounts in Mobile Social Networks

PubMed Central

Guo, Dong; Cao, Jian; Wang, Xiaoqi; Fu, Qiang; Li, Qiang

2016-01-01

Cyber Physical Social Sensing makes mobile social networks (MSNs) popular with users. However, such attacks are rampant as malicious URLs are spread covertly through quick response (QR) codes to control compromised accounts in MSNs to propagate malicious messages. Currently, there are generally two types of methods to identify compromised accounts in MSNs: one type is to analyze the potential threats on wireless access points and the potential threats on handheld devices’ operation systems so as to stop compromised accounts from spreading malicious messages; the other type is to apply the method of detecting compromised accounts in online social networks to MSNs. The above types of methods above focus neither on the problems of MSNs themselves nor on the interaction of sensors’ messages, which leads to the restrictiveness of platforms and the simplification of methods. In order to stop the spreading of compromised accounts in MSNs effectively, the attacks have to be traced to their sources first. Through sensors, users exchange information in MSNs and acquire information by scanning QR codes. Therefore, analyzing the traces of sensor-related information helps to identify the compromised accounts in MSNs. This paper analyzes the diversity of information sending modes of compromised accounts and normal accounts, analyzes the regularity of GPS (Global Positioning System)-based location information, and introduces the concepts of entropy and conditional entropy so as to construct an entropy-based model based on machine learning strategies. To achieve the goal, about 500,000 accounts of Sina Weibo and about 100 million corresponding messages are collected. Through the validation, the accuracy rate of the model is proved to be as high as 87.6%, and the false positive rate is only 3.7%. Meanwhile, the comparative experiments of the feature sets prove that sensor-based location information can be applied to detect the compromised accounts in MSNs. PMID:27657071

Perceived Career Compromise, Affect and Work-Related Satisfaction in College Students

ERIC Educational Resources Information Center

Tsaousides, Theodore; Jome, LaRae

2008-01-01

The objective of this study was to investigate the effects of career compromise on positive affect (PA), negative affect (NA), and work-related satisfaction (WRS). Career compromise refers to the modification of occupational preferences under pressing external circumstances [Gottfredson, L. S. (1981). Circumscription and compromise: A…

Genetic and phenotypic characterization of complex hereditary spastic paraplegia

PubMed Central

Kara, Eleanna; Tucci, Arianna; Manzoni, Claudia; Lynch, David S.; Elpidorou, Marilena; Bettencourt, Conceicao; Chelban, Viorica; Manole, Andreea; Hamed, Sherifa A.; Haridy, Nourelhoda A.; Federoff, Monica; Preza, Elisavet; Hughes, Deborah; Pittman, Alan; Jaunmuktane, Zane; Brandner, Sebastian; Xiromerisiou, Georgia; Wiethoff, Sarah; Schottlaender, Lucia; Proukakis, Christos; Morris, Huw; Warner, Tom; Bhatia, Kailash P.; Korlipara, L.V. Prasad; Singleton, Andrew B.; Hardy, John; Wood, Nicholas W.; Lewis, Patrick A.

2016-01-01

cases, next generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35 ) (4/97) and two in ZFYVE26 / SPG15 . Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson’s disease-associated gene ATP13A2 , neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes. PMID:27217339

Framings of Career Compromises: How Career Counselors can Help.

ERIC Educational Resources Information Center

Gati, Itamar; Houminer, Daphna; Fassa, Naomi

1997-01-01

Presents a conceptual model for dealing with career compromise and discusses its implications for the career counseling process. The model identifies three possible framings that individuals may adopt when facing compromise. Suggestions are discussed for relevant intervention options aimed at decreasing the potentially harmful effects of the need…

The role of postoperative hematoma on free flap compromise.

PubMed

Ahmad, Faisal I; Gerecci, Deniz; Gonzalez, Javier D; Peck, Jessica J; Wax, Mark K

2015-08-01

Hematomas may develop in the postoperative setting after free tissue transfer. When hematomas occur, they can exert pressure on surrounding tissues. Their effect on the vascular pedicle of a free flap is unknown. We describe our incidence of hematoma in free flaps and outcomes when the flap is compromised. Retrospective chart review of 1,883 free flaps performed between July 1998 and June 2014 at a tertiary referral center. Patients with free flap compromise due to hematoma were identified. Etiology, demographic data, and outcomes were evaluated. Eighty-eight (4.7%) patients developed hematomas. Twenty (22.7%) of those had flap compromise. Twelve compromises (60%) showed evidence of pedicle thrombosis. The salvage rate was 75% versus 54% in 79 flaps with compromise from other causes (P = .12). Mean time to detection of the hematoma was 35.3 hours in salvaged flaps compared to 91.6 hours in unsalvageable flaps (P = .057). Time to operating room (OR) from detection was 2.8 hours in salvageable flaps compared to 12.4 hours in nonsalvageable flaps (P = .053). The salvage rate for flaps that returned to the OR in <5 hours was 93.3% compared to 20% (P = .0049) for those that did not. Vascular thrombosis reduced salvage rate to 58.3% from 100% (P = .002) when there was no thrombosis. In our series hematomas developed rarely. When they did, 23% went on to develop flap compromise. Prompt recognition and re-exploration allowed for a high salvage rate. Vessel thrombosis predicted inability to salvage the flap. 4 © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

White matter compromise predicts poor intellectual outcome in survivors of pediatric low-grade glioma.

PubMed

Liu, Fang; Scantlebury, Nadia; Tabori, Uri; Bouffet, Eric; Laughlin, Suzanne; Strother, Douglas; McConnell, Dina; Hukin, Juliette; Fryer, Chris; Brière, Marie-Eve; Montour-Proulx, Isabelle; Keene, Daniel; Wang, Frank; Mabbott, Donald J

2015-04-01

While the impact of cranial radiation on white matter following treatment for pediatric brain tumor has been the focus of many recent studies, the effect of treatment in the absence of radiation has received little attention. The relations between white matter and cognitive outcome have not been explored in patients who have undergone radiation-free treatment. As most patients treated without cranial radiation survive long after their diagnosis, it is critical to identify factors that may impact structural and neurocognitive outcomes. Using diffusion tensor imaging, we examined white matter structure in 32 patients with pediatric low-grade glioma (PLGG) (19 with subtentorial location and 13 with supratentorial location) and 32 healthy participants. Indices of intellectual functioning were also evaluated. Radiation was not used to treat this cohort, aged 8-19 years. We detected evidence of deficits in IQ and compromised supra- and subtentorial white matter in patients relative to healthy children (P < .05). Compromise of supratentorial white matter mediated the impact of treatment for PLGG on IQ. Greater white matter compromise was observed in patients who presented without multiple symptoms, were treated with biopsy/no surgery, had positive neurofibromatosis 1 status, were younger age at diagnosis, and whose parents had lower levels of education (P < .05). Our findings provide evidence of increased risk of intellectual and white matter compromise in patients treated for PLGG without radiation. We identify a neural origin of cognitive deficit useful for predicting outcome and mitigating long-term adverse effects in pediatric brain tumor patients treated without cranial radiation. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Surviving cancer without compromising aspirations.

PubMed

McGregor, Sandra

2011-07-01

This short paper is a reflection of how one person coped, survived and grew following numerous metastatic incidences over a 20 year period. Surviving cancer is a complex process but coping with the threat of regular recurrence has required a coping strategy that embraced the disease, set it aside and refused to compromise hopes, dreams and future life. Central to this personal journey has been the need to redefine normality, live with and set aside the fear of future metastases and death and find an answer and meaning in a changing biology, increased morbidity and possible mortality. This paper contends that not compromising the direction of travel and being able to focus on a career has ensured that survival was valuable and valued. A working environment in which students' problems have been immediate has produced different stressors. These have ultimately forced personal worries to be set aside, while living with cancer has become normal and accepted. Copyright © 2011 Elsevier Ltd. All rights reserved.

The effect of health compromising behaviors on preterm births.

PubMed

Dew, Paul C; Guillory, V James; Okah, Felix A; Cai, Jinwen; Hoff, Gerald L

2007-05-01

The objective of our study was to determine whether there were combined effects of smoking, alcohol, and illicit drug use during pregnancy on the frequency of preterm births, and if so, the magnitude of the association after adjusting for confounding factors. We conducted a retrospective cohort study of singleton live births in Kansas City, Missouri from 1990-2002. We defined health compromising behaviors as the use of cigarettes, alcohol, and illicit drugs. The effect of these behaviors on preterm births was considered for each substance individually, and in combination. The rates of preterm births for these groups were calculated. Using logistic regression, adjusted odds ratios were used to estimate the relative risk of preterm births among these groups. Over 13% of infants born to women who smoked were preterm, compared to 9.6% for non-smokers. Of infants born to women who reported alcohol use, 17.3% were preterm compared to 10.1% for non-drinkers. Smoking and alcohol use in combination was associated with 18.0% preterm births, while alcohol and drug use in combination was associated with 20.8% preterm births. The use of all three substances was associated with 31.4% preterm births. Women who engaged in health compromising behaviors during pregnancy showed an increased proportion of preterm births compared to those who did not. There is significant interaction between these behaviors leading to higher rates of preterm births than predicted by their additive effects. To decrease preterm births, we must deal with the effects of smoking, drinking, and drug use simultaneously.

Conscientious objection and compromising the patient: Response to Hughes.

PubMed

Savulescu, Julian; Schuklenk, Udo

2018-06-19

Hughes offers a consequentialist response to our rejection of accommodation of conscientious objection in medicine. We argue here that his compromise proposition has been tried in many jurisdictions and has failed to deliver unimpeded access to care for eligible patients. The compromise position, entailing an accommodation of conscientious objection provided there is unimpeded access, fails to grasp that the objectors are both determined not to provide services they object to as well as to subvert patient access to the objected to services. Unpredictable future developments in drug R&D and resulting treatment and prevention options in medicine make the compromise position unrealistic. © 2018 John Wiley & Sons Ltd.

Cloning of the chaperonin t-complex polypeptide 1 gene from Schistosoma mansoni and studies of its expression levels under heat shock and oxidative stress.

PubMed

Campos, E G; Hamdan, F F

2000-03-01

The protein TCP-1 (t-complex polypeptide 1) is a subunit of the hetero-oligomeric complex CCT (chaperonin containing TCP- 1) present in the eukaryotic cytosol. Chaperone function may be critical for the development and survival of the different life stages of Schistosoma mansoni, a parasite that is exposed to drastic environmental changes during its development. We isolated a full-length S. mansoni TCP-1 cDNA (SmTCP-1A) encoding a protein highly homologous with TCP-1. The deduced SmTCP-1A amino-acid sequence shows up to 65% identity with other eukaryotic CCT family members. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that the mRNA expression levels of SmTCP-1A in adult S. mansoni were down-regulated in worms subjected to heat shock and oxidative stress conditions. This down-regulation of SmTCP-1A mRNA may reflect a switch in CCT subunits as an adaptive response to heat shock and oxidative stress conditions.

Air Duster abuse causing rapid airway compromise

PubMed Central

Winston, Amanda; Kanzy, Abed; Bachuwa, Ghassan

2015-01-01

Inhalant abuse is potentially life-threatening and has resulted in many complications such as central nervous system depression, cardiac dysrhythmia and hypoxia. Inhalant abuse causing angioedema is rarely reported in the medical literature. In this report we present a case of rapidly progressive airway compromise following recreational huffing. Our patient required intubation and intensive care unit admission with complete recovery after 5 days. The aetiology of airway compromise is postulated to be due to commonly reported frost bite injury and rarely reported angioedema. To the best of our knowledge this the second case reporting angioedema secondary to huffing Air Duster. PMID:25568278

Air Duster abuse causing rapid airway compromise.

PubMed

Winston, Amanda; Kanzy, Abed; Bachuwa, Ghassan

2015-01-07

Inhalant abuse is potentially life-threatening and has resulted in many complications such as central nervous system depression, cardiac dysrhythmia and hypoxia. Inhalant abuse causing angioedema is rarely reported in the medical literature. In this report we present a case of rapidly progressive airway compromise following recreational huffing. Our patient required intubation and intensive care unit admission with complete recovery after 5 days. The aetiology of airway compromise is postulated to be due to commonly reported frost bite injury and rarely reported angioedema. To the best of our knowledge this the second case reporting angioedema secondary to huffing Air Duster. 2015 BMJ Publishing Group Ltd.

Compromise decision support problems for hierarchical design involving uncertainty

NASA Astrophysics Data System (ADS)

Vadde, S.; Allen, J. K.; Mistree, F.

1994-08-01

In this paper an extension to the traditional compromise Decision Support Problem (DSP) formulation is presented. Bayesian statistics is used in the formulation to model uncertainties associated with the information being used. In an earlier paper a compromise DSP that accounts for uncertainty using fuzzy set theory was introduced. The Bayesian Decision Support Problem is described in this paper. The method for hierarchical design is demonstrated by using this formulation to design a portal frame. The results are discussed and comparisons are made with those obtained using the fuzzy DSP. Finally, the efficacy of incorporating Bayesian statistics into the traditional compromise DSP formulation is discussed and some pending research issues are described. Our emphasis in this paper is on the method rather than the results per se.

Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

PubMed Central

Klebe, Stephan; Depienne, Christel; Gerber, Sylvie; Challe, Georges; Anheim, Mathieu; Charles, Perrine; Fedirko, Estelle; Lejeune, Elodie; Cottineau, Julien; Brusco, Alfredo; Dollfus, Hélène; Chinnery, Patrick F.; Mancini, Cecilia; Ferrer, Xavier; Sole, Guilhem; Destée, Alain; Mayer, Jean-Michel; Fontaine, Bertrand; de Seze, Jérôme; Clanet, Michel; Ollagnon, Elisabeth; Busson, Philippe; Cazeneuve, Cécile; Stevanin, Giovanni; Kaplan, Josseline; Rozet, Jean-Michel; Brice, Alexis

2012-01-01

Mutations in the spastic paraplegia 7 (SPG7) gene encoding paraplegin are responsible for autosomal recessive hereditary spasticity. We screened 135 unrelated index cases, selected in five different settings: SPG7-positive patients detected during SPG31 analysis using SPG31/SPG7 multiplex ligation-dependent probe amplification (n = 7); previously reported ambiguous SPG7 cases (n = 5); patients carefully selected on the basis of their phenotype (spasticity of the lower limbs with cerebellar signs and/or cerebellar atrophy on magnetic resonance imaging/computer tomography scan and/or optic neuropathy and without other signs) (n = 24); patients with hereditary spastic paraparesis referred consecutively from attending neurologists and the national reference centre in a diagnostic setting (n = 98); and the index case of a four-generation family with autosomal dominant optic neuropathy but no spasticity linked to the SPG7 locus. We identified two SPG7 mutations in 23/134 spastic patients, 21% of the patients selected according to phenotype but only 8% of those referred directly. Our results confirm the pathogenicity of Ala510Val, which was the most frequent mutation in our series (65%) and segregated at the homozygous state with spastic paraparesis in a large family with autosomal recessive inheritance. All SPG7-positive patients tested had optic neuropathy or abnormalities revealed by optical coherence tomography, indicating that abnormalities in optical coherence tomography could be a clinical biomarker for SPG7 testing. In addition, the presence of late-onset very slowly progressive spastic gait (median age 39 years, range 18–52 years) associated with cerebellar ataxia (39%) or cerebellar atrophy (47%) constitute, with abnormal optical coherence tomography, key features pointing towards SPG7-testing. Interestingly, three relatives of patients with heterozygote SPG7 mutations had cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower

48 CFR 232.616 - Compromise actions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Compromise actions. 232.616 Section 232.616 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM... actions. Only the department/agency contract financing offices (see 232.070(c)) are authorized to...

The Drosophila DOCK family protein Sponge is required for development of the air sac primordium

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

Morishita, Kazushge; Anh Suong, Dang Ngoc; Yoshida, Hideki

Dedicator of cytokinesis (DOCK) family genes are known as DOCK1-DOCK11 in mammals. DOCK family proteins mainly regulate actin filament polymerization and/or depolymerization and are GEF proteins, which contribute to cellular signaling events by activating small G proteins. Sponge (Spg) is a Drosophila counterpart to mammalian DOCK3/DOCK4, and plays a role in embryonic central nervous system development, R7 photoreceptor cell differentiation, and adult thorax development. In order to conduct further functional analyses on Spg in vivo, we examined its localization in third instar larval wing imaginal discs. Immunostaining with purified anti-Spg IgG revealed that Spg mainly localized in the air sacmore » primordium (ASP) in wing imaginal discs. Spg is therefore predicted to play an important role in the ASP. The specific knockdown of Spg by the breathless-GAL4 driver in tracheal cells induced lethality accompanied with a defect in ASP development and the induction of apoptosis. The monitoring of ERK signaling activity in wing imaginal discs by immunostaining with anti-diphospho-ERK IgG revealed reductions in the ERK signal cascade in Spg knockdown clones. Furthermore, the overexpression of D-raf suppressed defects in survival and the proliferation of cells in the ASP induced by the knockdown of Spg. Collectively, these results indicate that Spg plays a critical role in ASP development and tracheal cell viability that is mediated by the ERK signaling pathway. - Highlights: • Spg mainly localizes in the air sac primordium in wing imaginal discs. • Spg plays a critical role in air sac primordium development. • Spg positively regulates the ERK signal cascade.« less

7 CFR 1956.68 - Compromise or adjustment without debtor's signature.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 14 2010-01-01 2009-01-01 true Compromise or adjustment without debtor's signature... Loan Programs and Multi-Family Housing § 1956.68 Compromise or adjustment without debtor's signature... made to obtain the debtor's signature and the date(s) of such effort. (c) The specific reasons why it...

32 CFR 842.99 - Compromise, termination, and suspension of collection.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 6 2010-07-01 2010-07-01 false Compromise, termination, and suspension of collection. 842.99 Section 842.99 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR... States (31 U.S.C. 3701, 3711-3719) § 842.99 Compromise, termination, and suspension of collection. This...

Prediction of fetal compromise in labor.

PubMed

Prior, Tomas; Mullins, Edward; Bennett, Phillip; Kumar, Sailesh

2014-06-01

The majority of intrapartum fetal hypoxia occurs in uncomplicated pregnancies. Current intrapartum monitoring techniques have not resulted in a reduction in the incidence of cerebral palsy in term neonates. We report the development of a composite risk score to allow risk stratification of normal pregnancies before labor. Six hundred one women were recruited to this prospective observational study. All women underwent an ultrasound examination before active labor, during which fetal biometry and fetal Doppler flow resistance indices were measured. A composite risk score, amalgamating data from the umbilical artery, middle cerebral artery, and umbilical vein, was then developed and correlated with intrapartum outcomes. In cases with the highest composite risk scores, the incidence of fetal compromise (the primary outcome) was 80.0% compared with just 15.3% in cases with the lowest risk scores (relative risk 5.2, 95% confidence interval 2.7-10.1). These cases were also at increased risk of cesarean delivery (53.3% compared with 3.4%, P<.001) and of developing a fetal heart rate pattern considered pathologic by National Institute for Health and Clinical Excellence criteria (P=.003). No significant variation in Apgar scores or umbilical artery pH was observed. Intrapartum fetal compromise remains a significant global health issue. The composite risk score reported here can identify fetuses at both high risk and low risk of a subsequent diagnosis of intrapartum fetal compromise. This may enable more judicious use of current intrapartum fetal monitoring techniques, which are hampered by low specificity. II.

Vehicle influence on permeation through intact and compromised skin.

PubMed

Gujjar, Meera; Banga, Ajay K

2014-09-10

The purpose of this study was to compare the transdermal permeation of a model compound, diclofenac diethylamine, from a hydrophilic and lipophilic vehicle across in vitro models simulating compromised skin. Mineral oil served as a lipophilic vehicle while 10mM phosphate buffered saline served as a hydrophilic vehicle. Compromised skin was simulated by tape stripping, delipidization, or microneedle application and compared with intact skin as a control. Transepidermal water loss was measured to assess barrier function. Skin compromised with tape stripping and delipidization significantly (p<0.05) increased permeation of diclofenac diethylamine compared to intact and microneedle treated skin with phosphate buffered saline vehicle. A similar trend in permeation was observed with mineral oil as the vehicle. For both vehicles, permeation across skin increased in the same order and correlated with degree of barrier impairment as indicated by transepidermal water loss values: intactcompromised skin. Copyright © 2014 Elsevier B.V. All rights reserved.

Regulation of nuclear factor κB (NF-κB) transcriptional activity via p65 acetylation by the chaperonin containing TCP1 (CCT).

PubMed

Pejanovic, Nadja; Hochrainer, Karin; Liu, Tao; Aerne, Birgit L; Soares, Miguel P; Anrather, Josef

2012-01-01

The NF-κB family member p65 is central to inflammation and immunity. The purpose of this study was to identify and characterize evolutionary conserved genes modulating p65 transcriptional activity. Using an RNAi screening approach, we identified chaperonin containing TCP1 subunit η (CCTη) as a regulator of Drosophila NF-κB proteins, Dorsal and Dorsal-related immunity factor (Dif). CCTη was also found to regulate NF-κB-driven transcription in mammalian cells, acting in a promoter-specific context, downstream of IκB kinase (IKK). CCTη knockdown repressed IκBα and CXCL2/MIP2 transcription during the early phase of NF-κB activation while impairing the termination of CCL5/RANTES and CXCL10/IP10 transcription. The latter effect was associated with increased DNA binding and reduced p65 acetylation, presumably by altering the activity of histone acetyltransferase CREB-binding protein (CBP). We identified p65 lysines (K) 122 and 123 as target residues mediating the CCTη-driven termination of NF-κB-dependent transcription. We propose that CCTη regulates NF-κB activity in a manner that resolves inflammation.

Recombinant EPF/chaperonin 10 promotes the survival of O4-positive pro-oligodendrocytes prepared from neonatal rat brain.

PubMed

McCombe, P A

2008-12-01

Chaperonin 10 (cpn 10) is a small heat-shock protein that is usually intracellular. Early pregnancy factor (EPF), a biologically active protein that was first described in the serum of pregnant mammals, is homologous to cpn 10. EPF/cpn 10 has been reported to have effects on immunomodulation and cell survival and to inhibit activation of toll-like receptors by lipopolysaccharide. We found that recombinant EPF/cpn 10 was able to suppress experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, which is a disease causing inflammation and demyelination of the brain and spinal cord. This beneficial effect could be due to anti-inflammatory and/or cell survival properties of EPF/cpn 10. We aimed to assess the effects of cpn 10 on cells of the oligodendrocyte lineage because oligodendrocytes are the brain cells that produce myelin and that are depleted in multiple sclerosis. Two forms of recombinant EPF/cpn 10 were prepared in the pGEX expression system and in the baculovirus expression system. Purified O4(+) pro-oligodendrocytes were prepared from the brains of day-old Wistar rats and isolated by cell sorting with flow cytometry. Single cells were dispensed into micro-well plates and tested for survival in the presence of a range of concentrations of the two forms of cpn 10. We also studied the effects of bFGF, PDGF, IGF-1 and insulin as controls. With cpn 10 present, there was enhanced survival of O4(+) cells.

Mechanism and function of the chaperonin from Methanococcus maripaludis: implications for archaeal protein homeostasis and energy production

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

frydman, judith

Archaea offer a potentially cost effective and renewable source of energy. The methanogen M. maripaludis, a fast growing archaea that obtains energy by sequestering H2 and reducing CO2 to methane by the methanogenic pathway, is an attractive source for biofuel production. More recently, it has also been suggested that the methanogenesis pathway could be run in reverse, to produce H2 growing the organism in formate. A multi-level understanding of archaeal protein homeostasis, should be instrumental for improving the functionality and design of the enzyme pathways and complexes involved in energy production and storage. One additional importance consequence of a bettermore » understanding of archaeal protein homeostasis will be to increase their stress resistance, since their utilization for the efficient large-scale production of methane (and eventually also of H2) requires that the organisms are resistance to a range of growth conditions. This proposal was focused on understanding how archaea achieve protein folding and assembly and maintain protein homeostasis, which are essential for function and viability. We hypothesize that the homo-oligomeric ring shaped chaperonin from M. maripaludis, Mm-Cpn, is central to achaeal protein homeostasis and assists folding of a wide spectrum of metabolic, structural and regulatory archaeal proteins. Through a combination of biochemistry, systems biology, computational and structural biology, we have been testing this hypothesis through two complementary efforts: (i) identify the archaeal substrate repertoire of Mm-Cpn, and (ii) define mechanistic and structural principles of Mm-Cpn mediated protein folding.« less

Osteogenesis Imperfecta: Muscle-Bone Interactions when Bi-directionally Compromised.

PubMed

Phillips, Charlotte L; Jeong, Youngjae

2018-06-16

Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder of skeletal fragility and more recently muscle weakness. This review highlights our current knowledge of the impact of compromised OI muscle function on muscle-bone interactions and skeletal strength in OI. The ramifications of inherent muscle weakness in OI muscle-bone interactions are just beginning to be elucidated. Studies in patients and in OI mouse models implicate altered mechanosensing, energy metabolism, mitochondrial dysfunction, and paracrine/endocrine crosstalk in the pathogenesis of OI. Compromised muscle-bone unit impacts mechanosensing and the ability of OI muscle and bone to respond to physiotherapeutic and pharmacologic treatment strategies. Muscle and bone are both compromised in OI, making it essential to understand the mechanisms responsible for both impaired muscle and bone functions and their interdependence, as this will expand and drive new physiotherapeutic and pharmacological approaches to treat OI and other musculoskeletal disorders.

14 CFR 1261.414 - Compromise of claims.

Code of Federal Regulations, 2010 CFR

2010-01-01

... the Government's ability to enforce collection. The compromise should be for an amount which bears a... the settlement of small claims, but normally will not carry great weight in the settlement of large...

14 CFR 1261.414 - Compromise of claims.

Code of Federal Regulations, 2013 CFR

2013-01-01

... the Government's ability to enforce collection. The compromise should be for an amount which bears a... the settlement of small claims, but normally will not carry great weight in the settlement of large...

14 CFR 1261.414 - Compromise of claims.

Code of Federal Regulations, 2012 CFR

2012-01-01

... the Government's ability to enforce collection. The compromise should be for an amount which bears a... the settlement of small claims, but normally will not carry great weight in the settlement of large...

14 CFR 1261.414 - Compromise of claims.

Code of Federal Regulations, 2011 CFR

2011-01-01

... the Government's ability to enforce collection. The compromise should be for an amount which bears a... the settlement of small claims, but normally will not carry great weight in the settlement of large...

Chaperonin-based biolayer interferometry to assess the kinetic stability of metastable, aggregation-prone proteins

PubMed Central

Lea, Wendy A.; Naik, Subhashchandra; Chaudhri, Tapan; Machen, Alexandra J.; O’Neil, Pierce T.; McGinn-Straub, Wesley; Tischer, Alexander; Auton, Matthew T.; Burns, Joshua R.; Baldwin, Michael R.; Khar, Karen R.; Karanicolas, John; Fisher, Mark T.

2017-01-01

Stabilizing the folded state of metastable and/or aggregation-prone proteins through exogenous ligand binding is an appealing strategy to decrease disease pathologies brought on by protein folding defects or deleterious kinetic transitions. Current methods of examining ligand binding to these marginally stable native states are limited, because protein aggregation typically interferes with analysis. Here, we describe a rapid method for assessing the kinetic stability of folded proteins and monitoring the effects of ligand stabilization for both intrinsically stable proteins (monomers, oligomers, multi-domain) and metastable proteins (e.g. low Tm) that uses a new GroEL chaperonin-based biolayer interferometry (BLI) denaturant-pulse platform. A kinetically controlled denaturation isotherm is generated by exposing a target protein immobilized on a BLI biosensor to increasing denaturant concentrations (urea or GnHCl) in a pulsatile manner to induce partial or complete unfolding of the attached protein population. Following the rapid removal of the denaturant, the extent of hydrophobic unfolded/partially folded species that remain is detected by increased GroEL binding. Since this kinetic denaturant pulse is brief, the amplitude of the GroEL binding to the immobilized protein depends on the duration of exposure to denaturant, the concentration of denaturant, wash times, and the underlying protein unfolding/refolding kinetics; fixing all other parameters and plotting GroEL binding amplitude versus denaturant pulse concentration results in a kinetically controlled denaturation isotherm. When folding osmolytes or stabilizing ligands are added to the immobilized target proteins before and during the denaturant pulse, the diminished population of unfolded/partially folded protein is manifested by a decreased GroEL binding and/or a marked shift in these kinetically controlled denaturation profiles to higher denaturant concentrations. This particular platform approach can be

Indicators of safety compromise in gastrointestinal endoscopy.

PubMed

Borgaonkar, Mark Ram; Hookey, Lawrence; Hollingworth, Roger; Kuipers, Ernst J; Forster, Alan; Armstrong, David; Barkun, Alan; Bridges, Ron; Carter, Rose; de Gara, Chris; Dube, Catherine; Enns, Robert; Macintosh, Donald; Forget, Sylviane; Leontiadis, Grigorios; Meddings, Jonathan; Cotton, Peter; Valori, Roland

2012-02-01

The importance of quality indicators has become increasingly recognized in gastrointestinal endoscopy. Patient safety requires the identification and monitoring of occurrences associated with harm or the potential for harm. The identification of relevant indicators of safety compromise is, therefore, a critical element that is key to the effective implementation of endoscopy quality improvement programs. To identify key indicators of safety compromise in gastrointestinal endoscopy. The Canadian Association of Gastroenterology Safety and Quality Indicators in Endoscopy Consensus Group was formed to address issues of quality in endoscopy. A subcommittee was formed to identify key safety indicators. A systematic literature review was undertaken, and articles pertinent to safety in endoscopy were identified and reviewed. All complications and measures used to document safety were recorded. From this, a preliminary list of 16 indicators was compiled and presented to the 35-person consensus group during a three-day meeting. A revised list of 20 items was subsequently put to the consensus group for vote for inclusion on the final list of safety indicators. Items were retained only if the consensus group highly agreed on their importance. A total of 19 indicators of safety compromise were retained and grouped into the three following categories: medication-related - the need for CPR, use of reversal agents, hypoxia, hypotension, hypertension, sedation doses in patients older than 70 years of age, allergic reactions and laryngospasm⁄bronchospasm; procedure-related early - perforation, immediate postpolypectomy bleeding, need for hospital admission or transfer to emergency department from the gastroenterology unit, instrument impaction, severe persistent abdominal pain requiring evaluation proven to not be perforation; and procedure-related delayed - death within 30 days of procedure, 14-day unplanned hospitalization, 14-day unplanned contact with a health provider

Interleukin-4 and interleukin-13 compromise the sinonasal epithelial barrier and perturb intercellular junction protein expression.

PubMed

Wise, Sarah K; Laury, Adrienne M; Katz, Elizabeth H; Den Beste, Kyle A; Parkos, Charles A; Nusrat, Asma

2014-05-01

Altered expression of epithelial intercellular junction proteins has been observed in sinonasal biopsies from nasal polyps and epithelial layers cultured from nasal polyp patients. These alterations comprise a "leaky" epithelial barrier phenotype. We hypothesize that T helper 2 (Th2) cytokines interleukin (IL)-4 and IL-13 modulate epithelial junction proteins, thereby contributing to the leaky epithelial barrier. Differentiated primary sinonasal epithelial layers cultured at the air-liquid interface were exposed to IL-4, IL-13, and controls for 24 hours at 37°C. Epithelial resistance measurements were taken every 4 hours during cytokine exposure. Western blot and immunofluorescence staining/confocal microscopy were used to assess changes in a panel of tight and adherens junction proteins. Western blot densitometry was quantified with image analysis. IL-4 and IL-13 exposure resulted in a mean decrease in transepithelial resistance at 24 hours to 51.6% (n = 6) and 68.6% (n = 8) of baseline, respectively. Tight junction protein junctional adhesion molecule-A (JAM-A) expression decreased 42.2% with IL-4 exposure (n = 9) and 37.5% with IL-13 exposure (n = 9). Adherens junction protein E-cadherin expression decreased 35.3% with IL-4 exposure (n = 9) and 32.9% with IL-13 exposure (n = 9). Tight junction protein claudin-2 showed more variability but had a trend toward higher expression with Th2 cytokine exposure. There were no appreciable changes in claudin-1, occludin, or zonula occludens-1 (ZO-1) with IL-4 or IL-13 exposure. Sinonasal epithelial exposure to Th2 cytokines IL-4 and IL-13 results in alterations in intercellular junction proteins, reflecting increased epithelial permeability. Such changes may explain some of the phenotypic manifestations of Th2-mediated sinonasal disease, such as edema, nasal discharge, and environmental reactivity. © 2014 ARS-AAOA, LLC.

IL-4 and IL-13 Compromise the Sinonasal Epithelial Barrier and Perturb Intercellular Junction Protein Expression

PubMed Central

Wise, Sarah K.; Laury, Adrienne M.; Katz, Elizabeth H.; Den Beste, Kyle A.; Parkos, Charles A.; Nusrat, Asma

2014-01-01

Introduction Altered expression of epithelial intercellular junction proteins has been observed in sinonasal biopsies from nasal polyps and epithelial layers cultured from nasal polyp patients. These alterations comprise a “leaky” epithelial barrier phenotype. We hypothesize that Th2 cytokines IL-4 and IL-13 modulate epithelial junction proteins thereby contributing to the leaky epithelial barrier. Methods Differentiated primary sinonasal epithelial layers cultured at the air-liquid interface were exposed to IL-4, IL-13, and controls for 24 hours at 37°C. Epithelial resistance measurements were taken every 4 hours during cytokine exposure. Western blot and immunofluorescence staining/confocal microscopy were used to assess changes in a panel of tight and adherens junction proteins. Western blot densitometry was quantified with image analysis. Results IL-4 and IL-13 exposure resulted in a mean decrease in transepithelial resistance at 24 hours to 51.6% (n=6) and 68.6% (n=8) of baseline, respectively. Tight junction protein JAM-A expression decreased 42.2% with IL-4 exposure (n=9) and 37.5% with IL-13 exposure (n=9). Adherens junction protein E-cadherin expression decreased 35.3% with IL-4 exposure (n=9) and 32.9% with IL-13 exposure (n=9). Tight junction protein claudin-2 showed more variability but had a trend toward higher expression with Th2 cytokine exposure. There were no appreciable changes in claudin-1, occludin, or ZO-1 with IL-4 or IL-13 exposure. Conclusion Sinonasal epithelial exposure to Th2 cytokines IL-4 and IL-13 results in alterations in intercellular junction proteins, reflecting increased epithelial permeability. Such changes may explain some of the phenotypic manifestations of Th2-mediated sinonasal disease, such as edema, nasal discharge, and environmental reactivity. PMID:24510479

Alchemy or Science? Compromising Archaeology in the Deep Sea

NASA Astrophysics Data System (ADS)

Adams, Jonathan

2007-06-01

In the torrid debate between archaeology and treasure hunting, compromise is often suggested as the pragmatic solution, especially for archaeology carried out either in deep water or beyond the constraints that commonly regulate such activities in territorial seas. Both the wisdom and the need for such compromise have even been advocated by some archaeologists, particularly in forums such as the internet and conferences. This paper argues that such a compromise is impossible, not in order to fuel confrontation but simply because of the nature of any academic discipline. We can define what archaeology is in terms of its aims, theories, methods and ethics, so combining it with an activity founded on opposing principles must transform it into something else. The way forward for archaeology in the deep sea does not lie in a contradictory realignment of archaeology’s goals but in collaborative research designed to mesh with emerging national and regional research and management plans.

Identification of a Heterozygous SPG11 Mutation by Clinical Exome Sequencing in a Patient With Hereditary Spastic Paraplegia: A Case Report.

PubMed

Oh, Ja-Young; Do, Hyun Jung; Lee, Seungok; Jang, Ja-Hyun; Cho, Eun-Hae; Jang, Dae-Hyun

2016-12-01

Next-generation sequencing, such as whole-genome sequencing, whole-exome sequencing, and targeted panel sequencing have been applied for diagnosis of many genetic diseases, and are in the process of replacing the traditional methods of genetic analysis. Clinical exome sequencing (CES), which provides not only sequence variation data but also clinical interpretation, aids in reaching a final conclusion with regards to genetic diagnosis. Sequencing of genes with clinical relevance rather than whole exome sequencing might be more suitable for the diagnosis of known hereditary disease with genetic heterogeneity. Here, we present the clinical usefulness of CES for the diagnosis of hereditary spastic paraplegia (HSP). We report a case of patient who was strongly suspected of having HSP based on her clinical manifestations. HSP is one of the diseases with high genetic heterogeneity, the 72 different loci and 59 discovered genes identified so far. Therefore, traditional approach for diagnosis of HSP with genetic analysis is very challenging and time-consuming. CES with TruSight One Sequencing Panel, which enriches about 4,800 genes with clinical relevance, revealed compound heterozygous mutations in SPG11 . One workflow and one procedure can provide the results of genetic analysis, and CES with enrichment of clinically relevant genes is a cost-effective and time-saving diagnostic tool for diseases with genetic heterogeneity, including HSP.

Predicting intrapartum fetal compromise using the fetal cerebro-umbilical ratio.

PubMed

Sabdia, S; Greer, R M; Prior, T; Kumar, S

2015-05-01

The aim of this study was to explore the association between the cerebro-umbilical ratio measured at 35-37 weeks and intrapartum fetal compromise. This retrospective cross sectional study was conducted at the Mater Mothers' Hospital in Brisbane, Australia. Maternal demographics and fetal Doppler indices at 35-37 weeks gestation for 1381 women were correlated with intrapartum and neonatal outcomes. Babies born by caesarean section or instrumental delivery for fetal compromise had the lowest median cerebro-umbilical ratio 1.60 (IQR 1.22-2.08) compared to all other delivery groups (vaginal delivery, emergency delivery for failure to progress, emergency caesarean section for other reasons or elective caesarean section). The percentage of infants with a cerebro-umbilical ratio <10th centile that required emergency delivery (caesarean section or instrumental delivery) for fetal compromise was 22%, whereas only 7.3% of infants with a cerebro-umbilical ratio between the 10th-90th centile and 9.6% of infants with a cerebro-umbilical ratio > 90th centile required delivery for the same indication (p < 0.001). A lower cerebro-umbilical ratio was associated with an increased risk of emergency delivery for fetal compromise, OR 2.03 (95% CI 1.41-2.92), p < 0.0001. This study suggests that a low fetal cerebro-umbilical ratio measured at 35-37 weeks is associated with a greater risk of intrapartum compromise. This is a relatively simple technique which could be used to risk stratify women in diverse healthcare settings. Copyright © 2015 Elsevier Ltd. All rights reserved.

Intensity of Mobile Phone Use and Health Compromising Behaviours--How Is Information and Communication Technology Connected to Health-Related Lifestyle in Adolescence?

ERIC Educational Resources Information Center

Leena, Koivusilta; Tomi, Lintonen; Arja, Rimpela

2005-01-01

The association of mobile phone use with health compromising behaviours (smoking, snuffing, alcohol) was studied in a survey comprising a representative sample of 14-16-year-olds (N=3485) in 2001. Mobile phone was used by 89% of respondents and by 13% for at least 1 h daily. The intensity of use was positively associated with health compromising…

Sesquiterpenoids from the root of Panax Ginseng protect CCl4-induced acute liver injury by anti-inflammatory and anti-oxidative capabilities in mice.

PubMed

Wang, Weidong; Wang, Shijie; Liu, Jinping; Cai, Enbo; Zhu, Hongyan; He, Zhongmei; Gao, Yugang; Li, Pingya; Zhao, Yan

2018-06-01

The oxidative stress and inflammatory response play an important role in carbon tetracholoride (CCl 4 )-induced acute liver injury. In this work, sesquiterpenoids from the root of Panax Ginseng (SPG) were prepared, and then the hepatoprotective effects of SPG against CCl 4 -induced acute liver injury were investigated and the underlying mechanism was explored in mice. All mice were divided into four groups: the control, CCl 4 and SPG (2.5 and 10 mg/kg, dissolved in soybean oil, i.g.) groups. All mice were given continuous administration for 7 days, and injected with CCl 4 (0.1 mL/10 g body weight 0.2% CCl 4 solution in soybean oil, i.p.) 1 h after the end of the administration except the control group. Mice were sacrificed 24 h post-CCl 4 injection. The results indicated that SPG significantly reduced the increasement of serum AST and ALT levels induced by CCl 4 -treatment. And the histopathological analysis revealed that SPG treated mice had normal liver architecture and no necrosis. The decreased activities of SOD, GSH and CAT, and increased MDA level were inhibited by SPG treatment. At the same time, the levels of TNF-α, IL-1β and IL-6 were significantly decreased by SPG treatment. SPG treatment also reduced the heptic protein expressions of NF-κB p65, COX-2, MAPK p38, ERK and JNK in the liver. These fingdings demonstrated that SPG exhibited strong hepatoprective effect on the CCl 4 -induced acute liver injury, which was related to anti-oxidantive and anti-inflammatory capabilities; and the anti-inflammatory effect of SPG might mediated by the NF-κB and MAPKs signaling pathways. Taken together, SPG might be a potential material for drug and functional food development against chemical hepatic injury. Copyright © 2018. Published by Elsevier Masson SAS.

Clinical and genetic study of hereditary spastic paraplegia in Canada.

PubMed

Chrestian, Nicolas; Dupré, Nicolas; Gan-Or, Ziv; Szuto, Anna; Chen, Shiyi; Venkitachalam, Anil; Brisson, Jean-Denis; Warman-Chardon, Jodi; Ahmed, Sohnee; Ashtiani, Setareh; MacDonald, Heather; Mohsin, Noreen; Mourabit-Amari, Karim; Provencher, Pierre; Boycott, Kym M; Stavropoulos, Dimitri J; Dion, Patrick A; Ray, Peter N; Suchowersky, Oksana; Rouleau, Guy A; Yoon, Grace

2017-02-01

To describe the clinical, genetic, and epidemiologic features of hereditary spastic paraplegia (HSP) in Canada and to determine which clinical, radiologic, and genetic factors determine functional outcomes for patients with HSP. We conducted a multicenter observational study of patients who met clinical criteria for the diagnosis of HSP in the provinces of Alberta, Ontario, and Quebec from 2012 to 2015. Characteristics of the participants were analyzed using descriptive statistics. The main outcome measure for a subset of the cohort (n = 48) was the Spastic Paraplegia Rating Scale. We also used the SPATAX-EUROSPA disability stage (disability score) to assess disability (n = 65). A total of 526 patients were identified with HSP across the country, and 150 patients had a confirmed genetic diagnosis. Mutations were identified in 15 different genes; the most common were SPAST (SPG4, 48%), ATL1 (SPG3A, 16%), SPG11 (8%), SPG7 (7%), and KIAA0196 (SPG8, 5%). The diagnosis of SPG4 was associated with older age at symptom onset ( p = 0.0017). SPG4 and SPG3A were less associated with learning disabilities compared to other subtypes of HSP, and SPG11 was strongly associated with progressive cognitive deficits (odds ratio 87.75, 95% confidence interval 14.04-548.24, p < 0.0001). SPG3A was associated with better functional outcomes compared to other HSP subtypes ( p = 0.04) on multivariate analysis. The strongest predictor of significant disability was abnormal brain MRI ( p = 0.014). The most important predictors of disability in our HSP cohort were SPG11 mutations and abnormal brain MRI. Accurate molecular characterization of well-phenotyped cohorts and international collaboration are essential to establish the natural history of these rare neurodegenerative disorders.

Chaperonin Containing-TCP-1 Protein Level in Breast Cancer Cells Predicts Therapeutic Application of a Cytotoxic Peptide

PubMed Central

Bassiouni, Rania; Nemec, Kathleen; Iketani, Ashley; Flores, Orielyz; Showalter, Anne; Khaled, Amr S.; Vishnubhotla, Priya; Sprung, Robert W.; Kaittanis, Charalambos; Perez, Jesus M.; Khaled, Annette R.

2016-01-01

Purpose Metastatic disease is a leading cause of death for patients with breast cancer, driving the need for new therapies. CT20p is a peptide previously discovered by our group that displays cancer-specific cytotoxicity. To design the optimal therapeutic use of the peptide, we identified the intracellular target of CT20p in breast cancer cells, correlating expression patterns of the target with susceptibility to CT20p. Experimental Design Using polymeric nanoparticles to deliver CT20p, we assessed cytoskeletal changes, cell migration, adhesion, and viability in cells treated with the peptide. Protein pull-down experiments, coupled to mass spectrometry, enabled identification of the peptide’s intracellular target. Biochemical and histological techniques validated target identity in human cell lines and breast cancer tissue microarrays and revealed susceptibility patterns to CT20p. Results Chaperonin Containing TCP-1 (CCT) was identified as the intracellular target of CT20p. Cancer cells susceptible to CT20p had increased CCT, and overexpression of CCTβ, a subunit of the CCT complex, enhanced susceptibility to CT20p. Susceptible cells displayed reduced tubulin, a substrate of CCT, and inhibition of migration upon CT20p treatment. CCTβ levels were higher in invasive ductal carcinomas than in cancer adjacent tissues and increased with breast cancer stage. Decreased breast cancer patient survival correlated with genomic alternations in CCTβ and higher levels of the chaperone. Conclusion Increased CCT protein in breast cancer cells underlies the cytotoxicity of CT20p. CCT is thus a potential target for therapeutic intervention and serves as a companion diagnostic to personalize the therapeutic use of CT20p for breast cancer treatment. PMID:27012814

Placental angiogenesis in sheep models of compromised pregnancy

PubMed Central

Reynolds, Lawrence P; Borowicz, Pawel P; Vonnahme, Kimberly A; Johnson, Mary Lynn; Grazul-Bilska, Anna T; Redmer, Dale A; Caton, Joel S

2005-01-01

Because the placenta is the organ that transports nutrients, respiratory gases and wastes between the maternal and fetal systems, development of its vascular beds is essential to normal placental function, and thus in supporting normal fetal growth. Compromised fetal growth and development have adverse health consequences during the neonatal period and throughout adult life. To establish the role of placental angiogenesis in compromised pregnancies, we first evaluated the pattern of placental angiogenesis and expression of angiogenic factors throughout normal pregnancy. In addition, we and others have established a variety of sheep models to evaluate the effects on fetal growth of various factors including maternal nutrient excess or deprivation and specific nutrients, maternal age, maternal and fetal genotype, increased numbers of fetuses, environmental thermal stress, and high altitude (hypobaric) conditions. Although placental angiogenesis is altered in each of these models in which fetal growth is adversely affected, the specific effect on placental angiogenesis depends on the type of ‘stress’ to which the pregnancy is subjected, and also differs between the fetal and maternal systems and between genotypes. We believe that the models of compromised pregnancy and the methods described in this review will enable us to develop a much better understanding of the mechanisms responsible for alterations in placental vascular development. PMID:15760944

Methods for production of proteins in host cells

DOEpatents

Donnelly, Mark; Joachimiak, Andrzej

2004-01-13

The present invention provides methods for the production of proteins, particularly toxic proteins, in host cells. The invention provides methods which use a fusion protein comprising a chaperonin binding domain in host cells induced or regulated to have increased levels of chaperonin which binds the chaperonin binding domain.

Respiratory Compromise as a New Paradigm for the Care of Vulnerable Hospitalized Patients.

PubMed

Morris, Timothy A; Gay, Peter C; MacIntyre, Neil R; Hess, Dean R; Hanneman, Sandra K; Lamberti, James P; Doherty, Dennis E; Chang, Lydia; Seckel, Maureen A

2017-04-01

Acute respiratory compromise describes a deterioration in respiratory function with a high likelihood of rapid progression to respiratory failure and death. Identifying patients at risk for respiratory compromise coupled with monitoring of patients who have developed respiratory compromise might allow earlier interventions to prevent or mitigate further decompensation. The National Association for the Medical Direction of Respiratory Care (NAMDRC) organized a workshop meeting with representation from many national societies to address the unmet needs of respiratory compromise from a clinical practice perspective. Respiratory compromise may arise de novo or may complicate preexisting lung disease. The group identified distinct subsets of respiratory compromise that present similar opportunities for early detection and useful intervention to prevent respiratory failure. The subtypes were characterized by the pathophysiological mechanisms they had in common: impaired control of breathing, impaired airway protection, parenchymal lung disease, increased airway resistance, hydrostatic pulmonary edema, and right-ventricular failure. Classification of acutely ill respiratory patients into one or more of these categories may help in selecting the screening and monitoring strategies that are most appropriate for the patient's particular pathophysiology. Standardized screening and monitoring practices for patients with similar mechanisms of deterioration may enhance the ability to predict respiratory failure early and prevent its occurrence. Copyright © 2017 by Daedalus Enterprises.

β-tricalcium phosphate composite ceramics with high compressive strength, enhanced osteogenesis and inhibited osteoclastic activities.

PubMed

Tian, Ye; Lu, Teliang; He, Fupo; Xu, Yubin; Shi, Haishan; Shi, Xuetao; Zuo, Fei; Wu, Shanghua; Ye, Jiandong

2018-04-13

β-tricalcium phosphate (β-TCP) is well known as a resorbable bone repair material due to its inherent excellent biocompatibility and osteoconductivity. However, β-TCP is encountered with osteostimulation-deficiency and poor mechanical strength because of poor sinterability. Herein, we prepared novel β-TCP composite ceramics (TCP/SPGs) by introducing strontium-containing phosphate-based glass (SPG; 45P 2 O 5 -32SrO-23Na 2 O) as sintering additive. The SPG helped to achieve efficient liquid-phase sintering of β-TCP at 1100 °C. The compressive strength of TCP/SPGs with 15 wt.% SPG (TCP/SPG15) was 2.65 times as high as that of plain β-TCP ceramic. The SPG reacted with β-TCP, and the Sr 2+ and Na 2+ from SPG replaced Ca 2+ in the lattice structure of β-TCP, enabling the sustained release of strontium from TCP/SPGs. In vitro cytological test indicated that TCP/SPGs with certain amount of SPG were highly biocompatible, and noticeably promoted osteogenesis, and inhibited osteoclastic activities. Our results suggested that the TCP/SPG15 might be potential high-strength bone grafts used for bone defect repair, especially in the osteoporotic condition. Copyright © 2018 Elsevier B.V. All rights reserved.

Abrupt cooling over the North Atlantic in modern climate models

PubMed Central

Sgubin, Giovanni; Swingedouw, Didier; Drijfhout, Sybren; Mary, Yannick; Bennabi, Amine

2017-01-01

Observations over the 20th century evidence no long-term warming in the subpolar North Atlantic (SPG). This region even experienced a rapid cooling around 1970, raising a debate over its potential reoccurrence. Here we assess the risk of future abrupt SPG cooling in 40 climate models from the fifth Coupled Model Intercomparison Project (CMIP5). Contrary to the long-term SPG warming trend evidenced by most of the models, 17.5% of the models (7/40) project a rapid SPG cooling, consistent with a collapse of the local deep-ocean convection. Uncertainty in projections is associated with the models' varying capability in simulating the present-day SPG stratification, whose realistic reproduction appears a necessary condition for the onset of a convection collapse. This event occurs in 45.5% of the 11 models best able to simulate the observed SPG stratification. Thus, due to systematic model biases, the CMIP5 ensemble as a whole underestimates the chance of future abrupt SPG cooling, entailing crucial implications for observation and adaptation policy. PMID:28198383

Knowledge is power: averting safety-compromising events in the OR.

PubMed

Catalano, Kathleen

2008-12-01

Surgical procedures can be unpredictable, and safety-compromising events can jeopardize patient safety. Perioperative nurses should be watchful for factors that can contribute to safety-compromising events, as well as the errors that can follow, and know how to avert them if possible. Knowledge is power and increased awareness of patient safety issues and the resources that are available to both health care practitioners and consumers can help perioperative nurses ward off patient safety problems before they occur.

Vatican is lone opponent of world conference's compromises on abortion.

PubMed

1994-09-07

Three years in the making, the draft program of action of the 1994 International Conference on Population and Development sets nonbinding policy guidelines to contain the world's population at 7.27 billion in 2015. Although the Vatican was pleased to see Pakistan put forward a compromise formula developed to appease Catholic and Muslim objectors of abortion, the Church was unprepared to accept the compromise immediately and requested further discussion. The Vatican's rejection drew a strong chorus of vocal disapproval from other conference delegates. Even Iran accepted the draft as a "perfect text," while Sweden grudgingly accepted it as a "rock-bottom compromise." With no Catholic countries objecting to the compromise, the Vatican stood alone in its refusal to compromise with the rest of the world's leaders and peoples. Germany, speaking for the European Union, warned that enough concessions had already been made. The rationale for Vatican opposition was unclear since the section explicitly rejects abortion as a means of family planning and urges countries to minimize both the incidence of unsafe abortion and abortion overall by improving family planning. Prevention of unwanted pregnancies must be given highest priority and women should have ready access to compassionate counselling, with abortion never promoted as a means of family planning. Moreover, there is no longer a reference to sexual health education, a plea to governments to review their laws and policies on abortion, and a call to consider women's health rather than relying upon criminal codes and punitive measures. Participants said the Vatican objected to a phrase stating that abortions, where legal, should be safe, while the Church representative argued that any suggestion that abortion is safe contradicts church doctrine on the sanctity of life.

Adolescent Health-Compromising Behaviors: Motivating School Counselors.

ERIC Educational Resources Information Center

Nagel, Liza; Scherer, David G.; Lee, William

2000-01-01

Investigated middle and high school counselors' perceptions of adolescent health-compromising behaviors and motivations to intervene. Data from a survey based on protection motivation theory showed differences in counselors' perceptions of the severity of risk-taking behaviors. Perceptions were highly correlated with intentions to seek out…

The medically compromised patient: Are dental implants a feasible option?

PubMed

Vissink, A; Spijkervet, Fkl; Raghoebar, G M

2018-03-01

In healthy subjects, dental implants have evolved to be a common therapy to solve problems related to stability and retention of dentures as well as to replace failing teeth. Although dental implants are applied in medically compromised patients, it is often not well known whether this therapy is also feasible in these patients, whether the risk of implant failure and developing peri-implantitis is increased, and what specific preventive measures, if any, have to be taken when applying dental implants in these patients. Generally speaking, as was the conclusion by the leading review of Diz, Scully, and Sanz on placement of dental implants in medically compromised patients (J Dent, 41, 2013, 195), in a few disorders implant survival may be lower, and the risk of a compromised peri-implant health and its related complications be greater, but the degree of systemic disease control outweighs the nature of the disorder rather than the risk accompanying dental implant treatment. So, as dental implant treatment is accompanied by significant functional benefits and improved oral health-related quality of life, dental implant therapy is a feasible treatment in almost any medically compromised patient when the required preventive measures are taken and follow-up care is at a high level. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.

Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system.

PubMed

Zhang, Q; Ichimaru, N; Higuchi, S; Cai, S; Hou, J; Fujino, M; Nonomura, N; Kobayashi, M; Ando, H; Uno, A; Sakurai, K; Mochizuki, S; Adachi, Y; Ohno, N; Zou, H; Xu, J; Li, X-K; Takahara, S

2015-03-01

The CD40/CD154 co-stimulatory pathway is crucial in alloimmune response. We developed a novel small interfering RNA (siRNA) delivery system with a poly-dA extension at the 5'-end of the siRNA sense strand that was stably incorporated into 1,3-β-glucan (schizophyllan, SPG). This was captured and incorporated into dendritic cells (DCs) through its receptor, Dectin-1, specifically silencing CD40 genes (siCD40) to exert immunoregulatory activity. siCD40/SPG-treated CBA mice permanently accepted B10 fully mismatched cardiac allografts. Consistent with graft survival, the infiltration of CD4(+), CD8(+) T cells into the graft was lower, and that the numbers of CD40(low)CD11c(+) DCs cells and CD4(+)Foxp3(+)cells were increased in both the graft and in the recipient spleen. In addition, naive CBA recipients given an adoptive transfer of splenocytes from the primary recipients with siCD40/SPG accepted a heart graft from donor-type B10, but not third-party Balb/c mice. In conclusion, the treatment with siCD40/SPG targeting DCs could generate antigen-specific Tregs, resulting in the permanent acceptance of mouse cardiac allografts. These findings have important implications for clarifying the mechanism underlying the induction of tolerance in DCs, and also highlight the potential of immunomodulation and the feasibility of siRNA-based clinical therapy in the transplantation field.

14 CFR § 1261.414 - Compromise of claims.

Code of Federal Regulations, 2014 CFR

2014-01-01

... the Government's ability to enforce collection. The compromise should be for an amount which bears a... the settlement of small claims, but normally will not carry great weight in the settlement of large...

Compromise, Well-Being, and Action Behaviors in Young Adults in Career Transition

ERIC Educational Resources Information Center

Creed, Peter A.; Blume, Kellie

2013-01-01

The authors surveyed 186 first-year university students and assessed their level of career compromise associated with making the transition to university. Compromise was operationalized as the discrepancy between the job characteristics of ideal and expected occupations. The authors also assessed career well-being (satisfaction, distress), action…

22 CFR 213.25 - Standards for compromise.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT CLAIMS COLLECTION Compromise of Debts § 213.25... debt within a reasonable time, or the debtor refuses to pay the claim in full and the Government does... applicable exemptions available to the debtor under State and Federal law in determining the Government's...

22 CFR 213.25 - Standards for compromise.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT CLAIMS COLLECTION Compromise of Debts § 213.25... debt within a reasonable time, or the debtor refuses to pay the claim in full and the Government does... applicable exemptions available to the debtor under State and Federal law in determining the Government's...

22 CFR 213.25 - Standards for compromise.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT CLAIMS COLLECTION Compromise of Debts § 213.25... debt within a reasonable time, or the debtor refuses to pay the claim in full and the Government does... applicable exemptions available to the debtor under State and Federal law in determining the Government's...

22 CFR 213.25 - Standards for compromise.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT CLAIMS COLLECTION Compromise of Debts § 213.25... debt within a reasonable time, or the debtor refuses to pay the claim in full and the Government does... applicable exemptions available to the debtor under State and Federal law in determining the Government's...

22 CFR 213.25 - Standards for compromise.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT CLAIMS COLLECTION Compromise of Debts § 213.25... debt within a reasonable time, or the debtor refuses to pay the claim in full and the Government does... applicable exemptions available to the debtor under State and Federal law in determining the Government's...

Factors influencing treatment decision-making for maintaining or extracting compromised teeth.

PubMed

Lang-Hua, Bich Hue; McGrath, Colman P J; Lo, Edward C M; Lang, Niklaus P

2014-01-01

To evaluate treatment decision-making with respect to maintaining periodontally compromised teeth among dentists with or without postgraduate qualifications in implant dentistry. A series of patient scenarios with varying degrees of periodontal disease levels was presented to dental practitioners. Practitioners' decision-making outcome was determined, and intention to retain the compromised teeth was analyzed in bivariate and regression analyses (accounting for postgraduate implant training, gender, years in dental practice, and implant placement experience). This study involved 30 dental practitioners with postgraduate implant qualifications (GDPP), 33 dental practitioners without postgraduate implant qualifications (GDP), and 27 practitioners undergoing training for postgraduate implant qualifications (GDPT). Variations in treatment decision-making were evident between the three groups. Differences in treatment approaches to retaining compromised teeth were apparent. Furthermore, variations in rehabilitation of extracted scenarios existed in terms of use of implant and number of implants need for rehabilitation. Accounting for dentist and practice factors in regression analyses, GDPP/GDPT were three times as likely to retain periodontally compromised upper molar, with or without pain, compared to GDP (without pain OR 3.10, 95%CI 1.04, 10.62 P = 0.04; with pain OR 3.08, 95%CI 1.09, 8.14 P = 0.03). Variations in treatment decision-making with respect to retaining periodontally compromised teeth exist between dental practitioners with and those without postgraduate training in implant dentistry. Furthermore differences in management approaches in how they would retain the teeth or rehabilitate the dental arch were apparent. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

22 CFR 304.7 - Authority to adjust, determine, compromise, and settle claims.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 2 2011-04-01 2009-04-01 true Authority to adjust, determine, compromise, and settle claims. 304.7 Section 304.7 Foreign Relations PEACE CORPS CLAIMS AGAINST GOVERNMENT UNDER FEDERAL TORT CLAIMS ACT Procedures § 304.7 Authority to adjust, determine, compromise, and settle claims. The...

22 CFR 304.7 - Authority to adjust, determine, compromise, and settle claims.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 22 Foreign Relations 2 2014-04-01 2014-04-01 false Authority to adjust, determine, compromise, and settle claims. 304.7 Section 304.7 Foreign Relations PEACE CORPS CLAIMS AGAINST GOVERNMENT UNDER FEDERAL TORT CLAIMS ACT Procedures § 304.7 Authority to adjust, determine, compromise, and settle claims. The...

Fuzzy compromise: An effective way to solve hierarchical design problems

NASA Technical Reports Server (NTRS)

Allen, J. K.; Krishnamachari, R. S.; Masetta, J.; Pearce, D.; Rigby, D.; Mistree, F.

1990-01-01

In this paper, we present a method for modeling design problems using a compromise decision support problem (DSP) incorporating the principles embodied in fuzzy set theory. Specifically, the fuzzy compromise decision support problem is used to study hierarchical design problems. This approach has the advantage that although the system modeled has an element of uncertainty associated with it, the solution obtained is crisp and precise. The efficacy of incorporating fuzzy sets into the solution process is discussed in the context of results obtained for a portal frame.

Poor conditions of detention compromise ethical standards.

PubMed Central

Howitt, J

1995-01-01

The ethical standards of police surgeons are being compromised by conflict between obligations to their paymasters, the police authorities, and their responsibilities to their patients, when these patients are prisoners detained in unacceptable conditions and where even minimum standards of medical care and management are difficult to deliver. PMID:11644662

Ablation of the sphenopalatine ganglion does not attenuate the infarct reducing effect of vagus nerve stimulation

PubMed Central

Ay, Ilknur; Ay, Hakan

2013-01-01

Electrical stimulation of the cervical vagus nerve reduces infarct size by approximately 50% after cerebral ischemia in rats. The mechanism of ischemic protection by vagus nerve stimulation (VNS) is not known. In this study, we investigated whether the infarct reducing effect of VNS was mediated by activation of the parasympathetic vasodilator fibers that originate from the sphenopalatine ganglion (SPG) and innervate the anterior cerebral circulation. We examined the effects of electrical stimulation of the cervical vagus nerve in two groups of rats: one with and one without SPG ablation. Electrical stimulation was initiated 30 min after induction of ischemia, and lasted for 1h. Measurement of infarct size 24h later revealed that the volume of ischemic damage was smaller in those animals that received VNS treatment (41.32 ± 2.07% vs. 24.19 ± 2.62% of the contralateral hemispheric volume, n=6 in both; p<0.05). SPG ablation did not abolish this effect; the reduction in infarct volume following VNS was 58% in SPG-damaged animals, 41% in SPG-intact animals (p>0.05). In both SPG-intact and SPG-damaged animals VNS treatment resulted in better motor outcome (p<0.05 vs. corresponding controls for both). Our findings show that VNS can protect the brain against acute ischemic injury, and that this effect is not mediated by SPG projections. PMID:23273773

Ribulose-1,5-bis-phosphate carboxylase/oxygenase accumulation factor1 is required for holoenzyme assembly in maize.

PubMed

Feiz, Leila; Williams-Carrier, Rosalind; Wostrikoff, Katia; Belcher, Susan; Barkan, Alice; Stern, David B

2012-08-01

Most life is ultimately sustained by photosynthesis and its rate-limiting carbon fixing enzyme, ribulose-1,5-bis-phosphate carboxylase/oxygenase (Rubisco). Although the structurally comparable cyanobacterial Rubisco is amenable to in vitro assembly, the higher plant enzyme has been refractory to such manipulation due to poor understanding of its assembly pathway. Here, we report the identification of a chloroplast protein required for Rubisco accumulation in maize (Zea mays), RUBISCO ACCUMULATION FACTOR1 (RAF1), which lacks any characterized functional domains. Maize lines lacking RAF1 due to Mutator transposon insertions are Rubisco deficient and seedling lethal. Analysis of transcripts and proteins showed that Rubisco large subunit synthesis in raf1 plants is not compromised; however, newly synthesized Rubisco large subunit appears in a high molecular weight form whose accumulation requires a specific chaperonin 60 isoform. Gel filtration analysis and blue native gels showed that endogenous and recombinant RAF1 are trimeric; however, following in vivo cross-linking, RAF1 copurifies with Rubisco large subunit, suggesting that they interact weakly or transiently. RAF1 is predominantly expressed in bundle sheath chloroplasts, consistent with a Rubisco accumulation function. Our results support the hypothesis that RAF1 acts during Rubisco assembly by releasing and/or sequestering the large subunit from chaperonins early in the assembly process.

15 CFR 19.7 - When will Commerce entities compromise a Commerce debt?

Code of Federal Regulations, 2012 CFR

2012-01-01

... 15 Commerce and Foreign Trade 1 2012-01-01 2012-01-01 false When will Commerce entities compromise a Commerce debt? 19.7 Section 19.7 Commerce and Foreign Trade Office of the Secretary of Commerce COMMERCE DEBT COLLECTION Procedures To Collect Commerce Debts § 19.7 When will Commerce entities compromise...

15 CFR 19.7 - When will Commerce entities compromise a Commerce debt?

Code of Federal Regulations, 2011 CFR

2011-01-01

... 15 Commerce and Foreign Trade 1 2011-01-01 2011-01-01 false When will Commerce entities compromise a Commerce debt? 19.7 Section 19.7 Commerce and Foreign Trade Office of the Secretary of Commerce COMMERCE DEBT COLLECTION Procedures To Collect Commerce Debts § 19.7 When will Commerce entities compromise...

15 CFR 19.7 - When will Commerce entities compromise a Commerce debt?

Code of Federal Regulations, 2010 CFR

2010-01-01

... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false When will Commerce entities compromise a Commerce debt? 19.7 Section 19.7 Commerce and Foreign Trade Office of the Secretary of Commerce COMMERCE DEBT COLLECTION Procedures To Collect Commerce Debts § 19.7 When will Commerce entities compromise...

15 CFR 19.7 - When will Commerce entities compromise a Commerce debt?

Code of Federal Regulations, 2013 CFR

2013-01-01

... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 false When will Commerce entities compromise a Commerce debt? 19.7 Section 19.7 Commerce and Foreign Trade Office of the Secretary of Commerce COMMERCE DEBT COLLECTION Procedures To Collect Commerce Debts § 19.7 When will Commerce entities compromise...

15 CFR 19.7 - When will Commerce entities compromise a Commerce debt?

Code of Federal Regulations, 2014 CFR

2014-01-01

... 15 Commerce and Foreign Trade 1 2014-01-01 2014-01-01 false When will Commerce entities compromise a Commerce debt? 19.7 Section 19.7 Commerce and Foreign Trade Office of the Secretary of Commerce COMMERCE DEBT COLLECTION Procedures To Collect Commerce Debts § 19.7 When will Commerce entities compromise...

In vitro models to estimate drug penetration through the compromised stratum corneum barrier.

PubMed

Engesland, André; Škalko-Basnet, Nataša; Flaten, Gøril Eide

2016-11-01

The phospholipid vesicle-based permeation assay (PVPA) is a recently established in vitro stratum corneum model to estimate the permeability of intact and healthy skin. The aim here was to further evolve this model to mimic the stratum corneum in a compromised skin barrier by reducing the barrier functions in a controlled manner. To mimic compromised skin barriers, PVPA barriers were prepared with explicitly defined reduced barrier function and compared with literature data from both human and animal skin with compromised barrier properties. Caffeine, diclofenac sodium, chloramphenicol and the hydrophilic marker calcein were tested to compare the PVPA models with established models. The established PVPA models mimicking the stratum corneum in healthy skin showed good correlation with biological barriers by ranking drugs similar to those ranked by the pig ear skin model and were comparable to literature data on permeation through healthy human skin. The PVPA models provided reproducible and consistent results with a distinction between the barriers mimicking compromised and healthy skin. The trends in increasing drug permeation with an increasing degree of compromised barriers for the model drugs were similar to the literature data from other in vivo and in vitro models. The PVPA models have the potential to provide permeation predictions when investigating drugs or cosmeceuticals intended for various compromised skin conditions and can thus possibly reduce the time and cost of testing as well as the use of animal testing in the early development of drug candidates, drugs and cosmeceuticals.

The targeted delivery of the c-Src peptide complexed with schizophyllan to macrophages inhibits polymicrobial sepsis and ulcerative colitis in mice.

PubMed

Kim, Ye-Ram; Hwang, Jangsun; Koh, Hyun-Jung; Jang, Kiseok; Lee, Jong-Dae; Choi, Jonghoon; Yang, Chul-Su

2016-05-01

Hyper-inflammatory responses triggered by intracellular reactive oxygen species (ROS) can lead to a variety of diseases, including sepsis and colitis. However, the regulators of this process remain poorly defined. In this study, we demonstrate that c-Src is a negative regulator of cellular ROS generation through its binding to p47phox. This molecule also competitively inhibits the NADPH oxidase complex (NOX) assembly. Furthermore, we developed the schizophyllan (SPG)-c-Src SH3 peptide, which is a β-1,3-glucan conjugated c-Src SH3-derived peptide composed of amino acids 91-108 and 121-140 of c-Src. The SPG-SH3 peptide has a significant therapeutic effect on mouse ROS-mediated inflammatory disease models, cecal-ligation-puncture-induced sepsis, and dextran sodium sulfate-induced colitis. It does so by inhibiting the NOX subunit assembly and proinflammatory mediator production. Therefore, the SPG-SH3 peptide is a potential therapeutic agent for ROS-associated lethal inflammatory diseases. Our findings provide clues for the development of new peptide-base drugs that will target p47phox. Copyright © 2016 Elsevier Ltd. All rights reserved.

Developments in cognitive neuroscience: I. Conflict, compromise, and connectionism.

PubMed

Westen, Drew; Gabbard, Glen O

2002-01-01

The strength of psychoanalysis has always been its understanding of affect and motivation. Contemporary developments in cognitive neuroscience offer possibilities of integrating sophisticated, experimentally informed models of thought and memory with an understanding of dynamically and clinically meaningful processes. Aspects of contemporary theory and research in cognitive neuroscience are integrated with psychoanalytic theory and technique, particularly theories of conflict and compromise. After a description of evolving models of the mind in cognitive neuroscience, several issues relevant to psychoanalytic theory and practice are addressed. These include the nature of representations, the interaction of cognition and affect, and the mechanisms by which the mind unconsciously forges compromise solutions that best fit multiple cognitive and affective-motivational constraints.

Roles of Melatonin in Fetal Programming in Compromised Pregnancies

PubMed Central

Chen, Yu-Chieh; Sheen, Jiunn-Ming; Tiao, Miao-Meng; Tain, You-Lin; Huang, Li-Tung

2013-01-01

Compromised pregnancies such as those associated with gestational diabetes mellitus, intrauterine growth retardation, preeclampsia, maternal undernutrition, and maternal stress may negatively affect fetal development. Such pregnancies may induce oxidative stress to the fetus and alter fetal development through the epigenetic process that may affect development at a later stage. Melatonin is an oxidant scavenger that reverses oxidative stress during the prenatal period. Moreover, the role of melatonin in epigenetic modifications in the field of developmental programming has been studied extensively. Here, we describe the physiological function of melatonin in pregnancy and discuss the roles of melatonin in fetal programming in compromised pregnancies, focusing on its involvement in redox and epigenetic mechanisms. PMID:23466884

Compromises along the Way: Balancing Speed To Market with Sustainability while Delivering Knowledge Management Services.

ERIC Educational Resources Information Center

Heyman, Martha K.

This paper will discuss some of the compromises, and the path to those compromises, that must be made while implementing a successful knowledge management program within a for-profit enterprise. Specifically the following compromises are addressed: (1) manage knowledge where it is created, but do that within a global system; (2) no single scope…

36 CFR 1011.7 - When will the Presidio Trust compromise a debt?

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false When will the Presidio Trust... Procedures To Collect Presidio Trust Debts § 1011.7 When will the Presidio Trust compromise a debt? (a... debt owed to the Presidio Trust that is not recovered as the result of a compromise will be reported to...

Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia

PubMed Central

Denton, Kyle R.; Lei, Ling; Grenier, Jeremy; Rodionov, Vladimir; Blackstone, Craig; Li, Xue-Jun

2013-01-01

Human neuronal models of hereditary spastic paraplegias (HSP) that recapitulate disease-specific axonal pathology hold the key to understanding why certain axons degenerate in patients and to developing therapies. SPG4, the most common form of HSP, is caused by autosomal dominant mutations in the SPAST gene, which encodes the microtubule-severing ATPase spastin. Here, we have generated a human neuronal model of SPG4 by establishing induced pluripotent stem cells (iPSCs) from an SPG4 patient and differentiating these cells into telencephalic glutamatergic neurons. The SPG4 neurons displayed a significant increase in axonal swellings, which stained strongly for mitochondria and tau, indicating the accumulation of axonal transport cargoes. In addition, mitochondrial transport was decreased in SPG4 neurons, revealing that these patient iPSC-derived neurons recapitulate disease-specific axonal phenotypes. Interestingly, spastin protein levels were significantly decreased in SPG4 neurons, supporting a haploinsufficiency mechanism. Furthermore, cortical neurons derived from spastin-knockdown human embryonic stem cells (hESCs) exhibited similar axonal swellings, confirming that the axonal defects can be caused by loss of spastin function. These spastin-knockdown hESCs serve as an additional model for studying HSP. Finally, levels of stabilized acetylated-tubulin were significantly increased in SPG4 neurons. Vinblastine, a microtubule-destabilizing drug, rescued this axonal swelling phenotype in neurons derived from both SPG4 iPSCs and spastin-knockdown hESCs. Thus, this study demonstrates the successful establishment of human pluripotent stem cell-based neuronal models of SPG4, which will be valuable for dissecting the pathogenic cellular mechanisms and screening compounds to rescue the axonal degeneration in HSP. PMID:24123785

Differences in sensitivity of murine spermatogonia and somatic cells in vivo to sister-chromatid exchange induction by nitrosoureas.

PubMed

Morales-Ramírez, P; Cruz-Vallejo, V; Rodríguez-Reyes, R

2001-07-01

Previously published data indicate that spermatogonia (SPG) are less sensitive to a sister-chromatid exchange (SCE) induction for different mutagens. In an earlier study, we have observed that bromodeoxyuridine (BrdU) substituted murine SPG are less sensitive to SCE induction by gamma ray in cells, than bone marrow (BM) and salivary gland (SG) cells in vivo. This was interpreted to mean that SPG are more efficient in DNA repair or are less prone to SCE induction. That the lower induction of SCE could be due to a reduced accessibility of mutagens to the SPG by virtue of a physiological barrier, was discarded by using gamma radiation. The aim of the present study was to establish whether or not there are differences in SCE induction by nitrosoureas among SPG, SG and BM cells with BrdU substituted or unsubstituted DNA. It was observed that SCE induction by methylnitrosourea (MNU) or by ethylnitrosourea (ENU) in SPG was, respectively, five and two times lower than in SG, and ten and three times lower than in BM. In SPG after BrdU incorporation, there was no increase in efficiency of SCE induction; in fact, there was even a slight decrease by exposure to MNU or ENU. BM and SG cells showed an increased efficiency in SCE induction after BrdU incorporation. This implies that SPG are also less sensitive to SCE induction by nitrosoureas, which cause a different kind of damage from previously assayed mutagens.

45 CFR 30.4 - Compromise, waiver, or disposition under other statutes not precluded.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Compromise, waiver, or disposition under other statutes not precluded. 30.4 Section 30.4 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION CLAIMS COLLECTION General Provisions § 30.4 Compromise, waiver, or disposition under other...

Political Compromise Makes the World Go 'Round

ERIC Educational Resources Information Center

Everett, Diana

2007-01-01

Compromise in any context is often hard to accept. It feels like a person is giving up on his or her ideals. This is especially true in dealing with politics. Legislative and congressional bills can be written with the highest of ideals in mind. By the time the bill progresses through committees and the floor debate process, it can look like a…

Tragic choices and moral compromise: the ethics of allocating kidneys for transplantation.

PubMed

Hoffmaster, Barry; Hooker, Cliff

2013-09-01

For almost a decade, the Kidney Transplantation Committee of the United Network for Organ Sharing has been striving to revise its approach to allocating kidneys from deceased donors for transplantation. Two fundamental values, equality and efficiency, are central to distributing this scarce resource. The prevailing approach gives primacy to equality in the temporal form of first-come, first-served, whereas the motivation for a new approach is to redeem efficiency by increasing the length of survival of transplanted kidneys and their recipients. But decision making about a better way of allocating kidneys flounders because it is constrained by the amorphous notion of "balancing" values. This article develops a more fitting, productive approach to resolving the conflict between equality and efficiency by embedding the notion of compromise in the analysis of a tragic choice provided by Guido Calabresi and Philip Bobbitt. For Calabresi and Bobbitt, the goals of public policy with respect to tragic choices are to limit tragedy and to deal with the irreducible minimum of tragedy in the least offensive way. Satisfying the value of efficiency limits tragedy, and satisfying the value of equality deals with the irreducible minimum of tragedy in the least offensive way. But both values cannot be completely satisfied simultaneously. Compromise is occasioned when not all the several obligations that exist in a situation can be met and when neglecting some obligations entirely in order to fulfill others entirely is improper. Compromise is amalgamated with the notion of a tragic choice and then used to assess proposals for revising the allocation of kidneys considered by the Kidney Transplantation Committee. Compromise takes two forms in allocating kidneys: it occurs within particular approaches to allocating kidneys because neither equality nor efficiency can be fully satisfied, and it occurs over the course of sequential approaches to allocating kidneys that cycle between

32 CFR 2400.33 - Loss or possible compromise.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 6 2010-07-01 2010-07-01 false Loss or possible compromise. 2400.33 Section 2400.33 National Defense Other Regulations Relating to National Defense OFFICE OF SCIENCE AND TECHNOLOGY POLICY REGULATIONS TO IMPLEMENT E.O. 12356; OFFICE OF SCIENCE AND TECHNOLOGY POLICY INFORMATION...

32 CFR 2400.33 - Loss or possible compromise.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 6 2014-07-01 2014-07-01 false Loss or possible compromise. 2400.33 Section 2400.33 National Defense Other Regulations Relating to National Defense OFFICE OF SCIENCE AND TECHNOLOGY POLICY REGULATIONS TO IMPLEMENT E.O. 12356; OFFICE OF SCIENCE AND TECHNOLOGY POLICY INFORMATION...

32 CFR 2400.33 - Loss or possible compromise.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 6 2012-07-01 2012-07-01 false Loss or possible compromise. 2400.33 Section 2400.33 National Defense Other Regulations Relating to National Defense OFFICE OF SCIENCE AND TECHNOLOGY POLICY REGULATIONS TO IMPLEMENT E.O. 12356; OFFICE OF SCIENCE AND TECHNOLOGY POLICY INFORMATION...

32 CFR 2400.33 - Loss or possible compromise.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 6 2011-07-01 2011-07-01 false Loss or possible compromise. 2400.33 Section 2400.33 National Defense Other Regulations Relating to National Defense OFFICE OF SCIENCE AND TECHNOLOGY POLICY REGULATIONS TO IMPLEMENT E.O. 12356; OFFICE OF SCIENCE AND TECHNOLOGY POLICY INFORMATION...

32 CFR 2400.33 - Loss or possible compromise.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 6 2013-07-01 2013-07-01 false Loss or possible compromise. 2400.33 Section 2400.33 National Defense Other Regulations Relating to National Defense OFFICE OF SCIENCE AND TECHNOLOGY POLICY REGULATIONS TO IMPLEMENT E.O. 12356; OFFICE OF SCIENCE AND TECHNOLOGY POLICY INFORMATION...

Specific cross-reactivity of antibodies raised against two major stress proteins, stress 70 and chaperonin 60, in diverse species

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

Sanders, B.M.; Martin, L.S.; Nakagawa, P.A.

1994-08-01

Immunoblot analysis using several antibodies raised against two major families of stress proteins, stress 70 and chaperonin 60 (cpn60), which are highly conserved in mammals, was carried out in diverse species often used in environmental research, including molluscs, annelids, crustaceans, echinoderms, and fish. The study revealed surprisingly different patterns of antibody cross-reactivity among species. The monoclonal anti-stress 70 antibody (mAb) C92 was the least cross-reactive for all species tested. The mAbs anti-stress 70 N27, BRM-22, and 3a3 were more broadly cross-reactive, but their binding specifities to stress 70 isoforms in the diverse species tested did not correlate with one anothermore » or follow taxonomic lines. The polyclonal anti-stress 70 antibody reacted to proteins in the 70 to 74 kDa range in all fish examined and in most invertebrates. When a polyclonal antibody (pAb) raised against cpn60 from a moth was used as a probe, specific binding was observed with proteins in the 60 to 64 kDa range in all fish examined and in most invertebrates. However, the size and number of isoforms that reacted with the pAb were species specific. These data suggest that these two major stress protein families are less highly conserved in invertebrates and fish than in mammals. Therefore, to minimize misinterpretation when using antibodies in heterologous assays with species in which the stress response has not been well characterized, it is important to determine which isoforms of stress 70 react with a particular antibody and to take into account the differential regulation of each member of this multigene family.« less

The "booty call": a compromise between men's and women's ideal mating strategies.

PubMed

Jonason, Peter K; Li, Norman P; Cason, Margaret J

2009-01-01

Traditionally, research on romantic and sexual relationships has focused on one-night stands and monogamous pairs. However, as the result of men and women pursuing their ideal relationship types, various compromise relationships may emerge. One such compromise is explored here: the "booty call." The results of an act-nomination and frequency study of college students provided an initial definition and exploration of this type of relationship. Booty calls tend to utilize various communication mediums to facilitate sexual contact among friends who, for men, may represent low-investment, attractive sexual partners and, for women, may represent attractive test-mates. The relationship is discussed as a compromise between men's and women's ideal mating strategies that allows men greater sexual access and women an ongoing opportunity to evaluate potential long-term mates.

Compromise Approach-Based Genetic Algorithm for Constrained Multiobjective Portfolio Selection Model

NASA Astrophysics Data System (ADS)

Li, Jun

In this paper, fuzzy set theory is incorporated into a multiobjective portfolio selection model for investors’ taking into three criteria: return, risk and liquidity. The cardinality constraint, the buy-in threshold constraint and the round-lots constraints are considered in the proposed model. To overcome the difficulty of evaluation a large set of efficient solutions and selection of the best one on non-dominated surface, a compromise approach-based genetic algorithm is presented to obtain a compromised solution for the proposed constrained multiobjective portfolio selection model.

Poster - 52: Smoothing constraints in Modulated Photon Radiotherapy (XMRT) fluence map optimization

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

McGeachy, Philip; Villarreal-Barajas, Jose Eduardo

Purpose: Modulated Photon Radiotherapy (XMRT), which simultaneously optimizes photon beamlet energy (6 and 18 MV) and fluence, has recently shown dosimetric improvement in comparison to conventional IMRT. That said, the degree of smoothness of resulting fluence maps (FMs) has yet to be investigated and could impact the deliverability of XMRT. This study looks at investigating FM smoothness and imposing smoothing constraint in the fluence map optimization. Methods: Smoothing constraints were modeled in the XMRT algorithm with the sum of positive gradient (SPG) technique. XMRT solutions, with and without SPG constraints, were generated for a clinical prostate scan using standard dosimetricmore » prescriptions, constraints, and a seven coplanar beam arrangement. The smoothness, with and without SPG constraints, was assessed by looking at the absolute and relative maximum SPG scores for each fluence map. Dose volume histograms were utilized when evaluating impact on the dose distribution. Results: Imposing SPG constraints reduced the absolute and relative maximum SPG values by factors of up to 5 and 2, respectively, when compared with their non-SPG constrained counterparts. This leads to a more seamless conversion of FMS to their respective MLC sequences. This improved smoothness resulted in an increase to organ at risk (OAR) dose, however the increase is not clinically significant. Conclusions: For a clinical prostate case, there was a noticeable improvement in the smoothness of the XMRT FMs when SPG constraints were applied with a minor increase in dose to OARs. This increase in OAR dose is not clinically meaningful.« less

5 CFR 1215.32 - Compromise, suspension and termination.

Code of Federal Regulations, 2010 CFR

2010-01-01

... PROCEDURES DEBT MANAGEMENT Claims Collection § 1215.32 Compromise, suspension and termination. (a) The... outstanding principal is not greater than $20,000. MSPB procedures for writing off outstanding accounts are... debts where the outstanding principal is greater than $20,000 only with the approval of, or by referral...

Polyploidization of glia in neural development links tissue growth to blood-brain barrier integrity.

PubMed

Unhavaithaya, Yingdee; Orr-Weaver, Terry L

2012-01-01

Proper development requires coordination in growth of the cell types composing an organ. Many plant and animal cells are polyploid, but how these polyploid tissues contribute to organ growth is not well understood. We found the Drosophila melanogaster subperineurial glia (SPG) to be polyploid, and ploidy is coordinated with brain mass. Inhibition of SPG polyploidy caused rupture of the septate junctions necessary for the blood-brain barrier. Thus, the increased SPG cell size resulting from polyploidization is required to maintain the SPG envelope surrounding the growing brain. Polyploidization likely is a conserved strategy to coordinate tissue growth during organogenesis, with potential vertebrate examples.

Chaperones and protein folding in the archaea.

PubMed

Large, Andrew T; Goldberg, Martin D; Lund, Peter A

2009-02-01

A survey of archaeal genomes for the presence of homologues of bacterial and eukaryotic chaperones reveals several interesting features. All archaea contain chaperonins, also known as Hsp60s (where Hsp is heat-shock protein). These are more similar to the type II chaperonins found in the eukaryotic cytosol than to the type I chaperonins found in bacteria, mitochondria and chloroplasts, although some archaea also contain type I chaperonin homologues, presumably acquired by horizontal gene transfer. Most archaea contain several genes for these proteins. Our studies on the type II chaperonins of the genetically tractable archaeon Haloferax volcanii have shown that only one of the three genes has to be present for the organisms to grow, but that there is some evidence for functional specialization between the different chaperonin proteins. All archaea also possess genes for prefoldin proteins and for small heat-shock proteins, but they generally lack genes for Hsp90 and Hsp100 homologues. Genes for Hsp70 (DnaK) and Hsp40 (DnaJ) homologues are only found in a subset of archaea. Thus chaperone-assisted protein folding in archaea is likely to display some unique features when compared with that in eukaryotes and bacteria, and there may be important differences in the process between euryarchaea and crenarchaea.

Identifying genetic relatives without compromising privacy

PubMed Central

He, Dan; Furlotte, Nicholas A.; Hormozdiari, Farhad; Joo, Jong Wha J.; Wadia, Akshay; Ostrovsky, Rafail; Sahai, Amit; Eskin, Eleazar

2014-01-01

The development of high-throughput genomic technologies has impacted many areas of genetic research. While many applications of these technologies focus on the discovery of genes involved in disease from population samples, applications of genomic technologies to an individual’s genome or personal genomics have recently gained much interest. One such application is the identification of relatives from genetic data. In this application, genetic information from a set of individuals is collected in a database, and each pair of individuals is compared in order to identify genetic relatives. An inherent issue that arises in the identification of relatives is privacy. In this article, we propose a method for identifying genetic relatives without compromising privacy by taking advantage of novel cryptographic techniques customized for secure and private comparison of genetic information. We demonstrate the utility of these techniques by allowing a pair of individuals to discover whether or not they are related without compromising their genetic information or revealing it to a third party. The idea is that individuals only share enough special-purpose cryptographically protected information with each other to identify whether or not they are relatives, but not enough to expose any information about their genomes. We show in HapMap and 1000 Genomes data that our method can recover first- and second-order genetic relationships and, through simulations, show that our method can identify relationships as distant as third cousins while preserving privacy. PMID:24614977

Identifying genetic relatives without compromising privacy.

PubMed

He, Dan; Furlotte, Nicholas A; Hormozdiari, Farhad; Joo, Jong Wha J; Wadia, Akshay; Ostrovsky, Rafail; Sahai, Amit; Eskin, Eleazar

2014-04-01

The development of high-throughput genomic technologies has impacted many areas of genetic research. While many applications of these technologies focus on the discovery of genes involved in disease from population samples, applications of genomic technologies to an individual's genome or personal genomics have recently gained much interest. One such application is the identification of relatives from genetic data. In this application, genetic information from a set of individuals is collected in a database, and each pair of individuals is compared in order to identify genetic relatives. An inherent issue that arises in the identification of relatives is privacy. In this article, we propose a method for identifying genetic relatives without compromising privacy by taking advantage of novel cryptographic techniques customized for secure and private comparison of genetic information. We demonstrate the utility of these techniques by allowing a pair of individuals to discover whether or not they are related without compromising their genetic information or revealing it to a third party. The idea is that individuals only share enough special-purpose cryptographically protected information with each other to identify whether or not they are relatives, but not enough to expose any information about their genomes. We show in HapMap and 1000 Genomes data that our method can recover first- and second-order genetic relationships and, through simulations, show that our method can identify relationships as distant as third cousins while preserving privacy.

Cyber indicators of compromise: a domain ontology for security information and event management

DTIC Science & Technology

2017-03-01

COMPROMISE: A DOMAIN ONTOLOGY FOR SECURITY INFORMATION AND EVENT MANAGEMENT by Marsha D. Rowell March 2017 Thesis Co-Advisors: J. D...to automate this work is Security Information and Event Management (SIEM). In short, SIEM technology works by aggregating log information , and then...Distribution is unlimited. CYBER INDICATORS OF COMPROMISE: A DOMAIN ONTOLOGY FOR SECURITY INFORMATION AND EVENT MANAGEMENT Marsha D. Rowell

Ribulose-1,5-Bis-Phosphate Carboxylase/Oxygenase Accumulation Factor1 Is Required for Holoenzyme Assembly in Maize[C][W

PubMed Central

Feiz, Leila; Williams-Carrier, Rosalind; Wostrikoff, Katia; Belcher, Susan; Barkan, Alice; Stern, David B.

2012-01-01

Most life is ultimately sustained by photosynthesis and its rate-limiting carbon fixing enzyme, ribulose-1,5-bis-phosphate carboxylase/oxygenase (Rubisco). Although the structurally comparable cyanobacterial Rubisco is amenable to in vitro assembly, the higher plant enzyme has been refractory to such manipulation due to poor understanding of its assembly pathway. Here, we report the identification of a chloroplast protein required for Rubisco accumulation in maize (Zea mays), RUBISCO ACCUMULATION FACTOR1 (RAF1), which lacks any characterized functional domains. Maize lines lacking RAF1 due to Mutator transposon insertions are Rubisco deficient and seedling lethal. Analysis of transcripts and proteins showed that Rubisco large subunit synthesis in raf1 plants is not compromised; however, newly synthesized Rubisco large subunit appears in a high molecular weight form whose accumulation requires a specific chaperonin 60 isoform. Gel filtration analysis and blue native gels showed that endogenous and recombinant RAF1 are trimeric; however, following in vivo cross-linking, RAF1 copurifies with Rubisco large subunit, suggesting that they interact weakly or transiently. RAF1 is predominantly expressed in bundle sheath chloroplasts, consistent with a Rubisco accumulation function. Our results support the hypothesis that RAF1 acts during Rubisco assembly by releasing and/or sequestering the large subunit from chaperonins early in the assembly process. PMID:22942379

REEP1 Mutation Spectrum and Genotype/Phenotype Correlation in Hereditary Spastic Paraplegia Type 31

ERIC Educational Resources Information Center

Beetz, Christian; Schule, Rebecca; Deconinck, Tine; Tran-Viet, Khanh-Nhat; Zhu, Hui; Kremer, Berry P. H.; Frints, Suzanna G. M.; van Zelst-Stams, Wendy A. G.; Byrne, Paula; Otto, Susanne; Nygren, Anders O. H.; Baets, Jonathan; Smets, Katrien; Ceulemans, Berten; Dan, Bernard; Nagan, Narasimhan; Kassubek, Jan; Klimpe, Sven; Klopstock, Thomas; Stolze, Henning; Smeets, Hubert J. M.; Schrander-Stumpel, Constance T. R. M.; Hutchinson, Michael; van de Warrenburg, Bart P.; Braastad, Corey; Deufel, Thomas; Pericak-Vance, Margaret; Schols, Ludger; de Jonghe, Peter; Zuchner, Stephan

2008-01-01

Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for "REEP1" mutations and copy number variations. We identified 13 novel and 2 known "REEP1"…

Chaperonin containing T-complex polypeptide subunit eta is a potential marker of joint contracture: an experimental study in the rat.

PubMed

He, Ronghan; Wang, Zhe; Lu, Yunxiang; Huang, Junqi; Ren, Jianhua; Wang, Kun

2015-11-01

Joint contracture is a fibroproliferative disorder that restricts joint mobility, resulting in tissue degeneration and deformity. However, the etiology of joint contracture is still unknown. Chaperonin containing T-complex polypeptide subunit eta (CCT-eta) is reported to increase in fibrotic diseases. The purpose of this study was to investigate whether CCT-eta is implicated in joint contracture and to determine the role of CCT-eta in the progression of joint contracture by analyzing a rat model. We immobilized the left knee joint of rat by internal fixation for 8 weeks. The non-immobilized right leg served as a control. The range of motion (ROM) of the knee was investigated. Fibroblasts were obtained from the posterior joint capsule of the joints. The outcome was followed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, fibroblast migration assay, and collagen assay. The effect of CCT-eta on the functions of fibroblasts was observed by utilizing a short inhibitory RNA (siRNA) targeting CCT-eta. The ROM of the immobilized joints was significantly limited compared to the contralateral joints (p < 0.05). Fibroblasts derived from the contractive joints showed higher mRNA and protein expressions of CCT-eta in parallel with alpha-smooth muscle actin (α-SMA) compared to the cells from the contralateral knees (p < 0.05). siRNA-mediated downregulation of CCT-eta inhibited the expressions of both CCT-eta and α-SMA. Moreover, the reduction of CCT-eta also significantly decreased fibroblast functions such as cell mobility and collagen synthesis (all p < 0.05). Our findings indicate that CCT-eta appears to be a potential marker of joint contracture disease.

Molecular Diagnostic Tools for Detection and Differentiation of Phytoplasmas Based on Chaperonin-60 Reveal Differences in Host Plant Infection Patterns

PubMed Central

Dumonceaux, Tim J.; Green, Margaret; Hammond, Christine; Perez, Edel; Olivier, Chrystel

2014-01-01

Phytoplasmas (‘Candidatus Phytoplasma’ spp.) are insect-vectored bacteria that infect a wide variety of plants, including many agriculturally important species. The infections can cause devastating yield losses by inducing morphological changes that dramatically alter inflorescence development. Detection of phytoplasma infection typically utilizes sequences located within the 16S–23S rRNA-encoding locus, and these sequences are necessary for strain identification by currently accepted standards for phytoplasma classification. However, these methods can generate PCR products >1400 bp that are less divergent in sequence than protein-encoding genes, limiting strain resolution in certain cases. We describe a method for accessing the chaperonin-60 (cpn60) gene sequence from a diverse array of ‘Ca.Phytoplasma’ spp. Two degenerate primer sets were designed based on the known sequence diversity of cpn60 from ‘Ca.Phytoplasma’ spp. and used to amplify cpn60 gene fragments from various reference samples and infected plant tissues. Forty three cpn60 sequences were thereby determined. The cpn60 PCR-gel electrophoresis method was highly sensitive compared to 16S-23S-targeted PCR-gel electrophoresis. The topology of a phylogenetic tree generated using cpn60 sequences was congruent with that reported for 16S rRNA-encoding genes. The cpn60 sequences were used to design a hybridization array using oligonucleotide-coupled fluorescent microspheres, providing rapid diagnosis and typing of phytoplasma infections. The oligonucleotide-coupled fluorescent microsphere assay revealed samples that were infected simultaneously with two subtypes of phytoplasma. These tools were applied to show that two host plants, Brassica napus and Camelina sativa, displayed different phytoplasma infection patterns. PMID:25551224

Ferroptosis-inducing agents compromise in vitro human islet viability and function.

PubMed

Bruni, Antonio; Pepper, Andrew R; Pawlick, Rena L; Gala-Lopez, Boris; Gamble, Anissa F; Kin, Tatsuya; Seeberger, Karen; Korbutt, Gregory S; Bornstein, Stefan R; Linkermann, Andreas; Shapiro, A M James

2018-05-22

Human islet transplantation has been hampered by donor cell death associated with the islet preparation procedure before transplantation. Regulated necrosis pathways are biochemically and morphologically distinct from apoptosis. Recently, ferroptosis was identified as a non-apoptotic form of iron-dependent regulated necrosis implicated in various pathological conditions. Mediators of islet oxidative stress, including glutathione peroxidase-4 (GPX4), have been identified as inhibitors of ferroptosis, and mechanisms that affect GPX4 function can impact islet function and viability. Ferroptosis has not been investigated directly in human islets, and its relevance in islet transplantation remains unknown. Herein, we sought to determine whether in vitro human islet viability and function is compromised in the presence of two distinct ferroptosis-inducing agents (FIA), erastin or RSL3, and whether these effects could be rescued with ferroptosis inhibitors, ferrostatin-1 (Fer-1), or desferrioxamine (DFO). Viability, as assessed by lactate dehydrogenase (LDH) release, revealed significant death in erastin- and RSL3-treated islets, 20.3% ± 3.8 and 24.4% ± 2.5, 24 h post culture, respectively. These effects were ameliorated in islets pre-treated with Fer-1 or the iron chelator, desferrioxamine (DFO). Stimulation index, a marker of islet function revealed a significant reduction in function in erastin-treated islets (control 1.97 ± 0.13 vs. 50 μM erastin 1.32 ± 0.1) (p < 0.05). Fer-1 and DFO pre-treatment alone did not augment islet viability or function. Pre-treatment of islets with erastin or Fer-1 did not impact in vivo engraftment in an immunodeficient mouse transplant model. Our data reveal that islets are indeed susceptible to ferroptosis in vitro, and induction of this novel cell death modality leads to compromised islet function, which can be recoverable in the presence of the ferroptosis inhibitors. The in vivo impact of this pathway in

Functional characterization of recombinant prefoldin complexes from a hyperthermophilic archaeon, Thermococcus sp. strain KS-1.

PubMed

Iizuka, Ryo; Sugano, Yuri; Ide, Naoki; Ohtaki, Akashi; Yoshida, Takao; Fujiwara, Shinsuke; Imanaka, Tadayuki; Yohda, Masafumi

2008-03-28

Prefoldin is a heterohexameric molecular chaperone complex that is found in the eukaryotic cytosol and also in archaea. It captures a nonnative protein and subsequently delivers it to a group II chaperonin for proper folding. Archaeal prefoldin is a heterocomplex containing two alpha subunits and four beta subunits with the structure of a double beta-barrel assembly, with six long coiled coils protruding from it like a jellyfish with six tentacles. We have studied the protein folding mechanism of group II chaperonin using those of Thermococcus sp. strain KS-1 (T. KS-1) because they exhibit high protein folding activity in vitro. We have also demonstrated functional cooperation between T. KS-1 chaperonins and prefoldin from Pyrococcus horikoshii OT3. Recent genome analysis has shown that Thermococcus kodakaraensis KOD1 contains two pairs of prefoldin subunit genes, correlating with the existence of two different chaperonin subunits. In this study, we characterized four different recombinant prefoldin complexes composed of two pairs of prefoldin subunits (alpha1, alpha2, beta1, and beta2) from T. KS-1. All of them (alpha1-beta1, alpha2-beta1, alpha1-beta2, and alpha2-beta2) exist as alpha(2)beta(4) heterohexamers and can protect several proteins from forming aggregates with different activities. We have also compared the collaborative activity between the prefoldin complexes and the cognate chaperonins. Prefoldin complexes containing the beta1 subunit interacted with the chaperonins more strongly than those with the beta2 subunit. The results suggest that Thermococcus spp. express different prefoldins for different substrates or conditions as chaperonins.

Expression of messenger molecules and receptors in rat and human sphenopalatine ganglion indicating therapeutic targets.

PubMed

Steinberg, Anna; Frederiksen, Simona D; Blixt, Frank W; Warfvinge, Karin; Edvinsson, Lars

2016-12-01

Migraine and Cluster Headache (CH) are two primary headaches with severe disease burden. The disease expression and the mechanisms involved are poorly known. In some attacks of migraine and in most attacks of CH, there is a release of vasoactive intestinal peptide (VIP) originating from parasympathetic cranial ganglia such as the sphenopalatine ganglion (SPG). Patients suffering from these diseases are often deprived of effective drugs. The aim of the study was to examine the localization of the botulinum toxin receptor element synaptic vesicle glycoprotein 2A (SV-2A) and the vesicular docking protein synaptosomal-associated protein 25 (SNAP25) in human and rat SPG. Additionally the expression of the neurotransmitters pituitary adenylate cyclase activating polypeptide (PACAP-38), nitric oxide synthase (nNOS), VIP and 5-hydroxttryptamine subtype receptors (5-HT1B,1D,1F) were examined. SPG from adult male rats and from humans, the later removed at autopsy, were prepared for immunohistochemistry using specific antibodies against neurotransmitters, 5-HT1B,1D,1F receptors, and botulinum toxin receptor elements. We found that the selected neurotransmitters and 5-HT receptors were expressed in rat and human SPG. In addition, we found SV2-A and SNAP25 expression in both rat and human SPG. We report that all three 5-HT receptors studied occur in neurons and satellite glial cells (SGCs) of the SPG. 5-HT1B receptors were in addition found in the walls of intraganglionic blood vessels. Recent focus on the SPG has emphasized the role of parasympathetic mechanisms in the pathophysiology of mainly CH. The development of next generation's drugs and treatment of cranial parasympathetic symptoms, mediated through the SPG, can be modulated by treatment with BoNT-A and 5-HT receptor agonists.

De novo REEP2 missense mutation in pure hereditary spastic paraplegia.

PubMed

Roda, Ricardo H; Schindler, Alice B; Blackstone, Craig

2017-05-01

Alterations in proteins that regulate endoplasmic reticulum morphology are common causes of hereditary spastic paraplegia (SPG1-78, plus others). Mutations in the REEP1 gene that encodes an endoplasmic reticulum-shaping protein are well-known causes of SPG31, a common autosomal dominant spastic paraplegia. A closely-related gene, REEP2, is mutated in SPG72, with both autosomal and recessive inheritances. Here, we report a patient with a pure hereditary spastic paraplegia due to a de novo missense mutation (c.119T > G, p.Met40Arg) in REEP2 at a highly-conserved residue very close to another known pathogenic missense change. This represents only the second autosomal dominant SPG72 missense mutation reported.

Extrathyroidal Extension Is Associated with Compromised Survival in Patients with Thyroid Cancer.

PubMed

Youngwirth, Linda M; Adam, Mohamed A; Scheri, Randall P; Roman, Sanziana A; Sosa, Julie A

2017-05-01

Patients with thyroid cancer who have extrathyroidal extension (ETE) are considered to have more advanced tumors. However, data on the impact of ETE on patient outcomes remain limited. The purpose of this study was to evaluate the association between ETE and survival in patients with thyroid cancer. The National Cancer Database (1998-2012) was queried for all adult patients with differentiated thyroid cancer and medullary thyroid cancer. Patients were divided into three groups: no ETE (T1 and T2 tumors), minimal ETE (T3 tumors <4 cm), and extensive ETE (T4 tumors <4 cm). Patient demographic, clinical, and pathologic factors were evaluated for all patients. A Cox proportional hazards model was developed for each histology to identify factors associated with survival. In total, 241,118 patients with differentiated thyroid cancer met the inclusion criteria; 86.9% had no ETE, 9.1% minimal ETE, and 4.0% extensive ETE. Compared with patients with no ETE, patients with minimal and extensive ETE were more likely to have larger tumors (1.4 cm vs. 1.8 cm and 2.0 cm, respectively), lymphovascular invasion (8.6% vs. 28.0% and 35.1%, respectively), positive margins after thyroidectomy (6.1% vs. 35.2% and 45.9%, respectively), and regional lymph node metastases (32.5% vs. 67.0% and 74.6%, respectively; all p < 0.01). After adjustment, minimal ETE (hazard ratio [HR] = 1.13; p < 0.01) and extensive ETE (HR = 1.74; p < 0.01) were associated with compromised survival for patients with differentiated thyroid cancer. In total, 3415 patients with medullary thyroid cancer met the inclusion criteria; 87.9% had no ETE, 7.1% minimal ETE, and 5.0% extensive ETE. Compared with patients with no ETE, patients with minimal and extensive ETE were more likely to have larger tumors (1.7 cm vs. 2.2 cm and 2.2 cm, respectively), lymphovascular invasion (19.2% vs. 68.9% and 79.3%, respectively), positive margins after thyroidectomy (5.8% vs. 44.1% and 51

Gamma processing of Arabic bread for immune system-compromised cancer patients

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

Grecz, N.; Brannon, R.; Jaw, R.

Arabic bread prepared from local Saudi flour contained a total of up to 105/sup 4/ organisms per g. Most of these were bacterial spores that survived the baking process (1.3 x 10/sup 2/ to 3.5 x 10/sup 3/) and a small number of yeasts and molds (10 to 40 cells per g). The organisms in Arabic bread appear to be harmless to healthy individuals. However, for immune system-compromised cancer patients and bone marrow transplant recipients, it is prudent to irradiate the bread to reduce microbial contamination. The decimal reduction doses (10% survival) for the most radiation-resistant organisms (spore formers) inmore » bread were 0.11 to 0.15 Mrad. Accordingly, 0.6 Mrad was sufficient to reduce the number of spores in Arabic bread by a factor of 10,000, i.e., to <1/g. This treatment constitutes radiation pasteurization (radicidation), and to this extent, provides a margin of microbiological safety. Sensory evaluation by the nine-point hedonic scale showed no detectable loss of organoleptic quality of bread up to 0.6 Mrad, while irradiation to 2.5 Mrad induced unacceptable organoleptic changes.« less

Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait.

PubMed

Dubé, M P; Mlodzienski, M A; Kibar, Z; Farlow, M R; Ebers, G; Harper, P; Kolodny, E H; Rouleau, G A; Figlewicz, D A

1997-03-01

Hereditary spastic paraplegia (HSP) is a degenerative disorder of the motor system, defined by progressive weakness and spasticity of the lower limbs. HSP may be inherited as an autosomal dominant (AD), autosomal recessive, or an X-linked trait. AD HSP is genetically heterogeneous, and three loci have been identified so far: SPG3 maps to chromosome 14q, SPG4 to 2p, and SPG4a to 15q. We have undertaken linkage analysis with 21 uncomplicated AD families to the three AD HSP loci. We report significant linkage for three of our families to the SPG4 locus and exclude several families by multipoint linkage. We used linkage information from several different research teams to evaluate the statistical probability of linkage to the SPG4 locus for uncomplicated AD HSP families and established the critical LOD-score value necessary for confirmation of linkage to the SPG4 locus from Bayesian statistics. In addition, we calculated the empirical P-values for the LOD scores obtained with all families with computer simulation methods. Power to detect significant linkage, as well as type I error probabilities, were evaluated. This combined analytical approach permitted conclusive linkage analyses on small to medium-size families, under the restrictions of genetic heterogeneity.

Protrudin regulates endoplasmic reticulum morphology and function associated with the pathogenesis of hereditary spastic paraplegia.

PubMed

Hashimoto, Yutaka; Shirane, Michiko; Matsuzaki, Fumiko; Saita, Shotaro; Ohnishi, Takafumi; Nakayama, Keiichi I

2014-05-09

Protrudin is a membrane protein that regulates polarized vesicular trafficking in neurons. The protrudin gene (ZFYVE27) is mutated in a subset of individuals with hereditary spastic paraplegia (HSP), and protrudin is therefore also referred to as spastic paraplegia (SPG) 33. We have now generated mice that express a transgene for dual epitope-tagged protrudin under control of a neuron-specific promoter, and we have subjected highly purified protrudin-containing complexes isolated from the brain of these mice to proteomics analysis to identify proteins that associate with protrudin. Protrudin was found to interact with other HSP-related proteins including myelin proteolipid protein 1 (SPG2), atlastin-1 (SPG3A), REEP1 (SPG31), REEP5 (similar to REEP1), Kif5A (SPG10), Kif5B, Kif5C, and reticulon 1, 3, and 4 (similar to reticulon 2, SPG12). Membrane topology analysis indicated that one of three hydrophobic segments of protrudin forms a hydrophobic hairpin domain similar to those of other SPG proteins. Protrudin was found to localize predominantly to the tubular endoplasmic reticulum (ER), and forced expression of protrudin promoted the formation and stabilization of the tubular ER network. The protrudin(G191V) mutant, which has been identified in a subset of HSP patients, manifested an increased intracellular stability, and cells expressing this mutant showed an increased susceptibility to ER stress. Our results thus suggest that protrudin contributes to the regulation of ER morphology and function, and that its deregulation by mutation is a causative defect in HSP.

32 CFR 2001.48 - Loss, possible compromise or unauthorized disclosure.

Code of Federal Regulations, 2010 CFR

2010-07-01

... governments normally will not be advised of any security system vulnerabilities that contributed to the... INFORMATION SECURITY OVERSIGHT OFFICE, NATIONAL ARCHIVES AND RECORDS ADMINISTRATION CLASSIFIED NATIONAL SECURITY INFORMATION Safeguarding § 2001.48 Loss, possible compromise or unauthorized disclosure. (a...

Upper and lower limb functionality: are these compromised in obese children?

PubMed

Riddiford-Harland, Diane L; Steele, Julie R; Baur, Louise A

2006-01-01

The aim of this study was to investigate the effects of obesity on upper and lower limb functional strength and power in children, and to determine whether the ability to perform the daily activity of rising from a chair was compromised in obese children. It was hypothesised that obese children would display less upper and lower limb functionality compared to their non-obese counterparts. Upper and lower limb strength and power of 43 obese children (aged 8.4 +/- 0.5 y, BMI 24.1 +/- 2.3 kg/m(-2)) and 43 non-obese controls (aged 8.4 +/- 0.5 y, BMI 16.9 +/- 0.4 kg/m(-2)) were assessed using age-appropriate field-based tests: arm push/pull ability; basketball throw; vertical jump (VJ), and standing long jump (SLJ) performance. Functional lower limb strength was assessed for 13 obese and 13 non-obese children by quantifying their chair rising ability. Although obese children displayed significantly greater upper limb push (9.3 +/- 2.3 kg) and pull strength (9.6 +/- 3.0 kg) than their non-obese peers (push: 8.8 +/- 2.2 kg; pull: 8.8 +/- 2.3 kg; p < or = 0.05), their VJ (22.1 +/- 4.3 cm) and SLJ (94.6 +/- 12.8 cm) performance was significantly impaired relative to the non-obese children (VJ: 24.7 +/- 4.0 cm; SLJ: 101.7 +/- 14.0 cm; p < or = 0.05). Obese children spent significantly more time during all transfer phases of the chair rising task, compared to the non-obese children. Lower limb functionality in young obese children is impeded when they move their greater body mass against gravity.

Whatever It Takes: Health Compromising Behaviors in Female Athletes

ERIC Educational Resources Information Center

Waldron, Jennifer J.; Krane, Vikki

2005-01-01

The power and performance model of sport stresses a sport ethic of doing "whatever it takes" to win (Coakley, 2004). Uncritical acceptance of this model may lead to various health-compromising behaviors. Employing achievement goal theory, we examine why female athletes may adopt the power and performance approach. An ego motivational climate and a…

Stress Genes and Proteins in the Archaea

PubMed Central

Macario, Alberto J. L.; Lange, Marianne; Ahring, Birgitte K.; De Macario, Everly Conway

1999-01-01

The field covered in this review is new; the first sequence of a gene encoding the molecular chaperone Hsp70 and the first description of a chaperonin in the archaea were reported in 1991. These findings boosted research in other areas beyond the archaea that were directly relevant to bacteria and eukaryotes, for example, stress gene regulation, the structure-function relationship of the chaperonin complex, protein-based molecular phylogeny of organisms and eukaryotic-cell organelles, molecular biology and biochemistry of life in extreme environments, and stress tolerance at the cellular and molecular levels. In the last 8 years, archaeal stress genes and proteins belonging to the families Hsp70, Hsp60 (chaperonins), Hsp40(DnaJ), and small heat-shock proteins (sHsp) have been studied. The hsp70(dnaK), hsp40(dnaJ), and grpE genes (the chaperone machine) have been sequenced in seven, four, and two species, respectively, but their expression has been examined in detail only in the mesophilic methanogen Methanosarcina mazei S-6. The proteins possess markers typical of bacterial homologs but none of the signatures distinctive of eukaryotes. In contrast, gene expression and transcription initiation signals and factors are of the eucaryal type, which suggests a hybrid archaeal-bacterial complexion for the Hsp70 system. Another remarkable feature is that several archaeal species in different phylogenetic branches do not have the gene hsp70(dnaK), an evolutionary puzzle that raises the important question of what replaces the product of this gene, Hsp70(DnaK), in protein biogenesis and refolding and for stress resistance. Although archaea are prokaryotes like bacteria, their Hsp60 (chaperonin) family is of type (group) II, similar to that of the eukaryotic cytosol; however, unlike the latter, which has several different members, the archaeal chaperonin system usually includes only two (in some species one and in others possibly three) related subunits of ∼60 kDa. These

A libertarian perspective on the stem cell debate: compromising the uncompromisible.

PubMed

Block, Walter

2010-08-01

The present paper attempts to forge a compromise between those who maintain that stem cell research is out-and-out murder of young helpless human beings and those who favor this practice. The compromise is predicated upon the libertarian theory of private property rights. Starting out with the premise that not only the fetus but even the fertilized egg is a human being, with all rights thereto, it offers a competition between those who fertilize eggs for research and those who wish to adopt them. If and only if the former win this competition will they be allowed to use these very young human beings for the purposes they have constructed them. This is justified on grounds of avoiding child abuse.

Creating clones, kids & chimera: liberal democratic compromise at the crossroads.

PubMed

Adams, Nathan A

2004-01-01

The objective of this article is to find middle ground between the supporters and opponents of biotechnology by perpetuating the existing legal compromise pertaining to the complete range of health and welfare doctrines relevant to the biotechnological industry. The author aspires neither to add to nor detract from this liberal democratic consensus, but to preserve its constitutive balance between positivism and natural law and over-regulation and under-regulation in the hopes of stabilizing new political fault lines developing around the few biotechnological innovations already grabbing headlines. The most feasible solution is to extend the existing liberal democratic compromise with respect to equal protection, reproductive rights, the First Amendment, human subject experimentation, patent law, and parental rights. This includes banning or monopolizing certain biotechnologies and extending substantive special respect to the ex vivo living human embryo. Biotechnology must not be left to regulate itself.

Impaired Mitochondrial Dynamics Underlie Axonal Defects in Hereditary Spastic Paraplegias.

PubMed

Denton, Kyle; Mou, Yongchao; Xu, Chong-Chong; Shah, Dhruvi; Chang, Jaerak; Blackstone, Craig; Li, Xue-Jun

2018-05-02

Mechanisms by which long corticospinal axons degenerate in hereditary spastic paraplegia (HSP) are largely unknown. Here, we have generated induced pluripotent stem cells (iPSCs) from patients with two autosomal recessive forms of HSP, SPG15 and SPG48, which are caused by mutations in the ZFYVE26 and AP5Z1 genes encoding proteins in the same complex, the spastizin and AP5Z1 proteins, respectively. In patient iPSC-derived telencephalic glutamatergic and midbrain dopaminergic neurons, neurite number, length and branching are significantly reduced, recapitulating disease-specific phenotypes. We analyzed mitochondrial morphology and noted a significant reduction in both mitochondrial length and their densities within axons of these HSP neurons. Mitochondrial membrane potential was also decreased, confirming functional mitochondrial defects. Notably, mdivi-1, an inhibitor of the mitochondrial fission GTPase DRP1, rescues mitochondrial morphology defects and suppresses the impairment in neurite outgrowth and late-onset apoptosis in HSP neurons. Furthermore, knockdown of these HSP genes causes similar axonal defects, also mitigated by treatment with mdivi-1. Finally, neurite outgrowth defects in SPG15 and SPG48 cortical neurons can be rescued by knocking down DRP1 directly. Thus, abnormal mitochondrial morphology caused by an imbalance of mitochondrial fission and fusion underlies specific axonal defects and serves as a potential therapeutic target for SPG15 and SPG48.

Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish.

PubMed

Martin, Elodie; Yanicostas, Constantin; Rastetter, Agnès; Alavi Naini, Seyedeh Maryam; Maouedj, Alissia; Kabashi, Edor; Rivaud-Péchoux, Sophie; Brice, Alexis; Stevanin, Giovanni; Soussi-Yanicostas, Nadia

2012-12-01

Hereditary spastic paraplegias (HSPs) are rare neurological conditions caused by degeneration of the long axons of the cerebrospinal tracts, leading to locomotor impairment and additional neurological symptoms. There are more than 40 different causative genes, 24 of which have been identified, including SPG11 and SPG15 mutated in complex clinical forms. Since the vast majority of the causative mutations lead to loss of function of the corresponding proteins, we made use of morpholino-oligonucleotide (MO)-mediated gene knock-down to generate zebrafish models of both SPG11 and SPG15 and determine how invalidation of the causative genes (zspg11 and zspg15) during development might contribute to the disease. Micro-injection of MOs targeting each gene caused locomotor impairment and abnormal branching of spinal cord motor neurons at the neuromuscular junction. More severe phenotypes with abnormal tail developments were also seen. Moreover, partial depletion of both proteins at sub-phenotypic levels resulted in the same phenotypes, suggesting for the first time, in vivo, a genetic interaction between these genes. In conclusion, the zebrafish orthologues of the SPG11 and SPG15 genes are important for proper development of the axons of spinal motor neurons and likely act in a common pathway to promote their proper path finding towards the neuromuscular junction. Copyright © 2012 Elsevier Inc. All rights reserved.

CONCENTRATED AMBIENT PARTICULATE STUDIES IN HEALTHY AND COMPROMISED RODENTS

EPA Science Inventory

CONCENTRATED AMBIENT PARTICULATE STUDIES IN HEALTHY AND COMPROMISED RODENTS. WP Watkinson1, LB Wichers2, JP Nolan1, DW Winsett1, UP Kodavanti1, MCJ Schladweiler1, LC Walsh1, ER Lappi1, D Terrell1, R Slade1, AD Ledbetter1, and DL Costa1. 1USEPA, ORD/NHEERL/ETD/PTB, RTP, NC, US...

7 CFR 4290.1710 - Secretary's authority to collect or compromise claims.

Code of Federal Regulations, 2010 CFR

2010-01-01

... INVESTMENT COMPANY (âRBICâ) PROGRAM Financial Assistance for RBICs (Leverage) Miscellaneous § 4290.1710... consideration as he or she deems reasonable, collect or compromise all claims relating to obligations he or she...

Evidence for altered placental blood flow and vascularity in compromised pregnancies

PubMed Central

Reynolds, Lawrence P; Caton, Joel S; Redmer, Dale A; Grazul-Bilska, Anna T; Vonnahme, Kimberly A; Borowicz, Pawel P; Luther, Justin S; Wallace, Jacqueline M; Wu, Guoyao; Spencer, Thomas E

2006-01-01

The placenta is the organ that transports nutrients, respiratory gases, and wastes between the maternal and fetal systems. Consequently, placental blood flow and vascular development are essential components of normal placental function and are critical to fetal growth and development. Normal fetal growth and development are important to ensure optimum health of offspring throughout their subsequent life course. In numerous sheep models of compromised pregnancy, in which fetal or placental growth, or both, are impaired, utero-placental blood flows are reduced. In the models that have been evaluated, placental vascular development also is altered. Recent studies found that treatments designed to increase placental blood flow can ‘rescue’ fetal growth that was reduced due to low maternal dietary intake. Placental blood flow and vascular development are thus potential therapeutic targets in compromised pregnancies. PMID:16469783

Low body temperature does not compromise the treatment effect of alteplase.

PubMed

Lees, Jennifer S; Mishra, Nishant K; Saini, Monica; Lyden, Patrick D; Shuaib, Ashfaq

2011-09-01

Hypothermia is neuroprotective in ischemic stroke models. The influence of baseline body temperature on outcomes after thrombolytic therapy is unclear. We examined outcomes after alteplase treatment across baseline body temperature for patients with ischemic stroke in data held within the Virtual International Stroke Trials Archive (VISTA; 1998 to 2007). We collated data on age, baseline severity (National Institutes of Health Stroke Scale), and 90-day modified Rankin Scale score on patients presenting with acute ischemic stroke. We compared 90-day modified Rankin Scale score between thrombolyzed and nonthrombolyzed comparators across baseline body temperature. We report age and baseline National Institutes of Health Stroke Scale-adjusted Cochran-Mantel-Haenszel probability value and proportional OR with 95% CI for improved modified Rankin Scale distribution. We report temperature profiles over 72 hours after stroke by treatment group. Rankin data were available for 5586 patients with acute ischemic stroke in VISTA (1980 received alteplase). Age and baseline severity were similar (age 68.0±13.0 years versus 69.9±12.3 years, National Institutes of Health Stroke Scale 14.2±5.2 versus 13.0±5.6). Alteplase was associated with improved outcome (OR, 1.49; 95% CI, 1.35 to 1.65, P<0.0001). Alteplase treatment effect was not associated with baseline temperature (P=0.14). Point estimates showed benefit of alteplase treatment across 35.5°C to 37.5°C but showed a negative trend >37.5°C. Alteplase did not influence temperature profiles over 72 hours after stroke. There is no evidence of influence of body temperature on alteplase treatment response. These results are reassuring that low temperatures across a physiological range do not compromise therapeutic effect of alteplase.

The administration of probiotics and synbiotics in immune compromised adults: is it safe?

PubMed

Van den Nieuwboer, M; Brummer, R J; Guarner, F; Morelli, L; Cabana, M; Claasen, E

2015-03-01

This study aimed to systematically evaluate safety of probiotics and synbiotics in immune compromised adults (≥18 years). Safety was analysed using the Common Terminology Clinical Adverse Events (CTCAE version 4.0) classification, thereby providing an update on previous reports using the most recent available clinical data (2008-2013). Safety aspects are represented and related to number of participants per probiotic strain/culture, study duration, dosage, clinical condition and selected afflictions. Analysis of 57 clinical studies indicates that probiotic and/or synbiotic administration in immune compromised adults is safe with regard to the current evaluated probiotic strains, dosages and duration. Individuals were considered immune compromised if HIV-infected, critically ill, underwent surgery or had an organ- or an autoimmune disease. There were no major safety concerns in the study, as none of the serious adverse events (AE)s were related, or suspected to be related, to the probiotic or synbiotic product and the study products were well tolerated. Overall, AEs occurred less frequent in immune compromised subjects receiving probiotics and/or synbiotics compared to the control group. In addition, the results demonstrated a flaw in precise reporting and classification of AE in most studies. Furthermore, generalisability of conclusions are greatly limited by the inconsistent, imprecise and potentially incomplete reporting as well as the variation in probiotic strains, dosages, administration regimes, study populations and reported outcomes. We argue that standardised reporting on adverse events (CTCAE) in 'food' studies should be obligatory, thereby improving reliability of data and re-enforcing the safety profile of probiotics.

A double-blind, placebo-controlled study of repetitive transnasal sphenopalatine ganglion blockade with tx360(®) as acute treatment for chronic migraine.

PubMed

Cady, Roger; Saper, Joel; Dexter, Kent; Manley, Heather R

2015-01-01

bupivacaine group and 12 in the saline group. A repeated measures analysis of variance showed that subjects receiving treatment with bupivacaine experienced a significant reduction in the numeric rating scale scores compared with those receiving saline at baseline (M=3.78 vs M=3.18, P=.10), 15 minutes (M=3.51 vs M=2.53, P<.001), 30 minutes (M=3.45 vs M=2.41, P<.001), and 24 hours after treatment (M=4.20 vs M=2.85, P<.001), respectively. Headache Impact Test-6 scores were statistically significantly decreased in subjects receiving treatments with bupivacaine from before treatment to the final treatment (Mdiff  = -4.52, P=.005), whereas no significant change was seen in the saline group (Mdiff  = -1.50, P=.13). SPG blockade with bupivacaine delivered repetitively for 6 weeks with the Tx360(®) device demonstrates promise as an acute treatment of headache in some subjects with CM. Statistically significant headache relief is noted at 15 and 30 minutes and sustained at 24 hours for SPG blockade with bupivacaine vs saline. The Tx360(®) device was simple to use and not associated with any significant or lasting adverse events. Further research on sphenopalatine ganglion blockade is warranted. © 2014 The Authors. Headache published by Wiley Periodicals, Inc. on behalf of American Headache Society.

A Double-Blind, Placebo-Controlled Study of Repetitive Transnasal Sphenopalatine Ganglion Blockade With Tx360® as Acute Treatment for Chronic Migraine

PubMed Central

Cady, Roger; Saper, Joel; Dexter, Kent; Manley, Heather R

2015-01-01

included 38 subjects, 26 in the bupivacaine group and 12 in the saline group. A repeated measures analysis of variance showed that subjects receiving treatment with bupivacaine experienced a significant reduction in the numeric rating scale scores compared with those receiving saline at baseline (M = 3.78 vs M = 3.18, P = .10), 15 minutes (M = 3.51 vs M = 2.53, P < .001), 30 minutes (M = 3.45 vs M = 2.41, P < .001), and 24 hours after treatment (M = 4.20 vs M = 2.85, P < .001), respectively. Headache Impact Test-6 scores were statistically significantly decreased in subjects receiving treatments with bupivacaine from before treatment to the final treatment (Mdiff = −4.52, P = .005), whereas no significant change was seen in the saline group (Mdiff = −1.50, P = .13). Conclusion SPG blockade with bupivacaine delivered repetitively for 6 weeks with the Tx360® device demonstrates promise as an acute treatment of headache in some subjects with CM. Statistically significant headache relief is noted at 15 and 30 minutes and sustained at 24 hours for SPG blockade with bupivacaine vs saline. The Tx360® device was simple to use and not associated with any significant or lasting adverse events. Further research on sphenopalatine ganglion blockade is warranted. PMID:25338927

Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network

PubMed Central

Park, Seong H.; Zhu, Peng-Peng; Parker, Rell L.; Blackstone, Craig

2010-01-01

Hereditary spastic paraplegias (HSPs; SPG1–45) are inherited neurological disorders characterized by lower extremity spastic weakness. More than half of HSP cases result from autosomal dominant mutations in atlastin-1 (also known as SPG3A), receptor expression enhancing protein 1 (REEP1; SPG31), or spastin (SPG4). The atlastin-1 GTPase interacts with spastin, a microtubule-severing ATPase, as well as with the DP1/Yop1p and reticulon families of ER-shaping proteins, and SPG3A caused by atlastin-1 mutations has been linked pathogenically to abnormal ER morphology. Here we investigated SPG31 by analyzing the distribution, interactions, and functions of REEP1. We determined that REEP1 is structurally related to the DP1/Yop1p family of ER-shaping proteins and localizes to the ER in cultured rat cerebral cortical neurons, where it colocalizes with spastin and atlastin-1. Upon overexpression in COS7 cells, REEP1 formed protein complexes with atlastin-1 and spastin within the tubular ER, and these interactions required hydrophobic hairpin domains in each of these proteins. REEP proteins were required for ER network formation in vitro, and REEP1 also bound microtubules and promoted ER alignment along the microtubule cytoskeleton in COS7 cells. A SPG31 mutant REEP1 lacking the C-terminal cytoplasmic region did not interact with microtubules and disrupted the ER network. These data indicate that the HSP proteins atlastin-1, spastin, and REEP1 interact within the tubular ER membrane in corticospinal neurons to coordinate ER shaping and microtubule dynamics. Thus, defects in tubular ER shaping and network interactions with the microtubule cytoskeleton seem to be the predominant pathogenic mechanism of HSP. PMID:20200447

Autosomal dominant spastic paraplegia with peripheral neuropathy maps to chr12q23-24.

PubMed

Schüle, R; Bonin, M; Dürr, A; Forlani, S; Sperfeld, A D; Klimpe, S; Mueller, J C; Seibel, A; van de Warrenburg, B P; Bauer, P; Schöls, L

2009-06-02

Hereditary spastic paraplegias (HSP) are genetically exceedingly heterogeneous. To date, 37 genetic loci for HSP have been described (SPG1-41), among them 16 loci for autosomal dominant disease. Notwithstanding, further genetic heterogeneity is to be expected in HSP, as various HSP families do not link to any of the known HSP loci. In this study, we aimed to map the disease locus in a German family segregating autosomal dominant complicated HSP. A genome-wide linkage analysis was performed using the GeneChip Mapping 10Kv2.0 Xba Array containing 10,204 SNP markers. Suggestive loci were further analyzed by mapping of microsatellite markers. One locus on chromosome 12q23-24, termed SPG36, was confirmed by high density microsatellite fine mapping with a significant LOD score of 3.2. SPG36 is flanked by markers D12S318 and D12S79. Linkage to SPG36 was excluded in >20 additional autosomal dominant HSP families. Candidate genes were selected and sequenced. No disease-causing mutations were identified in the coding regions of ATXN2, HSPB8, IFT81, Myo1H, UBE3B, and VPS29. SPG36 is complicated by a sensory and motor neuropathy; it is therefore the eighth autosomal dominant subtype of complicated HSP. We report mapping of a new locus for autosomal dominant hereditary spastic paraplegia (HSP) (SPG36) on chromosome 12q23-24 in a German family with autosomal dominant HSP complicated by peripheral neuropathy.

spiel ohne grenzen/pou2 is required for zebrafish hindbrain segmentation.

PubMed

Hauptmann, Giselbert; Belting, Heinz-Georg; Wolke, Uta; Lunde, Karen; Söll, Iris; Abdelilah-Seyfried, Salim; Prince, Victoria; Driever, Wolfgang

2002-04-01

Segmentation of the vertebrate hindbrain leads to the formation of a series of rhombomeres with distinct identities. In mouse, Krox20 and kreisler play important roles in specifying distinct rhombomeres and in controlling segmental identity by directly regulating rhombomere-specific expression of Hox genes. We show that spiel ohne grenzen (spg) zebrafish mutants develop rhombomeric territories that are abnormal in both size and shape. Rhombomere boundaries are malpositioned or absent and the segmental pattern of neuronal differentiation is perturbed. Segment-specific expression of hoxa2, hoxb2 and hoxb3 is severely affected during initial stages of hindbrain development in spg mutants and the establishment of krx20 (Krox20 ortholog) and valentino (val; kreisler ortholog) expression is impaired. spg mutants carry loss-of-function mutations in the pou2 gene. pou2 is expressed at high levels in the hindbrain primordium of wild-type embryos prior to activation of krx20 and val. Widespread overexpression of Pou2 can rescue the segmental krx20 and val domains in spg mutants, but does not induce ectopic expression of these genes. This suggests that spg/pou2 acts in a permissive manner and is essential for normal expression of krx20 and val. We propose that spg/pou2 is an essential component of the regulatory cascade controlling hindbrain segmentation and acts before krx20 and val in the establishment of rhombomere precursor territories.

The Role of the AMOC in Forecast Cooling of the Atlantic Subpolar Gyre and Its Associated Impacts

NASA Astrophysics Data System (ADS)

Eade, R.; Hermanson, L.; Robinson, N.; Dunstone, N.; Andrews, M.; Knight, J.; Scaife, A. A.; Smith, D.

2014-12-01

Decadal variability in the North Atlantic and its subpolar gyre (SPG) has been shown to be predictable in climate models initialized with the concurrent ocean state. Numerous impacts over ocean and land have also been identified. Here we use three versions of the Met Office Decadal Prediction System to provide a multimodel ensemble forecast of the SPG and related impacts. The recent cooling trend in the SPG is predicted to continue in the next 5 years due to a decrease in the SPG heat convergence related to a slowdown of the Atlantic Meridional Overturning Circulation. We present evidence that the ensemble forecast is able to skilfully predict these quantities over recent decades. We also investigate the ability of the forecast to predict impacts on surface temperature, pressure, precipitation, and Atlantic tropical storms and compare the forecast to recent boreal summer climate.

Forecast cooling of the Atlantic subpolar gyre and associated impacts

PubMed Central

Hermanson, Leon; Eade, Rosie; Robinson, Niall H; Dunstone, Nick J; Andrews, Martin B; Knight, Jeff R; Scaife, Adam A; Smith, Doug M

2014-01-01

Decadal variability in the North Atlantic and its subpolar gyre (SPG) has been shown to be predictable in climate models initialized with the concurrent ocean state. Numerous impacts over ocean and land have also been identified. Here we use three versions of the Met Office Decadal Prediction System to provide a multimodel ensemble forecast of the SPG and related impacts. The recent cooling trend in the SPG is predicted to continue in the next 5 years due to a decrease in the SPG heat convergence related to a slowdown of the Atlantic Meridional Overturning Circulation. We present evidence that the ensemble forecast is able to skilfully predict these quantities over recent decades. We also investigate the ability of the forecast to predict impacts on surface temperature, pressure, precipitation, and Atlantic tropical storms and compare the forecast to recent boreal summer climate. PMID:25821269

Forecast cooling of the Atlantic subpolar gyre and associated impacts.

PubMed

Hermanson, Leon; Eade, Rosie; Robinson, Niall H; Dunstone, Nick J; Andrews, Martin B; Knight, Jeff R; Scaife, Adam A; Smith, Doug M

2014-07-28

Decadal variability in the North Atlantic and its subpolar gyre (SPG) has been shown to be predictable in climate models initialized with the concurrent ocean state. Numerous impacts over ocean and land have also been identified. Here we use three versions of the Met Office Decadal Prediction System to provide a multimodel ensemble forecast of the SPG and related impacts. The recent cooling trend in the SPG is predicted to continue in the next 5 years due to a decrease in the SPG heat convergence related to a slowdown of the Atlantic Meridional Overturning Circulation. We present evidence that the ensemble forecast is able to skilfully predict these quantities over recent decades. We also investigate the ability of the forecast to predict impacts on surface temperature, pressure, precipitation, and Atlantic tropical storms and compare the forecast to recent boreal summer climate.

Reactivation of the chloroplast CF1-ATPase beta subunit by trace amounts of the CF1 alpha subunit suggests a chaperonin-like activity for CF1 alpha.

PubMed

Avni, A; Avital, S; Gromet-Elhanan, Z

1991-04-25

Incubation of tobacco and lettuce thylakoids with 2 M LiCl in the presence of MgATP removes the beta subunit from their CF1-ATPase (CF1 beta) together with varying amounts of the CF1 alpha subunit (CF1 alpha). These 2 M LiCl extracts, as with the one obtained from spinach thylakoids (Avital, S., and Gromet-Elhanan, Z. (1991) J. Biol. Chem. 266, 7067-7072), could form active hybrid ATPases when reconstituted into inactive beta-less Rhodospirillum rubrum chromatophores. Pure CF1 beta fractions that have been isolated from these extracts could not form such active hybrids by themselves, but could do so when supplemented with trace amounts (less than 5%) of CF1 alpha. A mitochondrial F1-ATPase alpha subunit was recently reported to be a heat-shock protein, having two amino acid sequences that show a highly conserved identity with sequences found in molecular chaperones (Luis, A. M., Alconada, A., and Cuezva, J. M. (1990) J. Biol. Chem. 265, 7713-7716). These sequences are also conserved in CF1 alpha isolated from various plants, but not in F1 beta subunits. The above described reactivation of CF1 beta by trace amounts of CF1 alpha could thus be due to a chaperonin-like function of CF1 alpha, which involves the correct, active folding of isolated pure CF1 beta.

Validation of satellite based precipitation over diverse topography of Pakistan

NASA Astrophysics Data System (ADS)

Iqbal, Muhammad Farooq; Athar, H.

2018-03-01

This study evaluates the Tropical Rainfall Measuring Mission (TRMM) Multi-Satellite Precipitation Analysis (TMPA) product data with 0.25° × 0.25° spatial and post-real-time 3 h temporal resolution using point-based Surface Precipitation Gauge (SPG) data from 40 stations, for the period 1998-2013, and using gridded Asian Precipitation ˗ Highly Resolved Observational Data Integration Towards Evaluation of Water Resources (APHRODITE) data abbreviated as APH data with 0.25° × 0.25° spatial and daily temporal resolution for the period 1998-2007, over vulnerable and data sparse regions of Pakistan (24-37° N and 62-75° E). To evaluate the performance of TMPA relative to SPG and APH, four commonly used statistical indicator metrics including Mean Error (ME), Mean Absolute Error (MAE), Root Mean Square Error (RMSE), and Correlation Coefficient (CC) are employed on daily, monthly, seasonal as well as on annual timescales. The TMPA slightly overestimated both SPG and APH at daily, monthly, and annual timescales, however close results were obtained between TMPA and SPG as compared to those between TMPA and APH, on the same timescale. The TMPA overestimated both SPG and APH during the Pre-Monsoon and Monsoon seasons, whereas it underestimated during the Post-Monsoon and Winter seasons, with different magnitudes. Agreement between TMPA and SPG was good in plain and medium elevation regions, whereas TMPA overestimated APH in 31 stations. The magnitudes of MAE and RMSE were high at daily timescale as compared to monthly and annual timescales. Relatively large MAE was observed in stations located over high elevation regions, whereas minor MAE was recorded in plain area stations at daily, monthly, and annual timescales. A strong positive linear relationship between TMPA and SPG was established at monthly (0.98), seasonal (0.93 to 0.98) and annual (0.97) timescales. Precipitation increased with the increase of elevation, and not only elevation but latitude also affected the

Adolescent Occupational Aspirations: Test of Gottfredson's Theory of Circumscription and Compromise

ERIC Educational Resources Information Center

Cochran, Daria B.; Wang, Eugene W.; Stevenson, Sarah J.; Johnson, Leah E.; Crews, Charles

2011-01-01

The authors investigated the relationship between adolescent occupational aspirations and midlife career success. The model for adolescent occupational aspirations was derived from Gottfredson's (1981) theory of circumscription and compromise. The authors hypothesized that parental socioeconomic status (SES), ability, and gender predict adolescent…

Respect in forensic psychiatric nurse-patient relationships: a practical compromise.

PubMed

Rose, Donald N; Peter, Elizabeth; Gallop, Ruth; Angus, Jan E; Liaschenko, Joan

2011-03-01

The context of forensic psychiatric nursing is distinct from other psychiatric settings as, it involves placement of patients in secure environments with restrictions determined by the courts. Previous literature has identified that nurses morally struggle with respecting patients who have committed heinous offences, which can lead to the patient being depersonalized and dehumanized. Although respect is fundamental to ethical nursing practice, it has not been adequately explored conceptually or empirically. As a result, little knowledge exists that identifies how nurses develop, maintain, and express respect for patients. The purpose of this study is to analyze the concept of respect systematically, from a forensic psychiatric nurse's perspective using the qualitative methodology of focused ethnography. Forensic psychiatric nurses were recruited from two medium secure forensic rehabilitation units. In the first interview, 13 registered nurses (RNs) and two registered practical nurses (RPNs) participated, and although all informants were invited to the second interview, six RNs were lost to follow-up. Despite this loss, saturation was achieved and the data were interpreted through a feminist philosophical lens. Respect was influenced by factors categorized into four themes: (1) emotive-cognitive reactions, (2) nonjudgmental approach, (3) social identity and power, and (4) context. The data from the themes indicate that forensic psychiatric nurses strike a practical compromise, in their understanding and enactment of respect in therapeutic relationships with forensic psychiatric patients. © 2011 International Association of Forensic Nurses.

Sugar reduction without compromising sensory perception. An impossible dream?

PubMed

Hutchings, Scott C; Low, Julia Y Q; Keast, Russell S J

2018-03-21

Sugar reduction is a major technical challenge for the food industry to address in response to public health concerns regarding the amount of added sugars in foods. This paper reviews sweet taste perception, sensory methods to evaluate sugar reduction and the merits of different techniques available to reduce sugar content. The use of sugar substitutes (non-nutritive sweeteners, sugar alcohols, and fibres) can achieve the greatest magnitude of sugar and energy reduction, however bitter side tastes and varying temporal sweet profiles are common issues. The use of multisensory integration principles (particularly aroma) can be an effective approach to reduce sugar content, however the magnitude of sugar reduction is small. Innovation in food structure (modifying the sucrose distribution, serum release and fracture mechanics) offers a new way to reduce sugar without significant changes in food composition, however may be difficult to implement in food produced on a large scale. Gradual sugar reduction presents difficulties for food companies from a sales perspective if acceptability is compromised. Ultimately, a holistic approach where food manufacturers integrate a range of these techniques is likely to provide the best progress. However, substantial reduction of sugar in processed foods without compromising sensory properties may be an impossible dream.

Parental care compromises feeding in the pumpkinseed ( Lepomis gibbosus)

NASA Astrophysics Data System (ADS)

Zięba, G.; Dukowska, M.; Przybylski, M.; Fox, M. G.; Smith, C.

2018-04-01

Providing parental care is potentially costly. Costs can arise through elevated energy expenditure or from an increased risk of mortality. A cost of parental care can also occur because a parent is compromised in their ability to forage. We used pumpkinseed Lepomis gibbosus, a fish with an alternative male mating strategy, to test whether parental males differed in their feeding in comparison with females and cuckolder males. To address this question, we examined the stomach contents of female, cuckolder male, and parental male pumpkinseed during the breeding season over an entire diel cycle. We showed that parental males had a lower total weight of food in their stomachs in comparison with females, while cuckolder males did not. Parental males also had a lower weight and number of chironomids in their stomachs. The temporal pattern of feeding of parental males diverged from that of females, and they had a lower probability of pupal chironomids in their stomachs, which implies spatial segregation in foraging. Parental males had a greater probability of conspecific eggs in their stomachs than females, while the probability of egg cannibalism did not differ between cuckolder males and females. Overall, these finding meet predictions in accordance with an assumption that parental care and territoriality can compromise feeding.

Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia.

PubMed

Bouhouche, A; Benomar, A; Bouslam, N; Chkili, T; Yahyaoui, M

2006-05-01

Mutilating sensory neuropathy with spastic paraplegia is a very rare disease with both autosomal dominant and recessive modes of inheritance. We previously mapped the locus of the autosomal recessive form to a 25 cM interval between markers D5S2048 and D5S648 on chromosome 5p. In this candidate interval, the Cct5 gene encoding the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (CCT) was the most obvious candidate gene since mutation in the Cct4 gene encoding the CCT delta subunit has been reported to be associated with autosomal recessive mutilating sensory neuropathy in mutilated foot (mf) rat mutant. A consanguineous Moroccan family with four patients displaying mutilating sensory neuropathy associated with spastic paraplegia was investigated. To identify the disease causing gene, the 11 coding exons of the Cct5 gene were screened for mutations by direct sequencing in all family members including the four patients, parents, and six at risk relatives. Sequence analysis of the Cct5 gene revealed a missense A492G mutation in exon 4 that results in the substitution of a highly conserved histidine for arginine amino acid 147. Interestingly, R147 was absent in 384 control matched chromosomes tested. This is the first disease causing mutation that has been identified in the human CCT subunit genes; the mf rat mutant could serve as an animal model for studying these chaperonopathies.

Low ADAMTS-13 in plavix induced thrombotic thrombocytopenic purpura.

PubMed

Cao, Long Bao; Jones, Christopher; Movahed, Assad

2013-04-16

Thrombotic thrombocytopenia purpura (TTP) was first described in 1924 as a "pathologic alteration of the microvasculature, with detachment or swelling of the endothelium, amorphous material in the sub-endothelial space, and luminal platelet aggregation leading to compromise of the microcirculation". Ticlopidine induced TTP has been highly associated with autoimmune induced reduction in ADAMTS-13 activity. These findings, to a lesser extent, have also been found in clopidogrel induced TTP. We report a case of clopidogrel associated TTP in a patient that presented with acute stroke, renal failure, and non-ST elevation myocardial infarction.

No inter-gyre pathway for sea-surface temperature anomalies in the North Atlantic.

PubMed

Foukal, Nicholas P; Lozier, M Susan

2016-04-22

Recent Lagrangian analyses of surface drifters have questioned the existence of a surface current connecting the Gulf Stream (GS) to the subpolar gyre (SPG) and have cast doubt on the mechanism underlying an apparent pathway for sea-surface temperature (SST) anomalies between the two regions. Here we use modelled Lagrangian trajectories to determine the fate of surface GS water and satellite SST data to analyse pathways of GS SST anomalies. Our results show that only a small fraction of the surface GS water reaches the SPG, the water that does so mainly travels below the surface mixed layer, and GS SST anomalies do not propagate into the SPG on interannual timescales. Instead, the inter-gyre heat transport as part of the Atlantic Meridional Overturning Circulation must be accomplished via subsurface pathways. We conclude that the SST in the SPG cannot be predicted by tracking SST anomalies along the GS.

No inter-gyre pathway for sea-surface temperature anomalies in the North Atlantic

PubMed Central

Foukal, Nicholas P.; Lozier, M. Susan

2016-01-01

Recent Lagrangian analyses of surface drifters have questioned the existence of a surface current connecting the Gulf Stream (GS) to the subpolar gyre (SPG) and have cast doubt on the mechanism underlying an apparent pathway for sea-surface temperature (SST) anomalies between the two regions. Here we use modelled Lagrangian trajectories to determine the fate of surface GS water and satellite SST data to analyse pathways of GS SST anomalies. Our results show that only a small fraction of the surface GS water reaches the SPG, the water that does so mainly travels below the surface mixed layer, and GS SST anomalies do not propagate into the SPG on interannual timescales. Instead, the inter-gyre heat transport as part of the Atlantic Meridional Overturning Circulation must be accomplished via subsurface pathways. We conclude that the SST in the SPG cannot be predicted by tracking SST anomalies along the GS. PMID:27103496

Effects of inorganic polyphosphate on bone sialoprotein gene expression.

PubMed

Wang, Zhitao; Li, Xinyue; Li, Zhengyang; Yang, Li; Sasaki, Yoko; Wang, Shuang; Zhou, Liming; Araki, Shouta; Mezawa, Masaru; Takai, Hideki; Ogata, Yorimasa

2010-03-01

Inorganic polyphosphate (poly(P)) is a biopolymer existing in almost all cells and tissues. The biological functions of poly(P) in micro-organisms have been extensively investigated in studies of poly(P) in eukaryotic cells, especially osteoblasts, and are increasing. Bone sialoprotein (BSP) is thought to function in bone mineralization, and is selectively expressed by differentiated osteoblasts. In this study, application of sodium phosphate glass type 25 (SPG25, 12.5 and 125 microM) increased BSP mRNA levels at 12 h in osteoblast-like ROS 17/2.8 cells. In transient transfection assay, 12.5 and 125 microM SPG25 increased luciferase activities of the constructs pLUC3 (-116 to +60), pLUC4 (-425 to +60), pLUC5 (-801 to +60) and pLUC6 (-938 to +60). Introduction of 2 bp mutations to the luciferase constructs showed that the effects of SPG25 were mediated by a FGF2 response element (FRE) and a homeodomain protein binding site (HOX). Luciferase activities induced by SPG25 were blocked by tyrosine kinase inhibitor herbimycine A, MAP kinase kinase inhibitor U0126, PI3-kinase/Akt inhibitor LY249002 and inorganic phosphate transport inhibitor foscarnet. Gel shift analyses showed that both 12.5 and 125 microM SPG25 increased nuclear protein binding to FRE and HOX elements. These studies demonstrate that SPG25 stimulates BSP transcription by targeting FRE and HOX elements in the proximal promoter of the rat BSP gene. Copyright 2010 Elsevier B.V. All rights reserved.

Hereditary spastic paraparesis in adults. A clinical and genetic perspective from Tuscany.

PubMed

Orsucci, Daniele; Petrucci, Loredana; Ienco, Elena Caldarazzo; Chico, Lucia; Simi, Paolo; Fogli, Antonella; Baldinotti, Fulvia; Simoncini, Costanza; LoGerfo, Annalisa; Carlesi, Cecilia; Arnoldi, Alessia; Bassi, Maria Teresa; Siciliano, Gabriele; Bonuccelli, Ubaldo; Mancuso, Michelangelo

2014-05-01

Hereditary spastic paraparesis or paraplegias (HSPs) are a group of neurogenetic conditions with prominent involvement of the pyramidal tracts. Aim of this study is the clinical and molecular characterization of a cohort of patients with HSP. Moreover, we aim to study the minimum prevalence of HSP in our area and to propose a schematic diagnostic approach to HSP patients based on the available data from the literature. Retrospective/perspective study on the subjects with clinical signs and symptoms indicative of pure or complicated HSP, in whom other possible diagnosis were excluded by appropriate neuroradiological, neurophysiologic and laboratory studies, who have been evaluated by the Neurogenetic Service of our Clinic in last two years (2011-2012). 45 patients were identified. The minimum prevalence of HSP in our area was of about 2.17-3.43/100,000. The SF-36 (quality of life) and SPRS (disease progression) scores were inversely related; the time-saving, four-stage scale of motor disability could predict the SPRS scores with a high statistical significance, and we encourage its use in HSP. Our study confirms SPG4 as the major cause of HSP. All SPG4 patients had a pure HSP phenotype, and the dominant inheritance was evident in the great majority of these subjects. SPG7 was the second genetic cause. Other genotypes were rarer (SPG10, SPG11, SPG17). Exact molecular diagnosis will allow a more accurate patient counseling and, hopefully, will lead to specific, targeted, therapeutic options for these chronic, still incurable diseases. Copyright © 2014. Published by Elsevier B.V.

An abrupt weakening of the subpolar gyre as trigger of Little Ice Age-type episodes

NASA Astrophysics Data System (ADS)

Moreno-Chamarro, Eduardo; Zanchettin, Davide; Lohmann, Katja; Jungclaus, Johann H.

2017-02-01

We investigate the mechanism of a decadal-scale weakening shift in the strength of the subpolar gyre (SPG) that is found in one among three last millennium simulations with a state-of-the-art Earth system model. The SPG shift triggers multicentennial anomalies in the North Atlantic climate driven by long-lasting internal feedbacks relating anomalous oceanic and atmospheric circulation, sea ice extent, and upper-ocean salinity in the Labrador Sea. Yet changes throughout or after the shift are not associated with a persistent weakening of the Atlantic Meridional Overturning Circulation or shifts in the North Atlantic Oscillation. The anomalous climate state of the North Atlantic simulated after the shift agrees well with climate reconstructions from within the area, which describe a transition between a stronger and weaker SPG during the relatively warm medieval climate and the cold Little Ice Age respectively. However, model and data differ in the timing of the onset. The simulated SPG shift is caused by a rapid increase in the freshwater export from the Arctic and associated freshening in the upper Labrador Sea. Such freshwater anomaly relates to prominent thickening of the Arctic sea ice, following the cluster of relatively small-magnitude volcanic eruptions by 1600 CE. Sensitivity experiments without volcanic forcing can nonetheless produce similar abrupt events; a necessary causal link between the volcanic cluster and the SPG shift can therefore be excluded. Instead, preconditioning by internal variability explains discrepancies in the timing between the simulated SPG shift and the reconstructed estimates for the Little Ice Age onset.

20 CFR 404.515 - Collection and compromise of claims for overpayment.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., SURVIVORS AND DISABILITY INSURANCE (1950- ) Overpayments, Underpayments, Waiver of Adjustment or Recovery of... against an individual for recovery of overpayments under title II or title XVIII (not including title... services) of the Act, not exceeding the sum of $20,000, exclusive of interest, may be compromised, or...

Forensic Analysis of Compromised Computers

NASA Technical Reports Server (NTRS)

Wolfe, Thomas

2004-01-01

Directory Tree Analysis File Generator is a Practical Extraction and Reporting Language (PERL) script that simplifies and automates the collection of information for forensic analysis of compromised computer systems. During such an analysis, it is sometimes necessary to collect and analyze information about files on a specific directory tree. Directory Tree Analysis File Generator collects information of this type (except information about directories) and writes it to a text file. In particular, the script asks the user for the root of the directory tree to be processed, the name of the output file, and the number of subtree levels to process. The script then processes the directory tree and puts out the aforementioned text file. The format of the text file is designed to enable the submission of the file as input to a spreadsheet program, wherein the forensic analysis is performed. The analysis usually consists of sorting files and examination of such characteristics of files as ownership, time of creation, and time of most recent access, all of which characteristics are among the data included in the text file.

Tail loss compromises immunity in the many-lined skink, Eutropis multifasciata

NASA Astrophysics Data System (ADS)

Kuo, Chi-Chien; Yao, Chiou-Ju; Lin, Te-En; Liu, Hsu-Che; Hsu, Yu-Cheng; Hsieh, Ming-Kun; Huang, Wen-San

2013-04-01

Tail autotomy incurs energetic costs, and thus, a trade-off in resource allocation may lead to compromised immunity in lizards. We tested the hypothesis that tailless lizards will favor constitutive innate immunity responses over an energetically costly inflammatory response. The influence of fasting and colorful ornamentation was also investigated. We experimentally induced tail autotomy in the lizard Eutropis multifasciata and found that inflammation was suppressed by tail loss, but not further affected by fasting; the suppressive effect of colorful ornamentation was manifested only in males, but not in females. Constitutive innate immunity was not affected by any of these factors. As expected, only costly inflammation was compromised, and a less expensive constitutive innate immunity might be favored as a competent first-line defense during energetically demanding periods. After considering conventional trade-offs among tail regeneration and reproduction, further extending these studies to incorporate disease risk and how this influences escape responses to predators and future reproduction would make worthwhile studies.

20 CFR 410.565 - Collection and compromise of claims for overpayment.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 20 Employees' Benefits 2 2011-04-01 2011-04-01 false Collection and compromise of claims for overpayment. 410.565 Section 410.565 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL COAL MINE HEALTH AND SAFETY ACT OF 1969, TITLE IV-BLACK LUNG BENEFITS (1969- ) Payment of Benefits § 410.565...

Inadequate satellite cell replication compromises muscle regrowth following postnatal nutrient restriction

USDA-ARS?s Scientific Manuscript database

Perinatal growth impairment permanently compromises skeletal muscle mass. The present study assessed the contribution of muscle satellite cell replicative capacity to this deficit. Mouse dams were fed either a low protein (LP, n=7) or control (C, n=6) diet during lactation. Pups were weaned at 21 d ...

48 CFR 239.7102-2 - Compromising emanations-TEMPEST or other standard.

Code of Federal Regulations, 2010 CFR

2010-10-01

...-TEMPEST or other standard. 239.7102-2 Section 239.7102-2 Federal Acquisition Regulations System DEFENSE... INFORMATION TECHNOLOGY Security and Privacy for Computer Systems 239.7102-2 Compromising emanations—TEMPEST or....e., an established National TEMPEST standard (e.g., NACSEM 5100, NACSIM 5100A) or a standard used by...

48 CFR 239.7102-2 - Compromising emanations-TEMPEST or other standard.

Code of Federal Regulations, 2014 CFR

2014-10-01

...-TEMPEST or other standard. 239.7102-2 Section 239.7102-2 Federal Acquisition Regulations System DEFENSE... INFORMATION TECHNOLOGY Security and Privacy for Computer Systems 239.7102-2 Compromising emanations—TEMPEST or....e., an established National TEMPEST standard (e.g., NACSEM 5100, NACSIM 5100A) or a standard used by...

48 CFR 239.7102-2 - Compromising emanations-TEMPEST or other standard.

Code of Federal Regulations, 2011 CFR

2011-10-01

...-TEMPEST or other standard. 239.7102-2 Section 239.7102-2 Federal Acquisition Regulations System DEFENSE... INFORMATION TECHNOLOGY Security and Privacy for Computer Systems 239.7102-2 Compromising emanations—TEMPEST or....e., an established National TEMPEST standard (e.g., NACSEM 5100, NACSIM 5100A) or a standard used by...

48 CFR 239.7102-2 - Compromising emanations-TEMPEST or other standard.

Code of Federal Regulations, 2012 CFR

2012-10-01

...-TEMPEST or other standard. 239.7102-2 Section 239.7102-2 Federal Acquisition Regulations System DEFENSE... INFORMATION TECHNOLOGY Security and Privacy for Computer Systems 239.7102-2 Compromising emanations—TEMPEST or....e., an established National TEMPEST standard (e.g., NACSEM 5100, NACSIM 5100A) or a standard used by...

48 CFR 239.7102-2 - Compromising emanations-TEMPEST or other standard.

Code of Federal Regulations, 2013 CFR

2013-10-01

...-TEMPEST or other standard. 239.7102-2 Section 239.7102-2 Federal Acquisition Regulations System DEFENSE... INFORMATION TECHNOLOGY Security and Privacy for Computer Systems 239.7102-2 Compromising emanations—TEMPEST or....e., an established National TEMPEST standard (e.g., NACSEM 5100, NACSIM 5100A) or a standard used by...

32 CFR 321.13 - Exemptions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... investigations and relay law enforcement information without compromise of the information, protection of... enable DSS to conduct certain investigations and relay law enforcement information without compromise of the information, protection of investigative techniques and efforts employed, and identities of...

Evaluation of instant cup noodle, irradiated for immuno-compromised patients

NASA Astrophysics Data System (ADS)

Lee, Ji-Hye; Kim, Jae-Kyung; Park, Jae-Nam; Yoon, Young-Min; Sung, Nak-Yun; Kim, Jae-Hun; Song, Beom-Seok; Yook, Hong-Sun; Kim, Byeong-Keun; Lee, Ju-Woon

2012-08-01

In the present study, initial microbial load of instant cup noodle (ICN) was investigated and gamma irradiation applied to develop immuno-compromised patients food for their safe consumption. The initial microbial population of dried vegetable and meat, and noodle was below the detection limit (1 log CFU/g); however, that of seasoning powder was just above 4 log CFU/g. Moreover, rehydrated-ICN with water at 100 °C still show above 3 log CFU/g of microbial load, which indicates the need for an additional process to control microbial safety of the seasoning powder. The total aerobic bacteria in seasoning powder and rehydrated-ICN could be controlled with 17 kGy gamma irradiation. This result referred 17 kGy gamma irradiation could reach 'practical sterility' of ICN. The overall difference in sensory properties between the non-irradiated and irradiated ICN was insignificant. Thus, gamma irradiation could improve the microbial quality of ICN, and reduce the risk of infection posed by the seasoning powder, without any adverse effects on their sensory quality. These results suggest that gamma-irradiated ICN can be used as a snack food for immuno-compromised patients.

Intergroup perception as a compromise between in-group bias and fair-mindedness.

PubMed

Singh, Ramadhar; Sharmini; Choo, Ivy

2004-08-01

Previously, perceived competence of and attraction toward targets categorized by race showed in-group bias and no bias, respectively. Consequently, previous investigators regarded intergroup perception as a compromise between the norms of in-group bias and fair-mindedness. An alternative hypothesis for such findings is that attraction is not as relevant a dimension for intergroup discrimination as is competence. To test contrasting predictions of these hypotheses, the present authors asked participants from the majority and minority groups in Singapore (ns = 320) to evaluate either competence of or attraction toward one of the five targets. Consistent with the hypothesis that intergroup perception is a compromise, both dimensions yielded a uniform but weak in-group bias. The participants' equating of the in-group with one out-group further illustrated fair-mindedness. The authors discussed implications of the findings.

Construction of a Solid State Research Facility, Building 3150. Environmental Assessment

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

Not Available

1993-07-01

The Department of Energy (DOE) proposes to construct a new facility to house the Materials Synthesis Group (MSG) and the Semiconductor Physics Group (SPG) of the Solid State Division, Oak Ridge National Laboratory (ORNL). The location of the proposed action is Roane County, Tennessee. MSG is involved in the study of crystal growth and the preparation and characterization of advanced materials, such as high-temperature superconductors, while SPG is involved in semiconductor physics research. All MSG and a major pardon of SPG research activities are now conducted in Building 2000, a deteriorating structure constructed in the 1940. The physical deterioration ofmore » the roof; the heating, ventilation, and air conditioning (HVAC) system; and the plumbing make this building inadequate for supporting research activities. The proposed project is needed to provide laboratory and office space for MSG and SPG and to ensure that research activities can continue without interruption due to deficiencies in the building and its associated utility systems.« less

40 CFR 1620.6 - Authority to adjust, determine, compromise, and settle.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 32 2010-07-01 2010-07-01 false Authority to adjust, determine, compromise, and settle. 1620.6 Section 1620.6 Protection of Environment CHEMICAL SAFETY AND HAZARD... Chairperson or any other lawful designee can only be made after a legal review is conducted by an attorney...

40 CFR 1620.6 - Authority to adjust, determine, compromise, and settle.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Authority to adjust, determine, compromise, and settle. 1620.6 Section 1620.6 Protection of Environment CHEMICAL SAFETY AND HAZARD... Chairperson or any other lawful designee can only be made after a legal review is conducted by an attorney...

40 CFR 1620.6 - Authority to adjust, determine, compromise, and settle.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 34 2013-07-01 2013-07-01 false Authority to adjust, determine, compromise, and settle. 1620.6 Section 1620.6 Protection of Environment CHEMICAL SAFETY AND HAZARD... Chairperson or any other lawful designee can only be made after a legal review is conducted by an attorney...

[Cat-scratch disease with bone compromise: atypical manifestation].

PubMed

Rodríguez C, Magdalena; Giachetto L, Gustavo; Cuneo E, Alejandro; Gutiérrez B, María del C; Shimchack R, Mario; Pírez G, M Catalina

2009-08-01

Fever, headache, myalgias and lymphadenopathy are characteristic manifestations of cat-scratch disease but other less common findings are described in 2 to 10% of cases. We report two children that presented with hepatosplenic abscesses and bone involvement. One child, had multiple areas of increased uptake in the bone scintigram with a positive serology (IgG > 1/256, IgM slightly positive). The second child had destruction of the L2 vertebral body that compromised the channel and right foramen as visualized by MRI. In both cases, bacilli were observed in the bone biopsy by Warthing-Starry stain.

A psychiatrist in a bureaucracy: the unsettling compromises.

PubMed

Weitzel, W D

1976-09-01

Psychiatrists employed by bureaucracies must make a number of compromises in order to reconcile their employing organization's formally stated aims, their superiors' day-to-day expectations, and their traditional role model of physician and patient-oriented therapist. The author studied nine psychiatrists working for the U.S. Army during a two-year period in the mid-seventies. Their adaptation to expectations and pressures of the bureaucracy can be described in one of three general ways: through alignment with the official views of the Army, compartmentalization of roles to meet both patients' expectations and the Army's expectations, or rejection of a military identity.

The carina angle-new geometrical parameter associated with periprocedural side branch compromise and the long-term results in coronary bifurcation lesions with main vessel stenting only.

PubMed

Gil, Robert J; Vassilev, Dobrin; Formuszewicz, Radoslaw; Rusicka-Piekarz, Teresa; Doganov, Alexander

2009-12-01

The two main problems unresolved in coronary bifurcation stenting are periprocedural side branch compromise and higher restenosis at long term. The purpose of this study is to reveal the link between periprocedural side branch compromise and long-term results after main vessel stenting only in coronary bifurcations. Eighty-four patients formed the study population. The inclusion criteria were good-quality angiograms, with maximal between-branch angle opening, no overlap, permitting accurate angiographic analysis. Carina angle (alpha)-the distal angle between main vessel (MV) before bifurcation and side branch (SB)-was measured pre- and poststenting. Clinical follow-up 9-12 months was obtained with coronary angiography if needed. The patient population was high-risk with 33% diabetics and 84% two- and three-vessel disease. Ninety-five stents were implanted in 92 lesions, with three T-stenting cases. Drug-eluting stents were implanted in 54%. Kissing-balloon (KBI) or sequential inflation was performed in 35%. SB functional closure occurred in 17.4%, with independent predictors alpha < 40 degrees and diameter ratio MB/SB >1.22. After 12+/-4 months there were five myocardial infarctions (6%) and 13 (15%) target lesion revascularization procedures. Independent predictors of major cardiovascular events were carina angle <40 degrees , MB lesion length >8 mm, negative change of between-branch angle, DES usage, and KBI. Smaller carina angle with straightening of MV-main branch from stent implantation in coronary bifurcations predicted higher SB compromise, restenosis, and MACE rates during follow-up of 1 year.

A novel revision to the classical transnasal topical sphenopalatine ganglion block for the treatment of headache and facial pain.

PubMed

Candido, Kenneth D; Massey, Scott T; Sauer, Ruben; Darabad, Raheleh Rahimi; Knezevic, Nebojsa Nick

2013-01-01

The sphenopalatine ganglion (SPG) is located with some degree of variability near the tail or posterior aspect of the middle nasal turbinate. The SPG has been implicated as a strategic target in the treatment of various headache and facial pain conditions, some of which are featured in this manuscript. Interventions for blocking the SPG range from minimally to highly invasive procedures often associated with great cost and unfavorable risk profiles. The purpose of this pilot study was to present a novel, FDA-cleared medication delivery device, the Tx360® nasal applicator, incorporating a transnasal needleless topical approach for SPG blocks. This study features the technical aspects of this new device and presents some limited clinical experience observed in a small series of head and face pain cases. Case series. Pain management center, part of teaching-community hospital, major metropolitan city, United States. After Institutional Review Board (IRB) approval, the technical aspects of this technique were examined on 3 patients presenting with various head and face pain conditions including trigeminal neuralgia (TN), chronic migraine headache (CM), and post-herpetic neuralgia (PHN). The subsequent response to treatment and quality of life was quantified using the following tools: the 11-point Numeric Rating Scale (NRS), Modified Brief Pain Inventory - short form (MBPI-sf), Patient Global Impression of Change (PGIC), and patient satisfaction surveys. The Tx360® nasal applicator was used to deliver 0.5 mL of ropivacaine 0.5% and 2 mg of dexamethasone for SPG block. Post-procedural assessments were repeated at 15 and 30 minutes, and on days one, 7, 14, and 21 with a final assessment at 28 days post-treatment. All patients were followed for one year. Individual patients received up to 10 SPG blocks, as clinically indicated, after the initial 28 days. Three women, ages 43, 18, and 15, presented with a variety of headache and face pain disorders including TN, CM, and

32 CFR 321.13 - Exemptions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... investigations and relay law enforcement information without compromise of the information, protection of... investigations and relay law enforcement information without compromise of the information, protection of... subsection (c)(3) because it will enable DSS to conduct certain investigations and relay law enforcement...

Computation of optimal Mars trajectories via combined chemical/electrical propulsion, Part 3: Compromise solutions

NASA Astrophysics Data System (ADS)

Miele, A.; Wang, T.; Williams, P. N.

2005-12-01

The success of the solar-electric ion engine powering the DS1 spacecraft has paved the way toward the use of low-thrust electrical engines in future planetary/interplanetary missions. Vis-à-vis a chemical engine, an electrical engine has a higher specific impulse, implying a possible decrease in propellant mass; however, the low-thrust aspect discourages the use of an electrical engine in the near-planet phases of a trip, since this might result in an increase in flight time. Therefore, a fundamental design problem is to find the best combination of chemical propulsion and electrical propulsion for a given mission, for example, a mission from Earth to Mars. With this in mind, this paper is the third of a series dealing with the optimization of Earth Mars missions via the use of hybrid engines, namely the combination of high-thrust chemical engines for planetary flight and low-thrust electrical engines for interplanetary flight. We look at the deep-space interplanetary portion of the trajectory under rather idealized conditions. The two major performance indexes, the propellant mass and the flight time, are in conflict with one another for the following reason: any attempt at reducing the former causes an increase in the latter and vice versa. Therefore, it is natural to consider a compromise performance index involving the scaled values of the propellant mass and flight time weighted respectively by the compromise factor C and its complement 1-C. We use the compromise factor as the parameter of the one-parameter family of compromise trajectories. Analyses carried out with the sequential gradient-restoration algorithm for optimal control problems lead to results which can be highlighted as follows. Thrust profile. Generally speaking, the thrust profile of the compromise trajectory includes three subarcs: the first subarc is characterized by maximum thrust in conjunction with positive (upward) thrust direction; the second subarc is characterized by zero thrust

[Tuberculosis in compromised hosts].

PubMed

2003-11-01

Recent development of tuberculosis in Japan tends to converge on a specific high risk group. The proportion of tuberculosis developing particularly from the compromised hosts in the high risk group is especially high. At this symposium, therefore, we took up diabetes mellitus, gastrectomy, dialysis, AIDS and the elderly for discussion. Many new findings and useful reports for practical medical treatment are submitted; why these compromised hosts are predisposed to tuberculosis, tuberculosis diagnostic and remedial notes of those compromised hosts etc. It is an important question for the future to study how to prevent tuberculosis from these compromised hosts. 1. Tuberculosis in diabetes mellitus: aggravation and its immunological mechanism: Kazuyoshi KAWAKAMI (Department of Internal Medicine, Division of Infectious Diseases, Graduate School and Faculty of Medicine, University of the Ryukyus). It has been well documented that diabetes mellitus (DM) is a major aggravating factor in tuberculosis. The onset of this disease is more frequent in DM patients than in individuals with any underlying diseases. However, the precise mechanism of this finding remains to be fully understood. Earlier studies reported that the migration, phagocytosis and bactericidal activity of neutrophils are all impaired in DM patients, which is related to their reduced host defense to infection with extracellular bacteria, such as S. aureus and E. colli. Host defense to mycobacterial infection is largely mediated by cellular immunity, and Th1-related cytokines, such as IFN-gamma and IL-12, play a central role in this response. It is reported that serum level of these cytokines and their production by peripheral blood mononuclear cells (PBMC) are reduced in tuberculosis patients with DM, and this is supposed to be involved in the high incidence of tuberculosis in DM. Our study observed similar findings and furthermore indicated that IFN-gamma and IL-12 production by BCG-stimulated PBMC was lower

Bilateral sphenopalatine ganglion block reduces blood pressure in never treated patients with essential hypertension. A randomized controlled single-blinded study.

PubMed

Triantafyllidi, Helen; Arvaniti, Chrysa; Schoinas, Antonios; Benas, Dimitris; Vlachos, Stefanos; Palaiodimos, Leonidas; Pavlidis, George; Ikonomidis, Ignatios; Batistaki, Chrysanthi; Voumvourakis, Costas; Lekakis, John

2018-01-01

Sympathetic fibers connect sphenopalatine ganglion (SPG) with the central nervous system. We aimed to study the effect of SPG block in blood pressure (BP) in never treated patients with stage I-II essential hypertension. We performed bilateral SPG block with lidocaine 2% in 33 hypertensive patients (mean age 48±12years, 24 men) and a sham operation with water for injection in 11 patients who served as the control group (mean age 51±12years, 8 men). All patients have been subjected to 24h ambulatory blood pressure monitoring prior and a month after the SBG block in order to estimate any differences in blood pressure parameters. We defined as responders to SBG block those patients with a 24h SBP decrease ≥5mmHg. We found that 24h and daytime DBP (p=0.02) as well as daytime DBP load (p=0.03) were decreased in the study group a month after SPG block. In addition, a significant response was noted in 12/33 responders (36%) regarding: a. SBP and DBP during overall 24h and daytime (p<0.001) and night-time periods, b. pre-awake and early morning SBP and c. SBP (daytime and night-time) and DBP (daytime) load. No differences regarding BP were found in the sham operation group. SPG block is a promising, minimally invasive option of BP decrease in hypertensives, probably through SNS modulation. Additionally, due to its anesthetic effect, SPG block might act as a method of selection for those hypertensive patients with an activated SNS before any other invasive antihypertensive procedure. Copyright © 2017 Elsevier B.V. All rights reserved.

Happenstance and compromise: a gendered analysis of students' computing degree course selection

NASA Astrophysics Data System (ADS)

Lang, Catherine

2010-12-01

The number of students choosing to study computing at university continues to decline this century, with an even sharper decline in female students. This article presents the results of a series of interviews with university students studying computing courses in Australia that uncovered the influence of happenstance and compromise on course choice. This investigation provides an insight into the contributing factors into the continued downturn of student diversity in computing bachelor degree courses. Many females interviewed made decisions based on happenstance, many males interviewed had chosen computing as a compromise course, and family helped in the decision-making to a large degree in both genders. The major implication from this investigation is the finding that students of both genders appear to be socialised away from this discipline, which is perceived as a support or insurance skill, not a career in itself, in all but the most technical-oriented (usually male) student.

Is ridge preservation/augmentation at periodontally compromised extraction sockets safe? A retrospective study.

PubMed

Kim, Jung-Ju; Ben Amara, Heithem; Schwarz, Frank; Kim, Hae-Young; Lee, Jung-Won; Wikesjö, Ulf M E; Koo, Ki-Tae

2017-10-01

This study aimed to evaluate the safety of ridge preservation/augmentation procedures when performed at compromised extraction sockets. Patients subject to ridge preservation/augmentation at periodontally compromised sockets at Seoul National University Dental Hospital (SNUDH) were evaluated in a chart review. Tooth extractions due to acute infection were not included in our study as chronically formed lesions are the only lesions that can be detected from radiographic images. If inflammatory symptoms persisted following ridge preservation/augmentation and antimicrobial and anti-inflammatory therapy, the patient was categorized as a re-infection case and implanted biomaterial removed. Of 10,060 patients subject to tooth extractions at SNUDH, 2011 through 2015, 297 cases meeting inclusion criteria were reviewed. The severity and type of lesions were not specific because extracting data was only done by radiographic images and chart records. The review identified eight patients exhibiting inflammatory symptoms that required additional antimicrobial and anti-inflammatory therapy. Within this group, re-infection occurred in two patients requiring biomaterials removal. The final safety rate for the ridge preservation/augmentation was 99.3%. None of the demographic factors, systemic conditions or choice of biomaterial affected the safety of ridge preservation/augmentation. Alveolar ridge preservation/augmentation at periodontally compromised sockets appears safe following thorough removal of infectious source. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Corporate corruption of the environment: sustainability as a process of compromise.

PubMed

Nyberg, Daniel; Wright, Christopher

2013-09-01

A key response to environmental degradation, climate change and declining biodiversity has been the growing adoption of market principles in an effort to better value the social good of nature. Through concepts such as 'natural capitalism' and 'corporate environmentalism', nature is increasingly viewed as a domain of capitalist endeavour. In this article, we use convention theory and a pluralist understanding of social goods to investigate how the social good of the environment is usurped by the alternate social good of the market. Through analysis of interviews with sustainability managers and corporate documentation, we highlight how organizational actors employ compromise to temporally settle disputes between competing claims about environmental activities. Our findings contribute to an understanding of the processes of empirically grounded critique and the under-theorized concept of compromise between social goods. Rather than protecting the environment, the corporate promotion of sustainability facilitates the corruption of the social good of the environment and its conversion into a market commodity. © London School of Economics and Political Science 2013.

Optimizing Maxillary Aesthetics of a Severe Compromised Tooth through Orthodontic Movement and Dental Implants

PubMed Central

de Avila, Erica Dorigatti; Cirelli, Joni Augusto; Cardoso, Mauricio de Almeida; Capelozza-Filho, Leopoldino; Borelli Barros, Luiz Antonio

2014-01-01

Treatment of severe compromised tooth in the maxillary anterior area still poses great challenge to the clinicians. Several treatment modalities have been proposed to restore the function and aesthetics in teeth with advanced periodontal disease. The present study aims to report a case of traumatic injury of a left-maxillary central incisor with ridge preservation, orthodontic movement, and implant therapy. A 45-year-old woman underwent the proposed treatment for her left central incisor: basic periodontal therapy, xenogenous bone graft, and guided bone regeneration (GBR). Six months after the graft procedure, orthodontic movement by means of alignment and leveling was made and a coronal displacement of the gingival margin and vertical bone apposition could be observed after 13 months of active movement. Afterwards, a dental implant was placed followed by a connective tissue graft and immediate provisionalization of the crown. In conclusion, orthodontic movement was effective to improve the gingival tissue and alveolar bone prior to implant placement favoring the aesthetic results. Six years postoperatively, the results revealed height and width alveolar bone gain indicating that the treatment proposed was able to restore all the functional and aesthetic parameters. PMID:24523969

Health-compromising behaviors among Vietnamese adolescents: the role of education and extracurricular activities.

PubMed

Kaplan, Celia Patricia; Zabkiewicz, Denise; McPhee, Stephen J; Nguyen, Tung; Gregorich, Steven E; Disogra, Charles; Hilton, Joan F; Jenkins, Christopher

2003-05-01

behaviors. Also, older and more acculturated adolescents were at increased risk of engaging in health-compromising behaviors. Analysis by gender revealed that the variables age, educational risk, and chance of attending college were all related to health risk behavior for both males and females. Among the boys, those who reported achieving an average grade of B or better had a decreased risk of engaging in health-compromising behaviors; however, neither extracurricular activities nor acculturation was related to health-compromising behaviors in boys. Among the girls, the reverse was true: lack of participation in extracurricular activities was related to health-compromising behaviors, whereas grades were not a significant risk factor. Among sampled Vietnamese adolescents in California, health risk behaviors are common and inversely related to some school performance indicators. Using these indicators to identify high-risk groups could allow targeted educational programs or interventions for the mitigation of health-compromising behaviors.

Heavy Cigarette Smokers in a Chinese Population Display a Compromised Permeability Barrier

PubMed Central

Xin, Shujun; Ye, Li; Lv, Chengzhi; Elias, Peter M.

2016-01-01

Cigarette smoking is associated with various cutaneous disorders with defective permeability. Yet, whether cigarette smoking influences epidermal permeability barrier function is largely unknown. Here, we measured skin biophysical properties, including permeability barrier homeostasis, stratum corneum (SC) integrity, SC hydration, skin surface pH, and skin melanin/erythema index, in cigarette smokers. A total of 99 male volunteers were enrolled in this study. Smokers were categorized as light-to-moderate (<20 cigarettes/day) or heavy smokers (≥20 cigarettes/day). An MPA5 was used to measure SC hydration and skin melanin/erythema index on the dorsal hand, forehead, and cheek. Basal transepidermal water loss (TEWL) and barrier recovery rates were assessed on the forearm. A Skin-pH-Meter pH900 was used to measure skin surface pH. Our results showed that heavy cigarette smokers exhibited delayed barrier recovery after acute abrogation (1.02% ± 13.06 versus 16.48% ± 6.07), and barrier recovery rates correlated negatively with the number of daily cigarettes consumption (p = 0.0087). Changes in biophysical parameters in cigarette smokers varied with body sites. In conclusion, heavy cigarette smokers display compromised permeability barrier homeostasis, which could contribute, in part, to the increased prevalence of certain cutaneous disorders characterized by defective permeability. Thus, improving epidermal permeability barrier should be considered for heavy cigarette smokers. PMID:27437403

Methamphetamine compromises gap junctional communication in astrocytes and neurons

PubMed Central

Castellano, Paul; Nwagbo, Chisom; Martinez, Luis R.; Eugenin, Eliseo A.

2016-01-01

Methamphetamine (meth) is a central nervous system (CNS) stimulant that results in psychological and physical dependency. The long-term effects of meth within the CNS include neuronal plasticity changes, blood–brain barrier compromise, inflammation, electrical dysfunction, neuronal/glial toxicity, and an increased risk to infectious diseases including HIV. Most of the reported meth effects in the CNS are related to dysregulation of chemical synapses by altering the release and uptake of neurotransmitters, especially dopamine, norepinephrine, and epinephrine. However, little is known about the effects of meth on connexin (Cx) containing channels, such as gap junctions (GJ) and hemichannels (HC). We examined the effects of meth on Cx expression, function, and its role in NeuroAIDS. We found that meth altered Cx expression and localization, decreased GJ communication between neurons and astrocytes, and induced the opening of Cx43/Cx36 HC. Furthermore, we found that these changes in GJ and HC induced by meth treatment were mediated by activation of dopamine receptors, suggesting that dysregulation of dopamine signaling induced by meth is essential for GJ and HC compromise. Meth-induced changes in GJ and HC contributed to amplified CNS toxicity by dysregulating glutamate metabolism and increasing the susceptibility of neurons and astrocytes to bystander apoptosis induced by HIV. Together, our results indicate that connexin containing channels, GJ and HC, are essential in the pathogenesis of meth and increase the sensitivity of the CNS to HIV CNS disease. PMID:26953131

76 FR 15212 - Redelegation of Authority to Compromise and Close Civil Claims

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-21

... Division directive delegates to a Principal Deputy Assistant Attorney General all of the Assistant Attorney... Review, and the Deputy Assistant Attorneys General, to compromise and close civil claims. In addition... Section 11 hereof, each of the Deputy Assistant Attorneys General is authorized to: (A) Accept offers in...

Political realities of statewide smoking legislation: the passage of California's Assembly Bill 13.

PubMed

Macdonald, H R; Glantz, S A

1997-01-01

To prepare a history of the enactment of California Assembly Bill 13 (AB 13), a state law prohibiting smoking in most workplaces passed in 1994, and to discuss its initial impacts. Data were gathered from open ended interviews with representatives of voluntary health organisations, local government organisations, and principal legislators involved in the process, as well as observers around the state who could provide insight into the legislative process. Information was also obtained from legislative hearings and debates, public documents, letters and personal communications, internal memoranda, and news reports. The success of local tobacco control legislation in California led to a situation in which some health groups were willing to accept state preemption in order to attract the support of the state restaurant association for a bill. The decision to accept this preemption compromise was made by the state level offices of the voluntary health agencies without consulting the broader tobacco control community within California. In contrast, local tobacco control advocates did not accept this compromise, in part because of their belief that local legislation was a better device to educate the public, generate media coverage, and build community support for enforcement and implementation of clean indoor air and other tobacco control laws. Enactment of AB 13 was associated with a slowing of all local tobacco control legislation, including youth oriented laws. Because its supporters initially doubted that AB 13 would pass, there was never an effort to reconcile the policy differences between state oriented and locally oriented tobacco control policies. This lack of consensus, combined with the political realities inherent in passing any state legislation, led to a bill with ambiguous preemption language which replaced the "patchwork of local laws" with a "patchwork of local enforcement."

Human Milk for Ill and Medically Compromised Infants: Strategies and Ongoing Innovation.

PubMed

DiLauro, Sara; Unger, Sharon; Stone, Debbie; O'Connor, Deborah L

2016-08-01

The use of human milk (mother's own milk and/or donor milk) in ill or medically compromised infants frequently requires some adaptation to address medical diagnoses and/or altered nutrition requirements. This tutorial describes the nutrition and immunological benefits of breast milk as well as provides evidence for the use of donor milk when mother's own milk is unavailable. Several strategies used to modify human milk to meet the medical and nutrition needs of an ill or medically compromised infant are reviewed. These strategies include (1) the standard fortification of human milk to support adequate growth, (2) the novel concept of target fortification in preterm infants, (3) instructions on how to alter maternal diet to address cow's milk protein intolerance and/or allergy in breast milk-fed infants, and (4) the removal and modification of the fat in breast milk used in infants diagnosed with chylothorax. © 2016 American Society for Parenteral and Enteral Nutrition.

Substance Use Disorder and Suicide Attempt Among People Who Report Compromised Health.

PubMed

Prince, Jonathan

2018-01-02

Substance use disorder can increase the risk of suicide attempt. However, the relationship between substance use disorder and suicide attempt has yet to be explored among people who report compromised health, even though sick people are more likely to make an attempt. Among people who report fair or poor health on the National Survey of Drug Use and Health (2006-2014; N = 502,467), I examined whether people with commonly occurring substance use disorders are more likely to attempt suicide than people without substance use disorders. Logistic regression was used to predict suicide attempt from presence versus absence of substance use disorder. Among individuals reporting compromised health, those who had DSM-IV alcohol use disorders were 2.72 times (CI = 1.81-4.09, p <.001) as likely as people without SUD to attempt suicide, and people with prescription painkiller use disorders were 2.25 times (CI = 1.04-4.90, p <.05) as likely. Individuals with both alcohol and marijuana use disorders were 2.38 times (CI = 1.25-4.54, p <.01) as likely as people without substance use disorder to make an attempt, and people with both alcohol and cocaine use disorders were 3.15 times (CI = 1.16-8.60, p <.05) as likely. Conclusions/Importance: In order to help prevent suicide attempt among people who report compromised health, treatment programs that specialize in health, mental health, or substance abuse could address the drug-specific disorders that are most highly associated with the likelihood of suicide attempt. More research is needed that may underscore risk associated with other drug-specific disorders, or that substantiate the findings reported herein.

The Sub-Polar Gyre Index - a community data set for application in fisheries and environment research

NASA Astrophysics Data System (ADS)

Berx, Barbara; Payne, Mark R.

2017-04-01

Scientific interest in the sub-polar gyre of the North Atlantic Ocean has increased in recent years. The sub-polar gyre has contracted and weakened, and changes in circulation pathways have been linked to changes in marine ecosystem productivity. To aid fisheries and environmental scientists, we present here a time series of the Sub-Polar Gyre Index (SPG-I) based on monthly mean maps of sea surface height. The established definition of the SPG-I is applied, and the first EOF (empirical orthogonal function) and PC (principal component) are presented. Sensitivity to the spatial domain and time series length are explored but found not to be important factors in terms of the SPG-I's interpretation. Our time series compares well with indices presented previously. The SPG-I time series is freely available online (http://dx.doi.org/10.7489/1806-1), and we invite the community to access, apply, and publish studies using this index time series.

Algorithmic processing of intrinsic signals in affixed transmission speckle analysis (ATSA) (Conference Presentation)

NASA Astrophysics Data System (ADS)

Ghijsen, Michael T.; Tromberg, Bruce J.

2017-03-01

Affixed Transmission Speckle Analysis (ATSA) is a method recently developed to measure blood flow that is based on laser speckle imaging miniaturized into a clip-on form factor the size of a pulse-oximeter. Measuring at a rate of 250 Hz, ATSA is capable or obtaining the cardiac waveform in blood flow data, referred to as the Speckle-Plethysmogram (SPG). ATSA is also capable of simultaneously measuring the Photoplethysmogram (PPG), a more conventional signal related to light intensity. In this work we present several novel algorithms for extracting physiologically relevant information from the combined SPG-PPG waveform data. First we show that there is a slight time-delay between the SPG and PPG that can be extracted computationally. Second, we present a set of frequency domain algorithms that measure harmonic content on pulse-by-pulse basis for both the SPG and PPG. Finally, we apply these algorithms to data obtained from a set of subjects including healthy controls and individuals with heightened cardiovascular risk. We hypothesize that the time-delay and frequency content are correlated with cardiovascular health; specifically with vascular stiffening.

Chaperonin-containing T-complex Protein 1 Subunit ζ Serves as an Autoantigen Recognized by Human Vδ2 γδ T Cells in Autoimmune Diseases.

PubMed

Chen, Hui; You, Hongqin; Wang, Lifang; Zhang, Xuan; Zhang, Jianmin; He, Wei

2016-09-16

Human γδ T cells recognize conserved endogenous and stress-induced antigens typically associated with autoimmune diseases. However, the role of γδ T cells in autoimmune diseases is not clear. Few autoimmune disease-related antigens recognized by T cell receptor (TCR) γδ have been defined. In this study, we compared Vδ2 TCR complementarity-determining region 3 (CDR3) between systemic lupus erythematosus (SLE) patients and healthy donors. Results show that CDR3 length distribution differed significantly and displayed oligoclonal characteristics in SLE patients when compared with healthy donors. We found no difference in the frequency of Jδ gene fragment usage between these two groups. According to the dominant CDR3δ sequences in SLE patients, synthesized SL2 peptides specifically bound to human renal proximal tubular epithelial cell line HK-2; SL2-Vm, a mutant V sequence of SL2, did not bind. We identified the putative protein ligand chaperonin-containing T-complex protein 1 subunit ζ (CCT6A) using SL2 as a probe in HK-2 cell protein extracts by affinity chromatography and liquid chromatography-electrospray ionization-tandem mass spectrometry analysis. We found CCT6A expression on the surface of HK-2 cells. Cytotoxicity of only Vδ2 γδ T cells to HK-2 cells was blocked by anti-CCT6A antibody. Finally, we note that CCT6A concentration was significantly increased in plasma of SLE and rheumatoid arthritis patients. These data suggest that CCT6A is a novel autoantigen recognized by Vδ2 γδ T cells, which deepens our understanding of mechanisms in autoimmune diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

A compromised liver alters polychlorinated biphenyl-mediated toxicity.

PubMed

Wahlang, Banrida; Perkins, Jordan T; Petriello, Michael C; Hoffman, Jessie B; Stromberg, Arnold J; Hennig, Bernhard

2017-04-01

Exposure to environmental toxicants namely polychlorinated biphenyls (PCBs) is correlated with multiple health disorders including liver and cardiovascular diseases. The liver is important for both xenobiotic and endobiotic metabolism. However, the responses of an injured liver to subsequent environmental insults has not been investigated. The current study aims to evaluate the role of a compromised liver in PCB-induced toxicity and define the implications on overall body homeostasis. Male C57Bl/6 mice were fed either an amino acid control diet (CD) or a methionine-choline deficient diet (MCD) during the 12-week study. Mice were subsequently exposed to either PCB126 (4.9mg/kg) or the PCB mixture, Arcolor1260 (20mg/kg) and analyzed for inflammatory, calorimetry and metabolic parameters. Consistent with the literature, MCD diet-fed mice demonstrated steatosis, indicative of a compromised liver. Mice fed the MCD-diet and subsequently exposed to PCB126 showed observable wasting syndrome leading to mortality. PCB126 and Aroclor1260 exposure worsened hepatic fibrosis exhibited by the MCD groups. Interestingly, PCB126 but not Aroclor1260 induced steatosis and inflammation in CD-fed mice. Mice with liver injury and subsequently exposed to PCBs also manifested metabolic disturbances due to alterations in hepatic gene expression. Furthermore, PCB exposure in MCD-fed mice led to extra-hepatic toxicity such as upregulated circulating inflammatory biomarkers, implicating endothelial cell dysfunction. Taken together, these results indicate that environmental pollution can exacerbate toxicity caused by diet-induced liver injury which may be partially due to dysfunctional energy homeostasis. This is relevant to PCB-exposed human cohorts who suffer from alcohol or diet-induced fatty liver diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Treatment of Lung Cancer in Medically Compromised Patients.

PubMed

Crawford, Jeffrey; Wheatley-Price, Paul; Feliciano, Josephine Louella

2016-01-01

Outcomes for patients with lung cancer have been improved substantially through the integration of surgery, radiation, and systemic therapy for patients with early-stage disease. Meanwhile, advances in our understanding of molecular mechanisms have substantially advanced our treatment of patients with advanced lung cancer through the introduction of targeted therapies, immune approaches, improvements in chemotherapy, and better supportive care. However, the majority of these advances have occurred among patients with good functional status, normal organ function, and with the social and economic support systems to be able to benefit most from these treatments. The aim of this article is to bring greater attention to management of lung cancer in patients who are medically compromised, which remains a major barrier to care delivery. Impaired performance status is associated with poor outcomes and correlates with the high prevalence of cachexia among patients with advanced lung cancer. CT imaging is emerging as a research tool to quantify muscle loss in patients with cancer, and new therapeutics are on the horizon that may provide important adjunctive therapy in the future. The benefits of cancer therapy for patients with organ failure are poorly understood because of their exclusion from clinical trials. The availability of targeted therapy and immunotherapy may provide alternatives that may be easier to deliver in this population, but clinical trials of these new agents in this population are vital. Patients with lower socioeconomic status are disproportionately affected by lung cancer because of higher rates of tobacco addiction and the impact of socioeconomic status on delay in diagnosis, treatment, and outcomes. For all patients who are medically compromised with lung cancer, multidisciplinary approaches are particularly needed to evaluate these patients and to incorporate rapidly changing therapeutics to improve outcomes.

Discrimination of Pathogenic vs. Nonpathogenic Francisella tularensis and Burkholderia pseudomallei Using Proteomics Mass Spectrometry

DTIC Science & Technology

2011-03-01

GroEL AhpC/TSA family protein hypothetical protein FTL0617 heat shock protein DnaK succinyl-CoA synthetase subunit beta hypothetical protein...lipoprotein chaperonin GroEL co-chaperonin GroES DNA-directed RNA polymerase subunit beta intracellular growth locus, subunit C 3.2 Differentiation...thailandensis E264 Unique Proteins Whole Cell Lysates OMPs putative lipoprotein glucan 1,4-a-glucosidase glycosy hydrolase family protein putative

The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding

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

Ye, Qiaozhen; Kim, Dong Hyun; Dereli, Ihsan

Proteins of the conserved HORMA domain family, including the spindle assembly checkpoint protein MAD2 and the meiotic HORMADs, assemble into signaling complexes by binding short peptides termed “closure motifs”. The AAA+ ATPase TRIP13 regulates both MAD2 and meiotic HORMADs by disassembling these HORMA domain–closure motif complexes, but its mechanisms of substrate recognition and remodeling are unknown. Here, we combine X-ray crystallography and crosslinking mass spectrometry to outline how TRIP13 recognizes MAD2 with the help of the adapter protein p31comet. We show that p31comet binding to the TRIP13 N-terminal domain positions the disordered MAD2 N-terminus for engagement by the TRIP13 “poremore » loops”, which then unfold MAD2 in the presence of ATP. N-terminal truncation of MAD2 renders it refractory to TRIP13 action in vitro, and in cells causes spindle assembly checkpoint defects consistent with loss of TRIP13 function. Similar truncation of HORMAD1 in mouse spermatocytes compromises its TRIP13-mediated removal from meiotic chromosomes, highlighting a conserved mechanism for recognition and disassembly of HORMA domain–closure motif complexes by TRIP13.« less

Equilibria, prudent compromises, and the "waiting" game.

PubMed

Sim, Kwang Mong

2005-08-01

While evaluation of many e-negotiation agents are carried out through empirical studies, this work supplements and complements existing literature by analyzing the problem of designing market-driven agents (MDAs) in terms of equilibrium points and stable strategies. MDAs are negotiation agents designed to make prudent compromises taking into account factors such as time preference, outside option, and rivalry. This work shows that 1) in a given market situation, an MDA negotiates optimally because it makes minimally sufficient concession, and 2) by modeling negotiation of MDAs as a game gamma of incomplete information, it is shown that the strategies adopted by MDAs are stable. In a bilateral negotiation, it is proven that the strategy pair of two MDAs forms a sequential equilibrium for gamma. In a multilateral negotiation, it is shown that the strategy profile of MDAs forms a market equilibrium for gamma.

Comparison of Motor-Evoked Potentials Versus Somatosensory-Evoked Potentials as Early Indicators of Neural Compromise in Rat Model of Spinal Cord Compression.

PubMed

Morris, Susan H; Howard, Jason J; El-Hawary, Ron

2017-03-15

Randomized controlled study comparing the efficacy of intraoperative somatosensory-evoked potentials (SSEPs) versus transcranial motor-evoked potentials (TcMEPs) as early indicators of neural compromise and predictors of postoperative function in a rat model of spinal cord compression. To compare the relative efficacy of SSEPs and TcMEPs to detect spinal cord compromise and predict postoperative functional deficit after spinal cord compression. There is controversy regarding the efficacy of SSEPs versus TcMEPs to detect intraoperative spinal cord compromise and predict functional outcomes. Previous trials provide some guidance as to the role of each modality in spinal cord monitoring but randomized controlled trials, which are not feasible in humans, are lacking. Twenty-four adult male Wistar rats were evenly divided into three experimental groups and one control group. The experimental groups were determined according to the length of time that 100% TcMEP signal loss was maintained: 0, 5, or 15 minutes. All animals had standardized preoperative functional testing. Spinal cord compromise was initiated utilizing a validated protocol, which involved compression via a balloon catheter introduced into the thoracic sublaminar space. Both SSEPs and TcMEPs were recorded during cord compression for each experimental group. Functional behavioral testing using two validated methods (tilt and modified Tarlov) was repeated 24 hours after termination of spinal cord compression. Post hoc, animals were redistributed into two functional subgroups, noncompromised and compromised, for statistical analysis. TcMEPs consistently detected spinal cord compromise either in advance of or at the same time as SSEPs; however, the delay in SSEP response was not significant for cases when compromised postoperative function resulted. Both SSEP and TcMEP amplitude recovery correlated well with postoperative functional scores. TcMEPs are more sensitive to spinal cord compromise than SSEPs, but the

9 CFR 121.13 - Restricted experiments.

Code of Federal Regulations, 2014 CFR

2014-01-01

... naturally, if such acquisition could compromise the control of disease agents in humans, veterinary medicine... such acquisition could compromise the control of disease agents in humans, veterinary medicine, or... of select toxins lethal for vertebrates at an LD[50] body weight) resulting from, the...

9 CFR 121.13 - Restricted experiments.

Code of Federal Regulations, 2013 CFR

2013-01-01

... naturally, if such acquisition could compromise the control of disease agents in humans, veterinary medicine... such acquisition could compromise the control of disease agents in humans, veterinary medicine, or... of select toxins lethal for vertebrates at an LD[50] body weight) resulting from, the...

42 CFR 73.13 - Restricted experiments.

Code of Federal Regulations, 2013 CFR

2013-10-01

... acquisition could compromise the control of disease agents in humans, veterinary medicine, or agriculture, or... control of disease agents in humans, veterinary medicine, or agriculture, or recombinant and/or synthetic... trait naturally, if such acquisition could compromise the control of disease agents in humans...

Transcriptional regulation of the cytosolic chaperonin theta subunit gene, Cctq, by Ets domain transcription factors Elk-1, Sap-1a, and Net in the absence of serum response factor.

PubMed

Yamazaki, Yuji; Kubota, Hiroshi; Nozaki, Masami; Nagata, Kazuhiro

2003-08-15

The chaperonin-containing t-complex polypeptide 1 (CCT) is a molecular chaperone that facilitates protein folding in eukaryotic cytosol, and the expression of CCT is highly dependent on cell growth. We show here that transcription of the gene encoding the theta subunit of mouse CCT, Cctq, is regulated by the ternary complex factors (TCFs), Elk-1, Sap-1a, and Net (Sap-2). Reporter gene assay using HeLa cells indicated that the Cctq gene promoter contains a cis-acting element of the CCGGAAGT sequence (CQE1) at -36 bp. The major CQE1-binding proteins in HeLa cell nuclear extract was recognized by anti-Elk-1 or anti-Sap-1a antibodies in electrophoretic mobility shift assay, and recombinant Elk-1, Sap-1a, or Net specifically recognized CQE1. The CQE1-dependent transcriptional activity in HeLa cells was virtually abolished by overexpression of the DNA binding domains of TCFs. Overexpression of full-length TCFs with Ras indicated that exogenous TCFs can regulate the CQE1-dependent transcription in a Ras-dependent manner. PD98059, an inhibitor of MAPK, significantly repressed the CQE1-dependent transcription. However, no serum response factor was detected by electrophoretic mobility shift assay using the CQE1 element. These results indicate that transcription of the Cctq gene is regulated by TCFs under the control of the Ras/MAPK pathway, probably independently of serum response factor.

Impact of the North Atlantic circulation on the climate change patterns of North Sea.

NASA Astrophysics Data System (ADS)

Narayan, Nikesh; Mathis, Mortiz; Klein, Birgit; Klein, Holger; Mikolajewicz, Uwe

2017-04-01

The physical properties of the North Sea are characterized by the exchange of water masses with the North Atlantic at the northern boundary and Baltic Sea to the east. The combined effects of localized forcing, tidal mixing and advection of water masses make the North Sea a challenging study area. Previous investigations indicated a possibility that the variability of the North Atlantic circulation and the strength of the sub-polar gyre (SPG) might influence the physical properties of the North Sea. The assessment of the complex interaction between the North Atlantic and the North Sea in a climate change scenario requires regionally coupled global RCP simulations with enhanced resolution of the North Sea and the North Atlantic. In this study we analyzed result from the regionally coupled ocean-atmosphere-biogeochemistry model system (MPIOM-REMO-HAMOCC) with a hydrodynamic (HD) model. The ocean model has a zoomed grid which provides the highest resolution over the West European Shelf by shifting its poles over Chicago and Central Europe. An index for the intensity of SPG was estimated by averaging the barotropic stream function (ψ) over the North Atlantic. Various threshold values for ψ were tested to define the strength of the SPG. These SPG indices have been correlated with North Sea hydrographic parameters at various levels to identify areas affected by SPG variability. The influence of the Atlantic's eastern boundary current, contributing more saline waters to the North West European shelf area is also investigated.

Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation.

PubMed

Renvoisé, Benoît; Malone, Brianna; Falgairolle, Melanie; Munasinghe, Jeeva; Stadler, Julia; Sibilla, Caroline; Park, Seong H; Blackstone, Craig

2016-12-01

Hereditary spastic paraplegias (HSPs; SPG1-76 plus others) are length-dependent disorders affecting long corticospinal axons, and the most common autosomal dominant forms are caused by mutations in genes that encode the spastin (SPG4), atlastin-1 (SPG3A) and REEP1 (SPG31) proteins. These proteins bind one another and shape the tubular endoplasmic reticulum (ER) network throughout cells. They also are involved in lipid droplet formation, enlargement, or both in cells, though mechanisms remain unclear. Here we have identified evidence of partial lipoatrophy in Reep1 null mice in addition to prominent spastic paraparesis. Furthermore, Reep1-/- embryonic fibroblasts and neurons in the cerebral cortex both show lipid droplet abnormalities. The apparent partial lipodystrophy in Reep1 null mice, although less severe, is reminiscent of the lipoatrophy phenotype observed in the most common form of autosomal recessive lipodystrophy, Berardinelli-Seip congenital lipodystrophy. Berardinelli-Seip lipodystrophy is caused by autosomal recessive mutations in the BSCL2 gene that encodes an ER protein, seipin, that is also mutated in the autosomal dominant HSP SPG17 (Silver syndrome). Furthermore, REEP1 co-immunoprecipitates with seipin in cells. This strengthens the link between alterations in ER morphogenesis and lipid abnormalities, with important pathogenic implications for the most common forms of HSP. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.

Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval

PubMed Central

Hirst, Jennifer; Itzhak, Daniel N.; Antrobus, Robin; Borner, Georg H. H.

2018-01-01

The AP-5 adaptor protein complex is presumed to function in membrane traffic, but so far nothing is known about its pathway or its cargo. We have used CRISPR-Cas9 to knock out the AP-5 ζ subunit gene, AP5Z1, in HeLa cells, and then analysed the phenotype by subcellular fractionation profiling and quantitative mass spectrometry. The retromer complex had an altered steady-state distribution in the knockout cells, and several Golgi proteins, including GOLIM4 and GOLM1, were depleted from vesicle-enriched fractions. Immunolocalisation showed that loss of AP-5 led to impaired retrieval of the cation-independent mannose 6-phosphate receptor (CIMPR), GOLIM4, and GOLM1 from endosomes back to the Golgi region. Knocking down the retromer complex exacerbated this phenotype. Both the CIMPR and sortilin interacted with the AP-5–associated protein SPG15 in pull-down assays, and we propose that sortilin may act as a link between Golgi proteins and the AP-5/SPG11/SPG15 complex. Together, our findings suggest that AP-5 functions in a novel sorting step out of late endosomes, acting as a backup pathway for retromer. This provides a mechanistic explanation for why mutations in AP-5/SPG11/SPG15 cause cells to accumulate aberrant endolysosomes, and highlights the role of endosome/lysosome dysfunction in the pathology of hereditary spastic paraplegia and other neurodegenerative disorders. PMID:29381698

Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration.

PubMed

Branchu, Julien; Boutry, Maxime; Sourd, Laura; Depp, Marine; Leone, Céline; Corriger, Alexandrine; Vallucci, Maeva; Esteves, Typhaine; Matusiak, Raphaël; Dumont, Magali; Muriel, Marie-Paule; Santorelli, Filippo M; Brice, Alexis; El Hachimi, Khalid Hamid; Stevanin, Giovanni; Darios, Frédéric

2017-06-01

Mutations in SPG11 account for the most common form of autosomal recessive hereditary spastic paraplegia (HSP), characterized by a gait disorder associated with various brain alterations. Mutations in the same gene are also responsible for rare forms of Charcot-Marie-Tooth (CMT) disease and progressive juvenile-onset amyotrophic lateral sclerosis (ALS). To elucidate the physiopathological mechanisms underlying these human pathologies, we disrupted the Spg11 gene in mice by inserting stop codons in exon 32, mimicking the most frequent mutations found in patients. The Spg11 knockout mouse developed early-onset motor impairment and cognitive deficits. These behavioral deficits were associated with progressive brain atrophy with the loss of neurons in the primary motor cortex, cerebellum and hippocampus, as well as with accumulation of dystrophic axons in the corticospinal tract. Spinal motor neurons also degenerated and this was accompanied by fragmentation of neuromuscular junctions and muscle atrophy. This new Spg11 knockout mouse therefore recapitulates the full range of symptoms associated with SPG11 mutations observed in HSP, ALS and CMT patients. Examination of the cellular alterations observed in this model suggests that the loss of spatacsin leads to the accumulation of lipids in lysosomes by perturbing their clearance from these organelles. Altogether, our results link lysosomal dysfunction and lipid metabolism to neurodegeneration and pinpoint a critical role of spatacsin in lipid turnover. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

78 FR 53702 - User Fees for Processing Installment Agreements and Offers in Compromise

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-30

... User Fees for Processing Installment Agreements and Offers in Compromise AGENCY: Internal Revenue... document contains proposed amendments to the regulations that provide user fees for installment agreements... agencies to prescribe regulations that establish charges for services provided by the agencies (user fees...

Morgellons: contested illness, diagnostic compromise and medicalisation.

PubMed

Fair, Brian

2010-05-01

The case of Morgellons illustrates how the emergence of a new medically contested illness intersected with and impacted on the diagnostic processes of an existing uncontested psychiatric condition, Delusional Parasitosis (DP). More specifically, the sociopolitical processes at play in the contested illness, Morgellons, dubiously reflect patient empowerment, as well the resilience and power of medical jurisdiction. This research offers insights into the contested illness and medicalisation literatures, and aims to bridge these two approaches towards the relationship between patient empowerment and medical authority, which I do through the notion of doctor-patient compromise. The data for this research come from a comprehensive qualitative analysis of Morgellons discourse through four key sources: the pro-Morgellons website Morgellons.org; the anti-Morgellons website Morgellonswatch.com; the popular media's portrayal of Morgellons; and the DP and Morgellons articles published in peer-reviewed medical journals, as made available on PubMed.

Maternal high-fat diet and obesity compromise fetal hematopoiesis

PubMed Central

Kamimae-Lanning, Ashley N.; Krasnow, Stephanie M.; Goloviznina, Natalya A.; Zhu, Xinxia; Roth-Carter, Quinn R.; Levasseur, Peter R.; Jeng, Sophia; McWeeney, Shannon K.; Kurre, Peter; Marks, Daniel L.

2014-01-01

Objective Recent evidence indicates that the adult hematopoietic system is susceptible to diet-induced lineage skewing. It is not known whether the developing hematopoietic system is subject to metabolic programming via in utero high-fat diet (HFD) exposure, an established mechanism of adult disease in several organ systems. We previously reported substantial losses in offspring liver size with prenatal HFD. As the liver is the main hematopoietic organ in the fetus, we asked whether the developmental expansion of the hematopoietic stem and progenitor cell (HSPC) pool is compromised by prenatal HFD and/or maternal obesity. Methods We used quantitative assays, progenitor colony formation, flow cytometry, transplantation, and gene expression assays with a series of dietary manipulations to test the effects of gestational high-fat diet and maternal obesity on the day 14.5 fetal liver hematopoietic system. Results Maternal obesity, particularly when paired with gestational HFD, restricts physiological expansion of fetal HSPCs while promoting the opposing cell fate of differentiation. Importantly, these effects are only partially ameliorated by gestational dietary adjustments for obese dams. Competitive transplantation reveals compromised repopulation and myeloid-biased differentiation of HFD-programmed HSPCs to be a niche-dependent defect, apparent in HFD-conditioned male recipients. Fetal HSPC deficiencies coincide with perturbations in genes regulating metabolism, immune and inflammatory processes, and stress response, along with downregulation of genes critical for hematopoietic stem cell self-renewal and activation of pathways regulating cell migration. Conclusions Our data reveal a previously unrecognized susceptibility to nutritional and metabolic developmental programming in the fetal HSPC compartment, which is a partially reversible and microenvironment-dependent defect perturbing stem and progenitor cell expansion and hematopoietic lineage commitment. PMID

Relationship between Lower Tendency to Deceive in Aging and Inhibitory Compromise.

PubMed

El Haj, Mohamad; Antoine, Pascal

2018-01-01

Deception can be associated with a heterogeneous network of concepts such as exaggeration, misleading, white lies, and faking. This paper assesses the tendency to deceive in aging. Our main aim was to assess whether older adults would demonstrate a low tendency to deceive. A total of 42 older adults (mean age 67.64 years, SD 7.87) and 45 younger adults (mean age 21.71 years, SD 2.66) were administered a deception scale including items such as "I sometimes tell lies if I have to" or "I never take things that don't belong to me." Participants were also administered an inhibition task. The results demonstrated a low tendency to deceive and low inhibition in older adults compared with younger ones. The low tendency to deceive in the older adults was significantly correlated with their diminished inhibitory ability. The low tendency to deceive in aging seems to be related to a difficulty in inhibiting an honest response. Since inhibitory compromise has been considered mainly to trigger negative consequences for cognition, the present paper illustrates how this age-related compromise can be associated with positive social outcomes, i.e., a low tendency to deceive. © 2017 S. Karger AG, Basel.

Structure of GroEL in Complex with an Early Folding Intermediate of Alanine Glyoxylate Aminotransferase*

PubMed Central

Albert, Armando; Yunta, Cristina; Arranz, Rocío; Peña, Álvaro; Salido, Eduardo; Valpuesta, José María; Martín-Benito, Jaime

2010-01-01

Primary hyperoxaluria type 1 is a rare autosomal recessive disease caused by mutations in the alanine glyoxylate aminotransferase gene (AGXT). We have previously shown that P11L and I340M polymorphisms together with I244T mutation (AGXT-LTM) represent a conformational disease that could be amenable to pharmacological intervention. Thus, the study of the folding mechanism of AGXT is crucial to understand the molecular basis of the disease. Here, we provide biochemical and structural data showing that AGXT-LTM is able to form non-native folding intermediates. The three-dimensional structure of a complex between the bacterial chaperonin GroEL and a folding intermediate of AGXT-LTM mutant has been solved by cryoelectron microscopy. The electron density map shows the protein substrate in a non-native extended conformation that crosses the GroEL central cavity. Addition of ATP to the complex induces conformational changes on the chaperonin and the internalization of the protein substrate into the folding cavity. The structure provides a three-dimensional picture of an in vivo early ATP-dependent step of the folding reaction cycle of the chaperonin and supports a GroEL functional model in which the chaperonin promotes folding of the AGXT-LTM mutant protein through forced unfolding mechanism. PMID:20056599

Structure of GroEL in complex with an early folding intermediate of alanine glyoxylate aminotransferase.

PubMed

Albert, Armando; Yunta, Cristina; Arranz, Rocío; Peña, Alvaro; Salido, Eduardo; Valpuesta, José María; Martín-Benito, Jaime

2010-02-26

Primary hyperoxaluria type 1 is a rare autosomal recessive disease caused by mutations in the alanine glyoxylate aminotransferase gene (AGXT). We have previously shown that P11L and I340M polymorphisms together with I244T mutation (AGXT-LTM) represent a conformational disease that could be amenable to pharmacological intervention. Thus, the study of the folding mechanism of AGXT is crucial to understand the molecular basis of the disease. Here, we provide biochemical and structural data showing that AGXT-LTM is able to form non-native folding intermediates. The three-dimensional structure of a complex between the bacterial chaperonin GroEL and a folding intermediate of AGXT-LTM mutant has been solved by cryoelectron microscopy. The electron density map shows the protein substrate in a non-native extended conformation that crosses the GroEL central cavity. Addition of ATP to the complex induces conformational changes on the chaperonin and the internalization of the protein substrate into the folding cavity. The structure provides a three-dimensional picture of an in vivo early ATP-dependent step of the folding reaction cycle of the chaperonin and supports a GroEL functional model in which the chaperonin promotes folding of the AGXT-LTM mutant protein through forced unfolding mechanism.

Female genital alteration: a compromise solution.

PubMed

Arora, Kavita Shah; Jacobs, Allan J

2016-03-01

Despite 30 years of advocacy, the prevalence of non-therapeutic female genital alteration (FGA) in minors is stable in many countries. Educational efforts have minimally changed the prevalence of this procedure in regions where it has been widely practiced. In order to better protect female children from the serious and long-term harms of some types of non-therapeutic FGA, we must adopt a more nuanced position that acknowledges a wide spectrum of procedures that alter female genitalia. We offer a revised categorisation for non-therapeutic FGA that groups procedures by effect and not by process. Acceptance of de minimis procedures that generally do not carry long-term medical risks is culturally sensitive, does not discriminate on the basis of gender, and does not violate human rights. More morbid procedures should not be performed. However, accepting de minimis non-therapeutic f FGA procedures enhances the effort of compassionate practitioners searching for a compromise position that respects cultural differences but protects the health of their patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Conflict and Compromise: Catholic and Public Hospital Partnerships

PubMed Central

Wall, Barbra Mann

2010-01-01

This article analyzes the tensions and uneasy negotiations, based on a case study, that occurred among Catholic sisters, administrators, bishops, physicians, and the Vatican for more than seven years at a hospital in Austin, Texas. Here, the largest health care system in the city, which was Catholic, joined with the local public, tax-supported hospital that provided the majority of reproductive health care services in the region. A clash resulted over whether the hospital could continue providing sterilization and contraceptive services to its primarily poor patients. This article examines the fierce debates that occurred, especially over emergency contraception and attempts to develop creative solutions after a hierarchical crackdown from the Vatican. The end result was a compromise that included the creation of a “hospital within a hospital.” PMID:20067093

Food irradiation: Special solutions for the immuno-compromised

NASA Astrophysics Data System (ADS)

Mohácsi-Farkas, Csilla

2016-12-01

Safety of food is particularly important for immuno-compromised patients, because these people are vulnerable to all sorts of infectious complications and foodborne pathogens as well, and even organisms normally considered non-pathogenic may cause problems. According to the guidelines published by the FDA, immunocompromised patients have to avoid high-risk foods, and advised to consume only pasteurized juice, milk or cheese, and well-cooked eggs, poultry, meat and fish. In the frame of an IAEA CRP the objective was to develop, in collaborations with the healthcare community, the use of irradiation to increase the variety, availability and acceptability of foods for immunocompromised, for example irradiated fresh produce (fruits, vegetables, salads) and ready-to-eat meals. Further aim was to widen the acceptance of irradiated foods by the healthcare and regulatory communities.

Single pellet grasping following cervical spinal cord injury in adult rat using an automated full-time training robot

PubMed Central

Fenrich, Keith K.; May, Zacincte; Torres-Espín, Abel; Forero, Juan; Bennett, David J.; Fouad, Karim

2016-01-01

Task specific motor training is a common form of rehabilitation therapy in individuals with spinal cord injury (SCI). The single pellet grasping (SPG) task is a skilled forelimb motor task used to evaluate recovery of forelimb function in rodent models of SCI. The task requires animals to obtain food pellets located on a shelf beyond a slit at the front of an enclosure. Manually training and testing rats in the SPG task requires extensive time and often yields results with high outcome variability and small therapeutic windows (i.e., the difference between pre- and post-SCI success rates). Recent advances in automated SPG training using automated pellet presentation (APP) systems allow rats to train ad libitum 24 h a day, 7 days a week. APP trained rats have improved success rates, require less researcher time, and have lower outcome variability compared to manually trained rats. However, it is unclear whether APP trained rats can perform the SPG task using the APP system after SCI. Here we show that rats with cervical SCI can successfully perform the SPG task using the APP system. We found that SCI rats with APP training performed significantly more attempts, had slightly lower and less variable final score success rates, and larger therapeutic windows than SCI rats with manual training. These results demonstrate that APP training has clear advantages over manual training for evaluating reaching performance of SCI rats and represents a new tool for investigating rehabilitative motor training following CNS injury. PMID:26611563

Explaining the relation between pathological gambling and depression: Rumination as an underlying common cause.

PubMed

Krause, Kristian; Bischof, Anja; Lewin, Silvia; Guertler, Diana; Rumpf, Hans-Jürgen; John, Ulrich; Meyer, Christian

2018-05-30

Background and aims Symptoms of pathological gambling (SPG) and depression often co-occur. The nature of this relationship remains unclear. Rumination, which is well known to be associated with depression, might act as a common underlying factor explaining the frequent co-occurrence of both conditions. The aim of this study is to analyze associations between the rumination subfactors brooding and reflection and SPG. Methods Participants aged 14-64 years were recruited within an epidemiological study on pathological gambling in Germany. Cross-sectional data of 506 (80.4% male) individuals with a history of gambling problems were analyzed. The assessment included a standardized clinical interview. To examine the effects of rumination across different levels of problem gambling severity, sequential quantile regression was used to analyze the association between the rumination subfactors and SPG. Results Brooding (p = .005) was positively associated with the severity of problem gambling after adjusting for reflection, depressive symptoms, and sociodemographic variables. Along the distribution of problem gambling severity, findings hold for all but the lowest severity level. Reflection (p = .347) was not associated with the severity of problem gambling at the median. Along the distribution of problem gambling severity, there was an inverse association at only one quantile. Discussion and conclusions Brooding might be important in the development and maintenance of problem gambling. With its relations to depression and problem gambling, it might be crucial when it comes to explaining the high comorbidity rates between SPG and depression. The role of reflection in SPG remains inconclusive.

Single pellet grasping following cervical spinal cord injury in adult rat using an automated full-time training robot.

PubMed

Fenrich, Keith K; May, Zacincte; Torres-Espín, Abel; Forero, Juan; Bennett, David J; Fouad, Karim

2016-02-15

Task specific motor training is a common form of rehabilitation therapy in individuals with spinal cord injury (SCI). The single pellet grasping (SPG) task is a skilled forelimb motor task used to evaluate recovery of forelimb function in rodent models of SCI. The task requires animals to obtain food pellets located on a shelf beyond a slit at the front of an enclosure. Manually training and testing rats in the SPG task requires extensive time and often yields results with high outcome variability and small therapeutic windows (i.e., the difference between pre- and post-SCI success rates). Recent advances in automated SPG training using automated pellet presentation (APP) systems allow rats to train ad libitum 24h a day, 7 days a week. APP trained rats have improved success rates, require less researcher time, and have lower outcome variability compared to manually trained rats. However, it is unclear whether APP trained rats can perform the SPG task using the APP system after SCI. Here we show that rats with cervical SCI can successfully perform the SPG task using the APP system. We found that SCI rats with APP training performed significantly more attempts, had slightly lower and less variable final score success rates, and larger therapeutic windows than SCI rats with manual training. These results demonstrate that APP training has clear advantages over manual training for evaluating reaching performance of SCI rats and represents a new tool for investigating rehabilitative motor training following CNS injury. Copyright © 2015 Elsevier B.V. All rights reserved.

Heterotrophic organisms dominate nitrogen fixation in the South Pacific Gyre

PubMed Central

Halm, Hannah; Lam, Phyllis; Ferdelman, Timothy G; Lavik, Gaute; Dittmar, Thorsten; LaRoche, Julie; D'Hondt, Steven; Kuypers, Marcel MM

2012-01-01

Oceanic subtropical gyres are considered biological deserts because of the extremely low availability of nutrients and thus minimum productivities. The major source of nutrient nitrogen in these ecosystems is N2-fixation. The South Pacific Gyre (SPG) is the largest ocean gyre in the world, but measurements of N2-fixation therein, or identification of microorganisms involved, are scarce. In the 2006/2007 austral summer, we investigated nitrogen and carbon assimilation at 11 stations throughout the SPG. In the ultra-oligotrophic waters of the SPG, the chlorophyll maxima reached as deep as 200 m. Surface primary production seemed limited by nitrogen, as dissolved inorganic carbon uptake was stimulated upon additions of 15N-labeled ammonium and leucine in our incubation experiments. N2-fixation was detectable throughout the upper 200 m at most stations, with rates ranging from 0.001 to 0.19 nM N h−1. N2-fixation in the SPG may account for the production of 8–20% of global oceanic new nitrogen. Interestingly, comparable 15N2-fixation rates were measured under light and dark conditions. Meanwhile, phylogenetic analyses for the functional gene biomarker nifH and its transcripts could not detect any common photoautotrophic diazotrophs, such as, Trichodesmium, but a prevalence of γ-proteobacteria and the unicellular photoheterotrophic Group A cyanobacteria. The dominance of these likely heterotrophic diazotrophs was further verified by quantitative PCR. Hence, our combined results show that the ultra-oligotrophic SPG harbors a hitherto unknown heterotrophic diazotrophic community, clearly distinct from other oceanic gyres previously visited. PMID:22170429

Establishment of Normal Gut Microbiota Is Compromised under Excessive Hygiene Conditions

PubMed Central

Schmidt, Bettina; Mulder, Imke E.; Musk, Corran C.; Aminov, Rustam I.; Lewis, Marie; Stokes, Christopher R.; Bailey, Mick; Prosser, James I.; Gill, Bhupinder P.; Pluske, John R.; Kelly, Denise

2011-01-01

Background Early gut colonization events are purported to have a major impact on the incidence of infectious, inflammatory and autoimmune diseases in later life. Hence, factors which influence this process may have important implications for both human and animal health. Previously, we demonstrated strong influences of early-life environment on gut microbiota composition in adult pigs. Here, we sought to further investigate the impact of limiting microbial exposure during early life on the development of the pig gut microbiota. Methodology/Principal Findings Outdoor- and indoor-reared animals, exposed to the microbiota in their natural rearing environment for the first two days of life, were transferred to an isolator facility and adult gut microbial diversity was analyzed by 16S rRNA gene sequencing. From a total of 2,196 high-quality 16S rRNA gene sequences, 440 phylotypes were identified in the outdoor group and 431 phylotypes in the indoor group. The majority of clones were assigned to the four phyla Firmicutes (67.5% of all sequences), Proteobacteria (17.7%), Bacteroidetes (13.5%) and to a lesser extent, Actinobacteria (0.1%). Although the initial maternal and environmental microbial inoculum of isolator-reared animals was identical to that of their naturally-reared littermates, the microbial succession and stabilization events reported previously in naturally-reared outdoor animals did not occur. In contrast, the gut microbiota of isolator-reared animals remained highly diverse containing a large number of distinct phylotypes. Conclusions/Significance The results documented here indicate that establishment and development of the normal gut microbiota requires continuous microbial exposure during the early stages of life and this process is compromised under conditions of excessive hygiene. PMID:22164261

Metabolic Potential of Microbial Genomes Reconstructed from a Deep-Sea Oligotrophic Sediment Metagenome

NASA Astrophysics Data System (ADS)

Tully, B. J.; Huber, J. A.; Heidelberg, J. F.

2016-02-01

The South Pacific Gyre (SPG) possesses the lowest rates of sedimentation, surface chlorophyll concentration and primary productivity in the global oceans, making it one of the most oligotrophic environments on earth. As a direct result of the low-standing biomass in surface waters, deep-sea sediments are thin and contain small amount of labile organic carbon. It was recently shown that the sediment column within the SPG is fully oxic through to the underlying basalt basement and may be representative of 9-37% of the global marine environment. In addition, it appears that approximately 50% of the total organic carbon is removed from the oligotrophic sediments within the first 20 centimeters beneath the sea floor (cmbsf). To understand the microbial processes that contribute to the removal of the labile organic matter, metagenomic sequencing and analysis was carried out on a sample of sediment collected from 0-5 cmbsf from SPG site 10 (U1369). Analysis of 9 partially reconstructed environmental genomes revealed that the members of the SPG surface sediment microbial community are phylogenetically distinct from surface/upper ocean organisms, with deep branches within the Alpha- and Gammaproteobacteria, Nitrospirae, Nitrospina, the phylum NC10, and several unique phylogenetic groups. Within these partially complete genomes there is evidence for microbially mediated metal (iron/manganese) oxidation and carbon fixation linked to the nitrification. Additionally, despite low sedimentation and hypothesized energy-limitation, members of the SPG microbial community had motility and chemotactic genes and possessed mechanisms for the utilization of high molecular weight organic matter, including exoproteases and peptide specific membrane transporters. Simultaneously, the SPG genomes showed a limited potential for the degradation of recalcitrant carbon compounds. Finally, the presence of putative genes with functions involved with denitrification and the consumption of C1

The subpolar North Atlantic - Response to North Atlantic oscillation like forcing and Influence on the Atlantic meridional overturning circulation

NASA Astrophysics Data System (ADS)

Lohmann, Katja; Drange, Helge; Jungclaus, Johann

2010-05-01

The extent and strength of the North Atlantic subpolar gyre (SPG) changed rapidly in the mid-1990s, going from large and strong in 1995 to substantially weakened in the following years. The abrupt change in the intensity of the SPG is commonly linked to the reversal of the North Atlantic Oscillation (NAO) index, changing from strong positive to negative values, in the winter 1995/96. In this study we investigate the impact of the initial SPG state on its subsequent behavior by means of an ocean general circulation model driven by NCEP-NCAR reanalysis fields. Our sensitivity integrations suggest that the weakening of the SPG cannot be explained by the change in the atmospheric forcing alone. Rather, for the time period around 1995, the SPG was about to weaken, irrespective of the actual atmospheric forcing, due to the ocean state governed by the persistently strong positive NAO during the preceding seven years (1989 to 1995). Our analysis indicates that it was this preconditioning of the ocean, in combination with the sudden drop in the NAO in 1995/96, that lead to the strong and rapid weakening of the SPG in the second half of the 1990s. In the second part, the sensitivity of the low-frequency variability of the Atlantic meridional overturning circulation to changes in the subpolar North Atlantic is investigated using a 2000 year long control integration as well as sensitivity experiments with the MPI-M Earth System Model. Two 1000 year long sensitivity experiments will be performed, in which the low-frequency variability in the overflow transports from the Nordic Seas and in the subpolar deep water formation rates is suppressed respectively. This is achieved by nudging temperature and salinity in the GIN Sea or in the subpolar North Atlantic (up to about 1500m depth) towards a monthly climatology obtained from the last 1000 years of the control integration.

Hypothesis of demodicidosis rosacea flushing etiopathogenesis.

PubMed

Robledo, Mary Ann; Orduz, Mariana

2015-04-01

Most of the patients with erythematotelangiectatic rosacea are characterized by flushing, oedema and telangiectasia. The etiopathogenesis of the flushing in rosacea patients is unknown. Clinically the flushing in rosacea is similar to the "Asian flushing syndrome". Most Asians have an overactive alcohol dehydrogenase (ADH) that tends to break down alcohol into acetaldehyde faster. People with "Asians flushing syndrome" have a genetic disorder with the Aldehyde Dehydrogenase 2(∗)2 (ALDH2(∗)2) allele. This is the reason why they do not metabolize very well the acetaldehyde that comes from the alcohol, which means that acetaldehyde takes much longer to clear from their blood. ALDH2 enzyme is primarily responsible for oxidation of acetaldehyde derived from ethanol metabolism, as well as oxidation of various other endogenous and exogenous aldehydes. Acetaldehyde produces the vasodilatation in the "Asian flushing syndrome". The antibodies against the GroEl chaperonin protein, a 62-kDa heat shock protein were found in the Bacillus oleronius isolated from Demodex mites, in rosacea patients. The GroEl chaperonin protein is a protein that plays a key role in normal folding of ALDH2. If the GroEl chaperonin antibodies found in patients with rosacea, cross react with the human GroEl chaperonin protein, they will not fold normally the ALDH2, and then the enzyme will not metabolize the acetaldehyde. Many of the patients with rosacea have a concomitant infection with Helicobacter pylori in their stomach. The H.pylori produces high amounts of acetaldehyde, which comes from their metabolism of ethanol or carbohydrates. As a result, high amounts of acetaldehyde will circulate for longer time in the blood, until the liver CYP2E1(p450) enzyme system finally metabilizes the acetaldehyde, during that period of time the patients will experience a flushing as well as the people with the "Asian flushing syndrome" suffer when they drink ethanol. To prove the hypothesis it is necessary

Mitigating Reptile Road Mortality: Fence Failures Compromise Ecopassage Effectiveness

PubMed Central

Baxter-Gilbert, James H.; Riley, Julia L.; Lesbarrères, David; Litzgus, Jacqueline D.

2015-01-01

Roadways pose serious threats to animal populations. The installation of roadway mitigation measures is becoming increasingly common, yet studies that rigorously evaluate the effectiveness of these conservation tools remain rare. A highway expansion project in Ontario, Canada included exclusion fencing and ecopassages as mitigation measures designed to offset detrimental effects to one of the most imperial groups of vertebrates, reptiles. Taking a multispecies approach, we used a Before-After-Control-Impact study design to compare reptile abundance on the highway before and after mitigation at an Impact site and a Control site from 1 May to 31 August in 2012 and 2013. During this time, radio telemetry, wildlife cameras, and an automated PIT-tag reading system were used to monitor reptile movements and use of ecopassages. Additionally, a willingness to utilize experiment was conducted to quantify turtle behavioral responses to ecopassages. We found no difference in abundance of turtles on the road between the un-mitigated and mitigated highways, and an increase in the percentage of both snakes and turtles detected dead on the road post-mitigation, suggesting that the fencing was not effective. Although ecopassages were used by reptiles, the number of crossings through ecopassages was lower than road-surface crossings. Furthermore, turtle willingness to use ecopassages was lower than that reported in previous arena studies, suggesting that effectiveness of ecopassages may be compromised when alternative crossing options are available (e.g., through holes in exclusion structures). Our rigorous evaluation of reptile roadway mitigation demonstrated that when exclusion structures fail, the effectiveness of population connectivity structures is compromised. Our project emphasizes the need to design mitigation measures with the biology and behavior of the target species in mind, to implement mitigation designs in a rigorous fashion, and quantitatively evaluate road

Mitigating reptile road mortality: fence failures compromise ecopassage effectiveness.

PubMed

Baxter-Gilbert, James H; Riley, Julia L; Lesbarrères, David; Litzgus, Jacqueline D

2015-01-01

Roadways pose serious threats to animal populations. The installation of roadway mitigation measures is becoming increasingly common, yet studies that rigorously evaluate the effectiveness of these conservation tools remain rare. A highway expansion project in Ontario, Canada included exclusion fencing and ecopassages as mitigation measures designed to offset detrimental effects to one of the most imperial groups of vertebrates, reptiles. Taking a multispecies approach, we used a Before-After-Control-Impact study design to compare reptile abundance on the highway before and after mitigation at an Impact site and a Control site from 1 May to 31 August in 2012 and 2013. During this time, radio telemetry, wildlife cameras, and an automated PIT-tag reading system were used to monitor reptile movements and use of ecopassages. Additionally, a willingness to utilize experiment was conducted to quantify turtle behavioral responses to ecopassages. We found no difference in abundance of turtles on the road between the un-mitigated and mitigated highways, and an increase in the percentage of both snakes and turtles detected dead on the road post-mitigation, suggesting that the fencing was not effective. Although ecopassages were used by reptiles, the number of crossings through ecopassages was lower than road-surface crossings. Furthermore, turtle willingness to use ecopassages was lower than that reported in previous arena studies, suggesting that effectiveness of ecopassages may be compromised when alternative crossing options are available (e.g., through holes in exclusion structures). Our rigorous evaluation of reptile roadway mitigation demonstrated that when exclusion structures fail, the effectiveness of population connectivity structures is compromised. Our project emphasizes the need to design mitigation measures with the biology and behavior of the target species in mind, to implement mitigation designs in a rigorous fashion, and quantitatively evaluate road

Study of flood defense structural measures priorities using Compromise Programming technique

NASA Astrophysics Data System (ADS)

Lim, D.; Jeong, S.

2017-12-01

Recent climate change of global warming has led to the frequent occurrence of heavy regional rainfalls. As such, inundation vulnerability increases in urban areas with high population density due to the low runoff carrying capacity. This study selects a sample area (Janghang-eup, the Republic of Korea), which is one of the most vulnerable areas to flooding, analyzing the urban flood runoff model (XP-SWMM) and using the MCDM (Multi-Criteria Decision Making) technique to establish flood protection structural measures. To this end, we compare the alternatives and choose the optimal flood defense measure: our model is utilized with three flood prevention structural measures; (i) drainage pipe construction; (ii) water detention; and (iii) flood pumping station. Dividing the target area into three small basins, we propose flood evaluations for an inundation decrease by studying the flooded area, the maximum inundation depth, the damaged residential area, and the construction cost. In addition, Compromise Programming determines the priority of the alternatives. As a consequent, this study suggests flood pumping station for Zone 1 and drainage pipe construction for Zone 2 and Zone 3, respectively, as the optimal flood defense alternative. Keywords : MCDM; Compromise Programming; Urban Flood Prevention; This research was supported by a grant [MPSS-DP-2013-62] through the Disaster and Safety Management Institute funded by Ministry of Public Safety and Security of Korean government.

Long-term efficacy of a double-blind, placebo-controlled, randomized study for repetitive sphenopalatine blockade with bupivacaine vs. saline with the Tx360 device for treatment of chronic migraine.

PubMed

Cady, Roger K; Saper, Joel; Dexter, Kent; Cady, Ryan J; Manley, Heather R

2015-04-01

number of headache days 1 month post-treatment (Mdiff  = -5.71), whereas those receiving saline only saw a slight improvement (Mdiff  = -1.93). Headache Impact Test 6 scores were decreased in the bupivacaine group at 1 month (Mdiff  = -5.13) and 6 months (Mdiff  = -4.78) post-treatment, but only a modest reduction was seen for those receiving saline at 1 and 6 months, respectively (Mdiff  = -2.08, Mdiff  = -1.58). Furthermore, subjects receiving bupivacaine reported a reduction in acute medication usage and improved quality of life measures (average pain in the previous 24 hours, mood, normal work, and general activity) up to 6 months post-treatment. The changes in these measures for the saline group were minimal. Data from this exploratory pilot study suggest that there may be long-term clinical benefits with the use of repetitive SPG blockades with bupivacaine delivered with the simple to use Tx360 device. These include a sustained reduction of headache days and improvement in several important quality of life assessments. The SPG blockades were not associated with any significant or lasting adverse events. Further research on SPG blockade is warranted. © 2015 The Authors. Headache published by Wiley Periodicals, Inc. on behalf of American Headache Society.

Rofecoxib does not compromise platelet aggregation during anesthesia and surgery.

PubMed

Silverman, David G; Halaszynski, Thomas; Sinatra, Raymond; Luther, Martha; Rinder, Christine S

2003-12-01

This study was undertaken because, although there is evidence that cyclooxygenase type 2 (COX)-2 inhibitors do not compromise platelets in healthy volunteers, many clinicians remain hesitant to administer them perioperatively without definitive evidence of intact platelet function during anesthesia and surgery. In 20 patients scheduled for lower abdominal and pelvic surgery, 5 mL of blood were obtained for baseline platelet aggregometry. One hour prior to surgery, patients received an oral solution of either rofecoxib (ROF) 50 mg or placebo (PLAC) by randomized, double-blinded assignment. Approximately one hour after onset of anesthesia, an intraoperative blood sample was obtained. Baseline and postdrug samples were centrifuged to generate platelet-rich plasma, which was challenged with adenosine diphosphate (ADP) and arachidonic acid (AA). Aggregometry was performed with and without incubation with aspirin. The data in each subject were normalized to baseline aggregation in response to AA alone and ADP alone. Intergroup differences were assessed using paired t test; P < 0.05 was considered significant. Consistent with known effects of anesthesia on platelet function, both groups had approximately 25% intraoperative declines in aggregation in response to ADP (P = NS for PLAC vs ROF) and even greater declines in response to AA (P = NS for PLAC vs ROF). Aspirin eliminated aggregation in response to AA in both groups (P = NS), and it caused similar declines in PLAC and ROF groups during exposure to ADP (P = NS). This study provides strong evidence that ROF does not compromise platelet aggregation during anesthesia and surgery; nor does it interfere with the platelet inhibitory effect of aspirin.

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

Encapsulated eucalyptus oil in ionically cross-linked alginate microcapsules and its controlled release.

PubMed

Noppakundilograt, Supaporn; Piboon, Phianghathai; Graisuwan, Wilaiporn; Nuisin, Roongkan; Kiatkamjornwong, Suda

2015-10-20

Sodium alginate microcapsules containing eucalyptus oil were prepared by oil-in-water emulsification via Shirasu porous glass (SPG) membrane and cross-linked by calcium chloride (CaCl2). SPG membrane pore size of 5.2μm was used to control the size of eucalyptus oil microdroplets. Effects of sodium alginate, having a mannuronic acid/guluronic acid (M/G) ratio of 1.13, eucalyptus oil and CaCl2 amounts on microdroplet sizes and size distribution were elucidated. Increasing sodium alginate amounts from 0.1 to 0.5% (wv(-1)) sodium alginate, the average droplets size increased from 42.2±2.0 to 48.5±0.6μm, with CVs of 16.5±2.2 and 30.2±4.5%, respectively. CaCl2 successfully gave narrower size distribution of cross-linked eucalyptus oil microcapsules. The optimum conditions for preparing the microcapsules, oil loading efficiency, and controlled release of the encapsulated eucalyptus oil from the microcapsules as a function of time at 40°C were investigated. Release model for the oil from microcapsules fitted Ritger-Peppas model with non-Fickian transport mechanism. Copyright © 2015 Elsevier Ltd. All rights reserved.

Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis

PubMed Central

Henry, Curtis J.; Nemkov, Travis; Casás-Selves, Matias; Bilousova, Ganna; Zaberezhnyy, Vadym; Higa, Kelly C.; Serkova, Natalie J.; Hansen, Kirk C.; D’Alessandro, Angelo; DeGregori, James

2017-01-01

While dietary folate deficiency is associated with increased risk for birth defects and other diseases, evidence suggests that supplementation with folic acid can contribute to predisposition to some diseases, including immune dysfunction and cancer. Herein, we show that diets supplemented with folic acid both below and above the recommended levels led to significantly altered metabolism in multiple tissues in mice. Surprisingly, both low and excessive dietary folate induced similar metabolic changes, which were particularly evident for nucleotide biosynthetic pathways in B-progenitor cells. Diet-induced metabolic changes in these cells partially phenocopied those observed in mice treated with anti-folate drugs, suggesting that both deficiency and excessive levels of dietary folic acid compromise folate-dependent biosynthetic pathways. Both folate deficiency and excessive dietary folate levels compromise hematopoiesis, resulting in defective cell cycle progression, persistent DNA damage, and impaired production of lymphocytes. These defects reduce the reconstitution potential in transplantation settings and increase radiation-induced mortality. We conclude that excessive folic acid supplementation can metabolically mimic dietary folate insufficiency, leading to similar functional impairment of hematopoiesis. PMID:28883079

Understanding Youth's Health-Compromising Behaviors in Germany: An Application of the Risk-Behavior Framework.

ERIC Educational Resources Information Center

Hazard, Barbara P.; Lee, Che-Fu

1999-01-01

Analyzed the health-compromising behaviors of German youth using responses of 2,330 seventh, eighth, and ninth graders from the German Youth Study. Smoking and drinking are not seen by these students as health-threatening behaviors, but as socially appealing behaviors. Discusses implications for health education. (SLD)

Experience with protective isolation for infection prevention in the compromised host.

PubMed

Nagao, T

1986-01-01

Ten years of experience with protective isolation of compromised patients was analyzed. The total number of patients was 191 including 116 patients with leukemia. Isolation could significantly prevent exogenous infections such as pneumonia, and prophylactic antibiotic regimens consisting of vancomycin and other nonabsorbable antibiotics could reduce the onset of endogenous infections such as sepsis. Elimination of serious and fatal infections by isolation together with prophylactic antibiotics increased the chances of remission or long-term survival for cases of hematological malignancies, solid tumor and bone marrow transplantation.

Improved single pellet grasping using automated ad libitum full-time training robot.

PubMed

Fenrich, Keith K; May, Zacnicte; Hurd, Caitlin; Boychuk, Carolyn E; Kowalczewski, Jan; Bennett, David J; Whishaw, Ian Q; Fouad, Karim

2015-03-15

The single pellet grasping (SPG) task is a skilled forelimb motor task commonly used to evaluate reaching and grasp kinematics and recovery of forelimb function in rodent models of CNS injuries and diseases. To train rats in the SPG task, the animals are usually food restricted then placed in an SPG task enclosure and presented food pellets on a platform located beyond a slit located at the front of the task enclosure for 10-30 min, normally every weekday for several weeks. When the SPG task is applied in studies involving various experimental groups, training quickly becomes labor intensive, and can yield results with significant day-to-day variability. Furthermore, training is frequently done during the animals' light-cycle, which for nocturnal rodents such as mice and rats could affect performance. Here we describe an automated pellet presentation (APP) robotic system to train and test rats in the SPG task that reduces some of the procedural weaknesses of manual training. We found that APP trained rats performed significantly more trials per 24 h period, and had higher success rates with less daily and weekly variability than manually trained rats. Moreover, the results show that success rates are positively correlated with the number of dark-cycle trials, suggesting that dark-cycle training has a positive effect on success rates. These results demonstrate that automated training is an effective method for evaluating and training skilled reaching performance of rats, opening up the possibility for new approaches to investigating the role of motor systems in enabling skilled forelimb use and new approaches to investigating rehabilitation following CNS injury. Copyright © 2014 Elsevier B.V. All rights reserved.

Saint Petersburg magnetic observatory: from Voeikovo subdivision to INTERMAGNET certification

NASA Astrophysics Data System (ADS)

Sidorov, Roman; Soloviev, Anatoly; Krasnoperov, Roman; Kudin, Dmitry; Grudnev, Andrei; Kopytenko, Yury; Kotikov, Andrei; Sergushin, Pavel

2017-11-01

Since June 2012 the Saint Petersburg magnetic observatory is being developed and maintained by two institutions of the Russian Academy of Sciences (RAS) - the Geophysical Center of RAS (GC RAS) and the Saint Petersburg branch of the Pushkov Institute of Terrestrial Magnetism, Ionosphere and Radio Wave Propagation of RAS (IZMIRAN SPb). On 29 April 2016 the application of the Saint Petersburg observatory (IAGA code SPG) for introduction into the INTERMAGNET network was accepted after approval by the experts of the first definitive dataset over 2015, produced by the GC RAS, and on 9 June 2016 the SPG observatory was officially certified. One of the oldest series of magnetic observations, originating in 1834, was resumed in the 21st century, meeting the highest quality standards and all modern technical requirements. In this paper a brief historical and scientific background of the SPG observatory foundation and development is given, the stages of its renovation and upgrade in the 21st century are described, and information on its current state is provided. The first results of the observatory functioning are discussed and geomagnetic variations registered at the SPG observatory are assessed and compared with geomagnetic data from the INTERMAGNET observatories located in the same region.

Water Vapor Transfer and Near-Surface Salinity Contrasts in the North Atlantic Ocean.

PubMed

Reagan, James; Seidov, Dan; Boyer, Tim

2018-06-11

Maintaining North Atlantic (NA) intra-basin near-surface salinity (NSS) contrast between the high NSS (>37.0) in the subtropical NA (STNA) and low NSS (<35.0) in the subpolar NA (SPNA) has been shown to be important in sustaining the strength of the Atlantic Meridional Overturning Circulation. Evaporation (E) exceeding precipitation (P) in the STNA is primarily responsible for the high NSS there, whereas P dominating E in the SPNA contributes to its low NSS. With a basic understanding of NA intra-basin moisture transport, a correlation analysis was conducted between E-P/NSS over the NA subpolar gyre (SPG) and E-P across the rest of the NA over the 1985-2012 time period. Significant anti-correlations exist between E-P/NSS over the NA SPG and E-P over the central/northern STNA. This suggests that during times of high E over the central/northern STNA there is high (low) precipitation (NSS) over the SPG demonstrating a relationship likely exists between E over the STNA and NSS over the SPG. The maximum anti-correlated area is poleward of the maximum E-P location in the STNA, which is examined. These results provide a first step to ultimately utilizing NSS in the NA as a proxy for estimating changes in the hydrological cycle.

A deep oxic ecosystem in the subseafloor South Pacific Gyre

NASA Astrophysics Data System (ADS)

D'Hondt, S. L.; Inagaki, F.; Alvarez Zarikian, C. A.; Integrated Ocean Drilling Program Expedition 329 Shipboard Scientific Party

2011-12-01

Scientific ocean drilling has demonstrated the occurrence of rich microbial communities, abundant active cells and diverse anaerobic activities in anoxic subseafloor sediment. Buried organic matter from the surface photosynthetic world sustains anaerobic heterotrophs in anoxic sediment as deeply buried as 1.6 km below the seafloor. However, these studies have been mostly restricted to the organic-rich sediment of continental margins and biologically productive regions. IODP Expedition 329 discovered that subseafloor habitat and life are fundamentally different in the vast expanse of organic-poor sediment that underlies Earth's largest oceanic province, the South Pacific Gyre (SPG). Dissolved O2 and dissolved major nutrients (C, N, P) are present throughout the entire sediment sequence and the upper basaltic basement of the SPG. The drilled sediment is up to 75 m thick. Although heterotrophic O2 reduction (aerobic respiration) persists for millions of years in SPG sediment (which accumulates very slowly), it falls below minimum detection just a few meters to tens of meters beneath the SPG seafloor. Cell concentrations approach minimum detection at similar depths, but are intermittently detectable throughout the entire sediment sequence. In situ radiolysis of water may be a significant source of energy for the microbes that inhabit the deepest (oldest) sediment.

28 CFR 0.163 - Approval by Solicitor General of action on compromise offers in certain cases.

Code of Federal Regulations, 2010 CFR

2010-07-01

... advice from the Solicitor General that the principles of law involved do not require appellate review in... JUSTICE ORGANIZATION OF THE DEPARTMENT OF JUSTICE Authority To Compromise and Close Civil Claims and...

Efficient Enzymatic Preparation of (13) N-Labelled Amino Acids: Towards Multipurpose Synthetic Systems.

PubMed

da Silva, Eunice S; Gómez-Vallejo, Vanessa; Baz, Zuriñe; Llop, Jordi; López-Gallego, Fernando

2016-09-12

Nitrogen-13 can be efficiently produced in biomedical cyclotrons in different chemical forms, and its stable isotopes are present in the majority of biologically active molecules. Hence, it may constitute a convenient alternative to Fluorine-18 and Carbon-11 for the preparation of positron-emitter-labelled radiotracers; however, its short half-life demands for the development of simple, fast, and efficient synthetic processes. Herein, we report the one-pot, enzymatic and non-carrier-added synthesis of the (13) N-labelled amino acids l-[(13) N]alanine, [(13) N]glycine, and l-[(13) N]serine by using l-alanine dehydrogenase from Bacillus subtilis, an enzyme that catalyses the reductive amination of α-keto acids by using nicotinamide adenine dinucleotide (NADH) as the redox cofactor and ammonia as the amine source. The integration of both l-alanine dehydrogenase and formate dehydrogenase from Candida boidinii in the same reaction vessel to facilitate the in situ regeneration of NADH during the radiochemical synthesis of the amino acids allowed a 50-fold decrease in the concentration of the cofactor without compromising reaction yields. After optimization of the experimental conditions, radiochemical yields were sufficient to carry out in vivo imaging studies in small rodents. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

GroEL actively stimulates folding of the endogenous substrate protein PepQ.

PubMed

Weaver, Jeremy; Jiang, Mengqiu; Roth, Andrew; Puchalla, Jason; Zhang, Junjie; Rye, Hays S

2017-06-30

Many essential proteins cannot fold without help from chaperonins, like the GroELS system of Escherichia coli. How chaperonins accelerate protein folding remains controversial. Here we test key predictions of both passive and active models of GroELS-stimulated folding, using the endogenous E. coli metalloprotease PepQ. While GroELS increases the folding rate of PepQ by over 15-fold, we demonstrate that slow spontaneous folding of PepQ is not caused by aggregation. Fluorescence measurements suggest that, when folding inside the GroEL-GroES cavity, PepQ populates conformations not observed during spontaneous folding in free solution. Using cryo-electron microscopy, we show that the GroEL C-termini make physical contact with the PepQ folding intermediate and help retain it deep within the GroEL cavity, resulting in reduced compactness of the PepQ monomer. Our findings strongly support an active model of chaperonin-mediated protein folding, where partial unfolding of misfolded intermediates plays a key role.

Hydro-environmental management of groundwater resources: A fuzzy-based multi-objective compromise approach

NASA Astrophysics Data System (ADS)

Alizadeh, Mohammad Reza; Nikoo, Mohammad Reza; Rakhshandehroo, Gholam Reza

2017-08-01

Sustainable management of water resources necessitates close attention to social, economic and environmental aspects such as water quality and quantity concerns and potential conflicts. This study presents a new fuzzy-based multi-objective compromise methodology to determine the socio-optimal and sustainable policies for hydro-environmental management of groundwater resources, which simultaneously considers the conflicts and negotiation of involved stakeholders, uncertainties in decision makers' preferences, existing uncertainties in the groundwater parameters and groundwater quality and quantity issues. The fuzzy multi-objective simulation-optimization model is developed based on qualitative and quantitative groundwater simulation model (MODFLOW and MT3D), multi-objective optimization model (NSGA-II), Monte Carlo analysis and Fuzzy Transformation Method (FTM). Best compromise solutions (best management policies) on trade-off curves are determined using four different Fuzzy Social Choice (FSC) methods. Finally, a unanimity fallback bargaining method is utilized to suggest the most preferred FSC method. Kavar-Maharloo aquifer system in Fars, Iran, as a typical multi-stakeholder multi-objective real-world problem is considered to verify the proposed methodology. Results showed an effective performance of the framework for determining the most sustainable allocation policy in groundwater resource management.

Methamphetamine compromises gap junctional communication in astrocytes and neurons.

PubMed

Castellano, Paul; Nwagbo, Chisom; Martinez, Luis R; Eugenin, Eliseo A

2016-05-01

Methamphetamine (meth) is a central nervous system (CNS) stimulant that results in psychological and physical dependency. The long-term effects of meth within the CNS include neuronal plasticity changes, blood-brain barrier compromise, inflammation, electrical dysfunction, neuronal/glial toxicity, and an increased risk to infectious diseases including HIV. Most of the reported meth effects in the CNS are related to dysregulation of chemical synapses by altering the release and uptake of neurotransmitters, especially dopamine, norepinephrine, and epinephrine. However, little is known about the effects of meth on connexin (Cx) containing channels, such as gap junctions (GJ) and hemichannels (HC). We examined the effects of meth on Cx expression, function, and its role in NeuroAIDS. We found that meth altered Cx expression and localization, decreased GJ communication between neurons and astrocytes, and induced the opening of Cx43/Cx36 HC. Furthermore, we found that these changes in GJ and HC induced by meth treatment were mediated by activation of dopamine receptors, suggesting that dysregulation of dopamine signaling induced by meth is essential for GJ and HC compromise. Meth-induced changes in GJ and HC contributed to amplified CNS toxicity by dysregulating glutamate metabolism and increasing the susceptibility of neurons and astrocytes to bystander apoptosis induced by HIV. Together, our results indicate that connexin containing channels, GJ and HC, are essential in the pathogenesis of meth and increase the sensitivity of the CNS to HIV CNS disease. Methamphetamine (meth) is an extremely addictive central nervous system stimulant. Meth reduced gap junctional (GJ) communication by inducing internalization of connexin-43 (Cx43) in astrocytes and reducing expression of Cx36 in neurons by a mechanism involving activation of dopamine receptors (see cartoon). Meth-induced changes in Cx containing channels increased extracellular levels of glutamate and resulted in higher

Sensor Compromise Detection in Multiple-Target Tracking Systems

PubMed Central

Doucette, Emily A.; Curtis, Jess W.

2018-01-01

Tracking multiple targets using a single estimator is a problem that is commonly approached within a trusted framework. There are many weaknesses that an adversary can exploit if it gains control over the sensors. Because the number of targets that the estimator has to track is not known with anticipation, an adversary could cause a loss of information or a degradation in the tracking precision. Other concerns include the introduction of false targets, which would result in a waste of computational and material resources, depending on the application. In this work, we study the problem of detecting compromised or faulty sensors in a multiple-target tracker, starting with the single-sensor case and then considering the multiple-sensor scenario. We propose an algorithm to detect a variety of attacks in the multiple-sensor case, via the application of finite set statistics (FISST), one-class classifiers and hypothesis testing using nonparametric techniques. PMID:29466314

Safe and effective treatment of early suprahepatic inferior vena caval outflow compromise following orthotopic liver transplantation using percutaneous transluminal angioplasty and stent placement.

PubMed

Tasse, Jordan; Borge, Marc; Pierce, Kenneth; Brems, John

2011-01-01

To describe the safety and efficacy of percutaneous transluminal angioplasty and stent placement in patients presenting with suprahepatic inferior vena cava (IVC) outflow compromise in the early postoperative period following orthotopic liver transplantation. Between October 2002 and April 2009, 3 patients presented with IVC outflow compromise in the first 2 months following orthotopic liver transplantation. All 3 underwent percutaneous transluminal angioplasty and stent placement without complication and showed significant clinical improvement at short and intermediate term follow-up. Percutaneous transluminal angioplasty and Gianturco stent placement is a safe and effective treatment for IVC outflow compromise in the early postoperative period following orthotopic liver transplantation.

Sleep deprivation compromises resting-state emotional regulatory processes: An EEG study.

PubMed

Zhang, Jinxiao; Lau, Esther Yuet Ying; Hsiao, Janet H

2018-03-01

Resting-state spontaneous neural activities consume far more biological energy than stimulus-induced activities, suggesting their significance. However, existing studies of sleep loss and emotional functioning have focused on how sleep deprivation modulates stimulus-induced emotional neural activities. The current study aimed to investigate the impacts of sleep deprivation on the brain network of emotional functioning using electroencephalogram during a resting state. Two established resting-state electroencephalogram indexes (i.e. frontal alpha asymmetry and frontal theta/beta ratio) were used to reflect the functioning of the emotion regulatory neural network. Participants completed an 8-min resting-state electroencephalogram recording after a well-rested night or 24 hr sleep deprivation. The Sleep Deprivation group had a heightened ratio of the power density in theta band to beta band (theta/beta ratio) in the frontal area than the Sleep Control group, suggesting an effective approach with reduced frontal cortical regulation of subcortical drive after sleep deprivation. There was also marginally more left-lateralized frontal alpha power (left frontal alpha asymmetry) in the Sleep Deprivation group compared with the Sleep Control group. Besides, higher theta/beta ratio and more left alpha lateralization were correlated with higher sleepiness and lower vigilance. The results converged in suggesting compromised emotional regulatory processes during resting state after sleep deprivation. Our work provided the first resting-state neural evidence for compromised emotional functioning after sleep loss, highlighting the significance of examining resting-state neural activities within the affective brain network as a default functional mode in investigating the sleep-emotion relationship. © 2018 European Sleep Research Society.

'Compromise position' image alignment to accommodate independent motion of multiple clinical target volumes during radiotherapy: A high risk prostate cancer example.

PubMed

Rosewall, Tara; Yan, Jing; Alasti, Hamideh; Cerase, Carla; Bayley, Andrew

2017-04-01

Inclusion of multiple independently moving clinical target volumes (CTVs) in the irradiated volume causes an image guidance conundrum. The purpose of this research was to use high risk prostate cancer as a clinical example to evaluate a 'compromise' image alignment strategy. The daily pre-treatment orthogonal EPI for 14 consecutive patients were included in this analysis. Image matching was performed by aligning to the prostate only, the bony pelvis only and using the 'compromise' strategy. Residual CTV surrogate displacements were quantified for each of the alignment strategies. Analysis of the 388 daily fractions indicated surrogate displacements were well-correlated in all directions (r 2  = 0.95 (LR), 0.67 (AP) and 0.59 (SI). Differences between the surrogates displacements (95% range) were -0.4 to 1.8 mm (LR), -1.2 to 5.2 mm (SI) and -1.2 to 5.2 mm (AP). The distribution of the residual displacements was significantly smaller using the 'compromise' strategy, compared to the other strategies (p 0.005). The 'compromise' strategy ensured the CTV was encompassed by the PTV in all fractions, compared to 47 PTV violations when aligned to prostate only. This study demonstrated the feasibility of a compromise position image guidance strategy to accommodate simultaneous displacements of two independently moving CTVs. Application of this strategy was facilitated by correlation between the CTV displacements and resulted in no geometric excursions of the CTVs beyond standard sized PTVs. This simple image guidance strategy may also be applicable to other disease sites that concurrently irradiate multiple CTVs, such as head and neck, lung and cervix cancer. © 2016 The Royal Australian and New Zealand College of Radiologists.

Compromises produced by the dialectic between self-verification and self-enhancement.

PubMed

Morling, B; Epstein, S

1997-12-01

Three studies of people's reactions to evaluative feedback demonstrated that the dialectic between self-enhancement and self-verification results in compromises between these 2 motives, as hypothesized in cognitive-experiential self-theory. The demonstration was facilitated by 2 procedural improvements: Enhancement and verification were established by calibrating evaluative feedback against self appraisals, and degree of enhancement and of verification were varied along a continuum, rather than categorically. There was also support for the hypotheses that processing in an intuitive-experiential mode favors enhancement and processing in an analytical-rational mode favors verification in the kinds of situations investigated.

Chronic Lymphocytic Leukemia as an Unusual Cause of Rapid Airway Compromise

PubMed Central

Ezzell, Erin E.; Renshaw, John S.

2017-01-01

Chronic Lymphocytic Leukemia (CLL) is the most prevalent form of non-Hodgkin's lymphoma (NHL) in Western countries predominantly affecting adults over the age of 65. CLL is commonly indolent in nature but can present locally and aggressively at extranodal sites. Although CLL may commonly present with cervical lymphadenopathy, manifestation in nonlymphoid regions of the head and neck is not well described. CLL causing upper airway obstruction is even more uncommon. We describe a case of a patient with known history of CLL and stable lymphocytosis that developed an enlarging lymphoid base of tongue (BOT) mass resulting in rapid airway compromise. PMID:28396813

Silymarin-loaded solid nanoparticles provide excellent hepatic protection: physicochemical characterization and in vivo evaluation

PubMed Central

Yang, Kwan Yeol; Hwang, Du Hyeong; Yousaf, Abid Mehmood; Kim, Dong Wuk; Shin, Young-Jun; Bae, Ok-Nam; Kim, Yong-II; Kim, Jong Oh; Yong, Chul Soon; Choi, Han-Gon

2013-01-01

with the commercial product (P < 0.05). In particular, the area under the concentration-time curve of the drug provided by the nanoparticles was approximately 1.3-fold greater than that of the commercial product. In addition, the silymarin-loaded nanoparticles significantly reduced carbon tetrachloride-induced hepatotoxicity, indicating improved bioactivity compared with silymarin powder and the commercial product. Conclusion Silymarin-loaded nanoparticles developed using SPG membrane emulsification and spray-drying techniques could be a useful system for delivery of poorly water-soluble silymarin while affording excellent hepatic protection. PMID:24039417

Chiral recognition of phenylglycinol enantiomers based on N-acetyl-L-cysteine capped CdTe quantum dots in the presence of Ag+

NASA Astrophysics Data System (ADS)

Guo, Yuan; Zeng, Xiaoqing; Yuan, Haiyan; Huang, Yunmei; Zhao, Yanmei; Wu, Huan; Yang, Jidong

2017-08-01

In this study, a novel method for chiral recognition of phenylglycinol (PG) enantiomers was proposed. Firstly, water-soluble N-acetyl-L-cysteine (NALC)-capped CdTe quantum dots (QDs) were synthesized and experiment showed that the fluorescence intensity of the reaction system slightly enhancement when added PG enantiomers to NALC-capped CdTe quantum dots (QDs), but the R-PG and S-PG could not be distinguished. Secondly, when there was Ag+ presence in the reaction system, the experiment result was extremely interesting, the PG enantiomers cloud make NALC-capped CdTe QDs produce different fluorescence signal, in which the fluorescence of S-PG + Ag+ + NALC-CdTe system was significantly enhanced, and the fluorescence of R-PG + Ag+ + NALC-CdTe system was markedly decreased. Thirdly, all the enhanced and decreased of the fluorescence intensity were directly proportional to the concentration of R-PG and S-PG in the linearly range 10- 5-10- 7 mol·L- 1, respectively. So, the new method for simultaneous determination of the PG enantiomers was built too. The experiment result of the method was satisfactory with the detection limit of PG can reached 10- 7 mol·L- 1 and the related coefficient of S-PG and R-PG are 0.995 and 0.980, respectively. The method was highly sensitive, selective and had wider detection range compared with other methods.

Smoking Habit in Severe Obese after bariatric procedures.

PubMed

Maniscalco, Mauro; Carratù, Pierluigi; Faraone, Stanislao; Cerbone, Maria Rosaria; Cristiano, Stefano; Zedda, Anna; Resta, Onofrio

2015-01-01

Bariatric procedures provide an effective means of short term weight loss and sustained weight control for the morbidly obese. The effect of bariatric procedures on smoking habit in obese subjects is not well known. Therefore, we examined the short term effect of bariatric surgery on smoking habit of severe obese patients up to 12 months from the intervention. Smoking habit was assessed in a cohort of 78 morbid smoking obese patients followed at our clinic for bariatric procedures. They underwent non surgical intra-gastric balloon (IB) or surgical procedures such as lap-band laparoscopic surgery (LAGB) or sleeve gastrectomy/gastric by-pass (SPG). Subjects were administered a written questionnaire about their smoking habit before and 3, 6 and 12 months after the procedures. No differences were found among the three groups at 6 and 12 months after the procedures (IB 21 %, LAGB 6 %, SPG 5 %; and IB 14 %, LAGB 3 %, SPG 5 %). Only after 3 months, the rate of quitting of the IB group was higher than LAGB and SPG groups (36 %, 6 % and 5 %, respectively; p = 0.02). Bariatric procedures have no effects on smoking habit of moderate-to-heavy smoker severe obese patients. The use of other traditional smoking cessation methods in patients undergone to bariatric procedures should be implemented.

TEMPORAL ASSOCIATION BETWEEN PULMONARY AND SYSTEMIC EFFECTS OF PARTICULATE MATTER IN HEALTHY AND CARDIOVASCULAR COMPROMISED RATS

EPA Science Inventory

Temporal association between pulmonary and systemic effects of particulate matter in healthy and cardiovascular compromised rats

Urmila P. Kodavanti, Mette C. Schladweiler, Allen D. Ledbetter, Russ Hauser*, David C. Christiani*, John McGee, Judy R. Richards, Daniel L. Co...

2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells.

PubMed

Bauer, Matthias R; Joerger, Andreas C; Fersht, Alan R

2016-09-06

The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53's oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1(MET)(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells.

Using Emergence Theory-Based Curriculum to Teach Compromise Skills to Students with Autistic Spectrum Disorders

ERIC Educational Resources Information Center

Fein, Lance; Jones, Don

2015-01-01

This study addresses the compromise skills that are taught to students diagnosed with autistic spectrum disorders (ASD) and related social and communication deficits. A private school in the southeastern United States implemented an emergence theory-based curriculum to address these skills, yet no formal analysis was conducted to determine its…

Fungemia and interstitial lung compromise caused by Malassezia sympodialis in a pediatric patient.

PubMed

Aguirre, Clarisa; Euliarte, Cristina; Finquelievich, Jorge; Sosa, María de los Ángeles; Giusiano, Gustavo

2015-01-01

A case of fungemia with interstitial lung compromise caused by Malassezia sympodialis is reported in an obese pediatric patient on long-term treatment with inhaled corticosteroids for asthma. The patient was hospitalized due to a post-surgical complication of appendicitis. The patient was treated with amphotericin B for 3 weeks, with good clinical evolution and subsequent negative cultures. Copyright © 2013 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Intra- and Inter-Individual Variability in Location Data for Two U.S. Health-Compromised Elderly Cohorts

EPA Science Inventory

This study provides descriptive statistical data on daily time spent in three locations of exposure assessment interest for two panel studies of health-compromised elderly individuals > 65 y old having multi-days of human activity data. The panel studies include individuals livi...

Managing Campus Energy: Compromising between Rapid Needs and Environmental Requirement

NASA Astrophysics Data System (ADS)

Ambariyanto, Ambariyanto; Utama, Yos J.; Purwanto

2018-02-01

The utilization of energy, especially electricity at Diponegoro University campus continues to increase in line with the development of the university. This increase has a direct impact on the increased costs to be paid by the university. Some of the causes of increased utilization of electrical energy is the construction of new buildings to meet the needs, increased learning activities and education, research activities in the laboratory, and various other activities. On the other hand, the increase of energy utilization is considered not good from the environment point of view, especially the utilization of electrical energy coming from non sustainable resources. Efforts to compromise on both are to develop policies in developing environmentally friendly buildings, efficiency in utilization of electrical energy, and development of sustainable energy sources.

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.

Synthesis of highly interconnected 3D scaffold from Arothron stellatus skin collagen for tissue engineering application.

PubMed

Ramanathan, Giriprasath; Singaravelu, Sivakumar; Raja, M D; Sivagnanam, Uma Tiruchirapalli

2015-11-01

The substrate which is avidly used for tissue engineering applications should have good mechanical and biocompatible properties, and all these parameters are often considered as essential for dermal reformation. Highly interconnected three dimensional (3D) wound dressing material with enhanced structural integrity was synthesized from Arothron stellatus fish skin (AsFS) collagen for tissue engineering applications. The synthesized 3D collagen sponge (COL-SPG) was further characterized by different physicochemical methods. The scanning electron microscopy analysis of the material demonstrated that well interconnected pores with homogeneous microstructure on the surface aids higher swelling index and that the material also possessed good mechanical properties with a Young's modulus of 0.89±0.2 MPa. Biocompatibility of the 3D COL-SPG showed 92% growth for both NIH 3T3 fibroblasts and keratinocytes. Overall, the study revealed that synthesized 3D COL-SPG from fish skin will act as a promising wound dressing in skin tissue engineering. Copyright © 2015 Elsevier Ltd. All rights reserved.

Can Neglected Tropical Diseases Compromise Human Wellbeing in Sex-, Age-, and Trait-Specific Ways?

PubMed Central

Geary, David C.

2016-01-01

Traits that facilitate competition for reproductive resources or that influence mate choice have evolved to signal resilience to infectious disease and other stressors. As a result, the dynamics of competition and choice can, in theory, be used to generate predictions about sex-, age-, and trait-specific vulnerabilities for any sexually reproducing species, including humans. These dynamics and associated vulnerabilities are reviewed for nonhuman species, focusing on traits that are compromised by exposure to parasites. Using the same approach, sex-, age-, and trait-specific vulnerabilities to parasitic disease are illustrated for children’s and adolescent’s physical growth and fitness. Suggestions are then provided for widening the assessment of human vulnerabilities to include age-appropriate measures of behavioral (e.g., children’s play) and cognitive (e.g., language fluency) traits. These are traits that are likely to be compromised by infection in age- and sex-specific ways. Inclusion of these types of measures in studies of neglected tropic diseases has the potential to provide a more nuanced understanding of how these diseases undermine human wellbeing and may provide a useful means to study the efficacy of associated treatments. PMID:27077746

Natural Tooth Pontic: An Instant Esthetic Option for Periodontally Compromised Teeth—A Case Series

PubMed Central

Raj, Rishi; Narayan, Ipshita; Gowda, Triveni Mavinakote; Mehta, D. S.

2016-01-01

Sudden tooth loss in the esthetic zone of the maxillary or mandibular anterior region can be due to trauma, periodontal disease, or endodontic failure. The treatment options for replacing the missing tooth can vary between removable prosthesis, tooth-supported prosthesis, and implant-supported prosthesis. Irrespective of the final treatment, the first line of management would be to provisionally restore the patient's esthetic appearance at the earliest, while functionally stabilizing the compromised arch. Using the patient's own natural tooth as a pontic offers the benefits of being the right size, shape, and color and provides exact repositioning in its original intraoral three-dimensional position. Additionally, using the patient's platelet concentrate (platelet rich fibrin) facilitates early wound healing and preservation of alveolar ridge shape following tooth extraction. The abutment teeth can also be preserved with minimal or no preparation, thus keeping the technique reversible, and can be completed at the chair side thereby avoiding laboratory costs. This helps the patient better tolerate the effect of tooth loss psychologically. The article describes a successful, immediate, and viable technique for rehabilitation of three different patients requiring replacement of a single periodontally compromised tooth in an esthetic region. PMID:27994892

Prosthodontic decision-making relating to dentitions with compromised molars: the perspective of Swedish General Dental Practitioners.

PubMed

Korduner, E-K; Collin Bagewitz, I; Vult von Steyern, P; Wolf, E

2016-12-01

The aim of this investigation was to study the clinical prosthodontic decision-making process relating to dentitions with compromised molars among Swedish general dental practitioners (GDPs). Eleven Swedish GDPs were purposively selected, and all agreed to participate. Then, in-depth, semi-structured interviews were conducted and covered treatment considerations concerning two authentic patient cases, initially with complete dental arches, and later, a final treatment based on a shortened dental arch (SDA) was discussed. The cases involved patients with compromised teeth situated mainly in the molar regions. One patient suffered from extensive caries and the other from severe periodontal disease. Qualitative content analysis was used to analyse the data. In the systematic analysis, two main categories were identified: holistic and functional approach. Among the interviewed GDPs, focus was put on patients' needs, background history and motivation for treatment as well as the preservation of molar support. Within the limitations of this study, the following can be concluded: keeping a dental arch with molars seems to be important to Swedish general dental practitioners. The SDA concept does not seem to have a substantial impact on the prosthodontic decision-making relating to dentitions with compromised molars. The dentist's experiences, as well as colleagues' or consulting specialist advice together with aetiological factors and the patient's individual situation, influence the decision-making more than the SDA concept. The conflicting results in the prosthetic decision-making process concerning the relevance of age and the need for molar support need further investigation, for example based on decisions made in the dentist's own clinical practice. © 2016 John Wiley & Sons Ltd.

White matter fiber compromise contributes differentially to attention and emotion processing impairment in alcoholism, HIV-infection, and their comorbidity.

PubMed

Schulte, T; Müller-Oehring, E M; Sullivan, E V; Pfefferbaum, A

2012-10-01

Alcoholism (ALC) and HIV-1 infection (HIV) each affects emotional and attentional processes and integrity of brain white matter fibers likely contributing to functional compromise. The highly prevalent ALC+HIV comorbidity may exacerbate compromise. We used diffusion tensor imaging (DTI) and an emotional Stroop Match-to-Sample task in 19 ALC, 16 HIV, 15 ALC+HIV, and 15 control participants to investigate whether disruption of fiber system integrity accounts for compromised attentional and emotional processing. The task required matching a cue color to that of an emotional word with faces appearing between the color cue and the Stroop word in half of the trials. Nonmatched cue-word color pairs assessed selective attention, and face-word pairs assessed emotion. Relative to controls, DTI-based fiber tracking revealed lower inferior longitudinal fasciculus (ilf) integrity in HIV and ALC+HIV and lower uncinate fasciculus (uf) integrity in all three patient groups. Controls exhibited Stroop effects to positive face-word emotion, and greater interference was related to greater callosal, cingulum and ilf integrity. By contrast, HIV showed greater interference from negative Stroop words during color-nonmatch trials, correlating with greater uf compromise. For face trials, ALC and ALC+HIV showed greater Stroop-word interference, correlating with lower cingulate and callosal integrity. Thus, in HIV, conflict resolution was diminished when challenging conditions usurped resources needed to manage interference from negative emotion and to disengage attention from wrongly cued colors (nonmatch). In ALC and ALC+HIV, poorer callosal integrity was related to enhanced emotional interference suggesting curtailed interhemispheric exchange needed between preferentially right-hemispheric emotion and left-hemispheric Stroop-word functions. Copyright © 2012 Elsevier Ltd. All rights reserved.

Enhanced susceptibility to predation in corals of compromised condition

PubMed Central

Cameron, Caitlin M.; Miller, Margaret W.

2015-01-01

The marine gastropod, Coralliophila abbreviata, is an obligate corallivore that causes substantial mortality in Caribbean Acropora spp. Considering the imperiled status of Acropora cervicornis and A. palmata, a better understanding of ecological interactions resulting in tissue loss may enable more effective conservation strategies. We examined differences in susceptibility of A. cervicornis to C. abbreviata predation based on coral tissue condition. Coral tissue condition was a strong determinant of snail prey choice, with snails preferring A. cervicornis fragments that were diseased or mechanically damaged over healthy fragments. In addition, snails always chose fragments undergoing active predation by another snail, while showing no preference for a non-feeding snail when compared with an undisturbed prey fragment. These results indicate that the condition of A. cervicornis prey influenced foraging behavior of C. abbreviata, creating a potential feedback that may exacerbate damage from predation in coral populations compromised by other types of disturbance. PMID:26734500

Interferences of Silica Nanoparticles in Green Fluorescent Protein Folding Processes.

PubMed

Klein, Géraldine; Devineau, Stéphanie; Aude, Jean Christophe; Boulard, Yves; Pasquier, Hélène; Labarre, Jean; Pin, Serge; Renault, Jean Philippe

2016-01-12

We investigated the relationship between unfolded proteins, silica nanoparticles and chaperonin to determine whether unfolded proteins could stick to silica surfaces and how this process could impair heat shock protein activity. The HSP60 catalyzed green fluorescent protein (GFP) folding was used as a model system. The adsorption isotherms and adsorption kinetics of denatured GFP were measured, showing that denaturation increases GFP affinity for silica surfaces. This affinity is maintained even if the surfaces are covered by a protein corona and allows silica NPs to interfere directly with GFP folding by trapping it in its unstructured state. We determined also the adsorption isotherms of HSP60 and its chaperonin activity once adsorbed, showing that SiO2 NP can interfere also indirectly with protein folding through chaperonin trapping and inhibition. This inhibition is specifically efficient when NPs are covered first with a layer of unfolded proteins. These results highlight for the first time the antichaperonin activity of silica NPs and ask new questions about the toxicity of such misfolded proteins/nanoparticles assembly toward cells.

MRI contrast agent for targeting glioma: interleukin-13 labeled liposome encapsulating gadolinium-DTPA

PubMed Central

Liu, Xiaoli; Madhankumar, Achuthamangalam B.; Miller, Patti A.; Duck, Kari A.; Hafenstein, Susan; Rizk, Elias; Slagle-Webb, Becky; Sheehan, Jonas M.; Connor, James R.; Yang, Qing X.

2016-01-01

Background Detection of glioma with MRI contrast agent is limited to cases in which the blood-brain barrier (BBB) is compromised as contrast agents cannot cross the BBB. Thus, an early-stage infiltrating tumor is not detectable. Interleukin-13 receptor alpha 2 (IL-13Rα2), which has been shown to be overexpressed in glioma, can be used as a target moiety. We hypothesized that liposomes conjugated with IL-13 and encapsulating MRI contrast agent are capable of passing through an intact BBB and producing MRI contrast with greater sensitivity. Methods The targeted MRI contrast agent was created by encapsulating Magnevist (Gd-DTPA) into liposomes conjugated with IL-13 and characterized by particle size distribution, cytotoxicity, and MRI relaxivity. MR image intensity was evaluated in the brain in normal mice post injection of Gd-DTPA and IL-13-liposome-Gd-DTPA one day apart. The specificity for glioma detection by IL-13-liposome-Gd-DTPA was demonstrated in an intracranial glioma mouse model and validated histologically. Results The average size of IL-13-liposome-Gd-DTPA was 137 ± 43 nm with relaxivity of 4.0 ± 0.4 L/mmole-s at 7 Tesla. No significant cytotoxicity was observed with MTS assay and serum chemistry in mice. The MRI signal intensity was enhanced up to 15% post injection of IL-13-liposome-Gd-DTPA in normal brain tissue following a similar time course as that for the pituitary gland outside of the BBB. MRI enhanced by IL-13-liposome-Gd-DTPA detected small tumor masses in addition to those seen with Magnevist-enhanced MRI. Conclusions IL-13-liposome-Gd-DTPA is able to pass through the uncompromised BBB and detect an early stage glioma that cannot be seen with conventional contrast-enhanced MRI. PMID:26519740

LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARγ ligand synthesis

PubMed Central

Lefèvre, Lise; Authier, Hélène; Stein, Sokrates; Majorel, Clarisse; Couderc, Bettina; Dardenne, Christophe; Eddine, Mohamad Ala; Meunier, Etienne; Bernad, José; Valentin, Alexis; Pipy, Bernard; Schoonjans, Kristina; Coste, Agnès

2015-01-01

Liver receptor homologue-1 (LRH-1) is a nuclear receptor involved in the repression of inflammatory processes in the hepatointestinal tract. Here we report that LRH-1 is expressed in macrophages and induced by the Th2 cytokine IL-13 via a mechanism involving STAT6. We show that loss-of-function of LRH-1 in macrophages impedes IL-13-induced macrophage polarization due to impaired generation of 15-HETE PPARγ ligands. The incapacity to generate 15-HETE metabolites is at least partially caused by the compromised regulation of CYP1A1 and CYP1B1. Mice with LRH-1-deficient macrophages are, furthermore, highly susceptible to gastrointestinal and systemic Candida albicans infection. Altogether, these results identify LRH-1 as a critical component of the anti-inflammatory and fungicidal response of alternatively activated macrophages that acts upstream from the IL-13-induced 15-HETE/PPARγ axis. PMID:25873311

A combination of additives can synergically decrease acrylamide content in gingerbread without compromising sensory quality.

PubMed

Komprda, Tomáš; Pridal, Antonin; Mikulíková, Renata; Svoboda, Zdeněk; Cwiková, Olga; Nedomová, Šárka; Sýkora, Vladimír

2017-02-01

The present study tested whether replacement of the leavening agent ammonium carbonate by sodium hydrogen carbonate in combination with calcium cation and acidifying agent will synergically decrease acrylamide (AA) content in gingerbread. The type of leavening agent and the presence of Ca 2+ and citric acid accounted for 33.6%, 13.2% and 53.2% of the explained variability of the AA content, respectively (P < 0.01). The AA content in gingerbread produced with (NH 4 ) 2 CO 3 alone was 186.5 µg kg -1 . Irrespective of other tested additives, NaHCO 3 decreased (P < 0.05) AA content to 42% compared to (NH 4 ) 2 CO 3 . Combination of NaHCO 3 + CaCl 2 + citric acid in dough reduced (P < 0.05) AA content below the limit of detection (25 µg kg -1 ). The AA content in gingerbread (y; µg kg -1 ) decreased with an increasing number of additives used (x) according to the equation y = 158.8 - 47.94x (r 2 = 0.42; P < 0.0001). A comprehensive sensory analysis did not indicate any significant deterioration (P > 0.05) in the organoleptic quality of gingerbread produced using calcium cation and citric acid. The present study demonstrates that the combination of additives NaHCO 3 /Ca 2+ /citric acid synergically decreases AA content in gingerbread without compromising the sensory quality. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Orientation of handle for successful prosthetic treatment in patients with an anatomic compromise after a maxillectomy.

PubMed

Sumita, Yuka I; Hattori, Mariko; Elbashti, Mahmoud E; Taniguchi, Hisashi

2017-05-01

This clinical technique provides a key procedure for successful prosthetic treatment in patients with an anatomical compromise after a maxillectomy. When making a preliminary impression, the clinician must keep the handle of the stock tray parallel to the patient's interpupillary line extraorally to maintain the correct position of the tray and to make a record of the inclination of the occlusal plane. This simple consideration during this first step of making a preliminary impression can be an important guide for both dentists and dental technicians. Information about the correct positioning of the tray and the inclination of the occlusal plane obtained by using a stock tray handle will greatly reduce the stress experienced by dentists, dental technicians, and patients during the fabrication of the prosthesis and will ultimately lead to successful prosthetic treatment in patients with anatomic compromise resulting from a maxillectomy. Copyright © 2016 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

SPG specification for 2015 implementation.

DOT National Transportation Integrated Search

2015-04-01

For this project, Item 300, Asphalts, Oils, and Emulsions, of the Standard Specifications, is : hereby amended with respect to the clauses cited below, and no other clauses or requirements of : this Item are waived or changed hereby.

Hydraulic efficiency compromises compression strength perpendicular to the grain in Norway spruce trunkwood

PubMed Central

2011-01-01

The aim of this study was to investigate bending stiffness and compression strength perpendicular to the grain of Norway spruce (Picea abies (L.) Karst.) trunkwood with different anatomical and hydraulic properties. Hydraulically less safe mature sapwood had bigger hydraulic lumen diameters and higher specific hydraulic conductivities than hydraulically safer juvenile wood. Bending stiffness (MOE) was higher, whereas radial compression strength lower in mature than in juvenile wood. A density-based tradeoff between MOE and hydraulic efficiency was apparent in mature wood only. Across cambial age, bending stiffness did not compromise hydraulic efficiency due to variation in latewood percent and because of the structural demands of the tree top (e.g. high flexibility). Radial compression strength compromised, however, hydraulic efficiency because it was extremely dependent on the characteristics of the “weakest” wood part, the highly conductive earlywood. An increase in conduit wall reinforcement of earlywood tracheids would be too costly for the tree. Increasing radial compression strength by modification of microfibril angles or ray cell number could result in a decrease of MOE, which would negatively affect the trunk’s capability to support the crown. We propose that radial compression strength could be an easily assessable and highly predictive parameter for the resistance against implosion or vulnerability to cavitation across conifer species, which should be topic of further studies. PMID:22058609

Simultaneous analysis of retinol, all-trans- and 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in plasma by liquid chromatography using on-column concentration after single-phase fluid extraction.

PubMed

Teerlink, T; Copper, M P; Klaassen, I; Braakhuis, B J

1997-06-20

A reversed-phase high-performance liquid chromatographic method for the simultaneous analysis of retinol, all-trans-retinoic acid, 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in human plasma and cell culture medium is described. Sample preparation involves precipitation of proteins and extraction of retinoids with 60% acetonitrile. After centrifugation, the acetonitrile content of the supernatant is reduced to 45%, allowing on-column concentration of analytes. Injection volumes up to 2.0 ml (equivalent to 0.525 ml of sample) can be used without compromising chromatographic resolution of all-trans-retinoic acid and 13-cis-retinoic acid. Retinoids were stable in this extract and showed no isomerization when stored in the dark in a cooled autosampler, allowing automated analysis of large series of samples. Recoveries from spiked plasma samples were between 95 and 103%. Although no internal standard was used, the inter-assay precision for all retinoids was better than 6% and 4% at concentrations of 30 nM and 100 nM, respectively. The method is a valuable tool for the study of cellular metabolism of all-trans-retinoic acid, as polar metabolites of this compound can be detected with high sensitivity in cell culture media.

Multi-objective experimental design for (13)C-based metabolic flux analysis.

PubMed

Bouvin, Jeroen; Cajot, Simon; D'Huys, Pieter-Jan; Ampofo-Asiama, Jerry; Anné, Jozef; Van Impe, Jan; Geeraerd, Annemie; Bernaerts, Kristel

2015-10-01

(13)C-based metabolic flux analysis is an excellent technique to resolve fluxes in the central carbon metabolism but costs can be significant when using specialized tracers. This work presents a framework for cost-effective design of (13)C-tracer experiments, illustrated on two different networks. Linear and non-linear optimal input mixtures are computed for networks for Streptomyces lividans and a carcinoma cell line. If only glucose tracers are considered as labeled substrate for a carcinoma cell line or S. lividans, the best parameter estimation accuracy is obtained by mixtures containing high amounts of 1,2-(13)C2 glucose combined with uniformly labeled glucose. Experimental designs are evaluated based on a linear (D-criterion) and non-linear approach (S-criterion). Both approaches generate almost the same input mixture, however, the linear approach is favored due to its low computational effort. The high amount of 1,2-(13)C2 glucose in the optimal designs coincides with a high experimental cost, which is further enhanced when labeling is introduced in glutamine and aspartate tracers. Multi-objective optimization gives the possibility to assess experimental quality and cost at the same time and can reveal excellent compromise experiments. For example, the combination of 100% 1,2-(13)C2 glucose with 100% position one labeled glutamine and the combination of 100% 1,2-(13)C2 glucose with 100% uniformly labeled glutamine perform equally well for the carcinoma cell line, but the first mixture offers a decrease in cost of $ 120 per ml-scale cell culture experiment. We demonstrated the validity of a multi-objective linear approach to perform optimal experimental designs for the non-linear problem of (13)C-metabolic flux analysis. Tools and a workflow are provided to perform multi-objective design. The effortless calculation of the D-criterion can be exploited to perform high-throughput screening of possible (13)C-tracers, while the illustrated benefit of multi

42 CFR 405.376 - Suspension and termination of collection action and compromise of claims for overpayment.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false Suspension and termination of collection action and compromise of claims for overpayment. 405.376 Section 405.376 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICARE PROGRAM FEDERAL HEALTH INSURANCE FOR THE AGED...

42 CFR 405.376 - Suspension and termination of collection action and compromise of claims for overpayment.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 2 2011-10-01 2011-10-01 false Suspension and termination of collection action and compromise of claims for overpayment. 405.376 Section 405.376 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICARE PROGRAM FEDERAL HEALTH INSURANCE FOR THE AGED...

Tract-Specific Analyses of Diffusion Tensor Imaging Show Widespread White Matter Compromise in Autism Spectrum Disorder

ERIC Educational Resources Information Center

Shukla, Dinesh K.; Keehn, Brandon; Muller, Ralph-Axel

2011-01-01

Background: Previous diffusion tensor imaging (DTI) studies have shown white matter compromise in children and adults with autism spectrum disorder (ASD), which may relate to reduced connectivity and impaired function of distributed networks. However, tract-specific evidence remains limited in ASD. We applied tract-based spatial statistics (TBSS)…

[Pyr1]Apelin-13(1-12) Is a Biologically Active ACE2 Metabolite of the Endogenous Cardiovascular Peptide [Pyr1]Apelin-13.

PubMed

Yang, Peiran; Kuc, Rhoda E; Brame, Aimée L; Dyson, Alex; Singer, Mervyn; Glen, Robert C; Cheriyan, Joseph; Wilkinson, Ian B; Davenport, Anthony P; Maguire, Janet J

2017-01-01

-dependent decrease in blood pressure in anesthetized rat and dose-dependent increase in forearm blood flow in human volunteers. Conclusions: We provide evidence that ACE2 cleaves [Pyr 1 ]apelin-13 to [Pyr 1 ]apelin-13 (1-12) and this cleavage product is expressed in human cardiovascular tissues. We have demonstrated biological activity of [Pyr 1 ]apelin-13 (1-12) at the human and rodent apelin receptor in vitro and in vivo . Our data show that reported enhanced ACE2 activity in cardiovascular disease should not significantly compromise the beneficial effects of apelin based therapies for example in PAH.

Left Ventricular Gene Expression Profile of Healthy and Cardiovascular Compromised Rat Models Used in Air Pollution Studies

EPA Science Inventory

The link between pollutant exposure and cardiovascular disease (CVD) has prompted mechanistic research with animal models of CVD. We hypothesized that the cardiac gene expression patterns of healthy and genetically compromised, CVD-prone rat models, with or without metabolic impa...

Consequences of early extraction of compromised first permanent molar: a systematic review.

PubMed

Saber, Afnan M; Altoukhi, Doua H; Horaib, Mariam F; El-Housseiny, Azza A; Alamoudi, Najlaa M; Sabbagh, Heba J

2018-04-05

The aim of this study was to systematically review the literature to determine the sequelae of early extraction of compromised first permanent molars (FPMs) with regard to the skeletal and dental development of 5- to 15-year-old children. Meta-analysis was conducted when applicable. Our research protocol included a search strategy, inclusion/exclusion criteria, and a data extraction plan. The search engines used were PubMed, Scopus, and Science Direct. Study selection was performed independently by three reviewers. Articles published from 1960 to 2017 were reviewed based on inclusion and exclusion criteria. Meta-analysis was performed to compare space closure between upper and lower arches. Eleven studies fulfilled the inclusion criteria. The consequences were decrease in post extraction space, accelerated development and eruption of second permanents molars (SPMs) and third molars, a decrease in caries and/or fillings on the proximal surfaces of adjacent teeth, lingual tipping and retrusion of incisors, and counter clockwise rotation of the occlusal plane. There were several consequences of early extraction of FPMs, which were related to skeletal and dental development. Our systematic review suggests that comprehensive evaluation of the compromised FPMs should be performed before planning an extraction. The ideal time for FPM extraction is when the SPM is at the early bifurcation stage in order to achieve complete closure of the extraction space by the SPM. Benefits should be weighed over the risks to decrease the risk of unfavorable outcomes as much as possible. However, due to the limited evidence on the outcomes and variables that influence them, high-quality prospective studies are needed.

Widespread Volumetric Reductions in Schizophrenia and Schizoaffective Patients Displaying Compromised Cognitive Abilities.

PubMed

Van Rheenen, Tamsyn E; Cropley, Vanessa; Zalesky, Andrew; Bousman, Chad; Wells, Ruth; Bruggemann, Jason; Sundram, Suresh; Weinberg, Danielle; Lenroot, Roshel K; Pereira, Avril; Shannon Weickert, Cynthia; Weickert, Thomas W; Pantelis, Christos

2018-04-06

Progress toward understanding brain mechanisms in psychosis is hampered by failures to account for within-group heterogeneity that exists across neuropsychological domains. We recently identified distinct cognitive subgroups that might assist in identifying more biologically meaningful subtypes of psychosis. In the present study, we examined whether underlying structural brain abnormalities differentiate these cognitively derived subgroups. 1.5T T1 weighted structural scans were acquired for 168 healthy controls and 220 patients with schizophrenia/schizoaffective disorder. Based on previous work, 47 patients were categorized as being cognitively compromised (impaired premorbid and current IQ), 100 as cognitively deteriorated (normal premorbid IQ, impaired current IQ), and 73 as putatively cognitively preserved (premorbid and current IQ within 1 SD of controls). Global, subcortical and cortical volume, thickness, and surface area measures were compared among groups. Whole cortex, subcortical, and regional volume and thickness reductions were evident in all subgroups compared to controls, with the largest effect sizes in the compromised group. This subgroup also showed abnormalities in regions not seen in the other patient groups, including smaller left superior and middle frontal areas, left anterior and inferior temporal areas and right lateral medial and inferior frontal, occipital lobe and superior temporal areas. This pattern of more prominent brain structural abnormalities in the group with the most marked cognitive impairments-both currently and putatively prior to illness onset, is consistent with the concept of schizophrenia as a progressive neurodevelopmental disorder. In this group, neurodevelopmental and neurodegenerative factors may be important for cognitive function.

β-Cell Ca(2+) dynamics and function are compromised in aging.

PubMed

Barker, Christopher J; Li, Luosheng; Köhler, Martin; Berggren, Per-Olof

2015-01-01

Defects in pancreatic β-cell function and survival are key components in type 2 diabetes (T2D). An age-dependent deterioration in β-cell function has also been observed, but little is known about the molecular mechanisms behind this phenomenon. Our previous studies indicate that the regulation of cytoplasmic free Ca(2+) concentration ([Ca(2+)]i) may be critical and that this is dependent on the proper function of the mitochondria. The [Ca(2+)]i dynamics of the pancreatic β-cell are driven by an interplay between glucose-induced influx of extracellular Ca(2+) via voltage-dependent Ca(2+) channels and the inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)-mediated liberation of Ca(2+) from intracellular stores. Our previous work has indicated a direct relationship between disruption of Ins(1,4,5)P3-mediated Ca(2+) regulation and loss of β-cell function, including disturbed [Ca(2+)]i dynamics and compromised insulin secretion. To investigate these processes in aging we used three mouse models, a premature aging mitochondrial mutator mouse, a mature aging phenotype (C57BL/6) and an aging-resistant phenotype (129). Our data suggest that age-dependent impairment in mitochondrial function leads to modest changes in [Ca(2+)]i dynamics in mouse β-cells, particularly in the pattern of [Ca(2+)]i oscillations. These changes are driven by modifications in both PLC/Ins(1,4,5)P3-mediated Ca(2+) mobilization from intracellular stores and decreased β-cell Ca(2+) influx over the plasma membrane. Our findings underscore an important concept, namely that even relatively small, time-dependent changes in β-cell signal-transduction result in compromised insulin release and in a diabetic phenotype. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sphenopalatine (nasal) ganglion: remote effects including "psychosomatic" symptoms, rage reaction, pain, and spasm.

PubMed

Ruskin, A P

1979-08-01

Many articles implicate the nasal ganglion in the production of remote symptoms and discuss treatment. Symptoms are primarily spastic, involving both visceral and voluntary muscles including muscle spasm in the neck, shoulder, and low back; asthma, hypertension, intestinal spasm; diarrhea, angina pectoris, uterine spasm; intractable hiccup, and many others. All these symptoms appear to have 2 common denominators. They are mediated by the autonomic nervous system and at least in some instances can be "psychosomatic." The sphenopalatine ganglion (SPG) is a major autonomic ganglion located superficially in the pterygopalatine fossa, with major afferent distribution to the entire nasopharynx and important connections with the trigeminal nerve, facial nerve, internal carotid artery plexus of the sympathetic nervous system and, as shown in the rat, direct connection with the anterior pituitary gland. This paper presents arguments supporting the following hypotheses: 1. The SPG probably has a crucial role in lower animals in declenching the reflex responses known collectively as the rage reaction. 2. The SPG is a major point of entry to the autonomic system exposed to pathologic influences and readily accessible for therapeutic influences and readily accessible for therapeutic intervention. 3. A wide variety of symptoms are produced or maintained by alteration in autonomic system tonus and some of these may be affected by intervention on the SPG. 4. The possible relationship of some symptoms and "psychosomatic" conditions to the autonomic nervous system and the rage reaction must be considered.20

Designing and Operating Through Compromise: Architectural Analysis of CKMS for the Advanced Metering Infrastructure

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

Duren, Mike; Aldridge, Hal; Abercrombie, Robert K

2013-01-01

Compromises attributable to the Advanced Persistent Threat (APT) highlight the necessity for constant vigilance. The APT provides a new perspective on security metrics (e.g., statistics based cyber security) and quantitative risk assessments. We consider design principals and models/tools that provide high assurance for energy delivery systems (EDS) operations regardless of the state of compromise. Cryptographic keys must be securely exchanged, then held and protected on either end of a communications link. This is challenging for a utility with numerous substations that must secure the intelligent electronic devices (IEDs) that may comprise complex control system of systems. For example, distribution andmore » management of keys among the millions of intelligent meters within the Advanced Metering Infrastructure (AMI) is being implemented as part of the National Smart Grid initiative. Without a means for a secure cryptographic key management system (CKMS) no cryptographic solution can be widely deployed to protect the EDS infrastructure from cyber-attack. We consider 1) how security modeling is applied to key management and cyber security concerns on a continuous basis from design through operation, 2) how trusted models and key management architectures greatly impact failure scenarios, and 3) how hardware-enabled trust is a critical element to detecting, surviving, and recovering from attack.« less

Morphine induces albuminuria by compromising podocyte integrity.

PubMed

Lan, Xiqian; Rai, Partab; Chandel, Nirupama; Cheng, Kang; Lederman, Rivka; Saleem, Moin A; Mathieson, Peter W; Husain, Mohammad; Crosson, John T; Gupta, Kalpna; Malhotra, Ashwani; Singhal, Pravin C

2013-01-01

Morphine has been reported to accelerate the progression of chronic kidney disease. However, whether morphine affects slit diaphragm (SD), the major constituent of glomerular filtration barrier, is still unclear. In the present study, we examined the effect of morphine on glomerular filtration barrier in general and podocyte integrity in particular. Mice were administered either normal saline or morphine for 72 h, then urine samples were collected and kidneys were subsequently isolated for immunohistochemical studies and Western blot. For in vitro studies, human podocytes were treated with morphine and then probed for the molecular markers of slit diaphragm. Morphine-receiving mice displayed a significant increase in albuminuria and showed effacement of podocyte foot processes. In both in vivo and in vitro studies, the expression of synaptopodin, a molecular marker for podocyte integrity, and the slit diaphragm constituting molecules (SDCM), such as nephrin, podocin, and CD2-associated protein (CD2AP), were decreased in morphine-treated podocytes. In vitro studies indicated that morphine modulated podocyte expression of SDCM through opiate mu (MOR) and kappa (KOR) receptors. Since morphine also enhanced podocyte oxidative stress, the latter seems to contribute to decreased SDCM expression. In addition, AKT, p38, and JNK pathways were involved in morphine-induced down regulation of SDCM in human podocytes. These findings demonstrate that morphine has the potential to alter the glomerular filtration barrier by compromising the integrity of podocytes.

Which Statistic Should Be Used to Detect Item Preknowledge When the Set of Compromised Items Is Known?

PubMed

Sinharay, Sandip

2017-09-01

Benefiting from item preknowledge is a major type of fraudulent behavior during educational assessments. Belov suggested the posterior shift statistic for detection of item preknowledge and showed its performance to be better on average than that of seven other statistics for detection of item preknowledge for a known set of compromised items. Sinharay suggested a statistic based on the likelihood ratio test for detection of item preknowledge; the advantage of the statistic is that its null distribution is known. Results from simulated and real data and adaptive and nonadaptive tests are used to demonstrate that the Type I error rate and power of the statistic based on the likelihood ratio test are very similar to those of the posterior shift statistic. Thus, the statistic based on the likelihood ratio test appears promising in detecting item preknowledge when the set of compromised items is known.

Compromised regulation of tissue perfusion and arteriogenesis limit, in an AT1R-independent fashion, recovery of ischemic tissue in Cx40−/− mice

PubMed Central

Fang, Jennifer S.; Angelov, Stoyan N.; Simon, Alexander M.

2013-01-01

Recently, we reported that recovery of tissue perfusion in the ischemic hindlimb was reduced, inflammatory response increased, and survival of distal limb tissue compromised in connexin 40 (Cx40)-deficient (Cx40−/−) mice. Here we evaluate whether genotype-specific differences in tissue perfusion, native vascular density, arteriogenesis, blood pressure, and chronic ANG II type 1 receptor (AT1R) activation contribute to poor recovery of ischemic hindlimb tissue in Cx40−/− mice. Hindlimb ischemia was induced in wild-type (WT), Cx40−/−, and losartan-treated Cx40−/− mice by using surgical procedures that either maintained (mild surgery) or compromised (severe surgery) perfusion of major collateral vessels supplying the distal limb. Pre- and postsurgical hindlimb perfusion was evaluated, and tissue survival, microvascular density, and macrophage infiltration were documented during recovery. Hindlimb perfusion was compromised in presurgical Cx40−/− versus WT mice despite comparable native microvascular density. Hindlimb perfusion 24 h postsurgery in Cx40−/− and WT mice was comparable after mild surgery (collateral vessels maintained), but compromised arteriogenesis in Cx40−/− animals nevertheless limited subsequent recovery of tissue perfusion and compromised tissue survival. Prolonged pre- and postsurgical treatment of Cx40−/− mice with losartan (an AT1R antagonist) normalized blood pressure but did not improve tissue perfusion or survival, despite reduced macrophage infiltration. Thus it appears Cx40 is necessary for normal tissue perfusion and for recovery of perfusion, arteriogenesis, and tissue survival in the ischemic hindlimb. Our data suggest that Cx40−/− mice are at significantly greater risk for poor recovery from ischemic insult due to compromised regulation of tissue perfusion, vascular remodeling, and prolonged inflammatory response. PMID:23292716

A double-quadrature radiofrequency coil design for proton-decoupled carbon-13 magnetic resonance spectroscopy in humans at 7T.

PubMed

Serés Roig, Eulalia; Magill, Arthur W; Donati, Guillaume; Meyerspeer, Martin; Xin, Lijing; Ipek, Ozlem; Gruetter, Rolf

2015-02-01

Carbon-13 magnetic resonance spectroscopy ((13) C-MRS) is challenging because of the inherent low sensitivity of (13) C detection and the need for radiofrequency transmission at the (1) H frequency while receiving the (13) C signal, the latter requiring electrical decoupling of the (13) C and (1) H radiofrequency channels. In this study, we added traps to the (13) C coil to construct a quadrature-(13) C/quadrature-(1) H surface coil, with sufficient isolation between channels to allow simultaneous operation at both frequencies without compromise in coil performance. Isolation between channels was evaluated on the bench by measuring all coupling parameters. The quadrature mode of the quadrature-(13) C coil was assessed using in vitro (23) Na gradient echo images. The signal-to-noise ratio (SNR) was measured on the glycogen and glucose resonances by (13) C-MRS in vitro, compared with that obtained with a linear-(13) C/quadrature-(1) H coil, and validated by (13) C-MRS in vivo in the human calf at 7T. Isolation between channels was better than -30 dB. The (23) Na gradient echo images indicate a region where the field is strongly circularly polarized. The quadrature coil provided an SNR enhancement over a linear coil of 1.4, in vitro and in vivo. It is feasible to construct a double-quadrature (13) C-(1) H surface coil for proton decoupled sensitivity enhanced (13) C-NMR spectroscopy in humans at 7T. © 2014 Wiley Periodicals, Inc.

Comparative Accuracy of Facial Models Fabricated Using Traditional and 3D Imaging Techniques.

PubMed

Lincoln, Ketu P; Sun, Albert Y T; Prihoda, Thomas J; Sutton, Alan J

2016-04-01

The purpose of this investigation was to compare the accuracy of facial models fabricated using facial moulage impression methods to the three-dimensional printed (3DP) fabrication methods using soft tissue images obtained from cone beam computed tomography (CBCT) and 3D stereophotogrammetry (3D-SPG) scans. A reference phantom model was fabricated using a 3D-SPG image of a human control form with ten fiducial markers placed on common anthropometric landmarks. This image was converted into the investigation control phantom model (CPM) using 3DP methods. The CPM was attached to a camera tripod for ease of image capture. Three CBCT and three 3D-SPG images of the CPM were captured. The DICOM and STL files from the three 3dMD and three CBCT were imported to the 3DP, and six testing models were made. Reversible hydrocolloid and dental stone were used to make three facial moulages of the CPM, and the impressions/casts were poured in type IV gypsum dental stone. A coordinate measuring machine (CMM) was used to measure the distances between each of the ten fiducial markers. Each measurement was made using one point as a static reference to the other nine points. The same measuring procedures were accomplished on all specimens. All measurements were compared between specimens and the control. The data were analyzed using ANOVA and Tukey pairwise comparison of the raters, methods, and fiducial markers. The ANOVA multiple comparisons showed significant difference among the three methods (p < 0.05). Further, the interaction of methods versus fiducial markers also showed significant difference (p < 0.05). The CBCT and facial moulage method showed the greatest accuracy. 3DP models fabricated using 3D-SPG showed statistical difference in comparison to the models fabricated using the traditional method of facial moulage and 3DP models fabricated from CBCT imaging. 3DP models fabricated using 3D-SPG were less accurate than the CPM and models fabricated using facial moulage and CBCT

Effect of aromatase inhibitor letrozole on the proliferation of spermatogonia by regulating the MAPK pathway.

PubMed

Wang, Shunde; Wang, Shuhong; Li, Hang; Li, Xiaoxia; Xie, Menglin; Wen, Jiayu; Li, Meicai; Long, Tengbo

2018-06-01

The molecular mechanism of the aromatase inhibitor letrozole was investigated. It promotes the proliferation of spermatogonia by regulating the mitogen-activated protein kinase (MAPK) pathway. Six different concentrations were selected for letrozole in order to incubate mouse spermatogonia [GC-1 spermatogonia (spg)] for 24, 48 and 72 h, respectively. Cell Counting Kit-8 (CCK-8) was used to observe the effect of letrozole on the proliferation of GC-1 spg cells, and the effect was further verified by cell plate clone formation assay. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis were used to detect the effects of letrozole on MAPK signaling pathways [Ras/extracellular signal-regulated kinase 1 (ERK1)/c-Myc], proliferation indexes [Ki-67 and proliferating cell nuclear antigen (PCNA)]. Bromodeoxyuridine (BrdU) staining was used to study the effects of letrozole and MAPK signaling pathways on cell proliferation. The results of CCK-8 showed that the proliferation rate of GC-1 spg cells was improved. Study results also revealed a significant increase in letrozole concentration along with the time of action. The results of plate clone formation assay further indicated that letrozole could significantly promote the proliferation capacity of GC-1 spg cells (p<0.05). The results of RT-PCR and western blot analysis confirmed letrozole significantly activated the expression of Ras/ERK1/c-Myc in the classical MAPK pathway. A significant increase was noted in the protein levels of Ki-67 and PCNA (p<0.05). By contrast, inhibition of the MAPK pathway resulted in a significant decrease in the levels of the above indexes (p<0.05). The number of BrdU cells in the letrozole group was also higher than that of the control group, while the number of BrdU-stained cells in the letrozole + MAPK inhibition group showed a significant decrease in comparison to the letrozole group. In conclusion, letrozole activated the MAPK signaling pathway and promoted the

New inhibitors of colony spreading in Bacillus subtilis and Bacillus anthracis.

PubMed

Hao, Xin; Nguyen, Tam; Kearns, Daniel B; Arpin, Carolynn C; Fall, Ray; Sammakia, Tarek

2011-09-15

We have recently characterized sliding motility in Bacillus subtilis strains that lack functional flagella, and here describe the discovery of inhibitors of colony spreading in these strains as well as the aflagellate pathogen, Bacillus anthracis. Aflagellate B. subtilis strains were used to screen for new types of antibacterials that might inhibit colony spreading on semi-solid media. From a diverse set of organic structures, p-nitrophenylglycerol (NPG), an agent used primarily in clinical laboratories to control Proteus swarming, was found to inhibit colony spreading. The four stereoisomers of NPG were synthesized and tested, and only the 1R,2S-(1R-anti) and 1R,2R-(1R-syn) NPG isomers had significant activity in a quantitative colony-spreading assay. Twenty-six NPG analogs and related structures were synthesized and tested to identify more active inhibitors. p-Methylsulfonylphenylglycerol (p-SPG), but not its ortho or meta analogs, was found to be the most effective of these compounds, and synthesis and testing of all four p-SPG stereoisomers showed that the 1R-anti-isomer was the most active with an average IC(50) of 16 μM (3-5 μg mL(-1)). For B. anthracis, the colony-spreading IC(50) values for 1R-anti-SPG and 1R-anti-NPG are 12 μM (2-4 μg mL(-1)) and >150 μM, respectively. For both Bacillus species tested, 1R-anti-SPG inhibits colony spreading of surface cultures on agar plates, but is not bacteriostatic or bacteriocidal in liquid cultures. Work is in progress to find the cellular target(s) of the NPG/SPG class of compounds, since this could lead to an understanding of the mechanism(s) of colony spreading as well as design and development of more potent inhibitors for the control of B. anthracis surface cultures. Copyright © 2011 Elsevier Ltd. All rights reserved.

Neglecting legumes has compromised human health and sustainable food production.

PubMed

Foyer, Christine H; Lam, Hon-Ming; Nguyen, Henry T; Siddique, Kadambot H M; Varshney, Rajeev K; Colmer, Timothy D; Cowling, Wallace; Bramley, Helen; Mori, Trevor A; Hodgson, Jonathan M; Cooper, James W; Miller, Anthony J; Kunert, Karl; Vorster, Juan; Cullis, Christopher; Ozga, Jocelyn A; Wahlqvist, Mark L; Liang, Yan; Shou, Huixia; Shi, Kai; Yu, Jingquan; Fodor, Nandor; Kaiser, Brent N; Wong, Fuk-Ling; Valliyodan, Babu; Considine, Michael J

2016-08-02

The United Nations declared 2016 as the International Year of Pulses (grain legumes) under the banner 'nutritious seeds for a sustainable future'. A second green revolution is required to ensure food and nutritional security in the face of global climate change. Grain legumes provide an unparalleled solution to this problem because of their inherent capacity for symbiotic atmospheric nitrogen fixation, which provides economically sustainable advantages for farming. In addition, a legume-rich diet has health benefits for humans and livestock alike. However, grain legumes form only a minor part of most current human diets, and legume crops are greatly under-used. Food security and soil fertility could be significantly improved by greater grain legume usage and increased improvement of a range of grain legumes. The current lack of coordinated focus on grain legumes has compromised human health, nutritional security and sustainable food production.

Focal cartilage defect compromises fluid-pressure dependent load support in the knee joint.

PubMed

Dabiri, Yaghoub; Li, LePing

2015-06-01

A focal cartilage defect involves tissue loss or rupture. Altered mechanics in the affected joint may play an essential role in the onset and progression of osteoarthritis. The objective of the present study was to determine the compromised load support in the human knee joint during defect progression from the cartilage surface to the cartilage-bone interface. Ten normal and defect cases were simulated with a previously tested 3D finite element model of the knee. The focal defects were considered in both condyles within high load-bearing regions. Fluid pressurization, anisotropic fibril-reinforcement, and depth-dependent mechanical properties were considered for the articular cartilages and menisci. The results showed that a small cartilage defect could cause 25% reduction in the load support of the knee joint due to a reduced capacity of fluid pressurization in the defect cartilage. A partial-thickness defect could cause a fluid pressure decrease or increase in the remaining underlying cartilage depending on the defect depth. A cartilage defect also increased the shear strain at the cartilage-bone interface, which was more significant with a full-thickness defect. The effect of cartilage defect on the fluid pressurization also depended on the defect sites and contact conditions. In conclusion, a focal cartilage defect causes a fluid-pressure dependent load reallocation and a compromised load support in the joint, which depend on the defect depth, site, and contact condition. Copyright © 2015 John Wiley & Sons, Ltd.

Cerebral hematocrit decreases with hemodynamic compromise in carotid artery occlusion: a PET study.

PubMed

Yamauchi, H; Fukuyama, H; Nagahama, Y; Katsumi, Y; Okazawa, H

1998-01-01

This study investigated whether in patients with internal carotid artery occlusion the regional cerebral hematocrit correlates with cerebral hemodynamics or metabolic state and, if so, how the regional cerebral hematocrit changes in the hemodynamically compromised region. We used positron emission tomography to study seven patients with unilateral internal carotid artery occlusion and no cortical infarction in the chronic stage. The distributions of red blood cell and plasma volumes were assessed using oxygen-15-labeled carbon monoxide and copper-62-labeled human serum albumin-dithiosemicarbazone tracers, respectively. The calculated hematocrit value was compared with the hemodynamic and metabolic parameters measured with the oxygen-15 steady-state technique. In the cerebral cortex, the value of the cerebral hematocrit varied but was correlated with the hemodynamic and metabolic status. Stepwise regression analysis revealed that the large vessel hematocrit, the cerebral metabolic rate of oxygen, and the cerebral blood flow or the oxygen extraction fraction accounted for a significant proportion of variance of the cerebral hematocrit. The oxygen extraction fraction and the cerebral metabolic rate of oxygen negatively correlated with the cerebral hematocrit, whereas the cerebral blood flow correlated positively: patients with reduced blood supply relative to metabolic demand (decreased blood flow with increased oxygen extraction fraction) showed low hematocrit values. In carotid artery occlusion in the chronic stage, regional cerebral hematocrit may vary according to cerebral hemodynamics and metabolic status. Regional cerebral hematocrit may decrease with hemodynamic compromise unless oxygen metabolism concomitantly decreases.

[A multi-measure analysis of the similarity, attraction, and compromise effects in multi-attribute decision making].

PubMed

Tsuzuki, Takashi; Matsui, Hiroshi; Kikuchi, Manabu

2012-12-01

In multi-attribute decision making, the similarity, attraction, and compromise effects warrant specific investigation as they cause violations of principles in rational choice. In order to investigate these three effects simultaneously, we assigned 145 undergraduates to three context effect conditions. We requested them to solve the same 20 hypothetical purchase problems, each of which had three alternatives described along two attributes. We measured their choices, confidence ratings, and response times. We found that manipulating the third alternative had significant context effects for choice proportions and confidence ratings in all three conditions. Furthermore, the attraction effect was the most prominent with regard to choice proportions. In the compromise effect condition, although the choice proportion of the third alternative was high, the confidence rating was low and the response time was long. These results indicate that the relationship between choice proportions and confidence ratings requires further theoretical investigation. They also suggest that a combination of experimental and modeling studies is imperative to reveal the mechanisms underlying the context effects in multi-attribute, multi-alternative decision making.

In vitro mechanistic study of endosulfan-induced spermatogenic cell apoptosis in the mouse.

PubMed

Xu, Ying; Wang, Na; Shi, Zhi-Xiong; Li, Yan-Bo; Zhou, Xian-Qing; Sun, Zhi-Wei

2016-09-01

To investigate the mechanisms of endosulfan-induced reproductive toxicity, the spermatogenic cell lines (GC-1 spg) of mice were treated with 0, 6, 12, and 24 μg/ml endosulfan for 24 h in vitro The results showed that endosulfan induced apoptosis as well as oxidative stress and mitochondrial dysfunction. Reactive oxygen species and damage of mitochondrial structure were considered as major factors to GC-1 spg cells apoptosis. We further examined the expression of apoptosis-related proteins in mitochondria pathway by Western blot and immunohistochemistry analysis as well as activities. The results showed that endosulfan significantly improved the expressions of cytochrome c and B-cell lymphoma 2 (Bcl-2)-associated X protein and increased the activities of caspases 9 and 3 as well as the downregulation of the expression of Bcl-2 in GC-1 spg cells. The results suggested that exposure to endosulfan might induce the apoptosis of spermatogenic cells via mitochondria-dependent pathway mediated by oxidative stress resulting in the damage of mitochondrial structure and mitochondrial dysfunction. © The Author(s) 2015.

On the evolution of Atlantic Meridional Overturning Circulation Fingerprint and implications for decadal predictability in the North Atlantic

NASA Astrophysics Data System (ADS)

Zhang, Jinting; Zhang, Rong

2015-07-01

It has been suggested previously that the Atlantic Meridional Overturning Circulation (AMOC) anomaly associated with changes in the North Atlantic Deep Water formation propagates southward with an advection speed north of 34°N. In this study, using Geophysical Fluid Dynamics Laboratory Coupled Model version 2.1 (GFDL CM2.1), we show that this slow southward propagation of the AMOC anomaly is crucial for the evolution and the enhanced decadal predictability of the AMOC fingerprint—the leading mode of upper ocean heat content (UOHC) in the extratropical North Atlantic. A positive AMOC anomaly in northern high latitudes leads to a convergence/divergence of the Atlantic meridional heat transport (MHT) anomaly in the subpolar/Gulf Stream region, thus warming in the subpolar gyre (SPG) and cooling in the Gulf Stream region after several years. Recent decadal prediction studies successfully predicted the observed warm shift in the SPG in the mid-1990s. Our results here provide the physical mechanism for the enhanced decadal prediction skills in the SPG UOHC.

Juggling land retirement objectives on an agricultural landscape: coordination, conflict, or compromise?

PubMed

Marshall, Elizabeth P; Homans, Frances R

2006-07-01

Strategic land retirement in agricultural settings has been used as one way to achieve a combination of social objectives, which include ameliorating water quality problems and enhancing existing systems of wildlife habitat. This study uses a simulation model operating on a virtual landscape, along with the compromise programming method, to illustrate the implications of alternative weighting schemes for the long-term performance of the landscape toward various objectives. The analysis suggests that particular spatial patterns may be related to how various objectives are weighted. The analysis also illustrates the inevitable trade-offs among objectives, although it may be tempting to present retirement strategies as "win-win."

Congenital band syndrome with pseudarthrosis of the radius and ulna and impending vascular compromise: a case report.

PubMed

Ho, Christine A; Richards, B Stephens; Ezaki, Marybeth

2014-09-01

Although amniotic band syndrome is relatively rare, reports of pseudarthrosis in conjunction with amniotic band syndrome are even rarer, as are reports of impending vascular compromise in the neonatal period. Careful serial examinations and timely surgical intervention can successfully avoid the catastrophic event of limb loss. We report on a case of upper extremity amniotic band syndrome with pseudarthrosis of the radius and ulna that was complicated by vascular compromise in a neonate. Chart and radiographic data for this single case were reviewed and reported retrospectively. A 1-day-old neonate born at 28 3/7 weeks of gestational age was transferred to our institution for increased swelling to the forearm distal to a congenital band associated with an underlying radius and ulna pseudarthrosis. Although the forearm and hand were soft and viable initially, severe edema and swelling occurred after fluid resuscitation, and on the fourth day of life, the patient underwent simple band releases at bedside with 2 longitudinal incisions over the radius and ulna. Circulation was restored, and the pseudarthrosis healed with no further surgical intervention. Successful delayed reconstruction of the band with Z-plasties was performed when the baby was 7 months of age. In this case, a relatively simple, straightforward procedure that is familiar to most pediatric orthopaedists salvaged a compromised neonatal limb with amniotic band syndrome and allowed healing of a pseudarthrosis, allowing more complex reconstruction to be performed in a delayed, elective manner. Careful observation is necessary in the neonatal period of the baby with a severe band; a viable, well-perfused, compressible extremity may still be at risk.

Protecting privacy of shared epidemiologic data without compromising analysis potential.

PubMed

Cologne, John; Grant, Eric J; Nakashima, Eiji; Chen, Yun; Funamoto, Sachiyo; Katayama, Hiroaki

2012-01-01

Ensuring privacy of research subjects when epidemiologic data are shared with outside collaborators involves masking (modifying) the data, but overmasking can compromise utility (analysis potential). Methods of statistical disclosure control for protecting privacy may be impractical for individual researchers involved in small-scale collaborations. We investigated a simple approach based on measures of disclosure risk and analytical utility that are straightforward for epidemiologic researchers to derive. The method is illustrated using data from the Japanese Atomic-bomb Survivor population. Masking by modest rounding did not adequately enhance security but rounding to remove several digits of relative accuracy effectively reduced the risk of identification without substantially reducing utility. Grouping or adding random noise led to noticeable bias. When sharing epidemiologic data, it is recommended that masking be performed using rounding. Specific treatment should be determined separately in individual situations after consideration of the disclosure risks and analysis needs.

Recording 13C-15N HMQC 2D sparse spectra in solids in 30 s

NASA Astrophysics Data System (ADS)

Kupče, Ēriks; Trébosc, Julien; Perrone, Barbara; Lafon, Olivier; Amoureux, Jean-Paul

2018-03-01

We propose a dipolar HMQC Hadamard-encoded (D-HMQC-Hn) experiment for fast 2D correlations of abundant nuclei in solids. The main limitation of the Hadamard methods resides in the length of the encoding pulses, which results from a compromise between the selectivity and the sensitivity due to losses. For this reason, these methods should mainly be used with sparse spectra, and they profit from the increased separation of the resonances at high magnetic fields. In the case of the D-HMQC-Hn experiments, we give a simple rule that allows directly setting the optimum length of the selective pulses, versus the minimum separation of the resonances in the indirect dimension. The demonstration has been performed on a fully 13C,15N labelled f-MLF sample, and it allowed recording the build-up curves of the 13C-15N cross-peaks within 10 min. However, the method could also be used in the case of less sensitive samples, but with more accumulations.

Rheological characterization of schizophyllan aqueous solutions after denaturation-renaturation treatment.

PubMed

Fang, Yapeng; Takahashi, Rheo; Nishinari, Katsuyoshi

2004-07-01

Schizophyllan (SPG) with a molecular weight of 2.6x10(6), designated SPG-1, is denatured and then renatured at a concentration of 1.8 wt % by alkalization-neutralization. The prepared denatured-renatured samples (DRSPG-1) are diluted to various concentrations and equilibrated for 10 days before rheological and intrinsic viscosity measurements. When concentration (C(p)) is above 0.75 wt %, DRSPG-1 aqueous systems have weak gel-type rheological properties. However, for 0.28 wt % SPG in water while far smaller than that of 4.3 for SPG in DMSO. This is considered to be due to the strong interactions of DRSPG-1 chains in water, further confirmed by the intrinsic viscosity measurements in which the DRSPG-1 aqueous solution shows an abnormally large value of Huggins constant. Regarding the structure of DRSPG-1 weak gels, multiruns of dynamic strain sweep measurements suggest that the dominant structures are aggregates formed by hydrogen-bonding associations of DRSPG-1 chains rather than the permanent three-dimensional network. In addition, the step-shear rate tests are performed to study the thixotropic properties of DRSPG-1 aqueous systems. Copyright 2004 Wiley Periodicals, Inc. Biopolymers, 2004

A prospective randomized trial of postoperative pain following different insufflation pressures during gynecologic laparoscopy.

PubMed

Topçu, H O; Cavkaytar, S; Kokanalı, K; Guzel, A I; Islimye, M; Doganay, M

2014-11-01

To determine the effects of different intra-abdominal pressure values on visceral pain following gynecologic laparoscopic surgery in the Trendelenburg position. This randomized, controlled prospective trial was conducted at a tertiary education hospital and included 150 patients who underwent gynecologic laparoscopy with different abdominal insufflation pressures. There were 54 patients in the 8 mmHg low pressure group (LPG), 45 in the 12 mmHg standard pressure group (SPG), and 51 in the 15 mmHg high pressure group (HPG). We assessed mean age, body mass index (BMI), duration of surgery, analgesic consumption, length of hospital stay, amount of CO2 expended and volume of hemorrhage. Visceral pain and referred visceral pain were assessed 6, 12, and 24 h postoperatively using a visual analog scale (VAS). There was no significant difference in age, BMI, analgesic consumption or length of hospital stay among groups. The mean operative time and total CO2 expended during surgery were higher in the LPG compared with the SPG and HPG. The mean intensity of postoperative pain assessed by the VAS score at 6 and 12 h was less in the LPG than in the SPG and HPG and was reduced significantly at 12 h. VAS scores at 24 h in the LPG and SPG were lower than in the HPG. Pain is reduced by low insufflation pressure compared with standard and high insufflation pressure following gynecologic laparoscopic surgery in the Trendelenburg position. However, low insufflation pressure may result in longer operation times and increased hemorrhage. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Streptomyces songpinggouensis sp. nov., a Novel Actinomycete Isolated from Soil in Sichuan, China.

PubMed

Guan, Xuejiao; Li, Wenchao; Liu, Chongxi; Jin, Pinjiao; Guo, Siyu; Wang, Xiangjing; Xiang, Wensheng

2016-12-01

During a screening for novel and biotechnologically useful actinobacteria, a novel actinobacteria with weak antifungal activity, designated strain NEAU-Spg19 T , was isolated from a soil sample collected from pine forest in Songpinggou, Sichuan, southwest China. The strain was characterized using a polyphasic taxonomic approach which confirmed that it belongs to the genus Streptomyces. Growth occurred at a temperature range of 10-30 °C, pH 5.0-11.0 and NaCl concentrations of 0-5 %. The cell wall peptidoglycan consisted of LL-diaminopimelic acid and glycine. The major menaquinones were MK-9(H 6 ), MK-9(H 8 ) and MK-9(H 4 ). The phospholipid profile contained diphosphatidylglycerol (DPG), phosphatidylethanolamine and phosphatidylinositol. The major fatty acids were iso-C 15:0 , iso-C 16:0 , and C 16:0 . 16S rRNA gene sequence similarity studies showed that strain NEAU-Spg19 T belongs to the genus Streptomyces with the highest sequence similarities to Streptomyces tauricus JCM 4837 T (98.6 %) and Streptomyces rectiviolaceus JCM 9092 T (98.3 %). Some physiological and biochemical properties and low DNA-DNA relatedness values enabled the strain to be differentiated from S. tauricus JCM 4837 T and S. rectiviolaceus JCM 9092 T . Hence, on the basis of phenotypic and genetic analyses, it is proposed that strain NEAU-Spg19 T represents a novel species of the genus Streptomyces, for which the name Streptomyces songpinggouensis sp. nov. is proposed. The type strain is NEAU-Spg19 T (=CGMCC 4.7140 T =DSM 42141 T ).

Expression, purification, crystallization and X-ray diffraction studies of the molecular chaperone prefoldin from Homo sapiens.

PubMed

Aikawa, Yoshiki; Kida, Hiroshi; Nishitani, Yuichi; Miki, Kunio

2015-09-01

Proper protein folding is an essential process for all organisms. Prefoldin (PFD) is a molecular chaperone that assists protein folding by delivering non-native proteins to group II chaperonin. A heterohexamer of eukaryotic PFD has been shown to specifically recognize and deliver non-native actin and tubulin to chaperonin-containing TCP-1 (CCT), but the mechanism of specific recognition is still unclear. To determine its crystal structure, recombinant human PFD was reconstituted, purified and crystallized. X-ray diffraction data were collected to 4.7 Å resolution. The crystals belonged to space group P21212, with unit-cell parameters a = 123.2, b = 152.4, c = 105.9 Å.

MRI contrast agent for targeting glioma: interleukin-13 labeled liposome encapsulating gadolinium-DTPA.

PubMed

Liu, Xiaoli; Madhankumar, Achuthamangalam B; Miller, Patti A; Duck, Kari A; Hafenstein, Susan; Rizk, Elias; Slagle-Webb, Becky; Sheehan, Jonas M; Connor, James R; Yang, Qing X

2016-05-01

Detection of glioma with MRI contrast agent is limited to cases in which the blood-brain barrier (BBB) is compromised as contrast agents cannot cross the BBB. Thus, an early-stage infiltrating tumor is not detectable. Interleukin-13 receptor alpha 2 (IL-13Rα2), which has been shown to be overexpressed in glioma, can be used as a target moiety. We hypothesized that liposomes conjugated with IL-13 and encapsulating MRI contrast agent are capable of passing through an intact BBB and producing MRI contrast with greater sensitivity. The targeted MRI contrast agent was created by encapsulating Magnevist (Gd-DTPA) into liposomes conjugated with IL-13 and characterized by particle size distribution, cytotoxicity, and MRI relaxivity. MR image intensity was evaluated in the brain in normal mice post injection of Gd-DTPA and IL-13-liposome-Gd-DTPA one day apart. The specificity for glioma detection by IL-13-liposome-Gd-DTPA was demonstrated in an intracranial glioma mouse model and validated histologically. The average size of IL-13-liposome-Gd-DTPA was 137 ± 43 nm with relaxivity of 4.0 ± 0.4 L/mmole-s at 7 Tesla. No significant cytotoxicity was observed with MTS assay and serum chemistry in mice. The MRI signal intensity was enhanced up to 15% post injection of IL-13-liposome-Gd-DTPA in normal brain tissue following a similar time course as that for the pituitary gland outside of the BBB. MRI enhanced by IL-13-liposome-Gd-DTPA detected small tumor masses in addition to those seen with Magnevist-enhanced MRI. IL-13-liposome-Gd-DTPA is able to pass through the uncompromised BBB and detect an early stage glioma that cannot be seen with conventional contrast-enhanced MRI. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

HIV Infection and Compromised Mucosal Immunity: Oral Manifestations and Systemic Inflammation

PubMed Central

Heron, Samantha E.; Elahi, Shokrollah

2017-01-01

Mucosal surfaces account for the vast majority of HIV transmission. In adults, HIV transmission occurs mainly by vaginal and rectal routes but rarely via oral route. By contrast, pediatric HIV infections could be as the result of oral route by breastfeeding. As such mucosal surfaces play a crucial role in HIV acquisition, and spread of the virus depends on its ability to cross a mucosal barrier. HIV selectively infects, depletes, and/or dysregulates multiple arms of the human immune system particularly at the mucosal sites and causes substantial irreversible damage to the mucosal barriers. This leads to microbial products translocation and subsequently hyper-immune activation. Although introduction of antiretroviral therapy (ART) has led to significant reduction in morbidity and mortality of HIV-infected patients, viral replication persists. As a result, antigen presence and immune activation are linked to “inflammaging” that attributes to a pro-inflammatory environment and the accelerated aging process in HIV patients. HIV infection is also associated with the prevalence of oral mucosal infections and dysregulation of oral microbiota, both of which may compromise the oral mucosal immunity of HIV-infected individuals. In addition, impaired oral immunity in HIV infection may predispose the patients to periodontal diseases that are associated with systemic inflammation and increased risk of cardiovascular diseases. The purpose of this review is to examine existing evidence regarding the role of innate and cellular components of the oral cavity in HIV infection and how HIV infection may drive systemic hyper-immune activation in these patients. We will also discuss current knowledge on HIV oral transmission, HIV immunosenescence in relation to the oral mucosal alterations during the course of HIV infection and periodontal disease. Finally, we discuss oral manifestations associated with HIV infection and how HIV infection and ART influence the oral microbiome

HIV Infection and Compromised Mucosal Immunity: Oral Manifestations and Systemic Inflammation.

PubMed

Heron, Samantha E; Elahi, Shokrollah

2017-01-01

Mucosal surfaces account for the vast majority of HIV transmission. In adults, HIV transmission occurs mainly by vaginal and rectal routes but rarely via oral route. By contrast, pediatric HIV infections could be as the result of oral route by breastfeeding. As such mucosal surfaces play a crucial role in HIV acquisition, and spread of the virus depends on its ability to cross a mucosal barrier. HIV selectively infects, depletes, and/or dysregulates multiple arms of the human immune system particularly at the mucosal sites and causes substantial irreversible damage to the mucosal barriers. This leads to microbial products translocation and subsequently hyper-immune activation. Although introduction of antiretroviral therapy (ART) has led to significant reduction in morbidity and mortality of HIV-infected patients, viral replication persists. As a result, antigen presence and immune activation are linked to "inflammaging" that attributes to a pro-inflammatory environment and the accelerated aging process in HIV patients. HIV infection is also associated with the prevalence of oral mucosal infections and dysregulation of oral microbiota, both of which may compromise the oral mucosal immunity of HIV-infected individuals. In addition, impaired oral immunity in HIV infection may predispose the patients to periodontal diseases that are associated with systemic inflammation and increased risk of cardiovascular diseases. The purpose of this review is to examine existing evidence regarding the role of innate and cellular components of the oral cavity in HIV infection and how HIV infection may drive systemic hyper-immune activation in these patients. We will also discuss current knowledge on HIV oral transmission, HIV immunosenescence in relation to the oral mucosal alterations during the course of HIV infection and periodontal disease. Finally, we discuss oral manifestations associated with HIV infection and how HIV infection and ART influence the oral microbiome. Therefore

Autophagy Deficiency Compromises Alternative Pathways of Respiration following Energy Deprivation in Arabidopsis thaliana.

PubMed

Barros, Jessica A S; Cavalcanti, João Henrique F; Medeiros, David B; Nunes-Nesi, Adriano; Avin-Wittenberg, Tamar; Fernie, Alisdair R; Araújo, Wagner L

2017-09-01

Under heterotrophic conditions, carbohydrate oxidation inside the mitochondrion is the primary energy source for cellular metabolism. However, during energy-limited conditions, alternative substrates are required to support respiration. Amino acid oxidation in plant cells plays a key role in this by generating electrons that can be transferred to the mitochondrial electron transport chain via the electron transfer flavoprotein/ubiquinone oxidoreductase system. Autophagy, a catabolic mechanism for macromolecule and protein recycling, allows the maintenance of amino acid pools and nutrient remobilization. Although the association between autophagy and alternative respiratory substrates has been suggested, the extent to which autophagy and primary metabolism interact to support plant respiration remains unclear. To investigate the metabolic importance of autophagy during development and under extended darkness, Arabidopsis ( Arabidopsis thaliana ) mutants with disruption of autophagy ( atg mutants) were used. Under normal growth conditions, atg mutants showed lower growth and seed production with no impact on photosynthesis. Following extended darkness, atg mutants were characterized by signatures of early senescence, including decreased chlorophyll content and maximum photochemical efficiency of photosystem II coupled with increases in dark respiration. Transcript levels of genes involved in alternative pathways of respiration and amino acid catabolism were up-regulated in atg mutants. The metabolite profiles of dark-treated leaves revealed an extensive metabolic reprogramming in which increases in amino acid levels were partially compromised in atg mutants. Although an enhanced respiration in atg mutants was observed during extended darkness, autophagy deficiency compromises protein degradation and the generation of amino acids used as alternative substrates to the respiration. © 2017 American Society of Plant Biologists. All Rights Reserved.

Safety and Efficacy of Alginate Adhesion Barrier Gel in Compromised Intestinal Anastomosis.

PubMed

Chaturvedi, Ankit A; Yauw, Simon T K; Lomme, Roger M L M; Hendriks, Thijs; van Goor, Harry

For any anti-adhesive barrier developed for abdominal surgery, the use under conditions in which anastomotic healing is compromised needs to be investigated. The current study evaluates the effect of a new ultrapure alginate gel on early healing of high-risk anastomoses in the ileum and compares this with the gold standard used in clinical practice. In 75 adult male Wistar rats, a 5 mm ileal segment was resected and continuity was restored by construction of an inverted anastomosis. Rats were divided randomly into a control group and groups receiving either alginate gel or a sodium hyaluronate carboxymethylcellulose (HA/CMC) film around the anastomosis (n = 25 each). Carprofen, given in a daily dose of 1.25 mg/kg, was used to compromise anastomotic healing. At day three, animals were killed and scored for signs of anastomotic leakage and the presence of adhesions. The incidence of adhesion formation was 95% in the HA/CMC film group, which was significantly higher than in the controls (64%, p = 0.010) and the alginate gel group (52%, p = 0.004). The adhesion score was nearly 40% lower in the alginate gel group compared with the HA/CMC film group. The incidence of ileal leakage in the HA/CMC film group (92%) was significantly higher than in the controls (68%, p = 0.016). Leakage rate did not differ between the alginate gel and control groups. There was no significant difference between groups in either incision bursting pressure or incision breaking strength. Ultrapure alginate gel does not interfere with repair of ileal anastomoses constructed under conditions in which chances of anastomotic dehiscence are high. The alginate gel performs better than the HA/CMC film.

Do low-income lone mothers compromise their nutrition to feed their children?

PubMed Central

McIntyre, Lynn; Glanville, N. Theresa; Raine, Kim D.; Dayle, Jutta B.; Anderson, Bonnie; Battaglia, Noreen

2003-01-01

Background Women who live in disadvantaged circumstances in Canada exhibit dietary intakes below recommended levels, but their children often do not. One reason for this difference may be that mothers modify their own food intake to spare their children nutritional deprivation. The objective of our study was to document whether or not low-income lone mothers compromise their own diets to feed their children. Methods We studied 141 low-income lone mothers with at least 2 children under the age of 14 years who lived in Atlantic Canada. Women were identified through community organizations using a variety of recruitment strategies. The women were asked weekly for 1 month to recall their food intake over the previous 24 hours; they also reported their children's (n = 333) food intake. Mothers also completed a questionnaire about “food insecurity,” that is, a lack of access to adequate, nutritious food through socially acceptable means, during each interview. Results Household food insecurity was reported by 78% of mothers during the study month. Mothers' dietary intakes and the adequacy of intake were consistently poorer than their children's intake overall and over the course of a month. The difference in adequacy of intake between mothers and children widened from Time 1, when the family had the most money to purchase food, to Time 4, when the family had the least money. The children experienced some improvement in nutritional intake at Time 3, which was possibly related to food purchases for them associated with receipt of the Child Tax Benefit Credit or the Goods and Services Tax Credit. Interpretation Our study demonstrates that low-income lone mothers compromise their own nutritional intake in order to preserve the adequacy of their children's diets. PMID:12642423

Identifying compromised systems through correlation of suspicious traffic from malware behavioral analysis

NASA Astrophysics Data System (ADS)

Camilo, Ana E. F.; Grégio, André; Santos, Rafael D. C.

2016-05-01

Malware detection may be accomplished through the analysis of their infection behavior. To do so, dynamic analysis systems run malware samples and extract their operating system activities and network traffic. This traffic may represent malware accessing external systems, either to steal sensitive data from victims or to fetch other malicious artifacts (configuration files, additional modules, commands). In this work, we propose the use of visualization as a tool to identify compromised systems based on correlating malware communications in the form of graphs and finding isomorphisms between them. We produced graphs from over 6 thousand distinct network traffic files captured during malware execution and analyzed the existing relationships among malware samples and IP addresses.

Protecting Privacy of Shared Epidemiologic Data without Compromising Analysis Potential

DOE PAGES

Cologne, John; Grant, Eric J.; Nakashima, Eiji; ...

2012-01-01

Objective . Ensuring privacy of research subjects when epidemiologic data are shared with outside collaborators involves masking (modifying) the data, but overmasking can compromise utility (analysis potential). Methods of statistical disclosure control for protecting privacy may be impractical for individual researchers involved in small-scale collaborations. Methods . We investigated a simple approach based on measures of disclosure risk and analytical utility that are straightforward for epidemiologic researchers to derive. The method is illustrated using data from the Japanese Atomic-bomb Survivor population. Results . Masking by modest rounding did not adequately enhance security but rounding to remove several digits of relativemore » accuracy effectively reduced the risk of identification without substantially reducing utility. Grouping or adding random noise led to noticeable bias. Conclusions . When sharing epidemiologic data, it is recommended that masking be performed using rounding. Specific treatment should be determined separately in individual situations after consideration of the disclosure risks and analysis needs.« less

Protecting Privacy of Shared Epidemiologic Data without Compromising Analysis Potential

PubMed Central

Cologne, John; Grant, Eric J.; Nakashima, Eiji; Chen, Yun; Funamoto, Sachiyo; Katayama, Hiroaki

2012-01-01

Objective. Ensuring privacy of research subjects when epidemiologic data are shared with outside collaborators involves masking (modifying) the data, but overmasking can compromise utility (analysis potential). Methods of statistical disclosure control for protecting privacy may be impractical for individual researchers involved in small-scale collaborations. Methods. We investigated a simple approach based on measures of disclosure risk and analytical utility that are straightforward for epidemiologic researchers to derive. The method is illustrated using data from the Japanese Atomic-bomb Survivor population. Results. Masking by modest rounding did not adequately enhance security but rounding to remove several digits of relative accuracy effectively reduced the risk of identification without substantially reducing utility. Grouping or adding random noise led to noticeable bias. Conclusions. When sharing epidemiologic data, it is recommended that masking be performed using rounding. Specific treatment should be determined separately in individual situations after consideration of the disclosure risks and analysis needs. PMID:22505949

The CarbonTracker Data Assimilation System for CO2 and δ13C (CTDAS-C13 v1.0): retrieving information on land-atmosphere exchange processes

NASA Astrophysics Data System (ADS)

van der Velde, Ivar R.; Miller, John B.; van der Molen, Michiel K.; Tans, Pieter P.; Vaughn, Bruce H.; White, James W. C.; Schaefer, Kevin; Peters, Wouter

2018-01-01

To improve our understanding of the global carbon balance and its representation in terrestrial biosphere models, we present here a first dual-species application of the CarbonTracker Data Assimilation System (CTDAS). The system's modular design allows for assimilating multiple atmospheric trace gases simultaneously to infer exchange fluxes at the Earth surface. In the prototype discussed here, we interpret signals recorded in observed carbon dioxide (CO2) along with observed ratios of its stable isotopologues 13CO2/12CO2 (δ13C). The latter is in particular a valuable tracer to untangle CO2 exchange from land and oceans. Potentially, it can also be used as a proxy for continent-wide drought stress in plants, largely because the ratio of 13CO2 and 12CO2 molecules removed from the atmosphere by plants is dependent on moisture conditions.The dual-species CTDAS system varies the net exchange fluxes of both 13CO2 and CO2 in ocean and terrestrial biosphere models to create an ensemble of 13CO2 and CO2 fluxes that propagates through an atmospheric transport model. Based on differences between observed and simulated 13CO2 and CO2 mole fractions (and thus δ13C) our Bayesian minimization approach solves for weekly adjustments to both net fluxes and isotopic terrestrial discrimination that minimizes the difference between observed and estimated mole fractions.With this system, we are able to estimate changes in terrestrial δ13C exchange on seasonal and continental scales in the Northern Hemisphere where the observational network is most dense. Our results indicate a decrease in stomatal conductance on a continent-wide scale during a severe drought. These changes could only be detected after applying combined atmospheric CO2 and δ13C constraints as done in this work. The additional constraints on surface CO2 exchange from δ13C observations neither affected the estimated carbon fluxes nor compromised our ability to match observed CO2 variations. The prototype presented

Compromised zinc status of experimental rats as a consequence of prolonged iron & calcium supplementation.

PubMed

Jayalakshmi, S; Platel, Kalpana

2016-02-01

Iron supplementation is usually given to pregnant and lactating women who may also have marginal deficiency of zinc. The negative impact of supplemental iron and calcium on zinc status is a cause of concern. The present investigation was undertaken to examine the effect of inclusion of iron and calcium in the diet at supplementary levels on zinc status of experimental rats. Groups of experimental rats were maintained on diets supplemented with iron (Molar ratio - Zn:Fe 1:30) and calcium (Molar ratio - Zn:Ca 1:667) both individually and in combination for six weeks. Zinc status of these rats was assessed by determining zinc concentration in circulation and in organs, and the activities of zinc containing enzymes in serum and liver. The zinc status of experimental rats receiving supplemental levels of iron and calcium was significantly compromised. Zinc concentration in serum, kidney, spleen and liver was reduced significantly by both these minerals. Six weeks of supplementation of iron and calcium individually, significantly reduced the activity of liver and serum superoxide dismutase and alkaline phosphatase. Activity of liver alcohol dehydrogenase was lowered in calcium supplemented group and in calcium + iron supplemented group, while that of carbonic anhydrase was significantly reduced by iron, calcium and their combination. Supplemental levels of iron and calcium, both individually and in combination, significantly compromised the zinc status of experimental rats. This negative effect of these two minerals was more prominent when these were supplemented for a period of six weeks.

The Women's Army Auxiliary Corps: A Compromise to Overcome the Conflict of Women Serving in the Army

ERIC Educational Resources Information Center

Permeswaran, Yashila

2008-01-01

Though people now take the idea of women in the military for granted, in the 1940s it was a vigorously debated suggestion. Men protected their country; women stayed at home. Because of the conflict over whether women should serve in the army, Congress compromised by creating the Women's Army Auxiliary Corps (WAAC). This article describes the…

Representational and Executive Selection Resources in "Theory of Mind": Evidence from Compromised Belief-Desire Reasoning in Old Age

ERIC Educational Resources Information Center

German, Tim P.; Hehman, Jessica A.

2006-01-01

Effective belief-desire reasoning requires both specialized representational capacities--the capacity to represent the mental states as such--as well as executive selection processes for accurate performance on tasks requiring the prediction and explanation of the actions of social agents. Compromised belief-desire reasoning in a given population…

Compromised careers: the occupational transition of immigration and resettlement.

PubMed

Suto, Melinda

2009-01-01

Work is a significant occupational transition that occurs with immigration and resettlement. Problems finding work and regaining economic capital are multi-factorial, differentiated by gender and mediated by specific contexts. Surprisingly, past education and work experience are unreliable predictors of successful employment outcomes. Critical theory and ethnographic concepts informed the methodological approach. Data were generated primarily through in-depth interviews, conducted in English, with 14 well-educated women who immigrated to Canada as adults and sought employment in their professions. The thematic findings were analyzed using Bourdieu's [7] concepts of capital, field and habitus. The theme Compromised Careers describes the downward occupational (work) mobility that occurs despite expectations that education, credentials and work experience are transferable to desirable employment. A devaluation of foreign qualifications and no relevant Canadian work experience function with gendered responsibilities, less social support, and time spent in resettlement activities to create negative work trajectories. The role that federal policies and professional organizations play is examined to reveal the tension between individuals' efforts to find employment and institutional barriers that impede these actions. A critical inquiry approach examined the ruling relations to show how power and privilege function in relation to migrants' occupational transitions.

Metabolic Stress and Compromised Identity of Pancreatic Beta Cells.

PubMed

Swisa, Avital; Glaser, Benjamin; Dor, Yuval

2017-01-01

Beta cell failure is a central feature of type 2 diabetes (T2D), but the molecular underpinnings of the process remain only partly understood. It has been suggested that beta cell failure in T2D involves massive cell death. Other studies ascribe beta cell failure to cell exhaustion, due to chronic oxidative or endoplasmic reticulum stress leading to cellular dysfunction. More recently it was proposed that beta cells in T2D may lose their differentiated identity, possibly even gaining features of other islet cell types. The loss of beta cell identity appears to be driven by glucotoxicity inhibiting the activity of key beta cell transcription factors including Pdx1, Nkx6.1, MafA and Pax6, thereby silencing beta cell genes and derepressing alternative islet cell genes. The loss of beta cell identity is at least partly reversible upon normalization of glycemia, with implications for the reversibility of T2D, although it is not known if beta cell failure reaches eventually a point of no return. In this review we discuss current evidence for metabolism-driven compromised beta cell identity, key knowledge gaps and opportunities for utility in the treatment of T2D.

RNA interference targeting carbohydrate sulfotransferase 3 diminishes macrophage accumulation, inhibits MMP-9 expression and promotes lung recovery in murine pulmonary emphysema.

PubMed

Kai, Yoshiro; Tomoda, Koichi; Yoneyama, Hiroyuki; Yoshikawa, Masanori; Kimura, Hiroshi

2015-12-09

Chondroitin sulfate proteoglycans are an important mediators in inflammation and leukocyte trafficking. However, their roles in pulmonary emphysema have not been explored. In a murine model of elastase-induced pulmonary emphysema, we found increased carbohydrate sulfotransferase 3 (CHST3), a specific enzyme that synthesizes chondroitin 6-sulfate proteoglycan (C6SPG). To elucidate the role of C6SPG, we investigated the effect of small interfering RNA (siRNA) targeting CHST3 that inhibits C6SPG-synthesis on the pathogenesis of pulmonary emphysema. Mice were intraperitoneally injected with CHST3 siRNA or negative control siRNA on day0 and 7 after intratracheal instillation of elastase. Histology, respiratory function, glycosaminoglycans (GAGs) content, bronchoalveolar lavage (BAL), elastin staining and gene expressions of tumor necrosis factor (TNF)-α and matrix metalloproteinase (MMP)-9 mRNA were evaluated on day7 and/or day21. CHST3 mRNA increased at day 7 and decreased thereafter in lung. CHST3 siRNA successfully inhibited the expression of CHST3 mRNA throughout the study and this was associated with significant reduction of GAGs and C6SPG. Airway destruction and respiratory function were improved by the treatment with CHST3 siRNA. CHST3 siRNA reduced the number of macrophages both in BAL and lung parenchyma and also suppressed the increased expressions of TNF-α and MMP-9 mRNA. Futhermore, CHST3 siRNA improved the reduction of the elastin in the alveolar walls. CHST3 siRNA diminishes accumulation of excessive macrophages and the mediators, leading to accelerate the functional recovery from airway damage by repair of the elastin network associated with pulmonary emphysema.

Spastic Paraplegia Type 7 Is Associated with Multiple Mitochondrial DNA Deletions

PubMed Central

Wedding, Iselin Marie; Koht, Jeanette; Tran, Gia Tuong; Misceo, Doriana; Selmer, Kaja Kristine; Holmgren, Asbjørn; Frengen, Eirik; Bindoff, Laurence; Tallaksen, Chantal M. E.; Tzoulis, Charalampos

2014-01-01

Spastic paraplegia 7 is an autosomal recessive disorder caused by mutations in the gene encoding paraplegin, a protein located at the inner mitochondrial membrane and involved in the processing of other mitochondrial proteins. The mechanism whereby paraplegin mutations cause disease is unknown. We studied two female and two male adult patients from two Norwegian families with a combination of progressive external ophthalmoplegia and spastic paraplegia. Sequencing of SPG7 revealed a novel missense mutation, c.2102A>C, p.H 701P, which was homozygous in one family and compound heterozygous in trans with a known pathogenic mutation c.1454_1462del in the other. Muscle was examined from an additional, unrelated adult female patient with a similar phenotype caused by a homozygous c.1047insC mutation in SPG7. Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV. Molecular studies in single, microdissected fibres showed multiple mitochondrial DNA deletions segregating at high levels (38–97%) in respiratory deficient fibres. Our findings demonstrate for the first time that paraplegin mutations cause accumulation of mitochondrial DNA damage and multiple respiratory chain deficiencies. While paraplegin is not known to be directly associated with the mitochondrial nucleoid, it is known to process other mitochondrial proteins and it is possible therefore that paraplegin mutations lead to mitochondrial DNA deletions by impairing proteins involved in the homeostasis of the mitochondrial genome. These studies increase our understanding of the molecular pathogenesis of SPG7 mutations and suggest that SPG7 testing should be included in the diagnostic workup of autosomal recessive, progressive external ophthalmoplegia, especially if spasticity is present. PMID:24466038

Expression, purification, crystallization and X-ray diffraction studies of the molecular chaperone prefoldin from Homo sapiens

PubMed Central

Aikawa, Yoshiki; Kida, Hiroshi; Nishitani, Yuichi; Miki, Kunio

2015-01-01

Proper protein folding is an essential process for all organisms. Prefoldin (PFD) is a molecular chaperone that assists protein folding by delivering non-native proteins to group II chaperonin. A heterohexamer of eukaryotic PFD has been shown to specifically recognize and deliver non-native actin and tubulin to chaperonin-containing TCP-1 (CCT), but the mechanism of specific recognition is still unclear. To determine its crystal structure, recombinant human PFD was reconstituted, purified and crystallized. X-ray diffraction data were collected to 4.7 Å resolution. The crystals belonged to space group P21212, with unit-cell parameters a = 123.2, b = 152.4, c = 105.9 Å. PMID:26323306

Overexpression of prefoldin from the hyperthermophilic archaeum Pyrococcus horikoshii OT3 endowed Escherichia coli with organic solvent tolerance.

PubMed

Okochi, Mina; Kanie, Kei; Kurimoto, Masaki; Yohda, Masafumi; Honda, Hiroyuki

2008-06-01

Prefoldin is a jellyfish-shaped hexameric chaperone that captures a protein-folding intermediate and transfers it to the group II chaperonin for correct folding. In this work, we characterized the organic solvent tolerance of Escherichia coli cells that overexpress prefoldin and group II chaperonin from a hyperthermophilic archeaum, Pyrococcus horikoshii OT3. The colony-forming efficiency of E. coli cells overexpressing prefoldin increased by 1,000-fold and decreased the accumulation of intracellular organic solvent. The effect was impaired by deletions of the region responsible for the chaperone function of prefoldin. Therefore, we concluded that prefoldin endows E. coli cells by preventing accumulation of intracellular organic solvent through its molecular chaperone activity.

Lack of Spartin Protein in Troyer Syndrome

PubMed Central

Bakowska, Joanna C.; Wang, Heng; Xin, Baozhong; Sumner, Charlotte J.; Blackstone, Craig

2017-01-01

Background Hereditary spastic paraplegias (SPG1-SPG33) are characterized by progressive spastic weakness of the lower limbs. A nucleotide deletion (1110delA) in the (SPG20; OMIM 275900) spartin gene is the origin of autosomal recessive Troyer syndrome. This mutation is predicted to cause premature termination of the spartin protein. However, it remains unknown whether this truncated spartin protein is absent or is present and partially functional in patients. Objective To determine whether the truncated spartin protein is present or absent in cells derived from patients with Troyer syndrome. Design Case report. Setting Academic research. Patients We describe a new family with Troyer syndrome due to the 1110delA mutation. Main Outcome Measures We cultured primary fibroblasts and generated lymphoblasts from affected individuals, carriers, and control subjects and subjected these cells to immunoblot analyses. Results Spartin protein is undetectable in several cell lines derived from patients with Troyer syndrome. Conclusions Our data suggest that Troyer syndrome results from complete loss of spartin protein rather than from the predicted partly functional fragment. This may reflect increased protein degradation or impaired translation. PMID:18413476

Accomplishments and Compromises in Prediction Research for World Records and Best Performances in Track and Field and Swimming

ERIC Educational Resources Information Center

Liu, Yuanlong; Paul, Stanley; Fu, Frank H.

2012-01-01

The conductors of this study reviewed prediction research and studied the accomplishments and compromises in predicting world records and best performances in track and field and swimming. The results of the study showed that prediction research only promises to describe the historical trends in track and field and swimming performances, to study…

Compromised zinc status of experimental rats as a consequence of prolonged iron & calcium supplementation

PubMed Central

Jayalakshmi, S.; Platel, Kalpana

2016-01-01

Background & objectives: Iron supplementation is usually given to pregnant and lactating women who may also have marginal deficiency of zinc. The negative impact of supplemental iron and calcium on zinc status is a cause of concern. The present investigation was undertaken to examine the effect of inclusion of iron and calcium in the diet at supplementary levels on zinc status of experimental rats. Methods: Groups of experimental rats were maintained on diets supplemented with iron (Molar ratio - Zn:Fe 1:30) and calcium (Molar ratio - Zn:Ca 1:667) both individually and in combination for six weeks. Zinc status of these rats was assessed by determining zinc concentration in circulation and in organs, and the activities of zinc containing enzymes in serum and liver. Results: The zinc status of experimental rats receiving supplemental levels of iron and calcium was significantly compromised. Zinc concentration in serum, kidney, spleen and liver was reduced significantly by both these minerals. Six weeks of supplementation of iron and calcium individually, significantly reduced the activity of liver and serum superoxide dismutase and alkaline phosphatase. Activity of liver alcohol dehydrogenase was lowered in calcium supplemented group and in calcium + iron supplemented group, while that of carbonic anhydrase was significantly reduced by iron, calcium and their combination. Interpretation & conclusions: Supplemental levels of iron and calcium, both individually and in combination, significantly compromised the zinc status of experimental rats. This negative effect of these two minerals was more prominent when these were supplemented for a period of six weeks. PMID:27121523

Urinary C‑X‑C motif chemokine 13 is a noninvasive biomarker of antibody‑mediated renal allograft rejection.

PubMed

Chen, Dajin; Zhang, Jian; Peng, Wenhan; Weng, Chunhua; Chen, Jianghua

2018-06-22

Noninvasive monitoring methods of immune status are preferred by transplant recipients. The present study investigated whether urinary C‑X‑C motif chemokine 13 (CXCL13) had the potential to reflect ongoing immune processes within renal allografts. Using an ELISA assay, the level of urinary CXCL13 was quantified in a total of 146 renal allograft recipients and 40 healthy controls at scheduled intervals and at the time of the indicated or protocol biopsy. The results of the present study revealed that urinary CXCL13/creatinine (Cr) was lower in normal transplants compared with in those with acute tubular necrosis (ATN; P=0.001), chronic allograft nephropathy (CAN; P=0.01), and acute rejection (AR; P<0.0001), which was associated with a good diagnostic performance for AR [area under the curve (AUC)=0.818, P<0.0001). In addition, urinary CXCL13/Cr levels in patients with AR were also higher than that of patients with graft dysfunction but no rejection, including ATN and CAN (P=0.034). Notably, urinary CXCL13 distinguished between acute antibody‑mediated rejection (ABMR) and acute cellular rejection, with an AUC of 0.856. Furthermore, patients with steroid‑resistant AR exhibited significantly increased urinary CXCL13/Cr levels than patients with reversible AR (P=0.001). Additionally, elevated levels of urinary CXCL13/Cr within the first month of transplant were predictive of graft function at 3 and 6 months (P=0.044 and P=0.04, respectively). Collectively, the findings of the present study indicated that the noninvasive investigation of urinary CXCL13/Cr may be valuable for the detection of AR, particularly ABMR. In addition, high urinary CXCL13/Cr levels predicted a poor response to steroid treatment and compromised graft function.

Mapping spatial patterns of stream power and channel change along a gravel-bed river in northern Yellowstone

NASA Astrophysics Data System (ADS)

Lea, Devin M.; Legleiter, Carl J.

2016-01-01

Stream power represents the rate of energy expenditure along a river and can be calculated using topographic data acquired via remote sensing or field surveys. This study sought to quantitatively relate temporal changes in the form of Soda Butte Creek, a gravel-bed river in northeastern Yellowstone National Park, to stream power gradients along an 8-km reach. Aerial photographs from 1994 to 2012 and ground-based surveys were used to develop a locational probability map and morphologic sediment budget to assess lateral channel mobility and changes in net sediment flux. A drainage area-to-discharge relationship and DEM developed from LiDAR data were used to obtain the discharge and slope values needed to calculate stream power. Local and lagged relationships between mean stream power gradient at median peak discharge and volumes of erosion, deposition, and net sediment flux were quantified via spatial cross-correlation analyses. Similarly, autocorrelations of locational probabilities and sediment fluxes were used to examine spatial patterns of sediment sources and sinks. Energy expended above critical stream power was calculated for each time period to relate the magnitude and duration of peak flows to the total volumetric change in each time increment. Collectively, we refer to these methods as the stream power gradient (SPG) framework. The results of this study were compromised by methodological limitations of the SPG framework and revealed some complications likely to arise when applying this framework to small, wandering, gravel-bed rivers. Correlations between stream power gradients and sediment flux were generally weak, highlighting the inability of relatively simple statistical approaches to link sub-budget cell-scale sediment dynamics to larger-scale driving forces such as stream power gradients. Improving the moderate spatial resolution techniques used in this study and acquiring very-high resolution data from recently developed methods in fluvial remote

Protection characteristics of a Faraday cage compromised by lightning burnthrough.

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

Warne, Larry Kevin; Bystrom, Edward; Jorgenson, Roy Eberhardt

2012-01-01

A lightning flash consists of multiple, high-amplitude but short duration return strokes. Between the return strokes is a lower amplitude, continuing current which flows for longer duration. If the walls of a Faraday cage are made of thin enough metal, the continuing current can melt a hole through the metal in a process called burnthrough. A subsequent return stroke can couple energy through this newly-formed hole. This LDRD is a study of the protection provided by a Faraday cage when it has been compromised by burnthrough. We initially repeated some previous experiments and expanded on them in terms of scopemore » and diagnostics to form a knowledge baseline of the coupling phenomena. We then used a combination of experiment, analysis and numerical modeling to study four coupling mechanisms: indirect electric field coupling, indirect magnetic field coupling, conduction through plasma and breakdown through the hole. We discovered voltages higher than those encountered in the previous set of experiments (on the order of several hundreds of volts).« less