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1

Properties of a herpes simplex virus multiple immediate-early gene-deleted recombinant as a vaccine vector  

E-print Network

Properties of a herpes simplex virus multiple immediate-early gene-deleted recombinant as a vaccine 2006 Available online 23 September 2006 Abstract Herpes simplex virus (HSV) recombinants induce durable and test novel vaccine approaches as candidate AIDS vaccines. We have previously used herpes simplex virus

Knipe, David M.

2

Properties of a herpes simplex virus multiple immediate-early gene-deleted recombinant as a vaccine vector  

SciTech Connect

Herpes simplex virus (HSV) recombinants induce durable immune responses in rhesus macaques and mice and have induced partial protection in rhesus macaques against mucosal challenge with virulent simian immunodeficiency virus (SIV). In this study, we evaluated the properties of a new generation HSV vaccine vector, an HSV-1 multiple immediate-early (IE) gene deletion mutant virus, d106, which contains deletions in the ICP4, ICP27, ICP22, and ICP47 genes. Because several of the HSV IE genes have been implicated in immune evasion, inactivation of the genes encoding these proteins was expected to result in enhanced immunogenicity. The d106 virus expresses few HSV gene products and shows minimal cytopathic effect in cultured cells. When d106 was inoculated into mice, viral DNA accumulated at high levels in draining lymph nodes, consistent with an ability to transduce dendritic cells and activate their maturation and movement to lymph nodes. A d106 recombinant expressing Escherichia coli {beta}-galactosidase induced durable {beta}-gal-specific IgG and CD8{sup +} T cell responses in naive and HSV-immune mice. Finally, d106-based recombinants have been constructed that express simian immunodeficiency virus (SIV) gag, env, or a rev-tat-nef fusion protein for several days in cultured cells. Thus, d106 shows many of the properties desirable in a vaccine vector: limited expression of HSV gene products and cytopathogenicity, high level expression of transgenes, ability to induce durable immune responses, and an ability to transduce dendritic cells and induce their maturation and migration to lymph nodes.

Watanabe, Daisuke [Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115 (United States); Brockman, Mark A. [Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115 (United States); Ndung'u, Thumbi [Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115 (United States); Mathews, Lydia [Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115 (United States); Lucas, William T. [Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115 (United States); Murphy, Cynthia G. [Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115 (United States); Felber, Barbara K. [National Cancer Institute-Frederick, Frederick, MD 21702 (United States); Pavlakis, George N. [National Cancer Institute-Frederick, Frederick, MD 21702 (United States); Deluca, Neal A. [Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 (United States); Knipe, David M. [Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115 (United States)]. E-mail: david_knipe@hms.harvard.edu

2007-01-20

3

The green monster process for the generation of yeast strains carrying multiple gene deletions.  

PubMed

Phenotypes for a gene deletion are often revealed only when the mutation is tested in a particular genetic background or environmental condition(1,2). There are examples where many genes need to be deleted to unmask hidden gene functions(3,4). Despite the potential for important discoveries, genetic interactions involving three or more genes are largely unexplored. Exhaustive searches of multi-mutant interactions would be impractical due to the sheer number of possible combinations of deletions. However, studies of selected sets of genes, such as sets of paralogs with a greater a priori chance of sharing a common function, would be informative. In the yeast Saccharomyces cerevisiae, gene knockout is accomplished by replacing a gene with a selectable marker via homologous recombination. Because the number of markers is limited, methods have been developed for removing and reusing the same marker(5,6,7,8,9,10). However, sequentially engineering multiple mutations using these methods is time-consuming because the time required scales linearly with the number of deletions to be generated. Here we describe the Green Monster method for routinely engineering multiple deletions in yeast(11). In this method, a green fluorescent protein (GFP) reporter integrated into deletions is used to quantitatively label strains according to the number of deletions contained in each strain (Figure 1). Repeated rounds of assortment of GFP-marked deletions via yeast mating and meiosis coupled with flow-cytometric enrichment of strains carrying more of these deletions lead to the accumulation of deletions in strains (Figure 2). Performing multiple processes in parallel, with each process incorporating one or more deletions per round, reduces the time required for strain construction. The first step is to prepare haploid single-mutants termed 'ProMonsters,' each of which carries a GFP reporter in a deleted locus and one of the 'toolkit' loci-either Green Monster GMToolkit-a or GMToolkit-? at the can1? locus (Figure 3). Using strains from the yeast deletion collection(12), GFP-marked deletions can be conveniently generated by replacing the common KanMX4 cassette existing in these strains with a universal GFP-URA3 fragment. Each GMToolkit contains: either the a- or ?-mating-type-specific haploid selection marker(1) and exactly one of the two markers that, when both GMToolkits are present, collectively allow for selection of diploids. The second step is to carry out the sexual cycling through which deletion loci can be combined within a single cell by the random assortment and/or meiotic recombination that accompanies each cycle of mating and sporulation. PMID:23271437

Suzuki, Yo; Stam, Jason; Novotny, Mark; Yachie, Nozomu; Lasken, Roger S; Roth, Frederick P

2012-01-01

4

Multiple genetic origins of histidine-rich protein 2 gene deletion in Plasmodium falciparum parasites from Peru  

PubMed Central

The majority of malaria rapid diagnostic tests (RDTs) detect Plasmodium falciparum histidine-rich protein 2 (PfHRP2), encoded by the pfhrp2 gene. Recently, P. falciparum isolates from Peru were found to lack pfhrp2 leading to false-negative RDT results. We hypothesized that pfhrp2-deleted parasites in Peru derived from a single genetic event. We evaluated the parasite population structure and pfhrp2 haplotype of samples collected between 1998 and 2005 using seven neutral and seven chromosome 8 microsatellite markers, respectively. Five distinct pfhrp2 haplotypes, corresponding to five neutral microsatellite-based clonal lineages, were detected in 1998-2001; pfhrp2 deletions occurred within four haplotypes. In 2003-2005, outcrossing among the parasite lineages resulted in eight population clusters that inherited the five pfhrp2 haplotypes seen previously and a new haplotype; pfhrp2 deletions occurred within four of these haplotypes. These findings indicate that the genetic origin of pfhrp2 deletion in Peru was not a single event, but likely occurred multiple times. PMID:24077522

Akinyi, Sheila; Hayden, Tonya; Gamboa, Dionicia; Torres, Katherine; Bendezu, Jorge; Abdallah, Joseph F.; Griffing, Sean M.; Quezada, Wilmer Marquino; Arrospide, Nancy; De Oliveira, Alexandre Macedo; Lucas, Carmen; Magill, Alan J.; Bacon, David J.; Barnwell, John W.; Udhayakumar, Venkatachalam

2013-01-01

5

Immediate early genes expressed in chlorovirus infections  

Microsoft Academic Search

Twenty-three chlorovirus genes expressed in host cells as early as 5–10 min postinfection (p.i.), or immediate early, were isolated and characterized. Some showed significant homology with those for transcriptional factors and mRNA-processing proteins including TFIIB, helicases, mRNA capping enzyme, nucleolin, and bean transcription factor. Others code for (i) factors influencing translation such as aminoacyl tRNA synthetases and ribosomal protein, and

Takeru Kawasaki; Masahiro Tanaka; Makoto Fujie; Shoji Usami; Takashi Yamada

2004-01-01

6

Immediate early genes expressed in chlorovirus infections.  

PubMed

Twenty-three chlorovirus genes expressed in host cells as early as 5-10 min postinfection (p.i.), or immediate early, were isolated and characterized. Some showed significant homology with those for transcriptional factors and mRNA-processing proteins including TFIIB, helicases, mRNA capping enzyme, nucleolin, and bean transcription factor. Others code for (i) factors influencing translation such as aminoacyl tRNA synthetases and ribosomal protein, and (ii) unknown proteins. Enzymes involved in polysaccharide synthesis were also found. All transcripts of these genes had a poly(A) tail, which decreased in size after 20 min p.i., possibly caused by the shortening by an exonuclease. Often, due to readthrough either from an upstream ORF or into a downstream ORF, a few extra transcripts for each gene appeared after 40 min p.i., suggesting a change in promoter selection and termination accuracy at this point. A typical TATA-box and a common element 5'-ATGACAA were in the promoter region of almost all of the immediate early genes, which may be recognized by host RNA polymerase and transcription factors. PMID:14972549

Kawasaki, Takeru; Tanaka, Masahiro; Fujie, Makoto; Usami, Shoji; Yamada, Takashi

2004-01-01

7

Constructing unmarked gene deletions in Legionella pneumophila.  

PubMed

The ability to construct recombinant alleles efficiently in strains of interest, particularly unmarked deletions that reduce the potential for polar effects, is essential to studies of both pathogenesis and basic bacterial physiology. Here we describe a three-phase approach for generating unmarked deletions in Legionella pneumophila by constructing a mutant allele in E. coli using ?-Red recombination, so-called recombineering; transferring the allele onto the L. pneumophila chromosome by natural transformation; and then removing the selectable marker by utilizing the Flp site-specific recombinase. This strategy can decrease the amount of clone screening required while also increasing the percentage of the time the desired allele is obtained on the first attempt. The approach is particularly suited for constructing multiple unmarked deletions in a single strain in fewer steps than traditional methods. PMID:23150396

Bryan, Andrew; Abbott, Zachary D; Swanson, Michele S

2013-01-01

8

Pancreatic function and gene deletion F508 in cystic fibrosis.  

PubMed Central

In view of the possible relation between pancreatic function and cystic fibrosis (CF) gene mutations, a detailed study on Italian patients was performed. Seventy pancreatic insufficient and 48 pancreatic sufficient patients were included after very accurate characterisation of their pancreatic and digestive function, all performed in the same CF centre. The CF gene deletion F508 was tested to define the patients' genotypes. The results confirm that the mutation correlates with pancreatic insufficiency, and is recessive to other, as yet unreported, mutant alleles that determine pancreatic sufficiency. An indication that duodenal bicarbonate output is more severely reduced in the presence of deletion F508 is also presented. The data are discussed in relation to a hypothesis on the primary effects of CF gene deletion F508. PMID:2277379

Borgo, G; Mastella, G; Gasparini, P; Zorzanello, A; Doro, R; Pignatti, P F

1990-01-01

9

Pancreatic function and gene deletion F508 in cystic fibrosis.  

PubMed

In view of the possible relation between pancreatic function and cystic fibrosis (CF) gene mutations, a detailed study on Italian patients was performed. Seventy pancreatic insufficient and 48 pancreatic sufficient patients were included after very accurate characterisation of their pancreatic and digestive function, all performed in the same CF centre. The CF gene deletion F508 was tested to define the patients' genotypes. The results confirm that the mutation correlates with pancreatic insufficiency, and is recessive to other, as yet unreported, mutant alleles that determine pancreatic sufficiency. An indication that duodenal bicarbonate output is more severely reduced in the presence of deletion F508 is also presented. The data are discussed in relation to a hypothesis on the primary effects of CF gene deletion F508. PMID:2277379

Borgo, G; Mastella, G; Gasparini, P; Zorzanello, A; Doro, R; Pignatti, P F

1990-11-01

10

Characterization of immediate early genes expressed in chlorovirus infection.  

PubMed

By Southern blot analysis of restriction fragments of a chlorovirus CVK2 genomic contig with probes of RNA expressed immediate early in infection, sixteen genes were specifically found to be expressed in the host cells. These genes include those for aminoacyl-tRNA synthetase, nucleolin, ribosomal protein S5, hyaluronan synthase, TFIID etc. All of these transcripts were polyadenylated and most likely expressed in the host nucleus. The structural characteristics of these genes are discussed in connection with their expression mechanism. The biological importance of the gene products in viral infection are also considered. PMID:12903318

Kawasaki, T; Nishida, K; Fujie, M; Usami, S; Yamada, T

2000-01-01

11

Digital nature of the immediate-early transcriptional response  

PubMed Central

Stimulation of transcription by extracellular signals is a major component of a cell's decision making. Yet the quantitative relationship between signal and acute transcriptional response is unclear. One view is that transcription is directly graded with inducer concentration. In an alternative model, the response occurs only above a threshold inducer concentration. Standard methods for monitoring transcription lack continuous information from individual cells or mask immediate-early transcription by measuring downstream protein expression. We have therefore used a technique for directly monitoring nascent RNA in living cells, to quantify the direct transcriptional response to an extracellular signal in real time, in single cells. At increasing doses of inducer, increasing numbers of cells displayed a transcriptional response. However, over the same range of doses, the change in cell response strength, measured as the length, frequency and intensity of transcriptional pulses, was small, with considerable variation between cells. These data support a model in which cells have different sensitivities to developmental inducer and respond in a digital manner above individual stimulus thresholds. Biased digital responses may be necessary for certain forms of developmental specification. Limiting bias in responsiveness is required to reduce noise in positional signalling. PMID:20110323

Stevense, Michelle; Muramoto, Tetsuya; Muller, Iris; Chubb, Jonathan R.

2010-01-01

12

Enhancer RNA Facilitates NELF Release from Immediate Early Genes.  

PubMed

Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers, whose function and action mechanism are yet to be firmly established. Here we show that eRNAs facilitate the transition of paused RNA polymerase II (RNAPII) into productive elongation by acting as a decoy for the negative elongation factor (NELF) complex upon induction of immediate early genes (IEGs) in neurons. eRNAs are synthesized prior to the culmination of target gene transcription and interact with the NELF complex. Knockdown of eRNAs expressed at neuronal enhancers impairs transient release of NELF from the specific target promoters during transcriptional activation, coinciding with a decrease in target mRNA induction. The enhancer-promoter interaction was unaffected by eRNA knockdown. Instead, chromatin looping might enable eRNAs to act locally at a specific promoter. Our findings highlight the spatiotemporally regulated action mechanism of eRNAs during early transcriptional elongation. PMID:25263592

Schaukowitch, Katie; Joo, Jae-Yeol; Liu, Xihui; Watts, Jonathan K; Martinez, Carlos; Kim, Tae-Kyung

2014-10-01

13

Enhanced Hydrogen Production in Escherichia coli Through Chemical Mutagenesis, Gene Deletion, and Transposon Mutagenesis  

E-print Network

ENHANCED HYDROGEN PRODUCTION IN ESCHERICHIA COLI THROUGH CHEMICAL MUTAGENESIS, GENE DELETION, AND TRANSPOSON MUTAGENESIS A Thesis by ANDREA JULIANA GARZON SANABRIA Submitted to the Office of Graduate Studies of Texas A...&M University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE May 2010 Major Subject: Chemical Engineering ENHANCED HYDROGEN PRODUCTION IN ESCHERICHIA COLI THROUGH CHEMICAL MUTAGENESIS, GENE DELETION...

Garzon Sanabria, Andrea Juliana

2011-08-08

14

Inhibition of human cytomegalovirus immediate-early gene expression by an antisense oligonucleotide complementary to immediate-early RNA.  

PubMed Central

ISIS 2922 is a phosphorothioate oligonucleotide that is complementary to human cytomegalovirus (CMV) immediate-early (IE) RNA and that exhibits potent and specific antiviral activity against CMV in cell culture assays. Specific assay systems were developed to separately characterize the antisense and nonantisense components of the antiviral activity mediated by ISIS 2922. In U373 cells transformed with cDNA encoding the CMV IE 55-kDa (IE55) protein, expression was inhibited at nanomolar concentrations comparable to effective concentrations in antiviral assays. The specificity of inhibition was demonstrated by using control oligonucleotides incorporating progressive base changes to destabilize oligonucleotide-RNA base pairing and by showing a lack of inhibition of the CMV IE72 product expressed from the same promoter. Inhibition of IE55 protein expression correlated with a reduction in mRNA levels consistent with an RNase H-mediated termination event. Studies with virus-infected cells demonstrated that antisense and nonantisense mechanisms contribute to the antiviral activity of ISIS 2922. Base complementarity to target RNA was important for optimal activity in antiviral assays, but base changes affecting parameters other than hybridization affinity also influenced antiviral activity. Sequence-independent inhibition of virus adsorption to host cells by phosphorothioate oligonucleotides was also observed at high concentrations. Therefore, at least three different mechanisms may contribute to the antiviral activity of ISIS 2922 in cell culture: antisense-mediated inhibition of target gene expression; nonantisense, sequence-dependent inhibition of virus replication; and sequence-independent inhibition of virus adsorption to host cells. PMID:8878571

Anderson, K P; Fox, M C; Brown-Driver, V; Martin, M J; Azad, R F

1996-01-01

15

Systematic targeted gene deletion using the gene-synthesis method in fission yeast.  

PubMed

Genome-wide targeted gene deletion, a systematic method to study gene function by replacing target genes with deletion cassettes, using serial-PCR or block-PCR requires elaborate skill. We developed a novel gene-synthesis method to systematically prepare deletion cassettes on a 96-well basis in fission yeast. We designed the 2129-bp deletion cassette as three modules: a central 1397-bp KanMX4 selection marker module and two flanking 366-bp gene-specific artificial linker modules. The central KanMX4 module can be used in multiple deletion cassettes in combination with different sets of flanking modules. The deletion cassettes consisted of 147 oligonucleotides (93 for the central module+25 for each of the flanking modules+4 for the joints) and the oligonucleotides were designed as ~29mers using an in-house program. Oligonucleotides were synthesized on a 96-well basis and ligated into deletion cassettes without gaps by ligase chain reaction, which was followed by two rounds of nested PCR to amplify trace amounts of the ligated cassettes. After the artificial linkers were removed from the deletion cassettes, the cassettes were transformed into wild-type diploid fission yeast strain SP286. We validated the transformed colonies via check PCR and subjected them to tetrad analysis to confirm functional integrity. Using this method, we systematically deleted 563 genes in the fission yeast Schizosaccharomyces pombe with a >90% success rate and a point-mutation rate of ~0.4 mutations per kb. Our method can be used to create systematic gene deletions in a variety of yeasts especially when it included a bar-code system for parallel analyses. PMID:25150109

Nam, Miyoung; Lee, Sook-Jeong; Han, Sangjo; Kim, Dongsup; Lee, Minho; Kang, Eun-Jung; Park, Han-Oh; Lee, Ah-Reum; Lee, Sol; Kim, Cheol-Hee; Kim, Dong-Uk; Hoe, Kwang-Lae

2014-11-01

16

Genome-wide Gene Deletions in Streptococcus sanguinis by High Throughput PCR  

PubMed Central

Transposon mutagenesis and single-gene deletion are two methods applied in genome-wide gene knockout in bacteria 1,2. Although transposon mutagenesis is less time consuming, less costly, and does not require completed genome information, there are two weaknesses in this method: (1) the possibility of a disparate mutants in the mixed mutant library that counter-selects mutants with decreased competition; and (2) the possibility of partial gene inactivation whereby genes do not entirely lose their function following the insertion of a transposon. Single-gene deletion analysis may compensate for the drawbacks associated with transposon mutagenesis. To improve the efficiency of genome-wide single gene deletion, we attempt to establish a high-throughput technique for genome-wide single gene deletion using Streptococcus sanguinis as a model organism. Each gene deletion construct in S. sanguinis genome is designed to comprise 1-kb upstream of the targeted gene, the aphA-3 gene, encoding kanamycin resistance protein, and 1-kb downstream of the targeted gene. Three sets of primers F1/R1, F2/R2, and F3/R3, respectively, are designed and synthesized in a 96-well plate format for PCR-amplifications of those three components of each deletion construct. Primers R1 and F3 contain 25-bp sequences that are complementary to regions of the aphA-3 gene at their 5' end. A large scale PCR amplification of the aphA-3 gene is performed once for creating all single-gene deletion constructs. The promoter of aphA-3 gene is initially excluded to minimize the potential polar effect of kanamycin cassette. To create the gene deletion constructs, high-throughput PCR amplification and purification are performed in a 96-well plate format. A linear recombinant PCR amplicon for each gene deletion will be made up through four PCR reactions using high-fidelity DNA polymerase. The initial exponential growth phase of S. sanguinis cultured in Todd Hewitt broth supplemented with 2.5% inactivated horse serum is used to increase competence for the transformation of PCR-recombinant constructs. Under this condition, up to 20% of S. sanguinis cells can be transformed using ~50 ng of DNA. Based on this approach, 2,048 mutants with single-gene deletion were ultimately obtained from the 2,270 genes in S. sanguinis excluding four gene ORFs contained entirely within other ORFs in S. sanguinis SK36 and 218 potential essential genes. The technique on creating gene deletion constructs is high throughput and could be easy to use in genome-wide single gene deletions for any transformable bacteria. PMID:23207952

Ge, Xiuchun; Xu, Ping

2012-01-01

17

Neuroinflammation and the plasticity-related immediate-early gene Arc  

PubMed Central

Neurons exist within a microenvironment that significantly influences their function and survival. While there are many environmental factors that can potentially impact neuronal function, activation of the innate immune system (microglia) is an important element common to many neurological and pathological conditions associated with memory loss. Learning and memory processes rely on the ability of neurons to alter their transcriptional programs in response to synaptic input. Recent advances in cell-based imaging of plasticity-related immediate-early gene (IEG) expression have provided a tool to investigate plasticity-related changes across multiple brain regions. The activity-regulated, cytoskeleton-associated IEG Arc is a regulator of protein synthesis–dependent forms of synaptic plasticity, which are essential for memory formation. Visualisation of Arc provides cellular level resolution for the mapping of neuronal networks. Chronic activation of the innate immune system alters Arc activity patterns, and this may be a mechanism by which it induces the cognitive dysfunction frequently associated with neuroinflammatory conditions. This review discusses the use of Arc expression during activation of the innate immune system as a valid marker of altered plasticity and a predictor of cognitive dysfunction. PMID:21320587

Rosi, Susanna

2011-01-01

18

Human cytomegalovirus UL29/28 protein interacts with components of the NuRD complex which promote accumulation of immediate-early RNA.  

PubMed

Histone deacetylation plays a pivotal role in regulating human cytomegalovirus gene expression. In this report, we have identified candidate HDAC1-interacting proteins in the context of infection by using a method for rapid immunoisolation of an epitope-tagged protein coupled with mass spectrometry. Putative interactors included multiple human cytomegalovirus-coded proteins. In particular, the interaction of pUL38 and pUL29/28 with HDAC1 was confirmed by reciprocal immunoprecipitations. HDAC1 is present in numerous protein complexes, including the HDAC1-containing nucleosome remodeling and deacetylase protein complex, NuRD. pUL38 and pUL29/28 associated with the MTA2 component of NuRD, and shRNA-mediated knockdown of the RBBP4 and CHD4 constituents of NuRD inhibited HCMV immediate-early RNA and viral DNA accumulation; together this argues that multiple components of the NuRD complex are needed for efficient HCMV replication. Consistent with a positive acting role for the NuRD elements during viral replication, the growth of pUL29/28- or pUL38-deficient viruses could not be rescued by treating infected cells with the deacetylase inhibitor, trichostatin A. Transient expression of pUL29/28 enhanced activity of the HCMV major immediate-early promoter in a reporter assay, regardless of pUL38 expression. Importantly, induction of the major immediate-early reporter activity by pUL29/28 required functional NuRD components, consistent with the inhibition of immediate-early RNA accumulation within infected cells after knockdown of RBBP4 and CHD4. We propose that pUL29/28 modifies the NuRD complex to stimulate the accumulation of immediate-early RNAs. PMID:20585571

Terhune, Scott S; Moorman, Nathaniel J; Cristea, Ileana M; Savaryn, John Paul; Cuevas-Bennett, Christian; Rout, Michael P; Chait, Brian T; Shenk, Thomas

2010-01-01

19

Sequence analysis of EBV immediate-early gene BZLF1 and BRLF1 in lymphomas.  

PubMed

The immediate-early (IE) genes, BZLF1 and BRLF1, play an important role in switching Epstein-Barr virus from the latent to the lytic state. The functions of the two IE genes and their respective proteins: ZEBRA and Rta have been well studied, but little is known about their DNA coding sequence variations and disease association. In order to investigate the sequence variation patterns and elucidate their association with lymphomas, BZLF1 and BRLF1 were analyzed in 26 and 33 lymphomas using PCR-direct sequencing method respectively. Three sequence variation types of BZLF1 gene were identified. The type BZLF1-A and BZLF1-B was detected in 34.6% (9/26) and 57.7% (15/26) of the tumor specimens, respectively. Among the three functional domains of ZEBRA, the transactivation domain had the most mutations. Three variation types were also identified in BRLF1 gene where type BR1-A and BR1-C were detected in 27.3% (9/33) and 69.7% (23/33) of specimens, respectively. Among the three functional domains of Rta, the dimerization domain was well conserved while multiple mutations were detected in both the DNA binding domain and the transactivation domain. The variation types BZLF1-B and BR1-C were more frequent in the lymphomas, compared with the throat washing samples from the healthy donors. These results suggest that the type BZLF1-B and BR1-C may be associated with the tumorigenesis of lymphoma. PMID:24615673

Yang, Ying; Jia, Yuping; Wang, Yun; Wang, Xiaofeng; Sun, Zhifu; Luo, Bing

2014-10-01

20

Construction and characterization of herpes simplex type 1 viruses without introns in immediate early gene 1  

Microsoft Academic Search

Herpes simplex virus type 1 (HSV-1) encodes at least 70 distinct genes in a DNA genome sequence of about 150 kb. In contrast to most cellular genes and those of several other DNA viruses, the overwhelming majority of HSV-1 transcripts are not spliced. One exception is immediate early (IE) gene 1, which contains two introns in the Vmwll0 coding region.

Roger D. Everett

1991-01-01

21

Identification of new Nerve Growth Factor-responsive immediate-early genes  

Microsoft Academic Search

Stimulation of the PC12 pheochromocytoma cell line with the prototypical neurotrophin Nerve Growth Factor (NGF) induces a cellular response of neuronal differentiation and is therefore a widely used model to gain molecular insight into this process. Classically, the transcriptional response to extracellular stimuli such as NGF is divided in genes that require no protein synthesis prior to their induction (immediate-early

T. F. Dijkmans; L. W. A. van Hooijdonk; T. G. Schouten; J. T. Kamphorst; C. P. Fitzsimons; E. Vreugdenhil

2009-01-01

22

Mapping the termini and intron of the spliced immediate-early transcript of equine herpesvirus 1.  

PubMed Central

Equine herpesvirus 1 (EHV-1) has been shown to synthesize a 6.0-kilobase (kb) species of immediate-early (IE) mRNA in productively infected cells. This IE gene region maps within the outer portion (map units 0.79 to 0.83 and 0.96 to 1.00) of the two inverted repeat segments of the short genomic region, and elucidation of its DNA sequence has revealed multiple potential open reading frames (ORFs), including a major ORF of 4,461 nucleotides (F. J. Grundy, R. P. Baumann, and D. J. O'Callaghan, Virology 172:223-236, 1989). Analyses of IE polypeptides synthesized in EHV-1-infected cells (in vivo) and in vitro translation of hybrid-selected IE mRNA indicated that multiple species of IE proteins are encoded by this IE mRNA species. To address the nature of the 6.0-kb IE RNA species, Northern (RNA) blot hybridization, S1 nuclease mapping, and primer extension analyses have been employed. These data revealed that no major introns were detected within the body of the IE transcript. However, the IE mRNA was shown to be spliced at the 5' terminus, such that a 372-base intron containing two small ORFs (19 and 51 amino acids) was removed from the leader region of the transcript. This splicing event reduced the leader region from 625 to 253 bases. S1 and primer extension analyses of the 5' terminus of this transcript revealed that the transcription initiation site is located 24 to 26 bases downstream of the consensus TATAAA motif. The 3' transcription termination site was mapped by S1 nuclease analysis to approximately 10 to 20 bases downstream of the polyadenylation signal, AATAAA. The distance from the stop codon of the major ORF to the polyadenylation site is approximately 300 bases. Results from S1 nuclease experiments indicated that splicing does not occur at the 3' terminus. These studies indicated that the EHV-1 6.0-kb IE mRNA is spliced at the 5' terminus and that alternative splicing of this transcript may function in regulating translation of the IE mRNA species. Images PMID:2555546

Harty, R N; Colle, C F; Grundy, F J; O'Callaghan, D J

1989-01-01

23

Induction of transcription of {open_quotes}Immediate early genes{close_quotes} by low-dose ionizing radiation  

SciTech Connect

The induction of transition of specific genes after exposure to ionizing radiation has previously been reported after lethal doses of radiation (2-50 Gy). Little attention has been focused on expression of {open_quotes}immediate early genes{close_quotes} after low doses of ionizing radiation, where cell viability remains high. This dose range (0.25-2.0 Gy) is above the diagnostic dose level but at or below the doses typical for a single exposure in fractionated radiotherapy treatment of cancer. In this study, it was observed that doses in the range of 0.25-2.0 Gy induced different amounts of the mRNAs of the proto-oncogenes c-fos, c-jun, c-myc and c-Ha-ras at a given dose and time in Epstein-Barr virus-transformed human lymphoblastoid 244B cells. A maximum response was seen after a dose of 0.5 Gy for all but c-fos, which showed a maximum response after exposure to 0.25 Gy. Time-course studies demonstrated that the induction was transient, reaching a maximum at 1 h and declining to the constitutive level at 4 h after irradiation. Using second-messenger specific inhibitors, the signaling pathways involved in the induction of these proto-oncogenes was also investigated. The results showed that all four of the proto-oncogenes induced after 0.5 Gy shared a common pathway of tyrosine kinase activation. Other signaling pathways included protein kinase C, reactive oxygen intermediates and calcium-dependent kinases; these were found to be differentially involved in the induction of transcription of the individual proto-oncogenes. In summary, this study suggests that low-dose ionizing radiation (0.25-2.0 Gy) can modulate expression of immediate early genes. Secondly, the activation of immediate early genes after low-dose exposure involves multiple second-messenger signaling pathways. Third, the magnitude of involvement of the different signaling pathways after low-dose radiation is different for each proto-oncogene expressed. 43 refs., 6 figs., 1 tab.

Prasad, A.V.; Mohan, N.; Chandrasekar, B.; Meltz, M.L. [Univ. of Texas Health Science Center, San Antonio, TX (United States)

1995-09-01

24

Food-associated cues alter forebrain functional connectivity as assessed with immediate early gene and proenkephalin expression  

PubMed Central

Background Cues predictive of food availability are powerful modulators of appetite as well as food-seeking and ingestive behaviors. The neurobiological underpinnings of these conditioned responses are not well understood. Monitoring regional immediate early gene expression is a method used to assess alterations in neuronal metabolism resulting from upstream intracellular and extracellular signaling. Furthermore, assessing the expression of multiple immediate early genes offers a window onto the possible sequelae of exposure to food cues, since the function of each gene differs. We used immediate early gene and proenkephalin expression as a means of assessing food cue-elicited regional activation and alterations in functional connectivity within the forebrain. Results Contextual cues associated with palatable food elicited conditioned motor activation and corticosterone release in rats. This motivational state was associated with increased transcription of the activity-regulated genes homer1a, arc, zif268, ngfi-b and c-fos in corticolimbic, thalamic and hypothalamic areas and of proenkephalin within striatal regions. Furthermore, the functional connectivity elicited by food cues, as assessed by an inter-regional multigene-expression correlation method, differed substantially from that elicited by neutral cues. Specifically, food cues increased cortical engagement of the striatum, and within the nucleus accumbens, shifted correlations away from the shell towards the core. Exposure to the food-associated context also induced correlated gene expression between corticostriatal networks and the basolateral amygdala, an area critical for learning and responding to the incentive value of sensory stimuli. This increased corticostriatal-amygdalar functional connectivity was absent in the control group exposed to innocuous cues. Conclusion The results implicate correlated activity between the cortex and the striatum, especially the nucleus accumbens core and the basolateral amygdala, in the generation of a conditioned motivated state that may promote excessive food intake. The upregulation of a number of genes in unique patterns within corticostriatal, thalamic, and hypothalamic networks suggests that food cues are capable of powerfully altering neuronal processing in areas mediating the integration of emotion, cognition, arousal, and the regulation of energy balance. As many of these genes play a role in plasticity, their upregulation within these circuits may also indicate the neuroanatomic and transcriptional correlates of extinction learning. PMID:17462082

Schiltz, Craig A; Bremer, Quentin Z; Landry, Charles F; Kelley, Ann E

2007-01-01

25

In vivo carbon monoxide exposure and hypoxic hypoxia stimulate immediate early gene expression  

Microsoft Academic Search

This study aimed to examine the influence of acute tissue hypoxygenation on the expression of immediate early genes in different\\u000a rat tissues. To this end male Sprague-Dawley rats were exposed to 0.1% carbon monoxide for 0.5, 1 and 6 h or to 9% oxygen\\u000a for 6 h and mRNA levels for c-jun, c-fos, c-myc and EGR-1 were assayed by RNase

Bernhard Gess; Konrad Wolf; Michael Pfeifer; Günter A. J. Riegger; A. Kurtz

1997-01-01

26

Phenotypes of major immediate-early gene mutants of mouse cytomegalovirus  

Microsoft Academic Search

Immediate-early (IE) genes are the first genes to be transcribed during the lytic replication cycle of cytomegaloviruses (CMV),\\u000a and encode nonstructural proteins, which are assumed to have mainly regulatory functions. The IE proteins may play important\\u000a roles in the pathogenesis of CMV in vivo, for instance during the establishment of latency and during reactivation. We constructed\\u000a mouse CMV mutants with

Andreas Busche; Ana Angulo; Penelope Kay-Jackson; Peter Ghazal; Martin Messerle

2008-01-01

27

Human Cytomegalovirus Immediate-Early 2 Gene Expression Blocks Virus-Induced Beta Interferon Production  

Microsoft Academic Search

The effect of human cytomegalovirus (HCMV) gene expression on beta interferon (IFN-) expression was examined. We demonstrate that the HCMV immediate-early 2 (IE2) gene product IE86 can effectively block the induction of IFN- during HCMV infection. IE86 also efficiently blocked the induction of IFN- following Sendai virus infection, demonstrating that IE86's ability to block induction of IFN- is not limited

R. Travis Taylor; Wade A. Bresnahan

2005-01-01

28

Proportion and pattern of dystrophin gene deletions in North Indian Duchenne and Becker muscular dystrophy patients  

Microsoft Academic Search

Population-based variations in frequency and distribution of dystrophin gene deletions have been recognized in Duchenne\\/Becker\\u000a (DMD\\/BMD) muscular dystrophy patients. In the present study, DNA samples from 121 unrelated DMD\\/BMD patients from North India\\u000a were analyzed for deletional studies with multiplex PCR and Southern hybridization. A total of 88 (73%) patients showed intragenic\\u000a deletions in the dystrophin gene. The observed proportion

Vinita Singh; Shirish Sinha; Sudhish Mishra; Lakshmi Shankar Chaturvedi; Sunil Pradhan; Rama Devi Mittal; Balraj Mittal

1997-01-01

29

Efficient and simple generation of unmarked gene deletions in Mycobacterium smegmatis.  

PubMed

Genetic research in molecular laboratories relies heavily on directed mutagenesis and gene deletion techniques. In mycobacteria, however, genetic analysis is often hindered by difficulties in the preparation of deletion mutants. Indeed, in comparison to the allelic exchange systems available for the study of other common model organisms, such as Saccharomyces cerevisiae and Escherichia coli, mycobacterial gene disruption systems suffer from low mutant isolation success rates, mostly due to inefficient homologous recombination and a high degree of non-specific recombination. Here, we present a gene deletion system that combines efficient homologous recombination with advanced screening of mutants. This novel methodology allows for gene disruption in three consecutive steps. The first step relies on the use of phage Che9c recombineering proteins for directed insertion into the chromosome of a linear DNA fragment that encodes GFP and confers hygromycin resistance. In the second step, GFP positive and hygromycin resistant colonies are selected, and in the last step, the gfp-hyg cassette is excised from the chromosome, thus resulting in the formation of an unmarked deletion. We provide a detailed gene deletion methodology and demonstrate the use of this genetic system by deleting the prcSBA operon of Mycobacterium smegmatis. PMID:24100088

Shenkerman, Yael; Elharar, Yifat; Vishkautzan, Marina; Gur, Eyal

2014-01-01

30

Systematic gene deletions evidences that laccases are involved in several stages of wood degradation in the filamentous fungus Podospora anserina.  

PubMed

Transformation of plant biomass into biofuels may supply environmentally friendly alternative biological sources of energy. Laccases are supposed to be involved in the lysis of lignin, a prerequisite step for efficient breakdown of cellulose into fermentable sugars. The role in development and plant biomass degradation of the nine canonical laccases belonging to three different subfamilies and one related multicopper oxidase of the Ascomycota fungus Podospora anserina was investigated by targeted gene deletion. The 10 genes were inactivated singly, and multiple mutants were constructed by genetic crosses. lac6(?), lac8(?) and mco(?) mutants were significantly reduced in their ability to grow on lignin-containing materials, but also on cellulose and plastic. Furthermore, lac8(?), lac7(?), mco(?) and lac6(?) mutants were defective towards resistance to phenolic substrates and H2 O2 , which may also impact lignocellulose breakdown. Double and multiple mutants were generally more affected than single mutants, evidencing redundancy of function among laccases. Our study provides the first genetic evidences that laccases are major actors of wood utilization in a fungus and that they have multiple roles during this process apart from participation in lignin lysis. PMID:24102726

Xie, Ning; Chapeland-Leclerc, Florence; Silar, Philippe; Ruprich-Robert, Gwenaël

2014-01-01

31

Stress-induced hematopoietic failure in the absence of immediate early response gene X-1 (IEX-1, IER3)  

E-print Network

Expression of the immediate early response gene X-1 (IEX-1, IER3) is diminished significantly in hematopoietic stem cells in a subgroup of patients with early stage myelodysplastic syndromes, but it is not clear whether ...

Ramsey, Haley

32

trans activation of an immediate-early frog virus 3 promoter by a virion protein.  

PubMed

We investigated the protein and DNA sequence requirements for the expression of an immediate-early frog virus 3 (FV3) gene, infected-cell RNA (ICR) 169. We used a plasmid containing the 78 nucleotides 5' to the transcription start site of ICR-169 placed upstream from the coding sequence for the bacterial enzyme chloramphenicol acetyltransferase (CAT). This construction, when introduced by CaPO4-mediated transfection into various eucaryotic cell lines, promoted CAT synthesis only if the transfected cells were subsequently infected with FV3. Dot-blot hybridization of RNA extracted from transfected, FV3-infected cells with a radioactive CAT probe showed that the induction of CAT synthesis by FV3 was at the level of transcription. When transfected cells were infected with FV3 in the presence of cycloheximide, induction of CAT-specific RNA still occurred, demonstrating that a virion protein was responsible for the trans activation. FV3-induced CAT synthesis was inhibited by alpha-amanitin in wild-type Chinese hamster ovary (CHO) cells but not in CHO cells with an alpha-amanitin-resistant RNA polymerase II. The results suggest that a virion protein alters either the DNA template or the host polymerase to allow transcription from immediate-early FV3 promoters. PMID:3863966

Willis, D B; Granoff, A

1985-11-01

33

Kisspeptin Regulates Gonadotropin Genes via Immediate Early Gene Induction in Pituitary Gonadotropes  

PubMed Central

Kisspeptin signaling through its receptor, Kiss1R, is crucial for many reproductive functions including puberty, sex steroid feedback, and overall fertility. Although the importance of Kiss1R in the brain is firmly established, its role in regulating reproduction at the level of the pituitary is not well understood. This study presents molecular analysis of the role of kisspeptin and Kiss1R signaling in the transcriptional regulation of the gonadotropin gene ?-subunits, LH? and FSH?, using L?T2 gonadotrope cells and murine primary pituitary cells. We show that kisspeptin induces LH? and FSH? gene expression, and this induction is protein kinase C dependent and mediated by the immediate early genes, early growth response factor 1 and cFos, respectively. Additionally, kisspeptin induces transcription of the early growth response factor 1 and cFos promoters in L?T2 cells. Kisspeptin also increases gonadotropin gene expression in mouse primary pituitary cells in culture. Furthermore, we find that Kiss1r expression is enhanced in the pituitary of female mice during the estradiol-induced LH surge, a critical component of the reproductive cycle. Overall, our findings indicate that kisspeptin regulates gonadotropin gene expression through the activation of Kiss1R signaling through protein kinase C, inducing immediate early genes in vitro, and responds to physiologically relevant cues in vivo, suggesting that kisspeptin affects pituitary gene expression to regulate reproductive function. PMID:23770611

Witham, Emily A.; Meadows, Jason D.; Hoffmann, Hanne M.; Shojaei, Shadi; Coss, Djurdjica; Kauffman, Alexander S.

2013-01-01

34

Kisspeptin regulates gonadotropin genes via immediate early gene induction in pituitary gonadotropes.  

PubMed

Kisspeptin signaling through its receptor, Kiss1R, is crucial for many reproductive functions including puberty, sex steroid feedback, and overall fertility. Although the importance of Kiss1R in the brain is firmly established, its role in regulating reproduction at the level of the pituitary is not well understood. This study presents molecular analysis of the role of kisspeptin and Kiss1R signaling in the transcriptional regulation of the gonadotropin gene ?-subunits, LH? and FSH?, using L?T2 gonadotrope cells and murine primary pituitary cells. We show that kisspeptin induces LH? and FSH? gene expression, and this induction is protein kinase C dependent and mediated by the immediate early genes, early growth response factor 1 and cFos, respectively. Additionally, kisspeptin induces transcription of the early growth response factor 1 and cFos promoters in L?T2 cells. Kisspeptin also increases gonadotropin gene expression in mouse primary pituitary cells in culture. Furthermore, we find that Kiss1r expression is enhanced in the pituitary of female mice during the estradiol-induced LH surge, a critical component of the reproductive cycle. Overall, our findings indicate that kisspeptin regulates gonadotropin gene expression through the activation of Kiss1R signaling through protein kinase C, inducing immediate early genes in vitro, and responds to physiologically relevant cues in vivo, suggesting that kisspeptin affects pituitary gene expression to regulate reproductive function. PMID:23770611

Witham, Emily A; Meadows, Jason D; Hoffmann, Hanne M; Shojaei, Shadi; Coss, Djurdjica; Kauffman, Alexander S; Mellon, Pamela L

2013-08-01

35

Size of gene specific inverted repeat--dependent gene deletion In Saccharomyces cerevisiae.  

PubMed

We describe here an approach for rapidly producing scar-free and precise gene deletions in S. cerevisiae with high efficiency. Preparation of the disruption gene cassette in this approach was simply performed by overlap extension-PCR of an invert repeat of a partial or complete sequence of the targeted gene with URA3. Integration of the prepared disruption gene cassette to the designated position of a target gene leads to the formation of a mutagenesis cassette within the yeast genome, which consists of a URA3 gene flanked by the targeted gene and its inverted repeat between two short identical direct repeats. The inherent instability of the inverted sequences in close proximity facilitates the self-excision of the entire mutagenesis cassette deposited in the genome and promotes homologous recombination resulting in a seamless deletion via a single transformation. This rapid assembly circumvents the difficulty during preparation of disruption gene cassettes composed of two inverted repeats of the URA3, which requires the engineering of unique restriction sites for subsequent digestion and T4 DNA ligation in vitro. We further identified that the excision of the entire mutagenesis cassette flanked by two DRs in the transformed S. cerevisiae is dependent on the length of the inverted repeat of which a minimum of 800 bp is required for effective gene deletion. The deletion efficiency improves with the increase of the inverted repeat till 1.2 kb. Finally, the use of gene-specific inverted repeats of target genes enables simultaneous gene deletions. The procedure has the potential for application on other yeast strains to achieve precise and efficient removal of gene sequences. PMID:23977230

Lim, Chanyuen; Luhe, Annette Lin; Jingying, Crystal Tear; Balagurunathan, Balaji; Wu, Jinchuan; Zhao, Hua

2013-01-01

36

Unusual presentation of Kallmannn syndrome with contiguous gene deletion in three siblings of a family.  

PubMed

We report the case of 3 brothers aged 34, 24, and 22 years, unmarried, who presented to our endocrinology clinic with absence of secondary sexual characters. There was no such history in other siblings, but their maternal uncle had similar complaints. On examination, all 3 had pre-pubertal appearance, voice, and genitalia along with anosmia and bimanual synkinesia. Cryptorchidism was noticed in 2 while third person had small hypoplastic testes. It was also noted that all 3 patients had icthyosis mainly involving trunk, back, and limbs. The hormonal assays were consistent with isolated hypogonadotrophic hypogonadism. IQ testing revealed mental retardation in the 2 patients. Ultrasound showed ectopic right kidney in one patient, atrophic right kidney in the second patient while the third patient had normal kidneys. MRI brain of all the patients showed poorly visualized olfactory tract and bulb. Kallmann syndrome (KS) was diagnosed based on hormonal evaluation and MRI results. Of the four types of KS: Synkinesia, renal anomaly, and X-linked pedigree pattern in our patients pointed towards X-linked type 1 KS as the possible cause. But, icthyosis and mental retardation are not usual presentation of type 1 KS. They are usually seen as a result of contiguous gene deletion of KAL1, steroid sulfatase (STS), and mental retardation (MRX) gene on X chromosome. Hence, the possible gene defect in our cases is inherited defect in contiguous gene deletion. The contiguous gene deletion as the cause of KS in 3 patients of same family is very rare and worth reporting. Also, the significance of phenotype-genotypic association in Kallmann syndrome is discussed. PMID:23565415

Madhu, Sri Venkat; Kant, Saket; Holla, Vikram Venkappayya; Arora, Rakesh; Rathi, Sahaj

2012-12-01

37

Satb1 Ablation Alters Temporal Expression of Immediate Early Genes and Reduces Dendritic Spine Density during Postnatal Brain Development  

PubMed Central

Complex behaviors, such as learning and memory, are associated with rapid changes in gene expression of neurons and subsequent formation of new synaptic connections. However, how external signals are processed to drive specific changes in gene expression is largely unknown. We found that the genome organizer protein Satb1 is highly expressed in mature neurons, primarily in the cerebral cortex, dentate hilus, and amygdala. In Satb1-null mice, cortical layer morphology was normal. However, in postnatal Satb1-null cortical pyramidal neurons, we found a substantial decrease in the density of dendritic spines, which play critical roles in synaptic transmission and plasticity. Further, we found that in the cerebral cortex, Satb1 binds to genomic loci of multiple immediate early genes (IEGs) (Fos, Fosb, Egr1, Egr2, Arc, and Bdnf) and other key neuronal genes, many of which have been implicated in synaptic plasticity. Loss of Satb1 resulted in greatly alters timing and expression levels of these IEGs during early postnatal cerebral cortical development and also upon stimulation in cortical organotypic cultures. These data indicate that Satb1 is required for proper temporal dynamics of IEG expression. Based on these findings, we propose that Satb1 plays a critical role in cortical neurons to facilitate neuronal plasticity. PMID:22064485

Balamotis, Michael A.; Tamberg, Nele; Woo, Young Jae; Li, Jingchuan; Davy, Brian

2012-01-01

38

THOC5 controls 3?end-processing of immediate early genes via interaction with polyadenylation specific factor 100 (CPSF100)  

PubMed Central

Transcription of immediate early genes (IEGs) in response to extrinsic and intrinsic signals is tightly regulated at multiple stages. It is known that untranslated regions of the RNA can play a role in these processes. Here we show that THOC5, a member of the TREX (transcription/export) complex, plays a role in expression of only a subset of constitutively active genes, however transcriptome analysis reveals that more than 90% of IEG were not induced by serum in THOC5 depleted cells. Furthermore, THOC5 depletion does not influence the expression of the most rapidly induced IEGs, e.g. Fos and Jun. One group of THOC5 target genes, including Id1, Id3 and Wnt11 transcripts, were not released from chromatin in THOC5 depleted cells. Genes in another group, including Myc and Smad7 transcripts, were released with shortening of 3?UTR by alternative cleavage, and were spliced but export was impaired in THOC5 depleted cells. By interactome analysis using THOC5 as bait, we show that upon stimulation with serum THOC5 forms a complex with polyadenylation-specific factor 100 (CPSF100). THOC5 is required for recruitment of CPSF100 to 3?UTR of THOC5 target genes. These data suggest the presence of a novel mechanism for the control of IEG response by THOC5 via 3?end-processing. PMID:25274738

Tran, Doan Duy Hai; Saran, Shashank; Williamson, Andrew J.K.; Pierce, Andrew; Dittrich-Breiholz, Oliver; Wiehlmann, Lutz; Koch, Alexandra; Whetton, Anthony D.; Tamura, Teruko

2014-01-01

39

Stress-induced hematopoietic failure in the absence of immediate early response gene X-1 (IEX-1, IER3).  

PubMed

Expression of the immediate early response gene X-1 (IEX-1, IER3) is diminished significantly in hematopoietic stem cells in a subgroup of patients with early stage myelodysplastic syndromes, but it is not clear whether the deregulation contributes to the disease. The current study demonstrates increased apoptosis and a concomitant decrease in the number of hematopoietic stem cells lacking this early response gene. Null mutation of the gene also impeded platelet differentiation and shortened a lifespan of red blood cells. When bone marrow cells deficient in the gene were transplanted into wild-type mice, the deficient stem cells produced significantly fewer circulating platelets and red blood cells, despite their enhanced repopulation capability. Moreover, after exposure to a non-myeloablative dose of radiation, absence of the gene predisposed to thrombocytopenia, a significant decline in red blood cells, and dysplastic bone marrow morphology, typical characteristics of myelodysplastic syndromes. These findings highlight a previously unappreciated role for this early response gene in multiple differentiation steps within hematopoiesis, including thrombopoiesis, erythropoiesis and in the regulation of hematopoietic stem cell quiescence. The deficient mice offer a novel model for studying the initiation and progression of myelodysplastic syndromes as well as strategies to prevent this disorder. PMID:24056813

Ramsey, Haley; Zhang, Qi; Brown, Diane E; Steensma, David P; Lin, Charles P; Wu, Mei X

2014-02-01

40

Immediate early gene expression in dog thyrocytes in response to growth, proliferation, and differentiation stimuli.  

PubMed

In dog thyroid cells, insulin or IGF-1 induces cell growth and is required for the mitogenic action of TSH through cyclic AMP, of EGF, and of phorbol esters. HGF per se stimulates cell proliferation and is thus the only full mitogenic agent. TSH and cAMP enhance, whereas EGF phorbol esters and HGF repress differentiation expression. In this study, we have investigated for each factor and regulatory cascade of the intermediate step of immediate early gene induction, that is, c-myc, c-jun, jun D, jun B, c-fos, fos B, fra-1, fra-2, and egr1; fra-1 and fra-2 expressions were very low. TSH or forskolin increased the levels of c-myc, jun B, jun D, c-fos, and fos B while decreasing those of c-jun and egr1. Phorbol myristate ester stimulated the expression of all the genes. EGF and HGF stimulated the expression of all the genes except jun D and for EGF fos B. All these effects were obtained in the presence and in the absence of insulin, which shows that insulin is not necessary for the effects of the mitogens on immediate early gene expression. The definition of the repertoire of early immediate genes inductible by the various growth cascades provides a framework for the analysis of gene expression in tumors. (1) Insulin was able to induce all the protooncogenes investigated except fos B. This suggests that fos B could be the factor missing for insulin to induce mitogenesis. (2) No characteristic pattern of immediate early gene expression has been observed for insulin, which induces cell hypertrophy and is permissive for the action of the other growth factors. These effects are therefore not accounted for by a specific immediate early gene expression. On the other hand, insulin clearly enhances the effects of TSH, phorbol ester, and EGF on c-myc, junB, and c-fos expression. This suggests that the effect of insulin on mitogenesis might result from quantitative differences in the transcription complexes formed. (3) c-myc, c-fos, and jun B mRNA induction by all stimulating agents, whether inducing cell hypertrophy, or growth and dedifferentiation, or growth and differentiation, suggests that, although these expressions are not sufficient, they may be necessary for the various growth responses of thyroid cells. (4) The inhibition of c-jun and egr1 mRNA expression, and the marked induction of jun D mRNA appear to be specific features of the TSH cAMP pathway. They might be related to its differentiating action. (5) fos B, which is induced by TSH, forskolin, phorbol ester, and HGF but not by insulin, could be involved in the mitogenic action of the former factors. PMID:10497313

Deleu, S; Pirson, I; Clermont, F; Nakamura, T; Dumont, J E; Maenhaut, C

1999-11-01

41

DNA nucleotide sequence analysis of the immediate-early gene of pseudorabies virus.  

PubMed Central

The complete DNA sequence coding for the immediate-early protein (IE180) of pseudorabies virus was determined. The coding region of IE180 is 4380 nucleotides for 1460 amino acid residues. G+C content of the non-coding portion of the IE gene is 70.3% while the G+C content of the coding portion is considerably higher at 80.1%. Correspondingly, codons consisting mainly of Gs and Cs are favoured. Clusters of amino acid homologies are observed among IE180 of pseudorabies virus, ICP4 of herpes simplex virus type-1 and IE140 of varicella-zoster virus, and are organized similarly in all three polypeptides. Functions exhibited by IE180 are assigned, tentatively, to structural domains of the molecule by analogy to the HSV-1 ICP4 polypeptide. Images PMID:2546124

Cheung, A K

1989-01-01

42

Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles.  

PubMed

We used fluorescent in-situ hybridization and confocal microscopy to monitor the subcellular distribution of the immediate-early gene Arc. Arc RNA appeared in discrete intranuclear foci within minutes of neuronal activation and subsequently disappeared from the nucleus and accumulated in the cytoplasm by 30 minutes. The time course of nuclear versus cytoplasmic Arc RNA accumulation was distinct, and could therefore be used to infer the activity history of individual neurons at two times. Following sequential exposure of rats to two different environments or to the same environment twice, the proportion of CA1 neurons with cytoplasmic, nuclear or overlapping Arc expression profiles matched predictions derived from ensemble neurophysiological recordings of hippocampal neuronal ensembles. Arc gene induction is thus specifically linked to neural encoding processes. PMID:10570490

Guzowski, J F; McNaughton, B L; Barnes, C A; Worley, P F

1999-12-01

43

Inositol polyphosphate multikinase is a transcriptional coactivator required for immediate early gene induction  

PubMed Central

Profound induction of immediate early genes (IEGs) by neural activation is a critical determinant for plasticity in the brain, but intervening molecular signals are not well characterized. We demonstrate that inositol polyphosphate multikinase (IPMK) acts noncatalytically as a transcriptional coactivator to mediate induction of numerous IEGs. IEG induction by electroconvulsive stimulation is virtually abolished in the brains of IPMK-deleted mice, which also display deficits in spatial memory. Neural activity stimulates binding of IPMK to the histone acetyltransferase CBP and enhances its recruitment to IEG promoters. Interestingly, IPMK regulation of CBP recruitment and IEG induction does not require its catalytic activities. Dominant-negative constructs, which prevent IPMK-CBP binding, substantially decrease IEG induction. As IPMK is ubiquitously expressed, its epigenetic regulation of IEGs may influence diverse nonneural and neural biologic processes. PMID:24043835

Xu, Risheng; Paul, Bindu D.; Smith, Dani R.; Tyagi, Richa; Rao, Feng; Khan, A. Basit; Blech, Daniel J.; Vandiver, M. Scott; Harraz, Maged M.; Guha, Prasun; Ahmed, Ishrat; Sen, Nilkantha; Gallagher, Michela; Snyder, Solomon H.

2013-01-01

44

Adaptation of the Halobacterium salinarum ssp. NRC-1 gene deletion system for modification of chromosomal loci.  

PubMed

The model archaeon Halobacterium salinarum ssp. NRC-1 is an excellent system for the study of archaeal molecular biology. Unlike many other archaea, its only special growth requirement is high levels of sodium chloride and other salts; it requires neither high-temperature incubation nor anaerobic environments. Additionally, there are a number of well-developed post-genomic tools available, including whole-genome microarrays and a ura3-based gene deletion system. While some tools are available for protein expression, a system for measurement and purification of protein expressed from native promoters is lacking. We have adapted the established H. salinarum gene deletion system for this purpose, and have used this to place 8×-histidine tags on either the carboxyl or amino terminus of the protein encoded by the chromosomal rfa3 gene. To demonstrate the utility of this approach, we used Western blot analysis to determine levels of the Rfa3 protein under different conditions. This system provides another powerful molecular tool for studies of native protein expression and for simple protein purification in H. salinarum. PMID:24491836

Gygli, Patrick E; DeVeaux, Linda C

2014-04-01

45

Rb and p53 gene deletions in lung adenocarcinomas from irradiated and control mice  

SciTech Connect

This study was conducted on mouse lung adenocarcinoma tissues that were formalin-treated and paraffin-embedded 25 years ago to investigate the large gene deletions of mRb and p53 in B6CF{sub 1} male mice. A total of 80 lung tissue samples from irradiated mice and 40 lung samples from nonirradiated controls were randomly selected and examined in the mRb portion of this study. The results showed a significant (P < 0.05) higher percentage of mRb deletions in lung adenocarcinomas from mice exposed to 60 once-weekly {gamma}-ray doses than those from mice receiving 24 once-weekly {gamma}-ray doses at low doses and low dose rates; however, the percentage was not significantly different (P > 0.05) from that for spontaneous lung adenocarcinomas or lung adenocarcinomas from mice exposed to single-dose {gamma} irradiation at a similar total dose. mRb fragments 3 (71%) and 5 (67%), the parts of the gene that encoded the pocket binding region of Rb protein to adenovirus E1A and SV40 T-antigen, were the most frequently deleted fragments. p53 gene deletion analysis was carried out on normal lungs and lung adenocarcinomas that were initially found to bear mRb deletions. Exons 1,4,5,6, and 9 were chosen to be analyzed.

Zhang, Y.; Woloschak, G.E. [Argonne National Lab., IL (United States). Center for Mechanistic Biology and Biotechnology

1997-08-01

46

Identification of new Nerve Growth Factor-responsive immediate-early genes.  

PubMed

Stimulation of the PC12 pheochromocytoma cell line with the prototypical neurotrophin Nerve Growth Factor (NGF) induces a cellular response of neuronal differentiation and is therefore a widely used model to gain molecular insight into this process. Classically, the transcriptional response to extracellular stimuli such as NGF is divided in genes that require no protein synthesis prior to their induction (immediate-early genes) and genes that do (delayed-response genes). Because an increasing number of studies have reported important roles for immediate-early genes (IEGs) in neuronal differentiation, the goal of the present study was to identify previously unrecognized NGF-responsive IEGs. Stimulation with NGF for 15, 30, 60 and 120 min resulted in a typical transient induction of many known NGF-responsive IEGs. To identify candidate new genes, we analyzed 27000 measured expression profiles and selected 10 genes for further study. Five genes, including Cbp/p300-interacting transactivator 2 (Cited2), Kruppel-like factor 4 (Klf4), v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein F (Maff), Kruppel-like factor 10 (Klf10 or Tieg) and Activating transcription factor 3 (Atf3) were selected and positively validated by qPCR. NGF-induced activation of all five genes seems to be mediated by MAPK and PI3K-mediated pathways. Additionally, we tested translation-independent induction and showed that NGF induced upregulation of these genes in both the subclonal Neuroscreen-1 PC12 and parental PC12 cell line. These 5 transcription factors have not been previously reported as NGF-responsive IEGs, however have previously been reported as important regulators of cell differentiation and proliferation in different systems. These observations may therefore provide important new information on the molecular mechanisms underlying NGF-induced differentiation. PMID:19013137

Dijkmans, T F; van Hooijdonk, L W A; Schouten, T G; Kamphorst, J T; Fitzsimons, C P; Vreugdenhil, E

2009-01-16

47

Daily immediate early gene expression in the suprachiasmatic nucleus of male and female Octodon degus.  

PubMed

Diurnal and nocturnal species have different patterns of general activity, sleep-wake rhythms, and endocrine rhythms, but the mechanisms underlying these differences are not clear. Here, we tested the hypothesis that rhythms in immediate early gene (IEG) products in the suprachiasmatic nucleus (SCN) of a diurnal rodent (Octodon degus) reflect their diurnal chronotype. We also compared male and female degus with respect to temporal patterns of expression of one of these gene products, Fos-related Antigen (FRA). Animals were killed across the light:dark cycle, brains were collected, and sections through the SCN were stained for FRA (females and males) or c-Fos and Calbindin (males only) using immunocytochemistry. An additional set of females placed in constant darkness was pulsed with light (or not) during the subjective day or night. Labeled cells in the SCN were counted in all animals. In males, c-Fos/FRA positive (+) cell counts in the dorsomedial SCN were low after lights-on and peaked around the time of lights-off (ZT 13, ZT 0=lights-on). Effect size analyses indicated that females have a 24 h rhythm in FRA expression that is shifted relative to that of males. Light pulses in the subjective day and night produced area-specific changes in IEG expression in females that differs from that reported for males. Overall, these studies reveal the pattern of immediate early gene expression in the SCN of degus is not the same in males and females, and that it differs from the one seen in other species, both nocturnal and diurnal. PMID:19637045

Mahoney, Megan M; Smale, Laura; Lee, Theresa M

2009-07-01

48

Effects of Bax gene deletion on social behaviors and neural response to olfactory cues in mice.  

PubMed

Bax is a pro-death protein that plays a crucial role in developmental neuronal cell death. Bax(-/-) mice exhibit increased neuron number and lack several neural sex differences. Here we examined the effects of Bax gene deletion on social behaviors (olfactory preference, social recognition, social approach and aggression) and the neural processing of olfactory cues. Bax deletion eliminated the normal sex difference in olfactory preference behavior. In the social recognition test, both genotypes discriminated a novel conspecific, but wild-type males and Bax(-/-) animals of both sexes spent much more time than wild-type females investigating stimulus animals. Similarly, Bax(-/-) mice were more sociable than wild-type mice in a social approach test. Bax deletion had no effect on aggression in a resident/intruder paradigm where males, regardless of genotype, exhibited a shorter latency to attack. Thus, the prevention of neuronal cell death by Bax gene deletion results in greater sociability as well as the elimination of sex differences in some social behaviors. To examine olfactory processing of socially relevant cues, we counted c-Fos-immunoreactive (Fos-ir) cells in several nodes of the accessory olfactory pathway after exposure to male-soiled or control bedding. In both genotypes, exposure to male-soiled bedding increased Fos-ir cells in the posterodorsal medial amygdala, principal nucleus of the bed nucleus of the stria terminalis and medial preoptic nucleus (MPN), and the response in the MPN was greater in females than in males. However, a reduction in Fos-ir cells was seen in the anteroventral periventricular nucleus of Bax(-/-) mice. PMID:22034980

Holmes, Melissa M; Niel, Lee; Anyan, Jeff J; Griffith, Andrew T; Monks, D Ashley; Forger, Nancy G

2011-11-01

49

Temporal Decoding of MAP Kinase and CREB Phosphorylation by Selective Immediate Early Gene Expression  

PubMed Central

A wide range of growth factors encode information into specific temporal patterns of MAP kinase (MAPK) and CREB phosphorylation, which are further decoded by expression of immediate early gene products (IEGs) to exert biological functions. However, the IEG decoding system remain unknown. We built a data-driven based on time courses of MAPK and CREB phosphorylation and IEG expression in response to various growth factors to identify how signal is processed. We found that IEG expression uses common decoding systems regardless of growth factors and expression of each IEG differs in upstream dependency, switch-like response, and linear temporal filters. Pulsatile ERK phosphorylation was selectively decoded by expression of EGR1 rather than c-FOS. Conjunctive NGF and PACAP stimulation was selectively decoded by synergistic JUNB expression through switch-like response to c-FOS. Thus, specific temporal patterns and combinations of MAPKs and CREB phosphorylation can be decoded by selective IEG expression via distinct temporal filters and switch-like responses. The data-driven modeling is versatile for analysis of signal processing and does not require detailed prior knowledge of pathways. PMID:23469182

Saito, Takeshi H.; Uda, Shinsuke; Tsuchiya, Takaho; Ozaki, Yu-ichi; Kuroda, Shinya

2013-01-01

50

Analysis of DNA sequences which regulate the transcription of a herpes simplex virus immediate early gene.  

PubMed Central

The locations and functions of DNA sequences involved in transcription of the gene encoding herpes simplex virus type 1 immediate early (IE) mRNAs 4 and 5 were analyzed by use of a transient-expression assay. The region upstream of the genes encoding IE mRNAs 4 and 5 was fused to the thymidine kinase gene coding sequences, and production of enzyme or RNA was measured after transfection of plasmids into BHK cells. The effect of deletions in the upstream region was determined in the absence or presence of a virus structural component which stimulates herpes simplex virus IE transcription. Two distinct units were identified. One of these was a promoter which required not more than 69 base pairs of DNA specific for the genes encoding IE mRNAs 4 and 5 upstream from the mRNA 5' terminus. The other was a far-upstream region which mediated the response to the virion component and had an upstream boundary between nucleotides -347 and -335. An origin of DNA replication was interposed between these two units. The element TAATGAGATAC , which represents a consensus sequence present in the upstream regions of all herpes simplex type 1 IE genes, appeared to be essential for stimulation by the virion component. The activity of this element was modulated by the sequences which flank it, especially by regions having extremely high contents of guanine plus cytosine and which contain a conserved unit CCCGCCC or its complement GGGCGGG . Images PMID:6328000

Preston, C M; Cordingley, M G; Stow, N D

1984-01-01

51

Cytomegalovirus immediate early genes prevent the inhibitory effect of cyclosporin A on interleukin 2 gene transcription.  

PubMed Central

The use of cyclosporin A (CsA) as an immunosuppressive agent has markedly improved the clinical outcome in solid organ transplantation. However, posttransplantation infection remains a significant problem and may contribute to subsequent organ rejection. In this study the effect of cytomegalovirus (CMV) immediate early (IE) gene products on interleukin 2 (IL-2) gene transcription in the absence and presence of CsA was investigated using a transient transfection system. Jurkat T cells were transfected with plasmids expressing the CMV IE gene products or with a control plasmid. The presence of the CMV IE2 gene product abolished the inhibitory effect of CsA on IL-2 promoter activation and gene transcription. This effect was noted regardless of the time of CsA addition relative to the time of stimulation and was independent of CsA concentration. CsA had no effect on the CMV or the IL-2 receptor promoters. These studies suggest that the CMV IE gene products may play a role in graft rejection after solid organ transplantation. Images PMID:1331182

Geist, L J; Monick, M M; Stinski, M F; Hunninghake, G W

1992-01-01

52

Poly(ADP-ribosyl)ation of a herpes simplex virus immediate early polypeptide  

SciTech Connect

In vitro poly(ADP-ribosyl)ation of the herpes simplex virus type 1 (HSV-1) immediate early polypeptide Vmw175 is reported. The phenomenon was most clearly observed by use of the temperature-sensitive mutant tsK, which overproduces Vmw175 at the nonpermissive temperature (NPT) and has a mutation in the coding sequences for this polypeptide. Nuclei prepared from cells which were infected with tsK at NPT and subsequently downshifted to the permissive temperature incorporated (/sup 32/P)NAD into Vmw175. This reaction did not occur when nuclei were prepared from cells constantly maintained at NPT, showing that only functional Vmw175 can be radiolabeled with (/sup 32/P)NAD. The identity of the acceptor protein was confirmed by demonstrating the expected electrophoretic mobility differences between the HSV-1 and HSV-2 counterparts of Vmw175. The use of suitable inhibitors demonstrated that the reaction represented mono- or poly(ADP-ribosyl)ation, and further analysis showed the presence of long poly(ADP-ribose) chains attached to Vmw175. Poly(ADP-ribosyl)ation may be important as a cause or result of the regulation of viral transcription by Vmw175. Radiolabeling of another virus-specified polypeptide (approximate molecular weight 38,000), thought to be a structural component of the input virus, is also reported.

Preston, C.M.; Notarianni, E.L.

1983-12-01

53

Regulation of Immediate Early Gene Expression and AP1 Binding in the Rat Nucleus Accumbens by Chronic Cocaine  

Microsoft Academic Search

Chronic treatment of rats with cocaine leads to long-term biochemical changes in the nucleus accumbens (NAc), a brain region implicated in mediating the reinforcing effects of cocaine and other drugs of abuse. Immediate early genes (IEGs) and their protein products appear to play an important role in transducing extracellular stimuli into altered patterns of cellular gene expression and, therefore, into

Bruce Hope; Barry Kosofsky; Steven E. Hyman; Eric J. Nestler

1992-01-01

54

Acute ibogaine injection induces expression of the immediate early genes, egr-1 and c- fos, in mouse brain  

Microsoft Academic Search

The aim of the present study was to evaluate if an acute injection of ibogaine (IBO) induces immediate early gene expression in different regions of mouse brain. Adult male C57 mice received a single injection of IBO and were perfused transcardially with 1% paraformaldehyde 30 min after the drug administration. A single injection of IBO produced a significant increase of

Syed F Ali; Nathalie Thiriet; Jean Zwiller

1999-01-01

55

A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories  

Microsoft Academic Search

The induction of long-term potentiation (LTP) in the dentate gyrus of the hippocampus is associated with a rapid and robust transcription of the immediate early gene Zif268. We used a mutant mouse with a targeted disruption of Zif268 to ask whether this gene, which encodes a zinc finger transcription factor, is required for the maintenance of late LTP and for

M. W. Jones; M. L. Errington; P. J. French; A. Fine; T. V. P. Bliss; S. Garel; P. Charnay; B. Bozon; S. Laroche; S. Davis

2001-01-01

56

Profile of Immediate Early Gene Expression in the Lumbar Spinal Cord of Low-Thoracic Paraplegic Mice  

Microsoft Academic Search

Induction of immediate early gene (IEG) expression is believed to constitute one of the earliest steps in plasticity and long-term modification of neuronal properties. Although behavioral evidence of neuronal plasticity at the sublesional level after spinal cord injury exists, spatiotemporal changes of IEGs in spinal segments located caudally to such an injury have never been examined. Here, the authors studied

E. S. Landry; C. Rouillard; D. Levesque; P. A. Guertin

2006-01-01

57

Expression of the Immediate-Early Gene-Encoded Protein Egr-1 ("zif268") during in Vitro Classical Conditioning  

ERIC Educational Resources Information Center

Expression of the immediate-early genes (IEGs) has been shown to be induced by activity-dependent synaptic plasticity or behavioral training and is thought to play an important role in long-term memory. In the present study, we examined the induction and expression of the IEG-encoded protein Egr-1 during an in vitro neural correlate of eyeblink…

Mokin, Maxim; Keifer, Joyce

2005-01-01

58

TISSUE-PLASMINOGEN ACTIVATOR IS INDUCED AS AN IMMEDIATE-EARLY GENE DURING SEIZURE, KINDLING, AND LONG-TERM POTENTIATION  

EPA Science Inventory

Activity-dependent genes in brain have been identified using differential screening of hippocampal cDNA library from rats exposed to metrazol seizures under conditions of superconduction. Five immediate early genes whose expression is elevated by neural activity were identified. ...

59

A Form of Perforant Path LTP Can Occur without ERK1/2 Phosphorylation or Immediate Early Gene Induction  

ERIC Educational Resources Information Center

Stimulation paradigms that induce perforant path long-term potentiation (LTP) initiate phosphorylation of ERK1/2 and induce expression of a variety of immediate early genes (IEGs). These events are thought to be critical components of the mechanism for establishing the changes in synaptic efficacy that endure for hours or longer. Here we show that…

Steward, Oswald; Huang, Fen; Guzowski, John F.

2007-01-01

60

X-ray microfluorescence (?XRF) imaging of Aspergillus nidulans cell wall mutants reveals biochemical changes due to gene deletions.  

PubMed

We used synchrotron X-ray fluorescence to create the first semiquantitative, submicron resolution, element distribution maps of P, S, K, and Ca, in situ, in fungal samples. Data collection was performed at the European Synchrotron Radiation Facility beam line ID21, Grenoble, France. We studied developing hyphae, septa, and conidiophores in Aspergillus nidulans, comparing wild type and two cell wall biosynthesis gene deletion strains. The latter encode sequential enzymes for biosynthesis of galactofuranose, a minor wall carbohydrate. Each gene deletion caused hyphal morphogenesis defects, and reduced both colony growth and sporulation 500-fold. Elemental imaging has helped elucidate biochemical changes in the phenotype induced by the gene deletions that were not apparent from morphological examination. Here, we examined S as a proxy for protein content, P for nucleic acid content, as well as Ca and K, which also have important metabolic roles. Element distributions in wild-type fungi reflect biological aspects already known or expected from other types of analysis; however, the application of X-ray fluorescence (XRF) imaging reveals aspects of gene deletion phenotypes that were not previously available. We have demonstrated that deleting a dispensable gene involved in galactose metabolism (ugeA) and one involved in biosynthesis of a minor cell wall component (ugmA) led to changes in hyphal elemental distribution that may have resulted from compromised wall composition. PMID:24618991

Rak, Margaret; Salome, Murielle; Kaminskyj, Susan G W; Gough, Kathleen M

2014-05-01

61

Mutation of MeCP2 alters transcriptional regulation of select immediate-early genes  

PubMed Central

Loss-of-function mutations in the methyl-DNA binding protein MeCP2 are associated with neurological dysfunction and impaired neural plasticity. However, the transcriptional changes that underlie these deficits remain poorly understood. Here, we show that mice bearing a C-terminal truncating mutation in Mecp2 (Mecp2308) are hypersensitive to the locomotor stimulating effects of cocaine. Furthermore, these mice have gene-specific alterations in striatal immediate-early gene (IEG) induction following cocaine administration. MeCP2 mutant mice show normal levels of baseline and cocaine-induced striatal Fos expression compared with their wild-type littermates. However, the mutant mice have enhanced cocaine-induced transcription of Junb and Arc. At the chromatin level, we find increased histone H3 acetylation at gene promoters in the Mecp2 mutant mice compared with their wild-type littermates, whereas two sites of repressive histone methylation are unchanged. Interestingly, we find that MeCP2 mutant mice show increased steady-state association of elongation-competent RNA Polymerase II (RNAP II) with the Junb and Arc promoters, whereas levels of RNAP II association at the Fos promoter are unchanged. These data reveal a gene-specific effect of MeCP2 on the recruitment of RNAP II to gene promoters that may modulate the inducibility of IEGs. In addition, our findings raise the possibility that aberrant regulation of IEGs including Junb and Arc may contribute to altered cocaine-induced neuronal and behavioral plasticity in Mecp2 mutant mice. PMID:22395464

Su, Dan; Cha, Young May

2012-01-01

62

The dusp1 Immediate Early Gene is Regulated by Natural Stimuli Predominantly in Sensory Input Neurons  

PubMed Central

Many immediate early genes (IEGs) have activity-dependent induction in a subset of brain subdivisions or neuron types. However, none have been reported yet with regulation specific to thalamic-recipient sensory neurons of the telencephalon or in the thalamic sensory input neurons themselves. Here, we report the first such gene, dual specificity phosphatase 1 (dusp1). Dusp1 is an inactivator of mitogen-activated protein kinase (MAPK), and MAPK activates expression of egr1, one of the most commonly studied IEGs, as determined in cultured cells. We found that in the brain of naturally behaving songbirds and other avian species, hearing song, seeing visual stimuli, or performing motor behavior caused high dusp1 upregulation, respectively, in auditory, visual, and somatosensory input cell populations of the thalamus and thalamic-recipient sensory neurons of the telencephalic pallium, whereas high egr1 upregulation occurred only in subsequently connected secondary and tertiary sensory neuronal populations of these same pathways. Motor behavior did not induce high levels of dusp1 expression in the motor-associated areas adjacent to song nuclei, where egr1 is upregulated in response to movement. Our analysis of dusp1 expression in mouse brain suggests similar regulation in the sensory input neurons of the thalamus and thalamic-recipient layer IV and VI neurons of the cortex. These findings suggest that dusp1 has specialized regulation to sensory input neurons of the thalamus and telencephalon; they further suggest that this regulation may serve to attenuate stimulus-induced expression of egr1 and other IEGs, leading to unique molecular properties of forebrain sensory input neurons. PMID:20506480

Horita, Haruhito; Wada, Kazuhiro; Rivas, Miriam V.; Hara, Erina; Jarvis, Erich D.

2010-01-01

63

Host MicroRNA Regulation of Human Cytomegalovirus Immediate Early Protein Translation Promotes Viral Latency  

PubMed Central

ABSTRACT Reactivation of human cytomegalovirus (HCMV) is a significant cause of disease and death in immunocompromised patients, underscoring the need to understand how latency is controlled. Here we demonstrate that HCMV has evolved to utilize cellular microRNAs (miRNAs) in cells that promote latency to regulate expression of a viral protein critical for viral reactivation. Our data reveal that hsa-miR-200 miRNA family members target the UL122 (immediate early protein 2) 3? untranslated region, resulting in repression of this viral protein. Utilizing recombinant viruses that mutate the miRNA-binding site compared to the sequence of the wild-type virus results in lytic rather than latent infections in ex vivo infections of primary CD34+ cells. Cells permissive for lytic replication demonstrate low levels of these miRNAs. We propose that cellular miRNA regulation of HCMV is critical for maintenance of viral latency. IMPORTANCE Human cytomegalovirus (HCMV) is a herpesvirus that infects a majority of the population. Once acquired, individuals harbor the virus for life, where the virus remains, for the most part, in a quiet or latent state. Under weakened immune conditions, the virus can reactivate, which can cause severe disease and often death. We have found that members of a family of small RNAs, termed microRNAs, encoded by human myeloid progenitor cells are capable of repressing a key viral protein, thus enabling the virus to ensure a quiet/latent state. As these progenitor cells mature further down the myeloid lineage toward cells that support active viral replication, the levels of these microRNAs decrease. Together, our data suggest that host cell microRNA regulation of HCMV is important for the quiet/latent state of this pathogen. PMID:24599990

O'Connor, Christine M.

2014-01-01

64

Application of the FLP/FRT system for conditional gene deletion in yeast Saccharomyces cerevisiae.  

PubMed

The yeast Saccharomyces cerevisiae has proved to be an excellent model organism to study the function of proteins. One of the many advantages of yeast is the many genetic tools available to manipulate gene expression, but there are still limitations. To complement the many methods used to control gene expression in yeast, we have established a conditional gene deletion system by using the FLP/FRT system on yeast vectors to conditionally delete specific yeast genes. Expression of Flp recombinase, which is under the control of the GAL1 promoter, was induced by galactose, which in turn excised FRT sites flanked genes. The efficacy of this system was examined using the FRT site-flanked genes HSP104, URA3 and GFP. The pre-excision frequency of this system, which might be caused by the basal activity of the GAL1 promoter or by spontaneous recombination between FRT sites, was detected ca. 2% under the non-selecting condition. After inducing expression of Flp recombinase, the deletion efficiency achieved ca. 96% of cells in a population within 9 h. After conditional deletion of the specific gene, protein degradation and cell division then diluted out protein that was expressed from this gene prior to its excision. Most importantly, the specific protein to be deleted could be expressed under its own promoter, so that endogenous levels of protein expression were maintained prior to excision by the Flp recombinase. Therefore, this system provides a useful tool for the conditional deletion of genes in yeast. PMID:21823166

Park, Yang-Nim; Masison, Daniel; Eisenberg, Evan; Greene, Lois E

2011-09-01

65

A two-step integration method for seamless gene deletion in baker's yeast.  

PubMed

In this study, we developed a seamless gene deletion method through a two-step integration protocol to construct an industrial baker's yeast with NTH1 deletion. A fusion fragment consisted of the upstream sequence, and the downstream sequence of NTH1 was subcloned into an integrating plasmid containing a URA3 counter-selection marker for excision of unwanted DNA. The plasmid was integrated into the genomic NTH1 locus of recipient baker's yeast, leading to tandem repeats of the upstream flank and the downstream flank. Pop-out of the URA3 marker occurs by integration recombination between either the downstream flank repeats or the upstream flank repeats. Integration recombination between the repeats results in NTH1 deletion without any heterologous DNA and reversion to a wild-type strain. The desired deletion occurred with a frequency of approximately 10(-5). Polymerase chain reaction verification and sequence analysis confirmed the NTH1 disruption and the absence of integrated plasmid sequences in the genome of the selected strain. In addition, the mutant with NTH1 deletion exhibits a higher trehalose accumulation and consequently displays a higher viability of yeast cells after freezing. Thus, this method proposes a protocol to construct mutant yeast without leaving behind any heterologous DNA sequences and will facilitate the genetic engineering of any yeast. PMID:23597844

Dong, Jian; Wang, Guanglu; Zhang, Cuiying; Tan, Haigang; Sun, Xi; Wu, Mingyue; Xiao, Dongguang

2013-08-01

66

MODY type 2 in Greig cephalopolysyndactyly syndrome (GCPS) as part of a contiguous gene deletion syndrome.  

PubMed

Maturity-onset diabetes of the young type 2 (MODY2) is a form of monogenic diabetes, characterized by mild fasting hyperglycemia. MODY2 is caused by heterozygous mutations in the GCK gene that encodes the glucokinase enzyme. We describe the clinical features and the underlying genetic defect of MODY2 in a patient with atypical Greig cephalopolysyndactyly syndrome (GCPS). The patient presented with the limb formation and the craniofacial developmental abnormalities typical to GCPS, in addition to mental retardation and epilepsy (assigned as atypical syndrome). Fasting hyperglycemia in the diabetic range, impaired glucose tolerance, and lack of diabetes autoantibodies were compatible with MODY2. In order to delineate the genetic aberrations relevant both to MODY2 and Greig syndrome in this patient, we performed cytogenetic analysis, real-time PCR of the GCK gene, and comparative genomic hybridization (CGH) array. Cytogenetic study has shown a microscopic detectable deletion in the 7p13-15 chromosomal region. Real-time PCR demonstrated a deletion of the GCK gene in the patient but not her parents, and CGH array revealed a deleted region of approximately 12 Mb in the 7p13-15 region. This deleted region included GLI3 and GCK genes (where heterozygous mutations cause GCPS and MODY2, respectively), and many other contiguous genes. Our patient manifests a unique form of MODY2, where GCK gene deletion is part of a large deleted segment in the 7p13-15 chromosomal region. PMID:22043488

Zung, Amnon; Petek, Erwin; Ben-Zeev, Bruria; Schwarzbraun, Thomas; Ben-Yehoshua, Sagi Josefsberg

2011-10-01

67

Improved Techniques for Endogenous Epitope Tagging and Gene Deletion in Toxoplasma gondii  

PubMed Central

Toxoplasma gondii is an excellent model organism for studies on the biology of the Apicomplexa due to its ease of in vitro cultivation and genetic manipulation. Large-scale reverse genetic studies in T. gondii have, however, been difficult due to the low frequency of homologous recombination. Efforts to ensure homologous recombination have necessitated engineering long flanking regions in the targeting construct. This requirement makes it difficult to engineer chromosomally targeted epitope tags or gene knock out constructs only by restriction enzyme mediated cloning steps. To address this issue we employed multisite Gateway® recombination techniques to generate chromosomal gene manipulation targeting constructs. Incorporation of 1.5 to 2.0 kb flanking homologous sequences in PCR generated targeting constructs resulted in 90% homologous recombination events in wild type T. gondii (RH strain) as determined by epitope tagging and target gene deletion experiments. Furthermore, we report that split marker constructs were equally efficient for targeted gene disruptions using the T. gondii UPRT gene locus as a test case. The methods described in this paper represent an improved strategy for efficient epitope tagging and gene disruptions in T. gondii. PMID:21352857

Upadhya, Rajendra; Kim, Kami; Hogue-Angeletti, Ruth; Weiss, Louis M

2011-01-01

68

RESEARCH ARTICLE Cellular SNF2H Chromatin-Remodeling Factor Promotes Herpes Simplex Virus 1 Immediate-Early Gene Expression and Replication  

E-print Network

ABSTRACT Like other DNA viruses that replicate in the nucleus, herpes simplex virus 1 (HSV-1) regulates the association of histones with its genome to promote viral replication and gene expression. We previously demonstrated that SNF2H, a member of the ISWI family of chromatin-remodeling factors, is concentrated in HSV-1 replication compartments in the nuclei of infected cells, suggesting that this cellular enzyme plays a role in viral replication. We show here that small interfering RNA (siRNA)mediated knockdown of SNF2H in HEp-2 cells resulted in an approximately 20-fold decrease in HSV-1 replication, arguing that SNF2H promotes efficient HSV-1 replication. Decreases in HSV-1 replication were observed with multiple SNF2H-specific siRNAs, and the extent of the replication decrease correlated with the amount of SNF2H knockdown, indicating that the phenotype resulted from decreased SNF2H levels rather than off-target effects of the siRNAs. We also observed a decrease in the accumulation of immediate-early (IE) gene products in HSV-1-infected cells in which SNF2H was knocked down. Histone H3 occupancy on viral promoters was increased in HSV-1-infected cells that were transfected with SNF2H-specific siRNAs, suggesting that SNF2H promotes removal of histones from viral promoters during infection. Furthermore, chromatin immunoprecipitation (ChIP) studies showed that SNF2H associated with the HSV-1 genome during infection, which suggests that SNF2H may directly remodel viral chromatin. We hypothesize that SNF2H is recruited to viral promoters during HSV-1 infection, where it can remodel the chromatin state of the viral genome, facilitate the transcription of immediate-early genes, and enhance viral replication.

unknown authors

69

The 6-Aminoquinolone WC5 Inhibits Human Cytomegalovirus Replication at an Early Stage by Interfering with the Transactivating Activity of Viral Immediate-Early 2 Protein ? †  

PubMed Central

WC5 is a 6-aminoquinolone that potently inhibits the replication of human cytomegalovirus (HCMV) but has no activity, or significantly less activity, against other herpesviruses. Here we investigated the nature of its specific anti-HCMV activity. Structure-activity relationship studies on a small series of analogues showed that WC5 possesses the most suitable pattern of substitutions around the quinolone scaffold to give potent and selective anti-HCMV activity. Studies performed to identify the possible target of WC5 indicated that it prevents viral DNA synthesis but does not significantly affect DNA polymerase activity. In yield reduction experiments with different multiplicities of infection, the anti-HCMV activity of WC5 appeared to be highly dependent on the viral inoculum, suggesting that WC5 may act at an initial stage of virus replication. Consistently, time-of-addition and time-of-removal studies demonstrated that WC5 affects a phase of the HCMV replicative cycle that precedes viral DNA synthesis. Experiments to monitor the effects of the compound on virus attachment and entry showed that it does not inhibit either process. Evaluation of viral mRNA and protein expression revealed that WC5 targets an event of the HCMV replicative cycle that follows the transcription and translation of immediate-early genes and precedes those of early and late genes. In cell-based assays to test the effects of WC5 on the transactivating activity of the HCMV immediate-early 2 (IE2) protein, WC5 markedly interfered with IE2-mediated transactivation of viral early promoters. Finally, WC5 combined with ganciclovir in checkerboard experiments exhibited highly synergistic activity. These findings suggest that WC5 deserves further investigation as a candidate anti-HCMV drug with a novel mechanism of action. PMID:20194695

Loregian, Arianna; Mercorelli, Beatrice; Muratore, Giulia; Sinigalia, Elisa; Pagni, Silvana; Massari, Serena; Gribaudo, Giorgio; Gatto, Barbara; Palumbo, Manlio; Tabarrini, Oriana; Cecchetti, Violetta; Palu, Giorgio

2010-01-01

70

Regionspecific changes in immediate early gene expression in response to sleep deprivation and recovery sleep in the mouse brain  

Microsoft Academic Search

Previous studies have documented changes in expression of the immediate early gene (IEG) c-fos and Fos protein in the brain between sleep and wakefulness. Such expression differences implicate changes in transcriptional regulation across behavioral states and suggest that other transcription factors may also be affected. In the current study, we examined the expression of seven fos\\/jun family member mRNAs (c-fos,

A Terao; M. A Greco; R. W Davis; H. C Heller; T. S Kilduff

2003-01-01

71

Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation  

Microsoft Academic Search

THE requirement of protein and messenger RNA synthesis for long-term memory1,2 suggests that neural activity induced by learning initiates a cascade of gene expression3. Here we use differential screening to identify five immediate-early genes induced by neuronal activity. One of these is tissue-plasminogen activator (tPA), an extracellular serine protease, which is induced with different spatial patterns in the brain by

Zhuo Qian; Mary E. Gilbert; Michael A. Colicos; Eric R. Kandel; Dietmar Kuhl

1993-01-01

72

Immediate-Early Regulatory Gene Mutants Define Different Stages in the Establishment and Reactivation of Herpes Simplex Virus Latency  

Microsoft Academic Search

Using nonsense and deletion mutants of herpes simplex virus type 1, we investigated the roles of three immediate-early proteins (ICP4, ICP27 and ICPO) in the establishment and reactivation of ganglionic latency in a mouse ocular model. DNA hybridization, superinfection-rescue, and cocultivation techniques provided quantitative data that distinguished between the failure of a virus to establish latency in the ganglion and

DAVID A. LEIB; DONALD M. COEN; CONNIE L. BOGARD; KAREN A. HICKS; DORNE R. YAGER; DAVID M. KNIPE; KENNETH L. TYLER; PRISCILLA A. SCHAFFER

73

Novel temporal configurations of stimuli produce discrete changes in immediate-early gene expression in the rat hippocampus  

Microsoft Academic Search

Changes in limbic brain activity in response to novel configurations of visual stimuli were assessed by quantifying two immediate- early genes, c-fos and zif268. Rats were first trained to use distal, visual cues to support radial-arm maze performance. Two separate sets of visual cues were used, one in the morning (Set A) and the other in the afternoon (Set B).

Eman Amin; John M. Pearce; Malcolm W. Brown; John P. Aggleton

2006-01-01

74

Initial Characterization of 17 Viruses Harboring Mutant Forms of the Immediate-Early Gene of Equine Herpesvirus 1  

Microsoft Academic Search

The sole immediate-early (IE) gene of equine herpesvirus 1 (EHV-1) encodes a major regulatory protein of 1487 amino acids (aa) capable of modulating gene expression from both early and late promoters and also of trans-repressing its own promoter. Using a specially designed recombination system and a library of IE linker-insertion, deletion, point, and nonsense mutant constructs that encode forms of the IE

Kimberly A. Buczynski; Seong K. Kim; Dennis J. O’callaghan

2005-01-01

75

Splitting Hares and Tortoises: A Classification of Neuronal Immediate Early Gene Transcription Based on Poised RNA Polymerase II  

PubMed Central

Immediate early transcription is an integral part of the neuronal response to environmental stimulation and serves many brain processes including development, learning, triggers of programmed cell death, and reaction to injury and drugs. Following a stimulus, neurons express a select few genes within a short period of time without undergoing de novo protein translation. Referred to as the ‘gateway to genetic response’, these immediate early genes (IEGs) are either expressed within a few minutes of stimulation or later within the hour. In neuronal IEGs that are expressed rapidly, productive elongation in response to neuronal activity is jump-started by constitutive transcription initiation together with RNA polymerase II stalling in the vicinity of the promoter. IEGs expressed later in the hour do not depend on this mechanism. On the basis of this Polymerase II poising, we propose that the immediate early genes can be grouped in two distinct classes: the rapid and the delayed IEGs. The possible biological relevance of these classes in neurons is discussed. PMID:23711585

Saha, Ramendra N.; Dudek, Serena M.

2013-01-01

76

Rapid Diagnostic Tests for Malaria Diagnosis in the Peruvian Amazon: Impact of pfhrp2 Gene Deletions and Cross-Reactions  

PubMed Central

Background In the Peruvian Amazon, Plasmodium falciparum and Plasmodium vivax malaria are endemic in rural areas, where microscopy is not available. Malaria rapid diagnostic tests (RDTs) provide quick and accurate diagnosis. However, pfhrp2 gene deletions may limit the use of histidine-rich protein-2 (PfHRP2) detecting RDTs. Further, cross-reactions of P. falciparum with P. vivax-specific test lines and vice versa may impair diagnostic specificity. Methods Thirteen RDT products were evaluated on 179 prospectively collected malaria positive samples. Species diagnosis was performed by microscopy and confirmed by PCR. Pfhrp2 gene deletions were assessed by PCR. Results Sensitivity for P. falciparum diagnosis was lower for PfHRP2 compared to P. falciparum-specific Plasmodium lactate dehydrogenase (Pf-pLDH)- detecting RDTs (71.6% vs. 98.7%, p<0.001). Most (19/21) false negative PfHRP2 results were associated with pfhrp2 gene deletions (25.7% of 74 P. falciparum samples). Diagnostic sensitivity for P. vivax (101 samples) was excellent, except for two products. In 10/12 P. vivax-detecting RDT products, cross-reactions with the PfHRP2 or Pf-pLDH line occurred at a median frequency of 2.5% (range 0%–10.9%) of P. vivax samples assessed. In two RDT products, two and one P. falciparum samples respectively cross-reacted with the Pv-pLDH line. Two Pf-pLDH/pan-pLDH-detecting RDTs showed excellent sensitivity with few (1.0%) cross-reactions but showed faint Pf-pLDH lines in 24.7% and 38.9% of P. falciparum samples. Conclusion PfHRP2-detecting RDTs are not suitable in the Peruvian Amazon due to pfhrp2 gene deletions. Two Pf-pLDH-detecting RDTs performed excellently and are promising RDTs for this region although faint test lines are of concern. PMID:22952633

Maltha, Jessica; Gamboa, Dionicia; Bendezu, Jorge; Sanchez, Luis; Cnops, Lieselotte; Gillet, Philippe; Jacobs, Jan

2012-01-01

77

The 19S proteasome activator promotes human cytomegalovirus immediate early gene expression through proteolytic and nonproteolytic mechanisms.  

PubMed

Proteasomes are large, multisubunit complexes that support normal cellular activities by executing the bulk of protein turnover. During infection, many viruses have been shown to promote viral replication by using proteasomes to degrade cellular factors that restrict viral replication. For example, the human cytomegalovirus (HCMV) pp71 protein induces the proteasomal degradation of Daxx, a cellular transcriptional repressor that can silence viral immediate early (IE) gene expression. We previously showed that this degradation requires both the proteasome catalytic 20S core particle (CP) and the 19S regulatory particle (RP). The 19S RP associates with the 20S CP to facilitate protein degradation but also plays a 20S CP-independent role promoting transcription. Here, we present a nonproteolytic role of the 19S RP in HCMV IE gene expression. We demonstrate that 19S RP subunits are recruited to the major immediate early promoter (MIEP) that directs IE transcription. Depletion of 19S RP subunits generated a defect in RNA polymerase II elongation through the MIE locus during HCMV infection. Our results reveal that HCMV commandeers proteasome components for both proteolytic and nonproteolytic roles to promote HCMV lytic infection. Importance: Proteasome inhibitors decrease or eliminate 20S CP activity and are garnering increasing interest as chemotherapeutics. However, an increasing body of evidence implicates 19S RP subunits in important proteolytic-independent roles during transcription. Thus, pharmacological inhibition of the 20S CP as a means to modulate proteasome function toward therapeutic effect is an incomplete capitalization on the potential of this approach. Here, we provide an additional example of nonproteolytic 19S RP function in promoting HCMV transcription. These data provide a novel system with which to study the roles of different proteasome components during transcription, a rationale for previously described shifts in 19S RP subunit localization during HCMV infection, and a potential therapeutic intervention point at a pre-immediate early stage for the inhibition of HCMV infection. PMID:25078702

Winkler, Laura L; Kalejta, Robert F

2014-10-01

78

Epigenetic Regulations of Immediate Early Genes Expression Involved in Memory Formation by the Amyloid Precursor Protein of Alzheimer Disease  

PubMed Central

We previously demonstrated that APP epigenetically regulates Egr1 expression both in cultured neurons and in vivo. Since Egr1 is an immediate early gene involved in memory formation, we wondered whether other early genes involved in memory were regulated by APP and we studied molecular mechanisms involved. By comparing prefrontal (PF) cortex from wild type (APP+/+) and APP knockout mice (APP?/?), we observed that APP down regulates expression of four immediate early genes, Egr1, c-Fos, Bdnf and Arc. Down regulation of Egr1, c-Fos and Bdnf transcription resulted from a decreased enrichment of acetylated histone H4 on the corresponding gene promoter. Further characterization of H4 acetylation at Egr1 and c-Fos promoters revealed increased acetylation of H4K5 and H4K12 residues in APP?/? mice. Whereas APP affected Egr1 promoter activity by reducing access of the CREB transcription factor, its effect on c-Fos appeared to depend on increased recruitment of HDAC2 histone deacetylase to the gene promoter. The physiological relevance of the epigenetic regulation of Egr1 and c-Fos gene transcription by APP was further analyzed following exposure of mice to novelty. Although transcription of Egr1 and c-Fos was increased following exposure of APP+/+ mice to novelty, such an induction was not possible in APP?/? mice with a high basal level of expression of these immediate early genes. Altogether, these results demonstrate that APP-mediated regulation of c-Fos and Egr1 by different epigenetic mechanisms is needed for their induction during exposure to novelty. PMID:24919190

Hendrickx, Aurélie; Pierrot, Nathalie; Tasiaux, Bernadette; Schakman, Olivier; Kienlen-Campard, Pascal; De Smet, Charles; Octave, Jean-Noël

2014-01-01

79

Recombinant Monoclonal Antibody Recognizes a Unique Epitope on Varicella-Zoster Virus Immediate-Early 63 Protein  

PubMed Central

We previously constructed a recombinant monoclonal antibody (rec-MAb 63P4) that detects immediate-early protein IE63 encoded by varicella-zoster virus (VZV) in the cytoplasm of productively infected cells. Here, we used ORF63 truncation mutants to map the rec-MAb 63P4 binding epitope to amino acids 141 to 150 of VZV IE63, a region not shared with other widely used anti-IE63 antibodies, and found that the recombinant antibody does not bind to the simian IE63 counterpart. PMID:22438547

Mueller, Niklaus H.; Bos, Nathan L.; Seitz, Scott; Wellish, Mary; Mahalingam, Ravi; Gilden, Don

2012-01-01

80

A VNTR element associated with steroid sulfatase gene deletions stimulates recombination in cultured cells  

SciTech Connect

Steroid sulfatase deficiency is a common genetic disorder, with a prevalence of approximately one in every 3500 males world wide. About 90% of these patients have complete gene deletions, which appear to result from recombination between members of a low-copy repeat family (CRI-232 is the prototype) that flank the gene. RU1 and RU2 are two VNTR elements found within each of these family members. RU1 consists of 30 bp repeating units and its length shows minimal variation among individuals. The RU2 element consists of repeating sequences which are highly asymmetric, with about 90% purines and no C`s on one strand, and range from 0.6 kb to over 23 kb among different individuals. We conducted a study to determine if the RU1 or RU2 elements can promote recombination in an in vivo test system. We inserted these elements adjacent to the neo gene in each of two pSV2neo derivatives, one of which has a deletion in the 5{prime} portion of the neo gene and the other having a deletion in the 3{prime} portion. These plasmids were combined and used to transfect EJ cells. Survival of cells in G418 indicates restoration of a functional neo gene by recombination between two deletion constructs. Thus counting G418 resistant colonies gives a quantitative measure of the enhancement of recombination by the inserted VNTR elements. The results showed no effect on recombination by the inserted RU1 element (compared to the insertion of a nonspecific sequence), while the RU2 element stimulated recombination by 3.5-fold (P<0.01). A separate set of constructs placed RU1 or RU2 within the intron of an exon trapping vector. Following tranfection of cells, recombination events were monitored by a PCR assay that detected the approximation of primer binding sites (as a result of recombination). These studies showed that, as in the first set of experiments, the highly variable RU2 element is capable of stimulating somatic recombination in mammalian cells.

Gong, Y.; Li, X.M.; Shapiro, L.J. [UCSF School of Medicine, San Francisco, CA (United States)] [and others

1994-09-01

81

IL-2/15 receptor-beta gene deletion alters neurobehavioral performance.  

PubMed

The common IL-2/15 receptor-beta (IL-2/15Rbeta) is an essential signaling subunit that is shared exclusively by IL-2 and IL-15, and is enriched in the hippocampal formation and related limbic regions. We have previously shown that mice lacking IL-2 exhibit alterations in hippocampal-dependent learning, sensorimotor gating and accompanying reductions in hippocampal infrapyramidal mossy neuronal fiber length. Although the effects of exogenous IL-2 on various aspects of forebrain neuronal function are well documented, it is unclear whether IL-15 has neuromodulatory actions. Here we sought to test the hypothesis that the combined loss of the ability of IL-2 and IL-15 to signal through IL-2/15Rbeta in the brain would influence neurobehavioral performance, in particular spatial learning and memory performance. To test this hypothesis, we compared several different domains of behavior in mice that had one or both IL-2/15Rbeta gene alleles deleted. Compared with C57BL/6-IL-2/15Rbeta+/+ wild-type and C57BL/6-IL-2/15Rbeta+/- heterozygote littermates, C57BL/6-IL-2/15Rbeta-/- knockout mice exhibited a deficit in prepulse inhibition of the acoustic startle reflex (PPI). The IL-2/15Rbeta knockout mice also showed significant reductions in acoustic startle reactivity, and modest differences in behavior in the elevated plus-maze test indicative of reduced levels of fearfulness in response to novelty. The IL-2/15Rbeta knockout mice did not differ in locomotor activity in either the plus-maze or the Morris water-maze, and contrary to our working hypothesis, they did not differ in spatial learning or memory performance in the water-maze. Further studies are required to determine if these behavioral alterations may be attributable to factors such as the loss of the ability of IL-15 and/or IL-2 to modulate limbic neurons, autoimmunity or genetic factors associated with IL-2/15Rbeta gene deletion. PMID:11864627

Petitto, John M; Huang, Zhi; Hartemink, David A; Beck, Ray

2002-03-01

82

PYRETHROID INDUCED ALTERATIONS IN TRANSCRIPTION OF CALCIUM RESPONSIVE AND IMMEDIATE EARLY GENES IN VIVO.  

EPA Science Inventory

Multiple molecular targets for pyrethroid insecticides have been evaluated in in vitro preparations, including but not limited to voltage-sensitive sodium channels (VSSCs), voltage-sensitive calcium channels (VSCCs), GABAergic receptors, ATPases and mitochondrial respiratory chai...

83

The Immediate Early Gene Product EGR1 and Polycomb Group Proteins Interact in Epigenetic Programming during Chondrogenesis  

PubMed Central

Initiation of and progression through chondrogenesis is driven by changes in the cellular microenvironment. At the onset of chondrogenesis, resting mesenchymal stem cells are mobilized in vivo and a complex, step-wise chondrogenic differentiation program is initiated. Differentiation requires coordinated transcriptomic reprogramming and increased progenitor proliferation; both processes require chromatin remodeling. The nature of early molecular responses that relay differentiation signals to chromatin is poorly understood. We here show that immediate early genes are rapidly and transiently induced in response to differentiation stimuli in vitro. Functional ablation of the immediate early factor EGR1 severely deregulates expression of key chondrogenic control genes at the onset of differentiation. In addition, differentiating cells accumulate DNA damage, activate a DNA damage response and undergo a cell cycle arrest and prevent differentiation associated hyper-proliferation. Failed differentiation in the absence of EGR1 affects global acetylation and terminates in overall histone hypermethylation. We report novel molecular connections between EGR1 and Polycomb Group function: Polycomb associated histone H3 lysine27 trimethylation (H3K27me3) blocks chromatin access of EGR1. In addition, EGR1 ablation results in abnormal Ezh2 and Bmi1 expression. Consistent with this functional interaction, we identify a number of co-regulated targets genes in a chondrogenic gene network. We here describe an important role for EGR1 in early chondrogenic epigenetic programming to accommodate early gene-environment interactions in chondrogenesis. PMID:23483971

Caron, Marjolein M. J.; Prickaerts, Peggy; Rofel, Celine; Dahlmans, Vivian E. H.; Surtel, Don A. M.; Paulis, Yvette; Schweizer, Finja; Welting, Tim J. M.; Eijssen, Lars M.; Voncken, Jan Willem

2013-01-01

84

High-frequency stimulation induces gradual immediate early gene expression in maturing adult-generated hippocampal granule cells.  

PubMed

Increasing evidence shows that adult neurogenesis of hippocampal granule cells is advantageous for learning and memory. We examined at which stage of structural maturation and age new granule cells can be activated by strong synaptic stimulation. High-frequency stimulation of the perforant pathway in urethane-anesthetized rats elicited expression of the immediate early genes c-fos, Arc, zif268 and pCREB133 in almost 100% of mature, calbindin-positive granule cells. In contrast, it failed to induce immediate early gene expression in immature doublecortin-positive granule cells. Furthermore, doublecortin-positive neurons did not react with c-fos or Arc expression to mild theta-burst stimulation or novel environment exposure. Endogenous expression of pCREB133 was increasingly present in young cells with more elaborated dendrites, revealing a close correlation to structural maturation. Labeling with bromodeoxyuridine revealed cell age dependence of stimulation-induced c-fos, Arc and zif268 expression, with only a few cells reacting at 21 days, but with up to 75% of cells activated at 35-77 days of cell age. Our results indicate an increasing synaptic integration of maturing granule cells, starting at 21 days of cell age, but suggest a lack of ability to respond to activation with synaptic potentiation on the transcriptional level as long as immature cells express doublecortin. PMID:23425888

Jungenitz, Tassilo; Radic, Tijana; Jedlicka, Peter; Schwarzacher, Stephan W

2014-07-01

85

Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by an Sp1/Sp3-activated transcriptional program involving immediate-early gene induction.  

PubMed

Histone deacetylase inhibitors (HDACi) induce growth arrest and apoptosis in colon cancer cells and are being considered for colon cancer therapy. The underlying mechanism of action of these effects is poorly defined with both transcription-dependent and -independent mechanisms implicated. We screened a panel of 30 colon cancer cell lines for sensitivity to HDACi-induced apoptosis and correlated the differences with gene expression patterns induced by HDACi in the five most sensitive and resistant lines. A robust and reproducible transcriptional response involving coordinate induction of multiple immediate-early (fos, jun, egr1, egr3, atf3, arc, nr4a1) and stress response genes (Ndrg4, Mt1B, Mt1E, Mt1F, Mt1H) was selectively induced in HDACi sensitive cells. Notably, a significant percentage of these genes were basally repressed in colon tumors. Bioinformatics analysis revealed that the promoter regions of the HDACi-induced genes were enriched for KLF4/Sp1/Sp3 transcription factor binding sites. Altering KLF4 levels failed to modulate apoptosis or transcriptional responses to HDACi treatment. In contrast, HDACi preferentially stimulated the activity of Spl/Sp3 and blocking their action attenuated both the transcriptional and apoptotic responses to HDACi treatment. Our findings link HDACi-induced apoptosis to activation of a Spl/Sp3-mediated response that involves derepression of a transcriptional network basally repressed in colon cancer. PMID:20068171

Wilson, Andrew J; Chueh, Anderly C; Tögel, Lars; Corner, Georgia A; Ahmed, Naseem; Goel, Sanjay; Byun, Do-Sun; Nasser, Shannon; Houston, Michele A; Jhawer, Minaxi; Smartt, Helena J M; Murray, Lucas B; Nicholas, Courtney; Heerdt, Barbara G; Arango, Diego; Augenlicht, Leonard H; Mariadason, John M

2010-01-15

86

SULT1A1 gene deletion in BRCA2-associated male breast cancer: a link between genes and environmental exposures?  

PubMed

SULT1A1, a member of sulfotransferase superfamily, is a drug and hormone metabolizing enzyme involved in the metabolism of a variety of potential mammary carcinogens of endogenous and exogenous origin. Interestingly, the metabolic activity of SULT1A1 can be affected by variations in gene copy number. Male Breast Cancer (MBC) is a rare disease and less investigated disease compared to female BC (FBC). As in FBC, the concurrent effects of genetic risk factors, particularly BRCA2 mutations, increased exposure to estrogens and environmental carcinogens play a relevant role in MBC. By quantitative real-time PCR with TaqMan probes, we investigated the presence of SULT1A1 gene copy number variations (CNVs) in a series of 72 MBCs. SULT1A1 gene deletion was observed in 10 of the 72 MBCs (13.9%). In a multivariate analysis association between BRCA2 mutation and SULT1A1 gene deletion emerged (p = 0.0005). Based on the evidence that the level of SULT1A1 enzyme activity is correlated with CNV, our data suggest that in male breast tumors SULT1A1 activity may be decreased. Thus, it can be hypothesized that in a proportion of MBCs, particularly in BRCA2-associated MBCs, the level of estrogens and environmental carcinogens exposure might be increased suggesting a link between gene and environmental exposure in the pathogenesis of MBC. PMID:23711090

Palli, Domenico; Rizzolo, Piera; Zanna, Ines; Silvestri, Valentina; Saieva, Calogero; Falchetti, Mario; Navazio, Anna Sara; Graziano, Veronica; Masala, Giovanna; Bianchi, Simonetta; Russo, Antonio; Tommasi, Stefania; Ottini, Laura

2013-05-01

87

Pattern of cerebrospinal immediate early gene c-fos expression in an ovine model of non-accidental head injury.  

PubMed

Expression of the immediate early gene, c-fos, was examined in a large animal model of non-accidental head injury ("shaken baby syndrome"). Lambs were used because they have a relatively large gyrencephalic brain and weak neck muscles resembling a human infant. Neonatal lambs were manually shaken in a manner similar to that believed to occur with most abused human infants, but there was no head impact. The most striking c-fos expression was in meningothelial cells of the cranial cervical spinal cord and, to a lesser degree, in hemispheric, cerebellar, and brainstem meninges. Vascular endothelial cells also frequently showed c-fos immunopositivity in the meninges and hemispheric white matter. It was hypothesised that this c-fos immunoreactivity was due to mechanical stress induced by shaking, with differential movement of different craniospinal components. PMID:24035422

Finnie, J W; Blumbergs, P C; Manavis, J; Vink, R

2013-12-01

88

Characterization of a Replication-Incompetent Pseudorabies Virus Mutant Lacking the Sole Immediate Early Gene IE180  

PubMed Central

ABSTRACT The alphaherpesvirus pseudorabies virus (PRV) encodes a single immediate early gene called IE180. The IE180 protein is a potent transcriptional activator of viral genes involved in DNA replication and RNA transcription. A PRV mutant with both copies of IE180 deleted was constructed 20 years ago (S. Yamada and M. Shimizu, Virology 199:366–375, 1994, doi:10.1006/viro.1994.1134), but propagation of the mutant depended on complementing cell lines that expressed the toxic IE180 protein constitutively. Recently, Oyibo et al. constructed a novel set of PRV IE180 mutants and a stable cell line with inducible IE180 expression (H. Oyibo, P. Znamenskiy, H. V. Oviedo, L. W. Enquist, A. Zador, Front. Neuroanat. 8:86, 2014, doi:10.3389/fnana.2014.00086), which we characterized further here. These mutants failed to replicate new viral genomes, synthesize immediate early, early, or late viral proteins, and assemble infectious virions. The PRV IE180-null mutant did not form plaques in epithelial cell monolayers and could not spread from primary infected neurons to second-order neurons in culture. PRV IE180-null mutants lacked the property of superinfection exclusion. When PRV IE180-null mutants infected cells first, subsequent superinfecting viruses were not blocked in cell entry and formed replication compartments in epithelial cells, fibroblasts, and neurons. Cells infected with PRV IE180-null mutants survived as long as uninfected cells in culture while expressing a fluorescent reporter gene. Transcomplementation with IE180 in epithelial cells restored all mutant phenotypes to wild type. The conditional expression of PRV IE180 protein enables the propagation of replication-incompetent PRV IE180-null mutants and will facilitate construction of long-term single-cell-infecting PRV mutants for precise neural circuit tracing and high-capacity gene delivery vectors. PMID:25389174

Wu, Brendan W.

2014-01-01

89

Cortical synaptic NMDA receptor deficits in ?7 nicotinic acetylcholine receptor gene deletion models: implications for neuropsychiatric diseases.  

PubMed

Microdeletion of the human CHRNA7 gene (?7 nicotinic acetylcholine receptor, nAChR) as well as dysfunction in N-methyl-d-aspartate receptors (NMDARs) have been associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia. However, the pathophysiological roles of synaptic vs. extrasynaptic NMDARs and their interactions with ?7 nAChRs in cortical dysfunction remain largely uncharacterized. Using a combination of in vivo and in vitro models, we demonstrate that ?7 nAChR gene deletion leads to specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in mouse cortex. ?7 nAChR null mice had decreased cortical NMDAR expression and glutamatergic synapse formation during postnatal development. Similar reductions in NMDAR expression and glutamatergic synapse formation were revealed in cortical cultures lacking ?7 nAChRs. Interestingly, synaptic, but not extrasynaptic, NMDAR currents were specifically diminished in cultured cortical pyramidal neurons as well as in acute prefrontal cortical slices of ?7 nAChR null mice. Moreover, d-serine responsive synaptic NMDAR-mediated currents and levels of the d-serine synthetic enzyme serine racemase were both reduced in ?7 nAChR null cortical pyramidal neurons. Our findings thus identify specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in ?7 nAChR gene deletion models of cortical dysfunction, thereby implicating ?7 nAChR-mediated control of synaptic NMDARs and serine racemase/d-serine pathways in cortical dysfunction underlying many neuropsychiatric and neurodevelopmental disorders, particularly those associated with deletion of human CHRNA7. PMID:24326163

Lin, Hong; Hsu, Fu-Chun; Baumann, Bailey H; Coulter, Douglas A; Lynch, David R

2014-03-01

90

Zinc rescue of Akt2 gene deletion-linked murine cardiac dysfunction and pathological changes is metallothionein-dependent.  

PubMed

We have demonstrated that zinc supplementation provides cardiac protection from diabetes in mice, but its underlying mechanism remains unclear. Since zinc mimics the function of insulin, it may provide benefit to the heart via stimulating Akt-mediated glucose metabolism. Akt2 plays an important role in cardiac glucose metabolism and mice with Akt2 gene deletion (Akt2-KO) exhibit a type 2 diabetes phenotype; therefore, we assumed that no cardiac protection by zinc supplementation from diabetes would be observed in Akt2-KO mice. Surprisingly, despite Akt2 gene deletion, zinc supplementation provided protection against cardiac dysfunction and other pathological changes in Akt2-KO mice, which were accompanied by significant decreases in Akt and GSK-3? phosphorylation. Correspondingly, glycogen synthase phosphorylation and hexokinase II and PGC-1? expression, all involved in the regulation of glucose metabolism, were significantly altered in diabetic hearts, along with a significantly increased expression of Akt negative regulators: PTEN, PTP1B, and TRB3. All these molecular, pathological, and functional changes were significantly prevented by 3-month zinc supplementation. Furthermore, the stimulation of Akt-mediated glucose metabolic kinases or enzymes by zinc treatment was metallothionein-dependent since it could not be observed in metallothionein-knockout mice. These results suggest that zinc preserves cardiac function and structure in Akt2-KO mice presumably due to its insulin mimetic effect on cardiac glucose-metabolism. The cardioprotective effects of zinc are metallothionein-dependent. This is very important since zinc supplementation may be required for patients with Akt2 gene deficiency or insulin resistance. PMID:24819347

Sun, Weixia; Miao, Xiao; Zhou, Shanshan; Zhang, Li; Epstein, Paul N; Mellen, Nicholas; Zheng, Yang; Fu, Yaowen; Wang, Yuehui; Cai, Lu

2014-09-01

91

In Vivo Replication of Recombinant Murine Cytomegalovirus Driven by the Paralogous Major Immediate-Early Promoter-Enhancer of Human Cytomegalovirus  

PubMed Central

Transcription of the major immediate-early (MIE) genes of cytomegaloviruses (CMV) is driven by a strong promoter-enhancer (MIEPE) complex. Transactivator proteins encoded by these MIE genes are essential for productive infection. Accordingly, the MIEPE is a crucial control point, and its regulation by activators and repressors is pertinent to virus replication. Since the MIEPE contains multiple regulatory elements, it was reasonable to assume that specific sequence motifs are irreplaceable for specifying the cell-type tropism and replication pattern. Recent work on murine CMV infectivity (A. Angulo, M. Messerle, U. H. Koszinowski, and P. Ghazal, J. Virol. 72:8502–8509, 1998) has documented the proposed enhancing function of the enhancer in that its resection or its replacement by a nonregulatory stuffer sequence resulted in a significant reduction of infectivity, even though replication competence was maintained by a basal activity of the spared authentic MIE promoter. Notably, full capacity for productive in vitro infection of fibroblasts was restored in recombinant viruses by the human CMV enhancer. Using two-color in situ hybridization with MIEPE-specific polynucleotide probes, we demonstrated that a murine CMV recombinant in which the complete murine CMV MIEPE is replaced by the paralogous human CMV core promoter and enhancer (recombinant virus mCMVhMIEPE) retained the potential to replicate in vivo in all tissues relevant to CMV disease. Notably, mCMVhMIEPE was also found to replicate in the liver, a site at which transgenic hCMV MIEPE is silenced. We conclude that productive in vivo infection with murine CMV does not strictly depend on a MIEPE type-specific regulation. PMID:10233967

Grzimek, Natascha K. A.; Podlech, Jurgen; Steffens, Hans-Peter; Holtappels, Rafaela; Schmalz, Susanne; Reddehase, Matthias J.

1999-01-01

92

Chemotherapy refractory testicular germ cell tumor is associated with a variant in Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF)  

PubMed Central

Introduction: There is evidence that inherited genetic variation affects both testicular germ cell tumor (TGCT) treatment outcome and risks of late-complications arising from cisplatin-based chemotherapy. Using a candidate gene approach, we examined associations of three genes involved in the cisplatin metabolism pathway, GSTP1, COMT, and TPMT, with TGCT outcome and cisplatin-induced neurotoxicity. Materials and Methods: Our study population includes a subset of patients (n = 137) from a genome-wide association study at the University of Pennsylvania that evaluates inherited genetic susceptibility to TGCT. All patients in our study had at least one course of cisplatin-based chemotherapy with at least 1 year of follow-up. A total of 90 markers in GSTP1, COMT, and TPMT and their adjacent genomic regions (±20 kb) were analyzed for associations with refractory TGCT after first course of chemotherapy, progression-free survival (PFS), overall survival (OS), peripheral neuropathy, and ototoxicity. Results: After adjustment for multiple comparisons, one Single nucleotide polymorphism (SNP), rs2073743, in the flanking region (±20 kb) of COMT was associated with refractory TGCT after initial chemotherapy. This SNP lies within the intron region of the Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF). The G allele of rs2073743 predisposed patients to refractory disease with a relative risk of 2.6 (95% CI 1.1, 6.3; P = 0.03). Assuming recessive inheritance, patients with the GG genotype had 22.7 times higher risk (95% CI 3.3, 155.8; P = 0.04) of developing refractory disease when compared to those with the GC or CC genotypes. We found no association of our candidate genes with peripheral neuropathy, ototoxicity, PFS and OS. Discussion: This is the first study to suggest that germline genetic variants of ARVCF may affect TGCT outcome. The result of this study is hypothesis generating and should be validated in future studies. PMID:23248619

Fung, Chunkit; Vaughn, David J.; Mitra, Nandita; Ciosek, Stephanie L.; Vardhanabhuti, Saran; Nathanson, Katherine L.; Kanetsky, Peter A.

2012-01-01

93

Herpes simplex virus type 1 ICP0 regulates expression of immediate-early, early, and late genes in productively infected cells.  

PubMed Central

The herpes simplex virus type 1 protein, ICP0, can activate expression of all kinetic classes of viral promoters in transient expression assays. To examine the role of ICP0 in the regulation of viral gene expression during productive infection, we characterized the wild-type virus, an ICP0 null mutant (7134), and several ICP0 nonsense mutant viruses with regard to virus replication and protein synthesis in Vero cells. Relative to wild-type virus, 7134 was severely deficient in viral growth and protein synthesis at low multiplicities of infection but exhibited a nearly wild-type phenotype at high multiplicities. The phenotypes of the ICP0 nonsense mutants were intermediate between those of the wild-type virus and 7134 in that the more ICP0-coding sequence expressed by a given nonsense mutant, the more wild type-like was its phenotype. The location of the ICP0 domain responsible for transactivation during productive infection was confirmed to be within the N-terminal portion of the protein, as previously shown in transient expression assays. Immunoprecipitation and immunofluorescence tests were used to detect low-level expression of selected immediate-early (IE), early (E), and late (L) proteins by mutant and wild-type viruses following low-multiplicity infection. The 7134 deletion mutant and several nonsense mutants expressed markedly reduced levels of E and L proteins but wild-type levels of the IE protein, ICP4. Because the latency-associated transcripts (LATs) are specified by the strand opposite that which encodes ICP0, the ICP0 deletion and nonsense mutants are by definition ICP0-LAT double mutants. The ability of a LAT- ICP0+ mutant to replicate as efficiently as wild-type virus at low multiplicities and the ability of ICP0-expressing 0-28 cells to complement the defects of the mutants in E and L protein synthesis indicates that the phenotypes of the mutants are caused by mutations in ICP0 and not the LATs. Thus, we conclude that ICP0 up-regulates E and L but not necessarily IE gene expression during productive infection. The activation of IE gene expression by ICP0 during productive infection is likely overshadowed by the activity of the virion-associated protein, VP16. This hypothesis was tested by transfection of Vero cells with infectious mutant and wild-type viral DNAs. In such tests, no VP16 is present at early times posttransfection. Significantly fewer cells transfected with infectious 7134 DNA expressed ICP4 than cells transfected with KOS DNA. This reduction was fully reversed by cotransfection with an ICP0-expressing plasmid.(ABSTRACT TRUNCATED AT 400 WORDS) Images PMID:1313909

Cai, W; Schaffer, P A

1992-01-01

94

Human cytomegalovirus immediate early protein 2 enhances myocardin-mediated survival of rat aortic smooth muscle cells.  

PubMed

Human cytomegalovirus (HCMV) may increase the incidence of restenosis and predispose to atherosclerosis. The lesions of restenosis and atherosclerosis often contain smooth muscle cells (SMCs) with high rates of proliferation and apoptosis. One of the immediate early (IE) gene products of HCMV-IE2 affects transcriptional activities of some cellular factors in SMCs, including myocardin. In this study, we studied the effects of IE2 and myocardin on PI3K pathway inducer wortmannin induced apoptosis in rat aortic SMCs. We show that the transcriptional activity of myocardin on Mcl-1 promoter is enhanced by co-expression of HCMV IE2 in rat aortic SMCs; and the expressions of mRNA and protein of antiapoptotic genes-Mcl-1 and Bcl-2 are upregulated by IE2 alone and co-transfection of myocardin and IE2, but decreased by myocardin-specific shRNA in rat aortic SMCs. We further demonstrate that co-expression of myocardin and HCMV IE2 declines apoptotic cell numbers and caspase-3 activities induced by serum starvation plus wortmannin in rat aortic SMCs. The results suggest that HCMV IE2 enhances myocardin-mediated survival of rat aortic SMCs under serum deprivation and PI3-kinase inhibition, partly via activation of Mcl-1's antiapoptosis effect. Our study connects HCMV IE2 to myocardin-induced transcriptional program for rat aortic SMCs survival and proliferation, involving in HCMV related restenosis and atherosclerosis. PMID:25157858

Liao, Xing-Hua; Dong, Xiumei; Wu, Chenyu; Wang, Tao; Liu, Fenyong; Zhou, Jun; Zhang, Tong-Cun

2014-11-01

95

Amphetamine and Dopamine-Induced Immediate Early Gene Expression in Striatal Neurons Depends on Postsynaptic NMDA Receptors and Calcium  

PubMed Central

Amphetamine and cocaine induce the expression of both immediate early genes (IEGs) and neuropeptide genes in rat striatum. Despite the demonstrated dependence of these effects on D1 dopamine receptors, which activate the cyclic AMP pathway, there are several reports that amphetamine and cocaine-induced IEG expression can be inhibited in striatum in vivo by NMDA receptor antagonists. We find that in vivo, the NMDA receptor antagonist MK-801 inhibits amphetamine induction of c-fos acutely and also prevents downregulation of IEG expression with chronic amphetamine administration. Such observations raise the question of whether dopamine/glutamate interactions occur at the level of corticostriatal and mesostriatal circuitry or within striatal neurons. Therefore, we studied dissociated striatal cultures in which midbrain and cortical presynaptic inputs are removed. In these cultures, we find that dopamine- or forskolin-mediated IEG induction requires Ca2+ entry via NMDA receptors but not via L-type Ca2+ channels. Moreover, blockade of NMDA receptors diminishes the ability of dopamine to induce phosphorylation of the cyclic AMP responsive element binding protein CREB. Although these results do not rule out a role for circuit-level dopamine/glutamate interactions, they demonstrate a requirement at the cellular level for interactions between the cyclic AMP and NMDA receptor pathways in dopamine-regulated gene expression in striatal neurons. PMID:8753884

Konradi, Christine; Leveque, Jean-Christophe; Hyman, Steven E.

2014-01-01

96

Expression of immediate-early genes in the inferior colliculus and auditory cortex in salicylate-induced tinnitus in rat.  

PubMed

Tinnitus could be associated with neuronal hyperactivity in the auditory center. As a neuronal activity marker, immediate-early gene (IEG) expression is considered part of a general neuronal response to natural stimuli. Some IEGs, especially the activity-dependent cytoskeletal protein (Arc) and the early growth response gene-1 (Egr-1), appear to be highly correlated with sensory-evoked neuronal activity. We hypothesize, therefore, an increase of Arc and Egr-1 will be observed in a tinnitus model. In our study, we used the gap prepulse inhibition of acoustic startle (GPIAS) paradigm to confirm that salicylate induces tinnitus-like behavior in rats. However, expression of the Arc gene and Egr-1 gene were decreased in the inferior colliculus (IC) and auditory cortex (AC), in contradiction of our hypothesis. Expression of N-methyl d-aspartate receptor subunit 2B (NR2B) was increased and all of these changes returned to normal 14 days after treatment with salicylate ceased. These data revealed long-time administration of salicylate induced tinnitus markedly but reversibly and caused neural plasticity changes in the IC and the AC. Decreased expression of Arc and Egr-1 might be involved with instability of synaptic plasticity in tinnitus. PMID:24704997

Hu, S S; Mei, L; Chen, J Y; Huang, Z W; Wu, H

2014-01-01

97

Microarray and RT-PCR screening for white spot syndrome virus immediate-early genes in cycloheximide-treated shrimp  

SciTech Connect

Here, we report for the first time the successful use of cycloheximide (CHX) as an inhibitor to block de novo viral protein synthesis during WSSV (white spot syndrome virus) infection. Sixty candidate IE (immediate-early) genes were identified using a global analysis microarray technique. RT-PCR showed that the genes corresponding to ORF126, ORF242 and ORF418 in the Taiwan isolate were consistently CHX-insensitive, and these genes were designated ie1, ie2 and ie3, respectively. The sequences for these IE genes also appear in the two other WSSV isolates that have been sequenced. Three corresponding ORFs were identified in the China WSSV isolate, but only an ORF corresponding to ie1 was predicted in the Thailand isolate. In a promoter activity assay in Sf9 insect cells using EGFP (enhanced green fluorescence protein) as a reporter, ie1 showed very strong promoter activity, producing higher EGFP signals than the insect Orgyia pseudotsugata multicapsid nuclear polyhedrosis virus (OpMNPV) ie2 promoter.

Liu Wangjing [Institute of Zoology, National Taiwan University, Taipei 106, Taiwan (China); Chang Yunshiang [Institute of Zoology, National Taiwan University, Taipei 106, Taiwan (China); Wang Chunghsiung [Department of Entomology, National Taiwan University, Taipei 106, Taiwan (China); Kou, Guang-Hsiung [Institute of Zoology, National Taiwan University, Taipei 106, Taiwan (China); Lo Chufang [Institute of Zoology, National Taiwan University, Taipei 106, Taiwan (China)]. E-mail: gracelow@ntu.edu.tw

2005-04-10

98

Immediate early gene response to hearing song correlates with receptive behavior and depends on dialect in a female songbird.  

PubMed

Stimulus-induced expression of the immediate early gene ZENK (egr-1) in the songbird's auditory forebrain presumably depends on the behavioral significance of the stimulus. Few studies, however, have quantified both the ZENK and behavioral responses to a stimulus in the same individuals. We played conspecific male song of either hatch (local) or foreign dialect to female white-crowned sparrows (Zonotrichia leucophrys oriantha) and quantified both the auditory ZENK response and their behavioral response, which is known to depend on dialect. Birds hearing hatch dialect showed greater ZENK induction in the caudomedial hyperstriatum ventrale and the dorsal portion of the caudomedial neostriatum than birds hearing foreign dialect, supporting previous work showing a relationship between ZENK and salience of the stimulus. In the dorsal portion of the caudomedial neostriatum, ZENK induction was correlated with the amount of non-vocal courtship behavior; however, in the caudomedial hyperstriatum ventrale, ZENK induction was more highly correlated with the females' own vocal behavior and thus may have been partly self-induced. Some females sang and showed a male-like pattern of ZENK induction in their song systems. This study provides the first evidence that the ZENK response in a sensory area to a social stimulus is proportional to the animal's preference for the stimulus. PMID:12879354

Maney, D L; MacDougall-Shackleton, E A; MacDougall-Shackleton, S A; Ball, G F; Hahn, T P

2003-09-01

99

The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients.  

PubMed

Here, we report unbiased screens for genes expressed in metastatic tumor cells that are associated with cell motility. These screens identified Ier2, an immediate early gene of unknown function, as potentially having a role in tumor cell motility and metastasis. Knockdown of Ier2 in 3T3 fibroblasts inhibited their motility upon relief of contact inhibition in monolayer wounding assays. Furthermore, ectopic Ier2 expression promoted the motility and invasiveness of poorly metastatic 1AS pancreatic tumor cells in vitro. Relief of contact inhibition was associated with translocation of the Ier2 protein from the cytoplasm to the nucleus in both 3T3 fibroblasts and 1AS tumor cells. Importantly, ectopic Ier2 expression in 1AS cells stimulated metastasis formation when cells were implanted into experimental animals. Furthermore, we found elevated Ier2 expression in a wide variety of human tumor types. This correlated with poor metastasis-free and overall survival in patients with colorectal adenocarcinomas. Together, these data reveal Ier2 as a new player in the regulation of tumor progression and metastasis, and suggest that Ier2 may be useful prognostically and therapeutically in the management of cancer. PMID:22120713

Neeb, A; Wallbaum, S; Novac, N; Dukovic-Schulze, S; Scholl, I; Schreiber, C; Schlag, P; Moll, J; Stein, U; Sleeman, J P

2012-08-16

100

Low-level laser therapy effectively prevents secondary brain injury induced by immediate early responsive gene X-1 deficiency.  

PubMed

A mild insult to the brain can sometimes trigger secondary brain injury, causing severe postconcussion syndrome, but the underlying mechanism is ill understood. We show here that secondary brain injury occurs consistently in mice lacking immediate early responsive gene X-1 (IEX-1), after a gentle impact to the head, which closely simulates mild traumatic brain injury in humans. The pathologic lesion was characterized by extensive cell death, widespread leukocyte infiltrates, and severe tissue loss. On the contrary, a similar insult did not induce any secondary injury in wild-type mice. Strikingly, noninvasive exposure of the injured head to a low-level laser at 4 hours after injury almost completely prevented the secondary brain injury in IEX-1 knockout mice. The low-level laser therapy (LLLT) suppressed proinflammatory cytokine expression like interleukin (IL)-1? and IL-6 but upregulated TNF-?. Moreover, although lack of IEX-1 compromised ATP synthesis, LLLT elevated its production in injured brain. The protective effect of LLLT may be ascribed to enhanced ATP production and selective modulation of proinflammatory mediators. This new closed head injury model provides an excellent tool to investigate the pathogenesis of secondary brain injury as well as the mechanism underlying the beneficial effect of LLLT. PMID:24849666

Zhang, Qi; Zhou, Chang; Hamblin, Michael R; Wu, Mei X

2014-08-01

101

Immediate early gene activity-regulated cytoskeletal-associated protein regulates estradiol-induced lordosis behavior in female rats.  

PubMed

Sensory feedback is an important component of any behavior, with each instance influencing subsequent activity. Female sexual receptivity is mediated both by the steroid hormone milieu and interaction with the male. We tested the influence of repeated mating on the level of sexual receptivity in ovariectomized rats treated with estradiol benzoate (EB) once every fourth day to mimic the normal phasic changes of circulating estradiol. Females were divided into two groups: naïve, which were tested for lordosis behavior once, and experienced rats, which were tested for lordosis after each EB injection. To monitor the effect of mating, the number of neurons expressing the immediate early gene activity-regulated cytoskeleton-associated protein (Arc) were counted in the mediobasal hypothalamus. Females were unreceptive following the first EB treatment, but the mating induced Arc expression. In naïve rats, each subsequent EB injection increased the levels of sexual receptivity. This ramping was not observed in experienced rats, which achieved only a moderate level of sexual receptivity. However, experienced females treated with EB and progesterone were maximally receptive and did not have Arc expression. To test whether the expression of Arc attenuated lordosis, Arc antisense oligodeoxynucleotides (asODN) were microinjected into experienced females' arcuate nuclei. Arc expression was attenuated, and the experienced EB-treated females achieved maximal sexual receptivity. These results demonstrate that Arc expression in the hypothalamus might influence future sexual receptivity and provides evidence of learning in the arcuate nucleus. The loss of Arc results in unrestrained sexual receptivity. © 2014 Wiley Periodicals, Inc. PMID:25088303

Christensen, Amy; Dewing, Phoebe; Micevych, Pavel

2015-01-01

102

Somatic VHL gene deletion and point mutation in MEN 2A-associated pheochromocytoma  

Microsoft Academic Search

Multiple endocrine neoplasia type 2 (MEN 2) is an inherited cancer syndrome that includes pheochromocytoma. Germline mutations in RET are responsible for MEN 2 but the precise pathogenetic mechanisms of tumorigenesis are unknown. We have recently identified possible mechanisms of tumor formation in patients with MEN 2A-related pheochromocytoma. Two of nine tumors investigated, however, did not reveal either of these

Christian A Koch; Steve C Huang; Zhengping Zhuang; Catherine Stolle; Norio Azumi; George P Chrousos; Alexander O Vortmeyer; Karel Pacak

2002-01-01

103

Contrasting Networks for Recognition Memory and Recency Memory Revealed by Immediate-Early Gene Imaging in the Rat  

PubMed Central

The expression of the immediate-early gene c-fos was used to compare networks of activity associated with recency memory (temporal order memory) and recognition memory. In Experiment 1, rats were first familiarized with sets of objects and then given pairs of different, familiar objects to explore. For the recency test group, each object in a pair was separated by 110 min in the time between their previous presentations. For the recency control test, each object in a pair was separated by less than a 1 min between their prior presentations. Temporal discrimination of the objects correlated with c-fos activity in the recency test group in several sites, including area Te2, the perirhinal cortex, lateral entorhinal cortex, as well as the dentate gyrus, hippocampal fields CA3 and CA1. For both the test and control conditions, network models were derived using structural equation modeling. The recency test model emphasized serial connections from the perirhinal cortex to lateral entorhinal cortex and then to the CA1 subfield. The recency control condition involved more parallel pathways, but again highlighted CA1 within the hippocampus. Both models contrasted with those derived from tests of object recognition (Experiment 2), because stimulus novelty was associated with pathways from the perirhinal cortex to lateral entorhinal cortex that then involved both the dentate gyrus (and CA3) and CA1 in parallel. The present findings implicate CA1 for the processing of familiar stimuli, including recency discriminations, while the dentate gyrus and CA3 pathways are recruited when the perirhinal cortex signals novel stimuli. PMID:24933661

2014-01-01

104

Human Cytomegalovirus Major Immediate Early 1 Protein Targets Host Chromosomes by Docking to the Acidic Pocket on the Nucleosome Surface  

PubMed Central

The 72-kDa immediate early 1 (IE1) protein encoded by human cytomegalovirus (hCMV) is a nuclearly localized promiscuous regulator of viral and cellular transcription. IE1 has long been known to associate with host mitotic chromatin, yet the mechanisms underlying this interaction have not been specified. In this study, we identify the cellular chromosome receptor for IE1. We demonstrate that the viral protein targets human nucleosomes by directly binding to core histones in a nucleic acid-independent manner. IE1 exhibits two separable histone-interacting regions with differential binding specificities for H2A-H2B and H3-H4. The H2A-H2B binding region was mapped to an evolutionarily conserved 10-amino-acid motif within the chromatin-tethering domain (CTD) of IE1. Results from experimental approaches combined with molecular modeling indicate that the IE1 CTD adopts a ?-hairpin structure, docking with the acidic pocket formed by H2A-H2B on the nucleosome surface. IE1 binds to the acidic pocket in a way similar to that of the latency-associated nuclear antigen (LANA) of the Kaposi's sarcoma-associated herpesvirus. Consequently, the IE1 and LANA CTDs compete for binding to nucleosome cores and chromatin. Our work elucidates in detail how a key viral regulator is anchored to human chromosomes and identifies the nucleosomal acidic pocket as a joint target of proteins from distantly related viruses. Based on the striking similarities between the IE1 and LANA CTDs and the fact that nucleosome targeting by IE1 is dispensable for productive replication even in “clinical” strains of hCMV, we speculate that the two viral proteins may serve analogous functions during latency of their respective viruses. PMID:24227840

Mucke, Katrin; Paulus, Christina; Bernhardt, Katharina; Gerrer, Katrin; Schon, Kathrin; Fink, Alina; Sauer, Eva-Maria; Asbach-Nitzsche, Alexandra; Harwardt, Thomas; Kieninger, Barbel; Kremer, Werner; Kalbitzer, Hans Robert

2014-01-01

105

Modulation of Thymic Selection by Expression of an Immediate-early Gene, Early Growth Response 1 (Egr-1)  

PubMed Central

The potential involvement of early growth response (Egr)-1, a zinc-finger transcription factor belonging to the immediate-early genes, in positive/negative selection of thymocytes has been implicated by its expression in the population of CD4+CD8+ double positive (DP) cells undergoing selection. To further investigate this possibility, transgenic mice overexpressing Egr-1 in thymocytes were bred with a transgenic mouse line expressing a T cell receptor (TCR) recognizing the H-Y male antigen in the context of H-2b class I major histocompatibility complex (MHC) molecules. In Egr-1/TCR H-Y double-transgenic mice, efficient positive selection of H-Y CD8+ T cells occurred, even in mice on either a nonselecting H-2d background or a ?2-microglobulin (?2m)-deficient background in which the expression of class I MHC heavy chains is extremely low; no positive selection was observed on a Kb?/?Db?/??2m?/? background where class I MHC expression is entirely absent. Similarly, when the Egr-1 transgene was introduced into a class II MHC–restricted TCR transgenic mouse line, Egr-1/TCR double-transgenic mice revealed increased numbers of CD4+ T cells selected by class II MHC, as well as significant numbers of CD8+ T cells selected by class I MHC (for which the transgenic TCR might have weak affinity). Thus, Egr-1 overexpression allows positive selection of thymocytes via TCR–MHC interactions of unusually low avidity, possibly by lowering the threshold of avidity required for positive selection. Supporting this possibility, increased numbers of alloreactive T cells were positively selected in Egr-1 transgenic mice, resulting in a strikingly enhanced response against allo-MHC. These results suggest that expression of Egr-1 and/or its target gene(s) may directly influence the thresholds required for thymocyte selection. PMID:9705953

Miyazaki, Toru; Lemonnier, Francois A.

1998-01-01

106

Topographical evaluation of behavioural phenotype in a line of mice with targeted gene deletion of the D2 dopamine receptor.  

PubMed

The phenotype of spontaneous and dopamine D2-like agonist-induced behaviour was assessed topographically in a line of mice with targeted gene deletion of the D1 receptor. An ethologically-based, rapid time-sampling behavioural check-list technique was used to resolve and quantify all behaviours in the natural repertoire of the mouse. Relative to wildtypes [D2+/+], D2-null [D2-/-] mice evidenced over a 1 h period of initial exploration modest but significant reductions in locomotion, grooming, rearing free and rearing to wall; rearing seated, sniffing, sifting and stillness were not altered. Individual elements of behaviour habituated similarly over a 6 h period for both genotypes. The dose-dependent induction of stereotyped sniffing and ponderous locomotion by the D2-like agonist RU 24213 (0.1-12.5 mg/kg) in wildtypes was essentially absent in D2-null mice. The ethogram of spontaneous behaviour in D2-null mice was characterised by only modest reductions in, and topographical shifts between, certain individual elements of behaviour. Essential abolition of D2-like agonist responsivity in D2-null mice vis-à-vis considerable preservation of spontaneous behavioural topography suggests compensatory processes subsequent to developmental absence of the D2 receptor that are able to sustain function under naturalistic, tonic conditions but not during phasic challenge. PMID:10698004

Clifford, J J; Usiello, A; Vallone, D; Kinsella, A; Borrelli, E; Waddington, J L

2000-01-28

107

Rapid Detection of Haptoglobin Gene Deletion in Alkaline-Denatured Blood by Loop-Mediated Isothermal Amplification Reaction  

PubMed Central

Anhaptoglobinemic patients run the risk of severe anaphylactic transfusion reaction because they produce serum haptoglobin antibodies. Being homozygous for the haptoglobin gene deletion allele (HPdel) is the only known cause of congenital anhaptoglobinemia, and detection of HPdel before transfusion is important to prevent anaphylactic shock. In this study, we developed a loop-mediated isothermal amplification (LAMP)-based screening for HPdel. Optimal primer sets and temperature for LAMP were selected for HPdel and the 5? region of the HP using genomic DNA as a template. Then, the effects of diluent and boiling on LAMP amplification were examined using whole blood as a template. Blood samples diluted 1:100 with 50 mmol/L NaOH without boiling gave optimal results as well as those diluted 1:2 with water followed by boiling. The results from 100 blood samples were fully concordant with those obtained by real-time PCR methods. Detection of the HPdel allele by LAMP using alkaline-denatured blood samples is rapid, simple, accurate, and cost effective, and is readily applicable in various clinical settings because this method requires only basic instruments. In addition, the simple preparation of blood samples using NaOH saves time and effort for various genetic tests. PMID:21497293

Soejima, Mikiko; Egashira, Kouichi; Kawano, Hiroyuki; Kawaguchi, Atsushi; Sagawa, Kimitaka; Koda, Yoshiro

2011-01-01

108

Use of the Meganuclease I-SceI of Saccharomyces cerevisiae to select for gene deletions in actinomycetes  

PubMed Central

The search for new natural products is leading to the isolation of novel actinomycete species, many of which will ultimately require genetic analysis. Some of these isolates will likely exhibit low intrinsic frequencies of homologous recombination and fail to sporulate under laboratory conditions, exacerbating the construction of targeted gene deletions and replacements in genetically uncharacterised strains. To facilitate the genetic manipulation of such species, we have developed an efficient method to generate gene or gene cluster deletions in actinomycetes by homologous recombination that does not introduce any other changes to the targeted organism's genome. We have synthesised a codon optimised I-SceI gene for expression in actinomycetes that results in the production of the yeast I-SceI homing endonuclease which produces double strand breaks at a unique introduced 18 base pair recognition sequence. Only those genomes that undergo homologous recombination survive, providing a powerful selection for recombinants, approximately half of which possess the desired mutant genotype. To demonstrate the efficacy and efficiency of the system, we deleted part of the gene cluster for the red-pigmented undecylprodiginine complex of compounds in Streptomyces coelicolor M1141. We believe that the system we have developed will be broadly applicable across a wide range of actinomycetes. PMID:25403842

Fernández-Martínez, Lorena T.; Bibb, Mervyn J.

2014-01-01

109

Dual Glutathione-S-Transferase-?1 and -?1 Gene Deletions Determine Imatinib Failure in Chronic Myeloid Leukemia.  

PubMed

Approximately 40% of patients with chronic myeloid leukemia (CML) receiving imatinib fail treatment. There is an increased risk of CML in subjects with (i) deletions of genes encoding glutathione-S-transferase (GST)-?1 (GSTT1) and -?1, (GSTM1) and (ii) the GST-?1 (GSTP1) single-nucleotide polymorphism (SNP) Ile105Val (GSTP1*B; rs1695); however, their effects on imatinib treatment outcome are not known. Here, we assess the role of these GSTs in relation to imatinib treatment outcome in 193 CML patients. Deletion of GSTT1 alone, or in combination with deletion of the GSTM1 gene, significantly increased the likelihood of imatinib failure (P = 0.021 and P < 0.001, respectively). The GSTP1*B SNP was not associated with time to imatinib failure. Losses of the GSTT1 and GSTM1 genes are therefore important determinants of imatinib failure in CML. Screening for GSTT1 and GSTM1 gene deletions during diagnosis may identify patients who may be better treated using an alternative therapy. PMID:25188725

Davies, A; Giannoudis, A; Zhang, J E; Austin, G; Wang, L; Holyoake, T L; Müller, M C; Foroni, L; Kottaridis, P D; Pirmohamed, M; Clark, R E

2014-12-01

110

Use of the Meganuclease I-SceI of Saccharomyces cerevisiae to select for gene deletions in actinomycetes.  

PubMed

The search for new natural products is leading to the isolation of novel actinomycete species, many of which will ultimately require genetic analysis. Some of these isolates will likely exhibit low intrinsic frequencies of homologous recombination and fail to sporulate under laboratory conditions, exacerbating the construction of targeted gene deletions and replacements in genetically uncharacterised strains. To facilitate the genetic manipulation of such species, we have developed an efficient method to generate gene or gene cluster deletions in actinomycetes by homologous recombination that does not introduce any other changes to the targeted organism's genome. We have synthesised a codon optimised I-SceI gene for expression in actinomycetes that results in the production of the yeast I-SceI homing endonuclease which produces double strand breaks at a unique introduced 18 base pair recognition sequence. Only those genomes that undergo homologous recombination survive, providing a powerful selection for recombinants, approximately half of which possess the desired mutant genotype. To demonstrate the efficacy and efficiency of the system, we deleted part of the gene cluster for the red-pigmented undecylprodiginine complex of compounds in Streptomyces coelicolor M1141. We believe that the system we have developed will be broadly applicable across a wide range of actinomycetes. PMID:25403842

Fernández-Martínez, Lorena T; Bibb, Mervyn J

2014-01-01

111

A De Novo Whole GCK Gene Deletion Not Detected by Gene Sequencing, in a Boy with Phenotypic GCK Insufficiency.  

PubMed

We report on a boy with diabetes mellitus and a phenotype indicating glucokinase (GCK) insufficiency, but a normal GCK gene examination applying direct gene sequencing. The boy was referred for diabetes mellitus at 7.5 years old. His father, grandfather and great grandfather suffered type 2?DM. Several blood glucose profiles showed (BG) of 6.5-10?mmol/L L. After three years on neutral insulin Hagedorn (NPH) in a dose of 0.3?IU/kg/day haemoglobin A1c (HbA1c) was 6.8%. Treatment was changed to sulphonylurea 750?mg a day, and after 4 years HbA1c was 7%. At that time a multiplex ligation-dependent amplification gene dosage assay (MLPA) was done, revealing a whole GCK gene deletion. Medical treatment was ceased, and after one year HbA1c was 6.8%. This case underscores the importance of a MLPA examination if the phenotype of a patient is strongly indicative of GCK insufficiency and no mutation is identified using direct sequencing. PMID:23074679

Birkebæk, N H; Sørensen, J S; Vikre-Jørgensen, J; Jensen, P K A; Pedersen, O; Hansen, T

2011-01-01

112

trans-activation and autoregulation of gene expression by the immediate-early region 2 gene products of human cytomegalovirus.  

PubMed Central

The major immediate-early (IE) gene region mapping at coordinates 0.71 to 0.74 in the genome of human cytomegalovirus (HCMV) gives rise to a series of overlapping spliced IE mRNAs that are all under the transcriptional control of the complex IE68 promoter-enhancer region. We show here that one of the phosphorylated nuclear proteins encoded by this region behaves as a powerful but nonspecific trans-activator of gene expression. In transient chloramphenicol acetyltransferase (CAT) assay experiments with Vero cells all relatively weak heterologous target promoters tested, including those of herpes simplex virus IE175 and delayed-early genes, adenovirus E3, the enhancerless simian virus 40 early gene, and the human beta interferon gene, were stimulated between 30- and 800-fold by cotransfection with the HindIII C fragment of HCMV (Towne) DNA. In contrast, expression of the homologous HCMV IE68-CAT gene but not SV2-CAT was specifically repressed. Inactivation mapping studies of the effector DNA, together with dose-response comparisons with subclones from the region, revealed that an intact 7.1-kilobase sequence encompassing both the IE1 and IE2 coding regions (exons 1 to 5) in the major IE transcription complex was required for both the nonspecific trans-activation and autoregulatory responses. The IE1 coding region alone (exons 1 to 4) was inactive, but both functions were restored by insertion of the IE2 coding region (exon 5) in the correct orientation downstream from the IE1 coding region. Internal deletions or inserted terminator codons in IE1 (exon 4) still gave efficient trans-activation and autoregulation, whereas the insertion of terminator codons in IE2 (exon 5) abolished both activities. Finally, IE2 (exon 5) sequences only (under the direct transcriptional control of the strong simian CMV IE94 promoter) were still able to specifically down regulate IE68-CAT expression but failed to exhibit trans-activation properties. Therefore, the IE2 gene product(s) of HCMV appear likely to be key control proteins involved in gene regulation during HCMV infection. Images PMID:2831379

Pizzorno, M C; O'Hare, P; Sha, L; LaFemina, R L; Hayward, G S

1988-01-01

113

Differential regulation and transcriptional control of immediate early gene expression in forskolin-treated WEHI7.2 thymoma cells.  

PubMed

Agents that increase intracellular cAMP are frequently growth inhibitory for lymphocytes and induce apoptosis in cortical thymocytes by regulating gene expression. In the present study, immediate early gene expression was examined in WEHI7.2 thymoma cells undergoing cAMP-mediated apoptosis. Temporal differences in c-fos, junB, and inducible cAMP early repressor (ICER) steady-state mRNA levels were observed after forskolin exposure. Maximal induction of c-fos and junB occurred within 1 h, returning to basal levels by 3.5 h. In contrast, a 1.5-h time lag was observed before ICER transcript levels increased, reaching maximal levels after 3.5 h. This rise in expression, correlating with the decrease in c-fos and junB levels, preceded apoptotic DNA fragmentation by 1.5 h. Transient expression of ICER promoter constructs demonstrated that cAMP responsiveness occurred through cAMP-autoregulatory response element (CARE)3/4, two of the four proposed response elements in the ICER promoter. In contrast to the cAMP-responsive cell line JEG-3, CARE1/2 was not functional for cAMP-activated transcription in WEHI7.2 cells. An observed differential binding pattern of WEHI and JEG nuclear extracts to these elements may account for the cell-specific differences in expression patterns. To determine the role of endogenous ICER in regulating gene expression, cells were treated with two sequential doses of forskolin after which ICER and c-fos mRNA levels were measured. The high levels of cAMP-induced ICER expression dramatically reduced a second induction of c-fos. These data suggest that ICER expression may function as an antioncogene to attenuate the expression of certain protooncogenes, thereby preventing transformation and oncogenesis due to continuous overexpression. Moreover, inhibition of growth-stimulatory genes may be required for the activation of the cell death machinery in specific cells. PMID:9544985

Mao, D; Warner, E A; Gurwitch, S A; Dowd, D R

1998-04-01

114

Social contact elicits immediate-early gene expression in dopaminergic cells of the male prairie vole extended olfactory amygdala.  

PubMed

Male prairie voles (Microtus ochrogaster) are a valuable model in which to study the neurobiology of sociality because, unlike most mammals, they pair bond after mating and display paternal behaviors. Research on the regulation of these social behaviors has highlighted dopamine (DA) neurotransmission in both pair bonding and parenting. We recently described large numbers of dopaminergic cells in the male prairie vole principal nucleus of the bed nucleus of the stria terminalis (pBST) and posterodorsal medial amygdala (MeApd), but such cells were very few in number or absent in the non-monogamous species we examined, including meadow voles. This suggests that DA cells in these sites may be important for sociosexual behaviors in male prairie voles. To gain some insight into the function of these DAergic neurons in male prairie voles, we examined expression of the immediate-early genes (IEGs) Fos and Egr-1 in tyrosine hydroxylase (TH)-immunoreactive (TH-ir) cells of the pBST and MeApd after males interacted or not with one of several social stimuli. We found that IEGs were constitutively expressed in some TH-ir neurons under any social condition, but that IEG expression in these cells decreased after a 3.5-h social isolation. Thirty-minute mating bouts (but not 6- or 24-h bouts) that included ejaculation elicited greater IEG expression in TH-ir cells than did non-ejaculatory mating, interactions with a familiar female sibling, or interactions with pups. Furthermore, Fos expression in TH-ir cells was positively correlated with the display of copulatory, but not parental, behaviors. These effects of mating were not found in other DA-rich sites of the forebrain (including the anteroventral periventricular preoptic area, periventricular anterior hypothalamus, zona incerta, and arcuate nucleus). Thus, activity in DAergic cells of the male prairie vole pBST and MeApd is influenced by their social environment, and may be particularly involved in mating and its consequences, including pair bonding. PMID:19524021

Northcutt, K V; Lonstein, J S

2009-09-29

115

Insertion of myeloid-active elements into the human cytomegalovirus major immediate early promoter is not sufficient to drive its activation upon infection of undifferentiated myeloid cells.  

PubMed

The Major Immediate Early Promoter (MIEP) of human cytomegalovirus (HCMV) controls viral Immediate Early (IE) gene expression, which must be activated to initiate productive infection and repressed to establish latency. Regulation of the MIEP is critical for both viral spread and persistence. In addition to the Daxx-mediated intrinsic cellular defense that regulates the MIEP, the cell-type specific balance between cellular activators and repressors of the promoter may help dictate whether viral IE genes will be expressed or silenced. For example, in undifferentiated myeloid cells, transcriptional repressors of the MIEP may outnumber transcriptional activators, leading to promoter silencing and latency establishment. We created a recombinant viral genome in which a myeloid-active promoter replaced part of the MIEP. The viable virus generated failed to express the viral IE genes in an undifferentiated myeloid cell line. These observations have mechanistic implications regarding how viral IE gene expression is regulated during latency. PMID:24314643

Qin, Qingsong; Lee, Song Hee; Liang, Ruibin; Kalejta, Robert F

2014-01-01

116

The hallucinogen d-lysergic acid diethylamide ( d-LSD) induces the immediate-early gene c-Fos in rat forebrain  

Microsoft Academic Search

The hallucinogen d-lysergic acid diethylamide (d-LSD) evokes dramatic somatic and psychological effects. In order to analyze the neural activation induced by this unique psychoactive drug, we tested the hypothesis that expression of the immediate-early gene product c-Fos is induced in specific regions of the rat forebrain by a relatively low, behaviorally active, dose of d-LSD (0.16 mg\\/kg, i.p.); c-Fos protein

Paul S Frankel; Kathryn A Cunningham

2002-01-01

117

ICP27 immediate early gene, glycoprotein K (gK) and DNA helicase homologues of infectious laryngotracheitis virus (gallid herpesvirus 1) SA2 strain  

Microsoft Academic Search

Summary A 4.8 kilobase segment located at the left-terminal in the unique long (UL) region of infectious laryngotracheitis virus (ILTV) SA-2 strain contained three open reading frames (ORFs). The first of 421 amino acids (aa) was located at map units 0.065 to 0.07, and its predicted 48 kiloDaltons (kDa) protein product has significant homology to the immediate early regulatory protein

M. A. Johnson; C. T. Prideaux; K. Kongsuwan; S. G. Tyack; M. Sheppard

1995-01-01

118

Intraseptal administration of (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid induces immediate early gene expression in lateral septal neurons  

Microsoft Academic Search

Prior work has shown that activation of metabotropic glutamate receptors can induce burst firing and a form of NMDA receptor independent long term potentiation in lateral septal slice preparations. To study this phenomenon in vivo we used the expression of immediate early gene products as markers for increased neuronal activity following intraseptal injection of the metabotropic agonist 1S,3R-ACPD. Intraseptal injection

Kevin W. Kaatz; Roger L. Albin

1996-01-01

119

Expression of immediate early genes in the hippocampal formation of the black-capped chickadee ( Poecile atricapillus) during a food-hoarding task  

Microsoft Academic Search

Black-capped chickadees store food in many different locations in their home range and are able to accurately remember these locations. We measured the number of cells immunopositive for three different Immediate Early Gene products (Fra-1, c-Fos and ZENK) to map neuronal activity in the chickadee Hippocampal Formation (HF) during food storing and retrieval. Fra-1-like immunoreactivity is downregulated in the dorsal

Tom V. Smulders; Timothy J. Devoogd

2000-01-01

120

Differential effects of vocalization type, singer and listener on ZENK immediate early gene response in black-capped chickadees ( Poecile atricapillus)  

Microsoft Academic Search

Here we examined immediate early gene (ZENK) induction to vocalizations in the ascending auditory pathway of black-capped chickadees (Poecile atricapillus) to assess the impact that the sex of the producer and perceiver has on ZENK induction. We manipulated the playback by both the vocal type (song\\/call) and sex of producer (male\\/female), and then presented these stimuli classes to either male

M. T. Avey; R. A. Kanyo; E. L. Irwin; C. B. Sturdy

2008-01-01

121

Association of the angiotensin I converting enzyme gene deletion polymorphism with early onset of ESRF in PKD1 adult polycystic kidney disease  

Microsoft Academic Search

Association of the angiotensin I converting enzyme gene deletion polymorphism with early onset of ESRF in PKD1 adult polycystic kidney disease. To determine the effect of the ACE gene insertion\\/deletion (I\\/D) polymorphism, angiotensinogen gene M235T polymorphism and the angiotensin 1 receptor gene A1166C polymorphism on the age of onset of end-stage renal failure (ESRF) in PKD1 adult autosomal-dominant polycystic kidney

Keshwar Baboolal; David Ravine; Joe Daniels; Nigel Williams; Peter Holmans; Gerald A Coles; John D Williams

1997-01-01

122

RNA from an immediate early region of the type 1 herpes simplex virus genome is present in the trigeminal ganglia of latently infected mice  

SciTech Connect

Transcription of the type 1 herpes simplex virus (HSV-1) genome in trigeminal ganglia of latently infected mice was studied using in situ hybridization. Probes representative of each temporal gene class were used to determine the regions of the genome that encode the transcripts present in latently infected cells. Probes encoding HSV-1 sequences of the five immediate early genes and representative early (thymidine kinase), early-late (major capsid protein), and late (glycoprotein C) genes were used in these experiments. Of the probes tested, only those encoding the immediate early gene product infected-cell polypeptide (ICP) 0 hybridized to RNA in latently infected tissues. Probes containing the other immediate early genes (ICP4, ICP22, ICP27, and ICP47) and the representative early, early-late, and late genes did not hybridize. Two probes covering approx. = 30% of the HSV-1 genome and encoding over 20 early and late transcripts also did not hybridize to RNA in latently infected tissues. These results, with probes spanning > 60% of the HSV-1 genome, suggest that transcription of the HSV-1 genome is restricted to one region in latently infected mouse trigeminal ganglia.

Deatly, A.M.; Spivack, J.G.; Lavi, E.; Fraser, N.W.

1987-05-01

123

Identification of kakusei, a Nuclear Non-Coding RNA, as an Immediate Early Gene from the Honeybee, and Its Application for Neuroethological Study  

PubMed Central

The honeybee is a social insect that exhibits various social behaviors. To elucidate the neural basis of honeybee behavior, we detected neural activity in freely-moving honeybee workers using an immediate early gene (IEG) that is expressed in a neural activity-dependent manner. In European honeybees (Apis mellifera), we identified a novel nuclear non-coding RNA, termed kakusei, as the first insect IEG, and revealed the neural activity pattern in foragers. In addition, we isolated a homologue of kakusei, termed Acks, from the Japanese honeybee (Apis cerana), and detected active neurons in workers fighting with the giant hornet. PMID:23443077

Kiya, Taketoshi; Ugajin, Atsushi; Kunieda, Takekazu; Kubo, Takeo

2012-01-01

124

Development of a Double-Crossover Markerless Gene Deletion System in Bifidobacterium longum: Functional Analysis of the ?-Galactosidase Gene for Raffinose Assimilation  

PubMed Central

Functional analysis of Bifidobacterium genes is essential for understanding host-Bifidobacterium interactions with beneficial effects on human health; however, the lack of an effective targeted gene inactivation system in bifidobacteria has prevented the development of functional genomics in this bacterium. Here, we report the development of a markerless gene deletion system involving a double crossover in Bifidobacterium longum. Incompatible plasmid vectors were used to facilitate a second crossover step. The conditional replication vector pBS423-?repA, which lacks the plasmid replication gene repA, was integrated into the target gene by a first crossover event. Subsequently, the replicative plasmid pTBR101-CM, which harbors repA, was introduced into this integrant to facilitate the second crossover step and subsequent elimination of the excised conditional replication vector from the cells by plasmid incompatibility. The proposed system was confirmed to work as expected in B. longum 105-A using the chromosomal full-length ?-galactosidase gene as a target. Markerless gene deletion was tested using the aga gene, which encodes ?-galactosidase, whose substrates include raffinose. Almost all the pTBR101-CM-transformed strains became double-crossover recombinants after subculture, and 4 out of the 270 double-crossover recombinants had lost the ability to assimilate raffinose. Genotype analysis of these strains revealed markerless gene deletion of aga. Carbohydrate assimilation analysis and ?-galactosidase activity measurement were conducted using both the representative mutant and a plasmid-based aga-complemented strain. These functional analyses revealed that aga is the only gene encoding a functional ?-galactosidase enzyme in B. longum 105-A. PMID:22582061

Hirayama, Yosuke; Sakanaka, Mikiyasu; Fukuma, Hidenori; Murayama, Hiroki; Kano, Yasunobu; Yokota, Atsushi

2012-01-01

125

Induction of the plasticity-associated immediate early gene Arc by stress and hallucinogens: role of brain-derived neurotrophic factor.  

PubMed

Exposure to stress and hallucinogens in adulthood evokes persistent alterations in neurocircuitry and emotional behaviour. The structural and functional changes induced by stress and hallucinogen exposure are thought to involve transcriptional alterations in specific effector immediate early genes. The immediate early gene, activity regulated cytoskeletal-associated protein (Arc), is important for both activity and experience dependent plasticity. We sought to examine whether trophic factor signalling through brain-derived neurotrophic factor (BDNF) contributes to the neocortical regulation of Arc mRNA in response to distinct stimuli such as immobilization stress and the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI). Acute exposure to either immobilization stress or DOI induced Arc mRNA levels within the neocortex. BDNF infusion into the neocortex led to a robust up-regulation of local Arc transcript expression. Further, baseline Arc mRNA expression in the neocortex was significantly decreased in inducible BDNF knockout mice with an adult-onset, forebrain specific BDNF loss. The induction of Arc mRNA levels in response to both acute immobilization stress or a single administration of DOI was significantly attenuated in the inducible BDNF knockout mice. Taken together, our results implicate trophic factor signalling through BDNF in the regulation of cortical Arc mRNA expression, both under baseline conditions and following stress and hallucinogen exposure. These findings suggest the possibility that the regulation of Arc expression via BDNF provides a molecular substrate for the structural and synaptic plasticity observed following stimuli such as stress and hallucinogens. PMID:22404904

Benekareddy, Madhurima; Nair, Amrita R; Dias, Brian G; Suri, Deepika; Autry, Anita E; Monteggia, Lisa M; Vaidya, Vidita A

2013-03-01

126

Epstein-Barr virus immediate-early gene product trans-activates gene expression from the human immunodeficiency virus long terminal repeat  

SciTech Connect

Acquired immunodeficiency syndrome patients are frequently coinfected with Epstein-Barr virus (EBV). In this report, the authors demonstrate that an EBV immediate-early gene product, BamHI MLF1, stimulates expression of the bacterial chloramphenicol acetyltransferase (CAT) gene linked to the human immunodeficiency virus (HIV) promoter. The HIV promoter sequences necessary for trans-activation by EBV do not include the tat-responsive sequences. In addition, in contrast to the other herpesvirus trans-activators previously studied, the EBV BamHI MLF1 gene product appears to function in part by a posttranscriptional mechanism, since it increases pHIV-CAT protein activity more than it increases HIV-CAT mRNA. This ability of an EBV gene product to activate HIV gene expression may have biologic consequences in persons coinfected with both viruses.

Kenney, S.; Kamine, J.; Markovitz, D.; Fenrick, R.; Pagano, J.

1988-03-01

127

Variable rate of singing and variable song duration are associated with high immediate early gene expression in two anterior forebrain song nuclei  

PubMed Central

The duration of songs and the intervals between these songs are more variable when wild, adult, free-ranging chipping sparrows sing at dawn than when they sing during the day. The more variable delivery is used to interact with males, and the stereotyped delivery is used to attract females. In captive birds, however, the variability observed at dawn persists during the day. We quantified the expression of an immediate early gene, ZENK, in wild and captive birds and found that the level of song-associated ZENK expression in two song nuclei, Area X and lMAN, was positively related to variability in song duration and intersong interval and could be dissociated from the social context in which the song occurred. Thus, a combination of field and laboratory approaches helped us identify nuclei, context, and behavioral features associated with a change in gene expression thought to be a marker of behavioral variability. PMID:16030143

Liu, Wan-chun; Nottebohm, Fernando

2005-01-01

128

The 6-Aminoquinolone WC5 Inhibits Different Functions of the Immediate-Early 2 (IE2) Protein of Human Cytomegalovirus That Are Essential for Viral Replication.  

PubMed

The human cytomegalovirus (HCMV) immediate-early 2 (IE2) protein is a multifunctional factor essential for viral replication. IE2 modulates both viral and host gene expression, deregulates cell cycle progression, acts as an immunomodulator, and antagonizes cellular antiviral responses. Based on these facts, IE2 has been proposed as an important target for the development of innovative antiviral approaches. We previously identified the 6-aminoquinolone WC5 as a promising inhibitor of HCMV replication, and here, we report the dissection of its mechanism of action against the viral IE2 protein. Using glutathione S-transferase (GST) pulldown assays, mutagenesis, cell-based assays, and electrophoretic mobility shift assays, we demonstrated that WC5 does not interfere with IE2 dimerization, its interaction with TATA-binding protein (TBP), and the expression of a set of cellular genes that are stimulated by IE2. On the contrary, WC5 targets the regulatory activity exerted by IE2 on different responsive viral promoters. Indeed, WC5 blocked the IE2-dependent negative regulation of the major immediate-early promoter by preventing IE2 binding to the crs element. Moreover, WC5 reduced the IE2-dependent transactivation of a series of indicator constructs driven by different portions of the early UL54 gene promoter, and it also inhibited the transactivation of the murine CMV early E1 promoter by the IE3 protein, the murine cytomegalovirus (MCMV) IE2 homolog. In conclusion, our results indicate that the overall anti-HCMV activity of WC5 depends on its ability to specifically interfere with the IE2-dependent regulation of viral promoters. Importantly, our results suggest that this mechanism is conserved in murine CMV, thus paving the way for further preclinical evaluation in an animal model. PMID:25155603

Mercorelli, Beatrice; Luganini, Anna; Muratore, Giulia; Massari, Serena; Terlizzi, Maria Elena; Tabarrini, Oriana; Gribaudo, Giorgio; Palù, Giorgio; Loregian, Arianna

2014-11-01

129

Intranasal application of vasopressin fails to elicit changes in brain immediate early gene expression, neural activity and behavioral performance of rats  

PubMed Central

Intranasal administration has been widely used to investigate effects of the neuropeptides vasopressin and oxytocin on human behaviors and neurological disorders, but exactly what happens when these neuropeptides are administered intranasally is far from clear. In particular, it is not clear whether a physiological significant amount of peptide enters the brain to account for the observed effects. Here, we investigated whether intranasal administration of vasopressin and oxytocin to rats induces expression of the immediate-early gene product Fos in brain areas that are sensitive to centrally administered peptide, whether it alters neuronal activity in the way that centrally administered peptide does, and whether it affects behavior in ways expected from studies of centrally administered peptide. We found that, whereas intracerebroventricular (icv) injection of very low doses of vasopressin or oxytocin increased Fos expression in several distinct brain regions, intranasal administration of large doses of the peptides had no significant effect. In contrast to the effects of vasopressin applied topically to the main olfactory bulb, we saw no changes in the electrical activity of olfactory bulb mitral cells after intranasal vasopressin administration. In addition, vasopressin given intranasally had no significant effects on social recognition or short-term recognition memory. Finally, intranasal infusions of vasopressin had no significant effects on the parameters monitored on the elevated plus maze, a rodent model of anxiety. Our data in rats suggest that, after intranasal administration, significant amounts of vasopressin and oxytocin do not reach areas in the brain at levels sufficient to change immediate early gene expression, neural activity or behavior in the ways described for central administration of the peptides. PMID:23656518

Ludwig, Mike; Tobin, Vicky A.; Callahan, Michael F.; Papadaki, Eirini; Becker, Axel; Engelmann, Mario; Leng, Gareth

2013-01-01

130

In vivo imaging of immediate early gene expression reveals layer-specific memory traces in the mammalian brain  

PubMed Central

The dynamic processes of formatting long-term memory traces in the cortex are poorly understood. The investigation of these processes requires measurements of task-evoked neuronal activities from large numbers of neurons over many days. Here, we present a two-photon imaging-based system to track event–related neuronal activity in thousands of neurons through the quantitative measurement of EGFP proteins expressed under the control of the EGR1 gene promoter. A recognition algorithm was developed to detect GFP-positive neurons in multiple cortical volumes and thereby to allow the reproducible tracking of 4,000 neurons in each volume for 2 mo. The analysis revealed a context-specific response in sparse layer II neurons. The context-evoked response gradually increased during several days of training and was maintained 1 mo later. The formed traces were specifically activated by the training context and were linearly correlated with the behavioral response. Neuronal assemblies that responded to specific contexts were largely separated, indicating the sparse coding of memory-related traces in the layer II cortical circuit. PMID:24550309

Xie, Hong; Liu, Yu; Zhu, Youzhi; Ding, Xinlu; Yang, Yuhao; Guan, Ji-Song

2014-01-01

131

A novel contiguous gene deletion of AVPR2 and ARHGAP4 genes in male dizygotic twins with nephrogenic diabetes insipidus and intellectual disability.  

PubMed

The clinical features of loss of ARHGAP4 function remain unclear despite several reports of different patterns of deletions inactivating different functional regions of the protein. The protein encoded by ARHGAP4 is thought to function as a Rho GTPase activating protein. Characterization of the genetic defect causing X-linked nephrogenic diabetes insipidus (NDI) and intellectual disability in two dizygotic twin brothers revealed a novel contiguous deletion of 17,905?bp encompassing the entire AVPR2 gene and extending into intron 7 of the ARHGAP4 gene. Examination of their mother showed that she was a carrier of this deletion. An attempt was made to distinguish the putative clinical signs of an ARHGAP4 deletion from the well-defined phenotype of X-linked NDI caused by an AVPR2 gene deletion. By reviewing all characterized deletions encompassing ARHGAP4, we reconsider the potential role of ARHGAP4 in cognition. PMID:22965914

Huang, Lingli; Poke, Gemma; Gecz, Jozef; Gibson, Kate

2012-10-01

132

Roles of mechano-sensitive ion channels, cytoskeleton, and contractile activity in stretch-induced immediate-early gene expression and hypertrophy of cardiac myocytes.  

PubMed Central

Mechanical loading of cardiac and skeletal muscles in vivo and in vitro causes rapid activation of a number of immediate-early (IE) genes and hypertrophy of muscle cells. However, little is known as to how muscle cells sense mechanical load and transduce it into intracellular signals of gene regulation. We examined roles of putative cellular mechanotransducers, mechanosensitive ion channels, the cytoskeleton, and contractile activity in stretch-induced hypertrophy of cardiac myocytes grown on a deformable silicone sheet. Using the patch-clamp technique, we found a single class of stretch-activated cation channel that was completely blocked by gadolinium (Gd3+). Inhibition of this channel by Gd3+ did not affect either the stretch-induced expression of IE genes or the increase in protein synthesis. Neither disruption of microtubules with colchicine nor that of actin microfilaments by cytochalasin D prevented the stretch-induced IE gene expression and increase in protein synthesis. Arresting contractile activity of myocytes by high K+, tetrodotoxin, or Ba2+ did not affect the stretch-induced IE gene expression. Tetrodotoxin-arrested myocytes could increase protein synthesis in response to stretch. These results suggest that Gd(3+)-sensitive ion channels, microtubules, microfilaments, and contractile activity may not be necessary for transduction of mechanical stretch into the IE gene expression and hypertrophy. The stimulus of membrane stretch may be transmitted to the cell nucleus through some mechanisms other than electrical or direct mechanical transduction in cardiac myocytes. Images PMID:1384064

Sadoshima, J; Takahashi, T; Jahn, L; Izumo, S

1992-01-01

133

Down-regulation of immediate early gene egr-1 expression in rat C6 glioma cells by short-term exposure to high salt culture medium.  

PubMed

Influence of high salt culture conditions on the expression of immediate early gene egr-1 in rat C6 glioma cells was investigated by measuring both Egr-1 mRNA and protein levels in the cells exposed to the medium containing high concentrations of NaCl. The exposure to high salt medium reduced Egr-1 mRNA and protein levels, while Egr-1 mRNA levels were not altered by the medium containing either sucrose or glycerol. Veratridine and monensin also reduced Egr-1 mRNA levels, similar in extent to that induced by high salt medium. Imaging analysis indicated that the exposure to high salt medium induced the elevation of Na+ levels within the cells. These results indicate that neither hyperosmotic pressure nor ionic strength of high salt medium contribute to the reduction of Egr-1 expression, and suggest that the elevation of intracellular Na+ concentration is closely associated with the down-regulation of egr-1 gene expression. PMID:15905107

Morita, Kyoji; Arimochi, Hideki; Yoshida, Shigeru

2005-04-01

134

Interaction of HTLV-1 Tax1 with p67SRF causes the aberrant induction of cellular immediate early genes through CArG boxes.  

PubMed

Tax1 of human T-cell leukemia virus type 1 (HTLV-1) is a transcriptional activator for viral gene expression and is also a transforming protein through inducing the expression of several cellular genes under the control of mitogenic signals. We identified the CArG boxes as a Tax1-responsive cis-acting element for the cellular immediate early genes c-fos, egr-1, and egr-2. Using a chimeric protein consisting of the CArG-binding factor p67SRF and the heterologous DNA-binding domain of a yeast transcription factor GAL4, we demonstrated that Tax1 activates the transcriptional activity of p67SRF through the GAL4-binding site. The carboxy-terminal half of p67SRF, which lacks domains for DNA-binding, dimerization, and ternary complex formation with p62TCF, was sufficient for the activation by Tax1. Tax1 produced in Escherichia coli bound p67SRF in vitro. The complex formation in vivo was also indicated by the finding that the acidic activation domain of VP16, by fusion to p67SRF, can complement the transcriptional activation function of a mutant Tax1 in trans. Thus, Tax1 activates CArG-mediated transcription without mitogenic signals through interaction with a CArG-binding factor, p67SRF. This must be one of the primary steps by which Tax1 causes aberration in growth control of the infected cells. PMID:1427072

Fujii, M; Tsuchiya, H; Chuhjo, T; Akizawa, T; Seiki, M

1992-11-01

135

Effect of hypergravity on expression of the immediate early gene, c-fos, in central nervous system of medaka (Oryzias latipes)  

NASA Astrophysics Data System (ADS)

Immediate-early genes serve as useful neurobiological tools for mapping brain activity induced by a sensory stimulation. In this study, we have examined brain activity related to gravity perception of medaka (Oryzias latipes) by use of c-fos. The gene, which is homologous to the c-fos genes of other vertebrates, was identified in medaka. Functionally important domains are highly conserved among all the vertebrate species analyzed. Intraperitoneal administration of kainic acid transiently induced the c-fos mRNAs in medaka brains. The results indicate that the expression of c-fos can be utilized as a suitable anatomical marker for the increased neural activities in the central nervous system of medaka. Fish were continuously exposed to 3 g hypergravity by centrifugation. Investigation of c-fos mRNA expression indicated that c-fos mRNA significantly increased 30 min after a start of 3 g exposure. The distribution of its transcripts within the brains was analyzed by an in situ hybridization method. The 3-g treated medakas displayed c-fos positive cells in their brainstem regions, which are related to vestibular function, such as torus semicircularis, nucleus tangentialis, posterior octavu nucleus, and inferior olive. Our results established a method to follow the effect of gravity stimulation, which can be used to investigate gravity perception.

Sayaka, Shimomura-Umemura; Ijiri, Kenichi

2006-01-01

136

Differential effects of vocalization type, singer and listener on ZENK immediate early gene response in black-capped chickadees (Poecile atricapillus).  

PubMed

Here we examined immediate early gene (ZENK) induction to vocalizations in the ascending auditory pathway of black-capped chickadees (Poecile atricapillus) to assess the impact that the sex of the producer and perceiver has on ZENK induction. We manipulated the playback by both the vocal type (song/call) and sex of producer (male/female), and then presented these stimuli classes to either male or female black-capped chickadees. Neural response to the stimulus was quantified by the amount of protein of the IEG ZENK (also known as zif-268, egr-1, ngf-Ia and krox-24) in the caudal medial nidopallium (NCM) and caudomedial mesopallium (CMM). Overall, there was more ZENK induction in CMM and the dorsal parts of the caudal medial nidopallium (NCMd) than in the ventral parts of the caudal medial nidopallium (NCMv) and males had more ZENK induction than females. CMM had the most complex responding of ZENK induction to stimuli such that vocalization type, sex of producer, and sex of perceiver all affected ZENK induction. The silence controls had the least ZENK induction compared to any other group. PMID:18077008

Avey, M T; Kanyo, R A; Irwin, E L; Sturdy, C B

2008-03-17

137

ATM regulates NF-?B-dependent immediate-early genes via RelA Ser 276 phosphorylation coupled to CDK9 promoter recruitment  

PubMed Central

Ataxia-telangiectasia mutated (ATM), a member of the phosphatidylinositol 3 kinase-like kinase family, is a master regulator of the double strand DNA break-repair pathway after genotoxic stress. Here, we found ATM serves as an essential regulator of TNF-induced NF-kB pathway. We observed that TNF exposure of cells rapidly induced DNA double strand breaks and activates ATM. TNF-induced ROS promote nuclear IKK? association with ubiquitin and its complex formation with ATM for nuclear export. Activated cytoplasmic ATM is involved in the selective recruitment of the E3-ubiquitin ligase ?-TrCP to phospho-I?B? proteosomal degradation. Importantly, ATM binds and activates the catalytic subunit of protein kinase A (PKAc), ribosmal S6 kinase that controls RelA Ser 276 phosphorylation. In ATM knockdown cells, TNF-induced RelA Ser 276 phosphorylation is significantly decreased. We further observed decreased binding and recruitment of the transcriptional elongation complex containing cyclin dependent kinase-9 (CDK9; a kinase necessary for triggering transcriptional elongation) to promoters of NF-?B-dependent immediate-early cytokine genes, in ATM knockdown cells. We conclude that ATM is a nuclear damage-response signal modulator of TNF-induced NF-?B activation that plays a key scaffolding role in I?B? degradation and RelA Ser 276 phosphorylation. Our study provides a mechanistic explanation of decreased innate immune response associated with A-T mutation. PMID:24957606

Fang, Ling; Choudhary, Sanjeev; Zhao, Yingxin; Edeh, Chukwudi B; Yang, Chunying; Boldogh, Istvan; Brasier, Allan R.

2014-01-01

138

The Herpes Simplex Virus Immediate-Early Ubiquitin Ligase ICP0 Induces Degradation of the ICP0 Repressor Protein E2FBP1 ?  

PubMed Central

E2FBP1/hDRIL1, a DNA-binding A/T-rich interaction domain (ARID) family transcription factor, is expressed ubiquitously in human tissues and plays an essential role in maintaining the proliferation potential of passage-limited human fibroblasts by dissociating promyelocytic leukemia nuclear bodies (PML-NBs). This effect on PML-NBs is similar to that of viral immediate-early gene products, such as infected cellular protein 0 (ICP0) from human herpes simplex virus 1 (HSV-1), which also disrupts PML-NBs to override the intrinsic cellular defense. Here we report that E2FBP1 inhibits accumulation of ICP0 RNA and, at the same time, is degraded via ICP0's herpes ubiquitin ligase 2 (HUL-2) activity upon HSV-1 infection. These reciprocal regulatory roles of ICP0 and E2FBP1 are linked in an ARID-dependent fashion. Our results suggest that E2FBP1 functions as an intrinsic cellular defense factor in spite of its PML-NB dissociation function. PMID:21248039

Fukuyo, Yayoi; Horikoshi, Nobuo; Ishov, Alexander M.; Silverstein, Saul J.; Nakajima, Takuma

2011-01-01

139

Herpes Simplex Virus Immediate-Early ICP0 Protein Inhibits Toll-Like Receptor 2-Dependent Inflammatory Responses and NF-?B Signaling ?  

PubMed Central

The discovery of the Toll-like receptors (TLRs) and their importance in the regulation of host responses to infection raised attention to the complex interplay between viral gene products and the host innate immune responses in determining the outcome of virus infection. Robust inflammatory cytokine responses are observed in herpes simplex virus (HSV)-infected animals and cells. Our studies have demonstrated that Toll-like receptor 2 (TLR2) activation by HSV results in NF-?B activation with concomitant inflammatory cytokine production and that TLR2 activation plays a critical role in HSV-induced pathology and mortality. Here we demonstrate that the HSV-1 immediate-early ICP0 protein reduces the TLR2-mediated inflammatory response to HSV 1 (HSV-1) infection. Expression of ICP0 alone is sufficient to block TLR2-driven responses to both viral and nonviral ligands at or downstream of the MyD88 adaptor and upstream of p65. ICP0 alone can also reduce the levels of MyD88 and Mal (TIRAP). In HSV-infected cells, the E3 ligase function of ICP0 and cellular proteasomal activity are required for the inhibitory activity. Our results argue for a model in which ICP0 promotes the degradation of TLR adaptor molecules and inhibition of the inflammatory response, much as it inhibits the interferon response by sequestration and degradation of interferon regulatory factor 3 (IRF-3). PMID:20686034

van Lint, Allison L.; Murawski, Matthew R.; Goodbody, Rory E.; Severa, Martina; Fitzgerald, Katherine A.; Finberg, Robert W.; Knipe, David M.; Kurt-Jones, Evelyn A.

2010-01-01

140

Regulation of the immediate-early genes of white spot syndrome virus by Litopenaeus vannamei kruppel-like factor (LvKLF).  

PubMed

Kruppel-like factors (KLFs) belong to a subclass of Cys2/His2 zinc-finger DNA-binding proteins, and act as important regulators with diverse roles in cell growth, proliferation, differentiation, apoptosis and tumorigenesis. Our previous research showed that PmKLF from Penaeus monodon is crucial for white spot syndrome virus (WSSV) infection, yet the mechanisms by which PmKLF influences WSSV infection remain unclear. This study cloned KLF from Litopenaeus vannamei (LvKLF), which had 93% similarity with PmKLF. LvKLF formed a dimer via the C-terminal zinc-finger motif. Knockdown of LvKLF expression by dsRNA injection in WSSV-challenged shrimps was found to significantly inhibit the transcription of two important immediate-early (IE) genes, IE1 and WSSV304, and also reduced WSSV copy numbers. Moreover, reporter assays revealed that the promoter activities of these two WSSV IE genes were substantially enhanced by LvKLF. Mutations introduced in the promoter sequences of IE1 and WSSV304 were shown to abolish LvKLF activation of promoter activities; and an electrophoretic mobility shift assay demonstrated that LvKLF binds to putative KLF-response elements (KRE) in the promoters. Taken together, these results indicate that LvKLF transcriptional regulation of key IE genes is critical to WSSV replication. PMID:24881625

Huang, Ping-Han; Lu, Shao-Chia; Yang, Shu-Han; Cai, Pei-Si; Lo, Chu-Fang; Chang, Li-Kwan

2014-10-01

141

Expression of immediate early genes in the hippocampal formation of the black-capped chickadee (Poecile atricapillus) during a food-hoarding task.  

PubMed

Black-capped chickadees store food in many different locations in their home range and are able to accurately remember these locations. We measured the number of cells immunopositive for three different Immediate Early Gene products (Fra-1, c-Fos and ZENK) to map neuronal activity in the chickadee Hippocampal Formation (HF) during food storing and retrieval. Fra-1-like immunoreactivity is downregulated in the dorsal HF of both storing and retrieving chickadees compared to controls. In retrieving birds, the number of Fos-like immunoreactive neurons relates to the number of items remembered, while the number of ZENK-like immunoreactive neurons in the HF may be related to the accuracy of cache retrieval. These results imply that the brain might process complex information by recruiting more neurons into the network of active neurons. Thus, our results could help explain why food-hoarding birds have more HF neurons than non-hoarders, and why this number increases in autumn when large numbers of food items are cached. PMID:10996045

Smulders, T V; DeVoogd, T J

2000-09-01

142

Vasopressin up-regulates the expression of growth-related immediate-early genes via two distinct EGF receptor transactivation pathways  

PubMed Central

Activation of V1a receptor triggers the expression of growth-related immediate-early genes (IEGs), including c-Fos and Egr-1. Here we found that pre-treatment of rat vascular smooth muscle A-10 cell line with the EGF receptor inhibitor AG1478 or the over-expression of an EGFR dominant negative mutant (HEBCD533) blocked the vasopressin-induced expression of IEGs, suggesting that activation of these early genes mediated by V1a receptor is via transactivation of the EGF receptor. Importantly, the inhibition of the metalloproteinases, which catalyzed the shedding of the EGF receptor agonist HB-EGF, selectively blocked the vasopressin-induced expression c-Fos. On the other hand, the inhibition of c-Src selectively blocked the vasopressin-induced expression of Egr-1. Interestingly, in contrast to the expression of c-Fos, the expression of Egr-1 was mediated via the Ras/MEK/MAPK-dependent signalling pathway. Vasopressin-triggered expression of both genes required the release of intracellular calcium, activation of PKC and ?-arrestin 2. These findings demonstrated that vasopressin up-regulated the expression of c-Fos and Erg-1 via transactivation of two distinct EGF receptor-dependent signalling pathways. PMID:18571897

Fuentes, Lida Q.; Reyes, Carlos E.; Sarmiento, Jose M.; Villanueva, Carolina I.; Figueroa, Carlos D.; Navarro, Javier; Gonzalez, Carlos B.

2008-01-01

143

Molecular analysis of Rh transcripts and polypeptides from individuals expressing the DVI variant phenotype: an RHD gene deletion event does not generate All DVIccEe phenotypes.  

PubMed

The D antigen is a mosaic comprising at least 30 epitopes. Partial Rh D phenotypes occur when there is absence of one or more of these epitopes, with the remainder expressed. The DVI phenotype is the most common of the partial D phenotypes, lacking most D antigen epitopes (ep D) (epD1, 2, 5-8 using the 9-epitope model or epD 1-4, 7-22, 26-29 using the 30-epitope model). DVI mothers may become immunized by transfusion with D-positive blood (if typed as D-positive using polyclonal typing reagents) or by fetuses which have all of the D antigen. This situation can give rise to severe hemolytic disease of the newborn (HDN). The molecular basis of the DVI phenotype has previously been proposed to occur by two different genetic mechanisms, one (in individuals of DVICcee phenotype) where a gene conversion event generates a hybrid RHD-RHCE-RHD gene; the second (in individuals of DVIccEe phenotype) was proposed to be caused by a partial RHD gene deletion. We present evidence that in four DVICcee phenotypes studied, this phenotype is not generated by a partial RHD gene deletion, but occurs by a similar mechanism to the DVICcee phenotypes. In two individuals we have found hybrid RHD-RHCE-RHD transcripts in both DVICe and DVIcE haplotypes. These differ in that the DVICe transcripts are derived from an RHD gene where exons 4-6 have been replaced with RHCE equivalents (encoding Ala226); the DVIcE transcripts are derived from an RHD gene where exons 4 and 5 are replaced by RHCE equivalents (encoding Pro226). We provide direct evidence that Rh DVI polypeptides are expressed at the erythrocyte surface as full-length polypeptide products. We have used immunoprecipitation experiments using anti-D reactive with DVI erythrocytes followed by immunoblotting the immune complexes with rabbit sera immunoreactive to the fourth external and C-terminal domains of all Rh polypeptides. Our results illustrate that these domains are present on all Rh DVI proteins studied, and suggest that Rh DVI polypeptide species studied here exist as full-length Rh proteins. PMID:9057663

Avent, N D; Liu, W; Jones, J W; Scott, M L; Voak, D; Pisacka, M; Watt, J; Fletcher, A

1997-03-01

144

Potentially harmful advantage to athletes: a putative connection between UGT2B17 gene deletion polymorphism and renal disorders with prolonged use of anabolic androgenic steroids  

PubMed Central

Background and objective With prolonged use of anabolic androgenic steroids (AAS), occasional incidents of renal disorders have been observed. Independently, it has also been established that there are considerable inter-individual and inter-ethnic differences, in particular with reference to the uridine diphosphate-glucuronosyltransferase 2B17 (UGT2B17) gene, in metabolising these compounds. This report postulates the association of deletion polymorphism in the UGT2B17 gene with the occurrence of renal disorders on chronic exposure to AAS. Presentation of the hypothesis The major deactivation and elimination pathway of AASs is through glucuronide conjugation, chiefly catalyzed by the UGT2B17 enzyme, followed by excretion in urine. Excretion of steroids is affected in individuals with a deletion mutation in the UGT2B17 gene. We hypothesize that UGT2B17 deficient individuals are more vulnerable to developing renal disorders with prolonged use of AAS owing to increases in body mass index and possible direct toxic effects of steroids on the kidneys. Elevated serum levels of biologically active steroids due to inadequate elimination can lead to prolonged muscle build up. An increase in body mass index may cause renal injuries due to sustained elevated glomerular pressure and flow rate. Testing the hypothesis In the absence of controlled clinical trials in humans, observational studies can be carried out. Real time PCR with allelic discrimination should be employed to examine the prevalence of different UGT2B17 genotypes in patients with impaired renal function and AAS abuse. In individuals with the UGT2B17 deletion polymorphism, blood tests, biofluid analyses, urinalysis, and hair analyses following the administration of an anabolic steroid can be used to determine the fate of the substance once in the body. Implications of the hypothesis If the hypothesis is upheld, anabolic steroid users with a deletion mutation in the UGT2B17 gene may be exposed to an increased risk of developing renal disorders. In the current detecting - sanctioning anti-doping system, athletes motivated by the potential to evade detection owing to their unique genetic make-up could subject themselves to a serious health consequence. More research on AAS metabolism in the presence of UGT2B17 gene deletion is required. Benefit - harm evaluations in therapeutic use of anabolic steroids should also consider this potential link between UGT2B17 gene deletion polymorphism and renal disorders. PMID:20429943

2010-01-01

145

Chronic co-administration of nicotine and methamphetamine causes differential expression of immediate early genes in the dorsal striatum and nucleus accumbens  

PubMed Central

Nicotine and methamphetamine (METH) cause addiction by triggering neuroplastic changes in brain reward pathways though they each engage distinct molecular targets (nicotine receptors and dopamine transporters respectively). Addiction to both drugs is very prevalent, with the vast majority of METH users being also smokers of cigarettes. This co-morbid occurrence thus raised questions about potential synergistic rewarding effects of the drugs. However, few studies have investigated the chronic neurobiological changes associated with co-morbid nicotine and METH addiction. Here we investigated the effects of these two drugs alone and in combination on the expression of several immediate early genes (IEGs) that are sensitive to drug exposures. Chronic exposure to either nicotine or METH caused significant decreases in the expression of fosb, fra1, and fra2 in the nucleus accumbens (NAc) but not in the dorsal striatum whereas the drug combination increased fra2 expression in both structures. Except for junB mRNA levels that were decreased by the three drug treatments in the NAc, there were no significant changes in the Jun family members. Of the Egr family members, NAc egr2 expression was decreased after nicotine and the drug combination whereas NAc egr3 was decreased after METH and the drug combination. The drug combination also increased striatal egr3 expression. The Nr4a family member, nr4a2/nurr1, showed increased striatal expression after all 3 drug treatments, while striatal nr4a3/nor-1 expression was increased by the drug combination whereas NAc nr4a1/nurr77 was decreased by nicotine and the drug combination. These observations suggest that, when given in combination, the two drugs exert distinct effects on the expression of IEGs in dopaminergic projection areas from those elicited by each drug alone. The significance of these changes in IEG expression and in other molecular markers in fostering co-morbid METH and nicotine abuse needs to be further evaluated. PMID:23562942

Saint-Preux, Fabienne; Bores, Lorena Rodriguez; Tulloch, Ingrid; Ladenheim, Bruce; Kim, Ronald; Thanos, Panayotis K.; Volkow, Nora D.; Cadet, Jean Lud

2013-01-01

146

Chronic co-administration of nicotine and methamphetamine causes differential expression of immediate early genes in the dorsal striatum and nucleus accumbens of rats.  

PubMed

Nicotine and methamphetamine (METH) cause addiction by triggering neuroplastic changes in brain reward pathways though they each engage distinct molecular targets (nicotine receptors and dopamine transporters respectively). Addiction to both drugs is very prevalent, with the vast majority of METH users also being smokers of cigarettes. This co-morbid occurrence thus raised questions about potential synergistic rewarding effects of the drugs. However, few studies have investigated the chronic neurobiological changes associated with co-morbid nicotine and METH addiction. Here we investigated the effects of these two drugs alone and in combination on the expression of several immediate early genes (IEGs) that are sensitive to drug exposures. Chronic exposure to either nicotine or METH caused significant decreases in the expression of fosb, fra1, and fra2 in the nucleus accumbens (NAc) but not in the dorsal striatum whereas the drug combination increased fra2 expression in both structures. Except for junB mRNA levels that were decreased by the three drug treatments in the NAc, there were no significant changes in the Jun family members. Of the Egr family members, NAc egr2 expression was decreased after nicotine and the drug combination whereas NAc egr3 was decreased after METH and the drug combination. The drug combination also increased striatal egr3 expression. The Nr4a family member, nr4a2/nurr1, showed increased striatal expression after all three drug treatments, while striatal nr4a3/nor-1 expression was increased by the drug combination whereas NAc nr4a1/nurr77 was decreased by nicotine and the drug combination. These observations suggest that, when given in combination, the two drugs exert distinct effects on the expression of IEGs in dopaminergic projection areas from those elicited by each drug alone. The significance of these changes in IEG expression and in other molecular markers in fostering co-morbid METH and nicotine abuse needs to be further evaluated. PMID:23562942

Saint-Preux, F; Bores, L R; Tulloch, I; Ladenheim, B; Kim, R; Thanos, P K; Volkow, N D; Cadet, J L

2013-07-23

147

The Murine Gammaherpesvirus Immediate-Early Rta Synergizes with IRF4, Targeting Expression of the Viral M1 Superantigen to Plasma Cells  

PubMed Central

MHV68 is a murine gammaherpesvirus that infects laboratory mice and thus provides a tractable small animal model for characterizing critical aspects of gammaherpesvirus pathogenesis. Having evolved with their natural host, herpesviruses encode numerous gene products that are involved in modulating host immune responses to facilitate the establishment and maintenance of lifelong chronic infection. One such protein, MHV68 M1, is a secreted protein that has no known homologs, but has been shown to play a critical role in controlling virus reactivation from latently infected macrophages. We have previous demonstrated that M1 drives the activation and expansion of V?4+ CD8+ T cells, which are thought to be involved in controlling MHV68 reactivation through the secretion of interferon gamma. The mechanism of action and regulation of M1 expression are poorly understood. To gain insights into the function of M1, we set out to evaluate the site of expression and transcriptional regulation of the M1 gene. Here, using a recombinant virus expressing a fluorescent protein driven by the M1 gene promoter, we identify plasma cells as the major cell type expressing M1 at the peak of infection in the spleen. In addition, we show that M1 gene transcription is regulated by both the essential viral immediate-early transcriptional activator Rta and cellular interferon regulatory factor 4 (IRF4), which together potently synergize to drive M1 gene expression. Finally, we show that IRF4, a cellular transcription factor essential for plasma cell differentiation, can directly interact with Rta. The latter observation raises the possibility that the interaction of Rta and IRF4 may be involved in regulating a number of viral and cellular genes during MHV68 reactivation linked to plasma cell differentiation. PMID:25101696

O'Flaherty, Brigid M.; Soni, Tanushree; Wakeman, Brian S.; Speck, Samuel H.

2014-01-01

148

SUMO-conjugating enzyme E2 UBC9 mediates viral immediate-early protein SUMOylation in crayfish to facilitate reproduction of white spot syndrome virus.  

PubMed

Successful viruses have evolved superior strategies to escape host defenses or exploit host biological pathways. Most of the viral immediate-early (ie) genes are essential for viral infection and depend solely on host proteins; however, the molecular mechanisms are poorly understood. In this study, we focused on the modification of viral IE proteins by the crayfish small ubiquitin-related modifier (SUMO) and investigated the role of SUMOylation during the viral life cycle. SUMO and SUMO ubiquitin-conjugating enzyme 9 (UBC9) involved in SUMOylation were identified in red swamp crayfish (Procambarus clarkii). Both SUMO and UBC9 were upregulated in crayfish challenged with white spot syndrome virus (WSSV). Replication of WSSV genes increased in crayfish injected with recombinant SUMO or UBC9, but injection of mutant SUMO or UBC9 protein had no effect. Subsequently, we analyzed the mechanism by which crayfish SUMOylation facilitates WSSV replication. Crayfish UBC9 bound to all three WSSV IE proteins tested, and one of these IE proteins (WSV051) was covalently modified by SUMO in vitro. The expression of viral ie genes was affected and that of late genes was significantly inhibited in UBC9-silenced or SUMO-silenced crayfish, and the inhibition effect was rescued by injection of recombinant SUMO or UBC9. The results of this study demonstrate that viral IE proteins can be modified by crayfish SUMOylation, prompt the expression of viral genes, and ultimately benefit WSSV replication. Understanding of the mechanisms by which viruses exploit host components will greatly improve our knowledge of the virus-host "arms race" and contribute to the development of novel methods against virulent viruses. PMID:23097446

Chen, An-Jing; Gao, Lu; Wang, Xian-Wei; Zhao, Xiao-Fan; Wang, Jin-Xing

2013-01-01

149

Isolation Rearing Impairs Wound Healing and is Associated with Increased Locomotion and Decreased Immediate Early Gene Expression in the Medial Prefrontal Cortex of Juvenile Rats  

PubMed Central

In addition to its maladaptive effects on psychiatric function, psychosocial deprivation impairs recovery from physical illness. Previously, we found that psychosocial deprivation, modeled by isolation rearing, depressed immediate early gene (IEG) expression in the medial prefrontal cortex (mPFC) and increased locomotion in the open field test (Levine, Youngs et al. 2007). In the present study, we examined whether similar changes in behavior and gene expression are associated with the maladaptive effects of psychosocial deprivation on physical injury healing. After weaning, anesthetized rats were subjected to a 20% total body surface area third degree burn injury and were subsequently either group or isolation reared. After four weeks of either isolation or group rearing (a period that encompasses rodent childhood and early adolescence), rats were sacrificed, and their healing and gene expression in the mPFC were assessed. Locomotion in the open field test was examined at 3 weeks post burn injury. We found that: 1) gross wound healing was significantly impaired in isolation reared rats compared to group reared rats, 2) locomotion was increased and IEG expression was suppressed for isolation reared rats during burn injury healing, 3) the decreased activity in the open field and increased IEG expression was greater for burn injury healing group reared rats than for uninjured group reared rats, 4) the degree of hyperactivity and IEG suppression was relatively similar between isolation reared rats during burn injury compared to uninjured isolation reared rats, 5) behavioral hyperactivity to novelty (the open field test) along with IEG suppression may constitute a detectable biomarker of isolation rearing during traumatic physical injury. Implications of the findings for understanding, assessing, and treating the maladaptive effects of psychosocial deprivation on physical healing during childhood are discussed. PMID:18063315

Levine, John B.; Leeder, Avrum D.; Parekkadan, Biju; Berdichevsky, Yevgeny; Rauch, Scott L.; Smoller, Jordan W.; Konradi, Christine; Berthiaume, Francois; Yarmush, Martin L.

2014-01-01

150

Contrasting role of phospholipase C-{gamma}1 in the expression of immediate early genes induced by epidermal or platelet-derived growth factors  

SciTech Connect

While significant progress has been achieved in identifying the signal transduction elements that operate downstream of activated receptor tyrosine kinases, it remains unclear how different receptors utilize these signaling elements to achieve a common response. This study compares the capacity of epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) to elicit the induction of immediate early gene (IEG) mRNAs in the presence or absence of phospholipase C-{gamma}1 (PLC-{gamma}1). The results show that while PDGF induction of nearly all IEG mRNAs is abrogated in plcg1 null cells, EGF induction of the same genes is variable in the null cells and exhibits three distinct responses. Five IEG mRNAs (Nup475, Cyr61, TF, Gly, TS7) are completely inducible by EGF in the presence or absence of PLC-{gamma}1, while three others (JE, KC, FIC) exhibit a stringent requirement for the presence of PLC-{gamma}1. The third type of response is exhibited by c-fos and COX-2. While these mRNAs are completely induced by EGF in the absence of PLC-{gamma}1, the time course of their accumulation is significantly delayed. No IEG was identified as completely inducible by EGF and PDGF in the absence of PLC-{gamma}1. Electrophoretic mobility shift assays (EMSA) demonstrate that PLC-{gamma}1 is necessary for nuclear extracts from PDGF-treated cells, but not EGF-treated cells, to interact with probes for AP-1 or NF-{kappa}B.

Liao Hongjun [Department of Biochemistry, Vanderbilt University School of Medicine, 606 Light Hall, Nashville, TN 37232-0146 (United States); Santos, Josue de los [Department of Biochemistry, Vanderbilt University School of Medicine, 606 Light Hall, Nashville, TN 37232-0146 (United States); Carpenter, Graham [Department of Biochemistry, Vanderbilt University School of Medicine, 606 Light Hall, Nashville, TN 37232-0146 (United States)]. E-mail: graham.carpenter@vanderbilt.edu

2006-04-01

151

BZLF1, an Epstein-Barr virus immediate-early protein, induces p65 nuclear translocation while inhibiting p65 transcriptional function  

SciTech Connect

We have previously demonstrated that the Epstein-Barr virus immediate-early BZLF1 protein interacts with, and is inhibited by, the NF-{kappa}B family member p65. However, the effects of BZLF1 on NF-{kappa}B activity have not been intensively studied. Here we show that BZLF1 inhibits p65-dependent gene expression. BZLF1 inhibited the ability of IL-1, as well as transfected p65, to activate the expression of two different NF-{kappa}B-responsive genes, ICAM-1 and I{kappa}B-{alpha}. BZLF1 also reduced the constitutive level of I{kappa}B-{alpha} protein in HeLa and A549 cells, and increased the amount of nuclear NF-{kappa}B to a similar extent as tumor necrosis factor-alpha (TNF-{alpha}) treatment. In spite of this BZLF1-associated increase in the nuclear form of NF-{kappa}B, BZLF1 did not induce binding of NF-{kappa}B to NF-{kappa}B responsive promoters (as determined by chromatin immunoprecipitation assay) in vivo, although TNF-{alpha} treatment induced NF-{kappa}B binding as expected. Overexpression of p65 dramatically inhibited the lytic replication cycle of EBV in 293-EBV cells, confirming that NF-{kappa}B also inhibits BZLF1 transcriptional function. Our results are consistent with a model in which BZLF1 inhibits the transcriptional function of p65, resulting in decreased transcription of I{kappa}B-{alpha}, decreased expression of I{kappa}B-{alpha} protein, and subsequent translocation of NF-{kappa}B to the nucleus. This nuclear translocation of NF-{kappa}B may promote viral latency by negatively regulating BZLF1 transcriptional activity. In situations where p65 activity is limiting in comparison to BZLF1, the ability of BZLF1 to inhibit p65 transcriptional function may protect the virus from the host immune system during the lytic form of infection.

Morrison, Thomas E. [Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Kenney, Shannon C. [Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States) and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States) and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)]. E-mail: shann@med.unc.edu

2004-10-25

152

Topographical evaluation of the phenotype of spontaneous behaviour in mice with targeted gene deletion of the D1A dopamine receptor: paradoxical elevation of grooming syntax.  

PubMed

The phenotype of spontaneous behaviour in mice with targeted gene deletion of the DIA dopamine receptor was investigated topographically. Via direct visual observation, individual elements of behaviour were resolved and quantified using an ethologically-based, rapid time-sampling behavioural check-list procedure. Relative to wildtypes (D1A+/+), D1A-null (-/-) mice evidenced over initial exploration significant reductions in rearing free, sifting and chewing, but significant increases in locomotion, grooming and intense grooming. Sniffing and rearing to a wall habituated less readily in D1A-null mice such that these behaviours occurred subsequently to significant excess: increases in locomotion were persistent. The ethogram of spontaneous behaviour in D1A-null mice was characterised by neither 'hypoactivity' or 'hyperactivity' but, rather, by prominent topographical shifts between individual elements of behaviour that could not be encapsulated by either term. Given the substantial body of evidence that grooming and particularly intense grooming constitute the most widely accepted behavioural index of D1-like receptor function, the elevation of such behaviour in D1A-null mice was paradoxical; it may reflect (over)compensatory processes subsequent to developmental absence of D1A receptors and/or the involvement of a D1-like receptor other than/additional to the D1A subtype. PMID:9886682

Clifford, J J; Tighe, O; Croke, D T; Sibley, D R; Drago, J; Waddington, J L

1998-12-01

153

What is the relevance of Ikaros gene deletions as a prognostic marker in pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia?  

PubMed Central

New prognostic markers are needed for upfront identification of patients with acute lymphocytic leukemia with a high risk of relapse or who are not likely to respond to the most aggressive chemotherapy. We focused our analysis on Ikaros (IKZF1) gene deletions in a homogeneous cohort of 410 pediatric patients with Philadelphia chromosome-negative, B-cell precursor acute lymphoblastic leukemia enrolled in Italy into the AIEOP-BFM ALL2000 study. We confirm their reported poor prognostic value, although the associated event-free survival was relatively high (approximately 70%). The difference in the cumulative incidence of relapse between patients positive or not for IKZF1 deletions was not marked: 24.2% (5.9) versus 13.1% (1.8) overall and 23.9% (6.6) versus 16.5% (2.5) in the intermediate-risk subgroup. In line with this, IKZF1 deletions were not an independent prognostic factor for the hazard of relapse. Most IKZF1-deleted cases stratified in the high-risk group relapsed, suggesting that once identified, patients with these deletions require an alternative treatment. In conclusion, the need of and benefit from introducing IKZF1 deletions as an additional stratification marker for patients with Philadelphia-negative B-cell precursor acute lymphoblastic leukemia remain questionable. PMID:23585525

Palmi, Chiara; Valsecchi, Maria Grazia; Longinotti, Giulia; Silvestri, Daniela; Carrino, Valentina; Conter, Valentino; Basso, Giuseppe; Biondi, Andrea; Kronnie, Geertruy Te; Cazzaniga, Giovanni

2013-01-01

154

Association of GSTM1 and GSTT1 gene deletions with susceptibility to DNA damage in the pesticide-exposed workers of Punjab.  

PubMed

The main aim of this study was to evaluate genotoxic effects of pesticides in association with glutathione S-transferase (GST) polymorphism. To achieve this aim, DNA damage and the genotypes of the GSTM1 and GSTT1 genes were studied from blood lymphocytes of pesticide-exposed and unexposed (control) agricultural workers of the Punjab region of northwestern India. The blood samples were collected from 40 exposed and 27 unexposed subjects from the Kakrala and Sanour villages of Patiala district. DNA damage was evaluated by using an alkaline comet assay. The analysis of the comets was done through visual scoring and image analysis software (Tritek's CometScore). Damage Index (DI), Damage Frequency (DF) (calculated by visual scoring method), and % DNA in tail (measured by image analysis software) were considered for assessing DNA damage. The DNA extraction from blood cells was done using proteinase K and the phenol-chloroform method, and genotyping of GSTM1 and GSTT1 was done using multiplex PCR. It was found that all the pesticide-exposed subjects showed higher DI, DF, and % DNA in tail in comparison to the controls. The statistical comparison of DNA damage between the exposed group and unexposed group revealed highly significant differences (p < 0.05; Mann-Whitney U-test). In addition, the GSTT1 gene deletion and simultaneous deletions of GSTM1 and GSTT1 genes in increasing DNA damage were observed in the exposed group. PMID:20370484

Abhishek, S; Kaur, N; Kaur, S; Lata, M; Sharma, J K; Sharma, A

2010-01-01

155

Characterization of Xylan Utilization and Discovery of a New Endoxylanase in Thermoanaerobacterium saccharolyticum through Targeted Gene Deletions  

PubMed Central

The economical production of fuels and commodity chemicals from lignocellulose requires the utilization of both the cellulose and hemicellulose fractions. Xylanase enzymes allow greater utilization of hemicellulose while also increasing cellulose hydrolysis. Recent metabolic engineering efforts have resulted in a strain of Thermoanaerobacterium saccharolyticum that can convert C5 and C6 sugars, as well as insoluble xylan, into ethanol at high yield. To better understand the process of xylan solubilization in this organism, a series of targeted deletions were constructed in the homoethanologenic T. saccharolyticum strain M0355 to characterize xylan hydrolysis and xylose utilization in this organism. While the deletion of ?-xylosidase xylD slowed the growth of T. saccharolyticum on birchwood xylan and led to an accumulation of short-chain xylo-oligomers, no other single deletion, including the deletion of the previously characterized endoxylanase XynA, had a phenotype distinct from that of the wild type. This result indicates a multiplicity of xylanase enzymes which facilitate xylan degradation in T. saccharolyticum. Growth on xylan was prevented only when a previously uncharacterized endoxylanase encoded by xynC was also deleted in conjunction with xynA. Sequence analysis of xynC indicates that this enzyme, a low-molecular-weight endoxylanase with homology to glycoside hydrolase family 11 enzymes, is secreted yet untethered to the cell wall. Together, these observations expand our understanding of the enzymatic basis of xylan hydrolysis by T. saccharolyticum. PMID:23023741

Podkaminer, Kara K.; Guss, Adam M.; Trajano, Heather L.; Hogsett, David A.

2012-01-01

156

The growth hormone receptor gene deleted for exon three (GHRd3) polymorphism is associated with birth and placental weight  

PubMed Central

Context Human growth hormone receptor (GHR) transcripts have two isoforms, full-length (GHRfl) or exon 3 deleted (GHRd3). An association of these isoforms has been found with small for gestational age (SGA) infants but does not influence adult height. The role of this polymorphism in the birth size spectrum in the general population is unclear. Objective To determine the association of maternal and infants GHR exon 3 polymorphism with antenatal growth, birth size and early postnatal growth in two large, normal white European birth cohorts. Study design Pregnant women from white European families were recruited by the University College London Foetal Growth Study (n = 774) and the Moore normal pregnancy cohort (n = 274). GHR variants, wild-type (fl) and deleted for exon 3 (d3) were analysed using multiplex PCR. Results There was a significant underrepresentation of infants wild-type fl/fl (36%) and overrepresentation of d3/d3 (14%) genotypes in the SGA infants within the cohorts (?2 = 11·2, P = 0·003, df = 2). Fl/fl was overrepresented in large for gestational age (LGA) infants (?2 = 6·1, P = 0·047, df = 2). There was a significant association of infants GHR isoforms with placental weight (P < 0·001) and birth weight standard deviation scores (P = 0·04) with the fl/fl genotype associated with a larger placental and birth weight. In multiple regression analysis, the GHR isoform type, maternal booking weight and parity influenced placental weight (R2 = 0·35; P < 0·001, df = 7). The GHR isoform type was not related to antenatal anthropometric measurements or growth in infancy. Conclusion These data suggest that the GHR isoforms are associated with placental and birth weight. PMID:21913951

Padidela, Raja; Bryan, Sinead M; Abu-Amero, Sayeda; Hudson-Davies, Rebecca E; Achermann, John C; Moore, Gudrun E; Hindmarsh, Peter C

2012-01-01

157

Multiplication  

NSDL National Science Digital Library

How sharp are your multiplication skills? Give these great math games a try ! Play Asteroids blaster and test your multiplication skills. How fast can you solve the problem... play a round of Baseball multiplication and see! Multiplication is fun and delicious with Crazy Cones. Help Lemonade Larry determine the correct amount! Test your multiplication skills with Tic Tac Toe! ...

Ms.roberts

2009-02-24

158

Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan.  

PubMed

In Western countries, gene alterations involving the CRLF2-JAK signaling pathway are identified in approximately 50-60% of patients with Down syndrome-associated acute lymphoblastic leukemia (DS-ALL), and this pathway is considered a potential therapeutic target. The frequency of BTG1 deletions in DS-ALL is controversial. IKZF1 deletions, found in 20-30% of DS-ALL patients, are associated with a poor outcome and EBF1 deletions are very rare (?2%). We analyzed 38 patients to determine the frequencies and clinical implications of CRLF2-JAK pathway genetic alterations and recurrent gene deletions in Japanese DS-ALL patients. We confirmed a high incidence of P2RY8-CRLF2 (29%) and JAK2 mutations (16%), though the frequency of P2RY8-CRLF2 was slightly lower than that in Western countries (?50%). BTG1 deletions were common in our cohort (25%). IKZF1 deletions were detected in 25% of patients and associated with shorter overall survival (OS). EBF1 deletions were found at an unexpectedly high frequency (16%), and at a significantly higher level in P2RY8-CRLF2-positive patients than in P2RY8-CRLF2-negative patients (44% vs. 4%, P=0.015). Deletions of CDKN2A/B and PAX5 were common in P2RY8-CRLF2-negative patients (48 and 39%, respectively) but not in P2RY8-CRLF2-positive patients (11% each). Associations between these genetic alterations and clinical characteristics were not observed except for inferior OS in patients with IKZF1 deletions. These results suggest that differences exist between the genetic profiles of DS-ALL patients in Japan and in Western countries, and that P2RY8-CRLF2 and EBF1 deletions may cooperate in leukemogenesis in a subset of Japanese DS-ALL patients. PMID:25044358

Hanada, Isamu; Terui, Kiminori; Ikeda, Fumika; Toki, Tsutomu; Kanezaki, Rika; Sato, Tomohiko; Kamio, Takuya; Kudo, Ko; Sasaki, Shinya; Takahashi, Yoshihiro; Hayashi, Yasuhide; Inukai, Takeshi; Kojima, Seiji; Koike, Kenichi; Kosaka, Yoshiyuki; Kobayashi, Masao; Imaizumi, Masue; Mitsui, Tetsuo; Hori, Hiroki; Hara, Junichi; Horibe, Keizo; Nagai, Jun-ichi; Goto, Hiroaki; Ito, Etsuro

2014-11-01

159

A Suitable Streptomycin-Resistant Mutant for Constructing Unmarked In-Frame Gene Deletions Using rpsL as a Counter-Selection Marker  

PubMed Central

The streptomycin counter-selection system is a useful tool for constructing unmarked in-frame gene deletions, which is a fundamental approach to study bacteria and their pathogenicity at the molecular level. A prerequisite for this system is acquiring a streptomycin-resistant strain due to rpsL mutations, which encodes the ribosomal protein S12. However, in this study no streptomycin resistance was found to be caused by rpsL mutations in all 127 clinical strains of Klebsiella pneumoniae isolated from liver abscess patients. By screening 107 spontaneous mutants of streptomycin resistance from a clinical strain of K. pneumoniae, nucleotide substitution or insertion located within the rpsL was detected in each of these strains. Thirteen different mutants with varied S12 proteins were obtained, including nine streptomycin-dependent mutants. The virulence of all four streptomycin-resistant mutants was further evaluated. Compared with the parental strain, the K42N, K42T and K87R mutants showed a reduction in growth rate, and the K42N and K42T mutants became susceptible to normal human serum. In the mice LD50 (the bacterial dose that caused 50% death) assay, the K42N and K42T mutants were ?1,000-fold less lethal (?2×105 CFU) and the K87R mutant was ?50-fold less lethal (?1×104 CFU) than the parental strain (?2×102 CFU). A K42R mutant showed non-observable effects on the above assays, while this mutant exhibited a small cost (P<0.01) in an in vitro growth competition experiment. In summary, most of the K. pneumoniae strains with streptomycin resistance caused by rpsL mutations are less virulent than their parental strain in the absence of streptomycin. The K42R mutant showed similar pathogenicity to its parental strain and should be one of the best choices when using rpsL as a counter-selection marker. PMID:25268958

Tsai, Yu-Kuo; Liou, Ci-Hong; Lin, Jung-Chung; Ma, Ling; Fung, Chang-Phone; Chang, Feng-Yee; Siu, L. Kristopher

2014-01-01

160

Raf and Fibroblast Growth Factor Phosphorylate Elk1 and Activate the Serum Response Element of the Immediate Early Gene pip92 by Mitogen-Activated Protein Kinase-Independent as Well as -Dependent Signaling Pathways  

PubMed Central

Previous studies have shown that a mitogen activated protein (MAP) kinase (MEK)-independent signaling pathway is required by activated Raf or fibroblast-derived growth factor (FGF) for the differentiation of rat hippocampal neuronal H19-7 cells. We now demonstrate that both Raf and FGF similarly induce prolonged transcription and translation of the immediate early gene pip92 in the absence of activation of the MAP kinases (MAPKs) ERK1 and ERK2. To determine the mechanism by which this occurs and to identify novel Raf-activated signaling pathways, we investigated the induction of the pip92 promoter by both FGF and an estradiol-activated Raf-1–estrogen receptor fusion protein (?Raf-1:ER) in H19-7 cells. Deletion analysis of the pip92 promoter indicated that activation by the MAPK-independent pathway occurs primarily within the region containing a serum response element (SRE). Further analysis of the SRE by using a heterologous thymidine kinase promoter showed that both an Ets and CArG-like site are required. Elk1, which binds to the Ets site, was phosphorylated both in vitro and in vivo by the MAPK-independent pathway, and phosphorylation of an Elk1-GAL4 fusion protein by this pathway was sufficient for transactivation. Finally, at least two Elk1 kinases were fractionated by gel filtration, and analysis by an in-gel kinase assay revealed at least three novel Raf-activated Elk1 kinases. These results indicate that both FGF and Raf activate MAPK-independent kinases that can stimulate Elk1 phosphorylation and immediate early gene transcription. PMID:9528798

Chung, Kwang-Chul; Gomes, Ignatius; Wang, Danhui; Lau, Lester F.; Rosner, Marsha Rich

1998-01-01

161

Distal Xq28 microdeletions: Clarification of the spectrum of contiguous gene deletions involving ABCD1, BCAP31, and SLC6A8 with a new case and review of the literature.  

PubMed

The contiguous ABCD1/DXS1375E (BCAP31) deletion syndrome (CADDS) is a rare X-linked contiguous gene deletion syndrome with a severe clinical phenotype that includes marked delays, significant growth failure, liver dysfunction, and early death. The X-linked creatine transporter deficiency is a considerably more common and a cause of X-linked intellectual disability; however, multi-exon deletions of the creatine transporter are rare. We report the fifth case of CADDS, who also has a deletion of the X-linked creatine transporter. We also review reported cases of deletions in this region in order to clarify the clinical spectrum of contiguous microdeletions in this region. © 2014 Wiley Periodicals, Inc. PMID:25044748

Calhoun, Amy R U L; Raymond, Gerald V

2014-10-01

162

Detection of a complete autoimmune regulator gene deletion and two additional novel mutations in a cohort of patients with atypical phenotypic variants of autoimmune polyglandular syndrome type 1  

Microsoft Academic Search

Objective: Autoimmune polyglandular syndrome type 1 (APS-1) is characterised by multiple autoimmune diseases. Detection of autoimmune regulator (AIRE) gene mutations facilitates timely and precise diagnosis. Design: AIRE mutation detection was performed in a cohort of 11 patients. Two did not meet clinical APS-1 criteria and several started with atypical presentation. Methods: Sequencing and TaqMan genotyping were used to identify AIRE

Katarina Trebusak Podkrajsek; Tatjana Milenkovic ´; Roelof J Odink; Hedi L Claasen-van der Grinten; Nina Bratanic; Tinka Hovnik; Tadej Battelino

2008-01-01

163

Two Litopenaeus vannamei HMGB proteins interact with transcription factors LvSTAT and LvDorsal to activate the promoter of white spot syndrome virus immediate-early gene ie1.  

PubMed

White spot syndrome virus (WSSV) has caused great economic damage to shrimp aquaculture. Previous studies have shown that WSSV successfully usurps the immunity system of the host for its own gene regulation. To investigate the role of shrimp high mobility group box (HMGB) proteins in WSSV gene regulation, two Litopenaeus vannamei HMGB genes, LvHMGBa and LvHMGBb, were isolated by rapid amplification of cDNA ends (RACE). Recombinant LvHMGBa/b proteins were present in the nucleus of transfected Drosophila Schneider 2 (S2) cells. Luciferase reporter assays revealed that LvHMGBa/b upregulated the WSSV immediate-early (IE) gene (ie1) in a NF-?B and STAT binding site-dependent manner. GST pull-down assays demonstrated that LvHMGBa/b interacted with L. vannamei Dorsal (LvDorsal) and L. vannamei STAT (LvSTAT), respectively. LvHMGBa was highly expressed in hepatopancreas while HMGBb was highly expressed in stomach, intestine, heart, antennal gland, and epidermis. Moreover, an immune challenge assay demonstrated that the expression of LvHMGBa/b was upregulated by WSSV infection and that both mRNAs reached peak values at 24 h post-infection. To our knowledge, this is the first report that invertebrate HMGB proteins participates in viral gene regulation. PMID:21186060

Chen, Yi-Hong; Jia, Xiao-Ting; Huang, Xian-De; Zhang, Shuang; Li, Mei; Xie, Jun-Feng; Weng, Shao-Ping; He, Jian-Guo

2011-02-01

164

Combinatorial strategies for improving multiple-stress resistance in industrially relevant Escherichia coli strains.  

PubMed

High-cell-density fermentation for industrial production of chemicals can impose numerous stresses on cells due to high substrate, product, and by-product concentrations; high osmolarity; reactive oxygen species; and elevated temperatures. There is a need to develop platform strains of industrial microorganisms that are more tolerant toward these typical processing conditions. In this study, the growth of six industrially relevant strains of Escherichia coli was characterized under eight stress conditions representative of fed-batch fermentation, and strains W and BL21(DE3) were selected as platforms for transposon (Tn) mutagenesis due to favorable resistance characteristics. Selection experiments, followed by either targeted or genome-wide next-generation-sequencing-based Tn insertion site determination, were performed to identify mutants with improved growth properties under a subset of three stress conditions and two combinations of individual stresses. A subset of the identified loss-of-function mutants were selected for a combinatorial approach, where strains with combinations of two and three gene deletions were systematically constructed and tested for single and multistress resistance. These approaches allowed identification of (i) strain-background-specific stress resistance phenotypes, (ii) novel gene deletion mutants in E. coli that confer single and multistress resistance in a strain-background-dependent manner, and (iii) synergistic effects of multiple gene deletions that confer improved resistance over single deletions. The results of this study underscore the suboptimality and strain-specific variability of the genetic network regulating growth under stressful conditions and suggest that further exploration of the combinatorial gene deletion space in multiple strain backgrounds is needed for optimizing strains for microbial bioprocessing applications. PMID:25085490

Lennen, Rebecca M; Herrgård, Markus J

2014-10-01

165

Elucidating timing and function of endothelin-A receptor signaling during craniofacial development using neural crest cell-specific gene deletion and receptor antagonism  

PubMed Central

Cranial neural crest cells (NCCs) play an intimate role in craniofacial development. Multiple signaling cascades participate in patterning cranial NCCs, some of which are regulated by endothelin-A receptor (Ednra) signaling. Ednra?/? embryos die at birth from severe craniofacial defects resulting from disruption of neural crest cell patterning and differentiation. These defects include homeotic transformation of lower jaw structures into upper jaw-like structures, suggesting that some cephalic NCCs alter their “identity” in the absence of Ednra signaling. To elucidate the temporal necessity for Ednra signaling in vivo, we undertook two strategies. We first used a conditional knockout strategy in which mice containing a conditionally targeted Ednra allele (Ednrafl) were bred with mice from the Hand2-Cre and Wnt1-Cre transgenic mouse strains, two strains in which Cre expression occurs at different time periods within cranial NCCs. In our second approach, we used an Ednra-specific antagonist to treat wild type pregnant mice between embryonic days E8.0 and E10.0, a time frame encompassing the early migration and proliferation of cranial NCCs. The combined results suggest that Ednra function is crucial for NCC development between E8.25 and E9.0, a time period encompassing the arrival of NCCs in the arches and/or early post-migratory patterning. After this time period, Ednra signaling is dispensable. Interestingly, middle ear structures are enlarged and malformed in a majority of Ednrafl/fl;Wnt1-Cre embryos, instead resembling structures found in extinct predecessors of mammals. These observations suggest that the advent of Ednra signaling in cranial NCCs may have been a crucial event in the evolution of the mammalian middle ear ossicles. PMID:19185569

Ruest, Louis-Bruno; Clouthier, David E.

2009-01-01

166

Elucidating timing and function of endothelin-A receptor signaling during craniofacial development using neural crest cell-specific gene deletion and receptor antagonism.  

PubMed

Cranial neural crest cells (NCCs) play an intimate role in craniofacial development. Multiple signaling cascades participate in patterning cranial NCCs, some of which are regulated by endothelin-A receptor (Ednra) signaling. Ednra(-/-) embryos die at birth from severe craniofacial defects resulting from disruption of neural crest cell patterning and differentiation. These defects include homeotic transformation of lower jaw structures into upper jaw-like structures, suggesting that some cephalic NCCs alter their "identity" in the absence of Ednra signaling. To elucidate the temporal necessity for Ednra signaling in vivo, we undertook two strategies. We first used a conditional knockout strategy in which mice containing a conditionally targeted Ednra allele (Ednra(fl)) were bred with mice from the Hand2-Cre and Wnt1-Cre transgenic mouse strains, two strains in which Cre expression occurs at different time periods within cranial NCCs. In our second approach, we used an Ednra-specific antagonist to treat wild type pregnant mice between embryonic days E8.0 and E10.0, a time frame encompassing the early migration and proliferation of cranial NCCs. The combined results suggest that Ednra function is crucial for NCC development between E8.25 and E9.0, a time period encompassing the arrival of NCCs in the arches and/or early post-migratory patterning. After this time period, Ednra signaling is dispensable. Interestingly, middle ear structures are enlarged and malformed in a majority of Ednra(fl/fl);Wnt1-Cre embryos, instead resembling structures found in extinct predecessors of mammals. These observations suggest that the advent of Ednra signaling in cranial NCCs may have been a crucial event in the evolution of the mammalian middle ear ossicles. PMID:19185569

Ruest, Louis-Bruno; Clouthier, David E

2009-04-01

167

Inhibition of iridovirus protein synthesis and virus replication by antisense morpholino oligonucleotides targeted to the major capsid protein, the 18 kDa immediate-early protein, and a viral homolog of RNA polymerase II  

SciTech Connect

Frog virus 3 (FV3) is a large DNA virus that encodes {approx} 100 proteins. Although the general features of FV3 replication are known, the specific roles that most viral proteins play in the virus life cycle have not yet been elucidated. To address the question of viral gene function, antisense morpholino oligonucleotides (asMOs) were used to transiently knock-down expression of specific viral genes and thus infer their role in virus replication. We designed asMOs directed against the major capsid protein (MCP), an 18 kDa immediate-early protein (18K) that was thought to be a viral regulatory protein, and the viral homologue of the largest subunit of RNA polymerase II (vPol-II{alpha}). All three asMOs successfully inhibited translation of the targeted protein, and two of the three asMOs resulted in marked phenotypic changes. Knock-down of the MCP resulted in a marked reduction in viral titer without a corresponding drop in the synthesis of other late viral proteins. Transmission electron microscopy (TEM) showed that in cells treated with the anti-MCP MO assembly sites were devoid of viral particles and contained numerous aberrant structures. In contrast, inhibition of 18K synthesis did not block virion formation, suggesting that the 18K protein was not essential for replication of FV3 in fathead minnow (FHM) cells. Finally, consistent with the view that late viral gene expression is catalyzed by a virus-encoded or virus-modified Pol-II-like protein, knock-down of vPol-II{alpha} triggered a global decline in late gene expression and virus yields without affecting the synthesis of early viral genes. Collectively, these results demonstrate the utility of using asMOs to elucidate the function of FV3 proteins.

Sample, Robert [Department of Microbiology, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Bryan, Locke [Department of Microbiology, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Long, Scott [Department of Microbiology, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Majji, Sai [Department of Microbiology, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Hoskins, Glenn [Department of Anatomy, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Sinning, Allan [Department of Anatomy, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Olivier, Jake [Department of Preventive Medicine, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Chinchar, V. Gregory [Department of Microbiology, University of Mississippi Medical Center, Jackson, MS 39216 (United States)]. E-mail: vchinchar@microbio.umsmed.edu

2007-02-20

168

Sequence characterization, polymorphism, and tissue expression profile of an effector immediate-early gene: activity-regulated cytoskeletal associated protein gene (Arc/Arg3.1) in swamp and river buffalo.  

PubMed

The activity-regulated cytoskeletal associated protein (Arc/Arg3.1) has been implicated in experience-dependent synaptic plasticity and memory formation. However, information regarding its coding gene in buffalo remains scarce. In this study, the full-length of Arc/Arg3.1 was isolated and characterized (accession No. JX491649) and genetic variations of six river buffalo and eight swamp buffalo were investigated. A tissue expression profile was obtained using semi-quantitative reverse transcription-polymerase chain reaction. The coding region sequence of Arc/Arg3.1 contained 1191 nucleotides encoding a putative protein of 396 amino acids with a theoretical isoelectric point (pI) and molecular weight (Mw) of 5.4 and 45.2 kDa, respectively. Four polymorphisms (c.63T>C, c.228T>C, c.558G>A, and c.625G>C) were found in buffalo; however, only substitution c.625G>C was non-synonymous, leading to an amino acid change from Val to Leu at the 209th position of the Arc/Arg3.1 protein sequence. Bioinformatics analysis revealed that this substitution had no significant effect on Arc/Arg3.1 function (subPSEC = -1.4039, Pdeleterious = 0.1685), which indicated that Arc/Arg3.1 was highly conserved and functionally important in buffalo. Phylogenetic analysis revealed that the gene is closely related to that of Bos taurus and Bos grunniens. The gene was moderately expressed in the hypophysis and the placenta; it was weakly expressed in the kidney, milk, mammary gland, cerebrum, lung, heart, rumen, fat, and uterus; and it was almost silent in the muscle, liver, and skin. These findings will provide further insights into the structure and function of the immediate-early gene in buffalo. PMID:24737478

Yuan, F; Huo, J L; Li, D L; Yuan, Y Y; Lu, W Z; Song, S; Li, L J; Miao, Y W

2014-01-01

169

Recruitment of cdk9 to the Immediate-Early Viral Transcriptosomes during Human Cytomegalovirus Infection Requires Efficient Binding to Cyclin T1, a Threshold Level of IE2 86, and Active Transcription?  

PubMed Central

Human cytomegalovirus (HCMV) infection results in the formation of nuclear viral transcriptosomes, which are sites dedicated to viral immediate-early (IE) transcription. At IE times of the infection, viral and cellular factors, including several components of transcription such as cyclin-dependent kinase 9 (cdk9), localize at these sites. To determine the mechanism and requirements of specific recruitment of cdk9 to the viral transcriptosomes, infection in the presence of inhibitor drugs and infection of cell lines expressing exogenous mutant cdk9 were performed. We found that cdk9 localization to the viral transcriptosomes requires de novo protein synthesis. In addition, active transcription is required for recruitment and maintenance of cdk9 at the viral transcriptosomes. In cells infected with a recombinant IE2 HCMV (IE2 86 ?SX virus) in which IE2 gene expression is greatly reduced, cdk9 localization at the transcriptosome is delayed and corresponds to the kinetics of accumulation of the IE2 protein at these sites. Infection in the presence of the cdk9 inhibitors Flavopiridol and DRB (5,6-dichloro-1-?-d-ribofuranosylbenzimidazole) allowed cdk9 localization to the viral transcriptosomes. A kinase-inactive cdk9 (D167N) expressed during the infection also localizes to the viral transcriptosomes, indicating that kinase activity of cdk9 is not a requirement for its localization to the sites of IE transcription. Exogenous expression of additional cdk9 mutants indicates that binding of Brd4 to the cdk9 complex is not required but that efficient binding to cyclin T1 is essential. PMID:19297489

Kapasi, Anokhi J.; Clark, Charles L.; Tran, Karen; Spector, Deborah H.

2009-01-01

170

mdv1-miR-M7-5p, located in the newly identified first intron of the latency-associated transcript of Marek's disease virus, targets the immediate-early genes ICP4 and ICP27.  

PubMed

Marek's disease virus serotype 1 (MDV-1) is an oncogenic alphaherpesvirus causing fatal T-cell lymphoma in chickens. MDV latency is characterized by the production of latency-associated transcripts (LATs), a family of non-protein-coding spliced RNAs. A cluster of four microRNAs (cluster mdv1-miR-M8-M10) was identified, but not formally mapped, at the predicted LAT 5' end. We established a LAT cDNA library from latently MDV-infected cell line MSB-1. We identified 22 highly variable LATs, which were due to the extensive alternative splicing of a total of 14 introns. RACE PCR confirmed the predicted 3' end and allowed identification of the 5' end, 400 nt upstream of the previously predicted LAT end. The LATs share their transcription start site with the microRNA-expressing transcript described previously, localizing the microRNAs to the first LAT intron and identifying the LATs as the primary transcripts of the microRNAs. We identified MDV immediate-early (IE) genes ICP4 and ICP27 as putative targets of mdv1-miR-M7-5p, the third microRNA of the cluster mdv1-miR-M8-M10. Endogenously expressed mdv1-miR-M7-5p in MSB-1 cells reduced luciferase activity significantly when microRNA-responsive elements from ICP4 or ICP27 were cloned in the 3' UTR of the firefly luciferase gene. ICP27 protein levels were decreased by 70?% when the mdv1-miR-M7-5p precursor was co-expressed with an ICP27 expression plasmid. Additionally, we showed a negative correlation between the decreased expression of mdv1-miR-M7-5p and an increase in ICP27 expression during virus reactivation. Our results suggest that, by targeting two IE genes, MDV microRNAs produced from LAT transcripts may contribute to establish and/or maintain latency. PMID:22513387

Strassheim, S; Stik, G; Rasschaert, D; Laurent, S

2012-08-01

171

An Obligatory Role of NF-?B in Mediating Bone Marrow Derived Endothelial Progenitor Cell Recruitment and Proliferation Following Endotoxemic Multiple Organ Injury in Mice  

PubMed Central

Background Recruitment of bone marrow derived endothelial progenitor cells (BMDEPCs) alleviates multiple organ injury (MOI) and improves outcomes. However, mechanisms mediating BMDEPC recruitment following septic MOI remain largely unknown. This study characterized the kinetics of BMDEPC recruitment and proliferation and defined the role of NF-?B in regulating BMDEPC recruitment and proliferation. Methods and Main Findings Chimeric mice with an intact or disrupted NF-?B p50 gene and BMDEPC-restricted expression of green fluorescent protein were created and injected with LPS (2 mg/kg, i.p.). BMDEPC recruitment and proliferation in multiple organs were quantified. BMDEPC recruitment and proliferation are highly organ-dependent. Lungs had the highest number of BMDEPC recruitment, whereas heart, liver and kidney had only a small fraction of the number of BMDEPCs in lungs. Number of proliferating BMDEPCs was several-fold higher in lungs than in other 3 organs. Kinetically, BMDEPC recruitment into different organs showed different time course profiles. NF-?B plays obligatory roles in mediating BMDEPC recruitment and proliferation. Universal deletion of NF-?B p50 gene inhibited LPS-induced BMDEPC recruitment and proliferation by 95% and 69% in heart. However, the contribution of NF-?B to these regulations varies significantly between organs. In liver, universal p50 gene deletion reduced LPS-induced BMDEPC recruitment and proliferation only by 49% and 35%. NF-?B activities in different tissue compartments play distinct roles. Selective p50 gene deletion either in stromal/parenchymal cells or in BM/blood cells inhibited BMDEPC recruitment by a similar extent. However, selective p50 gene deletion in BM/blood cells inhibited, but in stromal/parenchymal cells augmented BMDEPC proliferation. Conclusions BMDEPC recruitment and proliferation display different kinetics in different organs following endotoxemic MOI. NF-?B plays obligatory and organ-dependent roles in regulating BMDEPC recruitment and proliferation. NF-?B activities in different tissue compartments play distinct roles in regulating BMDEPC proliferation. PMID:25333282

Mao, Sun-Zhong; Ye, Xiaobing; Liu, Gang; Song, Dongmei; Liu, Shu Fang

2014-01-01

172

Human cytomegalovirus immediate early proteins and cell growth control  

Microsoft Academic Search

It is widely accepted that small DNA tumor viruses, such as adenovirus, simian virus 40 and papillomavirus, push infected cells into S-phase to facilitate the replication of their genome. Until recently, it was believed that the large DNA viruses (i.e. herpesviruses) functioned very differently in this regard by inducing a G1 arrest in infected cells as part of their replication

Jonathan P. Castillo; Timothy F. Kowalik

2002-01-01

173

Progressive multiple sclerosis: pathology and pathogenesis.  

PubMed

Major progress has been made during the past three decades in understanding the inflammatory process and pathogenetic mechanisms in multiple sclerosis (MS). Consequently, effective anti-inflammatory and immunomodulatory treatments are now available for patients in the relapsing-remitting stage of the disease. This Review summarizes studies on the pathology of progressive MS and discusses new data on the mechanisms underlying its pathogenesis. In progressive MS, as in relapsing-remitting MS, active tissue injury is associated with inflammation, but the inflammatory response in the progressive phase occurs at least partly behind the blood-brain barrier, which makes it more difficult to treat. The other mechanisms that drive disease in patients with primary or secondary progressive MS are currently unresolved, although oxidative stress resulting in mitochondrial injury might participate in the induction of demyelination and neurodegeneration in both the relapsing-remitting and progressive stages of MS. Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process. PMID:23007702

Lassmann, Hans; van Horssen, Jack; Mahad, Don

2012-11-01

174

PGD for dystrophin gene deletions using fluorescence in situ hybridization  

Microsoft Academic Search

Duchenne muscular dystrophy and Becker muscular dystrophy (DMD and BMD) are caused by mutations in the dystrophin gene (Xp21). In two-thirds of DMD\\/BMD cases, the mutation is a large deletion of one or several exons. We have established PGD for DMD\\/BMD using interphase fluorescence in situ hybridization (FISH) analysis on single nuclei from blastomeres for the detection of deletions of

H. Malmgren; I. White; S. Johansson; L. Levkov; E. Iwarsson; M. Fridström; Elisabeth Blennow

2006-01-01

175

CaMK4 Gene Deletion Induces Hypertension  

PubMed Central

Background The expression of calcium/calmodulin-dependent kinase IV (CaMKIV) was hitherto thought to be confined to the nervous system. However, a recent genome-wide analysis indicated an association between hypertension and a single-nucleotide polymorphism (rs10491334) of the human CaMKIV gene (CaMK4), which suggests a role for this kinase in the regulation of vascular tone. Methods and Results To directly assess the role of CaMKIV in hypertension, we characterized the cardiovascular phenotype of CaMK4?/? mice. They displayed a typical hypertensive phenotype, including high blood pressure levels, cardiac hypertrophy, vascular and kidney damage, and reduced tolerance to chronic ischemia and myocardial infarction compared with wild-type littermates. Interestingly, in vitro experiments showed the ability of this kinase to activate endothelial nitric oxide synthase. Eventually, in a population study, we found that the rs10491334 variant associates with a reduction in the expression levels of CaMKIV in lymphocytes from hypertensive patients. Conclusions Taken together, our results provide evidence that CaMKIV plays a pivotal role in blood pressure regulation through the control of endothelial nitric oxide synthase activity. (J Am Heart Assoc. 2012;1:e001081 doi: 10.1161/JAHA.112.001081.) PMID:23130158

Santulli, Gaetano; Cipolletta, Ersilia; Sorriento, Daniela; Del Giudice, Carmine; Anastasio, Antonio; Monaco, Sara; Maione, Angela Serena; Condorelli, Gianluigi; Puca, Annibale; Trimarco, Bruno; Illario, Maddalena; Iaccarino, Guido

2012-01-01

176

Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease.  

PubMed

The inherited deficiency of the lysosomal glucocerebrosidase (GBA) due to mutations in the GBA gene results in Gaucher disease (GD). A vast majority of patients present with nonneuronopathic, type 1 GD (GD1). GBA deficiency causes the accumulation of two key sphingolipids, glucosylceramide (GL-1) and glucosylsphingosine (LysoGL-1), classically noted within the lysosomes of mononuclear phagocytes. How metabolites of GL-1 or LysoGL-1 produced by extralysosomal glucocerebrosidase GBA2 contribute to the GD1 pathophysiology is not known. We recently recapitulated hepatosplenomegaly, cytopenia, hypercytokinemia, and the bone-formation defect of human GD1 through conditional deletion of Gba in Mx1-Cre(+):GD1 mice. Here we show that the deletion of Gba2 significantly rescues the GD1 clinical phenotype, despite enhanced elevations in GL-1 and LysoGL-1. Most notably, the reduced bone volume and bone formation rate are normalized. These results suggest that metabolism of GL-1 or LysoGL-1 into downstream bioactive lipids is a major contributor to the bone-formation defect. Direct testing revealed a strong inhibition of osteoblast viability by nanomolar concentrations of sphingosine, but not of ceramide. These findings are consistent with toxicity of high circulating sphingosine levels in GD1 patients, which decline upon enzyme-replacement therapy; serum ceramide levels remain unchanged. Together, complementary results from mice and humans affected with GD1 not only pinpoint sphingosine as being an osteoblast toxin, but also set forth Gba2 as a viable therapeutic target for the development of inhibitors to ameliorate certain disabling consequences of GD1. PMID:24639522

Mistry, Pramod K; Liu, Jun; Sun, Li; Chuang, Wei-Lien; Yuen, Tony; Yang, Ruhua; Lu, Ping; Zhang, Kate; Li, Jianhua; Keutzer, Joan; Stachnik, Agnes; Mennone, Albert; Boyer, James L; Jain, Dhanpat; Brady, Roscoe O; New, Maria I; Zaidi, Mone

2014-04-01

177

Ornithine Decarboxylase Gene Deletion Mutants of Leishmania donovani*  

E-print Network

the Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland, Oregon 97201 of Leishmania donovani lacking both ornithine decarboxylase (ODC) alleles has been created by targeted gene. The lack of a polyamine catabolic pathway in intact parasites was confirmed radiometri- cally. In addition

Schnaufer, Achim

178

PHLPP1 gene deletion protects the brain from ischemic injury  

PubMed Central

A recently discovered protein phosphatase PHLPP (PH domain Leucine-rich repeat Protein Phosphatase) has been shown to dephosphorylate Akt on its hydrophobic motif (Ser473) thereby decreasing Akt kinase activity. We generated PHLPP1 knockout (KO) mice and used them to explore the ability of enhanced in vivo Akt signaling to protect the brain against ischemic insult. Brains from KO mice subjected to middle cerebral artery occlusion (MCAO) for 2?hours showed significantly greater increases in Akt activity and less neurovascular damage after reperfusion than wild-type (WT) mice. Remarkably, infarct volume in the PHLPP1 KO was significantly reduced compared with WT (12.7±2.7% versus 22.9±3.1%) and this was prevented by Akt inhibition. Astrocytes from KO mice and neurons in which PHLPP1 was downregulated showed enhanced Akt activation and diminished cell death in response to oxygen-glucose deprivation. Thus, deletion of PHLPP1 can enhance Akt activation in neurons and astrocytes, and can significantly increase cell survival and diminish infarct size after MCAO. Inhibition of PHLPP could be a therapeutic approach to minimize damage after focal ischemia. PMID:23072745

Chen, Bo; Van Winkle, Jessica A; Lyden, Patrick D; Brown, Joan H; Purcell, Nicole H

2013-01-01

179

PHLPP1 gene deletion protects the brain from ischemic injury.  

PubMed

A recently discovered protein phosphatase PHLPP (PH domain Leucine-rich repeat Protein Phosphatase) has been shown to dephosphorylate Akt on its hydrophobic motif (Ser473) thereby decreasing Akt kinase activity. We generated PHLPP1 knockout (KO) mice and used them to explore the ability of enhanced in vivo Akt signaling to protect the brain against ischemic insult. Brains from KO mice subjected to middle cerebral artery occlusion (MCAO) for 2?hours showed significantly greater increases in Akt activity and less neurovascular damage after reperfusion than wild-type (WT) mice. Remarkably, infarct volume in the PHLPP1 KO was significantly reduced compared with WT (12.7±2.7% versus 22.9±3.1%) and this was prevented by Akt inhibition. Astrocytes from KO mice and neurons in which PHLPP1 was downregulated showed enhanced Akt activation and diminished cell death in response to oxygen-glucose deprivation. Thus, deletion of PHLPP1 can enhance Akt activation in neurons and astrocytes, and can significantly increase cell survival and diminish infarct size after MCAO. Inhibition of PHLPP could be a therapeutic approach to minimize damage after focal ischemia. PMID:23072745

Chen, Bo; Van Winkle, Jessica A; Lyden, Patrick D; Brown, Joan H; Purcell, Nicole H

2013-02-01

180

Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease  

PubMed Central

The inherited deficiency of the lysosomal glucocerebrosidase (GBA) due to mutations in the GBA gene results in Gaucher disease (GD). A vast majority of patients present with nonneuronopathic, type 1 GD (GD1). GBA deficiency causes the accumulation of two key sphingolipids, glucosylceramide (GL-1) and glucosylsphingosine (LysoGL-1), classically noted within the lysosomes of mononuclear phagocytes. How metabolites of GL-1 or LysoGL-1 produced by extralysosomal glucocerebrosidase GBA2 contribute to the GD1 pathophysiology is not known. We recently recapitulated hepatosplenomegaly, cytopenia, hypercytokinemia, and the bone-formation defect of human GD1 through conditional deletion of Gba in Mx1–Cre+:GD1 mice. Here we show that the deletion of Gba2 significantly rescues the GD1 clinical phenotype, despite enhanced elevations in GL-1 and LysoGL-1. Most notably, the reduced bone volume and bone formation rate are normalized. These results suggest that metabolism of GL-1 or LysoGL-1 into downstream bioactive lipids is a major contributor to the bone-formation defect. Direct testing revealed a strong inhibition of osteoblast viability by nanomolar concentrations of sphingosine, but not of ceramide. These findings are consistent with toxicity of high circulating sphingosine levels in GD1 patients, which decline upon enzyme-replacement therapy; serum ceramide levels remain unchanged. Together, complementary results from mice and humans affected with GD1 not only pinpoint sphingosine as being an osteoblast toxin, but also set forth Gba2 as a viable therapeutic target for the development of inhibitors to ameliorate certain disabling consequences of GD1. PMID:24639522

Mistry, Pramod K.; Liu, Jun; Sun, Li; Chuang, Wei-Lien; Yuen, Tony; Yang, Ruhua; Lu, Ping; Zhang, Kate; Li, Jianhua; Keutzer, Joan; Stachnik, Agnes; Mennone, Albert; Boyer, James L.; Jain, Dhanpat; Brady, Roscoe O.; New, Maria I.; Zaidi, Mone

2014-01-01

181

Multiplication 2  

NSDL National Science Digital Library

Try some harder multiplication activities! Missing Factor Meteor Blasting Complete the Missing Step Batter s Up Multiplication Sum Sense Multiplication Challenge a Friend to Grand Prix Multiplication Double Digit Multiplication https://embed.espresso.co.uk/espresso/embed/images/logo_espresso.gif ) no-repeat center center"

Lerdahl, Miss

2010-11-16

182

Mastering Multiplication  

NSDL National Science Digital Library

Play the following games to practice your multiplication. Take a swing at Multplication Baseball! (Set with hard) Use your multiplication knowledge and defeat the Mayan Math Monster! (Set to hard) Quick! Stop the Multiplication Invader before it is too late! ...

Jackson, Ms.

2007-10-25

183

Multiplication Mania!  

NSDL National Science Digital Library

These assignments will help you practice your multiplication facts. Work through these multiplication facts. Click on each link and scroll down past the red box to the orange box. Click on \\"Start Multiplication\\". After you type in your answer click on the \\"Check\\" box to check your answer. 1. Practice your multiplication facts 0-3. ...

Packard, Mrs.

2005-10-25

184

Multiplication Rocks!!!  

NSDL National Science Digital Library

Let's practice what we've learned about multiplication. Play at least one game in each of the categories. Times Table Practice: Design the Ultimate Fashion Outfit with Math Models Blast the Meteors before they destroy the ship in Meteor Multiplication More Multiplication: Batter's Up in Baseball Multiplication Win $1,000,000 in Who Wants To Be A Millionaire? ...

Peake, Mrs.

2009-04-15

185

Multiple Sclerosis  

MedlinePLUS

Multiple sclerosis (MS) is a nervous system disease that affects your brain and spinal cord. It damages the ... attacks healthy cells in your body by mistake. Multiple sclerosis affects women more than men. It often begins ...

186

Multiple Sclerosis  

MedlinePLUS

... is multiple sclerosis (MS)? Multiple sclerosis is an autoimmune disease that affects the nervous system. Normally, antibodies produced ... of 20 and 40. If you have another autoimmune disease, such as thyroid disease or Type 1 diabetes, ...

187

Finger Multiplication  

ERIC Educational Resources Information Center

Multiplication facts are difficult to teach. Therefore many researchers have put a great deal of effort into finding multiplication strategies. Sherin and Fuson (2005) provided a good survey paper on the multiplication strategies research area. Kolpas (2002), Rendtorff (1908), Dabell (2001), Musser (1966) and Markarian (2009) proposed the finger…

Simanihuruk, Mudin

2011-01-01

188

Multiplication Mania!  

NSDL National Science Digital Library

Fun games to practice your multiplication facts! Need a refreshing break? Come on over to the lemonade stand...Lemonade Stand At the beach, you can swim, sun, and practice your multiplication facts...Beach Multiplication How fast are you? Click here to...Race the Clock Do you have your spacesuit and astronaut food, are you ready for your...Mission to the Moon ...

Hoeman, Ms.

2008-09-18

189

Multiplication Frenzy!  

NSDL National Science Digital Library

Let's practice multiplication! First, try to win the first place medal in the Fish Race. Then, test your skills by blowing up meteors by getting your multiplication tables right in Meteor Buster. Last, don't let the ants eat your lunch in The Ants Go Marching. ...

Burks, Ms.

2010-01-27

190

Multiple homicides.  

PubMed

A study of multiple homicides or multiple deaths involving a solitary incident of violence by another individual was performed on the case files of the Office of the Medical Examiner of Metropolitan Dade County in Miami, Florida, during 1983-1987. A total of 107 multiple homicides were studied: 88 double, 17 triple, one quadruple, and one quintuple. The 236 victims were analyzed regarding age, race, sex, cause of death, toxicologic data, perpetrator, locale of the incident, and reason for the incident. This article compares this type of slaying with other types of homicide including those perpetrated by serial killers. Suggestions for future research in this field are offered. PMID:2782297

Copeland, A R

1989-09-01

191

Multiplication Matho  

NSDL National Science Digital Library

This site has students practice their multiplication facts. They compete against the clock while picking the correct response from numerous choices. Student have Matho when they get five colored snakes in a row.

A + Math

2007-12-12

192

Multiple myeloma  

MedlinePLUS

Plasma cell dyscrasia; Plasma cell myeloma; Malignant plasmacytoma; Plasmacytoma of bone; Myeloma - multiple ... myeloma most commonly causes a low red blood cell count ( anemia ), which can lead to fatigue and ...

193

Multiplication Mania  

NSDL National Science Digital Library

Brush up on your multiplication skills with these fun games. Math Magician Let\\'s see how you can work your math magic! Choose either multiplication or division on Level 1. Once you feel comfortable, move on to Level 2. Multiflyer Play this fun game while learning about space exploration. Batter s Up Baseball Take me out to the ball game! Practice your math facts with ...

Thompson, Mrs.

2006-04-01

194

SAMSN1 Is a Tumor Suppressor Gene in Multiple Myeloma12  

PubMed Central

Multiple myeloma (MM), a hematological malignancy characterized by the clonal growth of malignant plasma cells (PCs) in the bone marrow, is preceded by the benign asymptomatic condition, monoclonal gammopathy of undetermined significance (MGUS). Several genetic abnormalities have been identified as critical for the development of MM; however, a number of these abnormalities are also found in patients with MGUS, indicating that there are other, as yet unidentified, factors that contribute to the onset of MM disease. In this study, we identify a Samsn1 gene deletion in the 5TGM1/C57BL/KaLwRij murine model of myeloma. In addition, SAMSN1 expression is reduced in the malignant CD138 + PCs of patients with MM and this reduced expression correlates to total PC burden. We identify promoter methylation as a potential mechanism through which SAMSN1 expression is modulated in human myeloma cell lines. Notably, re-expression of Samsn1 in the 5TGM1 murine PC line resulted in complete inhibition of MM disease development in vivo and decreased proliferation in stromal cell–PC co-cultures in vitro. This is the first study to identify deletion of a key gene in the C57BL/KaLwRij mice that also displays reduced gene expression in patients with MM and is therefore likely to play an integral role in MM disease development. PMID:25117979

Noll, Jacqueline E.; Hewett, Duncan R.; Williams, Sharon A.; Vandyke, Kate; Kok, Chung; To, Luen B.; Zannettino, Andrew C.W.

2014-01-01

195

Multiplication Mania  

NSDL National Science Digital Library

Multiplication Mania is alive & well in 4A! With this online project, you can click on the links below & turn into a multiplication maniac no matter where you are.... Who Wants to Be a Mathionaire? See if you can earn enough money to call yourself a Mathionaire Millionaire! What facts do you need to practice? Choose here & improve your Superstars status! Do you want to practice x5? x2? x4? Choose your number & then Race Against Red to see how well you ...

Macumber, Ms.

2008-10-01

196

Characterization of Multiple Bistratified Retinal Ganglion Cells in A Purkinje Cell Protein 2-Cre Transgenic Mouse Line  

PubMed Central

Retinal ganglion cells are categorized into multiple classes, including multiple types of bistratified ganglion cells (BGCs). The recent use of transgenic mouse lines with specific type(s) of ganglion cells that are labeled by fluorescent markers has facilitated the morphological and physiological studies of BGCs, particularly the directional-selective BGCs. The most important benefit from using transgenic animals is the capability to perform in vivo gene manipulation. In particular, the Cre/LoxP recombination system has become a powerful tool, allowing gene deletion, over-expression, and ectopic expression in a cell type-specific and temporally controlled fashion. The key to this tool is the availability of Cre mouse lines with cell or tissue type-specific expression of Cre recombinase. In this study, we characterized the Cre-positive retinal ganglion cells in a PCP2 (Purkinje cell protein 2)-cre mouse line. We found that all of the Cre-positive retinal ganglion cells were BGCs. Based on morphological criteria, we determined that they can be grouped into five types. The On- and Off-dendrites of three of these types stratified outside of the cholinergic bands and differed from directional selective ganglion cells (DSGCs) morphologically. These cells were negative for Brn-3b and positive for both calretinin and CART retina markers. The remaining two types were identified as putative On-Off and On-DSGCs. This Cre mouse line could be useful for further studies of the molecular and functional properties of BGCs in mice. PMID:23224947

Ivanova, Elena; Lee, Patrick; Pan, Zhuo-Hua

2012-01-01

197

Multiple Sclerosis.  

ERIC Educational Resources Information Center

This module on multiple sclerosis is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then…

Plummer, Nancy; Michael, Nancy, Ed.

198

Lattice Multiplication  

NSDL National Science Digital Library

Leonardo Fibonacci's multiplication algorithm arrays the digits of multiplicands along a rectangular lattice. Read an explanation of the technique, see a few worked examples, and watch the method in action with a Java applet. Clicking a little off-center of any digit of a multiplicand (left to increase, right to decrease) instantly changes resulting products and sums throughout the lattice.

Interactive Math Miscellany And Puzzles, Alexander B.

2011-01-01

199

Finger Multiplication  

ERIC Educational Resources Information Center

The author has been prompted to write this article about finger multiplication for a number of reasons. Firstly there are a number of related articles in past issues of "Mathematics Teaching" ("MT") which have connections to this algorithm. Secondly, very few of his primary teaching students and professional colleagues appear to be aware of the…

Holmes, Bill

2010-01-01

200

Multiple Sclerosis  

Microsoft Academic Search

New therapies challenge the very definition of multiple sclerosis (MS). By classic definitions, MS is a chronic neurological\\u000a disease characterized by plaques or scars in the central nervous system (CNS) as a result of demyelization and atrophy of\\u000a neuronal axons. However, for most diagnosed with MS, symptoms and progression are much more heterogeneous than that definition\\u000a would imply. For most

M. Patricia Leuschen; Kathleen M. Healey; Mary L. Filipi

201

Multiple osteochondromas  

Microsoft Academic Search

Multiple osteochondromas (MO) is characterised by development of two or more cartilage capped bony outgrowths (osteochondromas) of the long bones. The prevalence is estimated at 1:50,000, and it seems to be higher in males (male-to-female ratio 1.5:1). Osteochondromas develop and increase in size in the first decade of life, ceasing to grow when the growth plates close at puberty. They

Judith VMG Bovée

2008-01-01

202

Multiple Reflections  

NSDL National Science Digital Library

This activity on multiple reflections is produced by the International Society for Optical Engineering, the Optical Society of America, and the Association of Universities for Research in Astronomy. Two plane rectangular mirrors, that meet on one edge, produce various reflection patterns. Students learn the relationship between the number of images produced and the orientation of the two mirrors. The site lists all necessary tools and materials and includes numerous helpful photographs and diagrams.

2009-01-13

203

Long Multiplication  

NSDL National Science Digital Library

This Java applet offers an interactive version of the standard "long" multiplication algorithm. Click any digit of either multiplicand slightly off-center (left to increase, right to decrease) and watch the corresponding products change accordingly. In addition to check-boxes to toggle the appearance of trailing zeros and other display choices, the applet also lets you change bases -- from base 3 to base 36.

Interactive Math Miscellany And Puzzles, Alexander B.

2011-01-01

204

Multiple beamforming  

NASA Astrophysics Data System (ADS)

Beamforming techniques are generally based on the assumption that the received signal arrives from a single source. In a realistic situation, however, there is more than one source present and these sources can interact with each other in the beamformer. This paper describes a method that allows us to form multiple beams in order to steer the receiver toward two or more sound sources simultaneously. The main advantage of this procedure is that it includes the full interactions of the different sources in the beamformer. It describes a multiple beamformer in which the interaction of different sources is included in the algorithm. The maximum likelihood principle is used to find the different source amplitude and bearing estimates. The performance of the algorithm is compared for varying conditions with the Cramer-Rao lower bound. Two pre-processors necessary and suitable to ensure globally optimized results are derived from the ideas of Pisarenko and Prony. Finally, a post-processor is proposed to evaluate the success of the multiple beamformer.

Zimmer, W. M. X.

1985-07-01

205

Immediate early gene activation in hippocampus and dorsal striatum: Effects of explicit place and response training  

E-print Network

to associate a location with either food reward, as in the plus-maze task, or safety, as in the Morris water maze (McDonald & White, 1993; Pack- ard & McGaugh, 1996). In contrast, the association between discrete, McDon- ald, & White, 1999; Featherstone & McDonald, 2005). In certain instances, there appears

206

Rodent cell transformation and immediate early gene expression following 60-Hz magnetic field exposure.  

PubMed Central

Some epidemiological studies suggest that exposure to power frequency magnetic fields (MFs) may be associated with an elevated risk of human cancer, but the experimental database remains limited and controversial. We investigated the hypothesis that 60-Hz MF action at the cellular level produces changes in gene expression that can result in neoplastic transformation. Twenty-four hour 200 microT continuous MF exposure produced negative results in two standard transformation systems (Syrian hamster embryo cells and C3H/10T1/2 murine fibroblasts) with or without postexposure to a chemical promoter. This prompted a reexamination of previously reported MF-induced changes in gene expression in human HL60 cells. Extensive testing using both coded and uncoded analyses was negative for an MF effect. Using the same exposure conditions as in the transformation studies, no MF-induced changes in ornithine decarboxylase expression were observed in C3H/10T1/2 cells, casting doubt on a promotional role of MF for the tested cells and experimental conditions. Images Figure 1. Figure 2. A Figure 2. B Figure 2. C Figure 2. D Figure 3. A Figure 3. B Figure 4. Figure 5. A Figure 5. B Figure 5. C Figure 5. D Figure 5. E Figure 6. A Figure 6. B Figure 6. C Figure 6. D Figure 6. E Figure 7. Figure 8. A Figure 8. B Figure 8. C Figure 9. Figure 10. A Figure 10. B PMID:8959408

Balcer-Kubiczek, E K; Zhang, X F; Harrison, G H; McCready, W A; Shi, Z M; Han, L H; Abraham, J M; Ampey, L L; Meltzer, S J; Jacobs, M C; Davis, C C

1996-01-01

207

Stressor and Glucocorticoid-Dependent Induction of the Immediate Early Gene Kruppel-Like Factor 9  

E-print Network

is ex- perienced. Chronic stress leads to neurodegeneration and impair- ment of learning and memory (1­3). By contrast, short-term stress may enhance neurotransmission, promote long-term potentiation (LTP), increase dendritic spine density in the hippocampus, and facilitate memory consolidation and reconsolidation (1

Denver, Robert J.

208

Immediate Early Transcription Activation by Salicylic Acid via the Cauliflower Mosaic Virus as-1 Element  

Microsoft Academic Search

Transgenic tobacco plants carrying a number of regulatory sequences derived from the cauliflower mosaic virus 35s promoter were tested for their response to treatment with salicylic acid (SA), an endogenous signal involved in plant defense responses. PGlucuronidase (GUS) gene fusions with the full-length (-343 to +8) 35s promoter or the -90 truncation were found to be induced by SA. Time

Xiao-Feng Qin; Loreto Holuigue; Diana M. Horvath; Nam-Hai Chua

1994-01-01

209

Multiple sclerosis  

PubMed Central

Multiple sclerosis (MS) is a multifocal demyelinating disease with progressive neurodegeneration caused by an autoimmune response to self-antigens in a genetically susceptible individual. While the formation and persistence of meningeal lymphoid follicles suggest persistence of antigens to drive the continuing inflammatory and humoral response, the identity of an antigen or infectious agent leading to the oligoclonal expansion of B and T cells is unknown. In this review we examine new paradigms for understanding the immunopathology of MS, present recent data defining the common genetic variants underlying disease susceptibility, and explore how improved understanding of immune pathway disruption can inform MS prognosis and treatment decisions. PMID:22466660

Nylander, Alyssa; Hafler, David A.

2012-01-01

210

Engineering Multiple U7snRNA Constructs to Induce Single and Multiexon-skipping for Duchenne Muscular Dystrophy  

PubMed Central

Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disorder caused by mutations in the dystrophin gene. Antisense-mediated exon skipping is one of the most promising approaches for the treatment of DMD but still faces personalized medicine challenges as different mutations found in DMD patients require skipping of different exons. However, 70% of DMD patients harbor dystrophin gene deletions in a mutation-rich area or “hot-spot” in the central genomic region. In this study, we have developed 11 different U7 small-nuclear RNA, to shuttle antisense sequences designed to mask key elements involved in the splicing of exons 45 to 55. We demonstrate that these constructs induce efficient exon skipping both in vitro in DMD patients' myoblasts and in vivo in human DMD (hDMD) mice and that they can be combined into a single vector to achieve a multi skipping of at least 3 exons. These very encouraging results provide proof of principle that efficient multiexon-skipping can be achieved using adeno-associated viral (AAV) vectors encoding multiple U7 small-nuclear RNAs (U7snRNAs), offering therefore very promising tools for clinical treatment of DMD. PMID:22354379

Goyenvalle, Aurelie; Wright, Jordan; Babbs, Arran; Wilkins, Vivienne; Garcia, Luis; Davies, Kay E

2012-01-01

211

Effect of multiple mutations in tricarboxylic acid cycle and one-carbon metabolism pathways on Edwardsiella ictaluri pathogenesis.  

PubMed

Edwardsiella ictaluri is a Gram-negative facultative intracellular pathogen causing enteric septicemia of catfish (ESC). We have shown recently that tricarboxylic acid cycle (TCA) and one-carbon (C1) metabolism are involved in E. ictaluri pathogenesis. However, the effect of multiple mutations in these pathways is unknown. Here, we report four novel E. ictaluri mutants carrying double gene mutations in TCA cycle (Ei?mdh?sdhC, Ei?frdA?sdhC), C1 metabolism (Ei?glyA?gcvP), and both TCA and C1 metabolism pathways (Ei?gcvP?sdhC). In-frame gene deletions were constructed by allelic exchange and mutants' virulence and vaccine efficacy were evaluated using in vivo bioluminescence imaging (BLI) as well as end point mortality counts in catfish fingerlings. Results indicated that all the double gene mutants were attenuated compared to wild-type (wt) E. ictaluri. There was a 1.39-fold average reduction in bioluminescence, and hence bacterial numbers, from all the mutants except for Ei?frdA?sdhC at 144 h post-infection. Vaccination with mutants was very effective in protecting channel catfish against subsequent infection with virulent E. ictaluri 93-146 strain. In particular, immersion vaccination resulted in complete protection. Our results provide further evidence on the importance of TCA and C1 metabolism pathways in bacterial pathogenesis. PMID:24418045

Dahal, N; Abdelhamed, H; Lu, J; Karsi, A; Lawrence, M L

2014-02-21

212

Multiple Nuclear Localization Signals Mediate Nuclear Localization of the GATA Transcription Factor AreA  

PubMed Central

The Aspergillus nidulans GATA transcription factor AreA activates transcription of nitrogen metabolic genes in response to nitrogen limitation and is known to accumulate in the nucleus during nitrogen starvation. Sequence analysis of AreA revealed multiple nuclear localization signals (NLSs), five putative classical NLSs conserved in fungal AreA orthologs but not in the Saccharomyces cerevisiae functional orthologs Gln3p and Gat1p, and one putative noncanonical RRX33RXR bipartite NLS within the DNA-binding domain. In order to identify the functional NLSs in AreA, we constructed areA mutants with mutations in individual putative NLSs or combinations of putative NLSs and strains expressing green fluorescent protein (GFP)-AreA NLS fusion genes. Deletion of all five classical NLSs individually or collectively did not affect utilization of nitrogen sources or AreA-dependent gene expression and did not prevent AreA nuclear localization. Mutation of the bipartite NLS conferred the inability to utilize alternative nitrogen sources and abolished AreA-dependent gene expression likely due to effects on DNA binding but did not prevent AreA nuclear localization. Mutation of all six NLSs simultaneously prevented AreA nuclear accumulation. The bipartite NLS alone strongly directed GFP to the nucleus, whereas the classical NLSs collaborated to direct GFP to the nucleus. Therefore, AreA contains multiple conserved NLSs, which show redundancy and together function to mediate nuclear import. The noncanonical bipartite NLS is conserved in GATA factors from Aspergillus, yeast, and mammals, indicating an ancient origin. PMID:24562911

Hunter, Cameron C.; Siebert, Kendra S.; Downes, Damien J.; Wong, Koon Ho; Kreutzberger, Sara D.; Fraser, James A.; Clarke, David F.; Hynes, Michael J.; Davis, Meryl A.

2014-01-01

213

The Extraction of Simple Relationships in Growth Factor-Specific Multiple-Input and Multiple-Output Systems in Cell-Fate Decisions by Backward Elimination PLS Regression  

PubMed Central

Cells use common signaling molecules for the selective control of downstream gene expression and cell-fate decisions. The relationship between signaling molecules and downstream gene expression and cellular phenotypes is a multiple-input and multiple-output (MIMO) system and is difficult to understand due to its complexity. For example, it has been reported that, in PC12 cells, different types of growth factors activate MAP kinases (MAPKs) including ERK, JNK, and p38, and CREB, for selective protein expression of immediate early genes (IEGs) such as c-FOS, c-JUN, EGR1, JUNB, and FOSB, leading to cell differentiation, proliferation and cell death; however, how multiple-inputs such as MAPKs and CREB regulate multiple-outputs such as expression of the IEGs and cellular phenotypes remains unclear. To address this issue, we employed a statistical method called partial least squares (PLS) regression, which involves a reduction of the dimensionality of the inputs and outputs into latent variables and a linear regression between these latent variables. We measured 1,200 data points for MAPKs and CREB as the inputs and 1,900 data points for IEGs and cellular phenotypes as the outputs, and we constructed the PLS model from these data. The PLS model highlighted the complexity of the MIMO system and growth factor-specific input-output relationships of cell-fate decisions in PC12 cells. Furthermore, to reduce the complexity, we applied a backward elimination method to the PLS regression, in which 60 input variables were reduced to 5 variables, including the phosphorylation of ERK at 10 min, CREB at 5 min and 60 min, AKT at 5 min and JNK at 30 min. The simple PLS model with only 5 input variables demonstrated a predictive ability comparable to that of the full PLS model. The 5 input variables effectively extracted the growth factor-specific simple relationships within the MIMO system in cell-fate decisions in PC12 cells. PMID:24039801

Akimoto, Yuki; Yugi, Katsuyuki; Uda, Shinsuke; Kudo, Takamasa; Komori, Yasunori; Kubota, Hiroyuki; Kuroda, Shinya

2013-01-01

214

Modeling Multiplication with Fractions  

NSDL National Science Digital Library

Students will relate multiplication strategies with fractions through problem solving situations. This lesson connects prior understanding of multiplication and equal groups to multiplication of fractions.

Ratasky, Joseph

2012-08-18

215

Multiple sclerosis  

PubMed Central

Summary Preliminary studies have suggested that a high salt diet may play a role in the development of autoimmune disease and possibly multiple sclerosis (MS). Promising clinical trial results for 2 new therapies for MS have been reported. Dimethyl fumarate, also known by its investigational name BG-12, became the third oral disease-modifying therapy for MS to be Food and Drug Administration (FDA)–approved in March 2013. Interestingly, dimethyl fumarate served as the active compound used for the treatment of psoriasis for decades. Alemtuzumab remains under investigation and is not currently FDA-approved for treatment of MS. Other drugs currently approved for alternative indications are being investigated for use in MS. Additionally, an investigation of alternative dosing strategies for glatiramer acetate suggests that patients may benefit from a higher dose formulation and less frequent medication administration. Advances in basic science research have identified another potential autoantigenic target in MS, KIR4.1, which may provide further insight into MS pathophysiology. PMID:24175156

Boster, Aaron L.; Racke, Michael K.

2013-01-01

216

Multiple System Atrophy  

MedlinePLUS

NINDS Multiple System Atrophy Information Page Condensed from Multiple System Atrophy Fact Sheet Table of Contents (click to jump to sections) ... being done? Clinical Trials Organizations What is Multiple System Atrophy? Multiple system atrophy (MSA) is a progressive ...

217

Relatively low proportion of dystrophin gene deletions in Israeili Duchenne and Becker muscular dystrophy patients  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the X-linked dystrophin gene. The most common mutations in western populations are deletions that are spread non-randomly throughout the gene. Molecular analysis of the dystrophin gene structure by hybridization of the full length cDNA to Southern blots and by PCR in 62 unrelated Israeli

Ruth Shomrat; Eithan Gluck; Cyril Legum; Yosef Shiloh

1994-01-01

218

Genome-Wide Analysis of Syntenic Gene Deletion in the Grasses  

PubMed Central

The grasses, Poaceae, are one of the largest and most successful angiosperm families. Like many radiations of flowering plants, the divergence of the major grass lineages was preceded by a whole-genome duplication (WGD), although these events are not rare for flowering plants. By combining identification of syntenic gene blocks with measures of gene pair divergence and different frequencies of ancient gene loss, we have separated the two subgenomes present in modern grasses. Reciprocal loss of duplicated genes or genomic regions has been hypothesized to reproductively isolate populations and, thus, speciation. However, in contrast to previous studies in yeast and teleost fishes, we found very little evidence of reciprocal loss of homeologous genes between the grasses, suggesting that post-WGD gene loss may not be the cause of the grass radiation. The sets of homeologous and orthologous genes and predicted locations of deleted genes identified in this study, as well as links to the CoGe comparative genomics web platform for analyzing pan-grass syntenic regions, are provided along with this paper as a resource for the grass genetics community. PMID:22275519

Schnable, James C.; Freeling, Michael; Lyons, Eric

2012-01-01

219

Rare large homozygous CFTR gene deletion in an Iranian patient with cystic fibrosis.  

PubMed

Cystic fibrosis, a common autosomal recessive genetic disorder among Caucasians, is caused by defects in the transmembrane conductance regulatory (CFTR) gene. The analysis of CFTR gene mutations is useful to better characterize the disease, and for preconceptional screening, prenatal and preimplantation genetic diagnosis. Here we report the results of a genetic analysis in a 16-year-old boy from southwestern Iran diagnosed as having cystic fibrosis in infancy based on gastrointestinal and pulmonary manifestations, with positive sweat chloride tests. He lacked both normal and mutant forms of the fragment corresponding to the ?F508 allele in initial genetic studies. Multiplex ligation-dependent probe amplification-based testing revealed a homozygous deletion spanning exons 4 to 10 of the CFTR gene. We predict an in-frame deletion removing 373 amino acids based on our sequencing results. Determining CFTR gene mutations in patients and their family members would be helpful to prevent the occurrence of new cases, especially in populations in which consanguinity is common. PMID:25133155

Farjadian, Shirin; Moghtaderi, Mozhgan; Zuntini, Roberta; Ferrari, Simona

2014-08-16

220

Parathyroid hormone ablation alters erythrocyte parameters that are rescued by calcium-sensing receptor gene deletion.  

PubMed

The mechanisms by which parathyroid hormone (PTH) produces anemia are unclear. Parathyroid hormone secretion is regulated by the extracellular Ca2+ -sensing receptor. We investigated the effects of ablating PTH on hematological indices and erythrocytes volume regulation in wild-type, PTH-null, and Ca2+ -sensing receptor-null/PTH-null mice. The erythrocyte parameters were measured in whole mouse blood, and volume regulatory systems were determined by plasma membrane K+ fluxes, and osmotic fragility was measured by hemoglobin determination at varying osmolarities. We observed that the absence of PTH significantly increases mean erythrocyte volume and reticulocyte counts, while decreasing erythrocyte counts, hemoglobin, hematocrit, and mean corpuscular hemoglobin concentration. These changes were accompanied by increases in erythrocyte cation content, a denser cell population, and increased K+ permeability, which were in part mediated by activation of the K+ /Cl- cotransporter and Gardos channel. In addition we observed that erythrocyte osmotic fragility in PTH-null compared with wild-type mice was enhanced. When Ca2+ -sensing receptor gene was deleted on the background of PTH-null mice, we observed that several of the alterations in erythrocyte parameters of PTH-null mice were largely rescued, particularly those related to erythrocyte volume, K+ fluxes and osmotic fragility, and became similar to those observed in wild-type mice. Our results demonstrate that Ca2+ -sensing receptor and parathyroid hormone are functionally coupled to maintain erythrocyte homeostasis. PMID:23528155

Romero, Jose R; Youte, Rodeler; Brown, Edward M; Pollak, Martin R; Goltzman, David; Karaplis, Andrew; Pong, Lie-Chin; Chien, Lawrence; Chattopadhyay, Naibedya; Rivera, Alicia

2013-07-01

221

Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome  

Microsoft Academic Search

Williams-Beuren syndrome (WBS) is generally the consequence of an interstitial microdeletion at 7q11.23, which includes the elastin gene, thus causing hemizygosity at the elastin gene locus. The origin of the deletion has been reported by many authors to be maternal in ~60% and paternal in 40% of cases. Segregation analysis of grandparental markers flanking the microdeletion region in WBS patients

Fabrizio Dutly; Albert Schinzel

1996-01-01

222

Left-sided cryptorchidism in mice with Wilms' tumour 1 gene deletion in gubernaculum testis.  

PubMed

A significant number of patients with germline mutations in the Wilms' tumour 1 (WT1) gene, a transcriptional factor essential for early renal and gonadal development, display cryptorchidism or non-scrotal testis position. We show here that WT1 is expressed during development in the mouse gubernacular ligament connecting the testis to the abdominal wall. Conditional inactivation of Wt1 in the gubernaculum (GU-WT1KO animals) resulted in abnormal differentiation of the gubernacula during development and, in about 40% of adult males, unilateral, always left-sided, cryptorchidism. At birth the right testis was positioned above the processus vaginalis and eventually moved into the developing scrotal pouch. In affected mutants the left testis was displaced from the normal position and the left processus vaginalis failed to form. The analysis of testicular descent at different stages of postnatal development suggests that unilateral cryptorchidism might be caused by asymmetry in the positions of the abdominal organs providing a higher degree of mobility for the left testis. Spermatogenesis in GU-WT1KO animals was blocked in cryptorchid testes located in a high pararenal position, but was maintained in testes located in a low abdominal position. Conditional inactivation of both Wt1 and androgen receptor (Ar) genes in the gubernaculum led to a bilateral asymmetrical cryptorchidism in all mutant males, with the left testis again located higher than the right one. The malformations induced by WT1 and AR deficiency in the gubernaculum and processus vaginalis, in combination with mechanical constraints on testis descent, determine the final position of the testes. In summary, our data indicate that WT1 is directly involved in gubernaculum differentiation. Taken together, the results of the study underline the complex nature of testicular descent, with an involvement in this process of several genetic factors and developmental events. PMID:23288785

Kaftanovskaya, Elena M; Neukirchner, Giselle; Huff, Vicki; Agoulnik, Alexander I

2013-05-01

223

Dual involvement of G-substrate in motor learning revealed by gene deletion  

PubMed Central

In this study, we generated mice lacking the gene for G-substrate, a specific substrate for cGMP-dependent protein kinase uniquely located in cerebellar Purkinje cells, and explored their specific functional deficits. G-substrate–deficient Purkinje cells in slices obtained at postnatal weeks (PWs) 10–15 maintained electrophysiological properties essentially similar to those from WT littermates. Conjunction of parallel fiber stimulation and depolarizing pulses induced long-term depression (LTD) normally. At younger ages, however, LTD attenuated temporarily at PW6 and recovered thereafter. In parallel with LTD, short-term (1 h) adaptation of optokinetic eye movement response (OKR) temporarily diminished at PW6. Young adult G-substrate knockout mice tested at PW12 exhibited no significant differences from their WT littermates in terms of brain structure, general behavior, locomotor behavior on a rotor rod or treadmill, eyeblink conditioning, dynamic characteristics of OKR, or short-term OKR adaptation. One unique change detected was a modest but significant attenuation in the long-term (5 days) adaptation of OKR. The present results support the concept that LTD is causal to short-term adaptation and reveal the dual functional involvement of G-substrate in neuronal mechanisms of the cerebellum for both short-term and long-term adaptation. PMID:19218432

Endo, Shogo; Shutoh, Fumihiro; Dinh, Tung Le; Okamoto, Takehito; Ikeda, Toshio; Suzuki, Michiyuki; Kawahara, Shigenori; Yanagihara, Dai; Sato, Yamato; Yamada, Kazuyuki; Sakamoto, Toshiro; Kirino, Yutaka; Hartell, Nicholas A.; Yamaguchi, Kazuhiko; Itohara, Shigeyoshi; Nairn, Angus C.; Greengard, Paul; Nagao, Soichi; Ito, Masao

2009-01-01

224

Otx2 Gene Deletion in Adult Mouse Retina Induces Rapid RPE Dystrophy and Slow Photoreceptor Degeneration  

Microsoft Academic Search

BackgroundMany developmental genes are still active in specific tissues after development is completed. This is the case for the homeobox gene Otx2, an essential actor of forebrain and head development. In adult mouse, Otx2 is strongly expressed in the retina. Mutations of this gene in humans have been linked to severe ocular malformation and retinal diseases. It is, therefore, important

Francis Béby; Michael Housset; Nicolas Fossat; Coralie Le Greneur; Frédéric Flamant; Pierre Godement; Thomas Lamonerie; Thomas A. Reh

2010-01-01

225

Lymphopenia in Interleukin (IL)-7 Gene-deleted Mice Identifies IL7 as a Nonredundant Cytokine  

Microsoft Academic Search

Summary Interleukin (IL)-7 is a potent stimulus for immature T and B cells and, to a lesser extent, mature T ceils. We have inactivated the Ib7 gene in the mouse germline by using gene-targeting tech- niques to further understand the biology of IL-7. Mutant mice were highly lymphopenic in the peripheral blood and lymphoid organs. Bone marrow B lymphopoiesis was

Paulo Vieira; Linda A. Lucian; Tom McNeil; Stefan E. G. Burdach; Richard Murray

1995-01-01

226

Gene Deletions in Mycobacterium bovis BCG Stimulate Increased CD8+ T Cell Responses.  

PubMed

Mycobacteria, the etiological agents of tuberculosis and leprosy, have coevolved with mammals for millions of years and have numerous ways of suppressing their host's immune response. It has been suggested that mycobacteria may contain genes that reduce the host's ability to elicit CD8(+) T cell responses. We screened 3,290 mutant Mycobacterium bovis bacillus Calmette Guerin (BCG) strains to identify genes that decrease major histocompatibility complex (MHC) class I presentation of mycobacterium-encoded epitope peptides. Through our analysis, we identified 16 mutant BCG strains that generated increased transgene product-specific CD8(+) T cell responses. The genes disrupted in these mutant strains had disparate predicted functions. Reconstruction of strains via targeted deletion of genes identified in the screen recapitulated the enhanced immunogenicity phenotype of the original mutant strains. When we introduced the simian immunodeficiency virus (SIV) gag gene into several of these novel BCG strains, we observed enhanced SIV Gag-specific CD8(+) T cell responses in vivo. This study demonstrates that mycobacteria carry numerous genes that act to dampen CD8(+) T cell responses and suggests that genetic modification of these genes may generate a novel group of recombinant BCG strains capable of serving as more effective and immunogenic vaccine vectors. PMID:25287928

Panas, Michael W; Sixsmith, Jaimie D; White, KeriAnn; Korioth-Schmitz, Birgit; Shields, Shana T; Moy, Brian T; Lee, Sunhee; Schmitz, Joern E; Jacobs, William R; Porcelli, Steven A; Haynes, Barton F; Letvin, Norman L; Gillard, Geoffrey O

2014-12-01

227

Constraint-Based Analysis of Gene Deletion in a Metabolic Network  

E-print Network

deletion. #12;4 1 A 3 e ee 5 4 B 1 2 System boundary 7 6 5 e e2 3 e Fig. 1. Network ILLUSNET and the reversibility type of the reaction associated with the deleted gene. 1 Introduction Constraint-based models have. However, although the assumption of optimality for a wild-type biological system is justifiable, the same

Bockmayr, Alexander

228

In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome.  

PubMed

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies. PMID:12525539

Faivre, L; Gorlin, R J; Wirtz, M K; Godfrey, M; Dagoneau, N; Samples, J R; Le Merrer, M; Collod-Beroud, G; Boileau, C; Munnich, A; Cormier-Daire, V

2003-01-01

229

Partial ABCC8 gene deletion mutations causing diazoxide-unresponsive hyperinsulinaemic hypoglycaemia.  

PubMed

Inactivating mutations in the pancreatic beta cell ATP-sensitive potassium (K(ATP) ) channel genes are identified by sequencing in approximately 80% of patients with diazoxide-unresponsive hyperinsulinaemic hypoglycaemia (HH). Genetic testing is clinically important as the mode of inheritance of a K(ATP) channel mutation(s) provides information on the histological subtype. For example in patients with a single paternally inherited mutation a focal lesion is possible and once confirmed, the patient can undergo a curative lesionectomy. By contrast, recessive inheritance indicates diffuse disease, which requires near-total pancreatectomy, if medical management is unsuccessful. We investigated ABCC8 and KCNJ11 gene dosage in 29 probands from a cohort of 125 with diazoxide-unresponsive HH where sequencing did not provide a genetic diagnosis. We identified heterozygous partial ABCC8 deletions in four probands. In two cases with focal pancreatic disease, a paternally inherited deletion was found. Two other probands with diffuse pancreatic disease were compound heterozygotes for a deletion and a recessively acting mutation that had been identified by sequencing. Family member studies confirmed compound heterozygosity for the deletion and the missense mutation in two affected siblings of one proband. Heterozygous deletions of the ABCC8 gene are a rare, but important cause of diazoxide-unresponsive HH. Dosage analysis should be undertaken in all patients when sequencing analysis does not confirm the genetic diagnosis as confirmation of the mode of inheritance can guide clinical management and will provide important information regarding recurrence risk. PMID:21978130

Flanagan, Se; Damhuis, A; Banerjee, I; Rokicki, D; Jefferies, C; Kapoor, Rr; Hussain, K; Ellard, S

2012-05-01

230

PAX3 gene deletion detected by microarray analysis in a girl with hearing loss  

PubMed Central

Deletions of the PAX3 gene have been rarely reported in the literature. Mutations of this gene are a common cause of Waardenburg syndrome type 1 and 3. We report a 16?year old female presenting hearing loss and normal intellectual development, without major features of Waardenburg syndrome type 1, and without family history of the syndrome. Her phenotype, however, overlaps with features of craniofacial-deafness-hand syndrome. Microarray analysis showed ~862?kb de novo deletion at 2q36.1 including PAX3. The above findings suggest that the rearrangement found in our patient appeared de novo and with high probability is a cause of her phenotype. PMID:24839464

2014-01-01

231

A Partial Gene Deletion of SLC45A2 Causes Oculocutaneous Albinism in Doberman Pinscher Dogs  

PubMed Central

The first white Doberman pinscher (WDP) dog was registered by the American Kennel Club in 1976. The novelty of the white coat color resulted in extensive line breeding of this dog and her offspring. The WDP phenotype closely resembles human oculocutaneous albinism (OCA) and clinicians noticed a seemingly high prevalence of pigmented masses on these dogs. This study had three specific aims: (1) produce a detailed description of the ocular phenotype of WDPs, (2) objectively determine if an increased prevalence of ocular and cutaneous melanocytic tumors was present in WDPs, and (3) determine if a genetic mutation in any of the genes known to cause human OCA is causal for the WDP phenotype. WDPs have a consistent ocular phenotype of photophobia, hypopigmented adnexal structures, blue irides with a tan periphery and hypopigmented retinal pigment epithelium and choroid. WDPs have a higher prevalence of cutaneous melanocytic neoplasms compared with control standard color Doberman pinschers (SDPs); cutaneous tumors were noted in 12/20 WDP (<5 years of age: 4/12; >5 years of age: 8/8) and 1/20 SDPs (p<0.00001). Using exclusion analysis, four OCA causative genes were investigated for their association with WDP phenotype; TYR, OCA2, TYRP1 and SLC45A2. SLC45A2 was found to be linked to the phenotype and gene sequencing revealed a 4,081 base pair deletion resulting in loss of the terminus of exon seven of SLC45A2 (chr4?77,062,968–77,067,051). This mutation is highly likely to be the cause of the WDP phenotype and is supported by a lack of detectable SLC45A2 transcript levels by reverse transcriptase PCR. The WDP provides a valuable model for studying OCA4 visual disturbances and melanocytic neoplasms in a large animal model. PMID:24647637

Winkler, Paige A.; Gornik, Kara R.; Ramsey, David T.; Dubielzig, Richard R.; Venta, Patrick J.; Petersen-Jones, Simon M.; Bartoe, Joshua T.

2014-01-01

232

Telomeric gene deletion and intrachromosomal amplification in antimony-resistant Leishmania.  

PubMed

Antimonials are still the mainstay of treatment against leishmaniasis but drug resistance is increasing. We carried out short read next-generation sequencing (NGS) and comparative genomic hybridization (CGH) of three independent Leishmania major antimony-resistant mutants. Copy number variations were consistently detected with both NGS and CGH. A major attribute of antimony resistance was a novel terminal deletion of variable length (67?kb to 204?kb) of the polyploid chromosome 31 in the three mutants. Terminal deletions in two mutants occurred at the level of inverted repeated sequences. The AQP1 gene coding for an aquaglyceroporin was part of the deleted region and its transfection into resistant mutants reverted resistance to SbIII. We also highlighted an intrachromosomal amplification of a subtelomeric locus on chromosome 34 in one mutant. This region encoded for ascorbate-dependent peroxidase (APX) and glucose-6-phosphate dehydrogenase (G6PDH). Overexpression of these genes in revertant backgrounds demonstrated resistance to SbIII and protection from reactive oxygen species (ROS). Generation of a G6PDH null mutant in one revertant exhibited SbIII sensitivity and a decreased protection of ROS. Our genomic analyses and functional validation highlighted novel genomic rearrangements, functionally important resistant loci and the implication of new genes in antimony resistance in Leishmania. PMID:23421749

Mukherjee, Angana; Boisvert, Sébastien; Monte-Neto, Rubens Lima do; Coelho, Adriano C; Raymond, Frederic; Mukhopadhyay, Rita; Corbeil, Jacques; Ouellette, Marc

2013-04-01

233

Gene Deletion of VIP Leads to Increased Mortality Associated with Progressive Right Ventricular Hypertrophy  

PubMed Central

Vasoactive Intestinal Peptide (VIP) knockout mice exhibit asthma, pulmonary hypertension, and left ventricular wall thinning. Humans with these disorders have premature death. We show here that VIP KO mice have reduced survival (100% mortality at 20 months), vs. 100% survival among WT C57BL/6 mice. Moreover, the ratios of weights of right ventricle divided by left ventricle plus septum were progressively increased in VIP KO mice with age. Core temperatures were lower in VIP KO mice when compared to WT littermates, with an associated pro-inflammatory cytokine milieu. Overall, our results indicate that VIP is important for survival in mice. Its absence leads to increased mortality, with progressive right ventricular hypertrophy as a surrogate of pulmonary hypertension, lower body weight, hypothermia, and pro-inflammatory milieu. These studies support VIP as a novel therapeutic agent in pulmonary hypertension. PMID:24860842

Szema, Anthony M.; Hamidi, Sayyed A.

2014-01-01

234

Increased biomass production and glycogen accumulation in apcE gene deleted Synechocystis sp. PCC 6803  

PubMed Central

The effect of phycobilisome antenna-truncation in the cyanobacterium Synechocystis sp. PCC 6803 on biomass production and glycogen accumulation have not yet been fully clarified. To investigate these effects here, the apcE gene, which encodes the anchor protein linking the phycobilisome to the thylakoid membrane, was deleted in a glucose tolerant strain of Synechocystis sp. PCC 6803. Biomass production of the apcE-deleted strain under photoautotrophic and atmospheric air conditions was 1.6 times higher than that of strain PCC 6803 (1.32?±?0.01 versus 0.84?±?0.07 g cell-dry weight L?1, respectively) after 15 days of cultivation. In addition, the glycogen content of the apcE-deleted strain (24.2?±?0.7%) was also higher than that of strain PCC 6803 (11.1?±?0.3%). Together, these results demonstrate that antenna truncation by deleting the apcE gene was effective for increasing biomass production and glycogen accumulation under photoautotrophic and atmospheric air conditions in Synechocystis sp. PCC 6803. PMID:24949254

2014-01-01

235

gamma Heavy Chain Disease in Man: cDNA Sequence Supports Partial Gene Deletion Model  

Microsoft Academic Search

Human gamma heavy chain disease (HCD) is characterized by the presence in serum of a short monoclonal Ig gamma chain unattached to light chains. Although most HCD proteins have internal deletions, in some the defect is NH2-terminal. The OMM gamma 3 HCD serum protein is of the latter type, having undergone an extensive NH2-terminal deletion with a sequence starting within

Alice Alexander; Michael Steinmetz; Denis Barritault; Blas Frangione; Edward C. Franklin; Leroy Hood; Joel N. Buxbaum

1982-01-01

236

Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis: a new X linked contiguous gene deletion syndrome?  

Microsoft Academic Search

We describe a family with four members, a mother, two sons, and a daughter, who show clinical features consistent with X linked Alport syndrome. The two males presented with additional features including mental retardation, dysmorphic facies with marked midface hypoplasia, and elliptocytosis. The elliptocytosis was not associated with any detectable abnormalities in red cell membrane proteins; red cell membrane stability

J J Jonsson; A Renieri; P G Gallagher; C E Kashtan; E M Cherniske; M Bruttini; M Piccini; F Vitelli; A Ballabio; B R Pober

1998-01-01

237

p53 gene deletion and trisomy 12 in hairy cell leukemia and its variant  

Microsoft Academic Search

The deletion or mutation of the p53 tumour suppressor gene on chromosome 17p13 is known to be associated with aggressive disease in several B-cell malignancies. The present study describes the p53 gene status in 20 cases of hairy cell leukemia (HCL) and in 12 cases of its morphological variant (HCL-V) by fluorescsence in situ hybridization (FISH). A high incidence of

Kalliopi Vallianatou; Vasantha Brito-Babapulle; Estela Matutes; Shayne Atkinson; Daniel Catovsky

1999-01-01

238

The integrated response of primary metabolites to gene deletions and the environment.  

PubMed

Intracellular metabolites arise from the molecular integration of genomic and environmental factors that jointly determine metabolic activity. However, it is not clear how the interplay of genotype, nutrients, growth, and fluxes affect metabolite concentrations globally. Here we used quantitative metabolomics to assess the combined effect of environment and genotype on the metabolite composition of a yeast cell. We analyzed a panel of 34 yeast single-enzyme knockout mutants grown on three archetypical carbon sources, generating a dataset of 400 unique metabolome samples. The different carbon sources globally affected the concentrations of intermediates, both directly, by changing the thermodynamic potentials (?(r)G) as a result of the substrate influx, and indirectly, by cellular regulation. In contrast, enzyme deletion elicited only local accumulation of the metabolic substrate immediately upstream of the lesion. Key biosynthetic precursors and cofactors were generally robust under all tested perturbations in spite of changes in fluxes and growth rate. PMID:23340584

Ewald, Jennifer Christina; Matt, Tanja; Zamboni, Nicola

2013-03-01

239

Detection of 98% of DMD\\/BMD gene deletions by polymerase chain reaction  

Microsoft Academic Search

We describe oligonucleotide primer sequences that can be used to amplify eight exons plus the muscle promoter of the dystrophin gene in a single multiplex polymerase chain reaction (PCR). When used in conjunction with an existing primer set, these two multiplex reactions detect about 98% of deletions in patients with Duchenne or Becker muscular dystrophy (DMD, BMD). Furthermore, these primers

Alan H. Beggs; Michel Koenig; Frederick M. Boyce; Louis M. Kunkel

1990-01-01

240

PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas  

SciTech Connect

From 1971 to 1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF{sub 1} mice irradiated with {sup 60}Co {gamma} rays or JANUS fission-spectrum neutrons; normal and tumor tissues from mice in these studies were preserved in paraffin blocks. A polymerase chain reaction (PCR) technique has been developed to detect deletions in the mouse retinoblastoma (mRb) gene in the paraffin-embedded tissues. Microtomed sections were used as the DNA source in PCR reaction mixtures. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. The absence of any of these fragments (relative to control PCR products) on a Southern blot indicated a deletion of that portion of the mRb gene. The tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice (569 cGy of {sup 60}Co {gamma} rays or 60 cGy of JANUS neutrons, doses that have been found to have approximately equal biological effectiveness in the BCF, mouse) were analyzed for mRb deletions. In all normal mouse tissues studies, all six mRb exon fragments were present on Southem blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, I of 6 tumors from {gamma}-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice had a deletion in one or both mRb alleles. All deletions detected were in the 5{prime} region of the mRb gene.

Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

1993-04-01

241

PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas  

SciTech Connect

From 1971--1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF{sub 1} mice irradiated with {sup 60}Co {gamma}-rays or JANUS fission-spectrum neutrons. Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse retinoblastoma (mRb) gene. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice were analyzed for mRb deletions. In all normal mouse tissues studies all six mRb exon fragments were present on Southern blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, 1 of 6 tumors from {gamma}-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5{prime} region of the mRb gene.

Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

1994-05-01

242

Metabolic flux balance analysis and the in silico analysis of Escherichia coli K-12 gene deletions  

PubMed Central

Background Genome sequencing and bioinformatics are producing detailed lists of the molecular components contained in many prokaryotic organisms. From this 'parts catalogue' of a microbial cell, in silico representations of integrated metabolic functions can be constructed and analyzed using flux balance analysis (FBA). FBA is particularly well-suited to study metabolic networks based on genomic, biochemical, and strain specific information. Results Herein, we have utilized FBA to interpret and analyze the metabolic capabilities of Escherichia coli. We have computationally mapped the metabolic capabilities of E. coli using FBA and examined the optimal utilization of the E. coli metabolic pathways as a function of environmental variables. We have used an in silico analysis to identify seven gene products of central metabolism (glycolysis, pentose phosphate pathway, TCA cycle, electron transport system) essential for aerobic growth of E. coli on glucose minimal media, and 15 gene products essential for anaerobic growth on glucose minimal media. The in silico tpi-, zwf, and pta- mutant strains were examined in more detail by mapping the capabilities of these in silico isogenic strains. Conclusions We found that computational models of E. coli metabolism based on physicochemical constraints can be used to interpret mutant behavior. These in silica results lead to a further understanding of the complex genotype-phenotype relation. Supplementary information: PMID:11001586

Edwards, Jeremy S; Palsson, Bernhard O

2000-01-01

243

Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions  

PubMed Central

Systematic genetic interaction studies have illuminated many cellular processes. Here we quantitatively examine genetic interactions among 26 Saccharomyces cerevisiae genes conferring resistance to the DNA-damaging agent methyl methanesulfonate (MMS), as determined by chemogenomic fitness profiling of pooled deletion strains. We constructed 650 double-deletion strains, corresponding to all pairings of these 26 deletions. The fitness of single- and double-deletion strains were measured in the presence and absence of MMS. Genetic interactions were defined by combining principles from both statistical and classical genetics. The resulting network predicts that the Mph1 helicase has a role in resolving homologous recombination–derived DNA intermediates that is similar to (but distinct from) that of the Sgs1 helicase. Our results emphasize the utility of small molecules and multifactorial deletion mutants in uncovering functional relationships and pathway order. PMID:17206143

St Onge, Robert P; Mani, Ramamurthy; Oh, Julia; Proctor, Michael; Fung, Eula; Davis, Ronald W; Nislow, Corey; Roth, Frederick P; Giaever, Guri

2009-01-01

244

Left-sided cryptorchidism in mice with Wilms Tumour 1 gene deletion in gubernaculum testis  

PubMed Central

A significant number of patients with germline mutations in the Wilms tumour 1 (WT1) gene, a transcriptional factor essential for early renal and gonadal development, displays cryptorchidism or non-scrotal testis position. We show here that WT1 is expressed during development in the mouse gubernacular ligament connecting the testis to the abdominal wall. Conditional inactivation of Wt1 in the gubernaculum (GU-WT1KO animals) resulted in abnormal differentiation of the gubernacula during development and in about 40 % adult males, unilateral, always left-sided, cryptorchidism. At birth the right testis was positioned above the processus vaginalis and eventually moved into the developing scrotal pouch. In affected mutants the left testis was displaced from the normal position and the left processus vaginalis failed to form. The analysis of testicular descent at different stages of postnatal development suggests that the unilateral cryptorchidism might be caused by the asymmetry in the position of abdominal organs providing a higher degree of mobility for the left testis. Spermatogenesis in GU-WT1KO animals was blocked in cryptorchid testes located in a high pararenal position but was maintained in testes located in a low abdominal position. Conditional inactivation of both Wt1 and androgen receptor (Ar) genes in gubernaculum led to a bilateral asymmetrical cryptorchidism in all mutant males with the left testis again located higher than the right one. The malformations induced by WT1 and AR deficiency in gubernaculum and processus vaginalis, in combination with mechanical constraints on testis descent, determine the final position of the testes. In summary, our data indicate that WT1 is directly involved in gubernaculum differentiation. Taken together the results of the study underline the complex nature of testicular descent with an involvement in this process of several genetic factors and developmental events. PMID:23288785

Kaftanovskaya, Elena M.; Neukirchner, Giselle; Huff, Vicki; Agoulnik, Alexander I.

2013-01-01

245

T Cell Receptor Gene Deletion Circles Identify Recent Thymic Emigrants in the Peripheral T Cell Pool  

Microsoft Academic Search

Progenitor cells undergo T cell receptor (TCR) gene rearrangements during their intrathymic differentiation to become T cells. Rearrangements of the variable (V), diversity (D), and joining (J) segments of the TCR genes result in deletion of the intervening chromosomal DNA and the formation of circular episomes as a byproduct. Detection of these extrachromosomal excision circles in T cells located in

Fan-Kun Kong; Chen-Lo H. Chen; Adrien Six; Richard D. Hockett; Max D. Cooper

1999-01-01

246

Multiple Assessments for Multiple Intelligences. Third Edition.  

ERIC Educational Resources Information Center

This book is designed to align assessment with instructional practices that promote the development of the multiple intelligences outlined by Howard Gardner. To facilitate the use of multiple assessments for the multiple intelligences, the information in this book is transferable to the classroom. The book explains how a teacher can design…

Bellanca, James; Chapman, Carolyn; Swartz, Elizabeth

247

Multiple-Ring Digital Communication Network  

NASA Technical Reports Server (NTRS)

Optical-fiber digital communication network to support data-acquisition and control functions of electric-power-distribution networks. Optical-fiber links of communication network follow power-distribution routes. Since fiber crosses open power switches, communication network includes multiple interconnected loops with occasional spurs. At each intersection node is needed. Nodes of communication network include power-distribution substations and power-controlling units. In addition to serving data acquisition and control functions, each node acts as repeater, passing on messages to next node(s). Multiple-ring communication network operates on new AbNET protocol and features fiber-optic communication.

Kirkham, Harold

1992-01-01

248

Temporal Association of Herpes Simplex Virus ICP4 with Cellular Complexes Functioning at Multiple Steps in PolII Transcription  

PubMed Central

The herpes simplex virus type 1 (HSV-1) immediate early protein, ICP4, participates in the regulation of viral gene expression by both activating and repressing RNA polII transcription. We used affinity purification of ICP4 expressed in infected cells followed by mass spectrometry and western blot analysis to determine the composition of cellular complexes associated with ICP4 throughout infection. ICP4 was associated with TFIID complexes containing a distinct set of TAFs. These complexes were most abundant early, but were detected throughout infection, whereas Mediator was found in ICP4 containing complexes later in infection, indicating a temporal pattern for the utilization of these complexes for the transcription of the viral genome. The form of Mediator copurifying with ICP4 was enriched for the kinase domain and also lacked the activator-specific component, Med26, suggesting that Mediator-ICP4 interactions may be involved in repression of viral transcription. The N-terminal 774 amino acids of ICP4, which retains partial function, were sufficient to form complexes with TFIID and Mediator, although these interactions were not as strong as with full-length ICP4. Additionally, components involved in transcription elongation, chromatin remodeling, and mRNA processing were isolated with ICP4. Together our data indicate that ICP4 plays a more integrated role in mediating HSV transcription, possibly affecting multiple steps in transcription and gene expression. PMID:24147125

Wagner, Lauren M.; DeLuca, Neal A.

2013-01-01

249

Multiple Sclerosis Foundation  

MedlinePLUS

... in La Junta, CO more info 06 2014 Multiple Sclerosis Foundation Gala honoring Dr. Daniel Kantor, MD in ... LLC. Website Design by SimplexWeb © Copyright 2000-2013 Multiple Sclerosis Foundation - All Rights Reserved

250

Multiple sclerosis - discharge  

MedlinePLUS

Your doctor has told you that you have multiple sclerosis. This disease affects the brain and spinal cord ( ... bladder is not working correctly. Some people with multiple sclerosis need to use a urinary catheter . This is ...

251

Multiple alcohol dehydrogenases but no functional acetaldehyde dehydrogenase causing excessive acetaldehyde production from ethanol by oral streptococci  

PubMed Central

Ethanol consumption and poor oral hygiene are risk factors for oral and oesophageal cancers. Although oral streptococci have been found to produce excessive acetaldehyde from ethanol, little is known about the mechanism by which this carcinogen is produced. By screening 52 strains of diverse oral streptococcal species, we identified Streptococcus gordonii V2016 that produced the most acetaldehyde from ethanol. We then constructed gene deletion mutants in this strain and analysed them for alcohol and acetaldehyde dehydrogenases by zymograms. The results showed that S. gordonii V2016 expressed three primary alcohol dehydrogenases, AdhA, AdhB and AdhE, which all oxidize ethanol to acetaldehyde, but their preferred substrates were 1-propanol, 1-butanol and ethanol, respectively. Two additional dehydrogenases, S-AdhA and TdhA, were identified with specificities to the secondary alcohol 2-propanol and threonine, respectively, but not to ethanol. S. gordonii V2016 did not show a detectable acetaldehyde dehydrogenase even though its adhE gene encodes a putative bifunctional acetaldehyde/alcohol dehydrogenase. Mutants with adhE deletion showed greater tolerance to ethanol in comparison with the wild-type and mutant with adhA or adhB deletion, indicating that AdhE is the major alcohol dehydrogenase in S. gordonii. Analysis of 19 additional strains of S. gordonii, S. mitis, S. oralis, S. salivarius and S. sanguinis showed expressions of up to three alcohol dehydrogenases, but none showed detectable acetaldehyde dehydrogenase, except one strain that showed a novel ALDH. Therefore, expression of multiple alcohol dehydrogenases but no functional acetaldehyde dehydrogenase may contribute to excessive production of acetaldehyde from ethanol by certain oral streptococci. PMID:23637459

Pavlova, Sylvia I.; Jin, Ling; Gasparovich, Stephen R.

2013-01-01

252

Multiple Myeloma Research Foundation  

MedlinePLUS

We Are Beating Multiple Myeloma Now. Join Us. Multiple myeloma patients have options today because the status quo just a few years ago was, ... Support our success. Donate now. If you have multiple myeloma, you have options. At the MMRF, we’re ...

253

Neutron multiplicity analysis tool  

Microsoft Academic Search

I describe the capabilities of the EXCOM (EXcel based COincidence and Multiplicity) calculation tool which is used to analyze experimental data or simulated neutron multiplicity data. The input to the program is the count-rate data (including the multiplicity distribution) for a measurement, the isotopic composition of the sample and relevant dates. The program carries out deadtime correction and background subtraction

Scott L

2010-01-01

254

Multiple sclerosis and pregnancy  

PubMed Central

Multiple sclerosis causes disability in young adults and, like most autoimmune diseases, affects women more commonly than men. The disease can therefore present at a time when many have, or are considering, starting a family. The effect of pregnancy on the outcome of multiple sclerosis is reviewed and the management of pregnant women who have multiple sclerosis is discussed. PMID:12185217

Lorenzi, A; Ford, H

2002-01-01

255

Multiple Scattering Tomography  

NASA Astrophysics Data System (ADS)

Multiple scattering represents a challenge for numerous modern tomographic imaging techniques. In this Letter, we derive an appropriate line integral that allows for the tomographic reconstruction of angular resolved scattering distributions, even in the presence of multiple scattering. The line integral is applicable to a wide range of imaging techniques utilizing various kinds of probes. Here, we use x-ray grating interferometry to experimentally validate the framework and to demonstrate additional structural sensitivity, which exemplifies the impact of multiple scattering tomography.

Modregger, Peter; Kagias, Matias; Peter, Silvia; Abis, Matteo; Guzenko, Vitaliy A.; David, Christian; Stampanoni, Marco

2014-07-01

256

Multiple Endocrine Neoplasia  

Microsoft Academic Search

\\u000a The term “multiple endocrine neoplasia” was first used by Steiner in the late 1960s when he described three distinct endocrine\\u000a disorders. The first disorder, multiple endocrine neoplasia type I (MEN 1) (also known as Wermer syndrome), described patients\\u000a with familial pituitary, parathyroid, and pancreatic islet cell tumors. The second syndrome, multiple endocrine neoplasia\\u000a type II (MEN 2) (also known as

Christine S. Landry; Thereasa Rich; Camilo Jimenez; Elizabeth G. Grubbs; Jeffrey E. Lee; Nancy D. Perrier

257

Multiple UAV teams for multiple tasks  

Microsoft Academic Search

In a search and prosecute mission, multiple heterogeneous unmanned aerial vehicles UAVs that carry different resources need to perform the classify, prosecute and battle damage assessment (BDA) tasks on targets sequentially. Depending on the target resource requirement, it may be necessary to deploy a coalition of UAVs to perform the action. In this paper, we propose coalition formation algorithms that

P. B. Sujit; J. Sousa; F. Pereira

2009-01-01

258

Enriched environment impacts trimethylthiazoline-induced anxiety-related behavior and immediate early gene expression: critical role of Crhr1.  

PubMed

It has been shown previously (Sotnikov et al., ) that mice selectively inbred for high anxiety-related behavior (HAB) vs. low anxiety-related behavior in the elevated plus maze differentially respond to trimethylthiazoline (TMT), a synthetic fox fecal odor. However, less is known about whether environmental factors can rescue these extreme phenotypes. Here, we found that an enriched environment (EE) provided during early adolescence induced anxiolytic effects in HAB (HAB-EE) mice, rescuing their strong avoidance behavior induced by TMT. In a series of experiments, the contribution of maternal, juvenile and adolescent behavior to the anxiolytic effects elicited by EE was investigated. At the molecular level, using c-fos expression mapping, we found that the activity of the medial and basolateral amygdala was significantly reduced in HAB-EE mice after TMT exposure. We further analysed the expression of Crhr1, as its amount in the amygdala has been reported to be important for the regulation of anxiety-related behavior after EE. Indeed, in situ hybridisation indicated significantly decreased Crhr1 expression in the basolateral and central amygdala of HAB-EE mice. To further test the involvement of Crhr1 in TMT-induced avoidance, we exposed conditional glutamatergic-specific Crhr1-knockout mice to the odor. The behavioral response of Crhr1-knockout mice mimicked that of HAB-EE mice, and c-fos expression in the amygdala after TMT exposure was significantly lower compared with controls, thereby further supporting a critical involvement of Crhr1 in environmentally-induced anxiolysis. Altogether, our results indicate that EE can rescue strong avoidance of TMT by HAB mice with Crhr1 expression in the amygdala being critically involved. PMID:24840018

Sotnikov, S V; Chekmareva, N Y; Schmid, B; Harbich, D; Malik, V; Bauer, S; Kuehne, C; Markt, P O; Deussing, J M; Schmidt, M V; Landgraf, R

2014-08-01

259

Syngeneic Marek's Disease Virus (MDV)Specific Cell-Mediated Immune Responses against Immediate Early, Late, and Unique MDV Proteins  

Microsoft Academic Search

Marek's disease (MD) infection has been controlled effectively by vaccination using nononcogenic and\\/or attenuated oncogenic Marek's disease virus (MDV) vaccines. Thus far, there is little knowledge on the role of cell-mediated immune (CMI) responses during MDV infection or vaccination. To elucidate the importance of MDV proteins in CMI responses, the pp38, Meq, ICP4, or ICP22 genes of an oncogenic strain,

Abdul R. Omar; Karel A. Schat

1996-01-01

260

Novelty-Induced Increased Expression of Immediate-Early Genes c-fos and arg 3.1  

E-print Network

a danger for the animal). Most often, familiarization with a stimulus is demon- strated by exposing; amygdala; limbic system In nature, animals are constantly confronted with new situations. They continuously.e., the stimulus has never been experienced before) strongly arouses the animal's attention. This is usually

Kuhl, Dietmar

261

Identifying emotional adaptation: behavioural habituation to novelty and immediate early gene expression in two inbred mouse strains  

Microsoft Academic Search

Normal anxiety is an adaptive emotional response. However,\\u000awhen anxiety appears to lack adaptive value, it\\u000amight be defined as pathological. Adaptation in animals\\u000acan be assessed for example by changes in behavioural\\u000aresponses over time, i.e. habituation. We hypothesize\\u000athat non-adaptive anxiety might be reflected by\\u000aimpaired habituation. To test our hypothesis, we repeatedly\\u000aexposed male mice from two

A. R. Salomons; J. A. K. R. van Luijk; N. R. Reinders; S. Kirchhoff; S. S. Arndt; F. Ohl

2010-01-01

262

Group 2 coronaviruses prevent immediate early interferon induction by protection of viral RNA from host cell recognition  

SciTech Connect

Many viruses encode antagonists to prevent interferon (IFN) induction. Infection of fibroblasts with the murine hepatitis coronavirus (MHV) and SARS-coronavirus (SARS-CoV) did not result in nuclear translocation of interferon-regulatory factor 3 (IRF3), a key transcription factor involved in IFN induction, and induction of IFN mRNA transcription. Furthermore, MHV and SARS-CoV infection could not prevent IFN induction by poly (I:C) or Sendai virus, suggesting that these CoVs do not inactivate IRF3-mediated transcription regulation, but apparently prevent detection of replicative RNA by cellular sensory molecules. Our data indicate that shielding of viral RNA to host cell sensors might be the main general mechanism for coronaviruses to prevent IFN induction.

Versteeg, Gijs A. [Molecular Virology Laboratory, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, LUMC E4-P, P.O. Box 9600, 2300 RC Leiden (Netherlands); Bredenbeek, Peter J. [Molecular Virology Laboratory, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, LUMC E4-P, P.O. Box 9600, 2300 RC Leiden (Netherlands); Worm, Sjoerd H.E. van den [Molecular Virology Laboratory, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, LUMC E4-P, P.O. Box 9600, 2300 RC Leiden (Netherlands); Spaan, Willy J.M. [Molecular Virology Laboratory, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, LUMC E4-P, P.O. Box 9600, 2300 RC Leiden (Netherlands)]. E-mail: w.j.m.spaan@lumc.nl

2007-04-25

263

White Spot Syndrome Virus Annexes a Shrimp STAT To Enhance Expression of the Immediate-Early Gene ie1  

Microsoft Academic Search

Received 30 August 2006\\/Accepted 12 October 2006 Although the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is part of the antiviral response in arthropods such as Drosophila, here we show that white spot syndrome virus (WSSV) uses a shrimp STAT as a transcription factor to enhance viral gene expression in host cells. In a series of deletion

Wang-Jing Liu; Yun-Shiang Chang; Andrew H.-J. Wang; Guang-Hsiung Kou; Chu-Fang Lo

2007-01-01

264

Hexamethylene bisacetamide stimulates herpes simplex virus immediate early gene expression in the absence of trans-induction by Vmw65  

Microsoft Academic Search

Hexamethylene bisacetamide (HMBA) and DMSO are known to induce differentiation of cultured erythroleu- kaemic cells and to enhance the reactivation of latent herpes simplex virus (HSV) after explantation of ganglia. We report that the presence of these com- pounds in cell culture medium overcomes the replica- tion defect of in1814, an HSV-1 mutant with an insertion mutation that inactivates the

Morag McFarlane; Jasmine I. Daksis; Chris M. Preston

1992-01-01

265

Fractions--Rectangle Multiplication  

NSDL National Science Digital Library

This interactive applet provides a visual model of fraction multiplication using rectangular arrays. The applet offers both a demonstration/exploration mode ("show me") and a practice mode ("test me") in which students arrange the rectangle to display a given multiplication problem. Teaching ideas and applet instructions are available through the links at the top of the page.

2007-01-01

266

Multiple Endocrine Neoplasia  

Microsoft Academic Search

\\u000a Several genetic syndromes are associated with multiple endocrine tumors. In this chapter, we focus on Multiple Endocrine Neoplasia\\u000a (MEN) types 2 and 1. Von Hippel Lindau and Neurofibromatosis will be discussed in other sections.

Yariv J. Houvras; Gilbert H. Daniels

267

Orchestrating Multiple Intelligences  

ERIC Educational Resources Information Center

Education policymakers often go astray when they attempt to integrate multiple intelligences theory into schools, according to the originator of the theory, Howard Gardner, and his colleagues. The greatest potential of a multiple intelligences approach to education grows from the concept of a profile of intelligences. Each learner's intelligence…

Moran, Seana; Kornhaber, Mindy; Gardner, Howard

2006-01-01

268

Combination of Multiple Searches  

Microsoft Academic Search

The TREC-3 project at Virginia Tech focused on methods for combining the evidence from multiple retrieval runs and queries to improve retrieval performance over any single retrieval method or query. The largest improvements result from the combination of retrieval paradigms rather than from the use of multiple similar queries.

Joseph A. Shaw; Edward A. Fox

1994-01-01

269

Multiple scattering technique lidar  

NASA Technical Reports Server (NTRS)

The Bernouilli-Ricatti equation is based on the single scattering description of the lidar backscatter return. In practice, especially in low visibility conditions, the effects of multiple scattering can be significant. Instead of considering these multiple scattering effects as a nuisance, we propose here to use them to help resolve the problems of having to assume a backscatter-to-extinction relation and specifying a boundary value for a position far remote from the lidar station. To this end, we have built a four-field-of-view lidar receiver to measure the multiple scattering contributions. The system has been described in a number of publications that also discuss preliminary results illustrating the multiple scattering effects for various environmental conditions. Reported here are recent advances made in the development of a method of inverting the multiple scattering data for the determination of the aerosol scattering coefficient.

Bissonnette, Luc R.

1992-01-01

270

Multiple objective multiple allocation hub location problem  

Microsoft Academic Search

Hub networks are used to connect supply and demand nodes without establishing direct connections between any origin-destination nodes. The issue is to find optimum hub locations and allocate non-hub nods to them at minimum cost and\\/or travel time. Multiple allocation hub location problems deal with network in which non-hub nodes can be allocated to more than one hub. In this

Masoud Mirzaei; Mahdi Bashiri

2010-01-01

271

Multiple Principal Investigators  

Cancer.gov

Below is information to learn about NIH definitions, policies, and awards available to apply for support using the Multiple Principal Investigator (PI) model that supports team science. Answers to FAQs are included.

272

What Is Multiple Myeloma?  

MedlinePLUS

... Multiple myeloma is a cancer formed by malignant plasma cells. Normal plasma cells are found in the bone marrow and ... to an infection, they mature and change into plasma cells. Plasma cells make the antibodies (also called ...

273

Mobile multiple access study  

NASA Technical Reports Server (NTRS)

Multiple access techniques (FDMA, CDMA, TDMA) for the mobile user and attempts to identify the current best technique are discussed. Traffic loading is considered as well as voice and data modulation and spacecraft and system design. Emphasis is placed on developing mobile terminal cost estimates for the selected design. In addition, design examples are presented for the alternative techniques of multiple access in order to compare with the selected technique.

1977-01-01

274

Multiplication as Combinations  

NSDL National Science Digital Library

In this lesson plan students explore how to use multiplication to find the number of combinations possible in various situations. They follow the Cyberchase kids through two short videos as they explore creating a matrix and a tree diagram to solve the number of combinations; looking for patterns across data and leading to the conclusion that the same solutions could have been found through multiplication (counting principle). The lesson plan includes two student worksheets, two assessment options, and an answer key (rtf).

Education, Wnet O.

2006-01-01

275

Multiple endocrine neoplasia  

Microsoft Academic Search

\\u000a The multiple endocrine neoplasia (MEN) syndromes are a family of genetic conditions characterized by a predisposition to the\\u000a development of neoplasms in multiple endocrine glands. The pathologic change in affected glands is characteristically multicentric\\u000a and may be expressed as hyperplasia, adenoma, or carcinoma. The MEN syndromes are inherited in an autosomal dominant manner\\u000a and are classified according to the pattern

Julie A. Miller; Jeffrey A. Norton

276

Pyrochemical multiplicity counter development  

SciTech Connect

Impure plutonium-bearing materials from pyrochemical processes often display both significant self-multiplication and variable ({alpha},n) reaction rates. Standard neutron coincidence counting techniques usually fail to accurately measure these materials. Neutron multiplicity counters measure the third moment of the neutron multiplicity distribution and thus make it possible to deduce the fertile plutonium mass of a sample even when both the self-multiplication and the ({alpha},n) reaction rate are unknown. A multiplicity counter suitable for measuring pyrochemical materials has been designed and built. This paper describes the results of characterization studies for the new counter. The counter consists of 126 helium-3 tubes arranged in 4 concentric rings in a polyethylene moderator; the average spacing between the tubes is 1.59 cm. The end plugs for the counter are made of graphite, and the 24.1- by 37.5-cm sample cavity is cadmium lined. The counter consists of two distinct halves from which the neutron counts are summed. The counter is capable of operation in either a freestanding mode with the two halves coupled together by an external cabinet or in a glove-box mode with the two halves placed around a glovebox well and then mated. For a {sup 252}Cf source centered in the sample cavity, the measured efficiency of the new multiplicity counter is 57.7% and its die-away time is 47.2{mu}s. 8 refs., 9 figs.

Langner, D.G.; Dytlewski, N.; Krick, M.S.

1991-01-01

277

Multiple Indicators, Multiple Causes Measurement Error Models  

PubMed Central

Multiple Indicators, Multiple Causes Models (MIMIC) are often employed by researchers studying the effects of an unobservable latent variable on a set of outcomes, when causes of the latent variable are observed. There are times however when the causes of the latent variable are not observed because measurements of the causal variable are contaminated by measurement error. The objectives of this paper are: (1) to develop a novel model by extending the classical linear MIMIC model to allow both Berkson and classical measurement errors, defining the MIMIC measurement error (MIMIC ME) model, (2) to develop likelihood based estimation methods for the MIMIC ME model, (3) to apply the newly defined MIMIC ME model to atomic bomb survivor data to study the impact of dyslipidemia and radiation dose on the physical manifestations of dyslipidemia. As a by-product of our work, we also obtain a data-driven estimate of the variance of the classical measurement error associated with an estimate of the amount of radiation dose received by atomic bomb survivors at the time of their exposure. PMID:24962535

Tekwe, Carmen D.; Carter, Randy L.; Cullings, Harry M.; Carroll, Raymond J.

2014-01-01

278

Multiple indicators, multiple causes measurement error models.  

PubMed

Multiple indicators, multiple causes (MIMIC) models are often employed by researchers studying the effects of an unobservable latent variable on a set of outcomes, when causes of the latent variable are observed. There are times, however, when the causes of the latent variable are not observed because measurements of the causal variable are contaminated by measurement error. The objectives of this paper are as follows: (i) to develop a novel model by extending the classical linear MIMIC model to allow both Berkson and classical measurement errors, defining the MIMIC measurement error (MIMIC ME) model; (ii) to develop likelihood-based estimation methods for the MIMIC ME model; and (iii) to apply the newly defined MIMIC ME model to atomic bomb survivor data to study the impact of dyslipidemia and radiation dose on the physical manifestations of dyslipidemia. As a by-product of our work, we also obtain a data-driven estimate of the variance of the classical measurement error associated with an estimate of the amount of radiation dose received by atomic bomb survivors at the time of their exposure. Copyright © 2014 John Wiley & Sons, Ltd. PMID:24962535

Tekwe, Carmen D; Carter, Randy L; Cullings, Harry M; Carroll, Raymond J

2014-11-01

279

Fixed points of multiplicative contraction mappings on multiplicative metric spaces  

E-print Network

In this paper, we first discussed multiplicative metric mapping by giving some topological properties of the relevant multiplicative metric space. As an interesting result of our discussions, we observed that the set of positive real numbers $\\mathbb{R}_+$ is a complete multiplicative metric space with respect to the multiplicative absolute value function. Furthermore, we introduced concept of multiplicative contraction mapping and proved some fixed point theorems of such mappings on complete multiplicative metric spaces

Muttalip Ozavsar; Adem Cengiz Cevikel

2012-05-23

280

Quantum Multiple Scattering: Correspondence between  

E-print Network

Quantum Multiple Scattering: Correspondence between Particle and Photon Scattering A thesis Multiple Scattering: Correspondence between Particle and Photon Scattering Sheng Li, June 2003 Thesis advisor: Prof. Eric J. Heller This thesis discusses the quantum multiple scattering theory of both par

Heller, Eric

281

Multiple eccrine hidrocystomas.  

PubMed

The clinical and pathological features and treatment of two patients with multiple eccrine hidrocystomas are presented. The first case is characterized by multiple pearly papules with a bluish hue located in the periorbital region and the bridge of the nose. The second case is characterized by multiple, skin-coloured papules located in the periorbital area, forehead, chin and nose. Both were exacerbated by a hot and humid environment. Histopathologically, both demonstrated a unilocular cyst located in the dermis, with a 2-3-layer wall composed of cuboidal epithelium that was non-keratinizing. Treatment with topical atropine sulphate 1% in aqueous solution three times a day was instituted in the first case; however, this was poorly tolerated because of blurred vision and nausea. The lesions were subsequently hyfrecated with a good response. The second case was treated with topical atropine sulphate 1% in aqueous solution three times a day with a good response. PMID:15250898

Lee, Michael R; Ryman, William

2004-08-01

282

Rehabilitation in multiple sclerosis.  

PubMed

Despite the lack of a definitive remedy for central nervous system demyelination in multiple sclerosis, certain manifestations of the disease are treatable. Recognition and identification of specific impairments, disabilities, and handicaps faced by the patient afford the physician the best opportunity to provide effective intervention. Impairments are ameliorated with difficulty; however, when comprehensive methods of rehabilitation are applied to the associated disabilities and handicaps, meaningful improvements can be achieved. The goal of rehabilitation in multiple sclerosis is to maximize the patient's physical, emotional, social, and vocational independence. Through the multidisciplinary efforts of numerous health-care workers in close cooperation with the patient and the family, this goal can be attained. PMID:2528038

Erickson, R P; Lie, M R; Wineinger, M A

1989-07-01

283

Neutron multiplicity analysis tool  

SciTech Connect

I describe the capabilities of the EXCOM (EXcel based COincidence and Multiplicity) calculation tool which is used to analyze experimental data or simulated neutron multiplicity data. The input to the program is the count-rate data (including the multiplicity distribution) for a measurement, the isotopic composition of the sample and relevant dates. The program carries out deadtime correction and background subtraction and then performs a number of analyses. These are: passive calibration curve, known alpha and multiplicity analysis. The latter is done with both the point model and with the weighted point model. In the current application EXCOM carries out the rapid analysis of Monte Carlo calculated quantities and allows the user to determine the magnitude of sample perturbations that lead to systematic errors. Neutron multiplicity counting is an assay method used in the analysis of plutonium for safeguards applications. It is widely used in nuclear material accountancy by international (IAEA) and national inspectors. The method uses the measurement of the correlations in a pulse train to extract information on the spontaneous fission rate in the presence of neutrons from ({alpha},n) reactions and induced fission. The measurement is relatively simple to perform and gives results very quickly ({le} 1 hour). By contrast, destructive analysis techniques are extremely costly and time consuming (several days). By improving the achievable accuracy of neutron multiplicity counting, a nondestructive analysis technique, it could be possible to reduce the use of destructive analysis measurements required in safeguards applications. The accuracy of a neutron multiplicity measurement can be affected by a number of variables such as density, isotopic composition, chemical composition and moisture in the material. In order to determine the magnitude of these effects on the measured plutonium mass a calculational tool, EXCOM, has been produced using VBA within Excel. This program was developed to help speed the analysis of Monte Carlo neutron transport simulation (MCNP) data, and only requires the count-rate data to calculate the mass of material using INCC's analysis methods instead of the full neutron multiplicity distribution required to run analysis in INCC. This paper describes what is implemented within EXCOM, including the methods used, how the program corrects for deadtime, and how uncertainty is calculated. This paper also describes how to use EXCOM within Excel.

Stewart, Scott L [Los Alamos National Laboratory

2010-01-01

284

Practical Multiple Sequence Alignment  

NASA Astrophysics Data System (ADS)

Multiple sequence alignment as a means of comparing DNA, RNA, or amino acid sequences is an essential precondition for various analyses, including structure prediction, modeling binding sites, phylogeny, or function prediction. This range of applications implies a demand for versatile, flexible, and specialized methods to compute accurate alignments. This chapter summarizes the key algorithmic insights gained in the past years to facilitate an easy understanding of the current multiple sequence alignment literature and to enable the readers to use and apply current tools in their own research.

Rausch, Tobias; Reinert, Knut

285

Hereditary multiple exostosis.  

PubMed

Hereditary multiple exostosis is an intriguing genetic condition with a clinical impact in the field of orthopaedics, paediatrics and oncology. In this review we highlight the current knowledge about this condition from a clinical and scientific point of view. This gives us more insight into the molecular mechanisms and current models on which therapeutic agents are based. It allows for a multidisciplinary approach to the management of this complex condition. There is currently no exact pathological model that can accurately describe all the findings in the research on Hereditary Multiple Exostosis. Promising treatments with blocking agents are currently under investigation. PMID:24563962

Ryckx, Andries; Somers, Jan F A; Allaert, Lieven

2013-12-01

286

Multiple Endocrine Neoplasia Syndromes  

PubMed Central

The multiple endocrine neoplasia (MEN) syndromes consist of three distinct disease entities. They have in common adenomatous, carcinomatous or hyperplastic involvement of a variety of endocrine glands, and an autosomal dominant inheritance. MEN I includes hyperparathyroidism, islet cell and pituitary tumors. The components of MEN IIa are hyperparathyroidism, medullary thyroid carcinoma and pheochromocytoma. MEN IIb includes multiple neuromas, medullary thyroid carcinoma and pheochromocytoma. Effective tests are available for the early detection of components of the syndromes in potentially affected patients. Screening can lead to therapeutic intervention before clinical sequelae ensue. PMID:6247851

Pont, Allan

1980-01-01

287

Simplifying Algebraic Expressions: Multiplication  

NSDL National Science Digital Library

This learning object from Wisc-Online covers simplifying algebraic expressions using multiplication. The unit's activities include defining the terminology associated with algebraic operations, using the fundamental laws of algebra to simplify those expressions, removing the symbols of grouping and changing the signs of the appropriate terms to simplify expressions. Practice questions are also included.

Blohowiak, Chad; Jensen, Douglas; Reed, Allen

2011-02-01

288

What about multiple intelligence?  

Microsoft Academic Search

Gardner (1983) produced a multiple intelligence theory to question the previous generalised measurements for intelligence. He challenged these earlier theories of intelligence by producing a theory in which a group of intelligences could be identified in order to be more specific in the assessment of an individual's ability. Gardner proposed the following intelligences: verbal; mathematical; musical accomplishment; spatially analysing the

Jack K. Garlovsky

289

Multiplication in Newton's Principia  

E-print Network

Newton in his Principia gives an ingenious generalization of the Hellenistic theory of ratios and inspired experimentally gives a tensor-like definition of multiplication of quantities measured with his ratios. An extraordinary feature of his definition is generality: namely his definition a priori allows non commutativity of multiplication of measured quantities, which may give a non-trivial linkage to experimental facts subject to quantum mechanics discovered some two hundred years later. Mathematical scheme he introduces with this ingenious definition is closely related to the contemporary approach in spectral geometry. His definition reveals in particular that commutativity of the multiplication of quantities with physical dimension has the status of experimental assumption and does not have to be fulfilled in reality, although neither the mathematical tools nor experimental evidence could allow Newton to carry out the case when the multiplication is noncommutative. We present a detailed analysis of his definition as well as a linkage to the theory of representations of algebras with involution (and with normal forms of von Neumann algebras and Jordan Banach algebras).

Jaroslaw Wawrzycki

2012-09-24

290

Multiple Intelligences: A Collection.  

ERIC Educational Resources Information Center

As a concise resource for Howard Gardner's theory of multiple intelligences and its implications for schooling around the world, this collection is designed for educators, parents, and others interested in education. The first section discusses Gardner and his background, and the second section expounds his theory. The third section explores the…

Fogarty, Robin, Ed.; Bellanca, James, Ed.

291

Multiple Grammars and MOGUL  

ERIC Educational Resources Information Center

Optionality is a central phenomenon in second language acquisition (SLA), for which any adequate theory must account. Amaral and Roeper (this issue; henceforth A&R) offer an appealing approach to it, using Roeper's Multiple Grammars Theory, which was created with first language in mind but which extends very naturally to SLA. They include…

Truscott, John

2014-01-01

292

Reasoning About Multiplication & Division  

NSDL National Science Digital Library

This 7-minute video features Drew Crandall working with his third grade class to develop concepts involving properties of operations and the relationship between multiplication and division. His approach allows students to learn from each other, to construct and revise their own meaning, and to develop communication skills. A downloadable transcript of the video is available (doc).

2013-01-01

293

Mastering the Multiplication Facts  

ERIC Educational Resources Information Center

The purpose of this paper is to share the results of a six-week research project (after baseline data was collected) that focused on three different strategies (flashcards, interactive games, and music) and their effectiveness in helping fifth grade students memorize the basic multiplication facts. Many teachers face a serious problem when their…

D'Ettorre, Jenna

2009-01-01

294

Multiple Intelligences Meet Standards.  

ERIC Educational Resources Information Center

In the five years since a Trappe, Maryland elementary school put Gardner's multiple-intelligences theory into practice, students' overall achievement and confidence have risen substantially. Specialists helped teachers develop standards for grading students' art work and oral presentations. To prepare students for state assessments, written…

Greenhawk, Jan

1997-01-01

295

Combining Multiple Heuristics Online  

Microsoft Academic Search

We present black-box techniques for learning how to inter- leave the execution of multiple heuristics in order to improve average-case performance. In our model, a user is given a set of heuristics whose only observable behavior is their running time. Each heuristic can compute a solution to any problem instance, but its running time varies across instances. The user solves

Matthew J. Streeter; Daniel Golovin; Stephen F. Smith

2007-01-01

296

On Multiple Identities.  

ERIC Educational Resources Information Center

Identity is the complex way a person identifies with, and is identified by, his environment. Multiple identities result from the many ways a person has been successfully identified. Identities coexist; sometimes the dominance of one over others becomes evident, and a vertical structure of identities arises. (CS)

Graumann, Carl F.

1983-01-01

297

Multiple Choice Test  

NSDL National Science Digital Library

This site presents a guide to developing and deploying effective multiple choice tests. The site also discusses the costs and benefits of this method, as well as the philosophy of this commonly used assessment method. Links to more detailed information are included as well.

Parkes, Jay; Guide, Field-Tested L.

298

Multiple equilibrium laboratory devices  

NASA Astrophysics Data System (ADS)

Devices{* } will be demonstrated and videotapes played of a number of laboratory studies that exhibit multiple equilibrium. All devices have two competing effects driving the flow. In two of them, temperature and salinity oppose each other. In another, air and water compete. In a fourth, wave propagation is opposed by inertia. Connection with hypothesized ocean behavior will be made. {* } Whitehead, J. A. 2000 Stratified Convection with Multiple States. Ocean Modelling, 2, 109-121. Whitehead, J. A. W. Gregory Lawson and John Salzig. 2001 Multistate flow devices for geophysical fluid dynamics and climate. American Journal of Physics, 69 546-553. Whitehead, J. A. and P. G. Baines. 2000. Hydraulic Jump Location as a Multiple Equilibrium feature. 2000 Ocean Sciences Meeting, American Geophysical Union, San Antonio Texas, January 25, 2000. Abstract: EOS 80 #46 (Supplement), OS125. Whitehead, J. A. , M. L. E. Timmermans, W. Gregory Lawson, S. N. Bulgakov, A. M. Zatarian, J. F. A. Medina, and John Salzig, Laboratory studies of thermally and/or Salinity-driven flows with partial mixing: Part 1 Stommel transitions and multiple flow states. In preparation

Whitehead, J. A.

2001-12-01

299

IMMUNOLOGY OF MULTIPLE SCLEROSIS  

Microsoft Academic Search

Ke yW ords autoimmunity, autoimmune mechanisms, neuroimmunology, demyelinating dieseases, EAE ? Abstract Multiple sclerosis (MS) develops in young adults with a complex pre- disposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype is a crucial event

Mireia Sospedra; Roland Martin

2005-01-01

300

Automatic multiple applicator electrophoresis  

NASA Technical Reports Server (NTRS)

Easy-to-use, economical device permits electrophoresis on all known supporting media. System includes automatic multiple-sample applicator, sample holder, and electrophoresis apparatus. System has potential applicability to fields of taxonomy, immunology, and genetics. Apparatus is also used for electrofocusing.

Grunbaum, B. W.

1977-01-01

301

Multiple endocrine neoplasia  

Microsoft Academic Search

Multiple endocrine neoplasia (MEN) is characterized by tumours involving two or more endocrine glands within a single patient. There are two major forms of MEN: type 1 (MEN1, Wermer's syndrome) and type 2 (MEN2, Sipple's syndrome). MEN1 is characterized by the combined occurrence of tumours in the parathyroids, pancreatic islet cells and anterior pituitary; MEN2 is characterized by the association

Rajesh V. Thakker

2009-01-01

302

Effects of Early or Overexpression of the Autographa californica Multiple Nucleopolyhedrovirus orf94 (ODV-e25) on Virus Replication  

PubMed Central

odv-e25(e25) is one of the core genes of baculoviruses. To investigate how it functions in the replication cycle of a baculovirus, a number of Autographa californica multiple nucleopolyhedrovirus recombinants with e25 under control of the promoter of immediate early gene ie1, or the promoter of the very late hyperexpressed gene p10, were constructed using a bacmid system, and the effects of early expression or overexpression of e25 on replication of the virus were evaluated. Microscopy and titration assays demonstrated that bacmids with e25 under control of ie1 promoter were unable to produce budded viruses; and that the recombinant viruses with e25 under control of p10 promoter generated budded virus normally, but formation of occlusion bodies were dramatically reduced and delayed in the infected cells. Electron microscopy showed that there were no mature virions or intact nucleocapsids present in the cells transfected with a recombinant bacmid with e25 under control of ie1 promoter. Quantitative real-time PCR analysis demonstrated that alteration of the e25 promoter did not affect viral DNA synthesis. The reporter gene expression from the promoter of the major capsid protein gene vp39 was reduced 63% by early expression of e25. Confocal microscopy revealed that E25 was predominantly localized in nuclei by 24 hours post infection with wild-type virus, but it remained in the cytoplasm in the cells transfected with a recombinant bacmid with e25 under control of the ie1 promoter, suggesting that the transport of E25 into nuclei was regulated in a specific and strict time dependent manner. PMID:23825525

Luo, Xiao-Chun; Wang, Shan-Shan; Zhang, Jie; Qian, Duo-Duo; Wang, Si-Min; Li, Lu-Lin

2013-01-01

303

Multiple sclerosis and pregnancy.  

PubMed

Multiple sclerosis is one of the main reasons for invalidation of young adults of both sexes. The disease is more common in women than in men. The illness begins most frequently in patients between the ages of 20 and 40 years, which is also the most fertile period for women. MS is an immune-mediated disease with chronic evolution marked by exacerbations and remissions that amplify the degree of disability. The most common clinical picture is the one with relapse and remission whose evolution is greatly improved after immunomodulatory treatment. We have revised the literature together with the data from the national multiple sclerosis society and the cases that are in the National Programme of Multiple Sclerosis, mainly the ones that are assigned to the regional center of Ia?i, at the Neurology Clinic inside the Clinical Rehabilitation Hospital Ia?i. Pregnancy is quite frequent in female patients with MS. Certain risks are present during pregnancy, birth and breastfeeding and certain protocols must be applied, such as interrupting the immunomodulatory treatment before the conception. Child delivery must be closely monitored and it must take into consideration the dysfunction that the patient has and be adapted to the existing deficits. There are some methods that may be used during delivery for female patients with multiple sclerosis in order to make this process smooth and reduce the risk of postpartum complications. Multiple sclerosis is an invalidating disease, with a high prevalence in women. Pregnancy in patients with MS is not such a natural phenomenon as in a healthy female and it requires a multidisciplinary team in order to ensure the safety of both the mother and the newborn. PMID:24741771

Popescu, C D

2014-01-01

304

Color-deficient cone mosaics associated with Xq28 opsin mutations: A stop codon versus gene deletions  

E-print Network

rearrangements affects phenotype in terms of color vision behavior. Recently, high-resolution imaging of the cone associated with X-chromosome opsin gene arrays in which the first two head-to-tail genes at the 50 -end of the array encode L opsin. If the encoded opsins form pigments that differ in spectral sensitiv- ity

305

High Frequency of Monoallelic Retinoblastoma Gene Deletion in B-Cell Chronic Lymphoid Leukemia Shown by Interphase Cytogenetics  

Microsoft Academic Search

Inactivation of the retinoblastoma tumor-suppressor gene (RB-I ) has been associated with tumorigenicity in various human malignancies. In chronic lymphoid leukemias of B- cell origin (B-CLL) an involvement of RB-1 has been sug- gested based on cytogenetic data. We examined RB-1 and its chromosomal locus 13ql4 in 35 cases of B-CLL by dual- color in situ hybridization to interphase nuclei

Stephan Stilgenbauer; Hartmut Dohner; Mehtap Bulgay-Morschel; Sandra Weitz; Martin Bentz; Peter Lichter

1993-01-01

306

In ovo vaccination of commercial broilers with a glycoprotein J gene-deleted strain of infectious laryngotracheitis virus.  

PubMed

Conventional live attenuated vaccines have been used as the main tool worldwide for the control of infectious laryngotracheitis. However, their suboptimal attenuation combined with poor mass administration practices allowed chicken embryo origin vaccine-derived isolates to circulate in the field, regain virulence, and be the cause of continuous outbreaks of the disease. Previous studies indicated that stable attenuation of infectious laryngotracheitis virus (ILTV) can be achieved by the deletion of individual viral genes that are not essential for viral replication in vitro. One of these genes is the glycoprotein J (gJ) gene. Its deletion provided significant attenuation to virulent ILTV strains from Europe and the United States. The objective of this study was to construct an attenuated gJ-deleted ILTV strain and evaluate its safety and efficacy for in ovo (IO) administration of commercial broilers. A novel gJ-deleted virus (N(delta)gJ) was constructed, and a 10(3) median tissue culture infective dose administered at 18 days of embryo age was considered safe because it did not affect hatchability or survivability of chickens during the first week posthatch. Broilers vaccinated IO and IO + eye drop at 14 days of age presented a significant reduction in clinical signs and reduction of virus loads after challenge, as compared with the nonvaccinated challenged group of chickens. Therefore, this study presents initial proof that the N(delta)gJ strain is a potential ILTV live-attenuated vaccine candidate suitable for IO vaccination of commercial broilers. PMID:23901771

Mashchenko, Anna; Riblet, Sylva M; Zavala, Guillermo; García, Maricarmen

2013-06-01

307

Bone marrow–specific Cap gene deletion protects against high-fat diet–induced insulin resistance  

Microsoft Academic Search

Cbl-associated protein (Cap) is a member of a phosphatidylinositol 3-kinase–independent pathway for insulin-stimulated translocation of the glucose transporter GLUT4. Despite this positive role of Cap in glucose uptake, here we show that deletion of the gene encoding Cap (official gene name: Sorbs1) protects against high-fat diet (HFD)–induced insulin resistance in mice while also having an opposite, insulin-sensitizing effect, accompanied by

Lisa A Lesniewski; Sarah E Hosch; Jaap G Neels; Carl de Luca; Mohammad Pashmforoush; Carey N Lumeng; Shian-Huey Chiang; Miriam Scadeng; Alan R Saltiel; Jerrold M Olefsky

2007-01-01

308

Targeted Gene Deletion and In Vivo Analysis of Putative Virulence Gene Function in the Pathogenic Dermatophyte Arthroderma benhamiae?  

PubMed Central

Dermatophytes cause the majority of superficial mycoses in humans and animals. However, little is known about the pathogenicity of this specialized group of filamentous fungi, for which molecular research has been limited thus far. During experimental infection of guinea pigs by the human pathogenic dermatophyte Arthroderma benhamiae, we recently detected the activation of the fungal gene encoding malate synthase AcuE, a key enzyme of the glyoxylate cycle. By the establishment of the first genetic system for A. benhamiae, specific ?acuE mutants were constructed in a wild-type strain and, in addition, in a derivative in which we inactivated the nonhomologous end-joining pathway by deletion of the A. benhamiae KU70 gene. The absence of AbenKU70 resulted in an increased frequency of the targeted insertion of linear DNA by homologous recombination, without notably altering the monitored in vitro growth abilities of the fungus or its virulence in a guinea pig infection model. Phenotypic analyses of ?acuE mutants and complemented strains depicted that malate synthase is required for the growth of A. benhamiae on lipids, major constituents of the skin. However, mutant analysis did not reveal a pathogenic role of the A. benhamiae enzyme in guinea pig dermatophytosis or during epidermal invasion of the fungus in an in vitro model of reconstituted human epidermis. The presented efficient system for targeted genetic manipulation in A. benhamiae, paired with the analyzed infection models, will advance the functional characterization of putative virulence determinants in medically important dermatophytes. PMID:21478433

Grumbt, Maria; Defaweux, Valerie; Mignon, Bernard; Monod, Michel; Burmester, Anke; Wostemeyer, Johannes; Staib, Peter

2011-01-01

309

Gankyrin gene deletion followed by proteomic analysis: insight into the roles of Gankyrin in Tumorigenesis and Metastasis  

PubMed Central

Background Gankyrin was originally purified and characterized as the p28 component of the 26S proteasome, and later identified as an oncogenic protein in hepatocellular carcinomas (HCC). It has recently been found to be highly expressed in several other malignancies, and compelling evidence show gankyrin plays important roles in tumorigenesis. However, its mechanism of action remains unclear. Methods In order to further clarify the functions of gankyrin and better understand its molecular mechanisms, we generated a gankyrin null cell line, HCT116 gankyrin?/? , by targeted homologous recombination in human colon cancer cells, and then employed two-dimensional electrophoresis (2-DE) based proteomic approaches followed by MS identification to investigate alterations in the proteome due to the gankyrin knockout. Western blot and qRT-PCR assays were also used to examine the protein and mRNA levels of some identified proteins. Results Compared with wild-type control cells, gankyrin null cells were impaired in terms of their proliferation, migration and anchorage-independent growth. A total of 21 altered proteins were identified, which included 18 proteins that had not previously been reported to be related to gankyrin. Notably, eight metastasis-related proteins were identified. Western blot analyses confirmed that the changes in three examined proteins were consistent with 2-DE gel analysis. Conclusions In summary, we have generated a useful cell tool to clarify the functions of gankyrin. Our proteomic data provide novel information to better understand the roles and underlying mechanisms by which gankyrin is involved in tumorigenesis and cancer metastasis. PMID:22913272

2012-01-01

310

Fusion PCR-targeted tylCV gene deletion of Streptomyces fradiae for producing desmycosin, the direct precursor of tilmicosin  

Microsoft Academic Search

Tilmicosin is a semisynthetic macrolide antibiotic derived from tylosin. The disruption of tylCV gene from tylosin producer—Streptomyces fradiae would result in the accumulation of desmycosin, the direct precursor of tilmicosin. TylCV gene disruption cassette was constructed by fusion PCR. The tylCV replacement strain of S. fradiae was obtained through intergeneric conjugation between S. fradiae and E. coli. The antibiotic resistance

Yong Min; Heping Lv; Yinghua Zheng

2007-01-01

311

Aquaporin-4 regulates extracellular space volume dynamics during high-frequency synaptic stimulation: a gene deletion study in mouse hippocampus.  

PubMed

Little is known about the physiological roles of aquaporin-4 (AQP4) in the central nervous system. AQP4 water channels are concentrated in endfeet membranes of astrocytes but also localize to the fine astrocytic processes that abut central synapses. Based on its pattern of expression, we predicted that AQP4 could be involved in controlling water fluxes and changes in extracellular space (ECS) volume that are associated with activation of excitatory pathways. Here, we show that deletion of Aqp4 accentuated the shrinkage of the ECS that occurred in the mouse hippocampal CA1 region during activation of Schaffer collateral/commissural fibers. This effect was found in the stratum radiatum (where perisynaptic astrocytic processes abound) but not in the pyramidal cell layer (where astrocytic processes constitute but a minor volume fraction). For both genotypes the ECS shrinkage was most pronounced in the pyramidal cell layer. Our data attribute a physiological role to AQP4 and indicate that this water channel regulates extracellular volume dynamics in the mammalian brain. PMID:22419561

Haj-Yasein, Nadia Nabil; Jensen, Vidar; Østby, Ivar; Omholt, Stig W; Voipio, Juha; Kaila, Kai; Ottersen, Ole P; Hvalby, Øivind; Nagelhus, Erlend A

2012-05-01

312

Chromosome 9 Deletion Mapping Reveals Interferon a and Interferon ß-1 Gene Deletions in Human Glial Tumors  

Microsoft Academic Search

We have applied restriction fragment length polymorphism analysis to a 30-member panel of primary glioma DNAs, which had been previ ously examined for loss of genetic information (C. D. James, E. Carlbom, J. P. Dumanski, M. Hansen, M. Nordenskjold, V. P. Collins, and W. K. Cavenee, Cancer Res., 48:5546-5551, 1988), to determine the frequency and sublocalization of loss of genetic

C. David James; Ju He; Elisabeth Carlbom; Magnus Nordenskjold; Webster K. Cavenee; V. Peter Collins

313

Evaluation of a modified-live, gene deletion mutant pseudorabies virus vaccine for field use in swine  

E-print Network

in swine. However, 2 a . TM OmniMark -PRV, Fermenta Animal Health Co. , Kansas City, MO. a conventional ML PRV vaccine has been reported to cause high mortality in accidentally exposed lambs and chicks. ' The 39, 40 safety of one TK- PRV (BUK 013) gene... the Texas Animal Health Commission (TAHC) for experimental vaccination in the quarantined herd. The purpose of this study was to evaluate the safety of the experimental vaccine in neonatal pigs. b Kit et al. United States Patent No. 4, 609, 548, Sept. 2...

Lawhorn, Donald Bruce

2012-06-07

314

Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1  

PubMed Central

Deletions of claudin-2 (Cldn2) and aquaporin1 (AQP1) reduce proximal fluid reabsorption (PFR) by about 30% and 50%, respectively. Experiments were done to replicate these observations and to determine in AQP1/claudin-2 double knockout mice (DKO) if the effects of deletions of these established water pores are additive. PFR was determined in inactin/ketamine-anesthetized mice by free-flow micropuncture using single-nephron I125-iothalamate (io) clearance. Animal means of PFR [% of glomerular filtration rate (GFR)] derived from TF/Piothalamate ratios in 12 mice in each of four groups [wild type (WT), Cldn2?/?, AQP1?/?, and DKO) were 45.8 ± 0.85 (51 tubules), 35.4 ± 1 (54 tubules; P < 0.01 vs. WT), 36.8 ± 1 (63 tubules; P < 0.05 vs. WT), and 33.9 ± 1.4 (69 tubules; P < 0.01 vs. WT). Kidney and single-nephron GFRs (SNGFR) were significantly reduced in all mutant strains. The direct relationship between PFR and SNGFR was maintained in mutant mice, but the slope of this relationship was reduced in the absence of Cldn2 and/or AQP1. Transtubular osmotic pressure differences were not different between WT and Cldn2?/? mice, but markedly increased in DKO. In conclusion, the deletion of Cldn2, AQP1, or of both Cldn2 and AQP1 reduces PFR by 22.7%, 19.6%, and 26%, respectively. Our data are consistent with an up to 25% paracellular contribution to PFR. The reduced osmotic water permeability caused by absence of AQP1 augments luminal hypotonicity. Aided by a fall in filtered load, the capacity of non-AQP1-dependent transcellular reabsorption is sufficient to maintain PFR without AQP1 and claudin-2 at 75% of control. PMID:24049145

Huang, Yuning; Mizel, Diane

2013-01-01

315

Unexpected effects of gene deletion on mercury interactions with the methylation-deficient mutant hgcAB  

SciTech Connect

The hgcA and hgcB gene pair is essential for mercury (Hg) methylation by certain anaerobic bacteria,1 but little is known about how deletion of hgcAB affects cell surface interactions and intracellular uptake of Hg. Here, we compare hgcAB mutants with the wild-type (WT) strains of both Geobacter sulfurreducens PCA and Desulfovibrio desulfuricans ND132 and observe differences in Hg redox transformations, adsorption, and uptake in laboratory incubation studies. In both strains, deletion of hgcAB increased the reduction of Hg(II) but decreased the oxidation of Hg(0) under anaerobic conditions. The measured cellular thiol content in hgcAB mutants was lower than the WT, accounting for decreased adsorption and uptake of Hg. Despite the lack of methylation activity, Hg uptake by the hgcAB continued, albeit at a slower rate than the WT. These findings demonstrate that deletion of the hgcAB gene not only eliminates Hg methylation but also alters cell physiology, resulting in changes to Hg redox reactions, sorption, and uptake by cells.

Lin, Hui [ORNL] [ORNL; Hurt, Jr., Richard Ashley [ORNL; Johs, Alexander [ORNL] [ORNL; Parks, Jerry M [ORNL] [ORNL; Morrell-Falvey, Jennifer L [ORNL] [ORNL; Liang, Liyuan [ORNL] [ORNL; Elias, Dwayne A [ORNL] [ORNL; Gu, Baohua [ORNL] [ORNL

2014-01-01

316

Recombinant Epstein-Barr Virus with Small RNA (EBER) Genes Deleted Transforms Lymphocytes and Replicates in vitro  

Microsoft Academic Search

Strains of Epstein-Barr virus (EBV) with deletions of the small RNA (EBER) genes were made by homologous recombination using the EBV P3HR-1 strain, which has undergone deletion of the essential transforming gene that encodes the EBV nuclear antigen, EBNA-2, and a DNA fragment that was wild type at the EBNA-2 locus but from which the EBER genes had been deleted.

Sankar Swaminathan; Blake Tomkinson; Elliott Kieff

1991-01-01

317

Detection of IgA heavy chain constant region genes in IgA deficient donors: evidence against gene deletions.  

PubMed Central

Sixty-six donors with selective IgA deficiency and one patient with selective IgA2 deficiency were investigated for immunoglobulin gene defects using restriction enzyme digestions and Southern blot analysis. All patients carried alpha 1 and alpha 2 genes in their genome, suggesting that large deletions are uncommon causes for IgA deficiency. Digestion with Bam HI, Pst I and Pvu II, did not reveal any polymorphism in the studied samples. Images Fig. 1 PMID:2990782

Hammarstrom, L; Carlsson, B; Smith, C I; Wallin, J; Wieslander, L

1985-01-01

318

NeuroD1 is required for survival of photoreceptors but not pinealocytes: Results from targeted gene deletion studies  

PubMed Central

NeuroD1 encodes a basic helix-loop-helix (bHLH) transcription factor involved in the development of neural and endocrine structures, including the retina and pineal gland. To determine the effect of NeuroD1 knockout in these tissues, a Cre/loxP recombination strategy was used to target a NeuroD1 floxed gene and generate NeuroD1 conditional knockout (cKO) mice. Tissue specificity was conferred using Cre recombinase expressed under the control of the promoter of Crx, which is selectively expressed in the pineal gland and retina. At two months of age NeuroD1 cKO retinas have a dramatic reduction in rod- and cone-driven electroretinograms and contain shortened and disorganized outer segments; by four months NeuroD1 cKO retinas are devoid of photoreceptors. In contrast, the NeuroD1 cKO pineal gland appears histologically normal. Microarray analysis of two-month-old NeuroD1 cKO retina and pineal gland identified a subset of genes that were affected 2- to 100-fold; in addition, a small group of genes exhibit altered differential night/day expression. Included in the down-regulated genes are Aipl1, which is necessary to prevent retinal degeneration, and Ankrd33, which is selectively expressed in the outer segments. These findings suggest that NeuroD1 may act through Aipl1 and other genes to maintain photoreceptor homeostasis. PMID:22784109

Ochocinska, Margaret J.; Munoz, Estela M.; Veleri, Shobi; Weller, Joan L.; Coon, Steven L.; Pozdeyev, Nikita; Iuvone, P. Michael; Goebbels, Sandra; Furukawa, Takahisa; Klein, David C.

2012-01-01

319

Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles  

PubMed Central

Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-Down syndrome (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression, and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only two NDS cases (3.1%) (Fisher’s exact p = 0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters, and enrichment of highly methylated genes for specific pathways and transcription factor binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions. PMID:21647151

Loudin, Michael G.; Wang, Jinhua; Leung, Hon-Chiu Eastwood; Gurusiddappa, Sivashankarappa; Meyer, Julia; Condos, Gregory; Morrison, Debra; Tsimelzon, Anna; Devidas, Meenakshi; Heerema, Nyla A.; Carroll, Andrew J.; Plon, Sharon E.; Hunger, Stephen P.; Basso, Giuseppe; Pession, Andrea; Bhojwani, Deepa; Carroll, William L.; Rabin, Karen R.

2014-01-01

320

BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP\\/PS1 transgenic mice  

Microsoft Academic Search

Evidence suggests that ?-amyloid (A?) peptide triggers a pathogenic cascade leading to neuronal loss in Alzheimer’s disease (AD). However, the causal link between A? and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD. We have recently developed transgenic mice that overexpress human APP and PS1 with five familial

Masuo Ohno; Sarah L. Cole; Marina Yasvoina; Jie Zhao; Martin Citron; Robert Berry; John F. Disterhoft; Robert Vassar

2007-01-01

321

GJB1/Connexin 32 whole gene deletions in patients with X-linked Charcot-Marie-Tooth disease.  

PubMed

The X-linked form of Charcot-Marie-Tooth disease (CMTX) is the second most common form of this genetically heterogeneous inherited peripheral neuropathy. CMT1X is caused by mutations in the GJB1 gene. Most of the mutations causative for CMT1X are missense mutations. In addition, a few disease causative nonsense mutations and frameshift deletions that lead to truncated forms of the protein have also been reported to be associated with CMT1X. Previously, there have been reports of patients with deletions of the coding sequence of GJB1; however, the size and breakpoints of these deletions were not assessed. Here, we report five patients with deletions that range in size from 12.2 to 48.3 kb and that completely eliminate the entire coding sequence of the GJB1 gene, resulting in a null allele for this locus. Analyses of the breakpoints of these deletions showed that they are nonrecurrent and that they can be generated by different mechanisms. In addition to PMP22, GJB1 is the second CMT gene for which both point mutations and genomic rearrangements can cause a neuropathy phenotype, stressing the importance of CMT as a genomic disorder. PMID:20532933

Gonzaga-Jauregui, Claudia; Zhang, Feng; Towne, Charles F; Batish, Sat Dev; Lupski, James R

2010-10-01

322

GJB1 \\/Connexin 32 whole gene deletions in patients with X-linked Charcot–Marie–Tooth disease  

Microsoft Academic Search

The X-linked form of Charcot–Marie–Tooth disease (CMTX) is the second most common form of this genetically heterogeneous inherited\\u000a peripheral neuropathy. CMT1X is caused by mutations in the GJB1 gene. Most of the mutations causative for CMT1X are missense mutations. In addition, a few disease causative nonsense mutations\\u000a and frameshift deletions that lead to truncated forms of the protein have also

Claudia Gonzaga-Jauregui; Feng Zhang; Charles F. Towne; Sat Dev Batish; James R. Lupski

2010-01-01

323

GJB1/Connexin 32 whole gene deletions in patients with X-linked Charcot–Marie–Tooth disease  

PubMed Central

The X-linked form of Charcot–Marie–Tooth disease (CMTX) is the second most common form of this genetically heterogeneous inherited peripheral neuropathy. CMT1X is caused by mutations in the GJB1 gene. Most of the mutations causative for CMT1X are missense mutations. In addition, a few disease causative nonsense mutations and frameshift deletions that lead to truncated forms of the protein have also been reported to be associated with CMT1X. Previously, there have been reports of patients with deletions of the coding sequence of GJB1; however, the size and breakpoints of these deletions were not assessed. Here, we report five patients with deletions that range in size from 12.2 to 48.3 kb and that completely eliminate the entire coding sequence of the GJB1 gene, resulting in a null allele for this locus. Analyses of the breakpoints of these deletions showed that they are nonrecurrent and that they can be generated by different mechanisms. In addition to PMP22, GJB1 is the second CMT gene for which both point mutations and genomic rearrangements can cause a neuropathy phenotype, stressing the importance of CMT as a genomic disorder. PMID:20532933

Gonzaga-Jauregui, Claudia; Zhang, Feng; Towne, Charles F.; Batish, Sat Dev

2014-01-01

324

Characterizing the regulatory mechanisms in fusarium verticillioides secondary metabolism using functional genomics approaches  

E-print Network

the complex secondary metabolism regulations in F. verticillioides. First, using the reverse genetics approach, I characterized a putative protein phosphatase gene, CPP1 as a negative regulator of FB1 biosynthesis. CPP1 gene deletion also affected multiple...

Choi, Yoon E

2009-05-15

325

[Vaccination and multiple sclerosis].  

PubMed

Vaccinations to prevent communicable diseases are, like in other chronic diseases, of special importance in patients with multiple sclerosis (MS). Various bacterial and viral infections have been shown to induce relapses of MS. Reports of possible adverse effects of vaccinations on the course of multiple sclerosis have led patients and treating physicians to exercise caution in the use of vaccines. A number of vaccines have been studied with respect to the risk in MS patients. Some vaccines, for example against yellow fever, are not indicated in MS due to the risk of MS exacerbation. In contrast, tetanus or hepatitis B vaccines do not represent a risk for manifestation or disease progression of MS. Before and during immunomodulatory therapy of MS special attention should be given to adequate protection against vaccine preventable diseases.This paper reviews the indications and specific side effects of vaccinations in MS patients. Additionally, issues of vaccination under immunomodulatory therapy of MS are discussed. PMID:19838662

Löbermann, M; Winkelmann, A; Reisinger, E C; Zettl, U K

2010-02-01

326

Multiple zeros of polynomials  

NASA Technical Reports Server (NTRS)

For polynomials of higher degree, iterative numerical methods must be used. Four iterative methods are presented for approximating the zeros of a polynomial using a digital computer. Newton's method and Muller's method are two well known iterative methods which are presented. They extract the zeros of a polynomial by generating a sequence of approximations converging to each zero. However, both of these methods are very unstable when used on a polynomial which has multiple zeros. That is, either they fail to converge to some or all of the zeros, or they converge to very bad approximations of the polynomial's zeros. This material introduces two new methods, the greatest common divisor (G.C.D.) method and the repeated greatest common divisor (repeated G.C.D.) method, which are superior methods for numerically approximating the zeros of a polynomial having multiple zeros. These methods were programmed in FORTRAN 4 and comparisons in time and accuracy are given.

Wood, C. A.

1974-01-01

327

Subcritical multiplication determination studies  

SciTech Connect

A series of measurements and improvements to computational techniques are in progress at Los Alamos National Laboratory that are aimed at better understanding the determination of the reactivity of subcritical systems from measurements of the apparent multiplication of the system. Such studies are being performed in order to improve the special nuclear material (SNM) assays of unknown systems such as those encountered in SNM safeguards, arms-control verification, imports of foreign-generated SNM, etc. Improved techniques and understanding are needed since measured multiplication is not always an invariant characteristic of a subcritical system, especially if one has a system with no significant intrinsic internal neutron source that is illuminated nonuniformly with an external source (i.e., a non-normal mode system).

Estes, G.P.; Goulding, C.A.

1995-07-01

328

Multiple Miniature Avionic Displays  

NASA Technical Reports Server (NTRS)

A display screen for displaying multiple sets of information is provided. In one embodiment, an aviation display screen includes a main window and a plurality of miniature windows. The main window is adapted to illustrate one set of information. Each miniature window is adapted to display a set of avionic information. The avionic display is further adapted to toggle a select set of avionic information in one of the miniature windows into the main window.

Rye, Jeffrey M. (Inventor); Dorneich, Michael C. (Inventor); Gannon, Aaron J. (Inventor)

2008-01-01

329

Multiple Osteolytic Lesions  

PubMed Central

Several systemic diseases initially present with various oral manifestations. Investigation of these oral symptoms may at times lead to the diagnosis of grave underlying life-threatening conditions. We present one such case, where the patient manifested with gross enlargement of the mandible, along with lesions in the lower limbs. These lesions were the initial manifestation and on further investigations the patient was diagnosed with multiple myeloma. PMID:24516769

Vinayachandran, Divya; Sankarapandian, Sathasivasubramanian

2013-01-01

330

Fatigue in multiple sclerosis  

Microsoft Academic Search

Fatigue is among the most common, yet least understood, symptoms of multiple sclerosis (MS) [1·]. It can profoundly disrupt\\u000a the occupational and social functioning of patients, and is recognized as a criterion for MS disability by the Social Security\\u000a Administration. Most approaches to fatigue assessment can be classified as either self-report scales or performance-based\\u000a measures of motor or cognitive output.

Lauren B. Krupp; Christopher Christodoulou

2001-01-01

331

Multiple Primary Cancer Monograph  

Cancer.gov

To identify groups of cancer survivors that are at increased risk for multiple primary cancers, Radiation Epidemiology Branch (REB) investigators led a collaborative effort to provide the first comprehensive population-based analysis of the risk of subsequent cancer in the U.S. The 500-page monograph utilized data from nine cancer registries participating in the Surveillance, Epidemiology, and End Results (SEER) Program from 1973 to 2000.

332

Multiple Core Galaxies  

NASA Technical Reports Server (NTRS)

Nuclei of galaxies often show complicated density structures and perplexing kinematic signatures. In the past we have reported numerical experiments indicating a natural tendency for galaxies to show nuclei offset with respect to nearby isophotes and for the nucleus to have a radial velocity different from the galaxy's systemic velocity. Other experiments show normal mode oscillations in galaxies with large amplitudes. These oscillations do not damp appreciably over a Hubble time. The common thread running through all these is that galaxies often show evidence of ringing, bouncing, or sloshing around in unexpected ways, even though they have not been disturbed by any external event. Recent observational evidence shows yet another phenomenon indicating the dynamical complexity of central regions of galaxies: multiple cores (M31, Markarian 315 and 463 for example). These systems can hardly be static. We noted long-lived multiple core systems in galaxies in numerical experiments some years ago, and we have more recently followed up with a series of experiments on multiple core galaxies, starting with two cores. The relevant parameters are the energy in the orbiting clumps, their relative.masses, the (local) strength of the potential well representing the parent galaxy, and the number of cores. We have studied the dependence of the merger rates and the nature of the final merger product on these parameters. Individual cores survive much longer in stronger background potentials. Cores can survive for a substantial fraction of a Hubble time if they travel on reasonable orbits.

Miller, R.H.; Morrison, David (Technical Monitor)

1994-01-01

333

Multiplication in curvature processing.  

PubMed

Multiplication rather than addition of neural signals is believed to underpin a variety of sensory processes, yet the evidence for multiplication is rare. Here we provide psychophysical evidence for neural multiplication in human visual processing of shape. We show that the curvature of a contour is likely detected by a mechanism that multiplies rather than adds the signals from afferent sub-units that detect parts of the curve. Using a novel perceptual after-effect, in which the perceived shape of a sinusoidal-shaped contour is altered following adaptation to a contour of slightly different sinusoidal shape, a pronounced 'dip' in the size of the after-effect is found when the adapting contour is broken into segments of a particular length and spacing. Simulations reveal that the presence and shape of the dip is only expected if the afferent sub-units to curvature detectors are multiplied. The after-effect itself is then best explained in terms of the population response of a range of such curvature detectors tuned to different curvatures. PMID:19271933

Gheorghiu, Elena; Kingdom, Frederick A A

2009-01-01

334

Multiple protein structure alignment.  

PubMed Central

A method was developed to compare protein structures and to combine them into a multiple structure consensus. Previous methods of multiple structure comparison have only concatenated pairwise alignments or produced a consensus structure by averaging coordinate sets. The current method is a fusion of the fast structure comparison program SSAP and the multiple sequence alignment program MULTAL. As in MULTAL, structures are progressively combined, producing intermediate consensus structures that are compared directly to each other and all remaining single structures. This leads to a hierarchic "condensation," continually evaluated in the light of the emerging conserved core regions. Following the SSAP approach, all interatomic vectors were retained with well-conserved regions distinguished by coherent vector bundles (the structural equivalent of a conserved sequence position). Each bundle of vectors is summarized by a resultant, whereas vector coherence is captured in an error term, which is the only distinction between conserved and variable positions. Resultant vectors are used directly in the comparison, which is weighted by their error values, giving greater importance to the matching of conserved positions. The resultant vectors and their errors can also be used directly in molecular modeling. Applications of the method were assessed by the quality of the resulting sequence alignments, phylogenetic tree construction, and databank scanning with the consensus. Visual assessment of the structural superpositions and consensus structure for various well-characterized families confirmed that the consensus had identified a reasonable core. PMID:7849601

Taylor, W. R.; Flores, T. P.; Orengo, C. A.

1994-01-01

335

Identification of multiple proteins that interact with functional regions of the human cardiac alpha-actin promoter.  

PubMed

5' Sequences of the human cardiac alpha-actin gene are involved in the tissue-specific and developmental regulation of the gene. Deletion analyses combined with transient expression experiments in muscle cells have demonstrated three primary regions of functional importance (A. Minty and L. Kedes, Mol. Cell. Biol. 6:2125-2136, 1986; T. Miwa and L. Kedes, Mol. Cell. Biol. 7:2803-2813, 1987), and we have previously demonstrated binding of a protein indistinguishable from serum response factor (SRF) to the most proximal region (T.A. Gustafson, T. Miwa, L.M. Boxer, and L. Kedes, Mol. Cell. Biol. 8:4110-4119, 1988). In this report, we examine protein interaction with the remainder of the promoter. Gel shift and footprinting assays revealed that at least seven distinct nuclear proteins interacted with known and putative regulatory regions of the promoter. The transcription factor Sp1 bound to eight sites, as demonstrated by footprinting assays and gel shift analysis with purified Sp1. Purified CCAAT box-binding transcription factor CTF/NF-I and Sp1 were shown to interact with the far-upstream regulatory element at -410, and footprint analysis showed extensive overlap of these two sites. Two unidentified proteins with similar but distinct footprints interacted with the second region of functional importance at -140, which contains the second CArG motif [CC(A + T rich)6GG], and these proteins were shown to be distinct from SRF. SRF was found to bind to the remaining three CArG boxes, two of which were closely interdigitated with Sp1 sites. In addition, CArG box 4 was found to interact with SRF and another distinct protein whose footprint was contained within the SRF-binding site. Sequences surrounding the TATA box were also shown to bind proteins. Sp1 was shown to bind to a site immediately downstream from the TATA box and to a site within the first exon. Thus, each of the three functional upstream regions, as defined by transfection assays, was shown to interact with five factors: Sp1 and CTF/NF-I at the upstream site, two unidentified proteins at the central site, and SRF at the most proximal site. These results suggest that expression of the cardiac actin gene in muscle cells is controlled by complex interactions among multiple upstream and intragenic elements. PMID:2796988

Gustafson, T A; Kedes, L

1989-08-01

336

Identification of multiple proteins that interact with functional regions of the human cardiac alpha-actin promoter.  

PubMed Central

5' Sequences of the human cardiac alpha-actin gene are involved in the tissue-specific and developmental regulation of the gene. Deletion analyses combined with transient expression experiments in muscle cells have demonstrated three primary regions of functional importance (A. Minty and L. Kedes, Mol. Cell. Biol. 6:2125-2136, 1986; T. Miwa and L. Kedes, Mol. Cell. Biol. 7:2803-2813, 1987), and we have previously demonstrated binding of a protein indistinguishable from serum response factor (SRF) to the most proximal region (T.A. Gustafson, T. Miwa, L.M. Boxer, and L. Kedes, Mol. Cell. Biol. 8:4110-4119, 1988). In this report, we examine protein interaction with the remainder of the promoter. Gel shift and footprinting assays revealed that at least seven distinct nuclear proteins interacted with known and putative regulatory regions of the promoter. The transcription factor Sp1 bound to eight sites, as demonstrated by footprinting assays and gel shift analysis with purified Sp1. Purified CCAAT box-binding transcription factor CTF/NF-I and Sp1 were shown to interact with the far-upstream regulatory element at -410, and footprint analysis showed extensive overlap of these two sites. Two unidentified proteins with similar but distinct footprints interacted with the second region of functional importance at -140, which contains the second CArG motif [CC(A + T rich)6GG], and these proteins were shown to be distinct from SRF. SRF was found to bind to the remaining three CArG boxes, two of which were closely interdigitated with Sp1 sites. In addition, CArG box 4 was found to interact with SRF and another distinct protein whose footprint was contained within the SRF-binding site. Sequences surrounding the TATA box were also shown to bind proteins. Sp1 was shown to bind to a site immediately downstream from the TATA box and to a site within the first exon. Thus, each of the three functional upstream regions, as defined by transfection assays, was shown to interact with five factors: Sp1 and CTF/NF-I at the upstream site, two unidentified proteins at the central site, and SRF at the most proximal site. These results suggest that expression of the cardiac actin gene in muscle cells is controlled by complex interactions among multiple upstream and intragenic elements. Images PMID:2796988

Gustafson, T A; Kedes, L

1989-01-01

337

Complementary activation of hippocampal-cortical subregions and immature neurons following chronic training in single and multiple context versions of the water maze  

PubMed Central

Neurobiological studies of memory typically involve single learning sessions that last minutes or days. In natural settings, however, animals are constantly learning. Here we investigated how several weeks of spatial water maze training influences subsequent activation of neocortical and hippocampal subregions, including adult-born neurons. Mice were either trained in a single context or in a variant of the task in which the spatial cues and platform location changed every 3 days, requiring constant new learning. On the final day, half of the mice in each training group were tested in a novel context and the other half were tested in their previous, familiar context. Two hours later mice were perfused to measure subregion-specific expression of the immediate-early gene zif268, a marker of neuronal activation. None of the training paradigms affected the magnitude of adult neurogenesis. However, different neuronal populations were activated depending on prior training history, final context novelty, or a combination of these 2 factors. The anterior cingulate cortex was more activated by novel context exposure, regardless of the type of prior training. The suprapyramidal blade of the dentate gyrus and region CA3 showed greater activation in mice trained in multiple contexts, primarily after exposure to a familiar context. In immature granule neurons, multiple context training enhanced activation regardless of final context novelty. CA1 showed no significant changes in zif268 expression across any training condition. In naïve control mice, training on the final day increased zif268 expression in CA3, CA1 and the anterior cingulate cortex, but not the dentate gyrus, relative to mice that remained in their cages (transport controls). Unexpectedly, immature granule cells showed a decrease in zif268 expression in naïve learners relative to transport controls. These findings suggest novel and complementary roles for hippocampal, neocortical, and immature neuronal populations in learning and memory. PMID:21736899

Snyder, Jason S.; Clifford, Meredith A.; Jeurling, Sarah I.; Cameron, Heather A.

2011-01-01

338

Factorial Invariance in Multiple Populations: A Multiple Testing Procedure  

ERIC Educational Resources Information Center

A multiple testing method for examining factorial invariance for latent constructs evaluated by multiple indicators in distinct populations is outlined. The procedure is based on the false discovery rate concept and multiple individual restriction tests and resolves general limitations of a popular factorial invariance testing approach. The…

Raykov, Tenko; Marcoulides, George A.; Millsap, Roger E.

2013-01-01

339

Input Multiplicities in Process Control.  

ERIC Educational Resources Information Center

Describes research investigating potential effect of input multiplicity on multivariable chemical process control systems. Several simple processes are shown to exhibit the possibility of theoretical developments on input multiplicity and closely related phenomena are discussed. (JN)

Koppel, Lowell B.

1983-01-01

340

Factors and Multiples Puzzle  

NSDL National Science Digital Library

This puzzle, played with cards on a board (downloadable file), provides an interesting context in which students can apply their knowledge of number properties. Students attempt to arrange 25 numbers and 10 property headings into a 5 by 5 grid so that each number satisfies two conditions. Properties addressed include primes, square and triangular numbers, specific sets of multiples and factors, and parity. It can be worked individually or in small groups cooperatively. The Teachers' Notes page offers suggestions for implementation, discussion questions, ideas for extension and support, and links to an article, "Using Games in the Classroom" (catalogued separately).

2010-02-01

341

Multiple-pass reflectometer  

SciTech Connect

The multiple-pass reflectometer has been shown to be a convenient and precise instrument for measuring absolute spectral reflectance values in excess of 0.99. Given here is an extension of earlier work. We present details of the setup, operation, parameter optimization, and some limitations of the reflectometer. For a carefully aligned instrument the precision of the measurement is limited by the uncertainty in the computer fit of a straight line to the data. For the uv and visible spectral regions, typical reflectance precision is a few parts in 10/sup 4/. Systematic errors due to nonuniform photosurfaces and astigmatism have been minimized for the setup described here.

Edwards, D.F. (Los Alamos National Lab., NM); Baumeister, P.

1981-11-15

342

Multiple choice questions revisited.  

PubMed

MCQs of the multiple true/false (MTF) variety were widely used in summative assessment 25 years ago. They could test a number of skills in addition to recall of factual knowledge, and were reliable, discriminatory, reproducible and cost-effective. However, there are now considerable doubts about their construct validity, mainly because of the varying responses of examinees to negative countermarking and the 'don't know' option, and the strategies they use when sitting examinations. Extended matching and one-from-five questions are now preferable, and negative countermarking is outmoded. MTF questions are still valuable in formative assessment and revision but are not recommended for summative examinations. PMID:15203517

Anderson, John

2004-03-01

343

Modeling Multiple Information Seeking Episodes.  

ERIC Educational Resources Information Center

Discussion of information retrieval and information seeking behavior focuses on a multi-dimensional conceptual model called MISE (multiple information-seeking episodes). Identifies eight different reasons why people engage in multiple information-seeking episodes, characterizes them in terms of traits of Multiple Information Seeking Episode…

Lin, Shin-jeng; Belkin, Nicholas J.

2000-01-01

344

Multiple capillary biochemical analyzer  

DOEpatents

A multiple capillary analyzer allows detection of light from multiple capillaries with a reduced number of interfaces through which light must pass in detecting light emitted from a sample being analyzed, using a modified sheath flow cuvette. A linear or rectangular array of capillaries is introduced into a rectangular flow chamber. Sheath fluid draws individual sample streams through the cuvette. The capillaries are closely and evenly spaced and held by a transparent retainer in a fixed position in relation to an optical detection system. Collimated sample excitation radiation is applied simultaneously across the ends of the capillaries in the retainer. Light emitted from the excited sample is detected by the optical detection system. The retainer is provided by a transparent chamber having inward slanting end walls. The capillaries are wedged into the chamber. One sideways dimension of the chamber is equal to the diameter of the capillaries and one end to end dimension varies from, at the top of the chamber, slightly greater than the sum of the diameters of the capillaries to, at the bottom of the chamber, slightly smaller than the sum of the diameters of the capillaries. The optical system utilizes optic fibres to deliver light to individual photodetectors, one for each capillary tube. A filter or wavelength division demultiplexer may be used for isolating fluorescence at particular bands.

Dovichi, Norman J. (Edmonton, CA); Zhang, Jian Z. (Edmonton, CA)

1995-01-01

345

Multiple symbol differential detection  

NASA Technical Reports Server (NTRS)

A differential detection technique for multiple phase shift keying (MPSK) signals is provided which uses a multiple symbol observation interval on the basis of which a joint decision is made regarding the phase of the received symbols. In accordance with the invention, a first difference phase is created between first and second received symbols. Next, the first difference phase is correlated with the possible values thereof to provide a first plurality of intermediate output signals. A second difference phase is next created between second and third received symbols. The second difference phase is correlated with plural possible values thereof to provide a second plurality of intermediate output signals. Next, a third difference phase is created between the first and third symbols. The third difference phase is correlated with plural possible values thereof to provide a third plurality of intermediate output signals. Each of the first plurality of intermediate outputs are combined with each of the second plurality of intermediate outputs and each of the third plurality of intermediate outputs to provide a plurality of possible output values. Finally, a joint decision is made by choosing from the plurality of possible output values the value which represents the best combined correlation of the first, second and third difference values with the possible values thereof.

Divsalar, Dariush (inventor); Simon, Marvin K. (inventor)

1991-01-01

346

Multiple capillary biochemical analyzer  

DOEpatents

A multiple capillary analyzer allows detection of light from multiple capillaries with a reduced number of interfaces through which light must pass in detecting light emitted from a sample being analyzed, using a modified sheath flow cuvette. A linear or rectangular array of capillaries is introduced into a rectangular flow chamber. Sheath fluid draws individual sample streams through the cuvette. The capillaries are closely and evenly spaced and held by a transparent retainer in a fixed position in relation to an optical detection system. Collimated sample excitation radiation is applied simultaneously across the ends of the capillaries in the retainer. Light emitted from the excited sample is detected by the optical detection system. The retainer is provided by a transparent chamber having inward slanting end walls. The capillaries are wedged into the chamber. One sideways dimension of the chamber is equal to the diameter of the capillaries and one end to end dimension varies from, at the top of the chamber, slightly greater than the sum of the diameters of the capillaries to, at the bottom of the chamber, slightly smaller than the sum of the diameters of the capillaries. The optical system utilizes optic fibers to deliver light to individual photodetectors, one for each capillary tube. A filter or wavelength division demultiplexer may be used for isolating fluorescence at particular bands. 21 figs.

Dovichi, N.J.; Zhang, J.Z.

1995-08-08

347

Glutathione in multiple sclerosis.  

PubMed

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, characterised mainly as an autoimmune neurodegenerative disorder. Its cause is unknown but multifactorial; however, some studies suggest that oxidative stress may be one of the sources, or a consequence of the disease, from loss of oxidant/antioxidant balance. This review studies glutathione, one of the most important agents of the endogenous antioxidant defence system, protecting cells from damage caused by oxidative stress. It evaluates glutathione and the enzymes glutathione peroxidase and glutathione reductase in various forms and stages of the disease. Analysis of a literature search suggests that the scientific community is not unanimous in its views, so more studies are required of patients with different forms of the disease and its manifestations, taking into account that the body functions as a whole and reacts in a compensatory manner. It would seem imperative to achieve a consensus on the pathogenesis responsible for severe disability, and explore sensitive biomarkers of its progression and indicators of oxidative stress. It is also important to promote the development of new therapies, with more studies on other substances such as acrolein, lipoic acid and dimethyl fumarate. Clarification of the mechanisms involved in oxidative stress, in different forms of multiple sclerosis, could result in improvements in the monitoring and prognosis of the disease, with subsequent increases in a patient's quality of life. PMID:23888609

Ferreira, B; Mendes, F; Osório, N; Caseiro, A; Gabriel, A; Valado, A

2013-01-01

348

Ultrastructure of multiple sclerosis.  

PubMed

The electron microscopic features of 11 stereotaxic brain biopsies that demonstrated inflammatory primary demyelination consistent both morphologically and clinically with multiple sclerosis are addressed. Degeneration of inner oligodendroglial loops and uniform widening of inner myelin lamellae antedated complete destruction of myelin sheaths. Perivascular lymphocytes, macrophages, and plasma cells were in intimate contact with myelin sheaths. Astrocytes proliferated even away from demyelinated areas. In areas of chronic, established demyelination, oligodendrocyte numbers were greatly decreased, and fields of completely demyelinated axons were seen among astrocytic processes. Axonal injury, evidenced by the formation of axonal swellings, was apparent in maximally affected areas. At the edge of acute lesions with demyelinated axons, oligodendrocytes were preserved morphologically. Thinly myelinated axons indicative of central nervous system-type remyelination by oligodendrocytes were observed primarily at the edges of plaques. An unusual inclusion observed in presumed macrophages was "polelike" bodies 0.04- to 0.7-microns thick. Linearly arrayed, their presumably proteinaceous crystalline substance was moderately electron-dense. Many were membrane-bound and appeared to arise from the endoplasmic reticulum. We conclude that disturbance of the myelinating function of oligodendrocytes may be a critical event in the pathogenesis of multiple sclerosis. PMID:8191643

Rodriguez, M; Scheithauer, B

1994-01-01

349

Phase-multiplication holography  

SciTech Connect

This disclosure relates generally to nondestructive testing for identifying structural characteristics of an object by scanned holographic techniques using a known source of radiation, such as electromagnetic or acoustical radiation. It is an object of this invention to provide an apparatus and method for synthetic aperture expansion in holographic imaging applications to construct fringe patterns capable of holographic reproduction where aperture restrictions in nondestructive testing applications would conventionally make such imaging techniques impossible. The apparatus and method result in the production of a sharply defined frontal image of structural characteristics which could not otherwise be imaged because they occur either near the surface of the object or are confined by geometry restricting aperture dimensions available for scanning purposes. The depth of the structural characteristic below the surface of the object can also be determined by the reconstruction parameters which produce the sharpest focus. Lateral resolution is established by simulated reduction in the radiation wavelength and may easily be an order of magnitude less than the electromagnetic wavelength in the material or 2 times the standard depth of penetration. Since the phase multiplication technique is performed on the detected data, the penetration depth available due to the longer wavelength signals applied to the test object remains unchanged. The phase multiplication technique can also be applied to low frequency acoustic holography, resulting in a test which combines excellent penetration of difficult materials with high resolution images.

Collins, H.D.; Prince, J.M.; Davis, T.J.

1982-01-25

350

Comparison of multiple DNA vaccines for protection against cytomegalovirus infection in BALB/c mice  

PubMed Central

Background Human cytomegalovirus (HCMV) causes serious HCMV-related diseases in immunocompromised people. Vaccination is the most effective measure to control infection with the pathogen, yet no vaccine has been licensed till now. We performed a head-to-head comparison of the protective abilities of multiple DNA vaccines in murine model of murine cytomegalovirus (MCMV) infection. Methods Five DNA vaccines were constructed. Four encoding MCMV proteins gp34 (m04), p65 (M84), DNA helicase (M105), and immediate-early 1 protein pp89 (IE-1) , respectively, which were reported to induce CD8+ T cell responses, were compared with the one expressing gB (M55), the neutralizing antibody target antigen, for immune protection in BALB/c mice. Mice were immunized with these DNA vaccines 1 to 4 times via intramuscular injection followed by electroporation, and were subsequently infected with a lethal dose (3?×?LD50) of highly virulent SG-MCMV. Specific antibodies and IFN-? secreting splenocytes were detected by immunoblotting and ELISPOT, respectively. Protective abilities in mice provided by the vaccines were evaluated by residual virus titers in organs, survival rate and weight loss. Results These DNA vaccines, especially m04, M84 and IE-1, could effectively reduce the virus loads in salivary glands and spleens of mice, but they couldn’t completely clear the residual virus. Survival rates of 100% in mice after a lethal dose of MCMV infection could be reached by more than one dose of M84 vaccine or two doses of m04 or IE-1 vaccine. Immunization with M55 or M105 DNA at four doses offered mice only 62.5% survival rate after the lethal challenge. Conclusions The study demonstrated that DNA vaccines could effectively afford mice protection against infection with a highly virulent MCMV and that the protection offered by induced CD8+ T cell immunity might be superior to that by gB-specific antibodies. These results are valuable references for development and application of HCMV vaccines. PMID:24898886

2014-01-01

351

Bayes multiple decision functions  

PubMed Central

This paper deals with the problem of simultaneously making many (M) binary decisions based on one realization of a random data matrix X. M is typically large and X will usually have M rows associated with each of the M decisions to make, but for each row the data may be low dimensional. Such problems arise in many practical areas such as the biological and medical sciences, where the available dataset is from microarrays or other high-throughput technology and with the goal being to decide which among of many genes are relevant with respect to some phenotype of interest; in the engineering and reliability sciences; in astronomy; in education; and in business. A Bayesian decision-theoretic approach to this problem is implemented with the overall loss function being a cost-weighted linear combination of Type I and Type II loss functions. The class of loss functions considered allows for use of the false discovery rate (FDR), false nondiscovery rate (FNR), and missed discovery rate (MDR) in assessing the quality of decision. Through this Bayesian paradigm, the Bayes multiple decision function (BMDF) is derived and an efficient algorithm to obtain the optimal Bayes action is described. In contrast to many works in the literature where the rows of the matrix X are assumed to be stochastically independent, we allow a dependent data structure with the associations obtained through a class of frailty-induced Archimedean copulas. In particular, non-Gaussian dependent data structure, which is typical with failure-time data, can be entertained. The numerical implementation of the determination of the Bayes optimal action is facilitated through sequential Monte Carlo techniques. The theory developed could also be extended to the problem of multiple hypotheses testing, multiple classification and prediction, and high-dimensional variable selection. The proposed procedure is illustrated for the simple versus simple hypotheses setting and for the composite hypotheses setting through simulation studies. The procedure is also applied to a subset of a microarray data set from a colon cancer study.

Wu, Wensong; Peña, Edsel A.

2014-01-01

352

Multiple hypothesis clustering and multiple frame assignment tracking  

NASA Astrophysics Data System (ADS)

Tracking and initiating large numbers of closely spaced objects can pose significant real-time challenges to current state-of-the-art tracking systems. Cluster or group tracking has been suggested to reduce the computational complexity when closely spaced targets move with similar dynamical properties. While modern individual object tracking systems make association decisions over multiple frames of data, most cluster tracking systems make single-frame clustering decisions. In this paper we illustrate an extension of multiple frame assignment (MFA) individual object tracking to multiple frame cluster MFA tracking. In our approach, multiple single-frame clustering hypotheses are formed and the best clustering is selected over multiple frames of data. In recent work we formulated multiple frame cluster tracking assignment problems and demonstrated a single-frame cluster MFA tracking architecture. The work discussed in this paper extends the previous work and illustrates a multiple hypothesis clustering, multiple frame assignment (MHC-MFA), tracking system. We present simulations studies that motivate the benefits of the multiple frame cluster tracking approach over single-frame cluster tracking and discuss the computational efficiency of the multiple frame cluster tracking approach.

Gadaleta, Sabino; Poore, Aubrey B.; Roberts, Sean; Slocumb, Benjamin J.

2004-08-01

353

Multiple sclerosis and depression.  

PubMed

Clinically significant depression can affect up to 50% of patients with multiple sclerosis over the course of their lifetime. It is associated with an increased morbidity and mortality and is regarded by patients as one of the main determinants of their quality of life. This review summarizes current perspectives relating to diagnosis, the utility of self report screening questionnaires, warning signs of suicidal intent and the biological and psychosocial variables implicated in mood change. In particular, the association between depression and structural brain abnormalities, including those derived from diffusion tensor imaging, is highlighted. Depression is treatable, as the results from randomized controlled trials of antidepressant medication, cognitive behavior therapy and mindfulness therapy, reveal. These positive findings are offset by data showing that depression in a neurological setting is often overlooked and under treated. PMID:22058085

Feinstein, Anthony

2011-11-01

354

Pomalidomide for multiple myeloma.  

PubMed

Once characterized by a very poor outcome, multiple myeloma (MM) now has a significantly prolonged survival, with major improvements allowed by the use of 'novel agents': proteasome inhibitors (first-in-class bortezomib) and immunomodulatory compounds (IMiDs; first-in-class thalidomide and lenalidomide). However, the vast majority - if not all - of patients with MM ultimately end up being refractory to all existing drugs, including these efficient novel agents. There is a clear unmet medical need in this situation, which warrants the development of the next generation of proteasome inhibitors and IMiDs, as well as new drug classes. This drug profile focuses on pomalidomide, the next generation IMiD, recently approved by the US FDA and the EMA for patients with relapsed or refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy. PMID:25265911

Fouquet, Guillemette; Bories, Claire; Guidez, Stéphanie; Renaud, Loïc; Herbaux, Charles; Javed, Sahir; Facon, Thierry; Leleu, Xavier

2014-12-01

355

On Multiple Einstein Rings  

E-print Network

A number of recent surveys for gravitational lenses have found examples of double Einstein rings. Here, we investigate analytically the occurrence of multiple Einstein rings. We prove, under very general assumptions, that at most one Einstein ring can arise from a mass distribution in a single plane lensing a single background source. Two or more Einstein rings can therefore only occur in multi-plane lensing. Surprisingly, we show that it is possible for a single source to produce more than one Einstein ring. If two point masses (or two isothermal spheres) in different planes are aligned with observer and source on the optical axis, we show that there are up to three Einstein rings. We also discuss the image morphologies for these two models if axisymmetry is broken, and give the first instances of magnification invariants in the case of two lens planes.

M. C. Werner; J. An; N. W. Evans

2008-04-23

356

Dancing with Multiple Partners  

NSDL National Science Digital Library

Transmembrane proteins, such as G protein-coupled receptors (GPCRs) and integrins, activate intracellular signaling pathways through interactions with downstream binding partners. Woodside discusses two examples in which GPCRs and integrins interact in a noncompeting manner with more than one partner. The specific GPCR described is the thrombin receptor, in experiments where G protein peptides selectively block signaling through a particular G protein that does not appear to inhibit coupling of the receptor to other G proteins. The second system described is the αIIbβ3 integrin and its activation of the nonreceptor tyrosine kinase Syk. Syk appeared capable of interacting with both the integrin and intracellular domains of immune response receptors, because binding of Syk to the integrin was not inhibited by peptides based on the Syk binding site in immune response receptors. Thus, multiple, noncompeting binding partners add to the complexity of signal transduction outputs from a single receptor complex.

Darren G. Woodside (Texas Biotechnology Corporation; REV)

2002-03-19

357

Multiple intratesticular cysts.  

PubMed

Intratesticular cysts, once thought to be a rarity, are now being reported with an increasing prevalence as a result of the wider use of scrotal ultrasound scanning. Despite greater understanding of intratesticular cysts, their management remains unclear. Treatment has included enucleation and even radical orchiectomy over fear of the possibility of an associated malignancy. A more conservative approach with serial ultrasound scanning has been advocated if a clear distinction can be made between neoplastic and non-neoplastic testicular cysts. However, in view of the benign nature of such cysts, even repeated ultrasound scanning may not be necessary and may be considered over-treatment. In this study we present clinical and morphological characteristics of multiple cysts in the right testicle in a 62-year-old patient, where a slightly nodular lesion in the right testicle was detected. PMID:23658871

Kang, Sung Min; Hwang, Dae Sung; Lee, Jung Woo; Chon, Won Hee; Park, Nam Cheol; Park, Hyun Jun

2013-04-01

358

Multiple Intratesticular Cysts  

PubMed Central

Intratesticular cysts, once thought to be a rarity, are now being reported with an increasing prevalence as a result of the wider use of scrotal ultrasound scanning. Despite greater understanding of intratesticular cysts, their management remains unclear. Treatment has included enucleation and even radical orchiectomy over fear of the possibility of an associated malignancy. A more conservative approach with serial ultrasound scanning has been advocated if a clear distinction can be made between neoplastic and non-neoplastic testicular cysts. However, in view of the benign nature of such cysts, even repeated ultrasound scanning may not be necessary and may be considered over-treatment. In this study we present clinical and morphological characteristics of multiple cysts in the right testicle in a 62-year-old patient, where a slightly nodular lesion in the right testicle was detected. PMID:23658871

Kang, Sung Min; Hwang, Dae Sung; Lee, Jung Woo; Chon, Won Hee; Park, Nam Cheol

2013-01-01

359

Swamp Works- Multiple Projects  

NASA Technical Reports Server (NTRS)

My Surface Systems internship over the summer 2013 session covered a broad range of projects that utilized multiple fields of engineering and technology. This internship included a project to create a command center for a 120 ton regolith bin, for the design and assembly of a blast shield to add further protection for the Surface Systems engineers, for the design and assembly of a portable four monitor hyper wall strip that could extend as large as needed, research and programming a nano drill that could be utilized on a next generation robot or rover, and social media tasks including the making of videos, posting to social networking websites and creation of a new outreach program to help spread the word about the Swamp Works laboratory.

Carelli, Jonathan M.; Schuler, Jason M.; Chandler, Meredith L.

2013-01-01

360

IRON IN MULTIPLE MYELOMA  

PubMed Central

Multiple myeloma is a non-curable B cell malignancy in which iron metabolism plays an important role. Patients with this disorder almost universally suffer from a clinically significant anemia, which is often symptomatic, and which is due to impaired iron utilization. Recent studies indicate that the proximal cause of dysregulated iron metabolism and anemia in these patients is cytokine-induced upregulation of hepcidin expression. Malignant myeloma cells are dependent on an increased influx of iron and therapeutic efforts are being made to target this requirement. The studies detailing the characteristics and biochemical abnormalities in iron metabolism causing anemia and the initial attempts to target iron therapeutically are described in this review. PMID:23879589

VanderWall, Kristina; Daniels-Wells, Tracy R; Penichet, Manuel; Lichtenstein, Alan

2013-01-01

361

Mixed Mode Matrix Multiplication  

SciTech Connect

In modern clustering environments where the memory hierarchy has many layers (distributed memory, shared memory layer, cache,...), an important question is how to fully utilize all available resources and identify the most dominant layer in certain computations. When combining algorithms on all layers together, what would be the best method to get the best performance out of all the resources we have? Mixed mode programming model that uses thread programming on the shared memory layer and message passing programming on the distributed memory layer is a method that many researchers are using to utilize the memory resources. In this paper, they take an algorithmic approach that uses matrix multiplication as a tool to show how cache algorithms affect the performance of both shared memory and distributed memory algorithms. They show that with good underlying cache algorithm, overall performance is stable. When underlying cache algorithm is bad, superlinear speedup may occur, and an increasing number of threads may also improve performance.

Meng-Shiou Wu; Srinivas Aluru; Ricky A. Kendall

2004-09-30

362

Multiple asteroid rendezvous missions  

NASA Technical Reports Server (NTRS)

Asteroid missions, centered on multiple asteroid rendezvous missions to main belt asteroids, are discussed and the required solar electric propulsion for these missions as well as the current performance estimates are examined. A brief statistical analysis involving asteroid availability transfer requirements and propulsion system capabilities is given, leading to a prediction that 5 to 8 asteroids can be encountered with a single launch. Measurement techniques include visual imaging, radio tracking, magnetometry, and in the case of landers, seismometry. The spacecraft will be propelled by a solar electric system with a power level of 25 kW to 40 kW and tour possibilities for 13 different asteroids have been developed. Preliminary estimates of asteroid triaxiality are made to calculate the effect of close orbits.

Bender, D. F.; Friedlander, A. L.

1979-01-01

363

AM with Multiple Merlins  

E-print Network

We introduce and study a new model of interactive proofs: AM(k), or Arthur-Merlin with k non-communicating Merlins. Unlike with the better-known MIP, here the assumption is that each Merlin receives an independent random challenge from Arthur. One motivation for this model (which we explore in detail) comes from the close analogies between it and the quantum complexity class QMA(k), but the AM(k) model is also natural in its own right. We illustrate the power of multiple Merlins by giving an AM(2) protocol for 3SAT, in which the Merlins' challenges and responses consist of only n^{1/2+o(1)} bits each. Our protocol has the consequence that, assuming the Exponential Time Hypothesis (ETH), any algorithm for approximating a dense CSP with a polynomial-size alphabet must take n^{(log n)^{1-o(1)}} time. Algorithms nearly matching this lower bound are known, but their running times had never been previously explained. Brandao and Harrow have also recently used our 3SAT protocol to show quasipolynomial hardness for approximating the values of certain entangled games. In the other direction, we give a simple quasipolynomial-time approximation algorithm for free games, and use it to prove that, assuming the ETH, our 3SAT protocol is essentially optimal. More generally, we show that multiple Merlins never provide more than a polynomial advantage over one: that is, AM(k)=AM for all k=poly(n). The key to this result is a subsampling theorem for free games, which follows from powerful results by Alon et al. and Barak et al. on subsampling dense CSPs, and which says that the value of any free game can be closely approximated by the value of a logarithmic-sized random subgame.

Scott Aaronson; Russell Impagliazzo; Dana Moshkovitz

2014-01-27

364

Empathic Multiple Tutoring Agents for Multiple Learner Interface  

Microsoft Academic Search

This paper describes a multiple user e-learning interface with multiple tutoring character agents. The character agents use eye movement information to facilitate empathy-relevant reasoning and behavior. Eye Information is used to monitor user's attention and interests, to personalize the agent behaviors, and for exchanging information of different learners. The system reacts to multiple users' eye information in real-time and the

Hua Wang; Jie Yang; Mark H. Chignell; Mitsuru Ishizuka

2006-01-01

365

Cytogenetics of multiple myeloma.  

PubMed

Great studies of multiple myeloma (MM) strongly suggested that specific chromosomal changes are of prognostic significance in patients with MM1. We have performed cytogenetic analysis and recently fluorescent in situ hybridization (FISH) on 43 cases of MM. Clonal chromosomal changes were present in 24 (56%) cases. Hyperdiploid karyotype was found in 12 (50%) cases, hypodiploid in 8 (33%) cases, and 4 (17%) cases had a pseudodiploid karyotype. The most common numerical abnormalities were gains of whole chromosomes 15, 11, 3 and 6. Whole chromosome losses were also frequent involving chromosomes X, 13, 14, and 8. Most cases showed also structural rearrangements 71% (n = 17): del(1p), dup(1q), del(5q), del(13q), del(17p) and t(11;14)(q13;q32) (n = 4, 17%). Chromosome -13/13q deletion was found in 42% (n = 10) cases; complete loss of 13 was observed in 67% (n = 7) cases, whereas 33% (n = 3) had interstitial deletions. In the majority of the cases there was a mixture of abnormal and normal metaphases. PMID:20432732

Trci?, Ruzica Lasan; Skelin, Ika Kardum; Susterci?, Dunja; Planinc-Peraica, Ana; Ajdukovi?, Radmila; Haris, Visnja; Kusec, Rajko; Begovi?, Davor

2010-03-01

366

Multiple Gluon Exchange Webs  

E-print Network

Webs are weighted sets of Feynman diagrams which build up the logarithms of correlators of Wilson lines, and provide the ingredients for the computation of the soft anomalous dimension. We present a general analysis of multiple gluon exchange webs (MGEWs) in correlators of semi-infinite non-lightlike Wilson lines, as functions of the exponentials of the Minkowski cusp angles, $\\alpha_{ij}$, formed between lines $i$ and $j$. We compute a range of webs in this class, connecting up to five Wilson lines through four loops, we give an all-loop result for a special class of diagrams, and we discover a new kind of relation between webs connecting different numbers of Wilson lines, based on taking collinear limits. Our results support recent conjectures, stating that the contribution of any MGEW to the soft anomalous dimension is a sum of products of polylogarithms, each depending on a single cusp angle, and such that their symbol alphabet is restricted to $\\alpha_{i j}$ and $1 - \\alpha_{i j}^2$. Finally, we construc...

Falcioni, Giulio; Harley, Mark; Magnea, Lorenzo; White, Chris D

2014-01-01

367

Multiple Gluon Exchange Webs  

E-print Network

Webs are weighted sets of Feynman diagrams which build up the logarithms of correlators of Wilson lines, and provide the ingredients for the computation of the soft anomalous dimension. We present a general analysis of multiple gluon exchange webs (MGEWs) in correlators of semi-infinite non-lightlike Wilson lines, as functions of the exponentials of the Minkowski cusp angles, $\\alpha_{ij}$, formed between lines $i$ and $j$. We compute a range of webs in this class, connecting up to five Wilson lines through four loops, we give an all-loop result for a special class of diagrams, and we discover a new kind of relation between webs connecting different numbers of Wilson lines, based on taking collinear limits. Our results support recent conjectures, stating that the contribution of any MGEW to the soft anomalous dimension is a sum of products of polylogarithms, each depending on a single cusp angle, and such that their symbol alphabet is restricted to $\\alpha_{i j}$ and $1 - \\alpha_{i j}^2$. Finally, we construct a simple basis of functions, defined through a one-dimensional integral representation in terms of powers of logarithms, which has all the expected analytic properties. This basis allows us to compactly express the results of all MGEWs computed so far, and we conjecture that it is sufficient for expressing all MGEWs at any loop order.

Giulio Falcioni; Einan Gardi; Mark Harley; Lorenzo Magnea; Chris D. White

2014-07-13

368

Multiple stage railgun  

DOEpatents

A multiple stage magnetic railgun accelerator (10) for accelerating a projectile (15) by movement of a plasma arc (13) along the rails (11,12). The railgun (10) is divided into a plurality of successive rail stages (10a-n) which are sequentially energized by separate energy sources (14a-n) as the projectile (15) moves through the bore (17) of the railgun (10). Propagation of energy from an energized rail stage back towards the breech end (29) of the railgun (10) can be prevented by connection of the energy sources (14a-n) to the rails (11,12) through isolation diodes (34a-n). Propagation of energy from an energized rail stage back towards the breech end of the railgun can also be prevented by dividing the rails (11,12) into electrically isolated rail sections (11a-n, 12a-n). In such case means (55a-n) are used to extinguish the arc at the end of each energized stage and a fuse (31) or laser device (61) is used to initiate a new plasma arc in the next energized rail stage.

Hawke, Ronald S. (Livermore, CA); Scudder, Jonathan K. (Pleasanton, CA); Aaland, Kristian (Livermore, CA)

1982-01-01

369

Multiple gluon exchange webs  

NASA Astrophysics Data System (ADS)

Webs are weighted sets of Feynman diagrams which build up the logarithms of correlators of Wilson lines, and provide the ingredients for the computation of the soft anomalous dimension. We present a general analysis of multiple gluon exchange webs (MGEWs) in correlators of semi-infinite non-lightlike Wilson lines, as functions of the exponentials of the Minkowski cusp angles, $\\alpha_{ij}$, formed between lines $i$ and $j$. We compute a range of webs in this class, connecting up to five Wilson lines through four loops, we give an all-loop result for a special class of diagrams, and we discover a new kind of relation between webs connecting different numbers of Wilson lines, based on taking collinear limits. Our results support recent conjectures, stating that the contribution of any MGEW to the soft anomalous dimension is a sum of products of polylogarithms, each depending on a single cusp angle, and such that their symbol alphabet is restricted to $\\alpha_{i j}$ and $1 - \\alpha_{i j}^2$. Finally, we construct a simple basis of functions, defined through a one-dimensional integral representation in terms of powers of logarithms, which has all the expected analytic properties. This basis allows us to compactly express the results of all MGEWs computed so far, and we conjecture that it is sufficient for expressing all MGEWs at any loop order.

Falcioni, Giulio; Gardi, Einan; Harley, Mark; Magnea, Lorenzo; White, Chris D.

2014-10-01

370

Multiple cerebral arteriovenous malformations (AVMs)  

Microsoft Academic Search

From our series of 203 patients with cerebral vascular lesions, 18 (9%) could be included in the multiple arteriovenous malformation category. There were five patients with Rendu-Osler-Weber, one with Wyburn-Mason syndromes and two with concurrent arteriovenous malformations. The remaining ten patients (4%) had multiple brain arteriovenous malformations. Careful angiography with magnification is necessary to try to diagnose multiple brain AVMs,

R. A. Willinsky; P. Lasjaunias; K. Terbrugge; P. Burrows

1990-01-01

371

Thalamic neurodegeneration in multiple sclerosis.  

PubMed

Multiple sclerosis is still regarded primarily as a disease of the white matter. However, recent evidence suggests that there may be significant involvement of gray matter. Here, we have used magnetic resonance imaging and magnetic resonance spectroscopy in vivo and histopathology postmortem to estimate thalamic neuronal loss in patients with multiple sclerosis. Our results show that neuronal loss in multiple sclerosis can be substantial (30-35% reduction). We conclude that a neurodegenerative pathology may make a major contribution to the genesis of symptoms in multiple sclerosis. PMID:12402265

Cifelli, Alberto; Arridge, Marzena; Jezzard, Peter; Esiri, Margaret M; Palace, Jacqueline; Matthews, Paul M

2002-11-01

372

Design of Controllers for a Multiple Input Multiple Output System  

E-print Network

A method of controller design for multiple input multiple output (MIMO) system is needed that will not give the high order controllers of modern control theory but will be more systematic than the “ad hoc” method. The objective of this method...

Harris, Amanda Lynne

2012-07-16

373

MULTIPLE STRESS COMPONENTS FROM MULTIPLE CUTS FOR THE CONTOUR METHOD  

Microsoft Academic Search

An extension of the contour method is presented which allows the measurement of multiple stress components by making multiple cuts. In the contour method, a body is carefully cut in two using wire electric discharge machining (EDM). The contours, or shapes, of the cut surfaces are then measured and used to calculate the original residual stress normal to the cut

P. Pagliaro; M. B. Prime; B. Zuccarello

374

Homeopathy in multiple sclerosis.  

PubMed

Multiple sclerosis (MS) is the most common disease of the central nervous system affecting people between the ages of 20 and 40 years in the UK, Northern Europe and the USA. No definitive treatment yet exists to halt the almost inevitable decline in function and accumulation of disability over the years in sufferers. Management is largely directly of symptoms which arise variably in the course of the condition. Such problems as urinary incontinence, sexual dysfunction, cramps and spasms, tremor and trigeminal neuralgia can often be helped to some extent using conventional therapies. These treatments though are not effective in everyone, or cause unacceptable side-effects and there are some commonly reported symptoms, such as fatigue or emotional lability for which there are no generally accepted treatments. Here, a knowledge of complementary and alternative medicine (CAM) can bring benefits to the person with MS. CAM is widely used by people with MS and some studies in this area are briefly summarised. It is interesting to reflect what lies behind all this CAM use and what that might tell conventional medicine about just what it is the MS sufferer really wants from their carers. Homeopathy is a form of CAM unique in the UK in having been available in the NHS since the foundation in 1948. Medical homeopaths in the UK have always been concerned with the integration of the best of conventional and complementary treatments for the benefit of their patients. Glasgow Homeopathic Hospital has around 100 admissions each year of people with MS at different stages of the condition and aims at an integrated response to their distress. Different therapeutic modalities are employed, but a homeopathic approach in particular is of benefit in MS. By its nature, it is a whole-person approach and allows for complete individualisation of treatment, taking account of the minutiae of someone's life. This is discussed and some examples of homeopathic treatments, which seem to be more generalisable for commonly encountered MS symptoms, are given. PMID:12604318

Whitmarsh, Thomas E

2003-02-01

375

Swamp Works- Multiple Projects  

NASA Technical Reports Server (NTRS)

My Surface Systems internship over the summer 2013 session covered a broad range of projects that ranged multiple aspects and fields of engineering and technology. This internship included a project to create a command center for a 120 ton regolith bin, a design and build for a blast shield to add further protection for the Surface Systems engineers, a design for a portable four monitor hyper wall that can extend as large as needed, research and programming a nano drill for a next generation robot, and social media tasks including the making of videos, posting to social networking websites and implementation of a new weekly outreach program to help spread the word about the Swamp Works laboratory. The objectives for the command center were to create a central computer controlled area for the still in production lunar regolith bin. It needed to be easy to use and the operating systems had to be Linux. The objectives for the hyper wall were to build a mobile transport of monitors that could potentially attach to one another. It needed to be light but sturdy, and have the ability to last. The objectives for the blast shield included a robust design that could withstand a small equipment malfunction, while also being convenient for use. The objectives for the nano-drill included the research and implementation of programming for vertical and horizontal movement. The hyper wall and blasts shield project were designed by me in the Pro/Engineer/Creo2 software. Each project required a meeting with the Swamp Works engineers and was declared successful.

Carelli, Jonathan M.

2013-01-01

376

Multiple Intelligences and Business Diversity  

Microsoft Academic Search

This study tests the viability of using Gardner's theory of multiple intelligences as a structure for identifying knowledge diversity in business students and whether such knowledge increases identification of self and others as potential sources of knowledge. The results from business students with substantial work histories indicate that the Multiple Intelligence Preference Inventory gives a valid and reliable indication of

Joyce Martin

2003-01-01

377

Multiple Intelligences for Differentiated Learning  

ERIC Educational Resources Information Center

There is an intricate literacy to Gardner's multiple intelligences theory that unlocks key entry points for differentiated learning. Using a well-articulated framework, rich with graphic representations, Williams provides a comprehensive discussion of multiple intelligences. He moves the teacher and students from curiosity, to confidence, to…

Williams, R. Bruce

2007-01-01

378

The problem with multiple robots  

NASA Technical Reports Server (NTRS)

The issues that can arise in research associated with multiple, robotic agents are discussed. Two particular multi-robot projects are presented as examples. This paper was written in the hope that it might ease the transition from single to multiple robot research.

Huber, Marcus J.; Kenny, Patrick G.

1994-01-01

379

Kinesiology: Challenges of Multiple Agendas  

Microsoft Academic Search

This paper addresses the challenge of how the fi eld of kinesiology can exploit the advantages of multiple agendas while minimizing the disadvantages. Agendas here are the scholarly themes that help organize the field of study explicitly or implicitly and that give emphases to it with respect to its content and impact in society. The issue of multiple agendas is

Karl M. Newell

2007-01-01

380

Teaching for Mastery of Multiplication  

ERIC Educational Resources Information Center

The strategies for learning multiplication concepts are discussed. The strategies involve introduction of the multiplication concepts through problem solutions with linkage between new concepts and prior knowledge, provision of concrete experiences and semi-concrete representations prior to purely symbolic notations, explicit teaching of the rules…

Wallace, Ann H.; Gurganus, Susan P.

2005-01-01

381

Parameters of Multiple College Attendance.  

ERIC Educational Resources Information Center

This is a report analyzing the multiple community college attendance patterns of students from nine colleges in the Los Angeles Community College District (California) from 1990-2000. The assessment utilizes the Multiple College Index (MCI), which is a measure based on the proportion of units a student earns at different colleges. The study…

Dillon, Paul H.

382

Multiplication Fact Fluency Using Doubles  

ERIC Educational Resources Information Center

Not knowing multiplication facts creates a gap in a student's mathematics development and undermines confidence and disposition toward further mathematical learning. Learning multiplication facts is a first step in proportional reasoning, "the capstone of elementary arithmetic and the gateway to higher mathematics" (NRC 2001, p. 242). Proportional…

Flowers, Judith M.; Rubenstein, Rheta N.

2010-01-01

383

Multiple Regression Assumptions. ERIC Digest.  

ERIC Educational Resources Information Center

This Digest presents a discussion of the assumptions of multiple regression that is tailored to the practicing researcher. The focus is on the assumptions of multiple regression that are not robust to violation, and that researchers can deal with if violated. Assumptions of normality, linearity, reliability of measurement, and homoscedasticity are…

Osborne, Jason W.; Waters, Elaine

384

Multiple AUVS for coastal oceanography  

Microsoft Academic Search

This paper presents the recent developments of the project Multiple Autonomous Underwater Vehicles for Coastal Oceanography, of the University of Porto. The project envisages the development of a highly operational and low-cost system for scientific and environmental data collection in the Portuguese coastal waters. The project activities suggested the development of a generalized vehicle (GV) control architecture for multiple vehicles.

J. Sousa; N. Cruz; A. Matos; F. Lobo Pereira

1997-01-01

385

Generalized Constrained Multiple Correspondence Analysis.  

ERIC Educational Resources Information Center

Proposes a comprehensive approach, generalized constrained multiple correspondence analysis, for imposing both row and column constraints on multivariate discrete data. Each set of discrete data is decomposed into several submatrices and then multiple correspondence analysis is applied to explore relationships among the decomposed submatrices.…

Hwang, Heungsun; Takane, Yoshio

2002-01-01

386

Multiple Intelligences Centers and Projects.  

ERIC Educational Resources Information Center

Based upon Gardner's theory of multiple intelligences, this book guides elementary school teachers through the process of using classroom learning centers and projects by providing choices for students. The guide is divided into two sections, providing the theoretical background and information on how to develop multiple intelligences learning…

Chapman, Carolyn; Freeman, Lynn

387

Multiple criteria water supply planning  

Microsoft Academic Search

Models and associated analytical techniques are proposed to select, within a multiple objective framework, the best combination of long-term water supply strategies for the regional municipality of Waterloo, Ontario, Canada. The problem is formulated as a multiple criteria integer program with interdependent actions. To solve the problem, different types of interdependence must be addressed. Due to the large number of

Siamak Rajabi; K. W. Hipel; D. Marc Kilgour

1997-01-01

388

The Philosophy of Multiple Comparisons  

Microsoft Academic Search

This paper is based on the 1989 Miller Memorial Lecture at Stanford University. The topic was chosen because of Rupert Miller's long involvement and significant contributions to multiple comparison procedures and theory. Our emphasis will be on the major questions that have received relatively little attention--on what one wants multiple comparisons to do, on why one wants to do that,

John W. Tukey

1991-01-01

389

Quantum computation and real multiplication  

E-print Network

We propose a construction of anyon systems associated to quantum tori with real multiplication and the embedding of quantum tori in AF algebras. These systems generalize the Fibonacci anyons, with weaker categorical properties, and are obtained from the basic modules and the real multiplication structure.

Matilde Marcolli; John Napp

2013-12-12

390

Multiple Participants, Multiple Locations, Multiple Time Zones and Multitasking in the Synchronous Cyber Classroom  

Microsoft Academic Search

This paper describes the use of the synchronous cyber classroom with multiple participants from multiple locations and time-zones in socially networked learning communities around the world. It reports enhanced cognitive function, higher participation and lower attrition rates, and collaborative teaching and learning during facilitated synchronous sessions. Data was drawn from a seven year trial of synchronous teaching and learning with

Megan Hastie; Nian-shing Chen; Ross J. Todd

2008-01-01

391

On Multiple-Layered Vortices  

NASA Technical Reports Server (NTRS)

As part of an ongoing effort to find ways to make vortex flow fields decompose more quickly, photographs and observations are presented of vortex flow fields that indicate the presence of multiple layers of fluid rotating about a common axis. A survey of the literature indicates that multiple-layered vortices form in waterspouts, tornadoes and lift-generated vortices of aircraft. An explanation for the appearance of multiple-layered structures in vortices is suggested. The observations and data presented are intended to improve the understanding of the formation and persistence of vortex flow fields.

Rossow, Vernon J.

2011-01-01

392

Forum: A Multiple-Conclusion  

E-print Network

Forum: A Multiple] provides some primitives for concurrency but lacks abstraction mechanisms. In this paper we present Forum. To illustrate the new expressive strengths of Forum, we specify in it a sequent calculus proof system

Miller, Dale

393

Multiple Antibiotic Resistance Operon Assays.  

National Technical Information Service (NTIS)

An isolated and cloned region of a bacterial chromosome containing a multiple antibiotic resistance operon is disclosed. A description of the structure and function of the operon is provided as are assorted recombinant DNA constructs involving the operon ...

S. B. Levy

2004-01-01

394

Multiple Sclerosis and Vitamin D  

MedlinePLUS

... e100 Neurology Andrew J. Solomon Multiple sclerosis and vitamin D This information is current as of October ... vitamin D Andrew J. Solomon, MD WHAT IS VITAMIN D AND WHY IS IT IMPORTANT IN MS? ...

395

A Semantics of Multiple Inheritance  

Microsoft Academic Search

this paper is to present a clean semantics of multiple inheritance and to show that, in the context of strongly-typed, statically-scoped languages, a sound typechecking algorithm exists. Multiple inheritance is also interpreted in a broad sense: instead of being limited to objects, it is extended in a natural way to union types and to higher-order functional types. This constitutes a

Luca Cardelli

1988-01-01

396

Let's Practice Multiplication and Division!  

NSDL National Science Digital Library

Use the games below to improve your multiplication and division skills. Today, we are going to play some fun games that help us get better at multiplication and division. Follow the directions below: 1. Choose one of the following games. If you are a boy, you may wish to play with the catapult in Flight of the Knight. If you are a girl, you could ...

Aycock, Miss

2009-04-15

397

A multiple armature railgun launcher  

NASA Astrophysics Data System (ADS)

Railgun launchers with multiple armatures, which can distribute the accelerating force on the projectile, supply each armature with gun current for acceleration through its own set of rails. Test results are reported which confirm the feasibility of this concept; it is shown that the control of current distribution to multiple armatures is possible. Attention is given to gun behavior for the case of high length/diameter projectiles.

Challita, Antonios; Maas, Brian L.; Bauer, David P.; Heyse, Mark

1993-01-01

398

Genetics Home Reference: Multiple epiphyseal dysplasia  

MedlinePLUS

... literature OMIM Genetic disorder catalog Conditions > Multiple epiphyseal dysplasia On this page: Description Genetic changes Inheritance Diagnosis ... definitions Reviewed February 2008 What is multiple epiphyseal dysplasia? Multiple epiphyseal dysplasia is a disorder of cartilage ...

399

Convergence characteristics of the multiple input, multiple output LMS algorithm  

NASA Technical Reports Server (NTRS)

The convergence characteristics of the multiple input, multiple output LMS algorithm, as applied to active noise and vibration control systems, are examined. The mean square error during the convergence process, as well as the final converged value, are examined analytically and in computer simulation. It is shown that the ratio of number of error sensors to number of control sources has a significant influence upon both the converging and converged value of the mean square error. Other active control system variables, such as the inherent time delays and structural/acoustic transfer functions, are also shown to have a significant influence upon the convergence process.

Snyder, Scott D.; Hansen, Colin H.; Clark, Robert L.

1992-01-01

400

[Multiple myeloma with D immunoglobulin].  

PubMed

The immunoglobulin D multiple myeloma is a rare form of multiple myeloma and affects a young population. It is characterized by its clinical severity and poor prognosis. We report four cases of multiple myeloma immunoglobulin D diagnosed and supported in the university hospital Center of Sale and Rabat-Morocco. We propose to study the epidemiological, clinical and biological characteristics of this rare type of monoclonal gammopathy. Through the observations reported, the clinical aspect of myeloma is characterized by the high frequency of extra-bone manifestations including impaired kidney function. The immunoglobulin D multiple myeloma is mainly type ?, the IgD ? is rare, the predominance of ? light chains could be explained by rearrangements at the immunoglobulin genes. Bence-Jones proteinuria is almost constant in the multiple myeloma immunoglobulin D, it is mainly type ?, reflecting excess production of light chains by plasma cells. The marrow is invaded by plasma cells in very different proportions of up to 95%. It's a clinical entity, difficult to diagnose, particularly when low homogeneous band on electrophoresis goes unnoticed for an eye inexperienced or when immune serum anti-IgD was not used during the immunotyping. PMID:22008139

Benchekroun, Laila; Ouzzif, Zohra; Bouabdillah, Mounya; Jaouhar, Nouzha; Aoufir, Fatiha; Aoufi, Farida; Chabraoui, Layachi

2011-01-01

401

Modularization to Support Multiple Brand Platforms  

E-print Network

Methods to determine acceptable architecture for multiple platforms supporting multiple brands must represent both platform cost saving commonization as well as revenue enhancing brand distinctions. Functional architecting ...

Agus, Sudjianto

2001-09-09

402

Nanoliter Reactors Improve Multiple Displacement Amplification  

E-print Network

Nanoliter Reactors Improve Multiple Displacement Amplification of Genomes from Single Cells Yann) Nanoliter reactors improve multiple displacement amplification of genomes from single cells. PLoS Genet 3

Quake, Stephen R.

403

An indole alkaloid from a tribal folklore inhibits immediate early event in HSV-2 infected cells with therapeutic efficacy in vaginally infected mice.  

PubMed

Herpes genitalis, caused by HSV-2, is an incurable genital ulcerative disease transmitted by sexual intercourse. The virus establishes life-long latency in sacral root ganglia and reported to have synergistic relationship with HIV-1 transmission. Till date no effective vaccine is available, while the existing therapy frequently yielded drug resistance, toxicity and treatment failure. Thus, there is a pressing need for non-nucleotide antiviral agent from traditional source. Based on ethnomedicinal use we have isolated a compound 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (HM) from the traditional herb Ophiorrhiza nicobarica Balkr, and evaluated its efficacy on isolates of HSV-2 in vitro and in vivo. The cytotoxicity (CC50), effective concentrations (EC50) and the mode of action of HM was determined by MTT, plaque reduction, time-of-addition, immunofluorescence (IFA), Western blot, qRT-PCR, EMSA, supershift and co-immunoprecipitation assays; while the in vivo toxicity and efficacy was evaluated in BALB/c mice. The results revealed that HM possesses significant anti-HSV-2 activity with EC50 of 1.1-2.8 µg/ml, and selectivity index of >20. The time kinetics and IFA demonstrated that HM dose dependently inhibited 50-99% of HSV-2 infection at 1.5-5.0 µg/ml at 2-4 h post-infection. Further, HM was unable to inhibit viral attachment or penetration and had no synergistic interaction with acyclovir. Moreover, Western blot and qRT-PCR assays demonstrated that HM suppressed viral IE gene expression, while the EMSA and co-immunoprecipitation studies showed that HM interfered with the recruitment of LSD-1 by HCF-1. The in vivo studies revealed that HM at its virucidal concentration was nontoxic and reduced virus yield in the brain of HSV-2 infected mice in a concentration dependent manner, compared to vaginal tissues. Thus, our results suggest that HM can serve as a prototype to develop non-nucleotide antiviral lead targeting the viral IE transcription for the management of HSV-2 infections. PMID:24167591

Bag, Paromita; Ojha, Durbadal; Mukherjee, Hemanta; Halder, Umesh Chandra; Mondal, Supriya; Chandra, Nidhi S; Nandi, Suman; Sharon, Ashoke; Sarkar, Mamta Chawla; Chakrabarti, Sekhar; Chattopadhyay, Debprasad

2013-01-01

404

Viral Immediate-Early Proteins Abrogate the Modification by SUMO1 of PML and Sp100 Proteins, Correlating with Nuclear Body Disruption  

Microsoft Academic Search

PML nuclear bodies (NBs) are subnuclear structures whose integrity is compromised in certain human dis- eases, including leukemia and neurodegenerative disorders. Infection by a number of DNA viruses similarly triggers the reorganization of these structures, suggesting an important role for the NBs in the viral infection process. While expression of the adenovirus E4 ORF3 protein leads to only a moderate

STEFAN MULLER; ANNE DEJEAN

1999-01-01

405

Transcription of the dominant-negative helix-loop-helix protein Id1 is regulated by a protein complex containing the immediate-early response gene Egr-1.  

PubMed Central

The expression of Id1, a helix-loop-helix protein which inhibits the activity of basic helix-loop-helix transcription factors, is down-regulated during cellular differentiation and cell cycle withdrawal both in tissue culture models and in mouse embryos. In order to study the mechanism of control of Idl expression, we have isolated a 210-bp enhancer element in the upstream region of the Id1 gene whose activity recapitulates Id1 expression in C2C12 muscle cells and C3H10T1/2 fibroblasts: i.e., this element is active in proliferating cells in the presence of serum and completely inactivated upon mitogen depletion, cell cycle withdrawal, and (in the case of C2C12) induced myoblast differentiation. Using linker-scanning mutations and site-directed mutagenesis in transient transfection experiments, we have identified two functional elements within the 210-bp enhancer which are required for proper serum responsiveness. One element (A) contains a consensus Egr-1 binding site and additional flanking sequences required for optimal activity, and the other element (B) fits no known consensus. Gel shift experiments demonstrate that the protein complex binding to the A site contains Egr-1 and other proteins. This complex as well as a protein complex that binds to the B site is lost within 24 h of serum depletion, correlating with the down-regulation of Id1 expression. On the basis of these findings, we propose that the regulation of the Id1 response to serum is mediated in part by the early response gene Egr-1 and as such provides a signaling link between the early-growth-response transcription factors and dominant-negative helix-loop-helix proteins. PMID:8628310

Tournay, O; Benezra, R

1996-01-01

406

Immediate Early and Early Lytic Cycle Proteins Are Frequent Targets of the Epstein-Barr Virus-induced Cytotoxic T Cell Response  

Microsoft Academic Search

Summary Epstein-Barr virus (EBV), a human g -herpesvirus, can establish both nonproductive (latent) and productive (lytic) infections. Although the CD8 1 cytotoxic T lymphocyte (CTL) response to latently infected cells is well characterized, very little is known about T cell controls over lytic infection; this imbalance in our understanding belies the importance of virus-replicative lesions in several aspects of EBV

N. M. Steven; N. E. Annels; A. Kumar; A. M. Leese; M. G. Kurilla; A. B. Rickinson

1997-01-01

407

Immunization with the immediate-early tegument protein (open reading frame 62) of varicella-zoster virus protects guinea pigs against virus challenge.  

PubMed Central

The IE62 protein, the primary regulatory protein of varicella-zoster virus (VZV) and the major component of the virion tegument, was an effective immunogen in the guinea pig model of VZV infection, whereas the ORF 29 gene product, a nonstructural DNA replication protein, did not elicit protection. All animals immunized with the ORF 29 protein had cell-associated viremia compared with 2 of 11 guinea pigs given the IE62 protein (P = 0.005). VZV was detected in ganglia from 38% of the animals given the ORF 29 protein and 44% of the control animals compared with 9% of the animals immunized with the IE62 protein (P = 0.04). In contrast to the IE62 protein, immunization with the ORF 29 protein did not prime the animals for an enhanced T-cell response upon challenge with infectious virus. The VZV IE62 protein has potential value as a vaccine component. Images PMID:8230489

Sabella, C; Lowry, P W; Abbruzzi, G M; Koropchak, C M; Kinchington, P R; Sadegh-Zadeh, M; Hay, J; Ruyechan, W T; Arvin, A M

1993-01-01

408

Rapid Up-Regulation of Peptide Elongation Factor EF1? Protein Levels Is an Immediate Early Event during Oxidative Stress-Induced Apoptosis  

Microsoft Academic Search

Hydrogen peroxide (H2O2) induces apoptosis in cultured cells, in a dose-dependent manner. Treatment with H2O2 causes decreased mitochondrial respiration, along with DNA degradation and the formation of an oligonucleosomal ladder, all hallmarks of apoptotic cell death. In this report, we investigate alterations in expression of a peptide elongation factor, EF-1?, during oxidative challenge. EF-1? protein levels undergo rapid increase upon

Edwin Chen; Gregory Proestou; Denis Bourbeau; Eugenia Wang

2000-01-01

409

An Indole Alkaloid from a Tribal Folklore Inhibits Immediate Early Event in HSV-2 Infected Cells with Therapeutic Efficacy in Vaginally Infected Mice  

PubMed Central

Herpes genitalis, caused by HSV-2, is an incurable genital ulcerative disease transmitted by sexual intercourse. The virus establishes life-long latency in sacral root ganglia and reported to have synergistic relationship with HIV-1 transmission. Till date no effective vaccine is available, while the existing therapy frequently yielded drug resistance, toxicity and treatment failure. Thus, there is a pressing need for non-nucleotide antiviral agent from traditional source. Based on ethnomedicinal use we have isolated a compound 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (HM) from the traditional herb Ophiorrhiza nicobarica Balkr, and evaluated its efficacy on isolates of HSV-2 in vitro and in vivo. The cytotoxicity (CC50), effective concentrations (EC50) and the mode of action of HM was determined by MTT, plaque reduction, time-of-addition, immunofluorescence (IFA), Western blot, qRT-PCR, EMSA, supershift and co-immunoprecipitation assays; while the in vivo toxicity and efficacy was evaluated in BALB/c mice. The results revealed that HM possesses significant anti-HSV-2 activity with EC50 of 1.1-2.8 µg/ml, and selectivity index of >20. The time kinetics and IFA demonstrated that HM dose dependently inhibited 50-99% of HSV-2 infection at 1.5-5.0 µg/ml at 2-4 h post-infection. Further, HM was unable to inhibit viral attachment or penetration and had no synergistic interaction with acyclovir. Moreover, Western blot and qRT-PCR assays demonstrated that HM suppressed viral IE gene expression, while the EMSA and co-immunoprecipitation studies showed that HM interfered with the recruitment of LSD-1 by HCF-1. The in vivo studies revealed that HM at its virucidal concentration was nontoxic and reduced virus yield in the brain of HSV-2 infected mice in a concentration dependent manner, compared to vaginal tissues. Thus, our results suggest that HM can serve as a prototype to develop non-nucleotide antiviral lead targeting the viral IE transcription for the management of HSV-2 infections. PMID:24167591

Bag, Paromita; Ojha, Durbadal; Mukherjee, Hemanta; Halder, Umesh Chandra; Mondal, Supriya; Chandra, Nidhi S.; Nandi, Suman; Sharon, Ashoke; Sarkar, Mamta Chawla; Chakrabarti, Sekhar; Chattopadhyay, Debprasad

2013-01-01

410

Immediate early response of the marine sponge Suberites domuncula to heat stress: reduction of trehalose and glutathione concentrations and glutathione S-transferase activity  

Microsoft Academic Search

The marine sponge Suberites domuncula was used to identify early markers for thermal stress. Cubes from sponges have been kept for 30 min at 31°C (10 °C higher than the ambient temperature). After this treatment the sponge cubes were kept again at 21°C. To demonstrate that the animals reacted to the elevated temperature, the expression of heat shock protein (HSP)

Nilza Bachinski; Claudia Koziol; Renato Batel; Zeljka Labura; Heinz C. Schröder; Werner E. G. Müller

1997-01-01

411

Expression of Epstein–Barr virus BZLF1 immediate-early protein induces p53 degradation independent of MDM2, leading to repression of p53-mediated transcription  

Microsoft Academic Search

The Epstein–Barr virus (EBV) lytic program elicits ATM-dependent DNA damage response, resulting in phosphorylation of p53 at N-terminus, which prevents interaction with MDM2. Nevertheless, p53-downstream signaling is blocked. We found here that during the lytic infection p53 was actively degraded in a proteasome-dependent manner even with a reduced level of MDM2. BZLF1 protein enhanced the ubiquitination of p53 in SaOS-2

Yoshitaka Sato; Noriko Shirata; Ayumi Kudoh; Satoko Iwahori; Sanae Nakayama; Takayuki Murata; Hiroki Isomura; Yukihiro Nishiyama; Tatsuya Tsurumi

2009-01-01

412

Subpixel resolution from multiple images  

NASA Technical Reports Server (NTRS)

Multiple images taken from similar locations and under similar lighting conditions contain similar, but not identical, information. Slight differences in instrument orientation and position produces mismatches between the projected pixel grids. These mismatches ensure that any point on the ground is sampled differently in each image. If all the images can be registered with respect to each other to a small fraction of a pixel accuracy, then the information from the multiple images can be combined to increase linear resolution by roughly the square root of the number of images. In addition, the gray-scale resolution of the composite image is also improved. We describe methods for multiple image registration and combination, and discuss some of the problems encountered in developing and extending them. We display test results with 8:1 resolution enhancement, and Viking Orbiter imagery with 2:1 and 4:1 enhancements.

Cheeseman, Peter; Kanefsky, Rob; Stutz, John; Kraft, Richard

1994-01-01

413

Normalized Compression Distance of Multiples  

E-print Network

Normalized compression distance (NCD) is a parameter-free similarity measure based on compression. The NCD between pairs of objects is not sufficient for all applications. We propose an NCD of finite multisets (multiples) of objacts that is metric and is better for many applications. Previously, attempts to obtain such an NCD failed. We use the theoretical notion of Kolmogorov complexity that for practical purposes is approximated from above by the length of the compressed version of the file involved, using a real-world compression program. We applied the new NCD for multiples to retinal progenitor cell questions that were earlier treated with the pairwise NCD. Here we get significantly better results. We also applied the NCD for multiples to synthetic time sequence data. The preliminary results are as good as nearest neighbor Euclidean classifier.

Cohen, Andrew R

2012-01-01

414

Multiple Imputation Strategies for Multiple Group Structural Equation Models  

ERIC Educational Resources Information Center

Although structural equation modeling software packages use maximum likelihood estimation by default, there are situations where one might prefer to use multiple imputation to handle missing data rather than maximum likelihood estimation (e.g., when incorporating auxiliary variables). The selection of variables is one of the nuances associated…

Enders, Craig K.; Gottschall, Amanda C.

2011-01-01

415

The Multiple Factors of Multiple Sclerosis: A Darwinian Perspective  

Microsoft Academic Search

Purpose: Multiple sclerosis (MS), an autoimmune disease of the central nervous system, is often referred to as a multifactorial disease, but there is little consensus as to what factors are involved, besides genetic susceptibility and childhood infectious agents. The purpose of this paper is to identify plausible, environmental factors that contribute to the aetiology of MS. Design: Review of the

ASHTON F. EMBRY

2004-01-01

416

Convergence and Discriminant: Assessing Multiple Traits Using Multiple Methods  

ERIC Educational Resources Information Center

Multiple traits of language proficiency as well as test method effects were concurrently analyzed to investigate interrelations of construct validity, convergent validity, and discriminant validity using multitrait-multimethod (MTMM) matrices. A total of 585 test takers' scores were derived from the field test of the "Pearson Test of English…

Pae, Hye K.

2012-01-01

417

[HLA and familial multiple sclerosis].  

PubMed

Some data suggest an environmental perhaps a viral factor but also of a genetic factor in the etiology of multiple sclerosis. Among the latter is the notably increased risk for a twin when the other twin has the disease, a risk further increased if they are monozygotic. There is also a greater than chance frequency of common HLA haplotypes in 2 affected siblings. The frequency of familial forms of multiple sclerosis is estimated at approximately 6 p. 100. We have studied 14 families of which 12 included 2 members with multiple sclerosis and 2 with 3 affected members. Parental relation between patients was parent to child (7 cases), brother to sister (5 cases), sister to sister including two pairs of twins (4 cases) and cousin to cousin on the mother's side (2 cases). When compared with non-familial multiple sclerosis there were no particular features in clinical disorders or course: 4 forms were progressive, the others evolving by episodes. In 26 patients in whom HLA antigens were determined, the DR2 antigen was present 19 times, the B7 antigen 9 times and the A3 antigen 7 times. In the 8 pairs of siblings with multiple sclerosis, 2 were HLA-identical and 5 semi-identical. One pair had no common haplotype. Grouping of HLA in 22 healthy members allowed 8 genealogic trees to be established. If a gene for susceptibility to multiple sclerosis exists, it is of low penetration, of dominant transmission and of limited frequency. It probably lies close to the region D of chromosome 6, because of the disequilibrium of crossed linking with A3, B7 and DR2 antigens. PMID:3823705

Barroche, G; Perrier, P; Raffoux, C; Gehin, P; Streiff, F; Weber, M

1986-01-01

418

Polarimetry with multiple mirror telescopes  

NASA Technical Reports Server (NTRS)

The polarizations of multiple mirror telescopes are calculated using Mueller calculus. It is found that the Multiple Mirror Telescope (MMT) produces a constant depolarization that is a function of wavelength and independent of sky position. The efficiency and crosstalk are modeled and experimentally verified. The two- and four-mirror new generation telescopes are found to produce sinusoidal depolarization for which an accurate interpretation of the incident Stokes vector requires inverse matrix calculations. Finally, the depolarization of f/1 paraboloids is calculated and found to be less than 0.1 percent at 3000 A.

West, S. C.

1986-01-01

419

Multiple order common path spectrometer  

NASA Technical Reports Server (NTRS)

The present invention relates to a dispersive spectrometer. The spectrometer allows detection of multiple orders of light on a single focal plane array by splitting the orders spatially using a dichroic assembly. A conventional dispersion mechanism such as a defraction grating disperses the light spectrally. As a result, multiple wavelength orders can be imaged on a single focal plane array of limited spectral extent, doubling (or more) the number of spectral channels as compared to a conventional spectrometer. In addition, this is achieved in a common path device.

Newbury, Amy B. (Inventor)

2010-01-01

420

SPSS Tutorial for Multiple Comparisons  

NSDL National Science Digital Library

Authored by Laura Little of the University of Washington, this tutorial exposes students to conducting multiple comparisons in SPSS. This html based tutorial provides extensive screen shots and an example data set. Topics covered in the tutorial include: one way ANOVA, preplanned contrasts, Bonferroni, Post Hoc Tukey's HSD, and Scheffe's multiple contrasts. This is a great example of how to use statistical tools such as SPSS in a psychological statistics course. Little does excellent work in providing a step by step approach to learning these methods.

Little, Laura

2009-03-11

421

Variant morphology in multiple myeloma.  

PubMed

A 45-year-old man presented to the clinic with the chief complaints of low back pain, marked weight loss, and pallor of 2 months duration. He was found to have severe normocytic anemia with leukoerythroblastosis. Bone marrow aspirate resulted in a dry tap. Marrow trephine biopsy showed findings initially interpreted as poorly differentiated carcinoma involving marrow. Immunohistochemistry and protein studies established a diagnosis of IgG Kappa multiple myeloma. Correlation of marrow biopsy findings with clinical, radiological and immunological data remain an essential part of the diagnostic evaluation of multiple myeloma. PMID:25332545

Koduri, Prasad R; Gowrishankar, Swarnalata; Malladi, Vijay Kumar

2014-09-01

422

Multiple Spontaneous Simultaneous Intracerebral Hemorrhages  

PubMed Central

Simultaneous occurrence of intracerebral hemorrhage (ICH) in different arterial territories is an uncommon event. We report on two cases of multiple spontaneous simultaneous ICH for which we could find no specific cause. A 73-year-old man, with no related medical history, was admitted to the hospital with simultaneous bithalamic ICH, and subsequently died of recurrent pneumonia. Second patient was a 60-year-old man who presented with simultaneous ICH in the pons and thalamus; he died of recurrent bleeding. We review the possible pathological mechanisms, clinical and radiologic features of simultaneous multiple ICH. PMID:25045650

Seo, Jin-Suk; Nam, Taek-Kyun; Kwon, Jeong-Taik

2014-01-01

423

Multiple resonant railgun power supply  

DOEpatents

A multiple repetitive resonant railgun power supply provides energy for repetitively propelling projectiles from a pair of parallel rails. A plurality of serially connected paired parallel rails are powered by similar power supplies. Each supply comprises an energy storage capacitor, a storage inductor to form a resonant circuit with the energy storage capacitor and a magnetic switch to transfer energy between the resonant circuit and the pair of parallel rails for the propelling of projectiles. The multiple serial operation permits relatively small energy components to deliver overall relatively large amounts of energy to the projectiles being propelled.

Honig, Emanuel M. (Los Alamos, NM); Nunnally, William C. (Los Alamos, NM)

1988-01-01

424

Development of a Multimorbidity Illness Perceptions Scale (MULTIPleS)  

PubMed Central

Background Illness perceptions are beliefs about the cause, nature and management of illness, which enable patients to make sense of their conditions. These perceptions can predict adjustment and quality of life in patients with single conditions. However, multimorbidity (i.e. patients with multiple long-term conditions) is increasingly prevalent and a key challenge for future health care delivery. The objective of this research was to develop a valid and reliable measure of illness perceptions for multimorbid patients. Methods Candidate items were derived from previous qualitative research with multimorbid patients. Questionnaires were posted to 1500 patients with two or more exemplar long-term conditions (depression, diabetes, osteoarthritis, coronary heart disease and chronic obstructive pulmonary disease). Data were analysed using factor analysis and Rasch analysis. Rasch analysis is a modern psychometric technique for deriving unidimensional and intervally-scaled questionnaires. Results Questionnaires from 490 eligible patients (32.6% response) were returned. Exploratory factor analysis revealed five potential subscales ‘Emotional representations’, ‘Treatment burden’, ‘Prioritising conditions’, ‘Causal links’ and ‘Activity limitations’. Rasch analysis led to further item reduction and the generation of a summary scale comprising of items from all scales. All scales were unidimensional and free from differential item functioning or local independence of items. All scales were reliable, but for each subscale there were a number of patients who scored at the floor of the scale. Conclusions The MULTIPleS measure consists of five individual subscales and a 22-item summary scale that measures the perceived impact of multimorbidity. All scales showed good fit to the Rasch model and preliminary evidence of reliability and validity. A number of patients scored at floor of each subscale, which may reflect variation in the perception of multimorbidity. The MULTIPleS measure will facilitate research into the impact of illness perceptions on adjustment, clinical outcomes, quality of life, and costs in patients with multimorbidity. PMID:24376504

Gibbons, Chris J.; Kenning, Cassandra; Coventry, Peter A.; Bee, Penny; Bundy, Christine; Fisher, Louise; Bower, Peter

2013-01-01

425

Kinesiology: Challenges of Multiple Agendas  

ERIC Educational Resources Information Center

This paper addresses the challenge of how the field of kinesiology can exploit the advantages of multiple agendas while minimizing the disadvantages. Agendas here are the scholarly themes that help organize the field of study explicitly or implicitly and that give emphases to it with respect to its content and impact in society. The issue of…