Piracy of PGE2/EP receptor mediated signaling by Kaposi’s sarcoma associated herpes virus (KSHV/HHV-8) for latency gene expression: Strategy of a successful pathogen

PubMed Central

Paul, Arun George; Sharma-Walia, Neelam; Kerur, Nagaraj; White, Carl; Chandran, Bala

2010-01-01

KSHV is implicated in the pathogenesis of KS, a chronic inflammation associated malignancy. COX-2 and its metabolite PGE2, two pivotal proinflammatory/oncogeneic molecules, are proposed to play roles in the expression of major KSHV latency associated nuclear antigen-1 (LANA-1). Microsomal prostaglandin E2 synthase (mPGES), PGE2 and its receptors (EP1, EP2, EP3, and EP4) were detected in KS lesions with the distinct staining of EP2/EP4 in KS lesions. In latently infected endothelial TIVE-LTC cells, EP receptor antagonists down-regulated LANA-1 expression as well as Ca2+, p-Src, p-PI3K, p-PKCζ/λ, and p-NF-κB, which are also some of the signal molecules proposed to be important in KS pathogenesis. Exogenous PGE2 and EP receptor agonists induced the LANA-1 promoter in 293 cells, and YY1, Sp1, Oct-1, Oct-6, C/EBP and c-Jun transcription factors appear to be involved in this induction. PGE2/EP receptor induced LANA-1 promoter activity was down-regulated significantly by the inhibition of Ca2+, p-Src, p-PI3K, p-PKCζ/λ, and p-NF-κB. These findings implicate the inflammatory PGE2/EP receptors and the associated signal molecules in herpes virus latency and uncover a novel paradigm that demonstrates the evolution of KSHV genome plasticity to utilize inflammatory response for its survival advantage of maintaining latent gene expression. This data also suggests that potential use of anti-COX-2 and anti-EP receptor therapy may not only ameliorate the chronic inflammation associated with KS but could also lead to elimination of the KSHV latent infection and the associated KS lesions. PMID:20388794

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

Togi, Sumihito; Nakasuji, Misa; Muromoto, Ryuta

Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA), which interacts with cellular proteins, plays a central role in modification of viral and/or cellular gene expression. Here, we show that LANA associates with glucocorticoid receptor (GR), and that LANA enhances the transcriptional activity of GR. Co-immunoprecipitation revealed a physical interaction between LANA and GR in transiently transfected 293T and HeLa cells. In human B-lymphoma cells, LANA overexpression enhanced GR activity and cell growth suppression following glucocorticoid stimulation. Furthermore, confocal microscopy showed that activated GR was bound to LANA and accumulated in the nucleus, leading to an increase in binding of activatedmore » GR to the glucocorticoid response element of target genes. Taken together, KSHV-derived LANA acts as a transcriptional co-activator of GR. Our results might suggest a careful use of glucocorticoids in the treatment of patients with KSHV-related malignancies such as Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. - Highlights: • KSHV-LANA enhances the transcriptional activity of GR in 293T and HeLa cells. • KSHV-LANA physically associates with GR. • KSHV-LANA enhances GR activation and cell growth suppression in human B-lymphocytes. • KSHV-LANA influences the nuclear retention and DNA binding activity of GR.« less

Integrated systems biology analysis of KSHV latent infection reveals viral induction and reliance on peroxisome mediated lipid metabolism

PubMed Central

Sychev, Zoi E.; Hu, Alex; Lagunoff, Michael

2017-01-01

Kaposi’s Sarcoma associated Herpesvirus (KSHV), an oncogenic, human gamma-herpesvirus, is the etiological agent of Kaposi’s Sarcoma the most common tumor of AIDS patients world-wide. KSHV is predominantly latent in the main KS tumor cell, the spindle cell, a cell of endothelial origin. KSHV modulates numerous host cell-signaling pathways to activate endothelial cells including major metabolic pathways involved in lipid metabolism. To identify the underlying cellular mechanisms of KSHV alteration of host signaling and endothelial cell activation, we identified changes in the host proteome, phosphoproteome and transcriptome landscape following KSHV infection of endothelial cells. A Steiner forest algorithm was used to integrate the global data sets and, together with transcriptome based predicted transcription factor activity, cellular networks altered by latent KSHV were predicted. Several interesting pathways were identified, including peroxisome biogenesis. To validate the predictions, we showed that KSHV latent infection increases the number of peroxisomes per cell. Additionally, proteins involved in peroxisomal lipid metabolism of very long chain fatty acids, including ABCD3 and ACOX1, are required for the survival of latently infected cells. In summary, novel cellular pathways altered during herpesvirus latency that could not be predicted by a single systems biology platform, were identified by integrated proteomics and transcriptomics data analysis and when correlated with our metabolomics data revealed that peroxisome lipid metabolism is essential for KSHV latent infection of endothelial cells. PMID:28257516

Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi’s Sarcoma-Associated Herpesvirus Latent and Lytic Replications

PubMed Central

Gruffaz, Marion; Zhou, Shenghua; Vasan, Karthik; Rushing, Teresa; Michael, Qing Liu; Lu, Chu

2018-01-01

ABSTRACT Oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) is etiologically linked to primary effusion lymphoma (PEL), an aggressive and nontreatable malignancy commonly found in AIDS patients. In this study, we performed a high-throughput screening of 3,731 characterized compounds and identified cytarabine, approved by the FDA for treating numerous types of cancer, as a potent inhibitor of KSHV-induced PEL. We showed the high efficacy of cytarabine in the growth inhibition of various PEL cells by inducing cell cycle arrest and apoptosis. Cytarabine inhibited host DNA and RNA syntheses and therefore induced cellular cytotoxicity. Furthermore, cytarabine inhibited viral DNA and RNA syntheses and induced the rapid degradation of KSHV major latent protein LANA (latency-associated nuclear antigen), leading to the suppression of KSHV latent replication. Importantly, cytarabine effectively inhibited active KSHV replication and virion production in PEL cells. Finally, cytarabine treatments not only effectively inhibited the initiation and progression of PEL tumors but also induced regression of grown PEL tumors in a xenograft mouse model. Altogether, our study has identified cytarabine as a novel therapeutic agent for treating PEL as well as eliminating KSHV persistent infection. PMID:29739902

Transcriptional Downregulation of ORF50/Rta by Methotrexate Inhibits the Switch of Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8 from Latency to Lytic Replication

PubMed Central

Curreli, Francesca; Cerimele, Francesca; Muralidhar, Sumitra; Rosenthal, Leonard J.; Cesarman, Ethel; Friedman-Kien, Alvin E.; Flore, Ornella

2002-01-01

Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a cellular dihydrofolate reductase (DHFR) homologue. Methotrexate (MTX), a potent anti-inflammatory agent, inhibits cellular DHFR activity. We investigated the effect of noncytotoxic doses of MTX on latency and lytic KSHV replication in two KSHV-infected primary effusion lymphoma cell lines (BC-3 and BC-1) and in MTX-resistant BC-3 cells (MTX-R-BC-3 cells). Treatment with MTX completely prevented tetradecanoyl phorbol acetate-induced viral DNA replication and strongly decreased viral lytic transcript levels, even in MTX-resistant cells. However, the same treatment had no effect on transcription of cellular genes and KSHV latent genes. One of the lytic transcripts inhibited by MTX, ORF50/Rta (open reading frame), is an immediate-early gene encoding a replication-transcription activator required for expression of other viral lytic genes. Therefore, transcription of genes downstream of ORF50/Rta was inhibited, including those encoding the viral G-protein-coupled receptor (GPCR), viral interleukin-6, and K12/kaposin, which have been shown to be transforming in vitro and oncogenic in mice. Resistance to MTX has been documented in cultured cells and also in patients treated with this drug. However, MTX showed an inhibitory activity even in MTX-R-BC-3 cells. Two currently available antiherpesvirus drugs, cidofovir and foscarnet, had no effect on the transcription of these viral oncogenes and ORF50/Rta. MTX is the first example of a compound shown to downregulate the expression of ORF50/Rta and therefore prevent viral transforming gene transcription. Given that the expression of these genes may be important for tumor development, MTX could play a role in the future management of KSHV-associated malignancies. PMID:11967335

A chimeric protein composed of NuMA fused to the DNA binding domain of LANA is sufficient for the ori-P-dependent DNA replication

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

Ohsaki, Eriko; Ueda, Keiji, E-mail: kueda@virus.me

The Kaposi's sarcoma-associated herpesvirus (KSHV) genome is stably maintained in KSHV-infected PEL cell lines during cell division. We previously showed that accumulation of LANA in the nuclear matrix fraction could be important for the latent DNA replication, and that the functional significance of LANA should be its recruitment of ori-P to the nuclear matrix. Here, we investigated whether the forced localization of the LANA-DNA binding domain (DBD) to the nuclear matrix facilitated ori-P-containing plasmid replication. We demonstrated that chimeric proteins constructed by fusion of LANA DBD with the nuclear mitotic apparatus protein (NuMA), which is one of the components ofmore » the nuclear matrix, could bind with ori-P and enhance replication of an ori-P-containing plasmid, compared with that in the presence of DBD alone. These results further suggested that the ori-P recruitment to the nuclear matrix through the binding with DBD is important for latent viral DNA replication. - Highlights: •KSHV replication in latency depends on LANA localization to the nuclear matrix. •LANA DBD was fused with NuMA, a nuclear matrix protein, at the N- and C-terminus. •NuMA-DBD was in the nuclear matrix and supported the ori-P dependent replication. •LANA in the nuclear matrix should be important for the KSHV replication in latency.« less

Localization of latency-associated nuclear antigen (LANA) on mitotic chromosomes

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

Rahayu, Retno; Ohsaki, Eriko; Omori, Hiroko

In latent infection of Kaposi's sarcoma-associated herpesvirus (KSHV), viral gene expression is extremely limited and copy numbers of viral genomes remain constant. Latency-associated nuclear antigen (LANA) is known to have a role in maintaining viral genome copy numbers in growing cells. Several studies have shown that LANA is localized in particular regions on mitotic chromosomes, such as centromeres/pericentromeres. We independently examined the distinct localization of LANA on mitotic chromosomes during mitosis, using super-resolution laser confocal microscopy and correlative fluorescence microscopy–electron microscopy (FM-EM) analyses. We found that the majority of LANA were not localized at particular regions such as telomeres/peritelomeres, centromeres/pericentromeres,more » and cohesion sites, but at the bodies of condensed chromosomes. Thus, LANA may undergo various interactions with the host factors on the condensed chromosomes in order to tether the viral genome to mitotic chromosomes and realize faithful viral genome segregation during cell division. - Highlights: • This is the first report showing LANA dots on mitotic chromosomes by fluorescent microscopy followed by electron microscopy. • LANA dots localized randomly on condensed chromosomes other than centromere/pericentromere and telomere/peritelomre. • Cellular mitotic checkpoint should not be always involved in the segregation of KSHV genomes in the latency.« less

Understanding pathogenetic aspects and clinical presentation of primary effusion lymphoma (PEL) through its derived cell lines

PubMed Central

Carbone, Antonino; Cesarman, Ethel; Gloghini, Annunziata; Drexler, Hans G.

2013-01-01

Primary effusion lymphoma (PEL) is a very rare subgroup of B-cell lymphomas presenting as pleural, peritoneal and pericardial neoplastic effusions in the absence of a solid tumor mass or recognizable nodal involvement. There is strong evidence that Kaposi’s sarcoma associated herpesvirus (KSHV) is a causal agent of PEL. PEL tumor cells are latently infected by KSHV with consistent expression of several viral proteins and microRNAs that can affect cellular proliferation, differentiation and survival. The most relevant data on pathogenesis and biology of KSHV have been provided by studies on PEL derived cell lines. Fourteen continuous cell lines have been established from the malignant effusions of patients with AIDS-and non-AIDS-associated PEL. These KSHV+ EBV+/− cell lines are wellcharacterized, authenticated and mostly available from public biological ressource centers. The PEL cell lines display unique features and are clearly distinct from other lymphoma cell lines. PEL cell lines represent an indispensable tool for the understanding of KSHV biology and its impact on the clinical manifestation of PEL. Studies on PEL cell lines have shown that a number of viral genes, expressed during latency or lytic life cycle, have effects on cell binding, proliferation, angiogenesis and inflammation. Also PEL cell lines are important model systems for the study of the pathology of PEL including the lack of invasive or destructive growth patterns and the peculiar propensity of PEL to involve body cavity surfaces. PMID:20051807

Differences in Kaposi sarcoma-associated herpesvirus-specific and –nonspecific immune responses in classic Kaposi sarcoma cases and matched controls in Sicily

PubMed Central

Amodio, Emanuele; Goedert, James J.; Barozzi, Patrizia; Riva, Giovanni; Firenze, Alberto; Bonura, Filippa; Viviano, Enza; Romano, Nino; Luppi, Mario

2011-01-01

SUMMARY Kaposi sarcoma (KS) may develop because of incompetent immune responses, both nonspecifically and specifically against the KS-associated herpes virus (KSHV). Peripheral blood mononuclear cells from 15 classic (non-AIDS) KS cases, 13 KSHV seropositives (without KS), and 15 KSHV-seronegative controls were tested for interferon-γ T-cell (Elispot) responses to KSHV-LANA, KSHV-K8.1, and CMV/EBV peptide pools. The forearm and thigh of each participant also was tested for delayed-type hypersensitivity (DTH) against common recall antigens. Groups were compared with Fisher exact test and multinomial logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). KSHV Elispot response was detected in 10 (67%) classic KS cases, 11 (85%) KSHV seropositives (without KS), and 2 (13%) seronegative controls. All 4 cases with KSHV-LANA responses had current KS lesions, whereas 5 of 6 cases with KSHV-K8.1 responses had no lesions (P=0.048). No case responded to both LANA and K8.1. Compared to seronegative controls, risk for classic KS was inversely related to DTH in the thigh (OR 0.71, 95% CI 0.55–0.94, P=0.01), directly associated with DTH in the forearm (OR 1.35, 95% CI 1.02–1.80, P=0.04), and tended to be increased 5-fold per KSHV Elispot response (OR 5.13, 95% CI 0.86–30.77, P=0.07). Compared to KSHV seropositives (without KS), risk for classic KS, was reduced 5-fold (OR 0.20, CI 0.03–0.77, P=0.04) per KSHV response. CMV/EBV Elispot responses were irrelevant. Deficiency of both KSHV-specific and –nonspecific immunity is associated with classic KS. This may clarify why Kaposi sarcoma responds to immune reconstitution. PMID:21740480

G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV

PubMed Central

Madireddy, Advaitha; Purushothaman, Pravinkumar; Loosbroock, Christopher P.; Robertson, Erle S.; Schildkraut, Carl L.; Verma, Subhash C.

2016-01-01

Kaposi's sarcoma associated herpesvirus (KSHV) establishes life-long latent infection by persisting as an extra-chromosomal episome in the infected cells and by maintaining its genome in dividing cells. KSHV achieves this by tethering its epigenome to the host chromosome by latency associated nuclear antigen (LANA), which binds in the terminal repeat (TR) region of the viral genome. Sequence analysis of the TR, a GC-rich DNA element, identified several potential Quadruplex G-Rich Sequences (QGRS). Since quadruplexes have the tendency to obstruct DNA replication, we used G-quadruplex stabilizing compounds to examine their effect on latent DNA replication and the persistence of viral episomes. Our results showed that these G-quadruplex stabilizing compounds led to the activation of dormant origins of DNA replication, with preferential bi-directional pausing of replications forks moving out of the TR region, implicating the role of the G-rich TR in the perturbation of episomal DNA replication. Over time, treatment with PhenDC3 showed a loss of viral episomes in the infected cells. Overall, these data show that G-quadruplex stabilizing compounds retard the progression of replication forks leading to a reduction in DNA replication and episomal maintenance. These results suggest a potential role for G-quadruplex stabilizers in the treatment of KSHV-associated diseases. PMID:26837574

The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence*

PubMed Central

Li, Shijun; Tan, Min; Juillard, Franceline; Ponnusamy, Rajesh; Correia, Bruno; Simas, J. Pedro; Carrondo, Maria A.; McVey, Colin E.; Kaye, Kenneth M.

2015-01-01

Kaposi sarcoma-associated herpesvirus (KSHV) has a causative role in several human malignancies. KSHV latency-associated nuclear antigen (LANA) mediates persistence of viral episomes in latently infected cells. LANA mediates KSHV DNA replication and segregates episomes to progeny nuclei. The structure of the LANA DNA binding domain was recently solved, revealing a positive electrostatic patch opposite the DNA binding surface, which is the site of BET protein binding. Here we investigate the functional role of the positive patch in LANA-mediated episome persistence. As expected, LANA mutants with alanine or glutamate substitutions in the central, peripheral, or lateral portions of the positive patch maintained the ability to bind DNA by EMSA. However, all of the substitution mutants were deficient for LANA DNA replication and episome maintenance. Mutation of the peripheral region generated the largest deficiencies. Despite these deficiencies, all positive patch mutants concentrated to dots along mitotic chromosomes in cells containing episomes, similar to LANA. The central and peripheral mutants, but not the lateral mutants, were reduced for BET protein interaction as assessed by co-immunoprecipitation. However, defects in BET protein binding were independent of episome maintenance function. Overall, the reductions in episome maintenance closely correlated with DNA replication deficiencies, suggesting that the replication defects account for the reduced episome persistence. Therefore, the electrostatic patch exerts a key role in LANA-mediated DNA replication and episome persistence and may act through a host cell partner(s) other than a BET protein or by inducing specific structures or complexes. PMID:26420481

Chloroquine inhibits lytic replication of Kaposi's sarcoma-associated herpesvirus by disrupting mTOR and p38-MAPK activation.

PubMed

Yang, Mengtian; Huang, Lu; Li, Xiaojuan; Kuang, Ersheng

2016-09-01

Lytic infection is essential for the persistent infection and pathogenesis of Kaposi's sarcoma-associated herpesvirus (KSHV), and inhibiting KSHV lytic replication may effectively prevent the occurrence of KSHV-related diseases. Chloroquine (CQ), a well-known antimalarial drug and autophagy inhibitor, exerts broad-spectrum antiviral effects and shows anti-cancer therapeutic potential. However, the ability of CQ and its derivatives to control infection of oncogenic γ-herpesvirus remains undefined. Here we reveal that CQ suppresses KSHV lytic gene expression and virion production, and shows cytotoxicity toward KSHV lytically infected B cells at clinically acceptable doses. CQ suppresses mTOR and p38-MAPK pathway activation during KSHV lytic replication but not latent infection. Furthermore, CQ blocks Epstein-Barr virus (EBV) lytic replication via a distinct mechanism that is invoked to block virion production but does not affect viral gene expression. These results suggest that CQ is an effective antiviral drug against KSHV lytic infection. Our findings indicate that CQ treatment should be considered for controlling KSHV-related diseases, particularly for primary use in co-infection of KSHV with malaria. Copyright © 2016 Elsevier B.V. All rights reserved.

G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV.

PubMed

Madireddy, Advaitha; Purushothaman, Pravinkumar; Loosbroock, Christopher P; Robertson, Erle S; Schildkraut, Carl L; Verma, Subhash C

2016-05-05

Kaposi's sarcoma associated herpesvirus (KSHV) establishes life-long latent infection by persisting as an extra-chromosomal episome in the infected cells and by maintaining its genome in dividing cells. KSHV achieves this by tethering its epigenome to the host chromosome by latency associated nuclear antigen (LANA), which binds in the terminal repeat (TR) region of the viral genome. Sequence analysis of the TR, a GC-rich DNA element, identified several potential Quadruplex G-Rich Sequences (QGRS). Since quadruplexes have the tendency to obstruct DNA replication, we used G-quadruplex stabilizing compounds to examine their effect on latent DNA replication and the persistence of viral episomes. Our results showed that these G-quadruplex stabilizing compounds led to the activation of dormant origins of DNA replication, with preferential bi-directional pausing of replications forks moving out of the TR region, implicating the role of the G-rich TR in the perturbation of episomal DNA replication. Over time, treatment with PhenDC3 showed a loss of viral episomes in the infected cells. Overall, these data show that G-quadruplex stabilizing compounds retard the progression of replication forks leading to a reduction in DNA replication and episomal maintenance. These results suggest a potential role for G-quadruplex stabilizers in the treatment of KSHV-associated diseases. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence.

PubMed

Li, Shijun; Tan, Min; Juillard, Franceline; Ponnusamy, Rajesh; Correia, Bruno; Simas, J Pedro; Carrondo, Maria A; McVey, Colin E; Kaye, Kenneth M

2015-11-20

Kaposi sarcoma-associated herpesvirus (KSHV) has a causative role in several human malignancies. KSHV latency-associated nuclear antigen (LANA) mediates persistence of viral episomes in latently infected cells. LANA mediates KSHV DNA replication and segregates episomes to progeny nuclei. The structure of the LANA DNA binding domain was recently solved, revealing a positive electrostatic patch opposite the DNA binding surface, which is the site of BET protein binding. Here we investigate the functional role of the positive patch in LANA-mediated episome persistence. As expected, LANA mutants with alanine or glutamate substitutions in the central, peripheral, or lateral portions of the positive patch maintained the ability to bind DNA by EMSA. However, all of the substitution mutants were deficient for LANA DNA replication and episome maintenance. Mutation of the peripheral region generated the largest deficiencies. Despite these deficiencies, all positive patch mutants concentrated to dots along mitotic chromosomes in cells containing episomes, similar to LANA. The central and peripheral mutants, but not the lateral mutants, were reduced for BET protein interaction as assessed by co-immunoprecipitation. However, defects in BET protein binding were independent of episome maintenance function. Overall, the reductions in episome maintenance closely correlated with DNA replication deficiencies, suggesting that the replication defects account for the reduced episome persistence. Therefore, the electrostatic patch exerts a key role in LANA-mediated DNA replication and episome persistence and may act through a host cell partner(s) other than a BET protein or by inducing specific structures or complexes. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

ARID3B: a Novel Regulator of the Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycle

PubMed Central

Wood, Jennifer J.; Boyne, James R.; Paulus, Christina; Jackson, Brian R.; Nevels, Michael M.

2016-01-01

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of commonly fatal malignancies of immunocompromised individuals, including primary effusion lymphoma (PEL) and Kaposi's sarcoma (KS). A hallmark of all herpesviruses is their biphasic life cycle—viral latency and the productive lytic cycle—and it is well established that reactivation of the KSHV lytic cycle is associated with KS pathogenesis. Therefore, a thorough appreciation of the mechanisms that govern reactivation is required to better understand disease progression. The viral protein replication and transcription activator (RTA) is the KSHV lytic switch protein due to its ability to drive the expression of various lytic genes, leading to reactivation of the entire lytic cycle. While the mechanisms for activating lytic gene expression have received much attention, how RTA impacts cellular function is less well understood. To address this, we developed a cell line with doxycycline-inducible RTA expression and applied stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative proteomics. Using this methodology, we have identified a novel cellular protein (AT-rich interacting domain containing 3B [ARID3B]) whose expression was enhanced by RTA and that relocalized to replication compartments upon lytic reactivation. We also show that small interfering RNA (siRNA) knockdown or overexpression of ARID3B led to an enhancement or inhibition of lytic reactivation, respectively. Furthermore, DNA affinity and chromatin immunoprecipitation assays demonstrated that ARID3B specifically interacts with A/T-rich elements in the KSHV origin of lytic replication (oriLyt), and this was dependent on lytic cycle reactivation. Therefore, we have identified a novel cellular protein whose expression is enhanced by KSHV RTA with the ability to inhibit KSHV reactivation. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of fatal malignancies of immunocompromised individuals, including Kaposi's sarcoma (KS). Herpesviruses are able to establish a latent infection, in which they escape immune detection by restricting viral gene expression. Importantly, however, reactivation of productive viral replication (the lytic cycle) is necessary for the pathogenesis of KS. Therefore, it is important that we comprehensively understand the mechanisms that govern lytic reactivation, to better understand disease progression. In this study, we have identified a novel cellular protein (AT-rich interacting domain protein 3B [ARID3B]) that we show is able to temper lytic reactivation. We showed that the master lytic switch protein, RTA, enhanced ARID3B levels, which then interacted with viral DNA in a lytic cycle-dependent manner. Therefore, we have added a new factor to the list of cellular proteins that regulate the KSHV lytic cycle, which has implications for our understanding of KSHV biology. PMID:27512077

Glycolysis, Glutaminolysis, and Fatty Acid Synthesis Are Required for Distinct Stages of Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication.

PubMed

Sanchez, Erica L; Pulliam, Thomas H; Dimaio, Terri A; Thalhofer, Angel B; Delgado, Tracie; Lagunoff, Michael

2017-05-15

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS). KSHV infection induces and requires multiple metabolic pathways, including the glycolysis, glutaminolysis, and fatty acid synthesis (FAS) pathways, for the survival of latently infected endothelial cells. To determine the metabolic requirements for productive KSHV infection, we induced lytic replication in the presence of inhibitors of different metabolic pathways. We found that glycolysis, glutaminolysis, and FAS are all required for maximal KSHV virus production and that these pathways appear to participate in virus production at different stages of the viral life cycle. Glycolysis and glutaminolysis, but not FAS, inhibit viral genome replication and, interestingly, are required for different early steps of lytic gene expression. Glycolysis is necessary for early gene transcription, while glutaminolysis is necessary for early gene translation but not transcription. Inhibition of FAS resulted in decreased production of extracellular virions but did not reduce intracellular genome levels or block intracellular virion production. However, in the presence of FAS inhibitors, the intracellular virions are noninfectious, indicating that FAS is required for virion assembly or maturation. KS tumors support both latent and lytic KSHV replication. Previous work has shown that multiple cellular metabolic pathways are required for latency, and we now show that these metabolic pathways are required for efficient lytic replication, providing novel therapeutic avenues for KS tumors. IMPORTANCE KSHV is the etiologic agent of Kaposi's sarcoma, the most common tumor of AIDS patients. KS spindle cells, the main tumor cells, all contain KSHV, mostly in the latent state, during which there is limited viral gene expression. However, a percentage of spindle cells support lytic replication and production of virus and these cells are thought to contribute to overall tumor formation. Our previous findings showed that latently infected cells are sensitive to inhibitors of cellular metabolic pathways, including glycolysis, glutaminolysis, and fatty acid synthesis. Here we found that these same inhibitors block the production of infectious virus from lytically infected cells, each at a different stage of viral replication. Therefore, inhibition of specific cellular metabolic pathways can both eliminate latently infected cells and block lytic replication, thereby inhibiting infection of new cells. Inhibition of metabolic pathways provides novel therapeutic approaches for KS tumors. Copyright © 2017 American Society for Microbiology.

Glycolysis, Glutaminolysis, and Fatty Acid Synthesis Are Required for Distinct Stages of Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication

PubMed Central

Sanchez, Erica L.; Pulliam, Thomas H.; Dimaio, Terri A.; Thalhofer, Angel B.; Delgado, Tracie

2017-01-01

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS). KSHV infection induces and requires multiple metabolic pathways, including the glycolysis, glutaminolysis, and fatty acid synthesis (FAS) pathways, for the survival of latently infected endothelial cells. To determine the metabolic requirements for productive KSHV infection, we induced lytic replication in the presence of inhibitors of different metabolic pathways. We found that glycolysis, glutaminolysis, and FAS are all required for maximal KSHV virus production and that these pathways appear to participate in virus production at different stages of the viral life cycle. Glycolysis and glutaminolysis, but not FAS, inhibit viral genome replication and, interestingly, are required for different early steps of lytic gene expression. Glycolysis is necessary for early gene transcription, while glutaminolysis is necessary for early gene translation but not transcription. Inhibition of FAS resulted in decreased production of extracellular virions but did not reduce intracellular genome levels or block intracellular virion production. However, in the presence of FAS inhibitors, the intracellular virions are noninfectious, indicating that FAS is required for virion assembly or maturation. KS tumors support both latent and lytic KSHV replication. Previous work has shown that multiple cellular metabolic pathways are required for latency, and we now show that these metabolic pathways are required for efficient lytic replication, providing novel therapeutic avenues for KS tumors. IMPORTANCE KSHV is the etiologic agent of Kaposi's sarcoma, the most common tumor of AIDS patients. KS spindle cells, the main tumor cells, all contain KSHV, mostly in the latent state, during which there is limited viral gene expression. However, a percentage of spindle cells support lytic replication and production of virus and these cells are thought to contribute to overall tumor formation. Our previous findings showed that latently infected cells are sensitive to inhibitors of cellular metabolic pathways, including glycolysis, glutaminolysis, and fatty acid synthesis. Here we found that these same inhibitors block the production of infectious virus from lytically infected cells, each at a different stage of viral replication. Therefore, inhibition of specific cellular metabolic pathways can both eliminate latently infected cells and block lytic replication, thereby inhibiting infection of new cells. Inhibition of metabolic pathways provides novel therapeutic approaches for KS tumors. PMID:28275189

Transcription Mapping of the Kaposi’s Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Genome in a Body Cavity-Based Lymphoma Cell Line (BC-1)

PubMed Central

Sarid, Ronit; Flore, Ornella; Bohenzky, Roy A.; Chang, Yuan; Moore, Patrick S.

1998-01-01

Kaposi’s sarcoma-associated herpesvirus (KSHV) gene transcription in the BC-1 cell line (KSHV and Epstein-Barr virus coinfected) was examined by using Northern analysis with DNA probes extending across the viral genome except for a 3-kb unclonable rightmost region. Three broad classes of viral gene transcription have been identified. Class I genes, such as those encoding the v-cyclin, latency-associated nuclear antigen, and v-FLIP, are constitutively transcribed under standard growth conditions, are unaffected by tetradecanoylphorbol acetate (TPA) induction, and presumably represent latent viral transcripts. Class II genes are primarily clustered in nonconserved regions of the genome and include small polyadenylated RNAs (T0.7 and T1.1) as well as most of the virus-encoded cytokines and signal transduction genes. Class II genes are transcribed without TPA treatment but are induced to higher transcription levels by TPA treatment. Class III genes are primarily structural and replication genes that are transcribed only following TPA treatment and are presumably responsible for lytic virion production. These results indicate that BC-1 cells have detectable transcription of a number of KSHV genes, particularly nonconserved genes involved in cellular signal transduction and regulation, during noninduced (latent) virus culture. PMID:9444993

Viral MicroRNAs Repress the Cholesterol Pathway, and 25-Hydroxycholesterol Inhibits Infection.

PubMed

Serquiña, Anna K P; Kambach, Diane M; Sarker, Ontara; Ziegelbauer, Joseph M

2017-07-11

From various screens, we found that Kaposi's sarcoma-associated herpesvirus (KSHV) viral microRNAs (miRNAs) target several enzymes in the mevalonate/cholesterol pathway. 3-Hydroxy-3-methylglutaryl-coenzyme A (CoA) synthase 1 (HMGCS1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR [a rate-limiting step in the mevalonate pathway]), and farnesyl-diphosphate farnesyltransferase 1 (FDFT1 [a committed step in the cholesterol branch]) are repressed by multiple KSHV miRNAs. Transfection of viral miRNA mimics in primary endothelial cells (human umbilical vein endothelial cells [HUVECs]) is sufficient to reduce intracellular cholesterol levels; however, small interfering RNAs (siRNAs) targeting only HMGCS1 did not reduce cholesterol levels. This suggests that multiple targets are needed to perturb this tightly regulated pathway. We also report here that cholesterol levels were decreased in de novo -infected HUVECs after 7 days. This reduction is at least partially due to viral miRNAs, since the mutant form of KSHV lacking 10 of the 12 miRNA genes had increased cholesterol compared to wild-type infections. We hypothesized that KSHV is downregulating cholesterol to suppress the antiviral response by a modified form of cholesterol, 25-hydroxycholesterol (25HC). We found that the cholesterol 25-hydroxylase (CH25H) gene, which is responsible for generating 25HC, had increased expression in de novo -infected HUVECs but was strongly suppressed in long-term latently infected cell lines. We found that 25HC inhibits KSHV infection when added exogenously prior to de novo infection. In conclusion, we found that multiple KSHV viral miRNAs target enzymes in the mevalonate pathway to modulate cholesterol in infected cells during latency. This repression of cholesterol levels could potentially be beneficial to viral infection by decreasing the levels of 25HC. IMPORTANCE A subset of viruses express unique microRNAs (miRNAs), which act like cellular miRNAs to generally repress host gene expression. A cancer virus, Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus 8 [HHV-8]), encodes multiple miRNAs that repress gene expression of multiple enzymes that are important for cholesterol synthesis. In cells with these viral miRNAs or with natural infection, cholesterol levels are reduced, indicating these viral miRNAs decrease cholesterol levels. A modified form of cholesterol, 25-hydroxycholesterol, is generated directly from cholesterol. Addition of 25-hydroxycholesterol to primary cells inhibited KSHV infection of cells, suggesting that viral miRNAs may decrease cholesterol levels to decrease the concentration of 25-hydroxycholesterol and to promote infection. These results suggest a new virus-host relationship and indicate a previously unidentified viral strategy to lower cholesterol levels. Copyright © 2017 Serquiña et al.

Human I-mfa domain proteins specifically interact with KSHV LANA and affect its regulation of Wnt signaling-dependent transcription

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

Kusano, Shuichi, E-mail: skusano@m2.kufm.kagoshima-u.ac.jp; Eizuru, Yoshito

2010-06-04

Kaposi's sarcoma-associated herpes virus (KSHV)-encoded latency-associated nuclear antigen (LANA) protein has been reported to interact with glycogen synthase kinase 3{beta} (GSK-3{beta}) and to negatively regulate its activity, leading to stimulation of GSK-3{beta}-dependent {beta}-catenin degradation. We show here that the I-mfa domain proteins, HIC (human I-mfa domain-containing protein) and I-mfa (inhibitor of MyoD family a), interacted in vivo with LANA through their C-terminal I-mfa domains. This interaction affected the intracellular localization of HIC, inhibited the LANA-dependent transactivation of a {beta}-catenin-regulated reporter construct, and decreased the level of the LANA.GSK-3{beta} complex. These data reveal for the first time that I-mfa domain proteinsmore » interact with LANA and negatively regulate LANA-mediated activation of Wnt signaling-dependent transcription by inhibiting the formation of the LANA.GSK-3{beta} complex.« less

Latency-Associated Nuclear Antigen E3 Ubiquitin Ligase Activity Impacts Gammaherpesvirus-Driven Germinal Center B Cell Proliferation.

PubMed

Cerqueira, Sofia A; Tan, Min; Li, Shijun; Juillard, Franceline; McVey, Colin E; Kaye, Kenneth M; Simas, J Pedro

2016-09-01

Viruses have evolved mechanisms to hijack components of cellular E3 ubiquitin ligases, thus modulating the ubiquitination pathway. However, the biological relevance of such mechanisms for viral pathogenesis in vivo remains largely unknown. Here, we utilized murid herpesvirus 4 (MuHV-4) infection of mice as a model system to address the role of MuHV-4 latency-associated nuclear antigen (mLANA) E3 ligase activity in gammaherpesvirus latent infection. We show that specific mutations in the mLANA SOCS box (V199A, V199A/L202A, or P203A/P206A) disrupted mLANA's ability to recruit Elongin C and Cullin 5, thereby impairing the formation of the Elongin BC/Cullin 5/SOCS (EC5S(mLANA)) complex and mLANA's E3 ligase activity on host NF-κB and Myc. Although these mutations resulted in considerably reduced mLANA binding to viral terminal repeat DNA as assessed by electrophoretic mobility shift assay (EMSA), the mutations did not disrupt mLANA's ability to mediate episome persistence. In vivo, MuHV-4 recombinant viruses bearing these mLANA SOCS box mutations exhibited a deficit in latency amplification in germinal center (GC) B cells. These findings demonstrate that the E3 ligase activity of mLANA contributes to gammaherpesvirus-driven GC B cell proliferation. Hence, pharmacological inhibition of viral E3 ligase activity through targeting SOCS box motifs is a putative strategy to control gammaherpesvirus-driven lymphoproliferation and associated disease. The gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause lifelong persistent infection and play causative roles in several human malignancies. Colonization of B cells is crucial for virus persistence, and access to the B cell compartment is gained by virus-driven proliferation in germinal center (GC) B cells. Infection of B cells is predominantly latent, with the viral genome persisting as a multicopy episome and expressing only a small subset of viral genes. Here, we focused on latency-associated nuclear antigen (mLANA) encoded by murid herpesvirus-4 (MuHV-4), which exhibits homology in sequence, structure, and function to KSHV LANA (kLANA), thereby allowing the study of LANA-mediated pathogenesis in mice. Our experiments show that mLANA's E3 ubiquitin ligase activity is necessary for efficient expansion of latency in GC B cells, suggesting that the development of pharmacological inhibitors of LANA E3 ubiquitin ligase activity may allow strategies to interfere with gammaherpesvirus-driven lymphoproliferation and associated disease. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

RNA N6-adenosine methylation (m6A) steers epitranscriptomic control of herpesvirus replication

PubMed Central

Ye, Fengchun

2017-01-01

Latency is a hallmark of all herpesviruses, during which the viral genomes are silenced through DNA methylation and suppressive histone modifications. When latent herpesviruses reactivate to undergo productive lytic replication, the suppressive epigenetic marks are replaced with active ones to allow for transcription of viral genes. Interestingly, by using Kaposi’s sarcoma-associated herpesvirus (KSHV) as a model, we recently demonstrated that the newly transcribed viral RNAs are also subjected to post-transcriptional N6-adenosine methylation (m6A). Blockade of this post-transcriptional event abolishes viral protein expression and halts virion production. We found that m6A modification controls RNA splicing, stability, and protein translation to regulate viral lytic gene expression and replication. Thus, our finding for the first time reveals a critical role of this epitranscriptomic mechanism in the control of herpesviral replication, which shall shed lights on development of novel strategies for the control of herpesviral infection. PMID:29082271

Delta-9 tetrahydrocannabinol (THC) inhibits lytic replication of gamma oncogenic herpesviruses in vitro.

PubMed

Medveczky, Maria M; Sherwood, Tracy A; Klein, Thomas W; Friedman, Herman; Medveczky, Peter G

2004-09-15

The major psychoactive cannabinoid compound of marijuana, delta-9 tetrahydrocannabinol (THC), has been shown to modulate immune responses and lymphocyte function. After primary infection the viral DNA genome of gamma herpesviruses persists in lymphoid cell nuclei in a latent episomal circular form. In response to extracellular signals, the latent virus can be activated, which leads to production of infectious virus progeny. Therefore, we evaluated the potential effects of THC on gamma herpesvirus replication. Tissue cultures infected with various gamma herpesviruses were cultured in the presence of increasing concentrations of THC and the amount of viral DNA or infectious virus yield was compared to those of control cultures. The effect of THC on Kaposi's Sarcoma Associated Herpesvirus (KSHV) and Epstein-Barr virus (EBV) replication was measured by the Gardella method and replication of herpesvirus saimiri (HVS) of monkeys, murine gamma herpesvirus 68 (MHV 68), and herpes simplex type 1 (HSV-1) was measured by yield reduction assays. Inhibition of the immediate early ORF 50 gene promoter activity was measured by the dual luciferase method. Micromolar concentrations of THC inhibit KSHV and EBV reactivation in virus infected/immortalized B cells. THC also strongly inhibits lytic replication of MHV 68 and HVS in vitro. Importantly, concentrations of THC that inhibit virus replication of gamma herpesviruses have no effect on cell growth or HSV-1 replication, indicating selectivity. THC was shown to selectively inhibit the immediate early ORF 50 gene promoter of KSHV and MHV 68. THC specifically targets viral and/or cellular mechanisms required for replication and possibly shared by these gamma herpesviruses, and the endocannabinoid system is possibly involved in regulating gamma herpesvirus latency and lytic replication. The immediate early gene ORF 50 promoter activity was specifically inhibited by THC. These studies may also provide the foundation for the development of antiviral strategies utilizing non-psychoactive derivatives of THC.

Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV-MCD) and the KSHV Inflammatory Cytokine Syndrome.

PubMed

Polizzotto, Mark N; Uldrick, Thomas S; Hu, Duosha; Yarchoan, Robert

2012-01-01

Soon after the discovery of Kaposi sarcoma (KS)-associated herpesvirus (KSHV), it was appreciated that this virus was associated with most cases of multicentric Castleman disease (MCD) arising in patients infected with human immunodeficiency virus. It has subsequently been recognized that KSHV-MCD is a distinct entity from other forms of MCD. Like MCD that is unrelated to KSHV, the clinical presentation of KSHV-MCD is dominated by systemic inflammatory symptoms including fevers, cachexia, and laboratory abnormalities including cytopenias, hypoalbuminemia, hyponatremia, and elevated C-reactive protein. Pathologically KSHV-MCD is characterized by polyclonal, IgM-lambda restricted plasmacytoid cells in the intrafollicular areas of affected lymph nodes. A portion of these cells are infected with KSHV and a sizable subset of these cells express KSHV lytic genes including a viral homolog of interleukin-6 (vIL-6). Patients with KSHV-MCD generally have elevated KSHV viral loads in their peripheral blood. Production of vIL-6 and induction of human (h) IL-6 both contribute to symptoms, perhaps in combination with overproduction of IL-10 and other cytokines. Until recently, the prognosis of patients with KSHV-MCD was poor. Recent therapeutic advances targeting KSHV-infected B cells with the anti-CD20 monoclonal antibody rituximab and utilizing KSHV enzymes to target KSHV-infected cells have substantially improved patient outcomes. Recently another KSHV-associated condition, the KSHV inflammatory cytokine syndrome (KICS) has been described. Its clinical manifestations resemble those of KSHV-MCD but lymphadenopathy is not prominent and the pathologic nodal changes of KSHV-MCD are absent. Patients with KICS exhibit elevated KSHV viral loads and elevation of vIL-6, homolog of human interleukin-6 and IL-10 comparable to those seen in KSHV-MCD; the cellular origin of these is a matter of investigation. KICS may contribute to the inflammatory symptoms seen in some patients with severe KS or primary effusion lymphoma. Additional research is needed to better define the clinical spectrum of KICS and its relationship to KSHV-MCD. In additional, research is needed to better understand the pathogenesis and epidemiology of both KICS and KSHV-MCD, as well as the optimal therapy for both of these disorders.

Modified Cross-Linking, Ligation, and Sequencing of Hybrids (qCLASH) Identifies Kaposi's Sarcoma-Associated Herpesvirus MicroRNA Targets in Endothelial Cells.

PubMed

Gay, Lauren A; Sethuraman, Sunantha; Thomas, Merin; Turner, Peter C; Renne, Rolf

2018-04-15

Kaposi's sarcoma (KS) tumors are derived from endothelial cells and express Kaposi's sarcoma-associated herpesvirus (KSHV) microRNAs (miRNAs). Although miRNA targets have been identified in B cell lymphoma-derived cells and epithelial cells, little has been done to characterize the KSHV miRNA targetome in endothelial cells. A recent innovation in the identification of miRNA targetomes, cross-linking, ligation, and sequencing of hybrids (CLASH), unambiguously identifies miRNAs and their targets by ligating the two species while both species are still bound within the RNA-induced silencing complex (RISC). We developed a streamlined quick CLASH (qCLASH) protocol that requires a lower cell input than the original method and therefore has the potential to be used on patient biopsy samples. Additionally, we developed a fast-growing, KSHV-negative endothelial cell line derived from telomerase-immortalized vein endothelial long-term culture (TIVE-LTC) cells. qCLASH was performed on uninfected cells and cells infected with either wild-type KSHV or a mutant virus lacking miR-K12-11/11*. More than 1,400 cellular targets of KSHV miRNAs were identified. Many of the targets identified by qCLASH lacked a canonical seed sequence match. Additionally, most target regions in mRNAs originated from the coding DNA sequence (CDS) rather than the 3' untranslated region (UTR). This set of genes includes some that were previously identified in B cells and some new genes that warrant further study. Pathway analysis of endothelial cell targets showed enrichment in cell cycle control, apoptosis, and glycolysis pathways, among others. Characterization of these new targets and the functional consequences of their repression will be important in furthering our understanding of the role of KSHV miRNAs in oncogenesis. IMPORTANCE KS lesions consist of endothelial cells latently infected with KSHV. Cells that make up these lesions express KSHV miRNAs. Identification of the targets of KSHV miRNAs will help us understand their role in viral oncogenesis. The cross-linking and sequencing of hybrids (CLASH) protocol is a method for unambiguously identifying miRNA targetomes. We developed a streamlined version of CLASH, called quick CLASH (qCLASH). qCLASH requires a lower initial input of cells than for its parent protocol. Additionally, a new fast-growing KSHV-negative endothelial cell line, named TIVE-EX-LTC cells, was established. qCLASH was performed on TIVE-EX-LTC cells latently infected with wild-type (WT) KSHV or a mutant virus lacking miR-K12-11/11*. A number of novel targets of KSHV miRNAs were identified, including targets of miR-K12-11, the ortholog of the cellular oncogenic miRNA (oncomiR) miR-155. Many of the miRNA targets were involved in processes related to oncogenesis, such as glycolysis, apoptosis, and cell cycle control. Copyright © 2018 American Society for Microbiology.

The central repeat domain 1 of Kaposi's sarcoma-associated herpesvirus (KSHV) latency associated-nuclear antigen 1 (LANA1) prevents cis MHC class I peptide presentation

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

Kwun, Hyun Jin; Ramos da Silva, Suzane; Department of Pathology, Botucatu School of Medicine at Sao Paulo State University, Sao Paulo

KSHV LANA1, a latent protein expressed during chronic infection to maintain a viral genome, inhibits major histocompatibility complex class I (MHC I) peptide presentation in cis as a means of immune evasion. Through deletional cloning, we localized this function to the LANA1 central repeat 1 (CR1) subregion. Other CR subregions retard LANA1 translation and proteasomal processing but do not markedly inhibit LANA1 peptide processing by MHC I. Inhibition of proteasomal processing ablates LANA1 peptide presentation. Direct expression of LANA1 within the endoplasmic reticulum (ER) overcomes CR1 inhibition suggesting that CR1 acts prior to translocation of cytoplasmic peptides into the ER.more » By physically separating CR1 from other subdomains, we show that LANA1 evades MHC I peptide processing by a mechanism distinct from other herpesviruses including Epstein-Barr virus (EBV). Although LANA1 and EBV EBNA1 are functionally similar, they appear to use different mechanisms to evade host cytotoxic T lymphocyte surveillance.« less

KAPOSI’S SARCOMA–ASSOCIATED HERPESVIRUS IMMUNOEVASION AND TUMORIGENESIS: TWO SIDES OF THE SAME COIN?

PubMed Central

Moore, Patrick S.; Chang, Yuan

2013-01-01

Kaposi’s sarcoma–associated herpesvirus (KSHV) [or human herpesvirus 8 (HHV-8)] is the most frequent cause of malignancy among AIDS patients. KSHV and related herpesviruses have extensively pirated cellular cDNAs from the host genome, providing a unique opportunity to examine the range of viral mechanisms for controlling cell proliferation. Many of the viral regulatory homologs encode proteins that directly inhibit host adaptive and innate immunity. Other viral proteins target retinoblastoma protein and p53 control of tumor suppressor pathways, which also play key effector roles in intracellular immune responses. The immune evasion strategies employed by KSHV, by targeting tumor suppressor pathways activated during immune system signaling, may lead to inadvertent cell proliferation and tumorigenesis in susceptible hosts. PMID:14527293

Kaposi's Sarcoma Associated-Herpes Virus (KSHV) Seroprevalence in Pregnant Women in South Africa

PubMed Central

2010-01-01

Background Factors previously associated with Kaposi's sarcoma-associated herpesvirus (KSHV) transmission in Africa include sexual, familial, and proximity to river water. We measured the seroprevalence of KSHV in relation to HIV, syphilis, and demographic factors among pregnant women attending public antenatal clinics in the Gauteng province of South Africa. Methods We tested for antibodies to KSHV lytic K8.1 and latent Orf73 antigens in 1740 pregnant women attending antenatal clinics who contributed blood to the "National HIV and Syphilis Sero-Prevalence Survey - South Africa, 2001". Information on HIV and syphilis serology, age, education, residential area, gravidity, and parity was anonymously linked to evaluate risk factors for KSHV seropositivity. Clinics were grouped by municipality regions and their proximity to the two main river catchments defined. Results KSHV seropositivity (reactive to either lytic K8.1 and latent Orf73) was nearly twice that of HIV (44.6% vs. 23.1%). HIV and syphilis seropositivity was 12.7% and 14.9% in women without KSHV, and 36.1% and 19.9% respectively in those with KSHV. Women who are KSHV seropositive were 4 times more likely to be HIV positive than those who were KSHV seronegative (AOR 4.1 95%CI: 3.4 - 5.7). Although, women with HIV infection were more likely to be syphilis seropositive (AOR 1.8 95%CI: 1.3 - 2.4), no association between KSHV and syphilis seropositivity was observed. Those with higher levels of education had lower levels of KSHV seropositivity compared to those with lower education levels. KSHV seropositivity showed a heterogeneous pattern of prevalence in some localities. Conclusions The association between KSHV and HIV seropositivity and a lack of common association with syphilis, suggests that KSHV transmission may involve geographical and cultural factors other than sexual transmission. PMID:20807396

Superresolution microscopy reveals structural mechanisms driving the nanoarchitecture of a viral chromatin tether.

PubMed

Grant, Margaret J; Loftus, Matthew S; Stoja, Aiola P; Kedes, Dean H; Smith, M Mitchell

2018-05-08

By tethering their circular genomes (episomes) to host chromatin, DNA tumor viruses ensure retention and segregation of their genetic material during cell divisions. Despite functional genetic and crystallographic studies, there is little information addressing the 3D structure of these tethers in cells, issues critical for understanding persistent infection by these viruses. Here, we have applied direct stochastic optical reconstruction microscopy (dSTORM) to establish the nanoarchitecture of tethers within cells latently infected with the oncogenic human pathogen, Kaposi's sarcoma-associated herpesvirus (KSHV). Each KSHV tether comprises a series of homodimers of the latency-associated nuclear antigen (LANA) that bind with their C termini to the tandem array of episomal terminal repeats (TRs) and with their N termini to host chromatin. Superresolution imaging revealed that individual KSHV tethers possess similar overall dimensions and, in aggregate, fold to occupy the volume of a prolate ellipsoid. Using plasmids with increasing numbers of TRs, we found that tethers display polymer power law scaling behavior with a scaling exponent characteristic of active chromatin. For plasmids containing a two-TR tether, we determined the size, separation, and relative orientation of two distinct clusters of bound LANA, each corresponding to a single TR. From these data, we have generated a 3D model of the episomal half of the tether that integrates and extends previously established findings from epifluorescent, crystallographic, and epigenetic approaches. Our findings also validate the use of dSTORM in establishing novel structural insights into the physical basis of molecular connections linking host and pathogen genomes.

Activation of human herpesvirus replication by apoptosis.

PubMed

Prasad, Alka; Remick, Jill; Zeichner, Steven L

2013-10-01

A central feature of herpesvirus biology is the ability of herpesviruses to remain latent within host cells. Classically, exposure to inducing agents, like activating cytokines or phorbol esters that stimulate host cell signal transduction events, and epigenetic agents (e.g., butyrate) was thought to end latency. We recently showed that Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus-8 [HHV-8]) has another, alternative emergency escape replication pathway that is triggered when KSHV's host cell undergoes apoptosis, characterized by the lack of a requirement for the replication and transcription activator (RTA) protein, accelerated late gene kinetics, and production of virus with decreased infectivity. Caspase-3 is necessary and sufficient to initiate the alternative replication program. HSV-1 was also recently shown to initiate replication in response to host cell apoptosis. These observations suggested that an alternative apoptosis-triggered replication program might be a general feature of herpesvirus biology and that apoptosis-initiated herpesvirus replication may have clinical implications, particularly for herpesviruses that almost universally infect humans. To explore whether an alternative apoptosis-initiated replication program is a common feature of herpesvirus biology, we studied cell lines latently infected with Epstein-Barr virus/HHV-4, HHV-6A, HHV-6B, HHV-7, and KSHV. We found that apoptosis triggers replication for each HHV studied, with caspase-3 being necessary and sufficient for HHV replication. An alternative apoptosis-initiated replication program appears to be a common feature of HHV biology. We also found that commonly used cytotoxic chemotherapeutic agents activate HHV replication, which suggests that treatments that promote apoptosis may lead to activation of latent herpesviruses, with potential clinical significance.

Activation of Human Herpesvirus Replication by Apoptosis

PubMed Central

Prasad, Alka; Remick, Jill

2013-01-01

A central feature of herpesvirus biology is the ability of herpesviruses to remain latent within host cells. Classically, exposure to inducing agents, like activating cytokines or phorbol esters that stimulate host cell signal transduction events, and epigenetic agents (e.g., butyrate) was thought to end latency. We recently showed that Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus-8 [HHV-8]) has another, alternative emergency escape replication pathway that is triggered when KSHV's host cell undergoes apoptosis, characterized by the lack of a requirement for the replication and transcription activator (RTA) protein, accelerated late gene kinetics, and production of virus with decreased infectivity. Caspase-3 is necessary and sufficient to initiate the alternative replication program. HSV-1 was also recently shown to initiate replication in response to host cell apoptosis. These observations suggested that an alternative apoptosis-triggered replication program might be a general feature of herpesvirus biology and that apoptosis-initiated herpesvirus replication may have clinical implications, particularly for herpesviruses that almost universally infect humans. To explore whether an alternative apoptosis-initiated replication program is a common feature of herpesvirus biology, we studied cell lines latently infected with Epstein-Barr virus/HHV-4, HHV-6A, HHV-6B, HHV-7, and KSHV. We found that apoptosis triggers replication for each HHV studied, with caspase-3 being necessary and sufficient for HHV replication. An alternative apoptosis-initiated replication program appears to be a common feature of HHV biology. We also found that commonly used cytotoxic chemotherapeutic agents activate HHV replication, which suggests that treatments that promote apoptosis may lead to activation of latent herpesviruses, with potential clinical significance. PMID:23885073

Next-Generation Sequence Analysis of the Genome of RFHVMn, the Macaque Homolog of Kaposi's Sarcoma (KS)-Associated Herpesvirus, from a KS-Like Tumor of a Pig-Tailed Macaque

PubMed Central

Bruce, A. Gregory; Ryan, Jonathan T.; Thomas, Mathew J.; Peng, Xinxia; Grundhoff, Adam; Tsai, Che-Chung

2013-01-01

The complete sequence of retroperitoneal fibromatosis-associated herpesvirus Macaca nemestrina (RFHVMn), the pig-tailed macaque homolog of Kaposi's sarcoma-associated herpesvirus (KSHV), was determined by next-generation sequence analysis of a Kaposi's sarcoma (KS)-like macaque tumor. Colinearity of genes was observed with the KSHV genome, and the core herpesvirus genes had strong sequence homology to the corresponding KSHV genes. RFHVMn lacked homologs of open reading frame 11 (ORF11) and KSHV ORFs K5 and K6, which appear to have been generated by duplication of ORFs K3 and K4 after the divergence of KSHV and RFHV. RFHVMn contained positional homologs of all other unique KSHV genes, although some showed limited sequence similarity. RFHVMn contained a number of candidate microRNA genes. Although there was little sequence similarity with KSHV microRNAs, one candidate contained the same seed sequence as the positional homolog, kshv-miR-K12-10a, suggesting functional overlap. RNA transcript splicing was highly conserved between RFHVMn and KSHV, and strong sequence conservation was noted in specific promoters and putative origins of replication, predicting important functional similarities. Sequence comparisons indicated that RFHVMn and KSHV developed in long-term synchrony with the evolution of their hosts, and both viruses phylogenetically group within the RV1 lineage of Old World primate rhadinoviruses. RFHVMn is the closest homolog of KSHV to be completely sequenced and the first sequenced RV1 rhadinovirus homolog of KSHV from a nonhuman Old World primate. The strong genetic and sequence similarity between RFHVMn and KSHV, coupled with similarities in biology and pathology, demonstrate that RFHVMn infection in macaques offers an important and relevant model for the study of KSHV in humans. PMID:24109218

In vivo growth-restricted and reversible malignancy induced by Human Herpesvirus-8/ KSHV: a cell and animal model of virally induced Kaposi's sarcoma

PubMed Central

Mutlu, Agata D'Agostino; Cavallin, Lucas E.; Vincent, Loïc; Chiozzini, Chiara; Eroles, Pilar; Duran, Elda M.; Asgari, Zahra; Hooper, Andrea T.; La Perle, Krista M. D.; Hilsher, Chelsey; Gao, Shou-Jiang; Dittmer, Dirk P.; Rafii, Shahin; Mesri, Enrique A.

2007-01-01

Transfection of a Kaposi's sarcoma (KS) herpesvirus (KSHV) Bacterial Artificial Chromosome (KSHVBac36) into mouse bone marrow endothelial lineage cells generates a cell (mECK36) that forms KS-like tumors in mice. mECK36 expressed most KSHV genes and were angiogenic, but didn't form colonies in soft agar. In nude mice, mECK36 formed KSHV-harboring vascularized spindle-cell sarcomas that were LANA+/podoplanin+, overexpressed VEGF and Angiopoietin ligands and receptors, and displayed KSHV and host transcriptomes reminiscent of KS. mECK36 that lost the KSHV episome reverted to non-tumorigenicity. siRNA suppression of KSHV vGPCR, an angiogenic gene up-regulated in mECK36 tumors, inhibited angiogenicity and tumorigenicity. These results show that KSHV malignancy is in vivo growth-restricted and reversible, defining mECK36 as a biologically sensitive animal model of KSHV-dependent KS. PMID:17349582

Regulation of the Interaction between Glycogen Synthase Kinase 3 and the Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen

PubMed Central

Fujimuro, Masahiro; Liu, Jianyong; Zhu, Jian; Yokosawa, Hideyoshi; Hayward, S. Diane

2005-01-01

The Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA) protein stabilizes β-catenin by the novel mechanism of binding to the negative regulator, glycogen synthase kinase 3 (GSK-3), and depleting cytoplasmic GSK-3 levels. The two domains of LANA required for interaction with GSK-3 were further characterized. Evidence for similarity between the C-terminal LANA interaction domain and the axin GSK-3 interaction domain was obtained using GSK-3 and LANA mutants. GSK-3(F291L), which does not interact with axin, also failed to bind to LANA, and a mutation in the axin homology domain of LANA, L1132P, destroyed binding to GSK-3. The N-terminal LANA interaction domain was found to mediate interaction by acting as a substrate for GSK-3. GSK-3(R96A), a priming pocket mutant, did not bind to LANA, suggesting that LANA was a primed GSK-3 substrate. Phosphorylation of endogenous LANA precipitated from primary effusion lymphoma cells was inhibited by the GSK-3 inhibitor LiCl. GST-LANA(1-340) was phosphorylated by GSK-3, and mitogen-activated protein kinase (MAPK) and casein kinase I functioned as priming kinases in vitro. Mutation of consensus GSK-3 sites revealed that sites between LANA amino acids 219 and 268 were important for GSK-3 phosphorylation. Immunoprecipitation assays revealed that loss of GSK-3 phosphorylation of this N-terminal domain correlated with loss of GSK-3 interaction. Although LANA-associated GSK-3 actively phosphorylated LANA, GSK-3 coprecipitated with LANA was unable to phosphorylate an exogenous peptide substrate. LANA sequestration of GSK-3 may explain the ability of KSHV-infected cells to tolerate increased levels of nuclear GSK-3. PMID:16051835

Role of defective Oct-2 and OCA-B expression in immunoglobulin production and Kaposi's sarcoma-associated herpesvirus lytic reactivation in primary effusion lymphoma.

PubMed

Di Bartolo, Daniel L; Hyjek, Elizabeth; Keller, Shannon; Guasparri, Ilaria; Deng, Hongyu; Sun, Ren; Chadburn, Amy; Knowles, Daniel M; Cesarman, Ethel

2009-05-01

Primary effusion lymphoma (PEL) is a distinct type of B-cell non-Hodgkin lymphoma characterized by the presence of Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8). Despite having a genotype and gene expression signature of highly differentiated B cells, PEL does not usually express surface or cytoplasmic immunoglobulin (Ig). We show the lack of Oct-2 and OCA-B transcription factors to be responsible, at least in part, for this defect in Ig production. Like Ig genes, ORF50, the key regulator of the switch from latency to lytic reactivation, contains an octamer motif within its promoter. We therefore examined the impact of Oct-2 and OCA-B on ORF50 activation. The binding of Oct-1 to the ORF50 promoter has been shown to significantly enhance ORF50 transactivation. We found that Oct-2, on the other hand, inhibited ORF50 expression and consequently lytic reactivation by competing with Oct-1 for the octamer motif in the ORF50 promoter. Our data suggest that Oct-2 downregulation in infected cells would be favorable to KSHV in allowing for efficient viral reactivation.

Hsp70 Isoforms Are Essential for the Formation of Kaposi’s Sarcoma-Associated Herpesvirus Replication and Transcription Compartments

PubMed Central

Baquero-Pérez, Belinda; Whitehouse, Adrian

2015-01-01

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with various AIDS-related malignancies. Like other herpesviruses, multiple processes required for KSHV lytic replication, including viral transcription, viral DNA synthesis and capsid assembly occur in virus-induced intranuclear structures, termed replication and transcription compartments (RTCs). Here we utilised a novel methodology, combining subcellular fractionation and quantitative proteomics, to identify cellular proteins which are recruited to KSHV-induced RTCs and thus play a key role in KSHV lytic replication. We show that several isoforms of the HSP70 chaperone family, Hsc70 and iHsp70, are redistributed from the cytoplasm into the nucleus coinciding with the initial formation of KSHV-induced RTCs. We demonstrate that nuclear chaperone foci are dynamic, initially forming adjacent to newly formed KSHV RTCs, however during later time points the chaperones move within KSHV RTCs and completely co-localise with actively replicating viral DNA. The functional significance of Hsp70 isoforms recruitment into KSHV RTCs was also examined using the specific Hsp70 isoform small molecule inhibitor, VER-155008. Intriguingly, results highlight an essential role of Hsp70 isoforms in the KSHV replication cycle independent of protein stability and maturation. Notably, inhibition of Hsp70 isoforms precluded KSHV RTC formation and RNA polymerase II (RNAPII) relocalisation to the viral genome leading to the abolishment of global KSHV transcription and subsequent viral protein synthesis and DNA replication. These new findings have revealed novel mechanisms that regulate KSHV lytic replication and highlight the potential of HSP70 inhibitors as novel antiviral agents. PMID:26587836

Kaposi's-sarcoma-associated-herpesvirus-activated dendritic cells promote HIV-1 trans-infection and suppress CD4{sup +} T cell proliferation

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

Liu, Wan; Qin, Yan; Bai, Lei

2013-06-05

Infection of Kaposi's sarcoma-associated herpesvirus (KSHV) is commonly occurred in AIDS patients. KSHV and HIV-1 act cooperatively in regulating infection with each other and in human carcinogenesis. Dendritic cells (DCs), as the pivotal cells in host immunity, may be modulated by both viruses, for immunoevasion and dissemination, therefore, the interaction between DCs and each virus has been a prior focus for pathogenesis elucidation. Here, we assessed the potential effect of KSHV on DC–HIV-1 interaction. We found that KSHV stimulation could promote maturation of monocyte-derived DCs (MDDCs) and impaired the ability of MDDCs to drive proliferation of resting CD4{sup +} Tmore » cells, demonstrating the immunosuppression induced by KSHV. More importantly, KSHV-stimulated MDDCs could capture more HIV-1 and efficiently transferred these infectious viruses to Hut/CCR5 T cell line. Our results reveal the novel modulation of DC-mediated HIV-1 dissemination by KSHV, and highlight the importance of studying DC–HIV-1 interaction to elucidate HIV/AIDS pathogenesis. - Highlights: ► KSHV impaired the ability of MDDCs to drive proliferation of resting CD4{sup +} T cells. ► KSHV stimulation matured MDDCs and enhanced HIV-1 endocytosis. ► KSHV stimulated MDDCs increased ICAM-1 expression and tighten contact with T cells. ► KSHV-stimulated MDDCs promoted HIV-1 trans-infection of CD4{sup +} T cells.« less

Kaposi's sarcoma herpesvirus and HIV-1 seroprevalences in prostitutes in Djibouti.

PubMed

Marcelin, Anne-Geneviève; Grandadam, Marc; Flandre, Philippe; Nicand, Elisabeth; Milliancourt, Catherine; Koeck, Jean-Louis; Philippon, Michel; Teyssou, Remy; Agut, Henri; Dupin, Nicolas; Calvez, Vincent

2002-10-01

Kaposi's sarcoma herpesvirus (KSHV) is linked causally to Kaposi's sarcoma. Epidemiological studies have shown that KSHV transmission can occur during sex among homosexual men, but heterosexual transmission seems to be very rare in KSHV low prevalence countries. A seroepidemiological study was conducted to determine whether KSHV is transmitted sexually between heterosexuals in an endemic country. Sera from 282 subjects of African origin living in Djibouti were tested for antibodies to KSHV and HIV-1. Among the 282 individuals, 43 were female prostitutes working in the streets (group 1), 123 were female prostitutes working in luxury bars (group 2), 41 were non-prostitute females (group 3), and 75 were non-prostitute males (group 4). KSHV seroprevalence was 26, 20, 17, and 36% in groups 1, 2, 3, and 4, respectively. The seroprevalence of KSHV is not different between street or bar prostitutes and non-prostitute females (OR = 1.67; P = 0.34 and OR = 1.18; P = 0.73). These results suggest that in this endemic country commercial sex work does not seem to be a risk factor for KSHV infection and provides evidence against heterosexual transmission of KSHV in the female population studied. Copyright 2002 Wiley-Liss, Inc.

KSHV-associated multicentric Castleman disease: A tangle of different entities requiring multitarget treatment strategies.

PubMed

Carbone, Antonino; De Paoli, Paolo; Gloghini, Annunziata; Vaccher, Emanuela

2015-07-15

Multicentric Castleman Disease (MCD) is a lymphoproliferative disorder presenting with heterogeneous pathological and clinical features. It comprises disease entities with a complex aetiology and overlapping pathogenesis. MCD can be found in association with HIV infection, plasma-cell dyscrasias, Kaposi sarcoma (KS), B-cell lymphomas including primary effusion lymphoma (PEL) and its solid variant, and Hodgkin lymphoma. In KSHV-associated MCD cases, a common association is KS and a specific variant of lymphoma referred to as "plasmablastic lymphoma," also called "large B-cell lymphoma arising in KSHV-associated MCD" lacking EBV infection. MCD is often referred to as human interleukin-6 (hIL-6) syndrome, since an overproduction of IL-6 occurs in MCD-associated diseases as well as in MCD itself. hIL-6 and a viral IL-6 (vIL-6) homolog encoded by KSHV can independently or together lead to flares of KSHV-associated MCD. Recently, a new clinical entity was proposed to describe a severe systemic infection/reactivation of KSHV: KSHV inflammatory syndrome (KICS). KICS may contribute in inducing the inflammatory symptoms seen in some patients with severe KS or PEL. The precise relationship of KICS to KSHV-associated MCD is unclear and it is possible that KICS may be prodromal symptoms to frank KSHV-associated MCD. Options for treatment of KSHV-associated MCD and related diseases include monoclonal antibodies, chemotherapy, immune modulators, virus-activated cytotoxic therapy and antiviral therapies. A comprehensive understanding of the intricacies of the HIV-KSHV coinfection will probably lead to additional advances in therapy and managements for these disorders. © 2014 UICC.

Differentially regulated splice variants and systems biology analysis of Kaposi's sarcoma-associated herpesvirus-infected lymphatic endothelial cells.

PubMed

Chang, Ting-Yu; Wu, Yu-Hsuan; Cheng, Cheng-Chung; Wang, Hsei-Wei

2011-09-01

Alternative RNA splicing greatly increases proteome diversity, and the possibility of studying genome-wide alternative splicing (AS) events becomes available with the advent of high-throughput genomics tools devoted to this issue. Kaposi's sarcoma associated herpesvirus (KSHV) is the etiological agent of KS, a tumor of lymphatic endothelial cell (LEC) lineage, but little is known about the AS variations induced by KSHV. We analyzed KSHV-controlled AS using high-density microarrays capable of detecting all exons in the human genome. Splicing variants and altered exon-intron usage in infected LEC were found, and these correlated with protein domain modification. The different 3'-UTR used in new transcripts also help isoforms to escape microRNA-mediated surveillance. Exome-level analysis further revealed information that cannot be disclosed using classical gene-level profiling: a significant exon usage difference existed between LEC and CD34(+) precursor cells, and KSHV infection resulted in LEC-to-precursor, dedifferentiation-like exon level reprogramming. Our results demonstrate the application of exon arrays in systems biology research, and suggest the regulatory effects of AS in endothelial cells are far more complex than previously observed. This extra layer of molecular diversity helps to account for various aspects of endothelial biology, KSHV life cycle and disease pathogenesis that until now have been unexplored.

KSHV MicroRNAs Repress Tropomyosin 1 and Increase Anchorage-Independent Growth and Endothelial Tube Formation

PubMed Central

Kieffer-Kwon, Philippe; Happel, Christine; Uldrick, Thomas S.; Ramalingam, Dhivya; Ziegelbauer, Joseph M.

2015-01-01

Kaposi’s sarcoma (KS) is characterized by highly vascularized spindle-cell tumors induced after infection of endothelial cells by Kaposi’s sarcoma-associated herpesvirus (KSHV). In KS tumors, KSHV expresses only a few latent proteins together with 12 pre-microRNAs. Previous microarray and proteomic studies predicted that multiple splice variants of the tumor suppressor protein tropomyosin 1 (TPM1) were targets of KSHV microRNAs. Here we show that at least two microRNAs of KSHV, miR-K2 and miR-K5, repress protein levels of specific isoforms of TPM1. We identified a functional miR-K5 binding site in the 3’ untranslated region (UTR) of one TPM1 isoform. Furthermore, the inhibition or loss of miR-K2 or miR-K5 restores expression of TPM1 in KSHV-infected cells. TPM1 protein levels were also repressed in KSHV-infected clinical samples compared to uninfected samples. Functionally, miR-K2 increases viability of unanchored human umbilical vein endothelial cells (HUVEC) by inhibiting anoikis (apoptosis after cell detachment), enhances tube formation of HUVECs, and enhances VEGFA expression. Taken together, KSHV miR-K2 and miR-K5 may facilitate KSHV pathogenesis. PMID:26263384

KSHV inhibits stress granule formation by viral ORF57 blocking PKR activation

PubMed Central

Sharma, Nishi R.; Majerciak, Vladimir; Kruhlak, Michael J.

2017-01-01

TIA-1 positive stress granules (SG) represent the storage sites of stalled mRNAs and are often associated with the cellular antiviral response. In this report, we provide evidence that Kaposi’s sarcoma-associated herpesvirus (KSHV) overcomes the host antiviral response by inhibition of SG formation via a viral lytic protein ORF57. By immunofluorescence analysis, we found that B lymphocytes with KSHV lytic infection are refractory to SG induction. KSHV ORF57, an essential post-transcriptional regulator of viral gene expression and the production of new viral progeny, inhibits SG formation induced experimentally by arsenite and poly I:C, but not by heat stress. KSHV ORF37 (vSOX) bearing intrinsic endoribonuclease activity also inhibits arsenite-induced SG formation, but KSHV RTA, vIRF-2, ORF45, ORF59 and LANA exert no such function. ORF57 binds both PKR-activating protein (PACT) and protein kinase R (PKR) through their RNA-binding motifs and prevents PACT-PKR interaction in the PKR pathway which inhibits KSHV production. Consistently, knocking down PKR expression significantly promotes KSHV virion production. ORF57 interacts with PKR to inhibit PKR binding dsRNA and its autophosphorylation, leading to inhibition of eIF2α phosphorylation and SG formation. Homologous protein HSV-1 ICP27, but not EBV EB2, resembles KSHV ORF57 in the ability to block the PKR/eIF2α/SG pathway. In addition, KSHV ORF57 inhibits poly I:C-induced TLR3 phosphorylation. Altogether, our data provide the first evidence that KSHV ORF57 plays a role in modulating PKR/eIF2α/SG axis and enhances virus production during virus lytic infection. PMID:29084250

p130Cas scaffolds the signalosome to direct adaptor-effector cross talk during Kaposi's sarcoma-associated herpesvirus trafficking in human microvascular dermal endothelial cells.

PubMed

Bandyopadhyay, Chirosree; Veettil, Mohanan Valiya; Dutta, Sujoy; Chandran, Bala

2014-12-01

Kaposi's sarcoma-associated herpesvirus (KSHV) interacts with cell surface receptors, such as heparan sulfate, integrins (α3β1, αVβ3, and αVβ5), and EphrinA2 (EphA2), and activates focal adhesion kinase (FAK), Src, phosphoinositol 3-kinase (PI3-K), c-Cbl, and RhoA GTPase signal molecules early during lipid raft (LR)-dependent productive macropinocytic entry into human dermal microvascular endothelial cells. Our recent studies have identified CIB1 as a signal amplifier facilitating EphA2 phosphorylation and subsequent cytoskeletal cross talk during KSHV macropinocytosis. Although CIB1 lacks an enzymatic activity and traditional adaptor domain or known interacting sequence, it associated with the KSHV entry signal complex and the CIB1-KSHV association was sustained over 30 min postinfection. To identify factors scaffolding the EphA2-CIB1 signal axis, the role of major cellular scaffold protein p130Cas (Crk-associated substrate of Src) was investigated. Inhibitor and small interfering RNA (siRNA) studies demonstrated that KSHV induced p130Cas in an EphA2-, CIB1-, and Src-dependent manner. p130Cas and Crk were associated with KSHV, LRs, EphA2, and CIB1 early during infection. Live-cell microscopy and biochemical studies demonstrated that p130Cas knockdown did not affect KSHV entry but significantly reduced productive nuclear trafficking of viral DNA and routed KSHV to lysosomal degradation. p130Cas aided in scaffolding adaptor Crk to downstream guanine nucleotide exchange factor phospho-C3G possibly to coordinate GTPase signaling during KSHV trafficking. Collectively, these studies demonstrate that p130Cas acts as a bridging molecule between the KSHV-induced entry signal complex and the downstream trafficking signalosome in endothelial cells and suggest that simultaneous targeting of KSHV entry receptors with p130Cas would be an attractive potential avenue for therapeutic intervention in KSHV infection. Eukaryotic cell adaptor molecules, without any intrinsic enzymatic activity, are well known to allow a great diversity of specific and coordinated protein-protein interactions imparting signal amplification to different networks for physiological and pathological signaling. They are involved in integrating signals from growth factors, extracellular matrix molecules, bacterial pathogens, and apoptotic cells. The present study identifies human microvascular dermal endothelial (HMVEC-d) cellular scaffold protein p130Cas (Crk-associated substrate) as a platform to promote Kaposi's sarcoma-associated herpesvirus (KSHV) trafficking. Early during KSHV de novo infection, p130Cas associates with lipid rafts and scaffolds EphrinA2 (EphA2)-associated critical adaptor members to downstream effector molecules, promoting successful nuclear delivery of the KSHV genome. Hence, simultaneous targeting of the receptor EphA2 and scaffolding action of p130Cas can potentially uncouple the signal cross talk of the KSHV entry-associated upstream signal complex from the immediate downstream trafficking-associated signalosome, consequently routing KSHV toward lysosomal degradation and eventually blocking KSHV infection and associated malignancies. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

PubMed Central

Dittmer, Dirk P.

2016-01-01

Kaposi sarcoma–associated herpesvirus (KSHV), also known as human herpesvirus 8, is the etiologic agent underlying Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. This human gammaherpesvirus was discovered in 1994 by Drs. Yuan Chang and Patrick Moore. Today, there are over five thousand publications on KSHV and its associated malignancies. In this article, we review recent and ongoing developments in the KSHV field, including molecular mechanisms of KSHV pathogenesis, clinical aspects of KSHV-associated diseases, and current treatments for cancers associated with this virus. PMID:27584730

A Gammaherpesvirus Bcl-2 Ortholog Blocks B Cell Receptor-Mediated Apoptosis and Promotes the Survival of Developing B Cells In Vivo

PubMed Central

Coleman, Carrie B.; McGraw, Jennifer E.; Feldman, Emily R.; Roth, Alexa N.; Keyes, Lisa R.; Grau, Katrina R.; Cochran, Stephanie L.; Waldschmidt, Thomas J.; Liang, Chengyu; Forrest, J. Craig; Tibbetts, Scott A.

2014-01-01

Gammaherpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) establish lifelong latency in their hosts and are associated with the development of several types of malignancies, including a subset of B cell lymphomas. These viruses are thought to co-opt the process of B cell differentiation to latently infect a fraction of circulating memory B cells, resulting in the establishment of a stable latency setpoint. However, little is known about how this infected memory B cell compartment is maintained throughout the life of the host. We have previously demonstrated that immature and transitional B cells are long-term latency reservoirs for murine gammaherpesvirus 68 (MHV68), suggesting that infection of developing B cells contributes to the maintenance of lifelong latency. During hematopoiesis, immature and transitional B cells are subject to B cell receptor (BCR)-mediated negative selection, which results in the clonal deletion of autoreactive B cells. Interestingly, numerous gammaherpesviruses encode homologs of the anti-apoptotic protein Bcl-2, suggesting that virus inhibition of apoptosis could subvert clonal deletion. To test this, we quantified latency establishment in mice inoculated with MHV68 vBcl-2 mutants. vBcl-2 mutant viruses displayed a marked decrease in the frequency of immature and transitional B cells harboring viral genome, but this attenuation could be rescued by increased host Bcl-2 expression. Conversely, vBcl-2 mutant virus latency in early B cells and mature B cells, which are not targets of negative selection, was remarkably similar to wild-type virus. Finally, in vivo depletion of developing B cells during chronic infection resulted in decreased mature B cell latency, demonstrating a key role for developing B cells in the maintenance of lifelong latency. Collectively, these findings support a model in which gammaherpesvirus latency in circulating mature B cells is sustained in part through the recurrent infection and vBcl-2-mediated survival of developing B cells. PMID:24516386

An APE1 inhibitor reveals critical roles of the redox function of APE1 in KSHV replication and pathogenic phenotypes

PubMed Central

Wang, Yan; Xu, Jun

2017-01-01

APE1 is a multifunctional protein with a DNA base excision repair function in its C-terminal domain and a redox activity in its N-terminal domain. The redox function of APE1 converts certain transcription factors from inactive oxidized to active reduced forms. Given that among the APE1-regulated transcription factors many are critical for KSHV replication and pathogenesis, we investigated whether inhibition of APE1 redox function blocks KSHV replication and Kaposi’s sarcoma (KS) phenotypes. With an shRNA-mediated silencing approach and a known APE-1 redox inhibitor, we demonstrated that APE1 redox function is indeed required for KSHV replication as well as KSHV-induced angiogenesis, validating APE1 as a therapeutic target for KSHV-associated diseases. A ligand-based virtual screening yielded a small molecular compound, C10, which is proven to bind to APE1. C10 exhibits low cytotoxicity but efficiently inhibits KSHV lytic replication (EC50 of 0.16 μM and selective index of 165) and KSHV-mediated pathogenic phenotypes including cytokine production, angiogenesis and cell invasion, demonstrating its potential to become an effective drug for treatment of KS. PMID:28380040

KSHV-TK is a tyrosine kinase that disrupts focal adhesions and induces Rho-mediated cell contraction

PubMed Central

Gill, Michael B; Turner, Rachel; Stevenson, Philip G; Way, Michael

2015-01-01

Paradoxically, the thymidine kinase (TK) encoded by Kaposi sarcoma-associated herpesvirus (KSHV) is an extremely inefficient nucleoside kinase, when compared to TKs from related herpesviruses. We now show that KSHV-TK, in contrast to HSV1-TK, associates with the actin cytoskeleton and induces extensive cell contraction followed by membrane blebbing. These dramatic changes in cell morphology depend on the auto-phosphorylation of tyrosines 65, 85 and 120 in the N-terminus of KSHV-TK. Phosphorylation of tyrosines 65/85 and 120 results in an interaction with Crk family proteins and the p85 regulatory subunit of PI3-Kinase, respectively. The interaction of Crk with KSHV-TK leads to tyrosine phoshorylation of this cellular adaptor. Auto-phosphorylation of KSHV-TK also induces a loss of FAK and paxillin from focal adhesions, resulting in activation of RhoA-ROCK signalling to myosin II and cell contraction. In the absence of FAK or paxillin, KSHV-TK has no effect on focal adhesion integrity or cell morphology. Our observations demonstrate that by acting as a tyrosine kinase, KSHV-TK modulates signalling and cell morphology. PMID:25471072

Identification of the Essential Role of Viral Bcl-2 for Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication

PubMed Central

Liang, Qiming; Chang, Brian; Lee, Patrick; Brulois, Kevin F.; Ge, Jianning; Shi, Mude; Rodgers, Mary A.; Feng, Pinghui; Oh, Byung-Ha; Liang, Chengyu

2015-01-01

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) evades host defenses through tight suppression of autophagy by targeting each step of its signal transduction: by viral Bcl-2 (vBcl-2) in vesicle nucleation, by viral FLIP (vFLIP) in vesicle elongation, and by K7 in vesicle maturation. By exploring the roles of KSHV autophagy-modulating genes, we found, surprisingly, that vBcl-2 is essential for KSHV lytic replication, whereas vFLIP and K7 are dispensable. Knocking out vBcl-2 from the KSHV genome resulted in decreased lytic gene expression at the mRNA and protein levels, a lower viral DNA copy number, and, consequently, a dramatic reduction in the amount of progeny infectious viruses, as also described in the accompanying article (A. Gelgor, I. Kalt, S. Bergson, K. F. Brulois, J. U. Jung, and R. Sarid, J Virol 89:5298–5307, 2015). More importantly, the antiapoptotic and antiautophagic functions of vBcl-2 were not required for KSHV lytic replication. Using a comprehensive mutagenesis analysis, we identified that glutamic acid 14 (E14) of vBcl-2 is critical for KSHV lytic replication. Mutating E14 to alanine totally blocked KSHV lytic replication but showed little or no effect on the antiapoptotic and antiautophagic functions of vBcl-2. Our study indicates that vBcl-2 harbors at least three important and genetically separable functions to modulate both cellular signaling and the virus life cycle. IMPORTANCE The present study shows for the first time that vBcl-2 is essential for KSHV lytic replication. Removal of the vBcl-2 gene results in a lower level of KSHV lytic gene expression, impaired viral DNA replication, and consequently, a dramatic reduction in the level of progeny production. More importantly, the role of vBcl-2 in KSHV lytic replication is genetically separated from its antiapoptotic and antiautophagic functions, suggesting that the KSHV Bcl-2 carries a novel function in viral lytic replication. PMID:25740994

Transcription mapping and expression patterns of genes in the major immediate-early region of Kaposi's sarcoma-associated herpesvirus.

PubMed

Saveliev, Alexei; Zhu, Fan; Yuan, Yan

2002-08-01

Viral immediate-early (IE) genes are the first class of viral genes expressed during primary infection or reactivation from latency. They usually encode regulatory proteins that play crucial roles in viral life cycle. In a previous study, four regions in the KSHV genome were found to be actively transcribed in the immediate-early stage of viral reactivation in primary effusion lymphoma cells. Three immediate-early transcripts were characterized in these regions, as follows: mRNAs for ORF50 (KIE-1), ORF-45 (KIE-2), and ORF K4.2 (KIE-3) (F. X. Zhu, T. Cusano, and Y. Yuan, 1999, J. Virol. 73, 5556-5567). In the present study, we further analyzed the expression of genes in these IE regions in BC-1 and BCBL-1 cells. One of the immediate-early regions (KIE-1) that encompasses ORF50 and other genes was intensively studied to establish a detailed transcription map and expression patterns of genes in this region. This study led to identification of several novel IE transcripts in this region. They include a 2.6-kb mRNA which encodes ORF48/ORF29b, a family of transcripts that are complementary to ORF50 mRNA and a novel K8 IE mRNA of 1.5 kb. Together with the IE mRNA for ORF50 which was identified previously, four immediate-early genes have been mapped to KIE-1 region. Therefore, we would designate KIE-1 the major immediate-early region of KSHV. In addition, we showed that transcription of K8 gene is controlled by two promoters, yielding two transcripts, an immediate-early mRNA of 1.5 kb and a delayed-early mRNA of 1.3 kb.

Immunophenotypic analysis of the Kaposi sarcoma herpesvirus (KSHV; HHV-8)-infected B cells in HIV+ multicentric Castleman disease (MCD).

PubMed

Chadburn, A; Hyjek, E M; Tam, W; Liu, Y; Rengifo, T; Cesarman, E; Knowles, D M

2008-11-01

Kaposi sarcoma herpesvirus (KSHV) is aetiologically related to Kaposi sarcoma, classical and extracavitary primary effusion lymphoma (PEL; EC-PEL) and multicentric Castleman disease (MCD), entities preferentially occurring in HIV-infected individuals. Characterization of HIV-associated PELs/EC-PELs suggests that the KSHV-infected malignant cells originate from a pre-terminal stage of B-cell differentiation. However, only limited phenotypic studies have been performed on HIV+ MCD, including for PR domain containing 1 with zinc finger domain/B lymphocyte-induced maturation protein 1 (PRDM1/BLIMP1), a key regulator of terminal B-cell differentiation. The aim was to characterize KSHV-infected cells in 17 cases of HIV+ MCD. Double immunohistochemistry and immunohistochemistry-in situ hybridization were used to characterize the KSHV-infected cells in MCD; the results were compared with the phenotypic profiles of 39 PELs/EC-PELs and seven PEL cell lines. Whereas the immunophenotype of KSHV-infected cells in MCD and malignant KSHV+ PEL cells was similar (PAX5, Bcl-6-; PRDM1/BLIMP1, IRF4/MUM1+; Ki67+), the MCD KSHV-infected cells differed, as they expressed OCT2, cytoplasmic lambda immunoglobulin; variably expressed CD27; lacked CD138; and were Epstein-Barr virus negative. Although both PEL and MCD originate from KSHV-infected pre-terminally differentiated B cells, these findings, with previously reported genetic studies, indicate HIV+ MCD may arise from extrafollicular B cells, whereas PELs may originate from cells that have traversed the germinal centre.

Epidemiology of Kaposi's sarcoma-associated herpesvirus in Asia: Challenges and opportunities.

PubMed

Zhang, Tiejun; Wang, Linding

2017-04-01

Kaposi's sarcoma-associated herpes virus (KSHV) also referred to as human herpesvirus-8 (HHV-8), is a gamma herpes virus and recently discovered human virus. Since its discovery, a myriad of studies has been conducted to explore its pathogenesis mechanisms. However, despite our consistently increasing understanding of KSHV biology and its clinical manifestations, only little progress has been made in understanding of its epidemiology characteristics which in turn hampered the management of KSHV-associated diseases and public health. Asia, the largest continent with a diversity of populations, has been thought to be with relative lower KSHV prevalence and diseases burden. The epidemiology of KSHV in this area is obscure either. The present review summarizes the current knowledge pertaining to the epidemiology of KSHV across Asian countries. Studies available in the literature have shown a substantial variation in this region indicating the virus is not ubiquitous in Asia countries as is the case with other human herpes viruses. Also, the MSM has been reconfirmed to be at the highest risk of KSHV infection in Asia highlighting the need for an increased focus on this previously marginalized population. Because of the paucity of data available, the epidemiologic characteristics of KSHV are difficult to determine in Asian countries. Future systematic collection of data to inform KSHV prevention strategies in Asia is urgently needed. J. Med. Virol. 89:563-570, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

KSHV LANA inhibits TGF-β signaling through epigenetic silencing of the TGF-β type II receptor

PubMed Central

Di Bartolo, Daniel L.; Cannon, Mark; Liu, Yi-Fang; Renne, Rolf; Chadburn, Amy; Boshoff, Chris

2008-01-01

Signaling through the transforming growth factor–β (TGF-β) pathway results in growth inhibition and induction of apoptosis in various cell types. We show that this pathway is blocked in Kaposi sarcoma herpesvirus (KSHV)–infected primary effusion lymphoma through down-regulation of the TGF-β type II receptor (TβRII) by epigenetic mechanisms. Our data also suggest that KSHV infection may result in lower expression of TβRII in Kaposi sarcoma and multicentric Castleman disease. KSHV-encoded LANA associates with the promoter of TβRII and leads to its methylation and to the deacetylation of proximal histones. Reestablishment of signaling through this pathway reduces viability of these cells, inferring that KSHV-mediated blockage of TGF-β signaling plays a role in the establishment and progression of KSHV-associated neoplasia. These data suggest a mechanism whereby KSHV evades both the antiproliferative effects of TGF-β signaling by silencing TβRII gene expression and immune recognition by suppressing TGF-β–responsive immune cells through the elevated secretion of TGF-β1. PMID:18199825

KSHV Targeted Therapy: An Update on Inhibitors of Viral Lytic Replication

PubMed Central

Coen, Natacha; Duraffour, Sophie; Snoeck, Robert; Andrei, Graciela

2014-01-01

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman’s disease. Since the discovery of KSHV 20 years ago, there is still no standard treatment and the management of virus-associated malignancies remains toxic and incompletely efficacious. As the majority of tumor cells are latently infected with KSHV, currently marketed antivirals that target the virus lytic cycle have shown inconsistent results in clinic. Nevertheless, lytic replication plays a major role in disease progression and virus dissemination. Case reports and retrospective studies have pointed out the benefit of antiviral therapy in the treatment and prevention of KSHV-associated diseases. As a consequence, potent and selective antivirals are needed. This review focuses on the anti-KSHV activity, mode of action and current status of antiviral drugs targeting KSHV lytic cycle. Among these drugs, different subclasses of viral DNA polymerase inhibitors and compounds that do not target the viral DNA polymerase are being discussed. We also cover molecules that target cellular kinases, as well as the potential of new drug targets and animal models for antiviral testing. PMID:25421895

Global Metabolic Profiling of Infection by an Oncogenic Virus: KSHV Induces and Requires Lipogenesis for Survival of Latent Infection

PubMed Central

Delgado, Tracie; Sanchez, Erica L.; Camarda, Roman; Lagunoff, Michael

2012-01-01

Like cancer cells, virally infected cells have dramatically altered metabolic requirements. We analyzed global metabolic changes induced by latent infection with an oncogenic virus, Kaposi's Sarcoma-associated herpesvirus (KSHV). KSHV is the etiologic agent of Kaposi's Sarcoma (KS), the most common tumor of AIDS patients. Approximately one-third of the nearly 200 measured metabolites were altered following latent infection of endothelial cells by KSHV, including many metabolites of anabolic pathways common to most cancer cells. KSHV induced pathways that are commonly altered in cancer cells including glycolysis, the pentose phosphate pathway, amino acid production and fatty acid synthesis. Interestingly, over half of the detectable long chain fatty acids detected in our screen were significantly increased by latent KSHV infection. KSHV infection leads to the elevation of metabolites involved in the synthesis of fatty acids, not degradation from phospholipids, and leads to increased lipid droplet organelle formation in the infected cells. Fatty acid synthesis is required for the survival of latently infected endothelial cells, as inhibition of key enzymes in this pathway led to apoptosis of infected cells. Addition of palmitic acid to latently infected cells treated with a fatty acid synthesis inhibitor protected the cells from death indicating that the products of this pathway are essential. Our metabolomic analysis of KSHV-infected cells provides insight as to how oncogenic viruses can induce metabolic alterations common to cancer cells. Furthermore, this analysis raises the possibility that metabolic pathways may provide novel therapeutic targets for the inhibition of latent KSHV infection and ultimately KS tumors. PMID:22916018

Binding of the Kaposi's Sarcoma-Associated Herpesvirus to the Ephrin Binding Surface of the EphA2 Receptor and Its Inhibition by a Small Molecule

PubMed Central

Hahn, Alexander S.

2014-01-01

ABSTRACT The ephrin receptor tyrosine kinase A2 (EphA2) is an entry receptor for Kaposi's sarcoma-associated herpesvirus (KSHV) that is engaged by the virus through its gH/gL glycoprotein complex. We describe here that natural ephrin ligands inhibit the gH/gL-EphA2 interaction. The effects of point mutations within EphA2 demonstrated that KSHV gH/gL interacts with EphA2 through a restricted set of the same residues that mediate binding of A-type ephrins. Two previously described inhibitors of the EphA2 interaction with ephrin A5 also inhibited binding of KSHV gH/gL to EphA2. The more potent of the two compounds inhibited KSHV infection of blood vessel and lymphatic endothelial cells in the micromolar concentration range. Our results demonstrate that interaction of KSHV with EphA2 occurs in a fashion similar to that of the natural ephrin ligands. Our data further indicate a new avenue for drug development against KSHV. IMPORTANCE Our study reports two important findings. First, we show that KSHV engages its receptor, the receptor tyrosine kinase EphA2, at a site that overlaps the binding site of the natural ephrin ligands. Second, we demonstrate that KSHV infection of target cells can be blocked by a small-molecule inhibitor of the viral glycoprotein-EphA2 interaction. These findings represent a novel avenue for the development of strategies to treat KSHV-associated diseases. PMID:24899181

Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV–MCD) and the KSHV Inflammatory Cytokine Syndrome

PubMed Central

Polizzotto, Mark N.; Uldrick, Thomas S.; Hu, Duosha; Yarchoan, Robert

2012-01-01

Soon after the discovery of Kaposi sarcoma (KS)-associated herpesvirus (KSHV), it was appreciated that this virus was associated with most cases of multicentric Castleman disease (MCD) arising in patients infected with human immunodeficiency virus. It has subsequently been recognized that KSHV–MCD is a distinct entity from other forms of MCD. Like MCD that is unrelated to KSHV, the clinical presentation of KSHV–MCD is dominated by systemic inflammatory symptoms including fevers, cachexia, and laboratory abnormalities including cytopenias, hypoalbuminemia, hyponatremia, and elevated C-reactive protein. Pathologically KSHV–MCD is characterized by polyclonal, IgM-lambda restricted plasmacytoid cells in the intrafollicular areas of affected lymph nodes. A portion of these cells are infected with KSHV and a sizable subset of these cells express KSHV lytic genes including a viral homolog of interleukin-6 (vIL-6). Patients with KSHV–MCD generally have elevated KSHV viral loads in their peripheral blood. Production of vIL-6 and induction of human (h) IL-6 both contribute to symptoms, perhaps in combination with overproduction of IL-10 and other cytokines. Until recently, the prognosis of patients with KSHV–MCD was poor. Recent therapeutic advances targeting KSHV-infected B cells with the anti-CD20 monoclonal antibody rituximab and utilizing KSHV enzymes to target KSHV-infected cells have substantially improved patient outcomes. Recently another KSHV-associated condition, the KSHV inflammatory cytokine syndrome (KICS) has been described. Its clinical manifestations resemble those of KSHV–MCD but lymphadenopathy is not prominent and the pathologic nodal changes of KSHV–MCD are absent. Patients with KICS exhibit elevated KSHV viral loads and elevation of vIL-6, homolog of human interleukin-6 and IL-10 comparable to those seen in KSHV–MCD; the cellular origin of these is a matter of investigation. KICS may contribute to the inflammatory symptoms seen in some patients with severe KS or primary effusion lymphoma. Additional research is needed to better define the clinical spectrum of KICS and its relationship to KSHV–MCD. In additional, research is needed to better understand the pathogenesis and epidemiology of both KICS and KSHV–MCD, as well as the optimal therapy for both of these disorders. PMID:22403576

Kaposi sarcoma associated herpesvirus (KSHV) induces AKT hyperphosphorylation, bortezomib-resistance and GLUT-1 plasma membrane exposure in THP-1 monocytic cell line.

PubMed

Gonnella, Roberta; Santarelli, Roberta; Farina, Antonella; Granato, Marisa; D'Orazi, Gabriella; Faggioni, Alberto; Cirone, Mara

2013-10-23

Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway regulates multiple cellular processes such as cell proliferation, evasion from apoptosis, migration, glucose metabolism, protein synthesis and proper differentiation in immune cells. Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus associated with several human malignancies, expresses a variety of latent and lytic proteins able to activate PI3K/AKT pathway, promoting the growth of infected cells and a successful viral infection. We found that KSHV latent infection of THP-1 cells, a human monocytic cell line derived from an acute monocytic leukemia patient, resulted in an increase of AKT phoshorylation, not susceptible to bortezomib-induced dephosphorylation, compared to the mock-infected THP-1. Accordingly, THP-1-infected cells displayed increased resistance to the bortezomib cytotoxic effect in comparison to the uninfected cells, which was counteracted by pre-treatment with AKT-specific inhibitors. Finally, AKT hyperactivation by KSHV infection correlated with plasma membrane exposure of glucose transporter GLUT1, particularly evident during bortezomib treatment. GLUT1 membrane trafficking is a characteristic of malignant cells and underlies a change of glucose metabolism that ensures the survival to highly proliferating cells and render these cells highly dependent on glycolysis. GLUT1 membrane trafficking in KSHV-infected THP-1 cells indeed led to increased sensitivity to cell death induced by the glycolysis inhibitor 2-Deoxy-D-glucose (2DG), further potentiated by its combination with bortezomib. KSHV confers to the THP-1 infected cells an oncogenic potential by altering the phosphorylation, expression and localization of key molecules that control cell survival and metabolism such as AKT and GLUT1. Such modifications in one hand lead to resistance to cell death induced by some chemotherapeutic drugs such as bortezomib, but on the other hand, offer an Achilles heel, rendering the infected cells more sensitive to other treatments such as AKT or glycolysis inhibitors. These therapeutic strategies can be exploited in the anticancer therapy of KSHV-associated malignancies.

Relationship between Anaemia, Malaria Co-infection and Kaposi Sarcoma-associated Herpesvirus (KSHV) Seropositivity in a Population-based Study in Rural Uganda.

PubMed

Nalwoga, Angela; Cose, Stephen; Nash, Stephen; Miley, Wendell; Asiki, Gershim; Kusemererwa, Sylvia; Yarchoan, Robert; Labo, Nazzarena; Whitby, Denise; Newton, Robert

2018-05-08

We examined anaemia and malaria as risk factors for KSHV seropositivity and antibody levels in a long-standing rural Ugandan cohort, in which KSHV is prevalent. Samples from 4134 children, aged 1-17 years, with a sex ratio of 1:1 and 3149 adults aged 18-103 years, 41% of whom were males, were analysed. Among children, malaria infection was associated with higher KSHV prevalence (61% versus 41% prevalence among malaria infected and uninfected respectively); malaria was not assessed in adults. Additionally, lower haemoglobin level was associated with an increased prevalence of KSHV seropositivity, both in children and in adults.

Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease

PubMed Central

Polizzotto, Mark N.; Aleman, Karen; Wyvill, Kathleen M.; Marshall, Vickie; Whitby, Denise; Wang, Victoria; Pittaluga, Stefania; O’Mahony, Deirdre; Steinberg, Seth M.; Little, Richard F.; Yarchoan, Robert

2014-01-01

Kaposi sarcoma (KS) herpesvirus–associated multicentric Castleman disease (KSHV-MCD) is a lymphoproliferative disorder, most commonly seen in HIV-infected patients, that has a high mortality if untreated. Concurrent KS is common. Although rituximab has reported activity in KSHV-MCD, its use is often associated with KS progression. Within a natural history study of KSHV-MCD, we prospectively evaluated rituximab 375 mg/m2 combined with liposomal doxorubicin 20 mg/m2 (R-Dox) every 3 weeks in 17 patients. Patients received a median of 4 cycles (range 3-9). All received antiretroviral therapy, 11 received consolidation interferon-α, and 6 received consolidation high-dose zidovudine with valganciclovir. Using NCI KSHV-MCD response criteria, major clinical and biochemical responses were attained in 94% and 88% of patients, respectively. With a median 58 months’ potential follow-up, 3-year event-free survival was 69% and 3-year overall survival was 81%. During R-Dox therapy, cutaneous KS developed in 1 patient, whereas 5 of 6 patients with it had clinical improvement. R-Dox was associated with significant improvement in anemia and hypoalbuminemia. KSHV viral load, KSHV viral interleukin-6, C-reactive protein, human interleukin-6, and serum immunoglobulin free light chains decreased with therapy. R-Dox is effective in symptomatic KSHV-MCD and may be useful in patients with concurrent KS. This trial was registered at www.clinicaltrials.gov as #NCT00092222. PMID:25331113

Latent KSHV Infected Endothelial Cells Are Glutamine Addicted and Require Glutaminolysis for Survival

PubMed Central

Sanchez, Erica L.; Carroll, Patrick A.; Thalhofer, Angel B.; Lagunoff, Michael

2015-01-01

Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of Kaposi’s Sarcoma (KS). KSHV establishes a predominantly latent infection in the main KS tumor cell type, the spindle cell, which is of endothelial cell origin. KSHV requires the induction of multiple metabolic pathways, including glycolysis and fatty acid synthesis, for the survival of latently infected endothelial cells. Here we demonstrate that latent KSHV infection leads to increased levels of intracellular glutamine and enhanced glutamine uptake. Depletion of glutamine from the culture media leads to a significant increase in apoptotic cell death in latently infected endothelial cells, but not in their mock-infected counterparts. In cancer cells, glutamine is often required for glutaminolysis to provide intermediates for the tri-carboxylic acid (TCA) cycle and support for the production of biosynthetic and bioenergetic precursors. In the absence of glutamine, the TCA cycle intermediates alpha-ketoglutarate (αKG) and pyruvate prevent the death of latently infected cells. Targeted drug inhibition of glutaminolysis also induces increased cell death in latently infected cells. KSHV infection of endothelial cells induces protein expression of the glutamine transporter, SLC1A5. Chemical inhibition of SLC1A5, or knockdown by siRNA, leads to similar cell death rates as glutamine deprivation and, similarly, can be rescued by αKG. KSHV also induces expression of the heterodimeric transcription factors c-Myc-Max and related heterodimer MondoA-Mlx. Knockdown of MondoA inhibits expression of both Mlx and SLC1A5 and induces a significant increase in cell death of only cells latently infected with KSHV, again, fully rescued by the supplementation of αKG. Therefore, during latent infection of endothelial cells, KSHV activates and requires the Myc/MondoA-network to upregulate the glutamine transporter, SLC1A5, leading to increased glutamine uptake for glutaminolysis. These findings expand our understanding of the required metabolic pathways that are activated during latent KSHV infection of endothelial cells, and demonstrate a novel role for the extended Myc-regulatory network, specifically MondoA, during latent KSHV infection. PMID:26197457

Cellular corepressor TLE2 inhibits replication-and-transcription- activator-mediated transactivation and lytic reactivation of Kaposi's sarcoma-associated herpesvirus.

PubMed

He, Zhiheng; Liu, Yunhua; Liang, Deguang; Wang, Zhuo; Robertson, Erle S; Lan, Ke

2010-02-01

Replication and transcription activator (RTA) encoded by open reading frame 50 (ORF50) of Kaposi's sarcoma-associated herpesvirus (KSHV) is essential and sufficient to initiate lytic reactivation. RTA activates its target genes through direct binding with high affinity to its responsive elements or by interaction with cellular factors, such as RBP-Jkappa, Ap-1, C/EBP-alpha, and Oct-1. In this study, we identified transducin-like enhancer of split 2 (TLE2) as a novel RTA binding protein by using yeast two-hybrid screening of a human spleen cDNA library. The interaction between TLE2 and RTA was confirmed by glutathione S-transferase (GST) binding and coimmunoprecipitation assays. Immunofluorescence analysis showed that TLE2 and RTA were colocalized in the same nuclear compartment in KSHV-infected cells. This interaction recruited TLE2 to RTA bound to its recognition sites on DNA and repressed RTA auto-activation and transactivation activity. Moreover, TLE2 also inhibited the induction of lytic replication and virion production driven by RTA. We further showed that the Q (Gln-rich), SP (Ser-Pro-rich), and WDR (Trp-Asp repeat) domains of TLE2 and the Pro-rich domain of RTA were essential for this interaction. RBP-Jkappa has been shown previously to bind to the same Pro-rich domain of RTA, and this binding can be subject to competition by TLE2. In addition, TLE2 can form a complex with RTA to access the cognate DNA sequence of the RTA-responsive element at different promoters. Intriguingly, the transcription level of TLE2 could be upregulated by RTA during the lytic reactivation process. In conclusion, we identified a new RTA binding protein, TLE2, and demonstrated that TLE2 inhibited replication and transactivation mediated by RTA. This provides another potentially important mechanism for maintenance of KSHV viral latency through interaction with a host protein.

Was Kaposi's sarcoma-associated herpesvirus introduced into China via the ancient Silk Road? An evolutionary perspective.

PubMed

Liu, Zhenqiu; Fang, Qiwen; Zuo, Jialu; Minhas, Veenu; Wood, Charles; He, Na; Zhang, Tiejun

2017-10-01

Kaposi's sarcoma-associated herpesvirus (KSHV) has become widely dispersed worldwide since it was first reported in 1994, but the seroprevalence of KSHV varies geographically. KSHV is relatively ubiquitous in Mediterranean areas and the Xinjiang Uygur Autonomous Region, China. The origin of KSHV has long been puzzling. In the present study, we collected and analysed 154 KSHV ORF-K1 sequences obtained from samples originating from Xinjiang, Italy, Greece, Iran and southern Siberia using Bayesian evolutionary analysis in BEAST to test the hypothesis that KSHV was introduced into Xinjiang via the ancient Silk Road. According to the phylogenetic analysis, 72 sequences were subtype A and 82 subtype C, with C2 (n = 56) being the predominant subtype. The times to the most recent common ancestors (tMRCAs) of KSHV were 29,872 years (95% highest probability density [HPD], 26,851-32,760 years) for all analysed sequences and 2037 years (95% HPD, 1843-2229 years) for Xinjiang sequences in particular. The tMRCA of Xinjiang KSHV was exactly matched with the time period of the ancient Silk Road approximately two thousand years ago. This route began in Chang'an, the capital of the Han dynasty of China, and crossed Central Asia, ending in the Roman Empire. The evolution rate of KSHV was slow, with 3.44 × 10 -6 substitutions per site per year (95% HPD, 2.26 × 10 -6 to 4.71 × 10 -6 ), although 11 codons were discovered to be under positive selection pressure. The geographic distances from Italy to Iran and Xinjiang are more than 4000 and 7000 kilometres, respectively, but no explicit relationship between genetic distance and geographic distance was detected.

KSHV cell attachment sites revealed by ultra sensitive tyramide signal amplification (TSA) localize to membrane microdomains that are up-regulated on mitotic cells.

PubMed

Garrigues, H Jacques; Rubinchikova, Yelena E; Rose, Timothy M

2014-03-01

Cell surface structures initiating attachment of Kaposi's sarcoma-associated herpesvirus (KSHV) were characterized using purified hapten-labeled virions visualized by confocal microscopy with a sensitive fluorescent enhancement using tyramide signal amplification (TSA). KSHV attachment sites were present in specific cellular domains, including actin-based filopodia, lamellipodia, ruffled membranes, microvilli and intercellular junctions. Isolated microdomains were identified on the dorsal surface, which were heterogeneous in size with a variable distribution that depended on cellular confluence and cell cycle stage. KSHV binding domains ranged from scarce on interphase cells to dense and continuous on mitotic cells, and quantitation of bound virus revealed a significant increase on mitotic compared to interphase cells. KSHV also bound to a supranuclear domain that was distinct from microdomains in confluent and interphase cells. These results suggest that rearrangement of the cellular membrane during mitosis induces changes in cell surface receptors implicated in the initial attachment stage of KSHV entry. Copyright © 2014 Elsevier Inc. All rights reserved.

Geographic variation in the prevalence of Kaposi sarcoma-associated herpesvirus and risk factors for transmission.

PubMed

de Sanjose, Silvia; Mbisa, Georgina; Perez-Alvarez, Susana; Benavente, Yolanda; Sukvirach, Sukhon; Hieu, Nguyen Trong; Shin, Hai-Rim; Anh, Pham Thi Hoang; Thomas, Jaiyeola; Lazcano, Eduardo; Matos, Elena; Herrero, Rolando; Muñoz, Nubia; Molano, Monica; Franceschi, Silvia; Whitby, Denise

2009-05-15

The aim of the present study was to estimate the prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) in the female general population, to define geographic variation in and heterosexual transmission of the virus. The study included 10,963 women from 9 countries for whom information on sociodemographic characteristics and reproductive, sexual, and smoking behaviors were available. Antibodies against KSHV that encoded lytic antigen K8.1 and latent antigen ORF73 were determined. The range of prevalence of KSHV (defined as detection of any antigen) was 3.81%-46.02%, with significant geographic variation noted. In Nigeria, the prevalence was 46.02%; in Colombia, 13.32%; in Costa Rica, 9.81%; in Argentina, 6.40%; in Ho Chi Minh City, Vietnam, 15.50%; in Hanoi, Vietnam, 11.26%; in Songkla, Thailand, 10%; in Lampang, Thailand, 8.63%; in Korea, 4.93%; and in Spain, 3.65%. The prevalence of KSHV slightly increased with increasing age among subjects in geographic areas where the prevalence of KSHV was high, such as Nigeria and Colombia, and it significantly decreased with increases in the educational level attained by subjects in those areas. KSHV was not statistically associated with age at first sexual intercourse, number of sex partners, number of children, patterns of oral contraceptive use, presence of cervical human papillomavirus DNA, or smoking status. The study provides comparable estimates of KSHV prevalence in diverse cultural settings across 4 continents and provides evidence that sexual transmission of KSHV is not a major source of infection in the general population.

Constitutive activation of NF-kappa B and secretion of interleukin-8 induced by the G protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus involve G alpha(13) and RhoA.

PubMed

Shepard, L W; Yang, M; Xie, P; Browning, D D; Voyno-Yasenetskaya, T; Kozasa, T; Ye, R D

2001-12-07

The Kaposi's sarcoma herpesvirus (KSHV) open reading frame 74 encodes a G protein-coupled receptor (GPCR) for chemokines. Exogenous expression of this constitutively active GPCR leads to cell transformation and vascular overgrowth characteristic of Kaposi's sarcoma. We show here that expression of KSHV-GPCR in transfected cells results in constitutive transactivation of nuclear factor kappa B (NF-kappa B) and secretion of interleukin-8, and this response involves activation of G alpha(13) and RhoA. The induced expression of a NF-kappa B luciferase reporter was partially reduced by pertussis toxin and the G beta gamma scavenger transducin, and enhanced by co-expression of G alpha(13) and to a lesser extent, G alpha(q). These results indicate coupling of KSHV-GPCR to multiple G proteins for NF-kappa B activation. Expression of KSHV-GPCR led to stress fiber formation in NIH 3T3 cells. To examine the involvement of the G alpha(13)-RhoA pathway in KSHV-GPCR-mediated NF-kappa B activation, HeLa cells were transfected with KSHV-GPCR alone and in combination with the regulator of G protein signaling (RGS) from p115RhoGEF or a dominant negative RhoA(T19N). Both constructs, as well as the C3 exoenzyme from Clostritium botulinum, partially reduced NF-kappa B activation by KSHV-GPCR, and by a constitutively active G alpha(13)(Q226L). KSHV-GPCR-induced NF-kappa B activation is accompanied by increased secretion of IL-8, a function mimicked by the activated G alpha(13) but not by an activated G alpha(q)(Q209L). These results suggest coupling of KSHV-GPCR to the G alpha(13)-RhoA pathway in addition to other G proteins.

An Interaction between KSHV ORF57 and UIF Provides mRNA-Adaptor Redundancy in Herpesvirus Intronless mRNA Export

PubMed Central

Jackson, Brian R.; Boyne, James R.; Noerenberg, Marko; Taylor, Adam; Hautbergue, Guillaume M.; Walsh, Matthew J.; Wheat, Rachel; Blackbourn, David J.; Wilson, Stuart A.; Whitehouse, Adrian

2011-01-01

The hTREX complex mediates cellular bulk mRNA nuclear export by recruiting the nuclear export factor, TAP, via a direct interaction with the export adaptor, Aly. Intriguingly however, depletion of Aly only leads to a modest reduction in cellular mRNA nuclear export, suggesting the existence of additional mRNA nuclear export adaptor proteins. In order to efficiently export Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs from the nucleus, the KSHV ORF57 protein recruits hTREX onto viral intronless mRNAs allowing access to the TAP-mediated export pathway. Similarly however, depletion of Aly only leads to a modest reduction in the nuclear export of KSHV intronless mRNAs. Herein, we identify a novel interaction between ORF57 and the cellular protein, UIF. We provide the first evidence that the ORF57-UIF interaction enables the recruitment of hTREX and TAP to KSHV intronless mRNAs in Aly-depleted cells. Strikingly, depletion of both Aly and UIF inhibits the formation of an ORF57-mediated nuclear export competent ribonucleoprotein particle and consequently prevents ORF57-mediated mRNA nuclear export and KSHV protein production. Importantly, these findings highlight that redundancy exists in the eukaryotic system for certain hTREX components involved in the mRNA nuclear export of intronless KSHV mRNAs. PMID:21814512

Epidemiology of Epstein-Barr virus, cytomegalovirus, and Kaposi's sarcoma-associated herpesvirus infections in peripheral blood leukocytes revealed by a multiplex PCR assay.

PubMed

Nishiwaki, Morie; Fujimuro, Masahiro; Teishikata, Yasuhiro; Inoue, Hisanori; Sasajima, Hitoshi; Nakaso, Kazuhiro; Nakashima, Kenji; Sadanari, Hidetaka; Yamamoto, Tomohiro; Fujiwara, Yoshie; Ogawa, Naoki; Yokosawa, Hideyoshi

2006-12-01

A multiplex polymerase chain reaction (PCR) has been developed for the simultaneous detection of Epstein-Barr virus (EBV), cytomegalovirus (CMV), and Kaposi's sarcoma-associated herpesvirus (KSHV) in a clinical sample. Primers of multiplex PCR were designed to amplify specific regions of the EBV EBNA1, CMV IE2, and KSHV LANA genes. This multiplex PCR assay was found to have detection sensitivities of 1-10 copies of purified viral DNA cloned into the plasmid. To assess diagnostic and pre-clinical applications with this method, we utilized KSHV-positive primary effusion lymphoma (PEL) cells, EBV-positive Burkitt's lymphoma cells, CMV-infected fibroblast cells, and clinically prepared peripheral blood leukocytes (PBLs) that had been infected with viruses. We found that this multiplex PCR assay has high sensitivity and specificity for simultaneous detection of EBV, CMV, and KSHV genomes in a single amplification from a clinical material. Using this multiplex PCR assay, we investigated the prevalence of EBV, CMV, and KSHV in PBL samples from normal Japanese randomly selected. KSHV, EBV, and CMV genomes were detected in samples from 2 (0.2%), 377 (39.5%), and 27 (2.8%) of the 953 blood donors, respectively. Interestingly, both EBV and CMV genomes were detected in samples from all KSHV-positive donors. (c) 2006 Wiley-Liss, Inc.

Kaposi's Sarcoma-Associated Herpesvirus Can Productively Infect Primary Human Keratinocytes and Alter Their Growth Properties

PubMed Central

Cerimele, Francesca; Curreli, Francesca; Ely, Scott; Friedman-Kien, Alvin E.; Cesarman, Ethel; Flore, Ornella

2001-01-01

Previous studies have shown the presence of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) DNA in endothelial cells, in keratinocytes in the basal layer of the epidermis overlying plaque-stage nodular lesions of cutaneous Kaposi's sarcoma (KS), and in the epithelial cells of eccrine glands within KS lesions. We infected primary cell cultures of human keratinocytes with KSHV/HHV8. At 6 days post infection, transcription of viral genes was detected by reverse transcriptase PCR (RT-PCR), and protein expression was documented by an immunofluorescence assay with an anti-LANA monoclonal antibody. To determine whether the viral lytic cycle was inducible by chemical treatment, KSHV/HHV8-infected keratinocytes were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and RT-PCR was performed to confirm the transcription of lytic genes such as open reading frame 26, (which encodes a capsid protein). Finally, to assess infectious viral production, other primary human cells (human umbilical vein endothelial cells), were infected with concentrated supernatant of KSHV-infected, TPA-induced keratinocytes and the presence of viral transcripts was confirmed by RT-PCR. The uninfected keratinocytes senesced 3 to 5 weeks after mock infection, while the KSHV/HHV8-infected keratinocytes continued to proliferate and to date are still in culture. However, 8 weeks after infection, viral genomes were no longer detectable by nested PCR. Although the previously KSHV/HHV8-infected keratinocytes still expressed epithelial markers, they acquired new characteristics such as contact inhibition loss, telomerase activity, anchorage-independent growth, and changes in cytokine production. These results show that KSHV/HHV8, like other herpesviruses, can infect and replicate in epithelial cells in vitro and suggest that in vivo these cells may play a significant role in the establishment of KSHV/HHV8 infection and viral transmission. PMID:11160746

Infection of KSHV and Interaction with HIV: The Bad Romance.

PubMed

Qin, Jie; Lu, Chun

2017-01-01

Kaposi's sarcoma-associated herpesvirus (KSHV), namely, human herpesvirus 8 (HHV-8), is considered as the pathogen of Kaposi's sarcoma (KS), the most frequent cancer in untreated HIV-infected individuals. Patients infected with HIV have a much higher possibility developing KS than average individual. Researchers have found that HIV, which functions as a cofactor of KS, contributes a lot to the development of KS. In this article, we will give a brief introduction of KS and KSHV and how the interaction between KSHV and HIV contributes to the development of KS. Also we will take a glance at the development of treatment in KS, especially AIDS-KS.

Male hormones activate EphA2 to facilitate Kaposi’s sarcoma-associated herpesvirus infection: Implications for gender disparity in Kaposi’s sarcoma

PubMed Central

Deng, Zhaohui; Liang, Deguang; Zhou, Xin; Sun, Rui

2017-01-01

There is increasing consensus that males are more vulnerable than females to infection by several pathogens. However, the underlying mechanism needs further investigation. Here, it was showed that knockdown of androgen receptor (AR) expression or pre-treatment with 5α-dihydrotestosterone, the AR agonist, led to a considerably dysregulated Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. In endothelial cells, membrane-localized AR promoted the endocytosis and nuclear trafficking of KSHV. The AR interacted with ephrin receptor A2 (EphA2) and increased its phosphorylation at residue Ser897, which was specifically upregulated upon KSHV infection. This phosphorylation resulted from the AR-mediated recruitment of Src, which resulted in the activation of p90 ribosomal S6 kinase 1 (RSK1), which directly phosphorylates EphA2 at Ser897. Finally, the EphA2-mediated entry of KSHV was abolished in a Ser897Asn EphA2 mutant. Taken together, membrane-localized AR was identified as a KSHV entry factor that cooperatively activates Src/RSK1/EphA2 signaling, which subsequently promotes KSHV infection of both endothelial and epithelial cells. PMID:28957431

KSHV-Mediated Angiogenesis in Tumor Progression

PubMed Central

Purushothaman, Pravinkumar; Uppal, Timsy; Sarkar, Roni; Verma, Subhash C.

2016-01-01

Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), is a malignant human oncovirus belonging to the gamma herpesvirus family. HHV-8 is closely linked to the pathogenesis of Kaposi’s sarcoma (KS) and two other B-cell lymphoproliferative diseases: primary effusion lymphoma (PEL) and a plasmablastic variant of multicentric Castleman’s disease (MCD). KS is an invasive tumor of endothelial cells most commonly found in untreated HIV-AIDS or immuno-compromised individuals. KS tumors are highly vascularized and have abnormal, excessive neo-angiogenesis, inflammation, and proliferation of infected endothelial cells. KSHV directly induces angiogenesis in an autocrine and paracrine fashion through a complex interplay of various viral and cellular pro-angiogenic and inflammatory factors. KS is believed to originate due to a combination of KSHV’s efficient strategies for evading host immune systems and several pro-angiogenic and pro-inflammatory stimuli. In addition, KSHV infection of endothelial cells produces a wide array of viral oncoproteins with transforming capabilities that regulate multiple host-signaling pathways involved in the activation of angiogenesis. It is likely that the cellular-signaling pathways of angiogenesis and lymph-angiogenesis modulate the rate of tumorigenesis induction by KSHV. This review summarizes the current knowledge on regulating KSHV-mediated angiogenesis by integrating the findings reported thus far on the roles of host and viral genes in oncogenesis, recent developments in cell-culture/animal-model systems, and various anti-angiogenic therapies for treating KSHV-related lymphoproliferative disorders. PMID:27447661

A survey of the interactome of Kaposi's sarcoma-associated herpesvirus ORF45 revealed its binding to viral ORF33 and cellular USP7, resulting in stabilization of ORF33 that is required for production of progeny viruses.

PubMed

Gillen, Joseph; Li, Wenwei; Liang, Qiming; Avey, Denis; Wu, Jianjun; Wu, Fayi; Myoung, JinJong; Zhu, Fanxiu

2015-05-01

The ORF45 protein of Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus-specific immediate-early tegument protein. Our previous studies have revealed its crucial roles in both early and late stages of KSHV infection. In this study, we surveyed the interactome of ORF45 using a panel of monoclonal antibodies. In addition to the previously identified extracellular regulated kinase (ERK) and p90 ribosomal S6 kinase (RSK) proteins, we found several other copurified proteins, including prominent ones of ∼38 kDa and ∼130 kDa. Mass spectrometry revealed that the 38-kDa protein is viral ORF33 and the 130-kDa protein is cellular USP7 (ubiquitin-specific protease 7). We mapped the ORF33-binding domain to the highly conserved carboxyl-terminal 19 amino acids (aa) of ORF45 and the USP7-binding domain to the reported consensus motif in the central region of ORF45. Using immunofluorescence staining, we observed colocalization of ORF45 with ORF33 or USP7 both under transfected conditions and in KSHV-infected cells. Moreover, we noticed ORF45-dependent relocalization of a portion of ORF33/USP7 from the nucleus to the cytoplasm. We found that ORF45 caused an increase in ORF33 protein accumulation that was abolished if either the ORF33- or USP7-binding domain in ORF45 was deleted. Furthermore, deletion of the conserved carboxyl terminus of ORF45 in the KSHV genome drastically reduced the level of ORF33 protein in KSHV-infected cells and abolished production of progeny virions. Collectively, our results not only reveal new components of the ORF45 interactome, but also demonstrate that the interactions among these proteins are crucial for KSHV lytic replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of several human cancers. KSHV ORF45 is a multifunctional protein that is required for KSHV lytic replication, but the exact mechanisms by which ORF45 performs its critical functions are unclear. Our previous studies revealed that all ORF45 protein in cells exists in high-molecular-weight complexes. We therefore sought to characterize the interactome of ORF45 to provide insights into its roles during lytic replication. Using a panel of monoclonal antibodies, we surveyed the ORF45 interactome in KSHV-infected cells. We identified two new binding partners of ORF45: the viral protein ORF33 and cellular ubiquitin-specific protease 7 (USP7). We further demonstrate that the interaction between ORF45 and ORF33 is crucial for the efficient production of KSHV viral particles, suggesting that the targeted interference with this interaction may represent a novel strategy to inhibit KSHV lytic replication. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Activation and Repression of Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycles by Short- and Medium-Chain Fatty Acids

PubMed Central

Gorres, Kelly L.; Daigle, Derek; Mohanram, Sudharshan

2014-01-01

ABSTRACT The lytic cycles of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are induced in cell culture by sodium butyrate (NaB), a short-chain fatty acid (SCFA) histone deacetylase (HDAC) inhibitor. Valproic acid (VPA), another SCFA and an HDAC inhibitor, induces the lytic cycle of KSHV but blocks EBV lytic reactivation. To explore the hypothesis that structural differences between NaB and VPA account for their functional effects on the two related viruses, we investigated the capacity of 16 structurally related short- and medium-chain fatty acids to promote or prevent lytic cycle reactivation. SCFAs differentially affected EBV and KSHV reactivation. KSHV was reactivated by all SCFAs that are HDAC inhibitors, including phenylbutyrate. However, several fatty acid HDAC inhibitors, such as isobutyrate and phenylbutyrate, did not reactivate EBV. Reactivation of KSHV lytic transcripts could not be blocked completely by any fatty acid tested. In contrast, several medium-chain fatty acids inhibited lytic activation of EBV. Fatty acids that blocked EBV reactivation were more lipophilic than those that activated EBV. VPA blocked activation of the BZLF1 promoter by NaB but did not block the transcriptional function of ZEBRA. VPA also blocked activation of the DNA damage response that accompanies EBV lytic cycle activation. Properties of SCFAs in addition to their effects on chromatin are likely to explain activation or repression of EBV. We concluded that fatty acids stimulate the two related human gammaherpesviruses to enter the lytic cycle through different pathways. IMPORTANCE Lytic reactivation of EBV and KSHV is needed for persistence of these viruses and plays a role in carcinogenesis. Our direct comparison highlights the mechanistic differences in lytic reactivation between related human oncogenic gammaherpesviruses. Our findings have therapeutic implications, as fatty acids are found in the diet and produced by the human microbiota. Small-molecule inducers of the lytic cycle are desired for oncolytic therapy. Inhibition of viral reactivation, alternatively, may prove useful in cancer treatment. Overall, our findings contribute to the understanding of pathways that control the latent-to-lytic switch and identify naturally occurring molecules that may regulate this process. PMID:24807711

A Secreted Chemokine Binding Protein Encoded by Murine Gammaherpesvirus-68 Is Necessary for the Establishment of a Normal Latent Load

PubMed Central

Bridgeman, Anne; Stevenson, Philip G.; Simas, J. Pedro; Efstathiou, Stacey

2001-01-01

Herpesviruses encode a variety of proteins with the potential to disrupt chemokine signaling, and hence immune organization. However, little is known of how these might function in vivo. The B cell–tropic murine gammaherpesvirus-68 (MHV-68) is related to the Kaposi's sarcoma–associated herpesvirus (KSHV), but whereas KSHV expresses small chemokine homologues, MHV-68 encodes a broad spectrum chemokine binding protein (M3). Here we have analyzed the effect on viral pathogenesis of a targeted disruption of the M3 gene. After intranasal infection, an M3 deficiency had surprisingly little effect on lytic cycle replication in the respiratory tract or the initial spread of virus to lymphoid tissues. However, the amplification of latently infected B cells in the spleen that normally drives MHV-68–induced infectious mononucleosis failed to occur. Thus, there was a marked reduction in latent virus recoverable by in vitro reactivation, latency-associated viral tRNA transcripts detectable by in situ hybridization, total viral DNA load, and virus-driven B cell activation. In vivo CD8+ T cell depletion largely reversed this deficiency, suggesting that the chemokine neutralization afforded by M3 may function to block effective CD8+ T cell recruitment into lymphoid tissue during the expansion of latently infected B cell numbers. In the absence of M3, MHV-68 was unable to establish a normal latent load. PMID:11489949

Discovery of a Coregulatory Interaction between Kaposi's Sarcoma-Associated Herpesvirus ORF45 and the Viral Protein Kinase ORF36.

PubMed

Avey, Denis; Tepper, Sarah; Pifer, Benjamin; Bahga, Amritpal; Williams, Hunter; Gillen, Joseph; Li, Wenwei; Ogden, Sarah; Zhu, Fanxiu

2016-07-01

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of three human malignancies. KSHV ORF36 encodes a serine/threonine viral protein kinase, which is conserved throughout all herpesviruses. Although several studies have identified the viral and cellular substrates of conserved herpesvirus protein kinases (CHPKs), the precise functions of KSHV ORF36 during lytic replication remain elusive. Here, we report that ORF36 interacts with another lytic protein, ORF45, in a manner dependent on ORF36 kinase activity. We mapped the regions of ORF36 and ORF45 involved in the binding. Their association appears to be mediated by electrostatic interactions, since deletion of either the highly basic N terminus of ORF36 or an acidic patch of ORF45 abolished the binding. In addition, the dephosphorylation of ORF45 protein dramatically reduced its association with ORF36. Importantly, ORF45 enhances both the stability and kinase activity of ORF36. Consistent with previous studies of CHPK homologs, we detected ORF36 protein in extracellular virions. To investigate the roles of ORF36 in the context of KSHV lytic replication, we used bacterial artificial chromosome mutagenesis to engineer both ORF36-null and kinase-dead mutants. We found that ORF36-null/mutant virions are moderately defective in viral particle production and are further deficient in primary infection. In summary, our results uncover a functionally important interaction between ORF36 and ORF45 and indicate a significant role of ORF36 in the production of infectious progeny virions. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus with a significant public health burden. KSHV ORF36 encodes a serine/threonine viral protein kinase, whose functions throughout the viral life cycle have not been elucidated. Here, we report that ORF36 interacts with another KSHV protein, ORF45. We mapped the regions of ORF36 and ORF45 involved in their association and further characterized the consequences of this interaction. We engineered ORF36 mutant viruses in order to investigate the functional roles of ORF36 in the context of KSHV lytic replication, and we confirmed that ORF36 is a component of KSHV virions. Moreover, we found that ORF36 mutants are defective in virion production and primary infection. In summary, we discovered and characterized a functionally important interaction between KSHV ORF36 and ORF45, and our results suggest a significant role of ORF36 in the production of infectious progeny virions, a process critical for KSHV pathogenesis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Perturbs the G1-S Cell Cycle Progression via Deregulation of the cyclin D1 Gene.

PubMed

Lee, Hye-Ra; Mitra, Jaba; Lee, Stacy; Gao, Shou-Jiang; Oh, Tae-Kwang; Kim, Myung Hee; Ha, Taekjip; Jung, Jae U

2016-01-15

Kaposi's sarcoma-associated herpesvirus (KSHV) infection modulates the host cell cycle to create an environment optimal for its viral-DNA replication during the lytic life cycle. We report here that KSHV vIRF4 targets the β-catenin/CBP cofactor and blocks its occupancy on the cyclin D1 promoter, suppressing the G1-S cell cycle progression and enhancing KSHV replication. This shows that KSHV vIRF4 suppresses host G1-S transition, possibly providing an intracellular milieu favorable for its replication. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

ORF73 LANA homologs of RRV and MneRV2 contain an extended RGG/RG-rich nuclear and nucleolar localization signal that interacts directly with importin β1 for non-classical nuclear import.

PubMed

Howard, Kellie; Cherezova, Lidia; DeMaster, Laura K; Rose, Timothy M

2017-11-01

The latency-associated nuclear antigens (LANA) of KSHV and macaque RFHVMn, members of the RV1 rhadinovirus lineage, are closely related with conservation of complex nuclear localization signals (NLS) containing bipartite KR-rich motifs and RG-rich domains, which interact distinctly with importins α and ß1 for nuclear import via classical and non-classical pathways, respectively. RV1 LANAs are expressed in the nucleus of latently-infected cells where they inhibit replication and establish a dominant RV1 latency. Here we show that LANA homologs of macaque RRV and MneRV2 from the more distantly-related RV2 lineage, lack the KR-rich NLS, and instead have a large RG-rich NLS with multiple RG dipeptides and a conserved RGG motif. The RG-NLS interacts uniquely with importin β1, which mediates nuclear import and accumulation of RV2 LANA in the nucleolus. The alternative nuclear import and localization of RV2 LANA homologs may contribute to the dominant RV2 lytic replication phenotype. Copyright © 2017. Published by Elsevier Inc.

Lymphoid disorders associated with HHV-8/KSHV infection: facts and contentions.

PubMed

Gaidano, G; Castaños-Velez, E; Biberfeld, P

1999-04-01

Following the demonstration in 1994, that Kaposi's sarcoma (KS) was associated with a novel virus (KSHV or HHV-8) belonging to the lymphotropic herpes family, this virus was also found in certain lymphoid neoplasias of immunodeficient (HIV+) and immune competent hosts. The association of HHV-8/KSHV infection is now well established with primary effusion lymphoma (PEL) or body cavity based lymphoma (BCBL) and multicentric Castleman's disease (MCD) of the plasma cell type. A possible pathogenic role of HHV-8/KSHV in other lymphoid tumours including primary central nervous system lymphoma (PCNSL) and multiple myeloma (MM) as well as some atypical lymphoproliferations and sarcoidosis has also been suggested, but this is at present a controversial matter, or not confirmed. Several HHV-8/KSHV genes, including potential oncogenes, genes homologous to various cellular genes and growth factors have been incriminated in the pathogenesis of KS and PEL/BCBL, but a common pathogenic mechanism for the clearly diverse proliferations represented by PEL, MCD and KS is at present not evident.

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

Saji, Chiaki; Higashi, Chizuka; Niinaka, Yasufumi

Highlights: Black-Right-Pointing-Pointer Constitutive NF-{kappa}B signaling is essential for the survival and growth of PEL cells. Black-Right-Pointing-Pointer NF-{kappa}B signaling is upregulated by the proteasome-dependent degradation of I{kappa}B{alpha}. Black-Right-Pointing-Pointer Proteasome inhibitors suppress NF-{kappa}B signaling and induce apoptosis in PEL cells through stabilization of I{kappa}B{alpha}. Black-Right-Pointing-Pointer Proteasome inhibitors suppress viral replication in PEL cells during lytic KSHV infection. -- Abstract: Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV). This study provides evidence that proteasomal activity is required for both survival of PEL cells stably harboring the KSHV genome and viral replication of KSHV. We evaluated the cytotoxicmore » effects of proteasome inhibitors on PEL cells. The proteasome inhibitors MG132, lactacystin, and proteasome inhibitor I dramatically inhibited cell proliferation and induced apoptosis of PEL cells through the accumulation of p21 and p27. Furthermore, proteasome inhibitors induced the stabilization of NF-{kappa}B inhibitory molecule (I{kappa}B{alpha}) and suppressed the transcriptional activity of NF-{kappa}B in PEL cells. The NF-{kappa}B specific inhibitor BAY11-7082 also induced apoptosis in PEL cells. The constitutive activation of NF-{kappa}B signaling is essential for the survival and growth of B cell lymphoma cells, including PEL cells. NF-{kappa}B signaling is upregulated by proteasome-dependent degradation of I{kappa}B{alpha}. The suppression of NF-{kappa}B signaling by proteasome inhibitors may contribute to the induction of apoptosis in PEL cells. In addition, proteasome activity is required for KSHV replication in KSHV latently infected PEL cells. MG132 reduced the production of progeny virus from PEL cells at low concentrations, which do not affect PEL cell growth. These findings suggest that proteasome inhibitors may represent a novel strategy for the treatment of KSHV infection and KSHV-associated lymphomas.« less

Kaposi`s sarcoma associated herpesvirus infection among female sex workers and general population women in Shanghai, China: a cross-sectional study.

PubMed

Zhang, Tiejun; Yang, Ying; Yu, Feng; Zhao, Yanping; Lin, Feifei; Minhas, Veenu; Wood, Charles; He, Na

2014-02-05

Limited information on epidemiologic patterns of KSHV, with none focusing on heterosexual transmission, is available in mainland China. To clarify this, a cross-sectional study was conducted among a group of female sex workers (FSW) and general population women (GW) in Shanghai, China. An anonymous questionnaire interview was administrated among 600 FSW and 600 GW. Blood samples were collected and tested for antibodies to KSHV, HSV-2, HIV, syphilis and HBsAg. Correlates of KSHV and HSV-2 were examined using multiple logistic regression analysis. None of the study participants were tested positive for HIV. The seroprevalence of KSHV, HSV-2 , HBV and syphilis was 10.0%, 52.2%, 12.3% and 10.5%, respectively for FSW, and was 11.0%, 15.3%, 9.8% and 2.8%, respectively for GW. KSHV seropositivity was not associated with syphilis and HSV-2 infection as well as sexual practices among either FSW or GW. Nevertheless, HSV-2 infection among FSW was independently associated with being ever married (OR = 1.59; 95%CI: 1.04-2.45), >5 years of prostitution (OR = 2.06; 95%CI: 1.16-3.68) and being syphilis positive (OR = 2.65; 95%CI: 1.43-4.93). HSV-2 infection among GW was independently associated with an age of >35 years (OR = 2.29; 95%CI: 1.07-4.93), having had more than 2 sex partners in the prior 12 months (OR = 6.44; 95%CI: 1.67-24.93) and being syphilis positive (OR = 3.94; 95%CI: 1.38-11.23). A gradual increase of prevalence with the prostitution time group was also detected for HSV-2 and syphilis, but not for KSHV. KSHV is moderately and equivalently prevalent among FSW and GW. Heterosexual contact is not a predominant route for KSHV transmission among Chinese women.

The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA

PubMed Central

Ding, Xiangya; Shen, Chenyou; Hu, Minmin; Zhu, Ying; Qin, Di; Lu, Hongmei; Krueger, Brian J.; Renne, Rolf; Gao, Shou-Jiang; Lu, Chun

2016-01-01

Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is a gammaherpesvirus etiologically associated with KS, a highly disseminated angiogenic tumor of hyperproliferative spindle endothelial cells. KSHV encodes 25 mature microRNAs but their roles in KSHV-induced tumor dissemination and angiogenesis remain unknown. Here, we investigated KSHV-encoded miR-K12-6-3p (miR-K6-3p) promotion of endothelial cell migration and angiogenesis, which are the underlying mechanisms of tumor dissemination and angiogenesis. We found that ectopic expression of miR-K6-3p promoted endothelial cell migration and angiogenesis. Mass spectrometry, bioinformatics and luciferase reporter analyses revealed that miR-K6-3p directly targeted sequence in the 3’ untranslated region (UTR) of SH3 domain binding glutamate-rich protein (SH3BGR). Overexpression of SH3BGR reversed miR-K6-3p induction of cell migration and angiogenesis. Mechanistically, miR-K6-3p downregulated SH3BGR, hence relieved STAT3 from SH3BGR direct binding and inhibition, which was required for miR-K6-3p maximum activation of STAT3 and induction of cell migration and angiogenesis. Finally, deletion of miR-K6 from the KSHV genome abrogated its effect on the SH3BGR/STAT3 pathway, and KSHV-induced migration and angiogenesis. Our results illustrated that, by inhibiting SH3BGR, miR-K6-3p enhances cell migration and angiogenesis by activating the STAT3 pathway, and thus contributes to the dissemination and angiogenesis of KSHV-induced malignancies. PMID:27128969

Kaposi's Sarcoma-Associated Herpesvirus MicroRNA Single-Nucleotide Polymorphisms Identified in Clinical Samples Can Affect MicroRNA Processing, Level of Expression, and Silencing Activity

PubMed Central

Han, Soo-Jin; Marshall, Vickie; Barsov, Eugene; Quiñones, Octavio; Ray, Alex; Labo, Nazzarena; Trivett, Matthew; Ott, David; Renne, Rolf

2013-01-01

Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs that can produce 25 KSHV mature microRNAs. We previously reported single-nucleotide polymorphisms (SNPs) in KSHV-encoded pre-microRNA and mature microRNA sequences from clinical samples (V. Marshall et al., J. Infect. Dis., 195:645–659, 2007). To determine whether microRNA SNPs affect pre-microRNA processing and, ultimately, mature microRNA expression levels, we performed a detailed comparative analysis of (i) mature microRNA expression levels, (ii) in vitro Drosha/Dicer processing, and (iii) RNA-induced silencing complex-dependent targeting of wild-type (wt) and variant microRNA genes. Expression of pairs of wt and variant pre-microRNAs from retroviral vectors and measurement of KSHV mature microRNA expression by real-time reverse transcription-PCR (RT-PCR) revealed differential expression levels that correlated with the presence of specific sequence polymorphisms. Measurement of KSHV mature microRNA expression in a panel of primary effusion lymphoma cell lines by real-time RT-PCR recapitulated some observed expression differences but suggested a more complex relationship between sequence differences and expression of mature microRNA. Furthermore, in vitro maturation assays demonstrated significant SNP-associated changes in Drosha/DGCR8 and/or Dicer processing. These data demonstrate that SNPs within KSHV-encoded pre-microRNAs are associated with differential microRNA expression levels. Given the multiple reports on the involvement of microRNAs in cancer, the biological significance of these phenotypic and genotypic variants merits further studies in patients with KSHV-associated malignancies. PMID:24006441

Sero-Prevalence of Bloodborne Tumor Viruses (HCV, HBV, HTLV-I and KSHV Infections) and Related Risk Factors among Prisoners in Razavi Khorasan Province, Iran, in 2008

PubMed Central

Khajedaluee, Mohammad; Babaei, Ali; Vakili, Rosita; Valizade, Narges; Homaei Shandiz, Fateme; Alavian, Seyed Moayed; Seyed Nozadi, Mohsen; Jazayeri, Seyed Mohammad; Hassannia, Tahereh

2016-01-01

Background Prisoners are at high risk of blood borne and sexually transmitted infections due to their high involvement in risky behaviors. In this descriptive/cross-sectional study, the prevalence, sero-prevalence, and risk factors for bloodborne tumor viruses including HTLV-I, HBV, HCV, and KSHV were evaluated among inmates of two central prisons in the northeast of Iran. Methods Blood samples of 1114 inmates were analyzed for the presence of anti HTLV-I, KSHV, and HCV antibodies and HBsAg by ELISA. PCR tests were performed to confirm the presence of these viruses in plasma and identify the current infections. Results The sero-prevalence of HCV, HBV, HTLV-I, and KSHV was 24.5%, 4.2%, 3.4%, and 3.2% and the prevalence of HCV, HBV, HTLV-I, and KSHV was 19.1%, 2.1%, 2%, and 3%, respectively. HCV infection was significantly associated with history of imprisonment, tobacco consumption, alcohol consumption, intravenous drug use, length of imprisonment, and type of crime committed. Thirty one (2.8%) prisoners had HCV-KSHV co-infection, 16 (1.5%) had HCV-HTLV-I co-infection, and 14 (1.3%) had HBV-HCV co-infection. Triple co-infection was observed in seven cases and one case had four infections concomitantly. Conclusions This epidemiological study indicated different rates and transmission risks for these viruses. HCV was the most contagious viral infection and HTLV-I was the weakest in the prisoners. Apart from KSHV infection which its prevalence was as twice as in the general population, the prevalence of HBV and HTLV-I in prisoners was nearly in ranges of the general population. PMID:28123439

Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas.

PubMed

Cesarman, E; Chang, Y; Moore, P S; Said, J W; Knowles, D M

1995-05-04

DNA fragments that appeared to belong to an unidentified human herpesvirus were recently found in more than 90 percent of Kaposi's sarcoma lesions associated with the acquired immunodeficiency syndrome (AIDS). These fragments were also found in 6 of 39 tissue samples without Kaposi's sarcoma, including 3 malignant lymphomas, from patients with AIDS, but not in samples from patients without AIDS. We examined the DNA of 193 lymphomas from 42 patients with AIDS and 151 patients who did not have AIDS. We searched the DNA for sequences of Kaposi's sarcoma-associated herpesvirus (KSHV) by Southern blot hybridization, the polymerase chain reaction (PCR), or both. The PCR products in the positive samples were sequences and compared with the KSHV sequences in Kaposi's sarcoma tissues from patients with AIDS. KSHV sequences were identified in eight lymphomas in patients infected with the human immunodeficiency virus. All eight, and only these eight, were body-cavity-based lymphomas--that is, they were characterized by pleural, pericardial, or peritoneal lymphomatous effusions. All eight lymphomas also contained the Epstein-Barr viral genome. KSHV sequences were not found in the other 185 lymphomas. KSHV sequences were 40 to 80 times more abundant in the body-cavity-based lymphomas than in the Kaposi's sarcoma lesions. A high degree of conservation of KSHV sequences in Kaposi's sarcoma and in the eight lymphomas suggests the presence of the same agent in both lesions. The recently discovered KSHV DNA sequences occur in an unusual subgroup of AIDS-related B-cell lymphomas, but not in any other lymphoid neoplasm studied thus far. Our finding strongly suggests that a novel herpesvirus has a pathogenic role in AIDS-related body-cavity-based lymphomas.

Niclosamide inhibits lytic replication of Epstein-Barr virus by disrupting mTOR activation.

PubMed

Huang, Lu; Yang, Mengtian; Yuan, Yan; Li, Xiaojuan; Kuang, Ersheng

2017-02-01

Infection with the oncogenic γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause several severe malignancies in humans. Inhibition of the lytic replication of EBV and KSHV eliminates the reservoir of persistent infection and transmission, consequently preventing the occurrence of diseases from the sources of infection. Antiviral drugs are limited in controlling these viral infectious diseases. Here, we demonstrate that niclosamide, an old anthelmintic drug, inhibits mTOR activation during EBV lytic replication. Consequently, niclosamide effectively suppresses EBV lytic gene expression, viral DNA lytic replication and virion production in EBV-infected lymphoma cells and epithelial cells. Niclosamide exhibits cytotoxicity toward lymphoma cells and induces irreversible cell cycle arrest in lytically EBV-infected cells. The ectopic overexpression of mTOR reverses the inhibition of niclosamide in EBV lytic replication. Similarly, niclosamide inhibits KSHV lytic replication. Thus, we conclude that niclosamide is a promising candidate for chemotherapy against the acute occurrence and transmission of infectious diseases of oncogenic γ-herpesviruses. Copyright © 2016 Elsevier B.V. All rights reserved.

Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration.

PubMed

Giffin, Louise; West, John A; Damania, Blossom

2015-12-08

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of human Kaposi's sarcoma, a tumor that arises from endothelial cells, as well as two B cell lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman's disease. KSHV utilizes a variety of mechanisms to evade host immune responses and promote cellular transformation and growth in order to persist for the life of the host. A viral homolog of human interleukin-6 (hIL-6) named viral interleukin-6 (vIL-6) is encoded by KSHV and expressed in KSHV-associated cancers. Similar to hIL-6, vIL-6 is secreted, but the majority of vIL-6 is retained within the endoplasmic reticulum, where it can initiate functional signaling through part of the interleukin-6 receptor complex. We sought to determine how intracellular vIL-6 modulates the host endothelial cell environment by analyzing vIL-6's impact on the endothelial cell transcriptome. vIL-6 significantly altered the expression of many cellular genes associated with cell migration. In particular, vIL-6 upregulated the host factor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) at the protein and message levels. CEACAM1 has been implicated in tumor invasion and metastasis and promotes migration and vascular remodeling in endothelial cells. We report that vIL-6 upregulates CEACAM1 by a STAT3-dependent mechanism and that CEACAM1 promotes vIL-6-mediated migration. Furthermore, latent and de novo KSHV infections of endothelial cells also induce CEACAM1 expression. Collectively, our data suggest that vIL-6 modulates endothelial cell migration by upregulating the expression of cellular factors, including CEACAM1. Kaposi's sarcoma-associated herpesvirus (KSHV) is linked with the development of three human malignancies, Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. KSHV expresses many factors that enable the virus to manipulate the host environment in order to persist and induce disease. The viral interleukin-6 (vIL-6) produced by KSHV is structurally and functionally homologous to the human cytokine interleukin-6, except that vIL-6 is secreted slowly and functions primarily from inside the host cell. To investigate the unique intracellular role of vIL-6, we analyzed the impact of vIL-6 on endothelial cell gene expression. We report that vIL-6 significantly alters the expression of genes associated with cell movement, including that for CEACAM1. The gene for CEACAM1 was upregulated by vIL-6 and by latent and primary KSHV infection and promotes vIL-6-mediated endothelial cell migration. This work advances the field's understanding of vIL-6 function and its contribution to KSHV pathogenesis. Copyright © 2015 Giffin et al.

EphrinA2 Regulates Clathrin Mediated KSHV Endocytosis in Fibroblast Cells by Coordinating Integrin-Associated Signaling and c-Cbl Directed Polyubiquitination

PubMed Central

Dutta, Dipanjan; Chakraborty, Sayan; Bandyopadhyay, Chirosree; Valiya Veettil, Mohanan; Ansari, Mairaj Ahmed; Singh, Vivek Vikram; Chandran, Bala

2013-01-01

Kaposi's sarcoma-associated herpesvirus (KSHV) interacts with human dermal endothelial cell surface tyrosine kinase EphrinA2 (EphA2) and integrins (α3β1 and αVβ3) in the lipid raft (LR) region, and EphA2 regulates macropinocytic virus entry by coordinating integrin-c-Cbl associated signaling. In contrast, KSHV enters human foreskin fibroblast (HFF) cells by LR-independent clathrin mediated endocytosis. The present studies conducted to identify the key molecules regulating KSHV entry in HFF cells showed that KSHV induces association with integrins (αVβ5, αVβ3 and α3β1) and EphA2 in non-LR regions early during infection and activates EphA2, which in turn associates with phosphorylated c-Cbl, myosin IIA, FAK, Src, and PI3-K, as well as clathrin and its adaptor AP2 and effector Epsin-15 proteins. EphA2 knockdown significantly reduced these signal inductions, virus internalization and gene expression. c-Cbl knockdown ablated the c-Cbl mediated K63 type polyubiquitination of EphA2 and clathrin association with EphA2 and KSHV. Mutations in EphA2's tyrosine kinase domain (TKD) or sterile alpha motif (SAM) abolished its interaction with c-Cbl. Mutations in tyrosine kinase binding (TKB) or RING finger (RF) domains of c-Cbl resulted in very poor association of c-Cbl with EphA2 and decreased EphA2 polyubiquitination. These studies demonstrated the contributions of these domains in EphA2 and c-Cbl association, EphA2 polyubiquitination and virus-EphA2 internalization. Collectively, these results revealed for the first time that EphA2 influences the tyrosine phosphorylation of clathrin, the role of EphA2 in clathrin mediated endocytosis of a virus, and c-Cbl mediated EphA2 polyubiquitination directing KSHV entry in HFF cells via coordinated signal induction and progression of endocytic events, all of which suggest that targeting EphA2 and c-Cbl could block KSHV entry and infection. PMID:23874206

Molecular characterization of the rhesus rhadinovirus (RRV) ORF4 gene and the RRV complement control protein it encodes.

PubMed

Mark, Linda; Spiller, O Brad; Okroj, Marcin; Chanas, Simon; Aitken, Jim A; Wong, Scott W; Damania, Blossom; Blom, Anna M; Blackbourn, David J

2007-04-01

The diversity of viral strategies to modulate complement activation indicates that this component of the immune system has significant antiviral potential. One example is the Kaposi's sarcoma-associated herpesvirus (KSHV) complement control protein (KCP), which inhibits progression of the complement cascade. Rhesus rhadinovirus (RRV), like KSHV, is a member of the subfamily Gammaherpesvirinae and currently provides the only in vivo model of KSHV pathobiology in primates. In the present study, we characterized the KCP homologue encoded by RRV, RRV complement control protein (RCP). Two strains of RRV have been sequenced to date (H26-95 and 17577), and the RCPs they encode differ substantially in structure: RCP from strain H26-95 has four complement control protein (CCP) domains, whereas RCP from strain 17577 has eight CCP domains. Transcriptional analyses of the RCP gene (ORF4, referred to herein as RCP) in infected rhesus macaque fibroblasts mapped the ends of the transcripts of both strains. They revealed that H26-95 encodes a full-length, unspliced RCP transcript, while 17577 RCP generates a full-length unspliced mRNA and two alternatively spliced transcripts. Western blotting confirmed that infected cells express RCP, and immune electron microscopy disclosed this protein on the surface of RRV virions. Functional studies of RCP encoded by both RRV strains revealed their ability to suppress complement activation by the classical (antibody-mediated) pathway. These data provide the foundation for studies into the biological significance of gammaherpesvirus complement regulatory proteins in a tractable, non-human primate model.

Molecular Characterization of the Rhesus Rhadinovirus (RRV) ORF4 Gene and the RRV Complement Control Protein It Encodes▿

PubMed Central

Mark, Linda; Spiller, O. Brad; Okroj, Marcin; Chanas, Simon; Aitken, Jim A.; Wong, Scott W.; Damania, Blossom; Blom, Anna M.; Blackbourn, David J.

2007-01-01

The diversity of viral strategies to modulate complement activation indicates that this component of the immune system has significant antiviral potential. One example is the Kaposi's sarcoma-associated herpesvirus (KSHV) complement control protein (KCP), which inhibits progression of the complement cascade. Rhesus rhadinovirus (RRV), like KSHV, is a member of the subfamily Gammaherpesvirinae and currently provides the only in vivo model of KSHV pathobiology in primates. In the present study, we characterized the KCP homologue encoded by RRV, RRV complement control protein (RCP). Two strains of RRV have been sequenced to date (H26-95 and 17577), and the RCPs they encode differ substantially in structure: RCP from strain H26-95 has four complement control protein (CCP) domains, whereas RCP from strain 17577 has eight CCP domains. Transcriptional analyses of the RCP gene (ORF4, referred to herein as RCP) in infected rhesus macaque fibroblasts mapped the ends of the transcripts of both strains. They revealed that H26-95 encodes a full-length, unspliced RCP transcript, while 17577 RCP generates a full-length unspliced mRNA and two alternatively spliced transcripts. Western blotting confirmed that infected cells express RCP, and immune electron microscopy disclosed this protein on the surface of RRV virions. Functional studies of RCP encoded by both RRV strains revealed their ability to suppress complement activation by the classical (antibody-mediated) pathway. These data provide the foundation for studies into the biological significance of gammaherpesvirus complement regulatory proteins in a tractable, non-human primate model. PMID:17287274

Activation of DNA Damage Response Induced by the Kaposi’s Sarcoma-Associated Herpes Virus

PubMed Central

Di Domenico, Enea Gino; Toma, Luigi; Bordignon, Valentina; Trento, Elisabetta; D’Agosto, Giovanna; Cordiali-Fei, Paola; Ensoli, Fabrizio

2016-01-01

The human herpes virus 8 (HHV-8), also known as Kaposi sarcoma-associated herpes virus (KSHV), can infect endothelial cells often leading to cell transformation and to the development of tumors, namely Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and the plasmablastic variant of multicentric Castleman’s disease. KSHV is prevalent in areas such as sub-Saharan Africa and the Mediterranean region presenting distinct genotypes, which appear to be associated with differences in disease manifestation, according to geographical areas. In infected cells, KSHV persists in a latent episomal form. However, in a limited number of cells, it undergoes spontaneous lytic reactivation to ensure the production of new virions. During both the latent and the lytic cycle, KSHV is programmed to express genes which selectively modulate the DNA damage response (DDR) through the activation of the ataxia telangiectasia mutated (ATM) pathway and by phosphorylating factors associated with the DDR, including the major tumor suppressor protein p53 tumor suppressor p53. This review will focus on the interplay between the KSHV and the DDR response pathway throughout the viral lifecycle, exploring the putative molecular mechanism/s that may contribute to malignant transformation of host cells. PMID:27258263

The Immunomodulatory Capacity of an Epstein-Barr Virus Abortive Lytic Cycle: Potential Contribution to Viral Tumorigenesis

PubMed Central

2018-01-01

Epstein-Barr virus (EBV) is characterized by a bipartite life cycle in which latent and lytic stages are alternated. Latency is compatible with long-lasting persistency within the infected host, while lytic expression, preferentially found in oropharyngeal epithelial tissue, is thought to favor host-to-host viral dissemination. The clinical importance of EBV relates to its association with cancer, which we think is mainly a consequence of the latency/persistency mechanisms. However, studies in murine models of tumorigenesis/lymphomagenesis indicate that the lytic cycle also contributes to cancer formation. Indeed, EBV lytic expression is often observed in established cell lines and tumor biopsies. Within the lytic cycle EBV expresses a handful of immunomodulatory (BCRF1, BARF1, BNLF2A, BGLF5 & BILF1) and anti-apoptotic (BHRF1 & BALF1) proteins. In this review, we discuss the evidence supporting an abortive lytic cycle in which these lytic genes are expressed, and how the immunomodulatory mechanisms of EBV and related herpesviruses Kaposi Sarcoma herpesvirus (KSHV) and human cytomegalovirus (HCMV) result in paracrine signals that feed tumor cells. An abortive lytic cycle would reconcile the need of lytic expression for viral tumorigenesis without relaying in a complete cycle that would induce cell lysis to release the newly formed infective viral particles. PMID:29601503

Treating KSHV-Associated Multicentric Castleman Disease

Cancer.gov

In this study, patients with KSHV-associated multicentric Castleman disease will receive IV tocilizumab every other week for up to 12 weeks. Patients who do not benefit may go on to receive high-dose AZT and valganciclovir as well.

Kaposi’s sarcoma–associated herpesvirus stably clusters its genomes across generations to maintain itself extrachromosomally

PubMed Central

Chiu, Ya-Fang; Sugden, Arthur U.

2017-01-01

Genetic elements that replicate extrachromosomally are rare in mammals; however, several human tumor viruses, including the papillomaviruses and the gammaherpesviruses, maintain their plasmid genomes by tethering them to cellular chromosomes. We have uncovered an unprecedented mechanism of viral replication: Kaposi’s sarcoma–associated herpesvirus (KSHV) stably clusters its genomes across generations to maintain itself extrachromosomally. To identify and characterize this mechanism, we developed two complementary, independent approaches: live-cell imaging and a predictive computational model. The clustering of KSHV requires the viral protein, LANA1, to bind viral genomes to nucleosomes arrayed on both cellular and viral DNA. Clustering affects both viral partitioning and viral genome numbers of KSHV. The clustering of KSHV plasmids provides it with an effective evolutionary strategy to rapidly increase copy numbers of genomes per cell at the expense of the total numbers of cells infected. PMID:28696226

Establishment of an ELISA to detect Kaposi's sarcoma-associated herpesvirus using recombinant ORF73.

PubMed

Ouyang, Xin-xing; Fu, Bi-shi; Li, Bao-lin; Zeng, Yan; Xu, Fan-hong; Wang, Lin-ding

2010-06-01

Kaposi's sarcoma-associated herpesvirus (KSHV) is causally related to Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and a proportion of cases of multicentric Castleman's disease (MCD). The ORF73 protein was cloned into pQE80L-orf73 and expressed in E.coli and purified. The expressed recombinant ORF73 was identified by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE). A protein of about 27 kDa was expressed as expected. Western Blotting showed that the purified recombinant ORF73 reacted with KSHV positive serum. The immunogenicity of the recombinant ORF73 was further analysed by ELISA and the optimal conditions were determined. The ORF73 ELISA was used to compare the KSHV seroprevalence between Hubei and Xinjiang Han people. The Han people in Xinjiang have significantly higher KSHV seroprevalence than their counterparts in Hubei (6.7% vs 2.9%, P = 0.005).

Kaposi’s sarcoma–associated herpesvirus stably clusters its genomes across generations to maintain itself extrachromosomally

DOE PAGES

Chiu, Ya-Fang; Sugden, Arthur U.; Fox, Kathryn; ...

2017-07-10

Genetic elements that replicate extrachromosomally are rare in mammals; however, several human tumor viruses, including the papillomaviruses and the gammaherpesviruses, maintain their plasmid genomes by tethering them to cellular chromosomes. We have uncovered an unprecedented mechanism of viral replication: Kaposi’s sarcoma–associated herpesvirus (KSHV) stably clusters its genomes across generations to maintain itself extrachromosomally. To identify and characterize this mechanism, we developed two complementary, independent approaches: live-cell imaging and a predictive computational model. The clustering of KSHV requires the viral protein, LANA1, to bind viral genomes to nucleosomes arrayed on both cellular and viral DNA. Clustering affects both viral partitioning andmore » viral genome numbers of KSHV. The clustering of KSHV plasmids provides it with an effective evolutionary strategy to rapidly increase copy numbers of genomes per cell at the expense of the total numbers of cells infected.« less

Kaposi’s sarcoma–associated herpesvirus stably clusters its genomes across generations to maintain itself extrachromosomally

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

Chiu, Ya-Fang; Sugden, Arthur U.; Fox, Kathryn

Genetic elements that replicate extrachromosomally are rare in mammals; however, several human tumor viruses, including the papillomaviruses and the gammaherpesviruses, maintain their plasmid genomes by tethering them to cellular chromosomes. We have uncovered an unprecedented mechanism of viral replication: Kaposi’s sarcoma–associated herpesvirus (KSHV) stably clusters its genomes across generations to maintain itself extrachromosomally. To identify and characterize this mechanism, we developed two complementary, independent approaches: live-cell imaging and a predictive computational model. The clustering of KSHV requires the viral protein, LANA1, to bind viral genomes to nucleosomes arrayed on both cellular and viral DNA. Clustering affects both viral partitioning andmore » viral genome numbers of KSHV. The clustering of KSHV plasmids provides it with an effective evolutionary strategy to rapidly increase copy numbers of genomes per cell at the expense of the total numbers of cells infected.« less

Concurrent targeting of EP1/EP4 receptors and COX-2 induces synergistic apoptosis in KSHV and EBV associated non-Hodgkin lymphoma cell lines

PubMed Central

Paul, Arun George; Chandran, Bala; Sharma-Walia, Neelam

2014-01-01

The effective anti-tumorigenic potential of non-steroidal anti-inflammatory drugs (NSAIDs) and eicosonoid (EP; EP1–4) receptor antagonists prompted us to test their efficacy in Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) related lymphomas. Our study demonstrated that (1) EP1–4 receptor protein levels vary among the various non-Hodgkin’s lymphoma (NHL) cell lines tested (BCBL-1:KSHV+/EBV−;BC-3: KSHV+/EBV−; Akata/EBV+: KSHV−/EBV+; and JSC-1 cells: KSHV+/EBV+ cells); (2) 5.0 µM of EP1 antagonist (SC-51322) had a significant anti-proliferative effect on BCBL-1, BC-3, Akata/EBV+, and JSC-1 cells; (3) 50.0 µM of EP2 antagonist (AH6809) was required to induce a significant anti-proliferative effect on BCBL-1, Akata/EBV+, and JSC-1 cells; (4) 5.0 µM of EP4 antagonist (GW 627368X) had a significant anti-proliferative effect on BC-3, Akata/EBV+, and JSC-1 cells; (5) COX-2 selective inhibitor celecoxib (5.0µM) had significant anti-proliferative effects on BCBL-1, BC-3, Akata/EBV+, and JSC-1 cells; and (6) a combination of 1.0µM each of celecoxib, SC-51322 and GW 627368X could potentiate the pro-apoptotic properties of celecoxib or vice-versa. Overall, our studies identified the synergistic anti-proliferative effect of NSAIDs and EP receptor blockers on KSHV and EBV related B cell malignancies. PMID:23523954

K-bZIP Mediated SUMO-2/3 Specific Modification on the KSHV Genome Negatively Regulates Lytic Gene Expression and Viral Reactivation

PubMed Central

Yang, Wan-Shan; Hsu, Hung-Wei; Campbell, Mel; Cheng, Chia-Yang; Chang, Pei-Ching

2015-01-01

SUMOylation is associated with epigenetic regulation of chromatin structure and transcription. Epigenetic modifications of herpesviral genomes accompany the transcriptional switch of latent and lytic genes during the virus life cycle. Here, we report a genome-wide comparison of SUMO paralog modification on the KSHV genome. Using chromatin immunoprecipitation in conjunction with high-throughput sequencing, our study revealed highly distinct landscape changes of SUMO paralog genomic modifications associated with KSHV reactivation. A rapid and widespread deposition of SUMO-2/3, compared with SUMO-1, modification across the KSHV genome upon reactivation was observed. Interestingly, SUMO-2/3 enrichment was inversely correlated with H3K9me3 mark after reactivation, indicating that SUMO-2/3 may be responsible for regulating the expression of viral genes located in low heterochromatin regions during viral reactivation. RNA-sequencing analysis showed that the SUMO-2/3 enrichment pattern positively correlated with KSHV gene expression profiles. Activation of KSHV lytic genes located in regions with high SUMO-2/3 enrichment was enhanced by SUMO-2/3 knockdown. These findings suggest that SUMO-2/3 viral chromatin modification contributes to the diminution of viral gene expression during reactivation. Our previous study identified a SUMO-2/3-specific viral E3 ligase, K-bZIP, suggesting a potential role of this enzyme in regulating SUMO-2/3 enrichment and viral gene repression. Consistent with this prediction, higher K-bZIP binding on SUMO-2/3 enrichment region during reactivation was observed. Moreover, a K-bZIP SUMO E3 ligase dead mutant, K-bZIP-L75A, in the viral context, showed no SUMO-2/3 enrichment on viral chromatin and higher expression of viral genes located in SUMO-2/3 enriched regions during reactivation. Importantly, virus production significantly increased in both SUMO-2/3 knockdown and KSHV K-bZIP-L75A mutant cells. These results indicate that SUMO-2/3 modification of viral chromatin may function to counteract KSHV reactivation. As induction of herpesvirus reactivation may activate cellular antiviral regimes, our results suggest that development of viral SUMO E3 ligase specific inhibitors may be an avenue for anti-virus therapy. PMID:26197391

Kaposi's Sarcoma-Associated Herpesvirus Hijacks RNA Polymerase II To Create a Viral Transcriptional Factory

PubMed Central

Chen, Christopher Phillip; Lyu, Yuanzhi; Chuang, Frank; Nakano, Kazushi; Izumiya, Chie; Jin, Di; Campbell, Mel

2017-01-01

ABSTRACT Locally concentrated nuclear factors ensure efficient binding to DNA templates, facilitating RNA polymerase II recruitment and frequent reutilization of stable preinitiation complexes. We have uncovered a mechanism for effective viral transcription by focal assembly of RNA polymerase II around Kaposi's sarcoma-associated herpesvirus (KSHV) genomes in the host cell nucleus. Using immunofluorescence labeling of latent nuclear antigen (LANA) protein, together with fluorescence in situ RNA hybridization (RNA-FISH) of the intron region of immediate early transcripts, we visualized active transcription of viral genomes in naturally infected cells. At the single-cell level, we found that not all episomes were uniformly transcribed following reactivation stimuli. However, those episomes that were being transcribed would spontaneously aggregate to form transcriptional “factories,” which recruited a significant fraction of cellular RNA polymerase II. Focal assembly of “viral transcriptional factories” decreased the pool of cellular RNA polymerase II available for cellular gene transcription, which consequently impaired cellular gene expression globally, with the exception of selected ones. The viral transcriptional factories localized with replicating viral genomic DNAs. The observed colocalization of viral transcriptional factories with replicating viral genomic DNA suggests that KSHV assembles an “all-in-one” factory for both gene transcription and DNA replication. We propose that the assembly of RNA polymerase II around viral episomes in the nucleus may be a previously unexplored aspect of KSHV gene regulation by confiscation of a limited supply of RNA polymerase II in infected cells. IMPORTANCE B cells infected with Kaposi's sarcoma-associated herpesvirus (KSHV) harbor multiple copies of the KSHV genome in the form of episomes. Three-dimensional imaging of viral gene expression in the nucleus allows us to study interactions and changes in the physical distribution of these episomes following stimulation. The results showed heterogeneity in the responses of individual KSHV episomes to stimuli within a single reactivating cell; those episomes that did respond to stimulation, aggregated within large domains that appear to function as viral transcription factories. A significant portion of cellular RNA polymerase II was trapped in these factories and served to transcribe viral genomes, which coincided with an overall decrease in cellular gene expression. Our findings uncover a strategy of KSHV gene regulation through focal assembly of KSHV episomes and a molecular mechanism of late gene expression. PMID:28331082

Integrative systems control approach for reactivating Kaposi's sarcoma-associated herpesvirus (KSHV) with combinatory drugs

PubMed Central

Sun, Chien-Pin; Usui, Takane; Yu, Fuqu; Al-Shyoukh, Ibrahim; Shamma, Jeff; Sun, Ren; Ho, Chih-Ming

2009-01-01

Cells serve as basic units of life and represent intricate biological molecular systems. The vast number of cellular molecules with their signaling and regulatory circuitries forms an intertwined network. In this network, each pathway interacts non-linearly with others through different intermediates. Thus, the challenge of manipulating cellular functions for desired outcomes, such as cancer eradication and controlling viral infection lies within the integrative system of regulatory circuitries. By using a closed-loop system control scheme, we can efficiently analyze biological signaling networks and manipulate their behavior through multiple stimulations on a collection of pathways. Specifically, we aimed to maximize the reactivation of Kaposi's Sarcoma-associated Herpesvirus (KSHV) in a Primary Effusion Lymphoma cell line. The advantage of this approach is that it is well-suited to study complex integrated systems; it circumvents the need for detailed information of individual signaling components; and it investigates the network as a whole by utilizing key systemic outputs as indicators. PMID:19851479

Integrative systems control approach for reactivating Kaposi's sarcoma-associated herpesvirus (KSHV) with combinatory drugs.

PubMed

Sun, Chien-Pin; Usui, Takane; Yu, Fuqu; Al-Shyoukh, Ibrahim; Shamma, Jeff; Sun, Ren; Ho, Chih-Ming

2009-01-01

Cells serve as basic units of life and represent intricate biological molecular systems. The vast number of cellular molecules with their signaling and regulatory circuitries forms an intertwined network. In this network, each pathway interacts non-linearly with others through different intermediates. Thus, the challenge of manipulating cellular functions for desired outcomes, such as cancer eradication and controlling viral infection lies within the integrative system of regulatory circuitries. By using a closed-loop system control scheme, we can efficiently analyze biological signaling networks and manipulate their behavior through multiple stimulations on a collection of pathways. Specifically, we aimed to maximize the reactivation of Kaposi's Sarcoma-associated Herpesvirus (KSHV) in a Primary Effusion Lymphoma cell line. The advantage of this approach is that it is well-suited to study complex integrated systems; it circumvents the need for detailed information of individual signaling components; and it investigates the network as a whole by utilizing key systemic outputs as indicators.

Multiplex PCR-based DNA array for simultaneous detection of three human herpesviruses, EVB, CMV and KSHV.

PubMed

Fujimuro, Masahiro; Nakaso, Kazuhiro; Nakashima, Kenji; Sadanari, Hidetaka; Hisanori, Inoue; Teishikata, Yasuhiro; Hayward, S Diane; Yokosawa, Hideyoshi

2006-04-01

Human lymphotropic herpesviruses, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are responsible for a wide variety of human diseases. Due to an increase in diseased states associated with immunosuppression, more instances of co-morbid infections with these herpesviruses have resulted in viral reactivations that have caused numerous fatalities. Therefore, the development of rapid and accurate method to detect these viruses in immunocompromised patients is vital for immediate treatment with antiviral prophylactic drugs. In this study, we developed a new multiplex PCR method coupled to DNA array hybridization, which can simultaneously detect all three human herpesviruses in one single cell sample. Multiplex PCR primers were designed to amplify specific regions of the EBV (EBER1), CMV (IE) and KSHV (LANA) viral genomes. Pre-clinical application of this method revealed that this approach is capable of detecting as few as 1 copy of the viral genomes for KSHV and CMV and 100 copies of the genome for EBV. Furthermore, this highly sensitive test showed no cross-reactivity among the three viruses and is capable of detecting both KSHV and EBV viral genomes simultaneously in the lymphoblastoid cells that have been double infected with both viruses. Thus, this array-based approach serves as a rapid and reliable diagnostic tool for clinical applications.

Detection of Kaposi's Sarcoma Associated Herpesvirus Nucleic Acids Using a Smartphone Accessory

PubMed Central

Mancuso, Matthew; Cesarman, Ethel; Erickson, David

2014-01-01

Kaposi's sarcoma (KS) is an infectious cancer occurring in immune-compromised patients, caused by Kaposi's sarcoma associated herpesvirus (KSHV). Our vision is to simplify the process of KS diagnosis through the creation of a smartphone based point-of-care system capable of yielding an actionable diagnostic readout starting from a raw biopsy sample. In this work we develop the sensing mechanism for the overall system, a smartphone accessory capable of detecting KSHV nucleic acids. The accessory reads out microfluidic chips filled with a colorimetric nanoparticle assay targeted at KSHV. We calculate that our final device can read out gold nanoparticle solutions with an accuracy of .05 OD, and we demonstrate that it can detect DNA sequences from KSHV down to 1 nM. We believe that through integration with our previously developed components, a smartphone based system like the one studied here can provide accurate detection information, as well as a simple platform for field based clinical diagnosis and research. PMID:25117534

Computational analysis of ribonomics datasets identifies long non-coding RNA targets of γ-herpesviral miRNAs.

PubMed

Sethuraman, Sunantha; Thomas, Merin; Gay, Lauren A; Renne, Rolf

2018-05-29

Ribonomics experiments involving crosslinking and immuno-precipitation (CLIP) of Ago proteins have expanded the understanding of the miRNA targetome of several organisms. These techniques, collectively referred to as CLIP-seq, have been applied to identifying the mRNA targets of miRNAs expressed by Kaposi's Sarcoma-associated herpes virus (KSHV) and Epstein-Barr virus (EBV). However, these studies focused on identifying only those RNA targets of KSHV and EBV miRNAs that are known to encode proteins. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are also targeted by miRNAs. In this study, we performed a systematic re-analysis of published datasets from KSHV- and EBV-driven cancers. We used CLIP-seq data from lymphoma cells or EBV-transformed B cells, and a crosslinking, ligation and sequencing of hybrids dataset from KSHV-infected endothelial cells, to identify novel lncRNA targets of viral miRNAs. Here, we catalog the lncRNA targetome of KSHV and EBV miRNAs, and provide a detailed in silico analysis of lncRNA-miRNA binding interactions. Viral miRNAs target several hundred lncRNAs, including a subset previously shown to be aberrantly expressed in human malignancies. In addition, we identified thousands of lncRNAs to be putative targets of human miRNAs, suggesting that miRNA-lncRNA interactions broadly contribute to the regulation of gene expression.

Kaposi's Sarcoma-Associated Herpesvirus | Center for Cancer Research

Cancer.gov

The discovery of KSHV in 1994 was a historical landmark in tumor virology and human cancer research. KSHV's subsequent identification as a cause of Kaposi sarcoma and its association with primary effusion lymphoma and multicentric Castleman disease soon attracted the attention of hundreds of research laboratories and motivated thousands of virologists and oncologists to switch

Conservation of the glycoprotein B homologs of the Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV8) and Old World primate rhadinoviruses of chimpanzees and macaques

PubMed Central

Bruce, A. Gregory; Horst, Jeremy A.; Rose, Timothy M.

2016-01-01

The envelope-associated glycoprotein B (gB) is highly conserved within the Herpesviridae and plays a critical role in viral entry. We analyzed the evolutionary conservation of sequence and structural motifs within the Kaposi’s sarcoma-associated herpesvirus (KSHV) gB and homologs of Old World primate rhadinoviruses belonging to the distinct RV1 and RV2 rhadinovirus lineages. In addition to gB homologs of rhadinoviruses infecting the pig-tailed and rhesus macaques, we cloned and sequenced gB homologs of RV1 and RV2 rhadinoviruses infecting chimpanzees. A structural model of the KSHV gB was determined, and functional motifs and sequence variants were mapped to the model structure. Conserved domains and motifs were identified, including an “RGD” motif that plays a critical role in KSHV binding and entry through the cellular integrin αVβ3. The RGD motif was only detected in RV1 rhadinoviruses suggesting an important difference in cell tropism between the two rhadinovirus lineages. PMID:27070755

Gammaherpesvirus Infection of Human Neuronal Cells

PubMed Central

Jha, Hem Chandra; Mehta, Devan; Lu, Jie; El-Naccache, Darine; Shukla, Sanket K.; Kovacsics, Colleen; Kolson, Dennis

2015-01-01

ABSTRACT Gammaherpesviruses human herpesvirus 4 (HHV4) and HHV8 are two prominent members of the herpesvirus family associated with a number of human cancers. HHV4, also known as Epstein-Barr virus (EBV), a ubiquitous gammaherpesvirus prevalent in 90 to 95% of the human population, is clinically associated with various neurological diseases such as primary central nervous system lymphoma, multiple sclerosis, Alzheimer’s disease, cerebellar ataxia, and encephalitis. However, the possibility that EBV and Kaposi’s sarcoma-associated herpesvirus (KSHV) can directly infect neurons has been largely overlooked. This study has, for the first time, characterized EBV infection in neural cell backgrounds by using the Sh-Sy5y neuroblastoma cell line, teratocarcinoma Ntera2 neurons, and primary human fetal neurons. Furthermore, we also demonstrated KSHV infection of neural Sh-Sy5y cells. These neuronal cells were infected with green fluorescent protein-expressing recombinant EBV or KSHV. Microscopy, genetic analysis, immunofluorescence, and Western blot analyses for specific viral antigens supported and validated the infection of these cells by EBV and KSHV and showed that the infection was efficient and productive. Progeny virus produced from infected neuronal cells efficiently infected fresh neuronal cells, as well as peripheral blood mononuclear cells. Furthermore, acyclovir was effective at inhibiting the production of virus from neuronal cells similar to lymphoblastoid cell lines; this suggests active lytic replication in infected neurons in vitro. These studies represent a potentially new in vitro model of EBV- and KSHV-associated neuronal disease development and pathogenesis. PMID:26628726

Molecular piracy: manipulation of the ubiquitin system by Kaposi's sarcoma-associated herpesvirus.

PubMed

Fujimuro, Masahiro; Hayward, S Diane; Yokosawa, Hideyoshi

2007-01-01

Ubiquitination, one of several post-translational protein modifications, plays a key role in the regulation of cellular events, including protein degradation, signal transduction, endocytosis, protein trafficking, apoptosis and immune responses. Ubiquitin attachment at the lysine residue of cellular factors acts as a signal for endocytosis and rapid degradation by the 26S proteasome. It has recently been observed that viruses, especially oncogenic herpesviruses, utilise molecular piracy by encoding their own proteins to interfere with regulation of cell signalling. Kaposi's sarcoma- associated herpesvirus (KSHV) manipulates the ubiquitin system to facilitate cell proliferation, anti-apoptosis and evasion from immunity. In this review, we will describe the strategies used by KSHV at distinct stages of the viral life-cycle to control the ubiquitin system and promote oncogenesis and viral persistence. (c) 2007 John Wiley & Sons, Ltd.

A SHORT SEQUENCE IMMEDIATELY UPSTREAM OF THE INTERNAL REPEAT ELEMENTS IS CRITICAL FOR KSHV LANA MEDIATED DNA REPLICATION AND IMPACTS EPISOME PERSISTENCE

PubMed Central

León Vázquez, Erika De; Juillard, Franceline; Rosner, Bernard; Kaye, Kenneth M.

2013-01-01

Kaposi’s sarcoma-associated herpesvirus LANA (1162 residues) mediates episomal persistence of viral genomes during latency. LANA mediates viral DNA replication and segregates episomes to daughter nuclei. A 59 residue deletion immediately upstream of the internal repeat elements rendered LANA highly deficient for DNA replication and modestly deficient for the ability to segregate episomes, while smaller deletions did not. The 59 amino acid deletion reduced LANA episome persistence by ~14-fold, while sequentially smaller deletions resulted in ~3-fold, or no deficiency. Three distinct LANA regions reorganized heterochromatin, one of which contains the deleted sequence, but the deletion did not abolish LANA’s ability to alter chromatin. Therefore, this work identifies a short internal LANA sequence that is critical for DNA replication, has modest effects on episome segregation, and substantially impacts episome persistence; this region may exert its effects through an interacting host cell protein(s). PMID:24314665

Lytic and latent antigens of the human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus induce T-cell responses with similar functional properties and memory phenotypes.

PubMed

Bihl, Florian; Narayan, Murli; Chisholm, John V; Henry, Leah M; Suscovich, Todd J; Brown, Elizabeth E; Welzel, Tania M; Kaufmann, Daniel E; Zaman, Tauheed M; Dollard, Sheila; Martin, Jeff N; Wang, Fred; Scadden, David T; Kaye, Kenneth M; Brander, Christian

2007-05-01

The cellular immunity against Kaposi's sarcoma-associated herpesvirus (KSHV) is poorly characterized and has not been compared to T-cell responses against other human herpesviruses. Here, novel and dominant targets of KSHV-specific cellular immunity are identified and compared to T cells specific for lytic and latent antigens in a second human gammaherpesvirus, Epstein-Barr virus. The data identify a novel HLA-B57- and HLA-B58-restricted epitope in the Orf57 protein and show consistently close parallels in immune phenotypes and functional response patterns between cells targeting lytic or latent KSHV- and EBV-encoded antigens, suggesting common mechanisms in the induction of these responses.

Prevalence of Kaposi's sarcoma-associated herpesvirus among intravenous drug users: a systematic review and meta-analysis.

PubMed

Fang, Qiwen; Liu, Zhenqiu; Zhang, Zhijie; Zeng, Yan; Zhang, Tiejun

2017-10-01

Intravenous drug users (IDUs) have been demonstrated to be highly vulnerable to HIV/AIDS. Nevertheless, the prevalence of Kaposi's sarcoma associated herpesvirus (KSHV), an important co-infected agent with HIV, among this population remained obscure. We conducted a systematic review on the epidemiological features of KSHV among IDUs worldwide. Eligible studies were retrieved from 6 electronic databases (PubMed, EMBASE, Web of Science, CBM, CNKI and Wanfang). We calculated the pooled prevalence and 95% confidence interval (CI) overall and among subgroups using either random-effects model or fixed-effects model depending on between-study heterogeneity. The potential publication bias was assessed by the Egger's test. A meta-regression analysis was performed to explore the sources of heterogeneity. Finally, twenty-two studies with a total sample of 7881 IDUs were included in the analysis. The pooled prevalence of KSHV was 14.71% (95% CI 11.12%-19.46%) among IDUs. Specifically, KSHV prevalence was 10.86% (95% CI 6.95%-16.96%) in HIV-negative IDUs, and 13.56% (95% CI 10.57%-17.38%) in HIV-positive IDUs. Moreover, prevalence among IDUs from the three continents involved in the current study was similar: 16.10% (95%CI 7.73%-33.54%) in Asia; 14.22% (95%CI 8.96%-22.57%) in Europe and 14.06% (95%CI 11.38%-17.37%) in America. Globally, IDUs are at higher risk of the KSHV infection when compared with the general population, regardless of geographical region or HIV-infection status.

Lytic and Latent Antigens of the Human Gammaherpesviruses Kaposi's Sarcoma-Associated Herpesvirus and Epstein-Barr Virus Induce T-Cell Responses with Similar Functional Properties and Memory Phenotypes▿

PubMed Central

Bihl, Florian; Narayan, Murli; Chisholm, John V.; Henry, Leah M.; Suscovich, Todd J.; Brown, Elizabeth E.; Welzel, Tania M.; Kaufmann, Daniel E.; Zaman, Tauheed M.; Dollard, Sheila; Martin, Jeff N.; Wang, Fred; Scadden, David T.; Kaye, Kenneth M.; Brander, Christian

2007-01-01

The cellular immunity against Kaposi's sarcoma-associated herpesvirus (KSHV) is poorly characterized and has not been compared to T-cell responses against other human herpesviruses. Here, novel and dominant targets of KSHV-specific cellular immunity are identified and compared to T cells specific for lytic and latent antigens in a second human gammaherpesvirus, Epstein-Barr virus. The data identify a novel HLA-B57- and HLA-B58-restricted epitope in the Orf57 protein and show consistently close parallels in immune phenotypes and functional response patterns between cells targeting lytic or latent KSHV- and EBV-encoded antigens, suggesting common mechanisms in the induction of these responses. PMID:17329344

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

Watanabe, Tadashi; Nakamura, Shigeo; Ono, Toshiya

Highlights: • Seven fullerenes were evaluated in terms of their cytotoxic effects on B-lymphomas. • Pyrrolidinium fullerene induced apoptosis of KSHV-infected B-lymphoma PEL cells. • The activation of Akt is essential for PEL cell survival. • Pyrrolidinium fullerene activated caspase-9 by inactivating Akt in PEL cells. • Pyrrolidinium fullerene have potential as novel drugs for the treatment of PEL. - Abstract: Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin’s B-cell lymphoma and is an aggressive neoplasm caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. In general, PEL cells are derived from post-germinal center B-cells and are infected withmore » KSHV. To evaluate potential novel anti-tumor compounds against KSHV-associated PEL, seven water-soluble fullerene derivatives were evaluated as potential drug candidates for the treatment of PEL. Herein, we discovered a pyrrolidinium fullerene derivative, 1,1,1′,1′-tetramethyl [60]fullerenodipyrrolidinium diiodide, which induced apoptosis of PEL cells via a novel mechanism, the caspase-9 activation by suppressing the caspase-9 phosphorylation, causing caspase-9 inactivation. Pyrrolidinium fullerene treatment reduced significantly the viability of PEL cells compared with KSHV-uninfected lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage. Pyrrolidinium fullerene additionally reduced the Ser473 phosphorylation of Akt and Ser196 of procaspase-9. Ser473-phosphorylated Akt (i.e., activated Akt) phosphorylates Ser196 in procaspase-9, causing inactivation of procaspase-9. We also demonstrated that Akt inhibitors suppressed the proliferation of PEL cells compared with KSHV-uninfected cells. Our data therefore suggest that Akt activation is essential for cell survival in PEL and a pyrrolidinium fullerene derivative induced apoptosis by activating caspase-9 via suppression of Akt in PEL cells. In addition, we evaluated whether pyrrolidinium fullerene in combination with the HSP90 inhibitor (geldanamycin; GA) or valproate, potentiated the cytotoxic effects on PEL cells. Compared to treatment with pyrrolidinium fullerene alone, the addition of low-concentration GA or valproate enhanced the cytotoxic activity of pyrrolidinium fullerene. These results indicate that pyrrolidinium fullerene could be used as a novel therapy for the treatment of PEL.« less

Kaposi’s Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration

PubMed Central

Giffin, Louise; West, John A.

2015-01-01

ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of human Kaposi’s sarcoma, a tumor that arises from endothelial cells, as well as two B cell lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman’s disease. KSHV utilizes a variety of mechanisms to evade host immune responses and promote cellular transformation and growth in order to persist for the life of the host. A viral homolog of human interleukin-6 (hIL-6) named viral interleukin-6 (vIL-6) is encoded by KSHV and expressed in KSHV-associated cancers. Similar to hIL-6, vIL-6 is secreted, but the majority of vIL-6 is retained within the endoplasmic reticulum, where it can initiate functional signaling through part of the interleukin-6 receptor complex. We sought to determine how intracellular vIL-6 modulates the host endothelial cell environment by analyzing vIL-6’s impact on the endothelial cell transcriptome. vIL-6 significantly altered the expression of many cellular genes associated with cell migration. In particular, vIL-6 upregulated the host factor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) at the protein and message levels. CEACAM1 has been implicated in tumor invasion and metastasis and promotes migration and vascular remodeling in endothelial cells. We report that vIL-6 upregulates CEACAM1 by a STAT3-dependent mechanism and that CEACAM1 promotes vIL-6-mediated migration. Furthermore, latent and de novo KSHV infections of endothelial cells also induce CEACAM1 expression. Collectively, our data suggest that vIL-6 modulates endothelial cell migration by upregulating the expression of cellular factors, including CEACAM1. PMID:26646010

Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes.

PubMed

Liang, Xiaozhen; Collins, Christopher M; Mendel, Justin B; Iwakoshi, Neal N; Speck, Samuel H

2009-11-01

Gammaherpesviruses chronically infect their host and are tightly associated with the development of lymphoproliferative diseases and lymphomas, as well as several other types of cancer. Mechanisms involved in maintaining chronic gammaherpesvirus infections are poorly understood and, in particular, little is known about the mechanisms involved in controlling gammaherpesvirus reactivation from latently infected B cells in vivo. Recent evidence has linked plasma cell differentiation with reactivation of the human gammaherpesviruses EBV and KSHV through induction of the immediate-early viral transcriptional activators by the plasma cell-specific transcription factor XBP-1s. We now extend those findings to document a role for a gammaherpesvirus gene product in regulating plasma cell differentiation and thus virus reactivation. We have previously shown that the murine gammaherpesvirus 68 (MHV68) gene product M2 is dispensable for virus replication in permissive cells, but plays a critical role in virus reactivation from latently infected B cells. Here we show that in mice infected with wild type MHV68, virus infected plasma cells (ca. 8% of virus infected splenocytes at the peak of viral latency) account for the majority of reactivation observed upon explant of splenocytes. In contrast, there is an absence of virus infected plasma cells at the peak of latency in mice infected with a M2 null MHV68. Furthermore, we show that the M2 protein can drive plasma cell differentiation in a B lymphoma cell line in the absence of any other MHV68 gene products. Thus, the role of M2 in MHV68 reactivation can be attributed to its ability to manipulate plasma cell differentiation, providing a novel viral strategy to regulate gammaherpesvirus reactivation from latently infected B cells. We postulate that M2 represents a new class of herpesvirus gene products (reactivation conditioners) that do not directly participate in virus replication, but rather facilitate virus reactivation by manipulating the cellular milieu to provide a reactivation competent environment.

Combination of Arsenic and Interferon-α Inhibits Expression of KSHV Latent Transcripts and Synergistically Improves Survival of Mice with Primary Effusion Lymphomas

PubMed Central

El Hajj, Hiba; Ali, Jihane; Ghantous, Akram; Hodroj, Dana; Daher, Ahmad; Zibara, Kazem; Journo, Chloé; Otrock, Zaher; Zaatari, Ghazi; Mahieux, Renaud; El Sabban, Marwan; Bazarbachi, Ali; Abou Merhi, Raghida

2013-01-01

Background Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphomas (PEL). PEL cell lines infected with KSHV, but negative for Epstein-Barr virus have a tumorigenic potential in non-obese diabetic/severe combined immunodeficient mice and result in efficient engraftment and formation of malignant ascites with notable abdominal distension, consistent with the clinical manifestations of PEL in humans. Methodology/Principal Findings Using this preclinical mouse model, we demonstrate that the combination of arsenic trioxide and interferon-alpha (IFN) inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, v-FLIP and v-Cyc in PEL cells derived from malignant ascites. Furthermore, this combination decreases the peritoneal volume and synergistically increases survival of PEL mice. Conclusion/Significance These results provide a promising rationale for the therapeutic use of arsenic/IFN in PEL patients. PMID:24250827

Combination of arsenic and interferon-α inhibits expression of KSHV latent transcripts and synergistically improves survival of mice with primary effusion lymphomas.

PubMed

El Hajj, Hiba; Ali, Jihane; Ghantous, Akram; Hodroj, Dana; Daher, Ahmad; Zibara, Kazem; Journo, Chloé; Otrock, Zaher; Zaatari, Ghazi; Mahieux, Renaud; El Sabban, Marwan; Bazarbachi, Ali; Abou Merhi, Raghida

2013-01-01

Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphomas (PEL). PEL cell lines infected with KSHV, but negative for Epstein-Barr virus have a tumorigenic potential in non-obese diabetic/severe combined immunodeficient mice and result in efficient engraftment and formation of malignant ascites with notable abdominal distension, consistent with the clinical manifestations of PEL in humans. Using this preclinical mouse model, we demonstrate that the combination of arsenic trioxide and interferon-alpha (IFN) inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, v-FLIP and v-Cyc in PEL cells derived from malignant ascites. Furthermore, this combination decreases the peritoneal volume and synergistically increases survival of PEL mice. These results provide a promising rationale for the therapeutic use of arsenic/IFN in PEL patients.

The Conundrum of Causality in Tumor Virology: The Cases of KSHV and MCV

PubMed Central

Moore, Patrick S.; Chang, Yuan

2014-01-01

Controversy has plagued tumor virology since the first tumor viruses were described over 100 years ago. Methods to establish cancer causation, such as Koch’s postulates, work poorly or not at all for these viruses. Kaposi’s sarcoma herpesvirus (KSHV/HHV8) and Merkel cell polyomavirus (MCV) were both found using nucleic acid identification methods but they represent opposite poles in the patterns for tumor virus epidemiology. KSHV is uncommon and has specific risk factors that contribute to infection and subsequent cancers. MCV and Merkel cell carcinoma (MCC), in contrast, is an example in which mutations to our normal viral flora contribute to cancer. Given the near-ubiquity of human MCV infection, establishing cancer causality relies on molecular evidence that does not fit comfortably within traditional infectious disease epidemiological models. These two viruses reveal some of the challenges and opportunities for inferring viral cancer causation in the age of molecular biology. PMID:24304907

Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6.

PubMed

Aoki, Y; Jones, K D; Tosato, G

2000-04-01

Since the discovery of the virus in 1994, the rapid pace with which Karposi's sarcoma-associated herpesvirus (KSHV) research has progressed has quickly led to a broad understanding of the structure of the virus and its biology and pathology in humans. Molecular piracy of potentially useful cellular genes has emerged as a characteristic feature of this virus. The viral homolog of human IL-6, vIL-6 is an example in kind. Studies in vitro and in vivo have shown that vIL-6 can stimulate the growth of KSHV-infected primary infusion lymphoma (PEL) cells, can promote hematopoiesis, and act as an angiogenic factor through the induction of vascular endothelial growth factor (VEGF). It is not difficult to envision how vIL-6, through these properties and perhaps others yet to be identified, can contribute to KSHV survival and spread in the human population.

Using Proteomics to Identify Viral microRNA-Regulated Genes | Center for Cancer Research

Cancer.gov

Kaposi sarcoma is a soft tissue malignancy that affects the skin, the mucous membranes, the lymph nodes and other organs of individuals with compromised immune systems. It is caused by infection with human herpesvirus-8 also known as Kaposi sarcoma-associated herpesvirus or KSHV. The herpesvirus family is unique in that it is the only viral family currently known to express multiple microRNAs (miRNAs); KSHV produces 12 pre-miRNAs, which are processed into at least 25 mature miRNAs. While their functions are not well understood, these miRNAs may be a way for the virus to alter the host immune response without producing proteins that could be recognized and targeted by the immune system. Joseph Ziegelbauer, Ph.D., in CCR’s HIV and AIDS Malignancy Branch, and his colleagues set out to identify human targets of KSHV miRNAs and to understand their functional importance.

Ceramides promote apoptosis for virus-infected lymphoma cells through induction of ceramide synthases and viral lytic gene expression

PubMed Central

Dai, Lu; Trillo-Tinoco, Jimena; Bai, Aiping; Chen, Yihan; Bielawski, Jacek; Del Valle, Luis; Smith, Charles D.; Ochoa, Augusto C.; Qin, Zhiqiang; Parsons, Chris

2015-01-01

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent for several human cancers including primary effusion lymphoma (PEL), a rapidly progressive malignancy arising preferentially in immunocompromised patients. With conventional chemotherapy, PEL continues to portend high mortality, dictating the development of novel therapeutic strategies. Sphingosine kinase 2 (SphK2) represents a key gatekeeper for sphingolipid metabolism, responsible for conversion of ceramides to sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to intracellular accumulation of ceramides and induces apoptosis for KSHV-infected PEL cells, while suppressing tumor progression in vivo. In the current study, we sought to determine whether specific ceramide/dh-ceramide species and related ceramide synthases (CerS) impact viability for KSHV-infected PEL cells during targeting of SphK2. We found that several specific ceramide and dihydro(dh)-ceramide species and their associated CerS reduce PEL survival and tumor expansion in vitro and in vivo. Moreover, we found that dhC16-Cer induces PEL apoptosis in part through activation of KSHV lytic gene expression. These data further implicate bioactive sphingolipids in regulation of PEL survival, and provide justification for future studies evaluating clinically relevant ceramide analogs or mimetics for their potential as therapeutic agents for PEL. PMID:26327294

Detection and quantitation of Kaposi's sarcoma-associated herpesvirus (KSHV) by a single competitive-quantitative polymerase chain reaction.

PubMed

Curreli, Francesca; Robles, Monica A; Friedman-Kien, Alvin E; Flore, Ornella

2003-02-01

Kaposi's sarcoma-associated herpesvirus is a novel herpesvirus linked to AIDS-related neoplasms. Currently it is difficult to evaluate the number of virions in viral preparation or in samples obtained from patients with Kaposi's sarcoma (KS), since no protocol for determining the plaque forming units of KSHV exists. We constructed a fragment of a different size than the target viral DNA to carry out a competitive-quantitative PCR. Both fragment and viral DNA were added to a single PCR reaction to compete for the same set of primers. By knowing the amount of the competitor added to the reaction, we could determine the number of viral DNA molecules. We used this assay successfully to detect and quantify KSHV genomes from KS skin biopsies and pleural effusion lymphoma, and from different viral preparations. To date, this is the most convenient and economic method that allows an accurate and fast viral detection/quantitation with a single PCR.

The conundrum of causality in tumor virology: the cases of KSHV and MCV.

PubMed

Moore, Patrick S; Chang, Yuan

2014-06-01

Controversy has plagued tumor virology since the first tumor viruses were described over 100 years ago. Methods to establish cancer causation, such as Koch's postulates, work poorly or not at all for these viruses. Kaposi's sarcoma herpesvirus (KSHV/HHV8) and Merkel cell polyomavirus (MCV) were both found using nucleic acid identification methods but they represent opposite poles in the patterns for tumor virus epidemiology. KSHV is uncommon and has specific risk factors that contribute to infection and subsequent cancers. MCV and Merkel cell carcinoma (MCC), in contrast, is an example in which mutations to our normal viral flora contribute to cancer. Given the near-ubiquity of human MCV infection, establishing cancer causality relies on molecular evidence that does not fit comfortably within traditional infectious disease epidemiological models. These two viruses reveal some of the challenges and opportunities for inferring viral cancer causation in the age of molecular biology. Copyright © 2013 Elsevier Ltd. All rights reserved.

Attenuation of the suppressive activity of cellular splicing factor SRSF3 by Kaposi sarcoma–associated herpesvirus ORF57 protein is required for RNA splicing

PubMed Central

Majerciak, Vladimir; Lu, Mathew; Li, Xiaofan

2014-01-01

Kaposi sarcoma–associated herpesvirus (KSHV) ORF57 is a multifunctional post-transcriptional regulator essential for viral gene expression during KSHV lytic infection. ORF57 requires interactions with various cellular proteins for its function. Here, we identified serine/arginine-rich splicing factor 3 (SRSF3, formerly known as SRp20) as a cellular cofactor involved in ORF57-mediated splicing of KSHV K8β RNA. In the absence of ORF57, SRSF3 binds to a suboptimal K8β intron and inhibits K8β splicing. Knockdown of SRSF3 promotes K8β splicing, mimicking the effect of ORF57. The N-terminal half of ORF57 binds to the RNA recognition motif of SRSF3, which prevents SRSF3 from associating with the K8β intron RNA and therefore attenuates the suppressive effect of SRSF3 on K8β splicing. ORF57 also promotes splicing of heterologous non-KSHV transcripts that are negatively regulated by SRSF3, indicating that the effect of ORF57 on SRSF3 activity is independent of RNA target. SPEN proteins, previously identified as ORF57-interacting partners, suppress ORF57 splicing activity by displacing ORF57 from SRSF3–RNA complexes. In summary, we have identified modulation of SRSF3 activity as the molecular mechanism by which ORF57 promotes RNA splicing. PMID:25234929

Attenuation of the suppressive activity of cellular splicing factor SRSF3 by Kaposi sarcoma-associated herpesvirus ORF57 protein is required for RNA splicing.

PubMed

Majerciak, Vladimir; Lu, Mathew; Li, Xiaofan; Zheng, Zhi-Ming

2014-11-01

Kaposi sarcoma-associated herpesvirus (KSHV) ORF57 is a multifunctional post-transcriptional regulator essential for viral gene expression during KSHV lytic infection. ORF57 requires interactions with various cellular proteins for its function. Here, we identified serine/arginine-rich splicing factor 3 (SRSF3, formerly known as SRp20) as a cellular cofactor involved in ORF57-mediated splicing of KSHV K8β RNA. In the absence of ORF57, SRSF3 binds to a suboptimal K8β intron and inhibits K8β splicing. Knockdown of SRSF3 promotes K8β splicing, mimicking the effect of ORF57. The N-terminal half of ORF57 binds to the RNA recognition motif of SRSF3, which prevents SRSF3 from associating with the K8β intron RNA and therefore attenuates the suppressive effect of SRSF3 on K8β splicing. ORF57 also promotes splicing of heterologous non-KSHV transcripts that are negatively regulated by SRSF3, indicating that the effect of ORF57 on SRSF3 activity is independent of RNA target. SPEN proteins, previously identified as ORF57-interacting partners, suppress ORF57 splicing activity by displacing ORF57 from SRSF3-RNA complexes. In summary, we have identified modulation of SRSF3 activity as the molecular mechanism by which ORF57 promotes RNA splicing. Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Chromatin Immunoprecipitation and Microarray Analysis Suggest Functional Cooperation between Kaposi's Sarcoma-Associated Herpesvirus ORF57 and K-bZIP

PubMed Central

Hunter, Olga V.; Sei, Emi; Richardson, R. Blake

2013-01-01

The Kaposi's sarcoma-associated herpesvirus (KSHV) open reading frame 57 (ORF57)-encoded protein (Mta) is a multifunctional regulator of viral gene expression. ORF57 is essential for viral replication, so elucidation of its molecular mechanisms is important for understanding KSHV infection. ORF57 has been implicated in nearly every aspect of viral gene expression, including transcription, RNA stability, splicing, export, and translation. Here we demonstrate that ORF57 interacts with the KSHV K-bZIP protein in vitro and in cell extracts from lytically reactivated infected cells. To further test the biological relevance of the interaction, we performed a chromatin immunoprecipitation and microarray (ChIP-chip) analysis using anti-ORF57 antibodies and a KSHV tiling array. The results revealed four specific areas of enrichment, including the ORF4 and K8 (K-bZIP) promoters, as well as oriLyt, all of which interact with K-bZIP. In addition, ORF57 associated with DNA corresponding to the PAN RNA transcribed region, a known posttranscriptional target of ORF57. All of the peaks were RNase insensitive, demonstrating that ORF57 association with the viral genome is unlikely to be mediated exclusively by an RNA tether. Our data demonstrate that ORF57 associates with the viral genome by using at least two modes of recruitment, and they suggest that ORF57 and K-bZIP coregulate viral gene expression during lytic infection. PMID:23365430

Arctigenin induces the apoptosis of primary effusion lymphoma cells under conditions of glucose deprivation.

PubMed

Baba, Yusuke; Shigemi, Zenpei; Hara, Naoko; Moriguchi, Misato; Ikeda, Marina; Watanabe, Tadashi; Fujimuro, Masahiro

2018-02-01

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of primary effusion lymphoma (PEL) and Kaposi's sarcoma. PEL is a type of non-Hodgkin's B-cell lymphoma, affecting immunosuppressed individuals, such as post-transplant or AIDS patients. However, since PEL is resistant to chemotherapeutic regimens, new effective treatment strategies are required. Arctigenin, a natural lignan compound found in the plant Arctium lappa, has been widely investigated as a potential anticancer agent in the clinical setting. In the present study, we examined the cytotoxic effects of arctigenin by cell viability assay and found that arctigenin markedly inhibited the proliferation of PEL cells compared with KSHV-uninfected B-lymphoma cells under conditions of glucose deprivation. Arctigenin decreased cellular ATP levels, disrupted mitochondrial membrane potential and triggered caspase-9-mediated apoptosis in the glucose-deprived PEL cells. In addition, western blot analysis using phospho-specific antibodies were used to evaluate activity changes in the signaling pathways of interest. As a result, arctigenin suppressed the activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways by inhibiting ERK and p38 MAPK phosphorylation in the glucose-deprived PEL cells. We confirmed that an inhibitor of ERK (U0126) or p38 MAPK (SB202190 and SB203580) suppressed the proliferation of the BC3 PEL cells compared with the KSHV-negative DG75 cells. Moreover, RT-PCR and luciferase reporter assay revealed that arctigenin and p38 MAPK inhibition by SB202190 or SB203580 downregulated the transcriptional expression of unfolded protein response (UPR)‑related molecules, including GRP78 and ATF6α under conditions of glucose deprivation. Finally, we confirmed that arctigenin did not affect KSHV replication in PEL cells, suggesting that arctigenin treatment for PEL does not contribute to the risk of de novo KSHV production. These data thus indicate that arctigenin may serve as a lead compound for the development of novel and effective drugs for the treatment of PEL.

Fragment-based protein-protein interaction antagonists of a viral dimeric protease

PubMed Central

Gable, Jonathan E.; Lee, Gregory M.; Acker, Timothy M.; Hulce, Kaitlin R.; Gonzalez, Eric R.; Schweigler, Patrick; Melkko, Samu; Farady, Christopher J.; Craik, Charles S.

2016-01-01

Fragment-based drug discovery has shown promise as an approach for challenging targets such as protein-protein interfaces. We developed and applied an activity-based fragment screen against dimeric Kaposi’s sarcoma-associated herpesvirus protease (KSHV Pr) using an optimized fluorogenic substrate. Dose response determination was performed as a confirmation screen and NMR spectroscopy was used to map fragment inhibitor binding to KSHV Pr. Kinetic assays demonstrated that several initial hits also inhibit human cytomegalovirus protease (HCMV Pr). Binding of these hits to HCMV Pr was also confirmed via NMR spectroscopy. Despite the use of a target-agnostic fragment library, more than 80% of confirmed hits disrupted dimerization and bound to a previously reported pocket at the dimer interface of KSHV Pr, not to the active site. One class of fragments, an aminothiazole scaffold, was further explored using commercially available analogs. These compounds demonstrated greater than 100-fold improvement of inhibition. This study illustrates the power of fragment-based screening for these challenging enzymatic targets and provides an example of the potential druggability of pockets at protein-protein interfaces. PMID:26822284

Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envelope glycoprotein

PubMed Central

Chatterjee, Deboeeta; Chandran, Bala

2012-01-01

Kaposi sarcoma-associated herpesvirus (KSHV, human herpesvirus 8) is etiologically associated with three neoplastic syndromes: Kaposi sarcoma and the uncommon HIV-associated B-cell lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman disease. The incidence of the latter B-cell pathology has been increasing in spite of antiretroviral therapy; its association with lytic virus replication has prompted interest in therapeutic strategies aimed at this phase of the virus life cycle. We designed and expressed a recombinant immunotoxin (2014-PE38) targeting the gpK8.1A viral glycoprotein expressed on the surface of the virion and infected cells. We show that this immunotoxin selectively kills KSHV-infected cells in dose-dependent fashion, resulting in major reductions of infectious virus release. The immunotoxin and ganciclovir, an inhibitor of viral DNA replication, showed marked reciprocal potentiation of antiviral activities. These results suggest that the immunotoxin, alone or in combination, may represent a new approach to treat diseases associated with KSHV lytic replication. PMID:22377676

Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8)

PubMed Central

Russo, James J.; Bohenzky, Roy A.; Chien, Ming-Cheng; Chen, Jing; Yan, Ming; Maddalena, Dawn; Parry, J. Preston; Peruzzi, Daniela; Edelman, Isidore S.; Chang, Yuan; Moore, Patrick S.

1996-01-01

The genome of the Kaposi sarcoma-associated herpesvirus (KSHV or HHV8) was mapped with cosmid and phage genomic libraries from the BC-1 cell line. Its nucleotide sequence was determined except for a 3-kb region at the right end of the genome that was refractory to cloning. The BC-1 KSHV genome consists of a 140.5-kb-long unique coding region flanked by multiple G+C-rich 801-bp terminal repeat sequences. A genomic duplication that apparently arose in the parental tumor is present in this cell culture-derived strain. At least 81 ORFs, including 66 with homology to herpesvirus saimiri ORFs, and 5 internal repeat regions are present in the long unique region. The virus encodes homologs to complement-binding proteins, three cytokines (two macrophage inflammatory proteins and interleukin 6), dihydrofolate reductase, bcl-2, interferon regulatory factors, interleukin 8 receptor, neural cell adhesion molecule-like adhesin, and a D-type cyclin, as well as viral structural and metabolic proteins. Terminal repeat analysis of virus DNA from a KS lesion suggests a monoclonal expansion of KSHV in the KS tumor. PMID:8962146

The Role of Gammaherpesviruses in Cancer Pathogenesis

PubMed Central

Jha, Hem Chandra; Banerjee, Shuvomoy; Robertson, Erle S.

2016-01-01

Worldwide, one fifth of cancers in the population are associated with viral infections. Among them, gammaherpesvirus, specifically HHV4 (EBV) and HHV8 (KSHV), are two oncogenic viral agents associated with a large number of human malignancies. In this review, we summarize the current understanding of the molecular mechanisms related to EBV and KSHV infection and their ability to induce cellular transformation. We describe their strategies for manipulating major cellular systems through the utilization of cell cycle, apoptosis, immune modulation, epigenetic modification, and altered signal transduction pathways, including NF-kB, Notch, Wnt, MAPK, TLR, etc. We also discuss the important EBV latent antigens, namely EBNA1, EBNA2, EBNA3’s and LMP’s, which are important for targeting these major cellular pathways. KSHV infection progresses through the engagement of the activities of the major latent proteins LANA, v-FLIP and v-Cyclin, and the lytic replication and transcription activator (RTA). This review is a current, comprehensive approach that describes an in-depth understanding of gammaherpes viral encoded gene manipulation of the host system through targeting important biological processes in viral-associated cancers. PMID:26861404

Histone H2B-IFI16 Recognition of Nuclear Herpesviral Genome Induces Cytoplasmic Interferon-β Responses

PubMed Central

Iqbal, Jawed; Ansari, Mairaj Ahmed; Kumar, Binod; Dutta, Dipanjan; Roy, Arunava; Chikoti, Leela; Pisano, Gina; Dutta, Sujoy; Veettil, Mohanan Valiya; Chandran, Bala

2016-01-01

IFI16 (gamma-interferon-inducible protein 16), a predominantly nuclear protein involved in transcriptional regulation, also functions as an innate immune response DNA sensor and induces the IL-1β and antiviral type-1 interferon-β (IFN-β) cytokines. We have shown that IFI16, in association with BRCA1, functions as a sequence independent nuclear sensor of episomal dsDNA genomes of KSHV, EBV and HSV-1. Recognition of these herpesvirus genomes resulted in IFI16 acetylation, BRCA1-IFI16-ASC-procaspase-1 inflammasome formation, cytoplasmic translocation, and IL-1β generation. Acetylated IFI16 also interacted with cytoplasmic STING and induced IFN-β. However, the identity of IFI16 associated nuclear proteins involved in STING activation and the mechanism is not known. Mass spectrometry of proteins precipitated by anti-IFI16 antibodies from uninfected endothelial cell nuclear lysate revealed that histone H2B interacts with IFI16. Single and double proximity ligation microscopy, immunoprecipitation, EdU-genome labeled virus infection, and chromatin immunoprecipitation studies demonstrated that H2B is associated with IFI16 and BRCA1 in the nucleus in physiological conditions. De novo KSHV and HSV-1 infection as well as latent KSHV and EBV infection induces the cytoplasmic distribution of H2B-IFI16, H2B-BRCA1 and IFI16-ASC complexes. Vaccinia virus (dsDNA) cytoplasmic replication didn’t induce the redistribution of nuclear H2B-IFI16 or H2B into the cytoplasm. H2B is critical in KSHV and HSV-1 genome recognition by IFI16 during de novo infection. Viral genome sensing by IFI16-H2B-BRCA1 leads to BRCA1 dependent recruitment of p300, and acetylation of H2B and IFI16. BRCA1 knockdown or inhibition of p300 abrogated the acetylation of H2B-IFI16 or H2B. Ran-GTP protein mediated the translocation of acetylated H2B and IFI16 to the cytoplasm along with BRCA1 that is independent of IFI16-ASC inflammasome. ASC knockdown didn’t affect the acetylation of H2B, its cytoplasmic transportation, and the association of STING with IFI16 and H2B during KSHV infection. Absence of H2B didn’t affect IFI16-ASC association and cytoplasmic distribution and thus demonstrating that IFI16-H2B complex is independent of IFI16-ASC-procaspase-1-inflammasome complex formed during infection. The H2B-IFI16-BRCA1 complex interacted with cGAS and STING in the cytoplasm leading to TBK1 and IRF3 phosphorylation, nuclear translocation of pIRF3 and IFN-β production. Silencing of H2B, cGAS and STING inhibited IFN-β induction but not IL-1β secretion, and cGAMP activity is significantly reduced by H2B and IFI16 knockdown during infection. Silencing of ASC inhibited IL-1β secretion but not IFN-β secretion during de novo KSHV and HSV-1 infection. These studies identify H2B as an innate nuclear sensor mediating a novel extra chromosomal function, and reveal that two IFI16 complexes mediate KSHV and HSV-1 genome recognition responses, with recognition by the IFI16-BRCA1-H2B complex resulting in IFN-β responses and recognition by IFI16-BRCA1 resulting in inflammasome responses. PMID:27764250

Short-Chain Fatty Acids from Periodontal Pathogens Suppress Histone Deacetylases, EZH2, and SUV39H1 To Promote Kaposi's Sarcoma-Associated Herpesvirus Replication

PubMed Central

Yu, Xiaolan; Shahir, Abdel-Malek; Sha, Jingfeng; Feng, Zhimin; Eapen, Betty; Nithianantham, Stanley; Das, Biswajit; Karn, Jonathan; Weinberg, Aaron; Bissada, Nabil F.

2014-01-01

ABSTRACT Periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum produce five different short-chain fatty acids (SCFAs) as metabolic by-products. We detect significantly higher levels of SCFAs in the saliva of patients with severe periodontal disease. The different SCFAs stimulate lytic gene expression of Kaposi's sarcoma-associated herpesvirus (KSHV) dose dependently and synergistically. SCFAs inhibit class-1/2 histone deacetylases (HDACs) and downregulate expression of silent information regulator-1 (SIRT1). SCFAs also downregulate expression of enhancer of zeste homolog2 (EZH2) and suppressor of variegation 3-9 homolog1 (SUV39H1), which are two histone N-lysine methyltransferases (HLMTs). By suppressing the different components of host epigenetic regulatory machinery, SCFAs increase histone acetylation and decrease repressive histone trimethylations to transactivate the viral chromatin. These new findings provide mechanistic support that SCFAs from periodontal pathogens stimulate KSHV replication and infection in the oral cavity and are potential risk factors for development of oral Kaposi's sarcoma (KS). IMPORTANCE About 20% of KS patients develop KS lesions first in the oral cavity, while other patients never develop oral KS. It is not known if the oral microenvironment plays a role in oral KS tumor development. In this work, we demonstrate that a group of metabolic by-products, namely, short-chain fatty acids, from bacteria that cause periodontal disease promote lytic replication of KSHV, the etiological agent associated with KS. These new findings provide mechanistic support that periodontal pathogens create a unique microenvironment in the oral cavity that contributes to KSHV replication and development of oral KS. PMID:24501407

Fragment-Based Protein-Protein Interaction Antagonists of a Viral Dimeric Protease.

PubMed

Gable, Jonathan E; Lee, Gregory M; Acker, Timothy M; Hulce, Kaitlin R; Gonzalez, Eric R; Schweigler, Patrick; Melkko, Samu; Farady, Christopher J; Craik, Charles S

2016-04-19

Fragment-based drug discovery has shown promise as an approach for challenging targets such as protein-protein interfaces. We developed and applied an activity-based fragment screen against dimeric Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr) using an optimized fluorogenic substrate. Dose-response determination was performed as a confirmation screen, and NMR spectroscopy was used to map fragment inhibitor binding to KSHV Pr. Kinetic assays demonstrated that several initial hits also inhibit human cytomegalovirus protease (HCMV Pr). Binding of these hits to HCMV Pr was also confirmed by NMR spectroscopy. Despite the use of a target-agnostic fragment library, more than 80 % of confirmed hits disrupted dimerization and bound to a previously reported pocket at the dimer interface of KSHV Pr, not to the active site. One class of fragments, an aminothiazole scaffold, was further explored using commercially available analogues. These compounds demonstrated greater than 100-fold improvement of inhibition. This study illustrates the power of fragment-based screening for these challenging enzymatic targets and provides an example of the potential druggability of pockets at protein-protein interfaces. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hierarchical regulation of the genome: global changes in nucleosome organization potentiate genome response

PubMed Central

Sexton, Brittany S.; Druliner, Brooke R.; Vera, Daniel L.; Avey, Denis; Zhu, Fanxiu; Dennis, Jonathan H.

2016-01-01

Nucleosome occupancy is critically important in regulating access to the eukaryotic genome. Few studies in human cells have measured genome-wide nucleosome distributions at high temporal resolution during a response to a common stimulus. We measured nucleosome distributions at high temporal resolution following Kaposi's-sarcoma-associated herpesvirus (KSHV) reactivation using our newly developed mTSS-seq technology, which maps nucleosome distribution at the transcription start sites (TSS) of all human genes. Nucleosomes underwent widespread changes in organization 24 hours after KSHV reactivation and returned to their basal nucleosomal architecture 48 hours after KSHV reactivation. The widespread changes consisted of an indiscriminate remodeling event resulting in the loss of nucleosome rotational phasing signals. Additionally, one in six TSSs in the human genome possessed nucleosomes that are translationally remodeled. 72% of the loci with translationally remodeled nucleosomes have nucleosomes that moved to positions encoded by the underlying DNA sequence. Finally we demonstrated that these widespread alterations in nucleosomal architecture potentiated regulatory factor binding. These descriptions of nucleosomal architecture changes provide a new framework for understanding the role of chromatin in the genomic response, and have allowed us to propose a hierarchical model for chromatin-based regulation of genome response. PMID:26771136

A systems biology approach identified different regulatory networks targeted by KSHV miR-K12-11 in B cells and endothelial cells.

PubMed

Yang, Yajie; Boss, Isaac W; McIntyre, Lauren M; Renne, Rolf

2014-08-08

Kaposi's sarcoma associated herpes virus (KSHV) is associated with tumors of endothelial and lymphoid origin. During latent infection, KSHV expresses miR-K12-11, an ortholog of the human tumor gene hsa-miR-155. Both gene products are microRNAs (miRNAs), which are important post-transcriptional regulators that contribute to tissue specific gene expression. Advances in target identification technologies and molecular interaction databases have allowed a systems biology approach to unravel the gene regulatory networks (GRNs) triggered by miR-K12-11 in endothelial and lymphoid cells. Understanding the tissue specific function of miR-K12-11 will help to elucidate underlying mechanisms of KSHV pathogenesis. Ectopic expression of miR-K12-11 differentially affected gene expression in BJAB cells of lymphoid origin and TIVE cells of endothelial origin. Direct miRNA targeting accounted for a small fraction of the observed transcriptome changes: only 29 genes were identified as putative direct targets of miR-K12-11 in both cell types. However, a number of commonly affected biological pathways, such as carbohydrate metabolism and interferon response related signaling, were revealed by gene ontology analysis. Integration of transcriptome profiling, bioinformatic algorithms, and databases of protein-protein interactome from the ENCODE project identified different nodes of GRNs utilized by miR-K12-11 in a tissue-specific fashion. These effector genes, including cancer associated transcription factors and signaling proteins, amplified the regulatory potential of a single miRNA, from a small set of putative direct targets to a larger set of genes. This is the first comparative analysis of miRNA-K12-11's effects in endothelial and B cells, from tissues infected with KSHV in vivo. MiR-K12-11 was able to broadly modulate gene expression in both cell types. Using a systems biology approach, we inferred that miR-K12-11 establishes its GRN by both repressing master TFs and influencing signaling pathways, to counter the host anti-viral response and to promote proliferation and survival of infected cells. The targeted GRNs are more reproducible and informative than target gene identification, and our approach can be applied to other regulatory factors of interest.

Project Review: Teleoperation and Time Delays

NASA Technical Reports Server (NTRS)

Adelstein, Bernard D.; Ellis, Stephen; Yeom, Kiwon; Kaiser, Mary K.

2013-01-01

We plan to study the invariance in the shift in control strategy from continuous control to move-and-wait as a function of latency and control difficulty. To do so we have developed a theoretically understood way of introducing measurable levels of control difficulty using misalignment between display and control axes . We now use this understanding to study the interaction of control difficulty and system latency. We have conducted an experiment to calibrate our imposition of control difficulty using more representative control rotations. We use these levels of difficulty to directly study the interaction of control difficulty with latency. Results suggest a way to generalize latency requirements across control difficulties that should aid establishment of standards for managing latency in teleoperation.

Identification and characterization of Kaposi's sarcoma-associated herpesvirus open reading frame 11 promotor activation

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

Chen, Lei

2008-01-01

Open reading frame 11 (ORF11) of Kaposi's sarcoma-associated herpesvirus belongs to a herpesviral homologous protein family shared by some members of the gamma- herpesvirus subfamily. Little is known about this ORF11 homologous protein family. We have characterized an unknown open reading frame, ORF11, located adjacent and in the opposite orientation to a well-characterized viral IL-6 gene. Northern blot analysis reveals that ORF11 is expressed during the KSHV lytic cycle with delayed-early transcription kinetics. We have determined the 5{prime} and 3{prime} untranslated region of the unspliced ORF11 transcript and identified both the transcription start site and the transcription termination site. Coremore » promoter region, representing ORF11 promoter activity, was mapped to a 159nt fragment 5{prime} most proximal to the transcription start site. A functional TATA box was identified in the core promoter region. Interestingly, we found that ORF11 transcriptional activation is not responsive to Rta, the KSHV lytic switch protein. We also discovered that part of the ORF11 promoter region, the 209nt fragment upstream of the transcription start site, was repressed by phorbol esters. Our data help to understand transcription regulation of ORF11 and to elucidate roles of ORF11 in KSHV pathogenesis and life cycle.« less

KS-Detect – Validation of Solar Thermal PCR for the Diagnosis of Kaposi’s Sarcoma Using Pseudo-Biopsy Samples

PubMed Central

Snodgrass, Ryan; Gardner, Andrea; Jiang, Li; Fu, Cheng; Cesarman, Ethel; Erickson, David

2016-01-01

Resource-limited settings present unique engineering challenges for medical diagnostics. Diagnosis is often needed for those unable to reach central healthcare systems, making portability and independence from traditional energy infrastructure essential device parameters. In 2014, our group presented a microfluidic device that performed a solar-powered variant of the polymerase chain reaction, which we called solar thermal PCR. In this work, we expand on our previous effort by presenting an integrated, portable, solar thermal PCR system targeted towards the diagnosis of Kaposi’s sarcoma. We call this system KS-Detect, and we now report the system’s performance as a diagnostic tool using pseudo-biopsy samples made from varying concentrations of human lymphoma cell lines positive for the KS herpesvirus (KSHV). KS-Detect achieved 83% sensitivity and 70% specificity at high (≥10%) KSHV+ cell concentrations when diagnosing pseudo-biopsy samples by smartphone image. Using histology, we confirm that our prepared pseudo-biopsies contain similar KSHV+ cell concentrations as human biopsies positive for KS. Through our testing of samples derived from human cell lines, we validate KS-Detect as a viable, portable KS diagnostic tool, and we identify critical engineering considerations for future solar-thermal PCR devices. PMID:26799834

Lipoteichoic acid (LTA) and lipopolysaccharides (LPS) from periodontal pathogenic bacteria facilitate oncogenic herpesvirus infection within primary oral cells.

PubMed

Dai, Lu; DeFee, Michael R; Cao, Yueyu; Wen, Jiling; Wen, Xiaofei; Noverr, Mairi C; Qin, Zhiqiang

2014-01-01

Kaposi's sarcoma (KS) remains the most common tumor arising in patients with HIV/AIDS, and involvement of the oral cavity represents one of the most common clinical manifestations of this tumor. HIV infection incurs an increased risk for periodontal diseases and oral carriage of a variety of bacteria. Whether interactions involving pathogenic bacteria and oncogenic viruses in the local environment facilitate replication or maintenance of these viruses in the oral cavity remains unknown. In the current study, our data indicate that pretreatment of primary human oral fibroblasts with two prototypical pathogen-associated molecular patterns (PAMPs) produced by oral pathogenic bacteria-lipoteichoic acid (LTA) and lipopolysaccharide (LPS), increase KSHV entry and subsequent viral latent gene expression during de novo infection. Further experiments demonstrate that the underlying mechanisms induced by LTA and/or LPS include upregulation of cellular receptor, increasing production of reactive oxygen species (ROS), and activating intracellular signaling pathways such as MAPK and NF-κB, and all of which are closely associated with KSHV entry or gene expression within oral cells. Based on these findings, we hope to provide the framework of developing novel targeted approaches for treatment and prevention of oral KSHV infection and KS development in high-risk HIV-positive patients.

Oncogenic Viral Prevalence in Invasive Vulvar Cancer Specimens from HIV Positive and Negative Women in Botswana

PubMed Central

Tesfalul, Martha; Simbiri, Kenneth; Wheat, Chikoti M.; Motsepe, Didintle; Goldbach, Hayley; Armstrong, Kathleen; Hudson, Kathryn; Kayembe, Mukendi K.; Robertson, Erle; Kovarik, Carrie

2014-01-01

Objective The primary aim of this study is to describe the prevalence of select oncogenic viruses within vulvar squamous cell carcinoma (VSCC) and their association with Human Immunodeficiency Virus (HIV) status in women in Botswana, where the national HIV prevalence is the third highest in the world. Methods/materials A cross-sectional study of biopsy-confirmed VSCC specimens and corresponding clinical data was conducted in Gaborone, Botswana. Polymerase Chain Reaction (PCR) and Immunohistochemistry (IHC) viral testing were done for Epstein-Barr Virus (EBV), Human Papilloma Virus (HPV) strains, and Kaposi's Sarcoma Herpesvirus (KSHV), and PCR viral testing alone was done for John Cunningham Virus (JCV). Results HPV prevalence by PCR was 100% (39/39 35/35) among tested samples. HPV16 was the most prevalent HPV strain (82.9% by PCR, 94.7% by either PCR or IHC). KSHV prevalence by PCR had a significant association with HIV status (p = 0.013), but not by IHC (p = 0.650). Conclusions The high burden of HPV, specifically HPV16, in VSCC in Botswana suggests a distinct HPV profile that differs from other studied populations, which provides increased motivation for HPV vaccination efforts. Oncogenic viruses KSHV and EBV were also more prevalent in our study population though their potential role in VSCC pathology is unclear. PMID:24651632

Multiplexed colorimetric detection of Kaposi's sarcoma associated herpesvirus and Bartonella DNA using gold and silver nanoparticles

NASA Astrophysics Data System (ADS)

Mancuso, Matthew; Jiang, Li; Cesarman, Ethel; Erickson, David

2013-01-01

Kaposi's sarcoma (KS) is an infectious cancer occurring most commonly in human immunodeficiency virus (HIV) positive patients and in endemic regions, such as Sub-Saharan Africa, where KS is among the top four most prevalent cancers. The cause of KS is the Kaposi's sarcoma-associated herpesvirus (KSHV, also called HHV-8), an oncogenic herpesvirus that while routinely diagnosed in developed nations, provides challenges to developing world medical providers and point-of-care detection. A major challenge in the diagnosis of KS is the existence of a number of other diseases with similar clinical presentation and histopathological features, requiring the detection of KSHV in a biopsy sample. In this work we develop an answer to this challenge by creating a multiplexed one-pot detection system for KSHV DNA and DNA from a frequently confounding disease, bacillary angiomatosis. Gold and silver nanoparticle aggregation reactions are tuned for each target and a multi-color change system is developed capable of detecting both targets down to levels between 1 nM and 2 nM. The system developed here could later be integrated with microfluidic sample processing to create a final device capable of solving the two major challenges in point-of-care KS detection.

Simian Homologues of Human Gamma-2 and Betaherpesviruses in Mandrill and Drill Monkeys

PubMed Central

Lacoste, Vincent; Mauclere, Philippe; Dubreuil, Guy; Lewis, John; Georges-Courbot, Marie-Claude; Rigoulet, Jacques; Petit, Thierry; Gessain, Antoine

2000-01-01

Recent serological and molecular surveys of different primate species allowed the characterization of several Kaposi's sarcoma-associated herpesvirus (KSHV) homologues in macaques, African green monkeys, chimpanzees, and gorillas. Identification of these new primate rhadinoviruses revealed the existence of two distinct genogroups, called RV1 and RV2. Using a degenerate consensus primer PCR method for the herpesvirus DNA polymerase gene, the presence of KSHV homologues has been investigated in two semi-free-ranging colonies of eight drill (Mandrillus leucophaeus), five mandrill (Mandrillus sphinx), and two hybrid (Mandrillus leucophaeus-Mandrillus sphinx) monkeys, living in Cameroon and Gabon, Central Africa. This search revealed the existence of not only two distinct KSHV homologues, each one belonging to one of the two rhadinovirus genogroups, but also of two new betaherpesvirus sequences, one being close to cytomegaloviruses and the other being related to human herpesviruses 6 and 7 (HHV-6 and -7). The latter viruses are the first simian HHV-6 and -7 homologues identified to date. These data show that mandrill and drill monkeys are the hosts of at least four novel distinct herpesviruses. Moreover, mandrills, like macaques and African green monkeys, harbor also two distinct gamma-2 herpesviruses, thus strongly suggesting that a second gamma-2 herpesvirus, belonging to the RV2 genogroup, may exist in humans. PMID:11090203

Lipoteichoic Acid (LTA) and Lipopolysaccharides (LPS) from Periodontal Pathogenic Bacteria Facilitate Oncogenic Herpesvirus Infection within Primary Oral Cells

PubMed Central

Dai, Lu; DeFee, Michael R.; Cao, Yueyu; Wen, Jiling; Wen, Xiaofei; Noverr, Mairi C.; Qin, Zhiqiang

2014-01-01

Kaposi’s sarcoma (KS) remains the most common tumor arising in patients with HIV/AIDS, and involvement of the oral cavity represents one of the most common clinical manifestations of this tumor. HIV infection incurs an increased risk for periodontal diseases and oral carriage of a variety of bacteria. Whether interactions involving pathogenic bacteria and oncogenic viruses in the local environment facilitate replication or maintenance of these viruses in the oral cavity remains unknown. In the current study, our data indicate that pretreatment of primary human oral fibroblasts with two prototypical pathogen-associated molecular patterns (PAMPs) produced by oral pathogenic bacteria–lipoteichoic acid (LTA) and lipopolysaccharide (LPS), increase KSHV entry and subsequent viral latent gene expression during de novo infection. Further experiments demonstrate that the underlying mechanisms induced by LTA and/or LPS include upregulation of cellular receptor, increasing production of reactive oxygen species (ROS), and activating intracellular signaling pathways such as MAPK and NF-κB, and all of which are closely associated with KSHV entry or gene expression within oral cells. Based on these findings, we hope to provide the framework of developing novel targeted approaches for treatment and prevention of oral KSHV infection and KS development in high-risk HIV-positive patients. PMID:24971655

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

Wakao, Kazufumi; Watanabe, Tadashi; Takadama, Tadatoshi

Highlights: • Sangivamycin induces the apoptosis of B cell lymphoma PEL cells. • Sangivamycin suppresses Erk signaling by inhibiting Erk phosphorylation in PEL cells. • The activation of Erk signaling is essential for PEL cell survival. • Sangivamycin induces the apoptosis of PEL cells without production of progeny virus. • Sangivamycin may serve as a novel drug for the treatment of PEL. - Abstract: Sangivamycin, a structural analog of adenosine and antibiotic exhibiting antitumor and antivirus activities, inhibits protein kinase C and the synthesis of both DNA and RNA. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi’smore » sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients and HIV-infected homosexual males. PEL cells are derived from post-germinal center B cells, and are infected with KSHV. Herein, we asked if sangivamycin might be useful to treat PEL. We found that sangivamycin killed PEL cells, and we explored the underlying mechanism. Sangivamycin treatment drastically decreased the viability of PEL cell lines compared to KSHV-uninfected B lymphoma cell lines. Sangivamycin induced the apoptosis of PEL cells by activating caspase-7 and -9. Further, sangivamycin suppressed the phosphorylation of Erk1/2 and Akt, thus inhibiting activation of the proteins. Inhibitors of Akt and MEK suppressed the proliferation of PEL cells compared to KSHV-uninfected cells. It is known that activation of Erk and Akt signaling inhibits apoptosis and promotes proliferation in PEL cells. Our data therefore suggest that sangivamycin induces apoptosis by inhibiting Erk and Akt signaling in such cells. We next investigated whether sangivamycin, in combination with an HSP90 inhibitor geldanamycin (GA) or valproate (valproic acid), potentiated the cytotoxic effects of the latter drugs on PEL cells. Compared to treatment with GA or valproate alone, the addition of sangivamycin enhanced cytotoxic activity. Our data thus indicate that sangivamycin may find clinical utility as a novel anti-cancer agent targeting PEL.« less

N6-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi's sarcoma-associated herpesvirus infection

PubMed Central

Dominissini, Dan; He, Chuan

2018-01-01

Methylation at the N6 position of adenosine (m6A) is a highly prevalent and reversible modification within eukaryotic mRNAs that has been linked to many stages of RNA processing and fate. Recent studies suggest that m6A deposition and proteins involved in the m6A pathway play a diverse set of roles in either restricting or modulating the lifecycles of select viruses. Here, we report that m6A levels are significantly increased in cells infected with the oncogenic human DNA virus Kaposi’s sarcoma-associated herpesvirus (KSHV). Transcriptome-wide m6A-sequencing of the KSHV-positive renal carcinoma cell line iSLK.219 during lytic reactivation revealed the presence of m6A across multiple kinetic classes of viral transcripts, and a concomitant decrease in m6A levels across much of the host transcriptome. However, we found that depletion of the m6A machinery had differential pro- and anti-viral impacts on viral gene expression depending on the cell-type analyzed. In iSLK.219 and iSLK.BAC16 cells the pathway functioned in a pro-viral manner, as depletion of the m6A writer METTL3 and the reader YTHDF2 significantly impaired virion production. In iSLK.219 cells the defect was linked to their roles in the post-transcriptional accumulation of the major viral lytic transactivator ORF50, which is m6A modified. In contrast, although the ORF50 mRNA was also m6A modified in KSHV infected B cells, ORF50 protein expression was instead increased upon depletion of METTL3, or, to a lesser extent, YTHDF2. These results highlight that the m6A pathway is centrally involved in regulating KSHV gene expression, and underscore how the outcome of this dynamically regulated modification can vary significantly between cell types. PMID:29659627

Low-Latency Lunar Surface Telerobotics from Earth-Moon Libration Points

NASA Technical Reports Server (NTRS)

Lester, Daniel; Thronson, Harley

2011-01-01

Concepts for a long-duration habitat at Earth-Moon LI or L2 have been advanced for a number of purposes. We propose here that such a facility could also have an important role for low-latency telerobotic control of lunar surface equipment, both for lunar science and development. With distances of about 60,000 km from the lunar surface, such sites offer light-time limited two-way control latencies of order 400 ms, making telerobotic control for those sites close to real time as perceived by a human operator. We point out that even for transcontinental teleoperated surgical procedures, which require operational precision and highly dexterous manipulation, control latencies of this order are considered adequate. Terrestrial telerobots that are used routinely for mining and manufacturing also involve control latencies of order several hundred milliseconds. For this reason, an Earth-Moon LI or L2 control node could build on the technology and experience base of commercially proven terrestrial ventures. A lunar libration-point telerobotic node could demonstrate exploration strategies that would eventually be used on Mars, and many other less hospitable destinations in the solar system. Libration-point telepresence for the Moon contrasts with lunar telerobotic control from the Earth, for which two-way control latencies are at least six times longer. For control latencies that long, telerobotic control efforts are of the "move-and-wait" variety, which is cognitively inferior to near real-time control.

Handling qualities effects of display latency

NASA Technical Reports Server (NTRS)

King, David W.

1993-01-01

Display latency is the time delay between aircraft response and the corresponding response of the cockpit displays. Currently, there is no explicit specification for allowable display lags to ensure acceptable aircraft handling qualities in instrument flight conditions. This paper examines the handling qualities effects of display latency between 70 and 400 milliseconds for precision instrument flight tasks of the V-22 Tiltrotor aircraft. Display delay effects on the pilot control loop are analytically predicted through a second order pilot crossover model of the V-22 lateral axis, and handling qualities trends are evaluated through a series of fixed-base piloted simulation tests. The results show that the effects of display latency for flight path tracking tasks are driven by the stability characteristics of the attitude control loop. The data indicate that the loss of control damping due to latency can be simply predicted from knowledge of the aircraft's stability margins, control system lags, and required control bandwidths. Based on the relationship between attitude control damping and handling qualities ratings, latency design guidelines are presented. In addition, this paper presents a design philosophy, supported by simulation data, for using flight director display augmentation to suppress the effects of display latency for delays up to 300 milliseconds.

KSHV encoded ORF59 modulates histone arginine methylation of the viral genome to promote viral reactivation

PubMed Central

McDowell-Sargent, Maria; Uppal, Timsy; Purushothaman, Pravinkumar

2017-01-01

Kaposi’s sarcoma associated herpesvirus (KSHV) persists in a highly-ordered chromatin structure inside latently infected cells with the majority of the viral genome having repressive marks. However, upon reactivation the viral chromatin landscape changes into ‘open’ chromatin through the involvement of lysine demethylases and methyltransferases. Besides methylation of lysine residues of histone H3, arginine methylation of histone H4 plays an important role in controlling the compactness of the chromatin. Symmetric methylation of histone H4 at arginine 3 (H4R3me2s) negatively affects the methylation of histone H3 at lysine 4 (H3K4me3), an active epigenetic mark deposited on the viral chromatin during reactivation. We identified a novel binding partner to KSHV viral DNA processivity factor, ORF59-a protein arginine methyl transferase 5 (PRMT5). PRMT5 is an arginine methyltransferase that dimethylates arginine 3 (R3) of histone H4 in a symmetric manner, one hallmark of condensed chromatin. Our ChIP-seq data of symmetrically methylated H4 arginine 3 showed a significant decrease in H4R3me2s on the viral genome of reactivated cells as compared to the latent cells. Reduction in arginine methylation correlated with the binding of ORF59 on the viral chromatin and disruption of PRMT5 from its adapter protein, COPR5 (cooperator of PRMT5). Binding of PRMT5 through COPR5 is important for symmetric methylation of H4R3 and the expression of ORF59 competitively reduces the association of PRMT5 with COPR5, leading to a reduction in PRMT5 mediated arginine methylation. This ultimately resulted in a reduced level of symmetrically methylated H4R3 and increased levels of H3K4me3 marks, contributing to the formation of an open chromatin for transcription and DNA replication. Depletion of PRMT5 levels led to a decrease in symmetric methylation and increase in viral gene transcription confirming the role of PRMT5 in viral reactivation. In conclusion, ORF59 modulates histone-modifying enzymes to alter the chromatin structure during lytic reactivation. PMID:28678843

Viral Activation of MK2-hsp27-p115RhoGEF-RhoA Signaling Axis Causes Cytoskeletal Rearrangements, P-body Disruption and ARE-mRNA Stabilization

PubMed Central

Corcoran, Jennifer A.; Johnston, Benjamin P.; McCormick, Craig

2015-01-01

Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of several AIDS-related cancers, including the endothelial cell (EC) neoplasm Kaposi's sarcoma (KS). KSHV-infected ECs secrete abundant host-derived pro-inflammatory molecules and angiogenic factors that contribute to tumorigenesis. The precise contributions of viral gene products to this secretory phenotype remain to be elucidated, but there is emerging evidence for post-transcriptional regulation. The Kaposin B (KapB) protein is thought to contribute to the secretory phenotype in infected cells by binding and activating the stress-responsive kinase MK2, thereby selectively blocking decay of AU-rich mRNAs (ARE-mRNAs) encoding pro-inflammatory cytokines and angiogenic factors. Processing bodies (PBs) are cytoplasmic ribonucleoprotein foci in which ARE-mRNAs normally undergo rapid 5′ to 3′ decay. Here, we demonstrate that PB dispersion is a feature of latent KSHV infection, which is dependent on kaposin protein expression. KapB is sufficient to disperse PBs, and KapB-mediated ARE-mRNA stabilization could be partially reversed by treatments that restore PBs. Using a combination of genetic and chemical approaches we provide evidence that KapB-mediated PB dispersion is dependent on activation of a non-canonical Rho-GTPase signaling axis involving MK2, hsp27, p115RhoGEF and RhoA. PB dispersion in latently infected cells is likewise dependent on p115RhoGEF. In addition to PB dispersion, KapB-mediated RhoA activation in primary ECs caused actin stress fiber formation, increased cell motility and angiogenesis; these effects were dependent on the activity of the RhoA substrate kinases ROCK1/2. By contrast, KapB-mediated PB dispersion occurred in a ROCK1/2-independent manner. Taken together, these observations position KapB as a key contributor to viral reprogramming of ECs, capable of eliciting many of the phenotypes characteristic of KS tumor cells, and strongly contributing to the post-transcriptional control of EC gene expression and secretion. PMID:25569678

KSHV encoded ORF59 modulates histone arginine methylation of the viral genome to promote viral reactivation.

PubMed

Strahan, Roxanne C; McDowell-Sargent, Maria; Uppal, Timsy; Purushothaman, Pravinkumar; Verma, Subhash C

2017-07-01

Kaposi's sarcoma associated herpesvirus (KSHV) persists in a highly-ordered chromatin structure inside latently infected cells with the majority of the viral genome having repressive marks. However, upon reactivation the viral chromatin landscape changes into 'open' chromatin through the involvement of lysine demethylases and methyltransferases. Besides methylation of lysine residues of histone H3, arginine methylation of histone H4 plays an important role in controlling the compactness of the chromatin. Symmetric methylation of histone H4 at arginine 3 (H4R3me2s) negatively affects the methylation of histone H3 at lysine 4 (H3K4me3), an active epigenetic mark deposited on the viral chromatin during reactivation. We identified a novel binding partner to KSHV viral DNA processivity factor, ORF59-a protein arginine methyl transferase 5 (PRMT5). PRMT5 is an arginine methyltransferase that dimethylates arginine 3 (R3) of histone H4 in a symmetric manner, one hallmark of condensed chromatin. Our ChIP-seq data of symmetrically methylated H4 arginine 3 showed a significant decrease in H4R3me2s on the viral genome of reactivated cells as compared to the latent cells. Reduction in arginine methylation correlated with the binding of ORF59 on the viral chromatin and disruption of PRMT5 from its adapter protein, COPR5 (cooperator of PRMT5). Binding of PRMT5 through COPR5 is important for symmetric methylation of H4R3 and the expression of ORF59 competitively reduces the association of PRMT5 with COPR5, leading to a reduction in PRMT5 mediated arginine methylation. This ultimately resulted in a reduced level of symmetrically methylated H4R3 and increased levels of H3K4me3 marks, contributing to the formation of an open chromatin for transcription and DNA replication. Depletion of PRMT5 levels led to a decrease in symmetric methylation and increase in viral gene transcription confirming the role of PRMT5 in viral reactivation. In conclusion, ORF59 modulates histone-modifying enzymes to alter the chromatin structure during lytic reactivation.

Method for triggering an action

DOEpatents

Hall, David R.; Bartholomew, David B.; Johnson, Monte L.; Moon, Justin; Koehler, Roger O.

2006-10-17

A method for triggering an action of at least one downhole device on a downhole network integrated into a downhole tool string synchronized to an event comprises determining latency, sending a latency adjusted signal, and performing the action. The latency is determined between a control device and the at least one downhole device. The latency adjusted signal for triggering an action is sent to the downhole device. The action is performed downhole synchronized to the event. A preferred method for determining latency comprises the steps: a control device sends a first signal to the downhole device; after receiving the signal, the downhole device sends a response signal to the control device; and the control device analyzes the time from sending the signal to receiving the response signal.

The great escape: viral strategies to counter BST-2/tetherin.

PubMed

Douglas, Janet L; Gustin, Jean K; Viswanathan, Kasinath; Mansouri, Mandana; Moses, Ashlee V; Früh, Klaus

2010-05-13

The interferon-induced BST-2 protein has the unique ability to restrict the egress of HIV-1, Kaposi's sarcoma-associated herpesvirus (KSHV), Ebola virus, and other enveloped viruses. The observation that virions remain attached to the surface of BST-2-expressing cells led to the renaming of BST-2 as "tetherin". However, viral proteins such as HIV-1 Vpu, simian immunodeficiency virus Nef, and KSHV K5 counteract BST-2, thereby allowing mature virions to readily escape from infected cells. Since the anti-viral function of BST-2 was discovered, there has been an explosion of research into several aspects of this intriguing interplay between host and virus. This review focuses on recent work addressing the molecular mechanisms involved in BST-2 restriction of viral egress and the species-specific countermeasures employed by various viruses.

Viral Inhibition of PRR-Mediated Innate Immune Response: Learning from KSHV Evasion Strategies.

PubMed

Lee, Hye-Ra; Choi, Un Yung; Hwang, Sung-Woo; Kim, Stephanie; Jung, Jae U

2016-11-30

The innate immune system has evolved to detect and destroy invading pathogens before they can establish systemic infection. To successfully eradicate pathogens, including viruses, host innate immunity is activated through diverse pattern recognition receptors (PRRs) which detect conserved viral signatures and trigger the production of type I interferon (IFN) and pro-inflammatory cytokines to mediate viral clearance. Viral persistence requires that viruses co-opt cellular pathways and activities for their benefit. In particular, due to the potent antiviral activities of IFN and cytokines, viruses have developed various strategies to meticulously modulate intracellular innate immune sensing mechanisms to facilitate efficient viral replication and persistence. In this review, we highlight recent advances in the study of viral immune evasion strategies with a specific focus on how Kaposi's sarcoma-associated herpesvirus (KSHV) effectively targets host PRR signaling pathways.

(±)-Japonones A and B, two pairs of new enantiomers with anti-KSHV activities from Hypericum japonicum

NASA Astrophysics Data System (ADS)

Hu, Linzhen; Zhu, Hucheng; Li, Lei; Huang, Jinfeng; Sun, Weiguang; Liu, Junjun; Li, Hua; Luo, Zengwei; Wang, Jianping; Xue, Yongbo; Zhang, Yu; Zhang, Yonghui

2016-06-01

Two pairs of new enantiomers with unusual 5,5-spiroketal cores, termed (±)-japonones A and B [(±)-1 and (±)-2], were obtained from Hypericum japonicum Thunb. The absolute configurations of (±)-1 and (±)-2 were characterized by extensive analyses of spectroscopic data and calculated electronic circular dichroism (ECD) spectra, the application of modified Mosher’s methods, and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. Among these metabolites, (+)-1 exhibited some inhibitory activity on Kaposi’s sarcoma associated herpesvirus (KSHV). Virtual screening of (±)-1 and (±)-2 were conducted using the Surflex-Dock module in the Sybyl software, and (+)-1 exhibited ability to bind with ERK to form key interactions with residues Lys52, Pro56, Ile101, Asp165, Gly167 and Val99.

Emmprin and KSHV: new partners in viral cancer pathogenesis

PubMed Central

Dai, Lu; Bai, Lihua; Lu, Ying; Xu, Zengguang; Reiss, Krys; Valle, Luis Del; Kaleeba, Johnan; Toole, Bryan P.; Parsons, Chris; Qin, Zhiqiang

2013-01-01

Emmprin (CD147; basigin) is a multifunctional glycoprotein expressed at higher levels by cancer cells and stromal cells in the tumor microenvironment. Through direct effects within tumor cells and promotion of tumor-stroma interactions, emmprin participates in induction of tumor cell invasiveness, angiogenesis, metastasis and chemoresistance. Although its contribution to cancer progression has been widely studied, the role of emmprin in viral oncogenesis still remains largely unclear, and only a small body of available literature implicates emmprin-associated mechanisms in viral pathogenesis and tumorigenesis. We summarize these data in this review, focusing on the role of emmprin in pathogenesis associated with the Kaposi sarcoma-associated herpesvirus (KSHV), a common etiology for cancers arising in the setting of immune suppression. We also discuss future directions for mechanistic studies exploring roles for emmprin in viral cancer pathogenesis. PMID:23743354

Complete Genome Sequence of Pig-Tailed Macaque Rhadinovirus 2 and Its Evolutionary Relationship with Rhesus Macaque Rhadinovirus and Human Herpesvirus 8/Kaposi's Sarcoma-Associated Herpesvirus

PubMed Central

Bruce, A. Gregory; Thouless, Margaret E.; Haines, Anthony S.; Pallen, Mark J.; Grundhoff, Adam

2015-01-01

ABSTRACT Two rhadinovirus lineages have been identified in Old World primates. The rhadinovirus 1 (RV1) lineage consists of human herpesvirus 8, Kaposi's sarcoma-associated herpesvirus (KSHV), and closely related rhadinoviruses of chimpanzees, gorillas, macaques and other Old World primates. The RV2 rhadinovirus lineage is distinct and consists of closely related viruses from the same Old World primate species. Rhesus macaque rhadinovirus (RRV) is the RV2 prototype, and two RRV isolates, 26-95 and 17577, were sequenced. We determined that the pig-tailed macaque RV2 rhadinovirus, MneRV2, is highly associated with lymphomas in macaques with simian AIDS. To further study the role of rhadinoviruses in the development of lymphoma, we sequenced the complete genome of MneRV2 and identified 87 protein coding genes and 17 candidate microRNAs (miRNAs). A strong genome colinearity and sequence homology were observed between MneRV2 and RRV26-95, although the open reading frame (ORF) encoding the KSHV ORFK15 homolog was disrupted in RRV26-95. Comparison with MneRV2 revealed several genomic anomalies in RRV17577 that were not present in other rhadinovirus genomes, including an N-terminal duplication in ORF4 and a recombinative exchange of more distantly related homologs of the ORF22/ORF47 interacting glycoprotein genes. The comparison with MneRV2 has revealed novel genes and important conservation of protein coding domains and transcription initiation, termination, and splicing signals, which have added to our knowledge of RV2 rhadinovirus genetics. Further comparisons with KSHV and other RV1 rhadinoviruses will provide important avenues for dissecting the biology, evolution, and pathology of these closely related tumor-inducing viruses in humans and other Old World primates. IMPORTANCE This work provides the sequence characterization of MneRV2, the pig-tailed macaque homolog of rhesus rhadinovirus (RRV). MneRV2 and RRV belong to the rhadinovirus 2 (RV2) rhadinovirus lineage of Old World primates and are distinct but related to Kaposi's sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi's sarcoma. Pig-tailed macaques provide important models of human disease, and our previous studies have indicated that MneRV2 plays a causal role in AIDS-related lymphomas in macaques. Delineation of the MneRV2 sequence has allowed a detailed characterization of the genome structure, and evolutionary comparisons with RRV and KSHV have identified conserved promoters, splice junctions, and novel genes. This comparison provides insight into RV2 rhadinovirus biology and sets the groundwork for more intensive next-generation (Next-Gen) transcript and genetic analysis of this class of tumor-inducing herpesvirus. This study supports the use of MneRV2 in pig-tailed macaques as an important model for studying rhadinovirus biology, transmission and pathology. PMID:25609822

Emmprin and KSHV: new partners in viral cancer pathogenesis.

PubMed

Dai, Lu; Bai, Lihua; Lu, Ying; Xu, Zengguang; Reiss, Krys; Del Valle, Luis; Kaleeba, Johnan; Toole, Bryan P; Parsons, Chris; Qin, Zhiqiang

2013-09-01

Emmprin (CD147; basigin) is a multifunctional glycoprotein expressed at higher levels by cancer cells and stromal cells in the tumor microenvironment. Through direct effects within tumor cells and promotion of tumor-stroma interactions, emmprin participates in induction of tumor cell invasiveness, angiogenesis, metastasis and chemoresistance. Although its contribution to cancer progression has been widely studied, the role of emmprin in viral oncogenesis still remains largely unclear, and only a small body of available literature implicates emmprin-associated mechanisms in viral pathogenesis and tumorigenesis. We summarize these data in this review, focusing on the role of emmprin in pathogenesis associated with the Kaposi sarcoma-associated herpesvirus (KSHV), a common etiology for cancers arising in the setting of immune suppression. We also discuss future directions for mechanistic studies exploring roles for emmprin in viral cancer pathogenesis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Signal, noise, and variation in neural and sensory-motor latency

PubMed Central

Lee, Joonyeol; Joshua, Mati; Medina, Javier F.; Lisberger, Stephen G.

2016-01-01

Analysis of the neural code for sensory-motor latency in smooth pursuit eye movements reveals general principles of neural variation and the specific origin of motor latency. The trial-by-trial variation in neural latency in MT comprises: a shared component expressed as neuron-neuron latency correlations; and an independent component that is local to each neuron. The independent component arises heavily from fluctuations in the underlying probability of spiking with an unexpectedly small contribution from the stochastic nature of spiking itself. The shared component causes the latency of single neuron responses in MT to be weakly predictive of the behavioral latency of pursuit. Neural latency deeper in the motor system is more strongly predictive of behavioral latency. A model reproduces both the variance of behavioral latency and the neuron-behavior latency correlations in MT if it includes realistic neural latency variation, neuron-neuron latency correlations in MT, and noisy gain control downstream from MT. PMID:26971946

Antibody-Independent Control of γ-Herpesvirus Latency via B Cell Induction of Anti-Viral T Cell Responses

PubMed Central

McClellan, Kelly B; Gangappa, Shivaprakash; Speck, Samuel H; Virgin, Herbert W.

2006-01-01

B cells can use antibody-dependent mechanisms to control latent viral infections. It is unknown whether this represents the sole function of B cells during chronic viral infection. We report here that hen egg lysozyme (HEL)-specific B cells can contribute to the control of murine γ-herpesvirus 68 (γHV68) latency without producing anti-viral antibody. HEL-specific B cells normalized defects in T cell numbers and proliferation observed in B cell−/− mice during the early phase of γHV68 latency. HEL-specific B cells also reversed defects in CD8 and CD4 T cell cytokine production observed in B cell−/− mice, generating CD8 and CD4 T cells necessary for control of latency. Furthermore, HEL-specific B cells were able to present virally encoded antigen to CD8 T cells. Therefore, B cells have antibody independent functions, including antigen presentation, that are important for control of γ-herpesvirus latency. Exploitation of this property of B cells may allow enhanced vaccine responses to chronic virus infection. PMID:16789842

Kaposi's Sarcoma-Associated Herpesvirus G-Protein-Coupled Receptor Prevents AU-Rich-Element-Mediated mRNA Decay

PubMed Central

Corcoran, Jennifer A.; Khaperskyy, Denys A.; Johnston, Benjamin P.; King, Christine A.; Cyr, David P.; Olsthoorn, Alisha V.

2012-01-01

During lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection, host gene expression is severely restricted by a process of global mRNA degradation known as host shutoff, which rededicates translational machinery to the expression of viral proteins. A subset of host mRNAs is spared from shutoff, and a number of these contain cis-acting AU-rich elements (AREs) in their 3′ untranslated regions. AREs are found in labile mRNAs encoding cytokines, growth factors, and proto-oncogenes. Activation of the p38/MK2 signal transduction pathway reverses constitutive decay of ARE-mRNAs, resulting in increased protein production. The viral G-protein-coupled receptor (vGPCR) is thought to play an important role in promoting the secretion of angiogenic molecules from KSHV-infected cells during lytic replication, but to date it has not been clear how vGPCR circumvents host shutoff. Here, we demonstrate that vGPCR activates the p38/MK2 pathway and stabilizes ARE-mRNAs, augmenting the levels of their protein products. Using MK2-deficient cells, we demonstrate that MK2 is essential for maximal vGPCR-mediated ARE-mRNA stabilization. ARE-mRNAs are normally delivered to cytoplasmic ribonucleoprotein granules known as processing bodies (PBs) for translational silencing and decay. We demonstrate that PB formation is prevented during KSHV lytic replication or in response to vGPCR-mediated activation of RhoA subfamily GTPases. Together, these data show for the first time that vGPCR impacts gene expression at the posttranscriptional level, coordinating an attack on the host mRNA degradation machinery. By suppressing ARE-mRNA turnover, vGPCR may facilitate escape of certain target mRNAs from host shutoff and allow secretion of angiogenic factors from lytically infected cells. PMID:22696654

Suppression of Antigen-Specific T Cell Responses by the Kaposi's Sarcoma-Associated Herpesvirus Viral OX2 Protein and Its Cellular Orthologue, CD200

PubMed Central

Misstear, Karen; Chanas, Simon A.; Rezaee, S. A. Rahim; Colman, Rachel; Quinn, Laura L.; Long, Heather M.; Goodyear, Oliver; Lord, Janet M.; Hislop, Andrew D.

2012-01-01

Regulating appropriate activation of the immune response in the healthy host despite continual immune surveillance dictates that immune responses must be either self-limiting and therefore negatively regulated following their activation or prevented from developing inappropriately. In the case of antigen-specific T cells, their response is attenuated by several mechanisms, including ligation of CTLA-4 and PD-1. Through the study of the viral OX2 (vOX2) immunoregulator encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), we have identified a T cell-attenuating role both for this protein and for CD200, a cellular orthologue of the viral vOX2 protein. In vitro, antigen-presenting cells (APC) expressing either native vOX2 or CD200 suppressed two functions of cognate antigen-specific T cell clones: gamma interferon (IFN-γ) production and mobilization of CD107a, a cytolytic granule component and measure of target cell killing ability. Mechanistically, vOX2 and CD200 expression on APC suppressed the phosphorylation of ERK1/2 mitogen-activated protein kinase in responding T cells. These data provide the first evidence for a role of both KSHV vOX2 and cellular CD200 in the negative regulation of antigen-specific T cell responses. They suggest that KSHV has evolved to harness the host CD200-based mechanism of attenuation of T cell responses to facilitate virus persistence and dissemination within the infected individual. Moreover, our studies define a new paradigm in immune modulation by viruses: the provision of a negative costimulatory signal to T cells by a virus-encoded orthologue of CD200. PMID:22491458

Objective daytime sleepiness in patients with somnambulism or sleep terrors.

PubMed

Lopez, Régis; Jaussent, Isabelle; Dauvilliers, Yves

2014-11-25

To objectively measure daytime sleepiness and to assess for clinical and polysomnographic determinants of mean sleep latency in adult patients with somnambulism (sleepwalking [SW]) or sleep terrors (ST) compared with controls. Thirty drug-free adult patients with primary SW or ST, and age-, sex-, and body mass index-matched healthy controls underwent a standardized clinical interview, completed questionnaires including the Epworth Sleepiness Scale, and underwent one night of video polysomnography followed by the Multiple Sleep Latency Test (MSLT). Excessive daytime sleepiness defined as Epworth Sleepiness Scale score >10 was reported in 66.7% of patients and 6.7% of controls. The temporal pattern of sleep latencies in individual MSLT trials differed between patients and controls, with progressive increased sleep latency in patients across the trials in contrast to a "U curve" for controls. We did not find between-group differences regarding the mean sleep latency on the 5 MSLT trials, but did observe reduced sleep latencies in patients for the first 2 trials. Despite increased slow-wave sleep disruptions found in patients (i.e, more micro-arousals and hypersynchronous high-voltage delta waves arousals), we did not find polysomnographic characteristic differences when comparing sleepy patients for either subjective or objective daytime sleepiness on the MSLT compared with alert patients. Excessive daytime sleepiness is a common complaint in subjects with SW or ST and shorter sleep latencies in the early morning hours. Despite an increased slow-wave sleep fragmentation found in these patients, we did not identify any association with the level of daytime sleepiness. © 2014 American Academy of Neurology.

Multicentric Castleman Disease: Where are we now?

PubMed Central

Wang, Hao-Wei; Pittaluga, Stefania; Jaffe, Elaine S.

2016-01-01

Multicentric Castleman disease (MCD) encompasses a spectrum of conditions that give rise to overlapping clinicopathological manifestations. The fundamental pathogenetic mechanism involves dysregulated cytokine activity, which causes systemic inflammatory symptoms as well as lymphadenopathy. The histological changes in lymph nodes resemble in part the findings originally described in the unicentric forms Castleman disease, both hyaline vascular and plasma cell variants. In MCD caused by Kaposi sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/HHV8), the cytokine over activity is caused by viral products, which can also lead to atypical lymphoproliferations and potential progression to lymphoma. In cases negative for KSHV/HHV8, so-called idiopathic MCD, the hypercytokinemia can result from various mechanisms, which ultimately lead to different constellations of clinical presentations and varied pathology in lymphoid tissues. In this article, we review the evolving concepts and definitions of the various conditions under the eponym of Castleman disease, and summarize current knowledge regarding the histopathology and pathogenesis of lesions within the MCD spectrum. PMID:27296355

Latency causes and reduction in optical metro networks

NASA Astrophysics Data System (ADS)

Bobrovs, Vjaceslavs; Spolitis, Sandis; Ivanovs, Girts

2013-12-01

The dramatic growth of transmitted information in fiber optical networks is leading to a concern about the network latency for high-speed reliable services like financial transactions, telemedicine, virtual and augmented reality, surveillance, and other applications. In order to ensure effective latency engineering, the delay variability needs to be accurately monitored and measured, in order to control it. This paper in brief describes causes of latency in fiber optical metro networks. Several available latency reduction techniques and solutions are also discussed, namely concerning usage of different chromatic dispersion compensation methods, low-latency amplifiers, optical fibers as well as other network elements.

Postural response latencies are related to balance control during standing and walking in patients with multiple sclerosis

PubMed Central

Huisinga, Jessie M.; St. George, Rebecca J.; Spain, Rebecca; Overs, Shannon; Horak, Fay B.

2015-01-01

Objective To understand examined the relationship between postural response latencies obtained during postural perturbations and representative measures of balance during standing (sway variables) and during walking (trunk motion). Design Cross-sectional Setting University medical center balance disorders laboratory Participants Forty persons with MS were compared with 20 similar aged control subjects. Twenty subjects with MS had normal walking velocity group and 20 had slow walking velocity based on the 25-foot walk time greater than 5 seconds. Interventions None Main Outcome Measures Postural response latency, sway variables, trunk motion variables Results: We found that subjects with MS with either slow or normal walking velocities had significantly longer postural response latencies than the healthy control group. Postural response latency was not correlated with the 25-ft walk time. Postural response latency was significantly correlated with center of pressure sway variables during quiet standing: root mean square (ρ = 0.334, p=0.040), range (ρ=0.385, p=0.017), mean velocity (ρ=0.337, p=0.038), and total sway area (ρ=0.393, p=0.015). Postural response latency was also significantly correlated with motion of the trunk during walking: sagittal plane range of motion (ρ=0.316, p=0.050) and standard deviation of transverse plane range of motion (ρ=-0.430, p=0.006). Conclusions These findings clearly indicate that slow postural responses to external perturbations in patients with MS contribute to disturbances in balance control, both during standing and walking. PMID:24445088

Importance of cutaneous silent period in fibromyalgia and its relationship with disease characteristics, psychological disorders and quality of life of patients.

PubMed

Umay, Ebru; Ulas, Umit; Unlu, Ece; Akgun, Hakan; Cakci, Aytul; Odabasi, Zeki

2013-01-01

Cutaneous silent period (CSP) is an inhibitory spinal protective reflex and its afferents consist of A-delta nerve fibers. We aimed to evaluate patients with fibromyalgia (FM) and healthy controls to determine any differences between the groups in terms of CSP duration and latency, and if present, to determine whether there is any relationship with disease characteristics, psychological disorders and quality of life. Thirty-two patients with FM and 32 healthy volunteers were included in the study. The patient and control groups were compared in terms of CSP latency and duration in both upper and lower extremities. Disease characteristics, psychological disorders and quality of life of patients were assessed using the Fibromyalgia Impact Questionnaire (FIQ) and Short Form-36 (SF-36). Patients with CSP measurements equal to or lower than those of the control group were compared with those with higher values than controls in terms of disease characteristics, psychological status and quality of life. Significantly prolonged CSP latencies in both upper and lower extremities were determined in patients compared to controls. We found that prolongation of CSP latency in the lower extremity is associated with disease severity and functional disability. CSP latencies in both upper and lower extremities in patients with FM are longer than in healthy volunteers. Moreover, prolongation of CSP latency in the lower extremity is associated with disease severity and physical functional disability.

Empirical mode decomposition processing to improve multifocal-visual-evoked-potential signal analysis in multiple sclerosis

PubMed Central

2018-01-01

Objective To study the performance of multifocal-visual-evoked-potential (mfVEP) signals filtered using empirical mode decomposition (EMD) in discriminating, based on amplitude, between control and multiple sclerosis (MS) patient groups, and to reduce variability in interocular latency in control subjects. Methods MfVEP signals were obtained from controls, clinically definitive MS and MS-risk progression patients (radiologically isolated syndrome (RIS) and clinically isolated syndrome (CIS)). The conventional method of processing mfVEPs consists of using a 1–35 Hz bandpass frequency filter (XDFT). The EMD algorithm was used to decompose the XDFT signals into several intrinsic mode functions (IMFs). This signal processing was assessed by computing the amplitudes and latencies of the XDFT and IMF signals (XEMD). The amplitudes from the full visual field and from ring 5 (9.8–15° eccentricity) were studied. The discrimination index was calculated between controls and patients. Interocular latency values were computed from the XDFT and XEMD signals in a control database to study variability. Results Using the amplitude of the mfVEP signals filtered with EMD (XEMD) obtains higher discrimination index values than the conventional method when control, MS-risk progression (RIS and CIS) and MS subjects are studied. The lowest variability in interocular latency computations from the control patient database was obtained by comparing the XEMD signals with the XDFT signals. Even better results (amplitude discrimination and latency variability) were obtained in ring 5 (9.8–15° eccentricity of the visual field). Conclusions Filtering mfVEP signals using the EMD algorithm will result in better identification of subjects at risk of developing MS and better accuracy in latency studies. This could be applied to assess visual cortex activity in MS diagnosis and evolution studies. PMID:29677200

Primary display latency criteria based on flying qualities and performance data

NASA Technical Reports Server (NTRS)

Funk, John D., Jr.; Beck, Corin P.; Johns, John B.

1993-01-01

With a pilots' increasing use of visual cue augmentation, much requiring extensive pre-processing, there is a need to establish criteria for new avionics/display design. The timeliness and synchronization of the augmented cues is vital to ensure the performance quality required for precision mission task elements (MTEs) where augmented cues are the primary source of information to the pilot. Processing delays incurred while transforming sensor-supplied flight information into visual cues are unavoidable. Relationships between maximum control system delays and associated flying qualities levels are documented in MIL-F-83300 and MIL-F-8785. While cues representing aircraft status may be just as vital to the pilot as prompt control response for operations in instrument meteorological conditions, presently, there are no specification requirements on avionics system latency. To produce data relating avionics system latency to degradations in flying qualities, the Navy conducted two simulation investigations. During the investigations, flying qualities and performance data were recorded as simulated avionics system latency was varied. Correlated results of the investigation indicates that there is a detrimental impact of latency on flying qualities. Analysis of these results and consideration of key factors influencing their application indicate that: (1) Task performance degrades and pilot workload increases as latency is increased. Inconsistency in task performance increases as latency increases. (2) Latency reduces the probability of achieving Level 1 handling qualities with avionics system latency as low as 70 ms. (3) The data suggest that the achievement of desired performance will be ensured only at display latency values below 120 ms. (4) These data also suggest that avoidance of inadequate performance will be ensured only at display latency values below 150 ms.

Median sep and blink reflex in thyroid diseases.

PubMed

Oflazoğlu, B; Somay, G; Us, O; Surardamar, A; Tanridağ, T

2006-11-01

Pathological disturbances of thyroid hormones is associated with central and peripheral nervous system disturbances. The aim of this study is to evaluate median nerve stimulated somatosensory evoked potential (SEP) and blink reflex of thyroid patients (hypo and hyperthyroidism). Median SEP was performed in 40 patients (21 with hyperthyroidism and 19 with hypothyroidism). We evaluated the latencies of N9, N11, N13, P9, P11, P14, N20 and P25 waves and the N9-N20, N9-N13, N13-N20 and P14-N20 interpeak latencies. We compared the results of patients with the control group (26 persons). We found that the N20 latency was longer in patients with hyperthyroidism than in the control group and the difference was statistically significant. There was not any statistically significant difference regarding the N9, N11, N13, P9, P11, P14, N20 and P25 latencies and the N9-N20, N9-N13, N13-N20 and P14-N20 interpeak latencies between hypothyroid patients and controls. We performed the blink reflex study in 28 of 40 patients (14 patients with hyperthyroidism and 14 patients with hypothyroidism). Comparing the R1, R2, CR2 (contralateral R2) latencies and durations of the patients and controls, we found that R2 and CR2 duration was shorter in patients with hyperthyroidism. This difference was statistically significant.

Effects of low-frequency repetitive transcranial magnetic stimulation on event-related potential P300

NASA Astrophysics Data System (ADS)

Torii, Tetsuya; Sato, Aya; Iwahashi, Masakuni; Iramina, Keiji

2012-04-01

The present study analyzed the effects of repetitive transcranial magnetic stimulation (rTMS) on brain activity. P300 latency of event-related potential (ERP) was used to evaluate the effects of low-frequency and short-term rTMS by stimulating the supramarginal gyrus (SMG), which is considered to be the related area of P300 origin. In addition, the prolonged stimulation effects on P300 latency were analyzed after applying rTMS. A figure-eight coil was used to stimulate left-right SMG, and intensity of magnetic stimulation was 80% of motor threshold. A total of 100 magnetic pulses were applied for rTMS. The effects of stimulus frequency at 0.5 or 1 Hz were determined. Following rTMS, an odd-ball task was performed and P300 latency of ERP was measured. The odd-ball task was performed at 5, 10, and 15 min post-rTMS. ERP was measured prior to magnetic stimulation as a control. Electroencephalograph (EEG) was measured at Fz, Cz, and Pz that were indicated by the international 10-20 electrode system. Results demonstrated that different effects on P300 latency occurred between 0.5-1 Hz rTMS. With 1 Hz low-frequency magnetic stimulation to the left SMG, P300 latency decreased. Compared to the control, the latency time difference was approximately 15 ms at Cz. This decrease continued for approximately 10 min post-rTMS. In contrast, 0.5 Hz rTMS resulted in delayed P300 latency. Compared to the control, the latency time difference was approximately 20 ms at Fz, and this delayed effect continued for approximately 15 min post-rTMS. Results demonstrated that P300 latency varied according to rTMS frequency. Furthermore, the duration of the effect was not similar for stimulus frequency of low-frequency rTMS.

Middle Latency Auditory Evoked Potential (MLAEP) in Workers with and without Tinnitus who are Exposed to Occupational Noise.

PubMed

dos Santos Filha, Valdete Alves Valentins; Samelli, Alessandra Giannella; Matas, Carla Gentile

2015-09-11

Tinnitus is an important occupational health concern, but few studies have focused on the central auditory pathways of workers with a history of occupational noise exposure. Thus, we analyzed the central auditory pathways of workers with a history of occupational noise exposure who had normal hearing threshold, and compared middle latency auditory evoked potential in those with and without noise-induced tinnitus. Sixty individuals (30 with and 30 without tinnitus) underwent the following procedures: anamnesis, immittance measures, pure-tone air conduction thresholds at all frequencies between 0.25-8 kHz, and middle latency auditory evoked potentials. Quantitative analysis of latencies and amplitudes of middle latency auditory evoked potential showed no significant differences between the groups with and without tinnitus. In the qualitative analysis, we found that both groups showed increased middle latency auditory evoked potential latencies. The study group had more alterations of the "both" type regarding the Na-Pa amplitude, while the control group had more "electrode effect" alterations, but these alterations were not significantly different when compared to controls. Individuals with normal hearing with or without tinnitus who are exposed to occupational noise have altered middle latency auditory evoked potential, suggesting impairment of the auditory pathways in cortical and subcortical regions. Although differences did not reach significance, individuals with tinnitus seemed to have more abnormalities in components of the middle latency auditory evoked potential when compared to individuals without tinnitus, suggesting alterations in the generation and transmission of neuroelectrical impulses along the auditory pathway.

Gait bradykinesia in Parkinson's disease: a change in the motor program which controls the synergy of gait.

PubMed

Warabi, Tateo; Furuyama, Hiroyasu; Sugai, Eri; Kato, Masamichi; Yanagisawa, Nobuo

2018-01-01

This study examined how gait bradykinesia is changed by the motor programming in Parkinson's disease. Thirty-five idiopathic Parkinson's disease patients and nine age-matched healthy subjects participated in this study. After the patients fixated on a visual-fixation target (conditioning-stimulus), the voluntary-gait was triggered by a visual on-stimulus. While the subject walked on a level floor, soleus, tibialis anterior EMG latencies, and the y-axis-vector of the sole-floor reaction force were examined. Three paradigms were used to distinguish between the off-/on-latencies. The gap-task: the visual-fixation target was turned off; 200 ms before the on-stimulus was engaged (resulting in a 200 ms-gap). EMG latency was not influenced by the visual-fixation target. The overlap-task: the on-stimulus was turned on during the visual-fixation target presentation (200 ms-overlap). The no-gap-task: the fixation target was turned off and the on-stimulus was turned on simultaneously. The onset of EMG pause following the tonic soleus EMG was defined as the off-latency of posture (termination). The onset of the tibialis anterior EMG burst was defined as the on-latency of gait (initiation). In the gap-task, the on-latency was unchanged in all of the subjects. In Parkinson's disease, the visual-fixation target prolonged both the off-/on-latencies in the overlap-task. In all tasks, the off-latency was prolonged and the off-/on-latencies were unsynchronized, which changed the synergic movement to a slow, short-step-gait. The synergy of gait was regulated by two independent sensory-motor programs of the off- and on-latency levels. In Parkinson's disease, the delayed gait initiation was due to the difficulty in terminating the sensory-motor program which controls the subject's fixation. The dynamic gait bradykinesia was involved in the difficulty (long off-latency) in terminating the motor program of the prior posture/movement.

Overactive bladder and pontine reticular formation.

PubMed

Zorba, Orhan Ünal; Kırbaş, Serkan; Uzun, Hakkı; Cetinkaya, Mehmet; Önem, Kadir; Rifaioğlu, Mehmet Murat

2013-01-01

The etiology of overactive bladder (OAB) remains unclear. Observed neurogenic factors in the literature are limited to suprapontine or spinal pathologies. The blink reflex is a useful tool in the evaluation of brainstem functions. Blink reflex latency times were evaluated in order to reveal pathology in the brainstem. A total of 60 women, 30 patients with idiopathic OAB and 30 healthy controls, were enrolled in the study. Blink reflex latency times were analyzed by electrical stimulation of the supraorbital nerve. Two responses in the orbicularis oculi muscle, early ipsilateral response (R1) and late bilateral response (R2) latency times, were recorded. Mean ages of the patients and controls were 51.9 ± 5.3 and 49.2 ± 6.2 years, respectively. R2 latency times were significantly higher in patients than in controls. However, R1 latency times were similar between the two groups. The results of the study suggest a significant relation between late blink latency times and OAB. An oligosynaptic path via the trigeminal nuclei is responsible for R1; however, R2 response is relayed through the reticular formation. Stimulation of pontine reticular formation inhibits micturition contraction. In some patients, idiopathic OAB may result from reticular formation-originated pathology. Additional studies on other reticular formation-mediated reflexes are needed to reveal possible dysfunction of reticular formation. Copyright © 2013 S. Karger AG, Basel.

Control of Task Sequences: What Is the Role of Language?

ERIC Educational Resources Information Center

Mayr, Ulrich; Kleffner-Canucci, Killian; Kikumoto, Atsushi; Redford, Melissa A.

2014-01-01

It is almost a truism that language aids serial-order control through self-cuing of upcoming sequential elements. We measured speech onset latencies as subjects performed hierarchically organized task sequences while "thinking aloud" each task label. Surprisingly, speech onset latencies and response times (RTs) were highly synchronized,…

Imbalance in Multiple Sclerosis: A Result of Slowed Spinal Somatosensory Conduction

PubMed Central

Cameron, Michelle H.; Horak, Fay B.; Herndon, Robert R.; Bourdette, Dennis

2009-01-01

Balance problems and falls are common in people with multiple sclerosis (MS) but their cause and nature are not well understood. It is known that MS affects many areas of the central nervous system that can impact postural responses to maintain balance, including the cerebellum and the spinal cord. Cerebellar balance disorders are associated with normal latencies but reduced scaling of postural responses. We therefore examined the latency and scaling of automatic postural responses, and their relationship to somatosensory evoked potentials (SSEPs), in 10 people with MS and imbalance and 10 age-, sex-matched, healthy controls. The latency and scaling of postural responses to backward surface translations of 5 different velocities and amplitudes, and the latency of spinal and supraspinal somatosensory conduction, were examined. Subjects with MS had large, but very delayed automatic postural response latencies compared to controls (161ms ± 31 vs 102 ± 21, p < 0.01) and these postural response latencies correlated with the latencies of their spinal SSEPs (r=0.73, p< 0.01). Subjects with MS also had normal or excessive scaling of postural response amplitude to perturbation velocity and amplitude. Longer latency postural responses were associated with less velocity scaling and more amplitude scaling. Balance deficits in people with MS appear to be caused by slowed spinal somatosensory conduction and not by cerebellar involvement. People with MS appear to compensate for their slowed spinal somatosensory conduction by increasing the amplitude scaling and the magnitude of their postural responses. PMID:18570015

Discriminability of Prediction Artifacts in a Time Delayed Virtual Environment

NASA Technical Reports Server (NTRS)

Adelstein, Bernard D.; Jung, Jae Y.; Ellis, Stephen R.

2001-01-01

Overall latency remains an impediment to perceived image stability and consequently to human performance in virtual environment (VE) systems. Predictive compensators have been proposed as a means to mitigate these shortcomings, but they introduce rendering errors because of induced motion overshoot and heightened noise. Discriminability of these compensator artifacts was investigated by a protocol in which head tracked image stability for 35 ms baseline VE system latency was compared against artificially added (16.7 to 100 ms) latency compensated by a previously studied Kalman Filter (K-F) predictor. A control study in which uncompensated 16.7 to 100 ms latencies were compared against the baseline was also performed. Results from 10 subjects in the main study and 8 in the control group indicate that predictive compensation artifacts are less discernible than the disruptions of uncompensated time delay for the shorter but not the longer added latencies. We propose that noise magnification and overshoot are contributory cues to the presence of predictive compensation.

Simulation Based Studies of Low Latency Teleoperations for NASA Exploration Missions

NASA Technical Reports Server (NTRS)

Gernhardt, Michael L.; Crues, Edwin Z.; Bielski, Paul; Dexter, Dan; Litaker, Harry L.; Chappell, Steven P.; Beaton, Kara H.; Bekdash, Omar S.

2017-01-01

Human exploration of Mars will involve both crewed and robotic systems. Many mission concepts involve the deployment and assembly of mission support assets prior to crew arrival on the surface. Some of these deployment and assembly activities will be performed autonomously while others will be performed using teleoperations. However, significant communications latencies between the Earth and Mars make teleoperations challenging. Alternatively, low latency teleoperations are possible from locations in Mars orbit like Mars' moons Phobos and Deimos. To explore these latency opportunities, NASA is conducting a series of studies to investigate the effects of latency on telerobotic deployment and assembly activities. These studies are being conducted in laboratory environments at NASA's Johnson Space Center (JSC), the Human Exploration Research Analog (HERA) at JSC and the NASA Extreme Environment Mission Operations (NEEMO) underwater habitat off the coast of Florida. The studies involve two human-in-the-loop interactive simulations developed by the NASA Exploration Systems Simulations (NExSyS) team at JSC. The first simulation investigates manipulation related activities while the second simulation investigates mobility related activities. The first simulation provides a simple real-time operator interface with displays and controls for a simulated 6 degree of freedom end effector. The initial version of the simulation uses a simple control mode to decouple the robotic kinematic constraints and a communications delay to model latency effects. This provides the basis for early testing with more detailed manipulation simulations planned for the future. Subjects are tested using five operating latencies that represent teleoperation conditions from local surface operations to orbital operations at Phobos, Deimos and ultimately high Martian orbit. Subject performance is measured and correlated with three distance-to-target zones of interest. Each zone represents a target distance ranging from beyond 10m in Zone 1, through 1 cm to contact in Zone 5 with a step size factor of 10. Collected data consists of both objective simulation data (time, distance, hand controller inputs, velocity) and subjective questionnaire data. The second simulation provides a simple real-time operator interface with displays and control of a simulated surface rover. The rover traverses a synthetic Mars-like terrain and must be maneuvered to avoid obstacles while progressing to its destination. Like the manipulator simulation, subjects are tested using five operating latencies that represent teleoperation conditions from local surface operations to orbital operations at Phobos, Deimos and ultimately high Martian orbit. The rover is also operated at three different traverse speeds to assess the correlation between latency and speed. Collected data consisted of both objective simulation data (time, distance, hand controller inputs, braking) and subjective questionnaire data. These studies are exploring relationships between task complexity, operating speeds, operator efficiencies, and communications latencies for low latency teleoperations in support of human planetary exploration. This paper presents early results from these studies along with the current observations and conclusions. These and planned future studies will help to inform NASA on the potential for low latency teleoperations to support human exploration of Mars and inform the design of robotic systems and exploration missions.

[Visual perception of Kanji characters and complicated figures. II. Visual P300 event-related potentials in patients with mental retardation].

PubMed

Sata, Yoshimi; Inagaki, Masumi; Shirane, Seiko; Kaga, Makiko

2002-11-01

In order to objectively evaluate visual perception of patients with mental retardation (MR), the P300 event-related potentials (ERPs) for visual oddball tasks were recorded in 26 patients and 13 age-matched healthy volunteers. The latency and amplitude of visual P300 in response to the Japanese ideogram stimuli (a pair of familiar Kanji characters or unfamiliar Kanji characters) and a pair of meaningless complicated figures were measured. In almost all MR patients visual P300 was observed, however, the peak latency was significantly prolonged compared to control subjects. There was no significant difference of P300 latency among the three tasks. The distribution pattern of P300 in MR patients was different from that in the controls and the amplitudes in the frontal region was larger in MR patients. The latency decreased with age even in both groups. The developmental change of P300 latency corresponded to developmental age rather than the chronological age. These findings suggest that MR patients have impairment in processing of visual perception. Assessment of P300 latencies to the visual stimuli may be useful as an objective indicator of mental deficit.

Validation of prospective portion size and latency to eat as measures of reactivity to snack foods.

PubMed

van den Akker, Karolien; Bongers, Peggy; Hanssen, Imke; Jansen, Anita

2017-09-01

In experimental studies that investigate reactivity to the sight and smell of highly palatable snack foods, ad libitum food intake is commonly used as a behavioural outcome measure. However, this measure has several drawbacks. The current study investigated two intake-related measures not yet validated for food cue exposure research involving common snack foods: prospective portion size and latency to eat. We aimed to validate these measures by assessing prospective portion size and eating latencies in female undergraduate students who either underwent snack food exposure or a control exposure. Furthermore, we correlated prospective portion size and latency to eat with commonly used measures of food cue reactivity, i.e., self-reported desire to eat, salivation, and ad libitum food intake. Results showed increases in prospective portion size after food cue exposure but not after control exposure. Latency to eat did not differ between the two conditions. Prospective portion size correlated positively with desire to eat and food intake, and negatively with latency to eat. Latency to eat was also negatively correlated with desire to eat and food intake. It is concluded that the current study provides initial evidence for the prospective portion size task as a valid measure of reactivity to snack foods in a Dutch female and mostly healthy weight student population. Copyright © 2017 Elsevier Ltd. All rights reserved.

Low-Latency Science Exploration of Planetary Bodies: How ISS Might Be Used as Part of a Low-Latency Analog Campaign for Human Exploration

NASA Technical Reports Server (NTRS)

Thronson, Harley; Valinia, Azita; Bleacher, Jacob; Eigenbrode, Jennifer; Garvin, Jim; Petro, Noah

2014-01-01

We suggest that the International Space Station be used to examine the application and validation of low-latency telepresence for surface exploration from space as an alternative, precursor, or potentially as an adjunct to astronaut "boots on the ground." To this end, controlled experiments that build upon and complement ground-based analog field studies will be critical for assessing the effects of different latencies (0 to 500 milliseconds), task complexity, and alternate forms of feedback to the operator. These experiments serve as an example of a pathfinder for NASA's roadmap of missions to Mars with low-latency telerobotic exploration as a precursor to astronaut's landing on the surface to conduct geological tasks.

Multiple sleep latency measures in narcolepsy and behaviourally induced insufficient sleep syndrome.

PubMed

Marti, Isabelle; Valko, Philipp O; Khatami, Ramin; Bassetti, Claudio L; Baumann, Christian R

2009-12-01

Short mean latencies to the first epoch of non-rapid eye movement sleep stage 1 (NREM1) and the presence of >or= 2 sleep onset REM (SOREM) periods on multiple sleep latency test (MSLT) occur in both narcolepsy-cataplexy (NC) and behaviourally induced insufficient sleep syndrome (BIISS). It is not known whether specific MSLT findings help differentiate the two disorders. We analyzed MSLT data including sleep latencies to and between different sleep stages of 60 age-, gender- and body mass index (BMI)-matched subjects (hypocretin-deficient NC, actigraphy-confirmed BIISS, healthy controls: each 20). Mean latency (in minutes) to NREM1 sleep was significantly shorter in NC (1.8+/-1.5) than in BIISS (4.7+/-2.1, p<0.001) and controls (11.4+/-3.3, p<0.001). Mean latency to NREM2 sleep was similar in NC (8.6+/-4.7) and BIISS (8.1+/-2.7, p=0.64); latency to either NREM2 or rapid eye movement (REM) sleep (i.e., the sum of the sleep latency to NREM1 and the duration of the first NREM1 sleep sequence), however, was shorter in NC (4.4+/-2.9) than in BIISS (7.9+/-3.5, p<0.001). Referring to all naps with SOREM periods, the sequence NREM1-REM-NREM2 was more common (71%) in NC than in BIISS (15%, p<0.001), reflecting the shorter latency from NREM1 to NREM2 in BIISS (3.7+/-2.5) than in NC (6.1+/-5.9, p<0.001). Our findings show that both sleepiness (as measured by NREM1 sleep latency) and REM sleep propensity are higher in NC than in BIISS. Furthermore, our finding of frequent REM sleep prior to NREM2 sleep in NC is in line with the recent assumption of an insufficient NREM sleep intensity in NC. Together with detailed clinical interviews, sleep logs, actigraphy, and nocturnal polysomnography, mean sleep latencies to NREM1

Up-regulation of tumor suppressor genes by exogenous dhC16-Cer contributes to its anti-cancer activity in primary effusion lymphoma.

PubMed

Cao, Yueyu; Qiao, Jing; Lin, Zhen; Zabaleta, Jovanny; Dai, Lu; Qin, Zhiqiang

2017-02-28

Primary effusion lymphoma (PEL) is a rare and highly aggressive B-cell malignancy with Kaposi's sarcoma-associated herpesvirus (KSHV) infection, while lack of effective therapies. Our recent data indicated that targeting the sphingolipid metabolism by either sphingosine kinase inhibitor or exogenous ceramide species induces PEL cell apoptosis and suppresses tumor progression in vivo. However, the underlying mechanisms for these exogenous ceramides "killing" PEL cells remain largely unknown. Based on the microarray analysis, we found that exogenous dhC16-Cer treatment affected the expression of many cellular genes with important functions within PEL cells such as regulation of cell cycle, cell survival/proliferation, and apoptosis/anti-apoptosis. Interestingly, we found that a subset of tumor suppressor genes (TSGs) was up-regulated from dhC16-Cer treated PEL cells. One of these elevated TSGs, Thrombospondin-1 (THBS1) was required for dhC16-Cer induced PEL cell cycle arrest. Moreover, dhC16-Cer up-regulation of THBS1 was through the suppression of multiple KSHV microRNAs expression. Our data demonstrate that exogenous ceramides display anti-cancer activities for PEL through regulation of both host and oncogenic virus factors.

Descending pathways controlling visually guided updating of reaching in cats.

PubMed

Pettersson, L-G; Perfiliev, S

2002-10-01

This study uses a previously described paradigm (Pettersson et al., 1997) to investigate the ability of cats to change the direction of ongoing reaching when the target is shifted sideways; the effect on the switching latency of spinal cord lesions was investigated. Large ventral lesions transecting the ventral funicle and the ventral half of the lateral funicle gave a 20-30 ms latency prolongation of switching in the medial (right) direction, but less prolongation of switching directed laterally (left), and in one cat the latencies of switching directed laterally were unchanged. It may be inferred that the command for switching in the lateral direction can be mediated by the dorsally located cortico- and rubrospinal tracts whereas the command for short-latency switching in the medial direction is mediated by ventral pathways. A restricted ventral lesion transecting the tectospinal pathway did not change the switching latency. Comparison of different ventral lesions revealed prolongation of the latency if the lesion included a region extending dorsally along the ventral horn and from there ventrally as a vertical strip, so it may be postulated that the command for fast switching, directed medially, is mediated by a reticulospinal pathway within this location. A hypothesis is forwarded suggesting that the visual control is exerted via ponto-cerebellar pathways.

Neurophysiologic markers of primary motor cortex for laryngeal muscles and premotor cortex in caudal opercular part of inferior frontal gyrus investigated in motor speech disorder: a navigated transcranial magnetic stimulation (TMS) study.

PubMed

Rogić Vidaković, Maja; Jerković, Ana; Jurić, Tomislav; Vujović, Igor; Šoda, Joško; Erceg, Nikola; Bubić, Andreja; Zmajević Schönwald, Marina; Lioumis, Pantelis; Gabelica, Dragan; Đogaš, Zoran

2016-11-01

Transcranial magnetic stimulation studies have so far reported the results of mapping the primary motor cortex (M1) for hand and tongue muscles in stuttering disorder. This study was designed to evaluate the feasibility of repetitive navigated transcranial magnetic stimulation (rTMS) for locating the M1 for laryngeal muscle and premotor cortical area in the caudal opercular part of inferior frontal gyrus, corresponding to Broca's area in stuttering subjects by applying new methodology for mapping these motor speech areas. Sixteen stuttering and eleven control subjects underwent rTMS motor speech mapping using modified patterned rTMS. The subjects performed visual object naming task during rTMS applied to the (a) left M1 for laryngeal muscles for recording corticobulbar motor-evoked potentials (CoMEP) from cricothyroid muscle and (b) left premotor cortical area in the caudal opercular part of inferior frontal gyrus while recording long latency responses (LLR) from cricothyroid muscle. The latency of CoMEP in control subjects was 11.75 ± 2.07 ms and CoMEP amplitude was 294.47 ± 208.87 µV, and in stuttering subjects CoMEP latency was 12.13 ± 0.75 ms and 504.64 ± 487.93 µV CoMEP amplitude. The latency of LLR in control subjects was 52.8 ± 8.6 ms and 54.95 ± 4.86 in stuttering subjects. No significant differences were found in CoMEP latency, CoMEP amplitude, and LLR latency between stuttering and control-fluent speakers. These results indicate there are probably no differences in stuttering compared to controls in functional anatomy of the pathway used for transmission of information from premotor cortex to the M1 cortices for laryngeal muscle representation and from there via corticobulbar tract to laryngeal muscles.

Molecular biology of human herpesvirus 8: novel functions and virus-host interactions implicated in viral pathogenesis and replication.

PubMed

Cousins, Emily; Nicholas, John

2014-01-01

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), is the second identified human gammaherpesvirus. Like its relative Epstein-Barr virus, HHV-8 is linked to B-cell tumors, specifically primary effusion lymphoma and multicentric Castleman's disease, in addition to endothelial-derived KS. HHV-8 is unusual in its possession of a plethora of "accessory" genes and encoded proteins in addition to the core, conserved herpesvirus and gammaherpesvirus genes that are necessary for basic biological functions of these viruses. The HHV-8 accessory proteins specify not only activities deducible from their cellular protein homologies but also novel, unsuspected activities that have revealed new mechanisms of virus-host interaction that serve virus replication or latency and may contribute to the development and progression of virus-associated neoplasia. These proteins include viral interleukin-6 (vIL-6), viral chemokines (vCCLs), viral G protein-coupled receptor (vGPCR), viral interferon regulatory factors (vIRFs), and viral antiapoptotic proteins homologous to FLICE (FADD-like IL-1β converting enzyme)-inhibitory protein (FLIP) and survivin. Other HHV-8 proteins, such as signaling membrane receptors encoded by open reading frames K1 and K15, also interact with host mechanisms in unique ways and have been implicated in viral pathogenesis. Additionally, a set of micro-RNAs encoded by HHV-8 appear to modulate expression of multiple host proteins to provide conditions conducive to virus persistence within the host and could also contribute to HHV-8-induced neoplasia. Here, we review the molecular biology underlying these novel virus-host interactions and their potential roles in both virus biology and virus-associated disease.

The behaviour of the long-latency stretch reflex in patients with Parkinson's disease

PubMed Central

Rothwell, Jc; Obeso, Ja; Traub, Mm; Marsden, Cd

1983-01-01

The size of the long-latency stretch reflex was measured in a proximal (triceps) and distal (flexor pollicis longus) muscle in 47 patients with Parkinson's disease, and was compared with that seen in a group of 12 age-matched normal control subjects. The patients were classified clinically into four groups according to the degree of rigidity at the elbow or tremor. Stretch reflexes were evaluated while the subject was exerting a small force against a constant preload supplied by a torque motor, and the size of the reflex response was measured as fractional increase over basal levels of activity. When stretches were given at random intervals by increasing the force exerted by the motor by a factor of 2 or 3, there was a clear trend for the more severely affected patients to have larger long latency responses in the triceps muscle, although there was no change in the size of the short-latency, spinal component of the response. In contrast, there was no change in the size of the long-latency response of the flexor pollicis longus in any group of patients with Parkinson's disease. Despite any differences in reflex size, the inherent muscle stiffness of both muscles appeared to be normal in all groups of patients with Parkinson's disease, since the displacement trajectory of the limb following the force increase was the same as control values in the short (25 ms) period before reflex compensation could intervene. In 20 of the patients and in seven of the control subjects, servo-controlled, ramp positional disturbances were given to the thumb. Up to a velocity of 300°/s, the size of the long-latency stretch reflex was proportional to the log velocity of stretch. This technique revealed, in both moderately and severely rigid patients, increases in the reflex sensitivity of the flexor pollicis longus, which had not been clear using step torque stretches alone. However, whether using ramp or step displacements, long latency stretch reflex gain was not closely related to rigidity; reflex size was within the normal range in many patients with severe rigidity. Enhanced long latency stretch reflexes thus contribute to, but may not be solely responsible for, rigidity in Parkinson's disease. PMID:6842198

Neurotoxic effects of n-hexane on the human central nervous system: evoked potential abnormalities in n-hexane polyneuropathy.

PubMed Central

Chang, Y C

1987-01-01

An outbreak of n-hexane polyneuropathy as a result of industrial exposure occurred in printing factories in Taipei area from December 1983 to February 1985. Multimodality evoked potentials study was performed on 22 of the polyneuropathy cases, five of the subclinical cases, and seven of the unaffected workers. The absolute and interpeak latencies of patterned visual evoked potential (pVEP) in both the polyneuropathy and subclinical groups were longer than in the normal controls. The pVEP interpeak amplitude was also decreased in the polyneuropathy cases. Brainstem auditory evoked potentials (BAEP), showed no difference of wave I latency between factory workers and normal controls, but prolongation of the wave I-V interpeak latencies was noted, corresponding with the severity of the polyneuropathy. In somatosensory evoked potentials (SEPs), both the absolute latencies and central conduction time (CCT) were longer in subclinical and polyneuropathy cases than in the unaffected workers and normal controls. From this evoked potentials study, chronic toxic effects of n-hexane on the central nervous system were shown. PMID:3031221

RESPONSE LATENCIES OF NORMAL AND FOCAL-HEAD IRRADIATED MONKEYS

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

McDowell, A.A.; Brown, W.L.

1963-12-01

This study was designed to determine whether focal-head irradiated rhesus monkeys differ from normal monkeys in a manner analogous to that previously found in whole-body irradiated monkeys with respect to response latencies under both familiar and novel stimulus conditions. Five control and four focal-head irradiated rhesus monkeys with nearly identical training histories were used; the latter were survivors of a focal-head irradiation study conducted four years earlier. They had received 3000 r x radiation to the inferior parietal lobule and posterior aspect of the temporal lobe of the brain, and 30 days later the same dosage to the same areamore » of the brain. The testing was conducted in a modified version of the Wisconsin General Test Apparatus, with 24 trials per day for two days, on response latency to a single food-rewarded wooden block placed randomly over either of the two extreme food-well positions. Then, 24 trials were conducted per day for two days on response latency to either the same food-rewarded wooden block or to a novel nonrewarded wooden block presented simultaneously. On the single-block condition, median response latencies of the two groups were comparable and the groups improved in a similar manner with practice. Optimal performance latencies were also comparable for the two groups. When the novel nonrewarded stimulus block was introduced, both groups manifested comparable disruption of median response latencies, but disruption of optimal response latencies was shown only by the focalhead irradiated group. The findings show that monkeys with previous focal-head irradiation of the posterior association areas, unlike relatively high-dose whole-body irradiated monkeys, manifest median response latencies comparable to those of controls. These data indicate the lasting effects of focal-head irradiation with x rays, and suggest that the sites of permanent damage for monkeys given sublethal whole-body radiation exposure differ from the sites irradiated in the present subjects. (BBB)« less

SDN-controlled topology-reconfigurable optical mobile fronthaul architecture for bidirectional CoMP and low latency inter-cell D2D in the 5G mobile era.

PubMed

Cvijetic, Neda; Tanaka, Akihiro; Kanonakis, Konstantinos; Wang, Ting

2014-08-25

We demonstrate the first SDN-controlled optical topology-reconfigurable mobile fronthaul (MFH) architecture for bidirectional coordinated multipoint (CoMP) and low latency inter-cell device-to-device (D2D) connectivity in the 5G mobile networking era. SDN-based OpenFlow control is used to dynamically instantiate the CoMP and inter-cell D2D features as match/action combinations in control plane flow tables of software-defined optical and electrical switching elements. Dynamic re-configurability is thereby introduced into the optical MFH topology, while maintaining back-compatibility with legacy fiber deployments. 10 Gb/s peak rates with <7 μs back-to-back transmission latency and 29.6 dB total power budget are experimentally demonstrated, confirming the attractiveness of the new approach for optical MFH of future 5G mobile systems.

Visuospatial asymmetries and interocular transfer in the split-brain rat.

PubMed

Adelstein, A; Crowne, D P

1991-06-01

Interocular transfer (IOT), hemispheric superiority, and cerebral dominance were examined in split-brain female albino rats. Callosum-sectioned and intact animals were monocularly trained in the Morris water maze and tested in IOT and reversal phases. In the IOT phase, split-brain rats entered more nontarget quadrants and headed less accurately toward the platform than did controls. For both split-brain animals and controls, right-eye training resulted in shorter latencies and fewer nontarget entries than did left-eye training. Analyses of cerebral dominance showed shorter latencies and smaller heading errors over all 3 phases in rats that were trained with the nondominant eye. Right-eye dominant controls were less affected by platform reversal. Split-brain rats were inferior to controls in latency to find the platform and in target quadrant entries. This finding establishes a spatial cognitive deficit from callosum section.

Using Proteomics to Identify Viral microRNA-Regulated Genes | Center for Cancer Research

Cancer.gov

Kaposi sarcoma is a soft tissue malignancy that affects the skin, the mucous membranes, the lymph nodes and other organs of individuals with compromised immune systems. It is caused by infection with human herpesvirus-8 also known as Kaposi sarcoma-associated herpesvirus or KSHV. The herpesvirus family is unique in that it is the only viral family currently known to express

Effects of Reduced Acuity and Stereo Acuity on Saccades and Reaching Movements in Adults With Amblyopia and Strabismus.

PubMed

Niechwiej-Szwedo, Ewa; Goltz, Herbert C; Colpa, Linda; Chandrakumar, Manokaraananthan; Wong, Agnes M F

2017-02-01

Our previous work has shown that amblyopia disrupts the planning and execution of visually-guided saccadic and reaching movements. We investigated the association between the clinical features of amblyopia and aspects of visuomotor behavior that are disrupted by amblyopia. A total of 55 adults with amblyopia (22 anisometropic, 18 strabismic, 15 mixed mechanism), 14 adults with strabismus without amblyopia, and 22 visually-normal control participants completed a visuomotor task while their eye and hand movements were recorded. Univariate and multivariate analyses were performed to assess the association between three clinical predictors of amblyopia (amblyopic eye [AE] acuity, stereo sensitivity, and eye deviation) and seven kinematic outcomes, including saccadic and reach latency, interocular saccadic and reach latency difference, saccadic and reach precision, and PA/We ratio (an index of reach control strategy efficacy using online feedback correction). Amblyopic eye acuity explained 28% of the variance in saccadic latency, and 48% of the variance in mean saccadic latency difference between the amblyopic and fellow eyes (i.e., interocular latency difference). In contrast, for reach latency, AE acuity explained only 10% of the variance. Amblyopic eye acuity was associated with reduced endpoint saccadic (23% of variance) and reach (22% of variance) precision in the amblyopic group. In the strabismus without amblyopia group, stereo sensitivity and eye deviation did not explain any significant variance in saccadic and reach latency or precision. Stereo sensitivity was the best clinical predictor of deficits in reach control strategy, explaining 23% of total variance of PA/We ratio in the amblyopic group and 12% of variance in the strabismus without amblyopia group when viewing with the amblyopic/nondominant eye. Deficits in eye and limb movement initiation (latency) and target localization (precision) were associated with amblyopic acuity deficit, whereas changes in the sensorimotor reach strategy were associated with deficits in stereopsis. Importantly, more than 50% of variance was not explained by the measured clinical features. Our findings suggest that other factors, including higher order visual processing and attention, may have an important role in explaining the kinematic deficits observed in amblyopia.

The effect of monitor raster latency on VEPs, ERPs and Brain-Computer Interface performance.

PubMed

Nagel, Sebastian; Dreher, Werner; Rosenstiel, Wolfgang; Spüler, Martin

2018-02-01

Visual neuroscience experiments and Brain-Computer Interface (BCI) control often require strict timings in a millisecond scale. As most experiments are performed using a personal computer (PC), the latencies that are introduced by the setup should be taken into account and be corrected. As a standard computer monitor uses a rastering to update each line of the image sequentially, this causes a monitor raster latency which depends on the position, on the monitor and the refresh rate. We technically measured the raster latencies of different monitors and present the effects on visual evoked potentials (VEPs) and event-related potentials (ERPs). Additionally we present a method for correcting the monitor raster latency and analyzed the performance difference of a code-modulated VEP BCI speller by correcting the latency. There are currently no other methods validating the effects of monitor raster latency on VEPs and ERPs. The timings of VEPs and ERPs are directly affected by the raster latency. Furthermore, correcting the raster latency resulted in a significant reduction of the target prediction error from 7.98% to 4.61% and also in a more reliable classification of targets by significantly increasing the distance between the most probable and the second most probable target by 18.23%. The monitor raster latency affects the timings of VEPs and ERPs, and correcting resulted in a significant error reduction of 42.23%. It is recommend to correct the raster latency for an increased BCI performance and methodical correctness. Copyright © 2017 Elsevier B.V. All rights reserved.

The predictability of frequency-altered auditory feedback changes the weighting of feedback and feedforward input for speech motor control.

PubMed

Scheerer, Nichole E; Jones, Jeffery A

2014-12-01

Speech production requires the combined effort of a feedback control system driven by sensory feedback, and a feedforward control system driven by internal models. However, the factors that dictate the relative weighting of these feedback and feedforward control systems are unclear. In this event-related potential (ERP) study, participants produced vocalisations while being exposed to blocks of frequency-altered feedback (FAF) perturbations that were either predictable in magnitude (consistently either 50 or 100 cents) or unpredictable in magnitude (50- and 100-cent perturbations varying randomly within each vocalisation). Vocal and P1-N1-P2 ERP responses revealed decreases in the magnitude and trial-to-trial variability of vocal responses, smaller N1 amplitudes, and shorter vocal, P1 and N1 response latencies following predictable FAF perturbation magnitudes. In addition, vocal response magnitudes correlated with N1 amplitudes, vocal response latencies, and P2 latencies. This pattern of results suggests that after repeated exposure to predictable FAF perturbations, the contribution of the feedforward control system increases. Examination of the presentation order of the FAF perturbations revealed smaller compensatory responses, smaller P1 and P2 amplitudes, and shorter N1 latencies when the block of predictable 100-cent perturbations occurred prior to the block of predictable 50-cent perturbations. These results suggest that exposure to large perturbations modulates responses to subsequent perturbations of equal or smaller size. Similarly, exposure to a 100-cent perturbation prior to a 50-cent perturbation within a vocalisation decreased the magnitude of vocal and N1 responses, but increased P1 and P2 latencies. Thus, exposure to a single perturbation can affect responses to subsequent perturbations. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Does vitamin C and vitamin E supplementation prolong the latency period before delivery following the preterm premature rupture of membranes? A randomized controlled study.

PubMed

Gungorduk, Kemal; Asicioglu, Osman; Gungorduk, Ozgu Celikkol; Yildirim, Gokhan; Besimoğlu, Berhan; Ark, Cemal

2014-03-01

To determine whether maternal vitamin C and vitamin E supplementation after the premature rupture of membranes is associated with an increase in the latency period before delivery. In the present prospective open randomized trial, 229 pregnant women with preterm premature rupture of membranes (PPROM) at ≥ 24.0 and < 34.0 weeks' gestation were randomly assigned to receive either 1,000 mg of vitamin C and 400 IU of vitamin E (n = 126) or a placebo (n = 123). The primary outcome was the latency period until delivery. Analysis was performed on an intention-to-treat basis. No significant differences in demographic or clinical characteristics were observed between the groups. Latency period until delivery was significantly higher in the group that received vitamins compared with the control group (11.2 ± 6.3 days versus 6.2 ± 4.0 days; p < 0.001). Gestational age at delivery was also significantly higher in the vitamin group compared with the control group (31.9 ± 2.6 weeks versus 31.0 ± 2.6 weeks; p = 0.01). No significant differences in adverse maternal outcome (i.e., chorioamnionitis or endometritis) or neonatal outcome (i.e., neonatal sepsis, neonatal death, necrotizing enterocolitis, or grade 3 to 4 intraventricular hemorrhage) were noted between groups. The findings of the present study suggest that the use of vitamins C and E in women with PPROM is associated with a longer latency period before delivery. Moreover, adverse neonatal and maternal outcomes, which are often associated with prolonged latency periods, were similar between the groups. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Precision Quantum Control and Error-Suppressing Quantum Firmware for Robust Quantum Computing

DTIC Science & Technology

2014-09-24

Biercuk, Lorenza Viola. Long-time Low - latency Quantum Memory by Dynamical Decoupling, arXiv:1206.6087v1 (06 2012) L. Viola, G. A. Paz-Silva . A...International Patent Application (PCT/AU2013/000649) D. Hayes, K. Khodjasteh L. Viola, M.J. Biercuk, “Long-time low - latency quantum memory by dynamical...Khodjasteh L. Viola, M.J. Biercuk, University of Sydney A28 Physics Road Sydney NS 2006 Long-time low - latency quantum membory by dynamical decoupling

Auditory P300 event related potentials in acute and transient psychosis-Comparison with schizophrenia.

PubMed

Sahoo, Swapnajeet; Malhotra, Savita; Basu, Debasish; Modi, Manish

2016-10-01

Limited biological research data are available on acute and transient psychotic disorder (ATPD) vis-à-vis schizophrenia. P300 event related potentials (ERP) have been extensively studied as an important neurophysiological parameter in schizophrenia. However, no P300 ERP studies comparing the two disorders are available. We compared auditory P300 ERP in patients remitted from ATPD with schizophrenia in remission and biologically unrelated healthy controls. In this case-control study design, 25 subjects remitted from ATPD were age-/gender-matched with healthy controls and patients with schizophrenia in remission. Clinical assessment and auditory P300 ERP (amplitude and latencies at central and parietal sites, reaction time) were recorded. The ERP parameters were compared across the three groups. All three groups showed significant differences in P300 amplitudes and latencies at central and parietal sites. Schizophrenia group differed significantly (p<0.001) from the ATPD group in all the P300 parameters. The ATPD group was found to have lower Pz latency (p<0.05) and lower mean reaction time (p<0.001) as compared to healthy controls. The results suggest that P300 could easily distinguish between ATPD and schizophrenia in remission, thus neurophysiologically differentiating the two disorders. Lower P300 latency and reaction time, which indicate hyper-arousability, distinguished ATPD from normal controls, with implications for a better understanding of ATPD. Copyright © 2016 Elsevier B.V. All rights reserved.

Cooling modifies mixed median and ulnar palmar studies in carpal tunnel syndrome.

PubMed

Araújo, Rogério Gayer Machado de; Kouyoumdjian, João Aris

2007-09-01

Temperature is an important and common variable that modifies nerve conduction study parameters in practice. Here we compare the effect of cooling on the mixed palmar median to ulnar negative peak-latency difference (PMU) in electrodiagnosis of carpal tunnel syndrome (CTS). Controls were 22 subjects (19 women, mean age 42.1 years, 44 hands). Patients were diagnosed with mild symptomatic CTS (25 women, mean age 46.6 years, 34 hands). PMU was obtained at the usual temperature, >32 degrees C, and after wrist/hand cooling to <27 degrees C in ice water. After cooling, there was a significantly greater increase in PMU and mixed ulnar palmar latency in patients versus controls. We concluded that cooling significantly modifies the PMU. We propose that the latencies of compressed nerve overreact to cooling and that this response could be a useful tool for incipient CTS electrodiagnosis. There was a significant latency overreaction of the ulnar nerve to cooling in CTS patients. We hypothesize that subclinical ulnar nerve compression is associated with CTS.

In vivo expression of human cytomegalovirus (HCMV) microRNAs during latency.

PubMed

Meshesha, Mesfin K; Bentwich, Zvi; Solomon, Semaria A; Avni, Yonat Shemer

2016-01-01

Viral encoded microRNAs play key roles in regulating gene expression and the life cycle of human herpes viruses. Latency is one of the hallmarks of the human cytomegalovirus (HCMV or HHV5) life cycle, and its control may have immense practical applications. The present study aims to identify HCMV encoded microRNAs during the latency phase of the virus. We used a highly sensitive real time PCR (RTPCR) assay that involves a pre-amplification step before RTPCR. It can detect HCMV encoded microRNAs (miRNAs) during latency in purified monocytes and PBMCs from HCMV IgG positive donors and in latently infected monocytic THP-1 cell lines. During the latency phase, only eight HCMV encoded microRNAs were detected in PBMCs, monocytes and in the THP-1 cells. Five originated from the UL region of the virus genome and three from the US region. Reactivation of the virus from latency, in monocytes obtained from the same donor, using dexamethasone restored the expression of all known HCMV encoded miRNAs including those that were absent during latency. We observed a shift in the abundance of the two arms of mir-US29 between the productive and latency stages of the viral life cycle, suggesting that the star "passenger" form of this microRNA is preferentially expressed during latency. As a whole, our study demonstrates that HCMV expresses during the latency phase, both in vivo and in vitro, only a subset of its microRNAs, which may indicate that they play an important role in maintenance and reactivation of latency. Copyright © 2015 Elsevier B.V. All rights reserved.

Control of complex motor gestures: orofacial muscle responses to load perturbations of lip during speech.

PubMed

Abbs, J H; Gracco, V L

1984-04-01

The contribution of ascending afferents to the control of speech movement was evaluated by applying unanticipated loads to the lower lip during the generation of combined upper lip-lower lip speech gestures. To eliminate potential contamination due to anticipation or adaptation, loads were applied randomly on only 10-15% of the trials. Physical characteristics of the perturbations were within the normal range of forces and movements involved in natural lip actions for speech. Compensatory responses in multiple facial muscles and lip movements were observed the first time a load was introduced, and achievement of the multimovement speech goals was never disrupted by these perturbations. Muscle responses were seen in the lower lip muscles, implicating corrective, feedback processes. Additionally, compensatory responses to these lower lip loads were also observed in the independently controlled muscles of the upper lip, reflecting the parallel operation of open-loop, sensorimotor mechanisms. Compensatory responses from both the upper and lower lip muscles were observed with small (1 mm) as well as large (15 mm) perturbations. The latencies of these compensatory responses were not discernible by conventional ensemble averaging. Moreover, responses at latencies of lower brain stem-mediated reflexes (i.e., 10-18 ms) were not apparent with inspection of individual records. Response latencies were determined on individual loaded trials through the use of a computer algorithm that took into account the variability of electromyograms (EMG) among the control trials. These latency measures confirmed the absence of brain stem-mediated responses and yielded response latencies that ranged from 22 to 75 ms. Response latencies appeared to be influenced by the time relation between load onset and the initiation of muscle activation. Examination of muscle activity changes for individual loaded trials revealed complementary variations in the magnitude of responses among multiple muscles contributing to a movement compensation. These observations may have implications for limb movement control if multimovement speech gestures are considered analogous to a limb action requiring coordinated movements around multiple joints. In this context, these speech motor control data might be interpreted to suggest that for complex movements, both corrective feedback and open-loop predictive processes are operating, with the latter involved in the control of coordination among multiple movement subcomponents.

Therapeutic Remyelination Strategies in a Novel Model of Multiple Sclerosis: Japanese Macaque Encephalomyelitis

DTIC Science & Technology

2011-05-01

genome was determined and compared to simian and human herpesvirus genomes representing alpha-herpesvi- ruses, beta- herpesviruses and gamma-1 and...of JMRV Genome with Select Simian and Human Herpesvirus Genomes Showing Percent Nucleotide Sequence Identity Virus JMRV RRV KSHV HVS RhLCV EBV RhCMV...2 - Introduction Particular viruses, especially gama- herpesviruses , may act as a trigger of multiple sclerosis (MS) (Levin et

Kaposi sarcoma herpesvirus pathogenesis

PubMed Central

Koch, Sandra; Schulz, Thomas F.

2017-01-01

Kaposi sarcoma herpesvirus (KSHV), taxonomical name human gammaherpesvirus 8, is a phylogenetically old human virus that co-evolved with human populations, but is now only common (seroprevalence greater than 10%) in sub-Saharan Africa, around the Mediterranean Sea, parts of South America and in a few ethnic communities. KSHV causes three human malignancies, Kaposi sarcoma, primary effusion lymphoma, and many cases of the plasmablastic form of multicentric Castleman's disease (MCD) as well as occasional cases of plasmablastic lymphoma arising from MCD; it has also been linked to rare cases of bone marrow failure and hepatitis. As it has colonized humans physiologically for many thousand years, cofactors are needed to allow it to unfold its pathogenic potential. In most cases, these include immune defects of genetic, iatrogenic or infectious origin, and inflammation appears to play an important role in disease development. Our much improved understanding of its life cycle and its role in pathogenesis should now allow us to develop new therapeutic strategies directed against key viral proteins or intracellular pathways that are crucial for virus replication or persistence. Likewise, its limited (for a herpesvirus) distribution and transmission should offer an opportunity for the development and use of a vaccine to prevent transmission. This article is part of the themed issue ‘Human oncogenic viruses’. PMID:28893942

Up-regulation of tumor suppressor genes by exogenous dhC16-Cer contributes to its anti-cancer activity in primary effusion lymphoma

PubMed Central

Lin, Zhen; Zabaleta, Jovanny; Dai, Lu; Qin, Zhiqiang

2017-01-01

Primary effusion lymphoma (PEL) is a rare and highly aggressive B-cell malignancy with Kaposi's sarcoma-associated herpesvirus (KSHV) infection, while lack of effective therapies. Our recent data indicated that targeting the sphingolipid metabolism by either sphingosine kinase inhibitor or exogenous ceramide species induces PEL cell apoptosis and suppresses tumor progression in vivo. However, the underlying mechanisms for these exogenous ceramides “killing” PEL cells remain largely unknown. Based on the microarray analysis, we found that exogenous dhC16-Cer treatment affected the expression of many cellular genes with important functions within PEL cells such as regulation of cell cycle, cell survival/proliferation, and apoptosis/anti-apoptosis. Interestingly, we found that a subset of tumor suppressor genes (TSGs) was up-regulated from dhC16-Cer treated PEL cells. One of these elevated TSGs, Thrombospondin-1 (THBS1) was required for dhC16-Cer induced PEL cell cycle arrest. Moreover, dhC16-Cer up-regulation of THBS1 was through the suppression of multiple KSHV microRNAs expression. Our data demonstrate that exogenous ceramides display anti-cancer activities for PEL through regulation of both host and oncogenic virus factors. PMID:28146424

Delayed P100-Like Latencies in Multiple Sclerosis: A Preliminary Investigation Using Visual Evoked Spread Spectrum Analysis

PubMed Central

Kiiski, Hanni S. M.; Ní Riada, Sinéad; Lalor, Edmund C.; Gonçalves, Nuno R.; Nolan, Hugh; Whelan, Robert; Lonergan, Róisín; Kelly, Siobhán; O'Brien, Marie Claire; Kinsella, Katie; Bramham, Jessica; Burke, Teresa; Ó Donnchadha, Seán; Hutchinson, Michael; Tubridy, Niall; Reilly, Richard B.

2016-01-01

Conduction along the optic nerve is often slowed in multiple sclerosis (MS). This is typically assessed by measuring the latency of the P100 component of the Visual Evoked Potential (VEP) using electroencephalography. The Visual Evoked Spread Spectrum Analysis (VESPA) method, which involves modulating the contrast of a continuous visual stimulus over time, can produce a visually evoked response analogous to the P100 but with a higher signal-to-noise ratio and potentially higher sensitivity to individual differences in comparison to the VEP. The main objective of the study was to conduct a preliminary investigation into the utility of the VESPA method for probing and monitoring visual dysfunction in multiple sclerosis. The latencies and amplitudes of the P100-like VESPA component were compared between healthy controls and multiple sclerosis patients, and multiple sclerosis subgroups. The P100-like VESPA component activations were examined at baseline and over a 3-year period. The study included 43 multiple sclerosis patients (23 relapsing-remitting MS, 20 secondary-progressive MS) and 42 healthy controls who completed the VESPA at baseline. The follow-up sessions were conducted 12 months after baseline with 24 MS patients (15 relapsing-remitting MS, 9 secondary-progressive MS) and 23 controls, and again at 24 months post-baseline with 19 MS patients (13 relapsing-remitting MS, 6 secondary-progressive MS) and 14 controls. The results showed P100-like VESPA latencies to be delayed in multiple sclerosis compared to healthy controls over the 24-month period. Secondary-progressive MS patients had most pronounced delay in P100-like VESPA latency relative to relapsing-remitting MS and controls. There were no longitudinal P100-like VESPA response differences. These findings suggest that the VESPA method is a reproducible electrophysiological method that may have potential utility in the assessment of visual dysfunction in multiple sclerosis. PMID:26726800

Correlation between blink reflex abnormalities and magnetic resonance imaging findings in patients with multiple sclerosis.

PubMed

Degirmenci, Eylem; Erdogan, Cagdas; Bir, Levent Sinan

2013-09-01

This study investigates the correlation between brain magnetic resonance imaging findings and blink reflex abnormalities in patients with relapsing remitting multiple sclerosis. Twenty-six patients and 17 healthy subjects were included in this study. Blink reflex test (BRT) results were obtained using right and left stimulations; thus, 52 BRT results were recorded for the patient group, and 34 BRT results were recorded for the control group. The magnetic resonance imaging (MRI) findings were classified based on the existence of brainstem lesions (hyperintense lesion on T2 weighted (W) and fast fluid-attenuated inversion recovery MRI or contrast-enhancing lesion on T1W MRI). Correlation analysis was performed for the BRT and MRI findings. The percentage of individuals with abnormal BRT results (including R1 latency, ipsilateral R2 latency, and contralateral R2 latency) was significantly higher in the patient group as compared to the control group (p values: 0.015, 0.001, and 0.002, respectively). Correlation analysis revealed significant correlations between contralateral R2 latency abnormalities and brainstem lesions (p value: 0.011). Our results showed significant correlation correlations between contralateral R2 latency abnormalities and brainstem lesions and these results may be explained the effects of multiple demyelinating lesions of the brain stem of patients with relapsing remitting multiple sclerosis.

Vestibular evoked myogenic potential findings in multiple sclerosis.

PubMed

Escorihuela García, Vicente; Llópez Carratalá, Ignacio; Orts Alborch, Miguel; Marco Algarra, Jaime

2013-01-01

Multiple sclerosis is an inflammatory disease involving the occurrence of demyelinating, chronic neurodegenerative lesions in the central nervous system. We studied vestibular evoked myogenic potentials (VEMPs) in this pathology, to allow us to evaluate the saccule, inferior vestibular nerve and vestibular-spinal pathway non-invasively. There were 23 patients diagnosed with multiple sclerosis who underwent VEMP recordings, comparing our results with a control group consisting of 35 healthy subjects. We registered p13 and n23 wave latencies, interaural amplitude difference and asymmetry ratio between both ears. Subjects also underwent an otoscopy and audiometric examination. The prolongation of p13 and n23 wave latencies was the most notable characteristic, with a mean p13 wave latency of 19.53 milliseconds and a mean latency of 30.06 milliseconds for n23. In contrast, the asymmetry index showed no significant differences with our control group. In case of multiple sclerosis, the prolongation of the p13 and n23 VEMP wave latencies is a feature that has been attributed to slowing of conduction by demyelination of the vestibular-spinal pathway. In this regard, alteration of the response or lack thereof in these potentials has a locator value of injury to the lower brainstem. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Air Traffic Controller Performance and Acceptability of Multiple UAS in a Simulated NAS Environment

NASA Technical Reports Server (NTRS)

Vu, Kim-Phuong L.; Strybel, Thomas; Chiappe, Dan; Morales, Greg; Battiste, Vernol; Shively, Robert Jay

2014-01-01

Previously, we showed that air traffic controllers (ATCos) rated UAS pilot verbal response latencies as acceptable when a 1.5 s delay was added to the UAS pilot responses, but a 5 s delay was rated as mostly unacceptable. In the present study we determined whether a 1.5 s added delay in the UAS pilots' verbal communications would affect ATCos interactions with UAS and other conventional aircraft when the number and speed of the UAS were manipulated. Eight radar-certified ATCos participated in this simulation. The ATCos managed a medium altitude sector containing arrival aircraft, en route aircraft, and one to four UAS. The UAS were conducting a surveillance mission and flew at either a "slow" or "fast" speed. We measured both UAS and conventional pilots' verbal communication latencies, and obtained ATCos' acceptability ratings for these latencies. Although the UAS pilot response latencies were longer than those of conventional pilots, the ATCos rated UAS pilot verbal communication latencies to be as acceptable as those of conventional pilots. Because the overall traffic load within the sector was held constant, ATCos only performed slightly worse when multiple UAS were in their sector compared to when only one UAS was in the sector. Implications of these findings for UAS integration in the NAS are discussed.

Discrete Serotonin Systems Mediate Memory Enhancement and Escape Latencies after Unpredicted Aversive Experience in Drosophila Place Memory

PubMed Central

Sitaraman, Divya; Kramer, Elizabeth F.; Kahsai, Lily; Ostrowski, Daniela; Zars, Troy

2017-01-01

Feedback mechanisms in operant learning are critical for animals to increase reward or reduce punishment. However, not all conditions have a behavior that can readily resolve an event. Animals must then try out different behaviors to better their situation through outcome learning. This form of learning allows for novel solutions and with positive experience can lead to unexpected behavioral routines. Learned helplessness, as a type of outcome learning, manifests in part as increases in escape latency in the face of repeated unpredicted shocks. Little is known about the mechanisms of outcome learning. When fruit fly Drosophila melanogaster are exposed to unpredicted high temperatures in a place learning paradigm, flies both increase escape latencies and have a higher memory when given control of a place/temperature contingency. Here we describe discrete serotonin neuronal circuits that mediate aversive reinforcement, escape latencies, and memory levels after place learning in the presence and absence of unexpected aversive events. The results show that two features of learned helplessness depend on the same modulatory system as aversive reinforcement. Moreover, changes in aversive reinforcement and escape latency depend on local neural circuit modulation, while memory enhancement requires larger modulation of multiple behavioral control circuits. PMID:29321732

Low-latency Science Exploration of Planetary Bodies: a Demonstration Using ISS in Support of Mars Human Exploration

NASA Technical Reports Server (NTRS)

Thronson, Harley A.; Valinia, Azita; Bleacher, Jacob; Eigenbrode, Jennifer; Garvin, Jim; Petro, Noah

2014-01-01

We summarize a proposed experiment to use the International Space Station to formally examine the application and validation of low-latency telepresence for surface exploration from space as an alternative, precursor, or potentially as an adjunct to astronaut "boots on the ground." The approach is to develop and propose controlled experiments, which build upon previous field studies and which will assess the effects of different latencies (0 to 500 msec), task complexity, and alternate forms of feedback to the operator. These experiments serve as an example of a pathfinder for NASA's roadmap of missions to Mars with low-latency telerobotic exploration as a precursor to astronaut's landing on the surface to conduct geological tasks.

Targeting CTCF to Control Virus Gene Expression: A Common Theme amongst Diverse DNA Viruses.

PubMed

Pentland, Ieisha; Parish, Joanna L

2015-07-06

All viruses target host cell factors for successful life cycle completion. Transcriptional control of DNA viruses by host cell factors is important in the temporal and spatial regulation of virus gene expression. Many of these factors are recruited to enhance virus gene expression and thereby increase virus production, but host cell factors can also restrict virus gene expression and productivity of infection. CCCTC binding factor (CTCF) is a host cell DNA binding protein important for the regulation of genomic chromatin boundaries, transcriptional control and enhancer element usage. CTCF also functions in RNA polymerase II regulation and in doing so can influence co-transcriptional splicing events. Several DNA viruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV) and human papillomavirus (HPV) utilize CTCF to control virus gene expression and many studies have highlighted a role for CTCF in the persistence of these diverse oncogenic viruses. CTCF can both enhance and repress virus gene expression and in some cases CTCF increases the complexity of alternatively spliced transcripts. This review article will discuss the function of CTCF in the life cycle of DNA viruses in the context of known host cell CTCF functions.

Event-Related Potential responses to the acute and chronic effects of alcohol in adolescent and adult Wistar rats

PubMed Central

Ehlers, Cindy L.; Desikan, Anita; Wills, Derek N.

2014-01-01

Background The present study explored the hypothesis that adolescent ethanol exposure may cause long lasting changes in ethanol sensitivity by exploring the age-related effects of acute alcohol on intoxication and on event-related potential (ERP) responses to acoustic stimuli in ethanol naïve adolescent and adult male Wistar rats and in adult rats that were exposed to chronic ethanol/control conditions during adolescence. Methods Ethanol naïve adolescent (postnatal day 32 (PD32)) and adult male rats (PD99) were included in the first study. In a second study, rats were exposed to 5 weeks of ethanol vapor (Blood ethanol concentrations @ 175 mg%) or air from PD24 to PD59 and allowed to mature until PD90. In both studies rats were implanted with cortical recording electrodes, and the effects of acute ethanol (0.0, 1.5, and 3.0 g/kg) on behavioral and ERP responses were assessed. Results Adolescents were found to have higher amplitude and longer latency P3a and P3b components at baseline as compared to adult rats, and ethanol was found to produce a robust dose-dependent increase in the latency of the P3a and P3b components of the auditory ERP recorded in cortical sites in both adolescents and adults. However, ethanol produced significantly larger delays in P3a and P3b latencies in adults as compared to adolescents. Acute ethanol administration was also found to produce a robust dose dependent increase in the latency of the P3a and P3b components in adult animals exposed to ethanol vapor as adolescents and air exposed controls; however, larger acute ethanol-induced increases in P3a and P3b latencies were seen in controls as compared to adolescent vapor exposed rats. Conclusions Adolescent rats have a less intense P3 latency response to acute ethanol administration when compared to adult rats. Exposure to chronic ethanol during adolescence can cause “retention” of the adolescent phenotype of reduced P3 latency sensitivity to ethanol. PMID:24483322

A20 Functional Domains Regulate Subcellular Localization and NF-Kappa B Activation

DTIC Science & Technology

2013-08-15

that the first function to be described for A20 was that of an anti -apoptotic protein (55). They based their choice of experiments and preliminary...mediated apoptosis (55). After positive selection of the resulting clones with neomycin and verification of A20 expression, they compared the...Karposi sarcoma herpesvirus (KSHV) mediated cell transformation (72). K13 can directly activate NF-κB by interacting with the IKK complex and is

Method and system for downhole clock synchronization

DOEpatents

Hall, David R.; Bartholomew, David B.; Johnson, Monte; Moon, Justin; Koehler, Roger O.

2006-11-28

A method and system for use in synchronizing at least two clocks in a downhole network are disclosed. The method comprises determining a total signal latency between a controlling processing element and at least one downhole processing element in a downhole network and sending a synchronizing time over the downhole network to the at least one downhole processing element adjusted for the signal latency. Electronic time stamps may be used to measure latency between processing elements. A system for electrically synchronizing at least two clocks connected to a downhole network comprises a controlling processing element connected to a synchronizing clock in communication over a downhole network with at least one downhole processing element comprising at least one downhole clock. Preferably, the downhole network is integrated into a downhole tool string.

Real-Time Wavefront Control for the PALM-3000 High Order Adaptive Optics System

NASA Technical Reports Server (NTRS)

Truong, Tuan N.; Bouchez, Antonin H.; Dekany, Richard G.; Guiwits, Stephen R.; Roberts, Jennifer E.; Troy, Mitchell

2008-01-01

We present a cost-effective scalable real-time wavefront control architecture based on off-the-shelf graphics processing units hosted in an ultra-low latency, high-bandwidth interconnect PC cluster environment composed of modules written in the component-oriented language of nesC. The architecture enables full-matrix reconstruction of the wavefront at up to 2 KHz with latency under 250 us for the PALM-3000 adaptive optics systems, a state-of-the-art upgrade on the 5.1 meter Hale Telescope that consists of a 64 x 64 subaperture Shack-Hartmann wavefront sensor and a 3368 active actuator high order deformable mirror in series with a 241 active actuator tweeter DM. The architecture can easily scale up to support much larger AO systems at higher rates and lower latency.

Alternative diagnostic criteria for idiopathic hypersomnia: A 32-hour protocol.

PubMed

Evangelista, Elisa; Lopez, Régis; Barateau, Lucie; Chenini, Sofiene; Bosco, Adriana; Jaussent, Isabelle; Dauvilliers, Yves

2018-02-01

To assess the diagnostic value of extended sleep duration on a controlled 32-hour bed rest protocol in idiopathic hypersomnia (IH). One hundred sixteen patients with high suspicion of IH (37 clear-cut IH according to multiple sleep latency test criteria and 79 probable IH), 32 with hypersomnolence associated with a comorbid disorder (non-IH), and 21 controls underwent polysomnography, modified sleep latency tests, and a 32-hour bed rest protocol. Receiver operating characteristic curves were used to find optimal total sleep time (TST) cutoff values on various periods that discriminate patients from controls. TST was longer in patients with clear-cut IH than other groups (probable IH, non-IH, and controls) and in patients with probable IH than non-IH and controls. The TST cutoff best discriminating clear-cut IH and controls was 19 hours for the 32-hour recording (sensitivity = 91.9%, specificity = 85.7%) and 12 hours (100%, 85.7%) for the first 24 hours. The 19-hour cutoff displayed a specificity and sensitivity of 91.9% and 81.2% between IH and non-IH patients. Patients with IH above the 19-hour cutoff were overweight, had more sleep inertia, and had higher TST on all periods compared to patients below 19 hours, whereas no differences were found for the 12-hour cutoff. An inverse correlation was found between the mean sleep latency and TST during 32-hour recording in IH patients. In standardized and controlled stringent conditions, the optimal cutoff best discriminating patients from controls was 19 hours over 32 hours, allowing a clear-cut phenotypical characterization of major interest for research purposes. Sleepier patients on the multiple sleep latency test were also the more severe in terms of extended sleep. Ann Neurol 2018;83:235-247. © 2018 American Neurological Association.

Impaired Attentional Control in Pedophiles in a Sexual Distractor Task.

PubMed

Jordan, Kirsten; Fromberger, Peter; von Herder, Jakob; Steinkrauss, Henrike; Nemetschek, Rebekka; Witzel, Joachim; Müller, Jürgen L

2016-01-01

Pedophilic disorder, a subtype of paraphilia, is defined as a recurrent sexual interest in prepubescent children, which is characterized by persistent thoughts, fantasies, urges, sexual arousal, or behavior. Besides a deviant sexual preference, sexual preoccupation was found to be a dynamic risk factor for reoffending. Thus, it is conceivable that sex offenders and especially sex offenders against children have difficulties to control their responses to sexual stimuli. In the current study pedophiles, forensic and non-forensic control subjects had to solve a cognitive task, while sexual distractors were presented simultaneously. This kind of task also requires control functions. Therefore, data were analyzed with respect to attentional control while comparing eye movements toward sexual distractors and toward the cognitive task. We were mainly interested in how early (fixation latency) and late (relative fixation time) attentional processes were allocated to both, the cognitive target stimuli and the sexual distractors. Pedophiles demonstrated significantly lower attentional control in the sexual distractor task than both control groups (non-pedophiles). They showed a shorter fixation latency and longer fixation time for sexual distractors than non-pedophiles. Furthermore, pedophiles demonstrated a longer fixation latency and shorter fixation time for cognitive target stimuli. For classification analyses, an attentional control index (ACI) was built, i.e., the difference between eye movements on cognitive target stimuli and sexual distractors. For the ACI of early attentional processes, i.e., fixation latency, a good classification between pedophiles and non-pedophiles was found. We assumed that the measured attentional control represents inhibitory executive functions, specifically interference control. Further studies should examine if low attentional control in pedophiles is due to low motivation to solve the task or rather to a lack of ability to control attention with respect to sexual and/or neutral distractors. Prospectively, this design could be useful to generate hypotheses about clinical important aspects of controllability, the capacity of self-control, and the severity of a paraphilic disorder.

Impaired Attentional Control in Pedophiles in a Sexual Distractor Task

PubMed Central

Jordan, Kirsten; Fromberger, Peter; von Herder, Jakob; Steinkrauss, Henrike; Nemetschek, Rebekka; Witzel, Joachim; Müller, Jürgen L.

2016-01-01

Pedophilic disorder, a subtype of paraphilia, is defined as a recurrent sexual interest in prepubescent children, which is characterized by persistent thoughts, fantasies, urges, sexual arousal, or behavior. Besides a deviant sexual preference, sexual preoccupation was found to be a dynamic risk factor for reoffending. Thus, it is conceivable that sex offenders and especially sex offenders against children have difficulties to control their responses to sexual stimuli. In the current study pedophiles, forensic and non-forensic control subjects had to solve a cognitive task, while sexual distractors were presented simultaneously. This kind of task also requires control functions. Therefore, data were analyzed with respect to attentional control while comparing eye movements toward sexual distractors and toward the cognitive task. We were mainly interested in how early (fixation latency) and late (relative fixation time) attentional processes were allocated to both, the cognitive target stimuli and the sexual distractors. Pedophiles demonstrated significantly lower attentional control in the sexual distractor task than both control groups (non-pedophiles). They showed a shorter fixation latency and longer fixation time for sexual distractors than non-pedophiles. Furthermore, pedophiles demonstrated a longer fixation latency and shorter fixation time for cognitive target stimuli. For classification analyses, an attentional control index (ACI) was built, i.e., the difference between eye movements on cognitive target stimuli and sexual distractors. For the ACI of early attentional processes, i.e., fixation latency, a good classification between pedophiles and non-pedophiles was found. We assumed that the measured attentional control represents inhibitory executive functions, specifically interference control. Further studies should examine if low attentional control in pedophiles is due to low motivation to solve the task or rather to a lack of ability to control attention with respect to sexual and/or neutral distractors. Prospectively, this design could be useful to generate hypotheses about clinical important aspects of controllability, the capacity of self-control, and the severity of a paraphilic disorder. PMID:27994559

Human embryonic stem cell lines model experimental human cytomegalovirus latency.

PubMed

Penkert, Rhiannon R; Kalejta, Robert F

2013-05-28

Herpesviruses are highly successful pathogens that persist for the lifetime of their hosts primarily because of their ability to establish and maintain latent infections from which the virus is capable of productively reactivating. Human cytomegalovirus (HCMV), a betaherpesvirus, establishes latency in CD34(+) hematopoietic progenitor cells during natural infections in the body. Experimental infection of CD34(+) cells ex vivo has demonstrated that expression of the viral gene products that drive productive infection is silenced by an intrinsic immune defense mediated by Daxx and histone deacetylases through heterochromatinization of the viral genome during the establishment of latency. Additional mechanistic details about the establishment, let alone maintenance and reactivation, of HCMV latency remain scarce. This is partly due to the technical challenges of CD34(+) cell culture, most notably, the difficulty in preventing spontaneous differentiation that drives reactivation and renders them permissive for productive infection. Here we demonstrate that HCMV can establish, maintain, and reactivate in vitro from experimental latency in cultures of human embryonic stem cells (ESCs), for which spurious differentiation can be prevented or controlled. Furthermore, we show that known molecular aspects of HCMV latency are faithfully recapitulated in these cells. In total, we present ESCs as a novel, tractable model for studies of HCMV latency.

Reducing audio stimulus presentation latencies across studies, laboratories, and hardware and operating system configurations.

PubMed

Babjack, Destiny L; Cernicky, Brandon; Sobotka, Andrew J; Basler, Lee; Struthers, Devon; Kisic, Richard; Barone, Kimberly; Zuccolotto, Anthony P

2015-09-01

Using differing computer platforms and audio output devices to deliver audio stimuli often introduces (1) substantial variability across labs and (2) variable time between the intended and actual sound delivery (the sound onset latency). Fast, accurate audio onset latencies are particularly important when audio stimuli need to be delivered precisely as part of studies that depend on accurate timing (e.g., electroencephalographic, event-related potential, or multimodal studies), or in multisite studies in which standardization and strict control over the computer platforms used is not feasible. This research describes the variability introduced by using differing configurations and introduces a novel approach to minimizing audio sound latency and variability. A stimulus presentation and latency assessment approach is presented using E-Prime and Chronos (a new multifunction, USB-based data presentation and collection device). The present approach reliably delivers audio stimuli with low latencies that vary by ≤1 ms, independent of hardware and Windows operating system (OS)/driver combinations. The Chronos audio subsystem adopts a buffering, aborting, querying, and remixing approach to the delivery of audio, to achieve a consistent 1-ms sound onset latency for single-sound delivery, and precise delivery of multiple sounds that achieves standard deviations of 1/10th of a millisecond without the use of advanced scripting. Chronos's sound onset latencies are small, reliable, and consistent across systems. Testing of standard audio delivery devices and configurations highlights the need for careful attention to consistency between labs, experiments, and multiple study sites in their hardware choices, OS selections, and adoption of audio delivery systems designed to sidestep the audio latency variability issue.

Behavioral Treatment of Menopausal Hot Flashes: Evaluation by Objective Methods.

ERIC Educational Resources Information Center

Germaine, Leonard M.; Freedman, Robert R.

1984-01-01

Used latency to hot flash onset under heat stress to evaluate the effects of relaxation treatment or a control procedure in 14 menopausal women. Following treatment, the latency to hot flash onset during heat stress was increased in relaxation subjects. Reported symptom frequency was significantly reduced in relaxation subjects. (BH)

Controlled replication: reduce the capacity occupied by redundant replicas in tiled chip multiprocessors

NASA Astrophysics Data System (ADS)

Li, Hao; Xie, Lunguo

2013-03-01

The design of cache system for Chip Multiprocessor (CMP) face many challenges because future CMPs will have more cores and greater on-chip cache capacity. There are two base design schemes about L2 cache: private scheme in which each L2 slice is treated as a private L2 cache and shared scheme in which all L2 slices are treated as a large L2 cache shared by all cores. Private caches provide the lowest hit latency but reduce the total effective cache capacity. A shared L2 cache increases the effective cache capacity but has long hit latencies when data is on a remote tile. This paper present a new Controlled Replication (CR) policy to reduce the capacities occupied by redundant shared replicas. the new CR policy increases the effective capacity than victim replication scheme and has lower hit latency than shared scheme. We evaluate the various schemes using full-system simulation of parallel applications. Results show that CR reduces the average memory access latency of shared scheme by an average of 13%, providing better overall performance than victim replication and shared schemes.

Suprascapular nerve entrapment in newsreel cameramen.

PubMed

Karataş, Gülçin Kaymak; Göğüş, Feride

2003-03-01

To determine presence of suprascapular nerve entrapment in a group of newsreel cameramen. Thirty-six men working as newsreel cameramen participated in the study. In addition to musculoskeletal and neurologic examinations, bilateral suprascapular nerve conduction studies and needle electromyography were performed. A group of 19 healthy, male volunteers were included in the study as normal controls for suprascapular nerve conduction studies. In newsreel cameramen, mean suprascapular nerve latency was 3.20 +/- 0.56 msec and 2.84 +/- 0.36 msec for right and left shoulders, respectively (P = 0.001). The mean latency difference between right and left suprascapular nerves was -0.05 +/- 0.19 msec in the control group and 0.36 +/- 0.58 msec in the cameramen group (P < 0.001). Six subjects' right suprascapular nerve motor latencies were 2 SD above the normal mean values. There was no relationship between suprascapular nerve latencies and the age, professional life, and number of hours worked daily by the subjects. Carrying a heavy, mobile camera on the shoulder might cause suprascapular nerve entrapment in newsreel cameramen. This could be considered an occupational disorder of the suprascapular nerve, like meat-packer's neuropathy.

The Temporal Propagation of Intrinsic Brain Activity Associate With the Occurrence of PTSD.

PubMed

Weng, Yifei; Qi, Rongfeng; Chen, Feng; Ke, Jun; Xu, Qiang; Zhong, Yuan; Chen, Lida; Li, Jianjun; Zhang, Zhiqiang; Zhang, Li; Lu, Guangming

2018-01-01

The abnormal brain activity is a pivotal condition for the occurrence of posttraumatic stress disorder. However, the dynamic time features of intrinsic brain activities still remain unclearly in PTSD patients. Our study aims to perform the resting-state lag analysis (RS-LA) method to explore potential propagated patterns of intrinsic brain activities in PTSD patients. We recruited 27 drug-naive patients with PTSD, 33 trauma-exposed controls (TEC), and 30 demographically matched healthy controls (HC) in the final data statistics. Both RS-LA and conventional voxel-wise functional connectivity strength (FCS) methods were employed on the same dataset. Then, Spearman correlation analysis was conducted on time latency values of those abnormal brain regions with the clinical assessments. Compared with HC group, the time latency patterns of PTSD patients significantly shifted toward later in posterior cingulate cortex/precuneus, middle prefrontal cortex, right angular, and left pre- and post-central cortex. The TEC group tended to have similar time latency in right angular. Additionally, significant time latency in right STG was found in PTSD group relative to TEC group. Spearman correlation analysis revealed that the time latency value of mPFC negatively correlated to the PTSD checklist-civilian version scores (PCL_C) in PTSD group ( r = -0.578, P < 0.05). Furthermore, group differences map of FCS exhibited parts of overlapping areas with that of RS-LA, however, less specificity in detecting PTSD patients. In conclusion, apparent alterations of time latency were observed in DMN and primary sensorimotor areas of PTSD patients. These findings provide us with new evidence to explain the neural pathophysiology contributing to PTSD.

Online control of reaching and pointing to visual, auditory, and multimodal targets: Effects of target modality and method of determining correction latency.

PubMed

Holmes, Nicholas P; Dakwar, Azar R

2015-12-01

Movements aimed towards objects occasionally have to be adjusted when the object moves. These online adjustments can be very rapid, occurring in as little as 100ms. More is known about the latency and neural basis of online control of movements to visual than to auditory target objects. We examined the latency of online corrections in reaching-to-point movements to visual and auditory targets that could change side and/or modality at movement onset. Visual or auditory targets were presented on the left or right sides, and participants were instructed to reach and point to them as quickly and as accurately as possible. On half of the trials, the targets changed side at movement onset, and participants had to correct their movements to point to the new target location as quickly as possible. Given different published approaches to measuring the latency for initiating movement corrections, we examined several different methods systematically. What we describe here as the optimal methods involved fitting a straight-line model to the velocity of the correction movement, rather than using a statistical criterion to determine correction onset. In the multimodal experiment, these model-fitting methods produced significantly lower latencies for correcting movements away from the auditory targets than away from the visual targets. Our results confirm that rapid online correction is possible for auditory targets, but further work is required to determine whether the underlying control system for reaching and pointing movements is the same for auditory and visual targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Expression of Herpes Simplex Virus 1-Encoded MicroRNAs in Human Trigeminal Ganglia and Their Relation to Local T-Cell Infiltrates ▿

PubMed Central

Held, Kathrin; Junker, Andreas; Dornmair, Klaus; Meinl, Edgar; Sinicina, Inga; Brandt, Thomas; Theil, Diethilde; Derfuss, Tobias

2011-01-01

Herpes simplex type 1 (HSV-1) is a neurotropic virus which establishes lifelong latency in human trigeminal ganglia (TG). Currently, two nonexclusive control mechanisms of HSV-1 latency are discussed: antiviral CD8+ T cells and viral microRNAs (miRNAs) encoded by the latency associated transcript (LAT). We investigate here to what extent these mechanisms may contribute to the maintenance of HSV-1 latency. We show that only a small proportion of LAT+ neurons is surrounded by T cells in human TG. This indicates that viral latency in human TG might be controlled by other mechanisms such as viral miRNAs. Therefore, we assessed TG sections for the presence of HSV-1 miRNA, DNA, and mRNA by combining LAT in situ hybridization, T-cell immunohistochemistry, and single cell analysis of laser-microdissected sensory neurons. Quantitative reverse transcription-PCR (RT-PCR) revealed that LAT+ neurons with or without surrounding T cells were always positive for HSV-1 miRNAs and DNA. Furthermore, ICP0 mRNA could rarely be detected only in LAT+ neurons, as analyzed by single-cell RT-PCR. In contrast, in LAT− neurons that were surrounded by T cells, neither miRNAs nor the DNA of HSV-1, HSV-2, or varicella-zoster virus could be detected. These data indicate that the majority of LAT+ neurons is not directly controlled by T cells. However, miRNA expression in every latently infected neuron would provide an additional checkpoint before viral replication is initiated. PMID:21795359

Neurophysiological analyses in different color environments of cognitive function in patients with traumatic brain injury.

PubMed

Kodama, Takayuki; Morita, Kiichiro; Doi, Ryo; Shoji, Yoshihisa; Shigemori, Minoru

2010-09-01

Colors are thought to elicit various emotional effects. Red, with its high likelihood of attracting attention, is considered to have an exciting, active effect; whereas green, with its low attention value, is considered to have a relaxing, sedative effect. Colors are also thought to affect human cognition and emotion. However, there have been few studies of the influence of colors in one's surroundings (e.g., the color environment and its effect on cognitive function). In this study, we investigated the influence of differences in color environments (red, green, or darkness) on cognitive function by analyzing the P300 component of event-related potentials (ERPs) elicited by oddball visual paradigms as a measure of cognitive characteristics in patients who had sustained traumatic brain injury (TBI). In 18 patients with TBI and 18 age-matched control subjects, ERPs were recorded in response to photographs of crying babies. We found that P300 amplitudes in the red environment were significantly larger in controls than in TBI patients, while those in both the green environment and darkness showed no difference between controls and patients. P300 latencies in the red environment and in darkness were significantly longer in patients than in controls. P300 latency in the red environment was significantly shorter than that in darkness. However, P300 latency in the green environment showed no difference between controls and patients. In healthy individuals, the emotional effects of the red environment enhanced cognitive function. In patients with TBI, however, cognitive function was reduced in the red environment. Furthermore, P300 amplitude and latency were strongly correlated with the time on the Trail Making Test (TMT), and the value of the intelligence quotient of the Wechsler Adult Intelligence Scale-III (WAIS-III). These findings suggest that P300 amplitude and latency are useful indexes for the evaluation of TBI patients, and that color environments affect cognitive function.

Latency and User Performance in Virtual Environments and Augmented Reality

NASA Technical Reports Server (NTRS)

Ellis, Stephen R.

2009-01-01

System rendering latency has been recognized by senior researchers, such as Professor Fredrick Brooks of UNC (Turing Award 1999), as a major factor limiting the realism and utility of head-referenced displays systems. Latency has been shown to reduce the user's sense of immersion within a virtual environment, disturb user interaction with virtual objects, and to contribute to motion sickness during some simulation tasks. Latency, however, is not just an issue for external display systems since finite nerve conduction rates and variation in transduction times in the human body's sensors also pose problems for latency management within the nervous system. Some of the phenomena arising from the brain's handling of sensory asynchrony due to latency will be discussed as a prelude to consideration of the effects of latency in interactive displays. The causes and consequences of the erroneous movement that appears in displays due to latency will be illustrated with examples of the user performance impact provided by several experiments. These experiments will review the generality of user sensitivity to latency when users judge either object or environment stability. Hardware and signal processing countermeasures will also be discussed. In particular the tuning of a simple extrapolative predictive filter not using a dynamic movement model will be presented. Results show that it is possible to adjust this filter so that the appearance of some latencies may be hidden without the introduction of perceptual artifacts such as overshoot. Several examples of the effects of user performance will be illustrated by three-dimensional tracking and tracing tasks executed in virtual environments. These experiments demonstrate classic phenomena known from work on manual control and show the need for very responsive systems if they are indented to support precise manipulation. The practical benefits of removing interfering latencies from interactive systems will be emphasized with some classic final examples from surgical telerobotics, and human-computer interaction.

Development of Auditory Evoked Responses in Normally Developing Preschool Children and Children with Autism Spectrum Disorder.

PubMed

Stephen, Julia M; Hill, Dina E; Peters, Amanda; Flynn, Lucinda; Zhang, Tongsheng; Okada, Yoshio

2017-01-01

The cortical responses to auditory stimuli undergo rapid and dramatic changes during the first 3 years of life in normally developing (ND) children, with decreases in latency and changes in amplitude in the primary peaks. However, most previous studies have focused on children >3 years of age. The analysis of data from the early stages of development is challenging because the temporal pattern of the evoked responses changes with age (e.g., additional peaks emerge with increasing age) and peak latency decreases with age. This study used the topography of the auditory evoked magnetic field (AEF) to identify the auditory components in ND children between 6 and 68 months (n = 48). The latencies of the peaks in the AEF produced by a tone burst (ISI 2 ± 0.2 s) during sleep decreased with age, consistent with previous reports in awake children. The peak latencies of the AEFs in ND children and children with autism spectrum disorder (ASD) were compared. Previous studies indicate that the latencies of the initial components of the auditory evoked potential (AEP) and the AEF are delayed in children with ASD when compared to age-matched ND children >4 years of age. We speculated whether the AEF latencies decrease with age in children diagnosed with ASD as in ND children, but with uniformly longer latencies before the age of about 4 years. Contrary to this hypothesis, the peak latencies did not decrease with age in the ASD group (24-62 months, n = 16) during sleep (unlike in the age-matched controls), although the mean latencies were longer in the ASD group as in previous studies. These results are consistent with previous studies indicating delays in auditory latencies, and they indicate a different maturational pattern in ASD children and ND children. Longitudinal studies are needed to confirm whether the AEF latencies diverge with age, starting at around 3 years, in these 2 groups of children. © 2017 S. Karger AG, Basel.

Susceptibility of linear and nonlinear otoacoustic emission components to low-dose styrene exposure.

PubMed

Tognola, G; Chiaramello, E; Sisto, R; Moleti, A

2015-03-01

To investigate potential susceptibility of active cochlear mechanisms to low-level styrene exposure by comparing TEOAEs in workers and controls. Two advanced analysis techniques were applied to detect sub-clinical changes in linear and nonlinear cochlear mechanisms of OAE generation: the wavelet transform to decompose TEOAEs into time-frequency components and extract signal-to-noise ratio and latency of each component, and the bispectrum to detect and extract nonlinear TEOAE contributions as quadratic frequency couplings (QFCs). Two cohorts of workers were examined: subjects exposed exclusively to styrene (N = 9), and subjects exposed to styrene and noise (N = 6). The control group was perfectly matched by age and sex to the exposed group. Exposed subjects showed significantly lowered SNR in TEOAE components at mid-to-high frequencies (above 1.6 kHz) and a shift of QFC distribution towards lower frequencies than controls. No systematic differences were observed in latency. Low-level styrene exposure may have induced a modification of cochlear functionality as concerns linear and nonlinear OAE generation mechanisms. The lack of change in latency seems to suggest that the OAE components, where generation region and latency are tightly coupled, may not have been affected by styrene and noise exposure levels considered here.

Gain modulation of the middle latency cutaneous reflex in patients with chronic joint instability after ankle sprain.

PubMed

Futatsubashi, Genki; Sasada, Shusaku; Tazoe, Toshiki; Komiyama, Tomoyoshi

2013-07-01

To investigate the neural alteration of reflex pathways arising from cutaneous afferents in patients with chronic ankle instability. Cutaneous reflexes were elicited by applying non-noxious electrical stimulation to the sural nerve of subjects with chronic ankle instability (n=17) and control subjects (n=17) while sitting. Electromyographic (EMG) signals were recorded from each ankle and thigh muscle. The middle latency response (MLR; latency: 70-120 ms) component was analyzed. In the peroneus longus (PL) and vastus lateralis (VL) muscles, linear regression analyses between the magnitude of the inhibitory MLR and background EMG activity showed that, compared to the uninjured side and the control subjects, the gain of the suppressive MLR was increased in the injured side. This was also confirmed by the pooled data for both groups. The degree of MLR alteration was significantly correlated to that of chronic ankle instability in the PL. The excitability of middle latency cutaneous reflexes in the PL and VL is modulated in subjects with chronic ankle instability. Cutaneous reflexes may be potential tools to investigate the pathological state of the neural system that controls the lower limbs in subjects with chronic ankle instability. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Measurement and analysis of workload effects on fault latency in real-time systems

NASA Technical Reports Server (NTRS)

Woodbury, Michael H.; Shin, Kang G.

1990-01-01

The authors demonstrate the need to address fault latency in highly reliable real-time control computer systems. It is noted that the effectiveness of all known recovery mechanisms is greatly reduced in the presence of multiple latent faults. The presence of multiple latent faults increases the possibility of multiple errors, which could result in coverage failure. The authors present experimental evidence indicating that the duration of fault latency is dependent on workload. A synthetic workload generator is used to vary the workload, and a hardware fault injector is applied to inject transient faults of varying durations. This method makes it possible to derive the distribution of fault latency duration. Experimental results obtained from the fault-tolerant multiprocessor at the NASA Airlab are presented and discussed.

Sensor Spatial Distortion, Visual Latency, and Update Rate Effects on 3D Tracking in Virtual Environments

NASA Technical Reports Server (NTRS)

Ellis, S. R.; Adelstein, B. D.; Baumeler, S.; Jense, G. J.; Jacoby, R. H.; Trejo, Leonard (Technical Monitor)

1998-01-01

Several common defects that we have sought to minimize in immersing virtual environments are: static sensor spatial distortion, visual latency, and low update rates. Human performance within our environments during large amplitude 3D tracking was assessed by objective and subjective methods in the presence and absence of these defects. Results show that 1) removal of our relatively small spatial sensor distortion had minor effects on the tracking activity, 2) an Adapted Cooper-Harper controllability scale proved the most sensitive subjective indicator of the degradation of dynamic fidelity caused by increasing latency and decreasing frame rates, and 3) performance, as measured by normalized RMS tracking error or subjective impressions, was more markedly influenced by changing visual latency than by update rate.

A Simulation Base Investigation of High Latency Space Systems Operations

NASA Technical Reports Server (NTRS)

Li, Zu Qun; Crues, Edwin Z.; Bielski, Paul; Moore, Michael

2017-01-01

NASA's human space program has developed considerable experience with near Earth space operations. Although NASA has experience with deep space robotic missions, NASA has little substantive experience with human deep space operations. Even in the Apollo program, the missions lasted only a few weeks and the communication latencies were on the order of seconds. Human missions beyond the relatively close confines of the Earth-Moon system will involve missions with durations measured in months and communications latencies measured in minutes. To minimize crew risk and to maximize mission success, NASA needs to develop a better understanding of the implications of these types of mission durations and communication latencies on vehicle design, mission design and flight controller interaction with the crew. To begin to address these needs, NASA performed a study using a physics-based subsystem simulation to investigate the interactions between spacecraft crew and a ground-based mission control center for vehicle subsystem operations across long communication delays. The simulation, built with a subsystem modeling tool developed at NASA's Johnson Space Center, models the life support system of a Mars transit vehicle. The simulation contains models of the cabin atmosphere and pressure control system, electrical power system, drinking and waste water systems, internal and external thermal control systems, and crew metabolic functions. The simulation has three interfaces: 1) a real-time crew interface that can be use to monitor and control the vehicle subsystems; 2) a mission control center interface with data transport delays up to 15 minutes each way; 3) a real-time simulation test conductor interface that can be use to insert subsystem malfunctions and observe the interactions between the crew, ground, and simulated vehicle. The study was conducted at the 21st NASA Extreme Environment Mission Operations (NEEMO) mission between July 18th and Aug 3rd of year 2016. The NEEMO mission provides ideal conditions for this study with crew in the loop, an active control center, and real-time flow of high latency communications and data. NEEMO crew and ground support will work through procedures including activation of the transit vehicle power system, opening the hatch between the transit vehicle and a Mars ascent vehicle, transferring simulated crewmembers between vehicles, overcoming subsystem malfunctions, sending simulated crewmember on extra-vehicular activities, and other housekeeping activities. This study is enhancing the understanding of high latency operations and the advantages and disadvantages of different communication methods. It is also providing results that will help improve the design of simulation interfaces and inform the design of Mars transit vehicles.

The New Feedback Control System of RFX-mod Based on the MARTe Real-Time Framework

NASA Astrophysics Data System (ADS)

Manduchi, G.; Luchetta, A.; Soppelsa, A.; Taliercio, C.

2014-06-01

A real-time system has been successfully used since 2004 in the RFX-mod nuclear fusion experiment to control the position of the plasma and its Magneto Hydrodynamic (MHD) modes. However, its latency and the limited computation power of the used processors prevented the usage of more aggressive control algorithms. Therefore a new hardware and software architecture has been designed to overcome such limitations and to provide a shorter latency and a much increased computation power. The new system is based on a Linux multi-core server and uses MARTe, a framework for real-time control which is gaining interest in the fusion community.

Pooled analysis of case-control studies on acoustic neuroma diagnosed 1997-2003 and 2007-2009 and use of mobile and cordless phones.

PubMed

Hardell, Lennart; Carlberg, Michael; Söderqvist, Fredrik; Mild, Kjell Hansson

2013-10-01

We previously conducted a case-control study of acoustic neuroma. Subjects of both genders aged 20-80 years, diagnosed during 1997-2003 in parts of Sweden, were included, and the results were published. We have since made a further study for the time period 2007-2009 including both men and women aged 18-75 years selected from throughout the country. These new results for acoustic neuroma have not been published to date. Similar methods were used for both study periods. In each, one population-based control, matched on gender and age (within five years), was identified from the Swedish Population Registry. Exposures were assessed by a self-administered questionnaire supplemented by a phone interview. Since the number of acoustic neuroma cases in the new study was low we now present pooled results from both study periods based on 316 participating cases and 3,530 controls. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index (SEI). Use of mobile phones of the analogue type gave odds ratio (OR) = 2.9, 95% confidence interval (CI) = 2.0-4.3, increasing with >20 years latency (time since first exposure) to OR = 7.7, 95% CI = 2.8-21. Digital 2G mobile phone use gave OR = 1.5, 95% CI = 1.1-2.1, increasing with latency >15 years to an OR = 1.8, 95% CI = 0.8-4.2. The results for cordless phone use were OR = 1.5, 95% CI = 1.1-2.1, and, for latency of >20 years, OR = 6.5, 95% CI = 1.7-26. Digital type wireless phones (2G and 3G mobile phones and cordless phones) gave OR = 1.5, 95% CI = 1.1-2.0 increasing to OR = 8.1, 95% CI = 2.0-32 with latency >20 years. For total wireless phone use, the highest risk was calculated for the longest latency time >20 years: OR = 4.4, 95% CI = 2.2-9.0. Several of the calculations in the long latency category were based on low numbers of exposed cases. Ipsilateral use resulted in a higher risk than contralateral for both mobile and cordless phones. OR increased per 100 h cumulative use and per year of latency for mobile phones and cordless phones, though the increase was not statistically significant for cordless phones. The percentage tumour volume increased per year of latency and per 100 h of cumulative use, statistically significant for analogue phones. This study confirmed previous results demonstrating an association between mobile and cordless phone use and acoustic neuroma.

Pooled analysis of case-control studies on acoustic neuroma diagnosed 1997–2003 and 2007–2009 and use of mobile and cordless phones

PubMed Central

HARDELL, LENNART; CARLBERG, MICHAEL; SÖDERQVIST, FREDRIK; MILD, KJELL HANSSON

We previously conducted a case-control study of acoustic neuroma. Subjects of both genders aged 20–80 years, diagnosed during 1997–2003 in parts of Sweden, were included, and the results were published. We have since made a further study for the time period 2007–2009 including both men and women aged 18–75 years selected from throughout the country. These new results for acoustic neuroma have not been published to date. Similar methods were used for both study periods. In each, one population-based control, matched on gender and age (within five years), was identified from the Swedish Population Registry. Exposures were assessed by a self-administered questionnaire supplemented by a phone interview. Since the number of acoustic neuroma cases in the new study was low we now present pooled results from both study periods based on 316 participating cases and 3,530 controls. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index (SEI). Use of mobile phones of the analogue type gave odds ratio (OR) = 2.9, 95% confidence interval (CI) = 2.0–4.3, increasing with >20 years latency (time since first exposure) to OR = 7.7, 95% CI = 2.8–21. Digital 2G mobile phone use gave OR = 1.5, 95% CI = 1.1–2.1, increasing with latency >15 years to an OR = 1.8, 95% CI = 0.8–4.2. The results for cordless phone use were OR = 1.5, 95% CI = 1.1–2.1, and, for latency of >20 years, OR = 6.5, 95% CI = 1.7–26. Digital type wireless phones (2G and 3G mobile phones and cordless phones) gave OR = 1.5, 95% CI = 1.1–2.0 increasing to OR = 8.1, 95% CI = 2.0–32 with latency >20 years. For total wireless phone use, the highest risk was calculated for the longest latency time >20 years: OR = 4.4, 95% CI = 2.2–9.0. Several of the calculations in the long latency category were based on low numbers of exposed cases. Ipsilateral use resulted in a higher risk than contralateral for both mobile and cordless phones. OR increased per 100 h cumulative use and per year of latency for mobile phones and cordless phones, though the increase was not statistically significant for cordless phones. The percentage tumour volume increased per year of latency and per 100 h of cumulative use, statistically significant for analogue phones. This study confirmed previous results demonstrating an association between mobile and cordless phone use and acoustic neuroma. PMID:23877578

Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK.

PubMed

Letang, Emilio; Lewis, James J; Bower, Mark; Mosam, Anisa; Borok, Margareth; Campbell, Thomas B; Naniche, Denise; Newsom-Davis, Tom; Shaik, Fahmida; Fiorillo, Suzanne; Miro, Jose M; Schellenberg, David; Easterbrook, Philippa J

2013-06-19

To assess the incidence, predictors, and outcomes of Kaposi sarcoma-associated paradoxical immune reconstitution inflammatory syndrome (KS-IRIS) in antiretroviral therapy (ART)-naive HIV-infected patients with Kaposi sarcoma initiating ART in both well resourced and limited-resourced settings. Pooled analysis of three prospective cohorts of ART-naive HIV-infected patients with Kaposi sarcoma from sub-Saharan Africa (SSA) and one from the UK. KS-IRIS case definition was standardized across sites. Cox regression and Kaplan-Meier survival analysis were used to identify the incidence and predictors of KS-IRIS and Kaposi sarcoma-associated mortality. Fifty-eight of 417 (13.9%) eligible individuals experienced KS-IRIS with an incidence 2.5 times higher in the African vs. European cohorts (P=0.001). ART alone as initial Kaposi sarcoma treatment (hazard ratio 2.97, 95% confidence interval (CI) 1.02-8.69); T1 Kaposi sarcoma stage (hazard ratio 2.96, 95% CI 1.26-6.94); and plasma HIV-1 RNA more than 5 log₁₀ copies/ml (hazard ratio 2.14, 95% CI 1.25-3.67) independently predicted KS-IRIS at baseline. Detectable plasma Kaposi sarcoma-associated herpes virus (KSHV) DNA additionally predicted KS-IRIS among the 259 patients with KSHV DNA assessed (hazard ratio 2.98, 95% CI 1.23-7.19). Nineteen KS-IRIS patients died, all in SSA. Kaposi sarcoma mortality was 3.3-fold higher in Africa, and was predicted by KS-IRIS (hazard ratio 19.24, CI 7.62-48.58), lack of chemotherapy (hazard ratio 2.35, 95% CI 1.09-5.05), pre-ART CD4 cell count less than 200 cells/μl (hazard ratio 2.04, 95% CI 0.99-4.2), and detectable baseline KSHV DNA (hazard ratio 2.12, 95% CI 0.94-4.77). KS-IRIS incidence and mortality are higher in SSA than in the UK. This is largely explained by the more advanced Kaposi sarcoma disease and lower chemotherapy availability. KS-IRIS is a major contributor to Kaposi sarcoma-associated mortality in Africa. Our results support the need to increase awareness on KS-IRIS, encourage earlier presentation, referral and diagnosis of Kaposi sarcoma, and advocate on access to systemic chemotherapy in Africa. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins

IKKγ-Mimetic Peptides Block the Resistance to Apoptosis Associated with Kaposi's Sarcoma-Associated Herpesvirus Infection.

PubMed

Briggs, Louise C; Chan, A W Edith; Davis, Christopher A; Whitelock, Nicholas; Hotiana, Hajira A; Baratchian, Mehdi; Bagnéris, Claire; Selwood, David L; Collins, Mary K; Barrett, Tracey E

2017-12-01

Primary effusion lymphoma (PEL) is a lymphogenic disorder associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Key to the survival and proliferation of PEL is the canonical NF-κB pathway, which becomes constitutively activated following overexpression of the viral oncoprotein KSHV vFLIP (ks-vFLIP). This arises from its capacity to form a complex with the modulatory subunit of the IκB kinase (IKK) kinase, IKKγ (or NEMO), resulting in the overproduction of proteins that promote cellular survival and prevent apoptosis, both of which are important drivers of tumorigenesis. Using a combination of cell-based and biophysical assays together with structural techniques, we showed that the observed resistance to cell death is largely independent of autophagy or major death receptor signaling pathways and demonstrated that direct targeting of the ks-vFLIP-IKKγ interaction both in cells and in vitro can be achieved using IKKγ-mimetic peptides. Our results further reveal that these peptides not only induce cell killing but also potently sensitize PEL to the proapoptotic agents tumor necrosis factor alpha and etoposide and are the first to confirm ks-vFLIP as a tractable target for the treatment of PEL and related disorders. IMPORTANCE KSHV vFLIP (ks-vFLIP) has been shown to have a crucial role in cellular transformation, in which it is vital for the survival and proliferation of primary effusion lymphoma (PEL), an aggressive malignancy associated with infection that is resistant to the majority of chemotherapeutic drugs. It operates via subversion of the canonical NF-κB pathway, which requires a physical interaction between ks-vFLIP and the IKK kinase modulatory subunit IKKγ. While this interaction has been directly linked to protection against apoptosis, it is unclear whether the suppression of other cell death pathways implicated in ks-vFLIP pathogenesis is an additional contributor. We demonstrate that the interaction between ks-vFLIP and IKKγ is pivotal in conferring resistance to apoptosis. Additionally, we show that the ks-vFLIP-IKKγ complex can be disrupted using peptides leading to direct killing and the sensitization of PEL cells to proapoptotic agents. Our studies thus provide a framework for future therapeutic interventions. Copyright © 2017 Briggs et al.

Brainstem auditory evoked potentials with the use of acoustic clicks and complex verbal sounds in young adults with learning disabilities.

PubMed

Kouni, Sophia N; Giannopoulos, Sotirios; Ziavra, Nausika; Koutsojannis, Constantinos

2013-01-01

Acoustic signals are transmitted through the external and middle ear mechanically to the cochlea where they are transduced into electrical impulse for further transmission via the auditory nerve. The auditory nerve encodes the acoustic sounds that are conveyed to the auditory brainstem. Multiple brainstem nuclei, the cochlea, the midbrain, the thalamus, and the cortex constitute the central auditory system. In clinical practice, auditory brainstem responses (ABRs) to simple stimuli such as click or tones are widely used. Recently, complex stimuli or complex auditory brain responses (cABRs), such as monosyllabic speech stimuli and music, are being used as a tool to study the brainstem processing of speech sounds. We have used the classic 'click' as well as, for the first time, the artificial successive complex stimuli 'ba', which constitutes the Greek word 'baba' corresponding to the English 'daddy'. Twenty young adults institutionally diagnosed as dyslexic (10 subjects) or light dyslexic (10 subjects) comprised the diseased group. Twenty sex-, age-, education-, hearing sensitivity-, and IQ-matched normal subjects comprised the control group. Measurements included the absolute latencies of waves I through V, the interpeak latencies elicited by the classical acoustic click, the negative peak latencies of A and C waves, as well as the interpeak latencies of A-C elicited by the verbal stimulus 'baba' created on a digital speech synthesizer. The absolute peak latencies of waves I, III, and V in response to monoaural rarefaction clicks as well as the interpeak latencies I-III, III-V, and I-V in the dyslexic subjects, although increased in comparison with normal subjects, did not reach the level of a significant difference (p<0.05). However, the absolute peak latencies of the negative wave C and the interpeak latencies of A-C elicited by verbal stimuli were found to be increased in the dyslexic group in comparison with the control group (p=0.0004 and p=0.045, respectively). In the subgroup consisting of 10 patients suffering from 'other learning disabilities' and who were characterized as with 'light' dyslexia according to dyslexia tests, no significant delays were found in peak latencies A and C and interpeak latencies A-C in comparison with the control group. Acoustic representation of a speech sound and, in particular, the disyllabic word 'baba' was found to be abnormal, as low as the auditory brainstem. Because ABRs mature in early life, this can help to identify subjects with acoustically based learning problems and apply early intervention, rehabilitation, and treatment. Further studies and more experience with more patients and pathological conditions such as plasticity of the auditory system, cochlear implants, hearing aids, presbycusis, or acoustic neuropathy are necessary until this type of testing is ready for clinical application. © 2013 Elsevier Inc. All rights reserved.

Auditory Magnetic Mismatch Field Latency: A Biomarker for Language Impairment in Autism

PubMed Central

Roberts, Timothy P.L.; Cannon, Katelyn M.; Tavabi, Kambiz; Blaskey, Lisa; Khan, Sarah Y.; Monroe, Justin F.; Qasmieh, Saba; Levy, Susan E.; Edgar, J. Christopher

2011-01-01

Background Auditory processing abnormalities are frequently observed in Autism Spectrum Disorders (ASD), and these abnormalities may have sequelae in terms of clinical language impairment (LI). The present study assessed associations between language impairment and the amplitude and latency of the superior temporal gyrus magnetic mismatch field (MMF) in response to changes in an auditory stream of tones or vowels. Methods 51 children with ASD and 27 neurotypical controls, all aged 6-15 years, underwent neuropsychological evaluation, including tests of language function, as well as magnetoencephalographic (MEG) recording during presentation of tones and vowels. The MMF was identified in the difference waveform obtained from subtraction of responses to standard stimuli from deviant stimuli. Results MMF latency was significantly prolonged (p<0.001) in children with ASD compared to neurotypical controls. Furthermore, this delay was most pronounced (∼50ms) in children with concomitant LI, with significant differences in latency between children with ASD with LI and those without (p<0.01). Receiver operator characteristic analysis indicated a sensitivity of 82.4% and specificity of 71.2% for diagnosing LI based on MMF latency. Conclusion Neural correlates of auditory change detection (the MMF) are significantly delayed in children with ASD, and especially those with concomitant LI suggesting both a neurobiological basis for LI as well as a clinical biomarker for LI in ASD. PMID:21392733

Tibial nerve somatosensory evoked potentials in dogs with degenerative lumbosacral stenosis.

PubMed

Meij, Björn P; Suwankong, Niyada; van den Brom, Walter E; Venker-van Haagen, Anjop J; Hazewinkel, Herman A W

2006-02-01

To determine somatosensory evoked potentials (SEPs) in dogs with degenerative lumbosacral stenosis (DLS) and in healthy dogs. Clinical and experimental study. Dogs with DLS (n = 21) and 11 clinically normal dogs, age, and weight matched. Under anesthesia, the tibial nerve was stimulated at the caudolateral aspect of the stifle, and lumbar SEP (LSEP) were recorded percutaneously from S1 to T13 at each interspinous space. Cortical SEP (CSEP) were recorded from the scalp. LSEP were identified as the N1-P1 (latency 3-6 ms) and N2-P2 (latency 7-13 ms) wave complexes in the recordings of dogs with DLS and control dogs. Latency of N1-P1 increased and that of N2-P2 decreased as the active recording electrode was moved cranially from S1 to T13. Compared with controls, latencies were significantly delayed in DLS dogs: .8 ms for N1-P1 and 1.7 ms for the N2-P2 complex. CSEP were not different between groups. Surface needle recording of tibial nerve SEP can be used to monitor somatosensory nerve function of pelvic limbs in dogs. In dogs with DLS, the latency of LSEP, but not of CSEP, is prolonged compared with normal dogs. In dogs with lumbosacral pain from DLS, the cauda equina compression is sufficient to affect LSEP at the lumbar level.

Reconstructing the calibrated strain signal in the Advanced LIGO detectors

NASA Astrophysics Data System (ADS)

Viets, A. D.; Wade, M.; Urban, A. L.; Kandhasamy, S.; Betzwieser, J.; Brown, Duncan A.; Burguet-Castell, J.; Cahillane, C.; Goetz, E.; Izumi, K.; Karki, S.; Kissel, J. S.; Mendell, G.; Savage, R. L.; Siemens, X.; Tuyenbayev, D.; Weinstein, A. J.

2018-05-01

Advanced LIGO’s raw detector output needs to be calibrated to compute dimensionless strain h(t) . Calibrated strain data is produced in the time domain using both a low-latency, online procedure and a high-latency, offline procedure. The low-latency h(t) data stream is produced in two stages, the first of which is performed on the same computers that operate the detector’s feedback control system. This stage, referred to as the front-end calibration, uses infinite impulse response (IIR) filtering and performs all operations at a 16 384 Hz digital sampling rate. Due to several limitations, this procedure currently introduces certain systematic errors in the calibrated strain data, motivating the second stage of the low-latency procedure, known as the low-latency gstlal calibration pipeline. The gstlal calibration pipeline uses finite impulse response (FIR) filtering to apply corrections to the output of the front-end calibration. It applies time-dependent correction factors to the sensing and actuation components of the calibrated strain to reduce systematic errors. The gstlal calibration pipeline is also used in high latency to recalibrate the data, which is necessary due mainly to online dropouts in the calibrated data and identified improvements to the calibration models or filters.

The history of N-methanocarbathymidine: the investigation of a conformational concept leads to the discovery of a potent and selective nucleoside antiviral agent.

PubMed

Marquez, Victor E; Hughes, Stephen H; Sei, Shizuko; Agbaria, Riad

2006-09-01

Conformationally locked (North)-methanocarbathymidine (N-MCT) and (South)-methanocarbathymidine (S-MCT) have been used to investigate the conformational preferences of kinases and polymerases. The herpes kinases show a distinct bias for S-MCT, while DNA polymerases almost exclusively incorporate the North 5'-triphosphate (N-MCT-TP). Only N-MCT demonstrated potent antiviral activity against herpes simplex viruses (HSV-1 and 2) and Kaposi's sarcoma-associated herpesvirus (KSHV). The activity of N-MCT depends on its metabolic transformation to N-MCT-TP by the herpes kinases (HSV-tk or KSHV-tk), which catalyze the mono and diphosphorylation steps; cellular kinases generate the triphosphate. N-MCT at a dose of 5.6 mg/kg was totally protective for mice inoculated intranasally with HSV-1. Tumor cells that are not responsive to antiviral therapy became sensitive to N-MCT if the cells expressed HSV-tk. N-MCT given twice daily (100 mg/kg) for 7 days completely inhibited the growth of MC38 tumors derived from cells that express HSV-tk in mice while exhibiting no effect on tumors derived from non-transduced cells. After i.p. administration, N-MCT was rapidly absorbed and distributed in all organs examined with slow penetration into brain and testes. N-MCT-TP was also a potent inhibitor of HIV replication in human osteosarcoma (HOS) cells expressing HSV-tk.

Coupled Transcriptome and Proteome Analysis of Human Lymphotropic Tumor Viruses: Insights on the Detection and Discovery of Viral Genes

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

Dresang, Lindsay R.; Teuton, Jeremy R.; Feng, Huichen

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are related human tumor viruses that cause primary effusion lymphomas (PEL) and Burkitt's lymphomas (BL), respectively. Viral genes expressed in naturally-infected cancer cells contribute to disease pathogenesis; knowing which viral genes are expressed is critical in understanding how these viruses cause cancer. To evaluate the expression of viral genes, we used high-resolution separation and mass spectrometry coupled with custom tiling arrays to align the viral proteomes and transcriptomes of three PEL and two BL cell lines under latent and lytic culture conditions. Results The majority of viral genes were efficiently detected atmore » the transcript and/or protein level on manipulating the viral life cycle. Overall the correlation of expressed viral proteins and transcripts was highly complementary in both validating and providing orthogonal data with latent/lytic viral gene expression. Our approach also identified novel viral genes in both KSHV and EBV, and extends viral genome annotation. Several previously uncharacterized genes were validated at both transcript and protein levels. Conclusions This systems biology approach coupling proteome and transcriptome measurements provides a comprehensive view of viral gene expression that could not have been attained using each methodology independently. Detection of viral proteins in combination with viral transcripts is a potentially powerful method for establishing virus-disease relationships.« less

A viral microRNA functions as an ortholog of cellular miR-155

PubMed Central

Gottwein, Eva; Mukherjee, Neelanjan; Sachse, Christoph; Frenzel, Corina; Majoros, William H.; Chi, Jen-Tsan A.; Braich, Ravi; Manoharan, Muthiah; Soutschek, Jürgen; Ohler, Uwe; Cullen, Bryan R.

2008-01-01

All metazoan eukaryotes express microRNAs (miRNAs), ∼22 nt regulatory RNAs that can repress the expression of mRNAs bearing complementary sequences1. Several DNA viruses also express miRNAs in infected cells, suggesting a role in viral replication and pathogenesis2. While specific viral miRNAs have been shown to autoregulate viral mRNAs3,4 or downregulate cellular mRNAs5,6, the function of the majority of viral miRNAs remains unknown. Here, we report that the miR-K12−11 miRNA encoded by Kaposi's Sarcoma Associated Herpesvirus (KSHV) shows significant homology to cellular miR-155, including the entire miRNA “seed” region7. Using a range of assays, we demonstrate that expression of physiological levels of miR-K12−11 or miR-155 results in the downregulation of an extensive set of common mRNA targets, including genes with known roles in cell growth regulation. Our findings indicate that viral miR-K12−11 functions as an ortholog of cellular miR-155 and has likely evolved to exploit a pre-existing gene regulatory pathway in B-cells. Moreover, the known etiological role of miR-155 in B-cell transformation8-10 suggests that miR-K12−11 may contribute to the induction of KSHV-positive B-cell tumors in infected patients. PMID:18075594

[KAPOSI'S SARCOMA OF THE VULVA].

PubMed

Chokoeva, Aa; Tchernev, G; Wollina, U

2015-01-01

Kaposi's sarcoma represents multiple idiopathic hemorrhagic sarcoma--a mesenchymal tumor that affects the blood and lymph vessels. Its performance is associated with an infection with human herpes virus type 8--the so called KSHV (Kaposi's sarcoma -associated virus), and with the human immunodeficiency virus. Kaposi's sarcoma is considered as a typical clinical manifestation in male homosexuals suffering from acquired immune deficiency syndrome (AIDS), while his performance in HIV-positive women is unusual, with a ratio of men to women--10-15: 1. Vulvar localization is much rarer. It is up to 5 times more frequent in HIV- positive patients. It is clinically represented in most of the cases by the clinical picture of nonspecific tumor mass. Biopsy and further virological testing for establishing KSHV in lesional tissue is essential for confirming the diagnosis. Serological testing for HIV/AIDS in affected patients is required. Local treatment includes surgical excision of solitary lesions, cryotherapy as well as radiotherapy. The use of interferon alpha resulted in complete remission in approximately 40% of the affected patients. New trends in treatment tend to be pathogenetically directed as in the process of studies to date are inhibitors of angiogenesis. Due to the rarity of the occurrence, non-specific clinical picture and histological findings, Kaposi's sarcoma should be considered in the differential diagnosis of tumor masses with vulvar localization, especially in HIV-positive patients.

Novel flat datacenter network architecture based on scalable and flow-controlled optical switch system.

PubMed

Miao, Wang; Luo, Jun; Di Lucente, Stefano; Dorren, Harm; Calabretta, Nicola

2014-02-10

We propose and demonstrate an optical flat datacenter network based on scalable optical switch system with optical flow control. Modular structure with distributed control results in port-count independent optical switch reconfiguration time. RF tone in-band labeling technique allowing parallel processing of the label bits ensures the low latency operation regardless of the switch port-count. Hardware flow control is conducted at optical level by re-using the label wavelength without occupying extra bandwidth, space, and network resources which further improves the performance of latency within a simple structure. Dynamic switching including multicasting operation is validated for a 4 x 4 system. Error free operation of 40 Gb/s data packets has been achieved with only 1 dB penalty. The system could handle an input load up to 0.5 providing a packet loss lower that 10(-5) and an average latency less that 500 ns when a buffer size of 16 packets is employed. Investigation on scalability also indicates that the proposed system could potentially scale up to large port count with limited power penalty.

Study of cognitive functions in newly diagnosed cases of subclinical and clinical hypothyroidism.

PubMed

Sharma, Kirti; Behera, Joshil Kumar; Sood, Sushma; Rajput, Rajesh; Satpal; Praveen, Prashant

2014-01-01

Hypothyroidism is associated with significant neurocognitive deficits because hypothyroidism prevents the brain from adequately sustaining the energy consuming processes needed for neurotransmission, memory, and other higher brain functions. Hence, the study was done to assess the cognitive functions of newly diagnosed subclinical and clinical hypothyroid patients by evoked response potential P300. 75 patients each of newly diagnosed subclinical and clinical hypothyroid patients attending endocrinology clinic and 75 healthy age and sex matched euthyroid controls were considered for the study. P300 was recorded with Record Medicare System Polyrite, Chandigarh using auditory "oddball paradigm". The data was analyzed using ANOVA followed by post Tukey's test. Newly diagnosed clinical hypothyroid patients showed a significant increase in P300 latency compared to control (P < 0.05) and subclinical cases (P < 0.01) while there was no significant difference between the P300 latency of subclinical cases and control group. Also, there was no significant difference in P300 amplitude among the three groups. P300 latency in case of newly diagnosed hypothyroid clinical cases is significantly increased compared to newly diagnosed subclinical cases and control.

Normalization of auditory evoked potential and visual evoked potential in patients with idiot savant.

PubMed

Chen, X; Zhang, M; Wang, J; Lou, F; Liang, J

1999-03-01

To investigate the variations of auditory evoked potentials (AEP) and visual evoked potentials (VEP) of patients with idiot savant (IS) syndrome. Both AEP and VEP were recorded from 7 patients with IS syndrome, 21 mentally retarded (MR) children without the syndrome and 21 normally age-matched controls, using a Dantec concerto SEEG-16 BEAM instrument. Both AEP and VEP of MR group showed significantly longer latencies (P1 and P2 latencies of AEP, P < 0.01; N1 and N2 latencies of VEP, P < 0.01/0.05), lower P2 amplitudes (P < 0.01) and higher P3 amplitudes (P < 0.01), as compared with normal controls. But none of above-mentioned changes was found with IS group. Almost all MR patients (90.1%) presented P4 component in both AEP and VEP, which was also in sharp contrast with its incidence in other 2 groups (IS: 14.3%; normal controls: 9.5%). Patients with idiot savant syndrome presented normalized AEP and VEP.

Desipramine restricts estral cycle oscillations in swimming.

PubMed

Contreras, C M; Martínez-Mota, L; Saavedra, M

1998-10-01

1. Desipramine (DMI) is a tricyclic antidepressant which reduces the immobility in rats forced to swim; however, it is unknown whether estral cycle phases impinge on DMI actions on immobility in daily swimming tests during several weeks. 2. In female wistar rats, vaginal smears taken before testing defined four estral phases. Afterwards, the authors assessed the latency for the first period of immobility in five-min forced swim tests practiced on 21-day DMI (DMI group), 21-day washout saline given after a 21-day DMI treatment (washout-saline group), or non-treated rats (control group). 3. We observed a longer latency for the first period of immobility in proestrus-estrus from the control and washout-saline groups. The 21-day treatment with DMI (2.1 mg/kg i.p., once a day) significantly (p < 0.001) increased the latency by about 160% from control regardless of the estral cycle phase. 4. It is concluded that proestrus-estrus relates to increased struggling behavior. DMI enhances struggling behavior independently of hormonal state.

Auditory Brainstem Evoked Responses in Newborns with Down Syndrome

ERIC Educational Resources Information Center

Kittler, Phyllis M.; Phan, Ha T. T.; Gardner, Judith M.; Miroshnichenko, Inna; Gordon, Anne; Karmel, Bernard Z.

2009-01-01

Auditory brainstem evoked responses (ABRs) were compared in 15 newborns with Down syndrome and 15 sex-, age-, and weight-matched control newborns. Participants had normal ABRs based upon values specific to 32- to 42-weeks postconceptional age. Although Wave III and Wave V component latencies and the Wave I-III interpeak latency (IPL) were shorter…

75 FR 50017 - Self-Regulatory Organizations; EDGA Exchange, Inc.; Notice of Filing of Proposed Rule Change...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-16

... the user. \\5\\ In addition to the boundary-level Exchange latency information, match level information... system which the Exchange operates or controls. In particular, the Exchange notes that it operates in a... users of the Exchange real-time analytical tools to measure the latency of orders to and from that...

Meningioma patients diagnosed 2007-2009 and the association with use of mobile and cordless phones: a case-control study.

PubMed

Carlberg, Michael; Söderqvist, Fredrik; Hansson Mild, Kjell; Hardell, Lennart

2013-07-19

To study the association between use of wireless phones and meningioma. We performed a case-control study on brain tumour cases of both genders aged 18-75 years and diagnosed during 2007-2009. One population-based control matched on gender and age was used to each case. Here we report on meningioma cases including all available controls. Exposures were assessed by a questionnaire. Unconditional logistic regression analysis was performed. In total 709 meningioma cases and 1,368 control subjects answered the questionnaire. Mobile phone use in total produced odds ratio (OR) = 1.0, 95% confidence interval (CI) = 0.7-1.4 and cordless phone use gave OR = 1.1, 95% CI = 0.8-1.5. The risk increased statistically significant per 100 h of cumulative use and highest OR was found in the fourth quartile (>2,376 hours) of cumulative use for all studied phone types. There was no statistically significant increased risk for ipsilateral mobile or cordless phone use, for meningioma in the temporal lobe or per year of latency. Tumour volume was not related to latency or cumulative use in hours of wireless phones. No conclusive evidence of an association between use of mobile and cordless phones and meningioma was found. An indication of increased risk was seen in the group with highest cumulative use but was not supported by statistically significant increasing risk with latency. Results for even longer latency periods of wireless phone use than in this study are desirable.

Spatio-Temporal Features of Visual Exploration in Unilaterally Brain-Damaged Subjects with or without Neglect: Results from a Touchscreen Test

PubMed Central

Rabuffetti, Marco; Farina, Elisabetta; Alberoni, Margherita; Pellegatta, Daniele; Appollonio, Ildebrando; Affanni, Paola; Forni, Marco; Ferrarin, Maurizio

2012-01-01

Cognitive assessment in a clinical setting is generally made by pencil-and-paper tests, while computer-based tests enable the measurement and the extraction of additional performance indexes. Previous studies have demonstrated that in a research context exploration deficits occur also in patients without evidence of unilateral neglect at pencil-and-paper tests. The objective of this study is to apply a touchscreen-based cancellation test, feasible also in a clinical context, to large groups of control subjects and unilaterally brain-damaged patients, with and without unilateral spatial neglect (USN), in order to assess disturbances of the exploratory skills. A computerized cancellation test on a touchscreen interface was used for assessing the performance of 119 neurologically unimpaired control subjects and 193 patients with unilateral right or left hemispheric brain damage, either with or without USN. A set of performance indexes were defined including Latency, Proximity, Crossings and their spatial lateral gradients, and Preferred Search Direction. Classic outcome scores were computed as well. Results show statistically significant differences among groups (assumed p<0.05). Right-brain-damaged patients with USN were significantly slower (median latency per detected item was 1.18 s) and less efficient (about 13 search-path crossings) in the search than controls (median latency 0.64 s; about 3 crossings). Their preferred search direction (53.6% downward, 36.7% leftward) was different from the one in control patients (88.2% downward, 2.1% leftward). Right-brain-damaged patients without USN showed a significantly abnormal behavior (median latency 0.84 s, about 5 crossings, 83.3% downward and 9.1% leftward direction) situated half way between controls and right-brain-damaged patients with USN. Left-brain-damaged patients without USN were significantly slower and less efficient than controls (latency 1.19 s, about 7 crossings), preserving a normal preferred search direction (93.7% downward). Therefore, the proposed touchscreen-based assessment had evidenced disorders in spatial exploration also in patients without clinically diagnosed USN. PMID:22347489

Communication latencies of wireless devices suitable for time-critical messaging to anesthesia providers.

PubMed

Epstein, Richard H; Dexter, Franklin; Rothman, Brian

2013-04-01

Rapid and reliable methods of text communication to mobile anesthesia care providers are important to patient care and to efficient operating room management. Anesthesia departments are implementing automated methods to send text messages to mobile devices for abnormal vital signs, clinical recommendations, quality of care, and compliance or billing issues. The most time-critical communications determine maximum acceptable latencies. We studied the reliability of several alphanumeric messaging systems to identify an appropriate technology for such use. Latencies between message initiation and delivery to 3 alphanumeric paging devices were measured over weeks. Two devices used Internet pathways outside the hospital's local network with an external paging vendor (SkyTel). The third device used only the internal hospital network (Zetron). Sequential cell phone text page latencies were examined for lag-1 autocorrelation using the runs test, with results binned by hour and by day. Message latencies subsequently were batched in successive 1-week bins for calculation of the mean and 99th percentiles of latencies. We defined acceptance criteria as a mean latency <30 seconds and no more than 1 in 200 pages (0.5%) having a latency longer than 100 seconds. Cell phone texting was used as a positive control to assure that the analysis was appropriate, because such devices have (known) poor reliability during high network activity. There was substantial correlation among latencies for sequential cell phone text messages when binned by hours (P < 0.0001), but not by days (P = 0.61). The 2 devices using Internet pathways outside the hospital's network demonstrated unacceptable performance, with 1.3% and 33% of latencies exceeding 100 seconds, respectively. The device dependent only on the internal network had a mean latency of 8 seconds, with 100% of 40,200 pages having latencies <100 seconds. The findings suggest that the network used was the deciding factor. Developers of anesthesia communication systems need to measure latencies of proposed communication pathways and devices used to deliver urgent messages to mobile users. Similar evaluation is relevant for text pagers used on an ad hoc basis for delivery of time-critical notifications. Testing over a period of hours to days is adequate only for disqualification of a candidate paging system, because acceptable results are not necessarily indicative of long-term performance. Rather, weeks of testing are required, with appropriate batching of pages for analysis.

A low-latency high-port count optical switch with optical delay line buffering for disaggregated data centers

NASA Astrophysics Data System (ADS)

Moralis-Pegios, M.; Terzenidis, N.; Mourgias-Alexandris, G.; Vyrsokinos, K.; Pleros, N.

2018-02-01

Disaggregated Data Centers (DCs) have emerged as a powerful architectural framework towards increasing resource utilization and system power efficiency, requiring, however, a networking infrastructure that can ensure low-latency and high-bandwidth connectivity between a high-number of interconnected nodes. This reality has been the driving force towards high-port count and low-latency optical switching platforms, with recent efforts concluding that the use of distributed control architectures as offered by Broadcast-and-Select (BS) layouts can lead to sub-μsec latencies. However, almost all high-port count optical switch designs proposed so far rely either on electronic buffering and associated SerDes circuitry for resolving contention or on buffer-less designs with packet drop and re-transmit procedures, unavoidably increasing latency or limiting throughput. In this article, we demonstrate a 256x256 optical switch architecture for disaggregated DCs that employs small-size optical delay line buffering in a distributed control scheme, exploiting FPGA-based header processing over a hybrid BS/Wavelength routing topology that is implemented by a 16x16 BS design and a 16x16 AWGR. Simulation-based performance analysis reveals that even the use of a 2- packet optical buffer can yield <620nsec latency with >85% throughput for up to 100% loads. The switch has been experimentally validated with 10Gb/s optical data packets using 1:16 optical splitting and a SOA-MZI wavelength converter (WC) along with fiber delay lines for the 2-packet buffer implementation at every BS outgoing port, followed by an additional SOA-MZI tunable WC and the 16x16 AWGR. Error-free performance in all different switch input/output combinations has been obtained with a power penalty of <2.5dB.

The Temporal Propagation of Intrinsic Brain Activity Associate With the Occurrence of PTSD

PubMed Central

Weng, Yifei; Qi, Rongfeng; Chen, Feng; Ke, Jun; Xu, Qiang; Zhong, Yuan; Chen, Lida; Li, Jianjun; Zhang, Zhiqiang; Zhang, Li; Lu, Guangming

2018-01-01

The abnormal brain activity is a pivotal condition for the occurrence of posttraumatic stress disorder. However, the dynamic time features of intrinsic brain activities still remain unclearly in PTSD patients. Our study aims to perform the resting-state lag analysis (RS-LA) method to explore potential propagated patterns of intrinsic brain activities in PTSD patients. We recruited 27 drug-naive patients with PTSD, 33 trauma-exposed controls (TEC), and 30 demographically matched healthy controls (HC) in the final data statistics. Both RS-LA and conventional voxel-wise functional connectivity strength (FCS) methods were employed on the same dataset. Then, Spearman correlation analysis was conducted on time latency values of those abnormal brain regions with the clinical assessments. Compared with HC group, the time latency patterns of PTSD patients significantly shifted toward later in posterior cingulate cortex/precuneus, middle prefrontal cortex, right angular, and left pre- and post-central cortex. The TEC group tended to have similar time latency in right angular. Additionally, significant time latency in right STG was found in PTSD group relative to TEC group. Spearman correlation analysis revealed that the time latency value of mPFC negatively correlated to the PTSD checklist-civilian version scores (PCL_C) in PTSD group (r = −0.578, P < 0.05). Furthermore, group differences map of FCS exhibited parts of overlapping areas with that of RS-LA, however, less specificity in detecting PTSD patients. In conclusion, apparent alterations of time latency were observed in DMN and primary sensorimotor areas of PTSD patients. These findings provide us with new evidence to explain the neural pathophysiology contributing to PTSD. PMID:29887811

How strongly do word reading times and lexical decision times correlate? Combining data from eye movement corpora and megastudies.

PubMed

Kuperman, Victor; Drieghe, Denis; Keuleers, Emmanuel; Brysbaert, Marc

2013-01-01

We assess the amount of shared variance between three measures of visual word recognition latencies: eye movement latencies, lexical decision times, and naming times. After partialling out the effects of word frequency and word length, two well-documented predictors of word recognition latencies, we see that 7-44% of the variance is uniquely shared between lexical decision times and naming times, depending on the frequency range of the words used. A similar analysis of eye movement latencies shows that the percentage of variance they uniquely share either with lexical decision times or with naming times is much lower. It is 5-17% for gaze durations and lexical decision times in studies with target words presented in neutral sentences, but drops to 0.2% for corpus studies in which eye movements to all words are analysed. Correlations between gaze durations and naming latencies are lower still. These findings suggest that processing times in isolated word processing and continuous text reading are affected by specific task demands and presentation format, and that lexical decision times and naming times are not very informative in predicting eye movement latencies in text reading once the effect of word frequency and word length are taken into account. The difference between controlled experiments and natural reading suggests that reading strategies and stimulus materials may determine the degree to which the immediacy-of-processing assumption and the eye-mind assumption apply. Fixation times are more likely to exclusively reflect the lexical processing of the currently fixated word in controlled studies with unpredictable target words rather than in natural reading of sentences or texts.

[Evoked potentials N200/P300 disorders and clinical phenotype in Cuban families with paranoid schizophrenia: a family-based association study].

PubMed

Guerra López, Seidel; Martín Reyes, Migdyrai; Pedroso Rodríguez, María de Los Ángeles; Reyes Berazain, Adnelys; Mendoza Quiñones, Raúl; Bravo Collazo, Tania Martha; Días de Villarvilla, Thais; Machado Cano, María Julia; Bobés León, María Antonieta

2015-04-01

N200 and P300 event-related evoked potentials provide sensitive measurements of sensory and cognitive function and have been used to study information processing in patients with schizophrenia and their unaffected first-degree relatives. Reduced amplitude and increased latency of N200 and P300 potentials have been consistently reported in schizophrenia. Thus, event-related evoked potentials abnormalities are promising possible biological markers for genetic vulnerability to schizophrenia. To assess the association of changes in latency, amplitude and topographic distribution of potentials N200 and P300 of patients with paranoid schizophrenia and their healthy first-degree relatives, in families with schizophrenia multiplex. We measured latency and amplitude of the N200 and P300 component of evoked potentials using an auditory odd-ball paradigm in 25 schizophrenic patients (probands) from 60 families multiply affected with paranoid schizophrenia, 23 of their non-schizophrenic first-degree relatives and 25 unrelated healthy controls, through a study of family association. Schizophrenic patients and their relatives showed significant latency prolongation and amplitude reduction of the N200 and P300 waves compared to controls. Left-temporal as compared to right-temporal N200 and P300 were significantly smaller in schizophrenic patients and their non-schizophrenic first-degree relatives than in controls. Our results suggest that event-related evoked potentials abnormalities may serve as markers of genetic vulnerability in schizophrenia. Confirming results of other researchers, this present study suggests that latency prolongation and amplitude reduction of the N200 and P300 waves and an altered topography at temporal sites may be a trait “marker” of paranoid schizophrenia.

NF-κB as a target for oncogenic viruses

PubMed Central

Sun, Shao-Cong; Cesarman, Ethel

2013-01-01

NF-κB is a pivotal transcription factor that controls cell survival and proliferation in diverse physiological processes. The activity of NF-κB is tightly controlled through its cytoplasmic sequestration by specific inhibitors, IκBs. Various cellular stimuli induce the activation of an IκB kinase (IKK), which phosphorylates IκBs and triggers their proteasomal degradation, causing nuclear translocation of activated NF-κB. Under normal conditions, the activation of NF-κB occurs transiently, thus ensuring rapid but temporary induction of target genes. Deregulated NF-κB activation contributes to the development of various diseases, including cancers and immunological disorders. Accumulated studies demonstrate that the NF-κB signaling pathway is a target of several human oncogenic viruses, including the human T-cell leukemia virus type 1 (HTLV1), the Kaposi sarcoma-associated herpesvirus (KSHV), and the Epstein bar virus (EBV). These viruses encode specific oncoproteins that target different signaling components of the NF-κB pathway, leading to persistent activation of NF-κB. This chapter will discuss the molecular mechanisms by which NF-κB is activated by the viral oncoproteins. PMID:20845110

Stochastic Characterization of Communication Network Latency for Wide Area Grid Control Applications.

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

Ameme, Dan Selorm Kwami; Guttromson, Ross

This report characterizes communications network latency under various network topologies and qualities of service (QoS). The characterizations are probabilistic in nature, allowing deeper analysis of stability for Internet Protocol (IP) based feedback control systems used in grid applications. The work involves the use of Raspberry Pi computers as a proxy for a controlled resource, and an ns-3 network simulator on a Linux server to create an experimental platform (testbed) that can be used to model wide-area grid control network communications in smart grid. Modbus protocol is used for information transport, and Routing Information Protocol is used for dynamic route selectionmore » within the simulated network.« less

Changes to online control and eye-hand coordination with healthy ageing.

PubMed

O'Rielly, Jessica L; Ma-Wyatt, Anna

2018-06-01

Goal directed movements are typically accompanied by a saccade to the target location. Online control plays an important part in correction of a reach, especially if the target or goal of the reach moves during the reach. While there are notable changes to visual processing and motor control with healthy ageing, there is limited evidence about how eye-hand coordination during online updating changes with healthy ageing. We sought to quantify differences between older and younger people for eye-hand coordination during online updating. Participants completed a double step reaching task implemented under time pressure. The target perturbation could occur 200, 400 and 600 ms into a reach. We measured eye position and hand position throughout the trials to investigate changes to saccade latency, movement latency, movement time, reach characteristics and eye-hand latency and accuracy. Both groups were able to update their reach in response to a target perturbation that occurred at 200 or 400 ms into the reach. All participants demonstrated incomplete online updating for the 600 ms perturbation time. Saccade latencies, measured from the first target presentation, were generally longer for older participants. Older participants had significantly increased movement times but there was no significant difference between groups for touch accuracy. We speculate that the longer movement times enable the use of new visual information about the target location for online updating towards the end of the movement. Interestingly, older participants also produced a greater proportion of secondary saccades within the target perturbation condition and had generally shorter eye-hand latencies. This is perhaps a compensatory mechanism as there was no significant group effect on final saccade accuracy. Overall, the pattern of results suggests that online control of movements may be qualitatively different in older participants. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

Supraspinal control of automatic postural responses in people with multiple sclerosis.

PubMed

Peterson, D S; Gera, G; Horak, F B; Fling, B W

2016-06-01

The neural underpinnings of delayed automatic postural responses in people with multiple sclerosis (PwMS) are unclear. We assessed whether white matter pathways of two supraspinal regions (the cortical proprioceptive Broadman's Area-3; and the balance/locomotor-related pedunculopontine nucleus) were related to delayed postural muscle response latencies in response to external perturbations. 19 PwMS (48.8±11.4years; EDSS=3.5 (range: 2-4)) and 12 healthy adults (51.7±12.2years) underwent 20 discrete, backward translations of a support surface. Onset latency of agonist (medial-gastrocnemius) and antagonist (tibialis anterior) muscles were assessed. Diffusion tensor imaging assessed white-matter integrity (i.e. radial diffusivity) of cortical proprioceptive and balance/locomotor-related tracts. Latency of the tibialis anterior, but not medial gastrocnemius was larger in PwMS than control subjects (p=0.012 and 0.071, respectively). Radial diffusivity of balance/locomotor tracts was higher (worse) in PwMS than control subjects (p=0.004), and was significantly correlated with tibialis (p=0.002), but not gastrocnemius (p=0.06) onset latency. Diffusivity of cortical proprioceptive tracts was not correlated with muscle onset. Lesions in supraspinal structures including the pedunculopontine nucleus balance/locomotor network may contribute to delayed onset of postural muscle activity in PwMS, contributing to balance deficits in PwMS. Published by Elsevier B.V.

Visually Evoked Potentials after Panretinal Photocoagulation in Omani Patients with Uncontrolled Diabetes Mellitus

PubMed Central

Shenoy, Radha; Al-Belushi, Habiba; Al-Ajmi, Sadiqa; Al-Nabhani, Susan Margaret; Ganguly, Shyam Sunder; Bialasiewicz, Alexander A.

2008-01-01

Aim: To report on the changes of latency and amplitudes of the pattern VEP in patients with uncontrolled diabetes mellitus II and I before and after panretinal laser treatment. Design: Single center hospital based comparative study. Methods: One hundred eyes of patients with proliferative diabetic vitreoretinopathy, and HbA1C ≥ 10 percent were subjected to Pattern Visually Evoked Potentials (Medtronic keyopint system, Nicolet) prior to and 4 weeks after PRP. Results were compared to age-matched non-diabetic controls. Chi-Square test, and paired ‘t’ test were used for statistical analysis. Results: Preoperative mean VEP amplitude was 8.35mV±3.71, and not significantly different to the control group (mean 10.51mV±3.34) (chi square test p=1). Mean preoperative P100 latency was 106.93±7.90ms and significantly different to the control group (103.21±7.65ms) (paired t-test p=0.001). After laser treatment, VEP amplitudes decreased in 48/100 eyes (mean total 5.11mV±2.4), and P100 latency increased in 75/100 eyes (mean total 110.47±7.35ms). Conclusion: In this study, PRP was followed by a significant decrease in VEP amplitudes in 48 percent and increase in latency in 75 percent of eyes. PMID:21346837

Cue Utilization and Cognitive Load in Novel Task Performance

PubMed Central

Brouwers, Sue; Wiggins, Mark W.; Helton, William; O’Hare, David; Griffin, Barbara

2016-01-01

This study was designed to examine whether differences in cue utilization were associated with differences in performance during a novel, simulated rail control task, and whether these differences reflected a reduction in cognitive load. Two experiments were conducted, the first of which involved the completion of a 20-min rail control simulation that required participants to re-route trains that periodically required a diversion. Participants with a greater level of cue utilization recorded a consistently greater response latency, consistent with a strategy that maintained accuracy, but reduced the demands on cognitive resources. In the second experiment, participants completed the rail task, during which a concurrent, secondary task was introduced. The results revealed an interaction, whereby participants with lesser levels of cue utilization recorded an increase in response latency that exceeded the response latency recorded for participants with greater levels of cue utilization. The relative consistency of response latencies for participants with greater levels of cue utilization, across all blocks, despite the imposition of a secondary task, suggested that those participants with greater levels of cue utilization had adopted a strategy that was effectively minimizing the impact of additional sources of cognitive load on their performance. PMID:27064669

12-bit 32 channel 500 MS/s low-latency ADC for particle accelerators real-time control

NASA Astrophysics Data System (ADS)

Karnitski, Anton; Baranauskas, Dalius; Zelenin, Denis; Baranauskas, Gytis; Zhankevich, Alexander; Gill, Chris

2017-09-01

Particle beam control systems require real-time low latency digital feedback with high linearity and dynamic range. Densely packed electronic systems employ high performance multichannel digitizers causing excessive heat dissipation. Therefore, low power dissipation is another critical requirement for these digitizers. A described 12-bit 500 MS/s ADC employs a sub-ranging architecture based on a merged sample & hold circuit, a residue C-DAC and a shared 6-bit flash core ADC. The core ADC provides a sequential coarse and fine digitization featuring a latency of two clock cycles. The ADC is implemented in a 28 nm CMOS process and consumes 4 mW of power per channel from a 0.9 V supply (interfacing and peripheral circuits are excluded). Reduced power consumption and small on-chip area permits the implementation of 32 ADC channels on a 10.7 mm2 chip. The ADC includes a JESD204B standard compliant output data interface operated at the 7.5 Gbps/ch rate. To minimize the data interface related time latency, a special feature permitting to bypass the JESD204B interface is built in. DoE Phase I Award Number: DE-SC0017213.

A centre for accommodative vergence motor control

NASA Technical Reports Server (NTRS)

Wilson, D.

1973-01-01

Latencies in accommodation, accommodative-vergence, and pupil-diameter responses to changing accommodation stimuli, as well as latencies in pupil response to light-intensity changes were measured. From the information obtained, a block diagram has been derived that uses the least number of blocks for representing the accommodation, accommodative-vergence, and pupil systems. The signal transmission delays over the various circuits of the model have been determined and compared to known experimental physiological-delay data. The results suggest the existence of a motor center that controls the accommodative vergence and is completely independent of the accommodation system.

Sciatic Nerve Conductivity is Impaired by Hamstring Strain Injuries.

PubMed

Kouzaki, Karina; Nakazato, Koichi; Mizuno, Masuhiko; Yonechi, Tooru; Higo, Yusuke; Kubo, Yoshiaki; Kono, Tokuyoshi; Hiranuma, Kenji

2017-10-01

The aim of this study was to assess sciatic nerve conductivity in athletes with a history of hamstring strain injuries. Twenty-seven athletes with a history of hamstring strain injuries were included in the injured group. The control group consisted of 16 uninjured participants. We measured the proximal and distal latencies and calculated the sciatic nerve conduction velocity to evaluate neuronal conductivity. The results were expressed as median values and interquartile ranges. Both proximal latency and distal latency of the injured limb in the injured group were significantly longer than those of the uninjured limb (p<0.05). The nerve conduction velocity of the injured limb in the injured group was significantly lower than that of the uninjured limb (p<0.05). There were no significant side-to-side differences in the control group. Sciatic nerve conductivity impairments may exist in athletes with a history of hamstring strain injuries. © Georg Thieme Verlag KG Stuttgart · New York.

The low-order wavefront control system for the PICTURE-C mission: high-speed image acquisition and processing

NASA Astrophysics Data System (ADS)

Hewawasam, Kuravi; Mendillo, Christopher B.; Howe, Glenn A.; Martel, Jason; Finn, Susanna C.; Cook, Timothy A.; Chakrabarti, Supriya

2017-09-01

The Planetary Imaging Concept Testbed Using a Recoverable Experiment - Coronagraph (PICTURE-C) mission will directly image debris disks and exozodiacal dust around nearby stars from a high-altitude balloon using a vector vortex coronagraph. The PICTURE-C low-order wavefront control (LOWC) system will be used to correct time-varying low-order aberrations due to pointing jitter, gravity sag, thermal deformation, and the gondola pendulum motion. We present the hardware and software implementation of the low-order ShackHartmann and reflective Lyot stop sensors. Development of the high-speed image acquisition and processing system is discussed with the emphasis on the reduction of hardware and computational latencies through the use of a real-time operating system and optimized data handling. By characterizing all of the LOWC latencies, we describe techniques to achieve a framerate of 200 Hz with a mean latency of ˜378 μs

The effect of acute tyrosine phenylalanine depletion on emotion-based decision-making in healthy adults.

PubMed

Vrshek-Schallhorn, Suzanne; Wahlstrom, Dustin; White, Tonya; Luciana, Monica

2013-04-01

Despite interest in dopamine's role in emotion-based decision-making, few reports of the effects of dopamine manipulations are available in this area in humans. This study investigates dopamine's role in emotion-based decision-making through a common measure of this construct, the Iowa Gambling Task (IGT), using Acute Tyrosine Phenylalanine Depletion (ATPD). In a between-subjects design, 40 healthy adults were randomized to receive either an ATPD beverage or a balanced amino acid beverage (a control) prior to completing the IGT, as well as pre- and post-manipulation blood draws for the neurohormone prolactin. Together with conventional IGT performance metrics, choice selections and response latencies were examined separately for good and bad choices before and after several key punishment events. Changes in response latencies were also used to predict total task performance. Prolactin levels increased significantly in the ATPD group but not in the control group. However, no significant group differences in performance metrics were detected, nor were there sex differences in outcome measures. However, the balanced group's bad deck latencies speeded up across the task, while the ATPD group's latencies remained adaptively hesitant. Additionally, modulation of latencies to the bad decks predicted total score for the ATPD group only. One interpretation is that ATPD subtly attenuated reward salience and altered the approach by which individuals achieved successful performance, without resulting in frank group differences in task performance. Copyright © 2013 Elsevier Inc. All rights reserved.

Influence of P300 latency jitter on event related potential-based brain-computer interface performance

NASA Astrophysics Data System (ADS)

Aricò, P.; Aloise, F.; Schettini, F.; Salinari, S.; Mattia, D.; Cincotti, F.

2014-06-01

Objective. Several ERP-based brain-computer interfaces (BCIs) that can be controlled even without eye movements (covert attention) have been recently proposed. However, when compared to similar systems based on overt attention, they displayed significantly lower accuracy. In the current interpretation, this is ascribed to the absence of the contribution of short-latency visual evoked potentials (VEPs) in the tasks performed in the covert attention modality. This study aims to investigate if this decrement (i) is fully explained by the lack of VEP contribution to the classification accuracy; (ii) correlates with lower temporal stability of the single-trial P300 potentials elicited in the covert attention modality. Approach. We evaluated the latency jitter of P300 evoked potentials in three BCI interfaces exploiting either overt or covert attention modalities in 20 healthy subjects. The effect of attention modality on the P300 jitter, and the relative contribution of VEPs and P300 jitter to the classification accuracy have been analyzed. Main results. The P300 jitter is higher when the BCI is controlled in covert attention. Classification accuracy negatively correlates with jitter. Even disregarding short-latency VEPs, overt-attention BCI yields better accuracy than covert. When the latency jitter is compensated offline, the difference between accuracies is not significant. Significance. The lower temporal stability of the P300 evoked potential generated during the tasks performed in covert attention modality should be regarded as the main contributing explanation of lower accuracy of covert-attention ERP-based BCIs.

Visual Evoked Potential to Assess Retinopathy in Gestational Diabetes Mellitus.

PubMed

Hari Kumar, K V S; Ahmad, F M H; Sood, Sandeep; Mansingh, Sudhir

2016-04-01

We evaluated for early retinopathy using the visual evoked potential (VEP) in patients with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus during pregnancy. All patients with GDM and type 2 diabetes seen between June and October of 2014 were included in this cross-sectional, observational study. Patients with secondary diabetes, ocular or major illness were excluded from the study. VEP was recorded in both eyes to derive prominent positive peak latency (P100), amplitude and initial negative deflection (N75) latency. The data were compared with 10 gestational age-matched controls with normal glucose tolerance. Appropriate statistical methods were used for comparison among the 3 groups. The study participants (40 with GDM, 10 with type 2 diabetes, 10 with normal glucose tolerance) had a median (25th to 75th interquartile range) age of 26 (24.3, 30) years, a gestational age of 24.5 (21, 27) weeks and weights of 66.8 (63.4, 71.5) kg. The P100 latencies were comparable among the 3 groups (p=0.0577). However, patients with any diabetes (GDM and type 2 diabetes) had prolonged P100 latencies (p=0.0139) and low P100 amplitudes (p=0.0391) in comparison to controls. P100 latency showed a direct correlation with hyperglycemia (p=0.0118). Our data showed that VEP abnormalities are detectable even in the short-term hyperglycemia of GDM and type 2 diabetes. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

GBU-X bounding requirements for highly flexible munitions

NASA Astrophysics Data System (ADS)

Bagby, Patrick T.; Shaver, Jonathan; White, Reed; Cafarelli, Sergio; Hébert, Anthony J.

2017-04-01

This paper will present the results of an investigation into requirements for existing software and hardware solutions for open digital communication architectures that support weapon subsystem integration. The underlying requirements of such a communication architecture would be to achieve the lowest latency possible at a reasonable cost point with respect to the mission objective of the weapon. The determination of the latency requirements of the open architecture software and hardware were derived through the use of control system and stability margins analyses. Studies were performed on the throughput and latency of different existing communication transport methods. The two architectures that were tested in this study include Data Distribution Service (DDS) and Modular Open Network Architecture (MONARCH). This paper defines what levels of latency can be achieved with current technology and how this capability may translate to future weapons. The requirements moving forward within communications solutions are discussed.

Latency Requirements for Head-Worn Display S/EVS Applications

NASA Technical Reports Server (NTRS)

Bailey, Randall E.; Trey Arthur, J. J., III; Williams, Steven P.

2004-01-01

NASA s Aviation Safety Program, Synthetic Vision Systems Project is conducting research in advanced flight deck concepts, such as Synthetic/Enhanced Vision Systems (S/EVS), for commercial and business aircraft. An emerging thrust in this activity is the development of spatially-integrated, large field-of-regard information display systems. Head-worn or helmet-mounted display systems are being proposed as one method in which to meet this objective. System delays or latencies inherent to spatially-integrated, head-worn displays critically influence the display utility, usability, and acceptability. Research results from three different, yet similar technical areas flight control, flight simulation, and virtual reality are collectively assembled in this paper to create a global perspective of delay or latency effects in head-worn or helmet-mounted display systems. Consistent definitions and measurement techniques are proposed herein for universal application and latency requirements for Head-Worn Display S/EVS applications are drafted. Future research areas are defined.

Latency requirements for head-worn display S/EVS applications

NASA Astrophysics Data System (ADS)

Bailey, Randall E.; Arthur, Jarvis J., III; Williams, Steven P.

2004-08-01

NASA's Aviation Safety Program, Synthetic Vision Systems Project is conducting research in advanced flight deck concepts, such as Synthetic/Enhanced Vision Systems (S/EVS), for commercial and business aircraft. An emerging thrust in this activity is the development of spatially-integrated, large field-of-regard information display systems. Head-worn or helmet-mounted display systems are being proposed as one method in which to meet this objective. System delays or latencies inherent to spatially-integrated, head-worn displays critically influence the display utility, usability, and acceptability. Research results from three different, yet similar technical areas - flight control, flight simulation, and virtual reality - are collectively assembled in this paper to create a global perspective of delay or latency effects in head-worn or helmet-mounted display systems. Consistent definitions and measurement techniques are proposed herein for universal application and latency requirements for Head-Worn Display S/EVS applications are drafted. Future research areas are defined.

Maintenance of Wakefulness Test scores and driving performance in sleep disorder patients and controls.

PubMed

Philip, Pierre; Chaufton, Cyril; Taillard, Jacques; Sagaspe, Patricia; Léger, Damien; Raimondi, Monika; Vakulin, Andrew; Capelli, Aurore

2013-08-01

Sleepiness at the wheel is a risk factor for traffic accidents. Past studies have demonstrated the validity of the Maintenance of Wakefulness Test (MWT) scores as a predictor of driving impairment in untreated patients with obstructive sleep apnea syndrome (OSAS), but there is limited information on the validity of the maintenance of wakefulness test by MWT in predicting driving impairment in patients with hypersomnias of central origin (narcolepsy or idiopathic hypersomnia). The aim of this study was to compare the MWT scores with driving performance in sleep disorder patients and controls. 19 patients suffering from hypersomnias of central origin (9 narcoleptics and 10 idiopathic hypersomnia), 17 OSAS patients and 14 healthy controls performed a MWT (4×40-minute trials) and a 40-minute driving session on a real car driving simulator. Participants were divided into 4 groups defined by their MWT sleep latency scores. The groups were pathological (sleep latency 0-19 min), intermediate (20-33 min), alert (34-40 min) and control (>34 min). The main driving performance outcome was the number of inappropriate line crossings (ILCs) during the 40 minute drive test. Patients with pathological MWT sleep latency scores (0-19 min) displayed statistically significantly more ILC than patients from the intermediate, alert and control groups (F (3, 46)=7.47, p<0.001). Pathological sleep latencies on the MWT predicted driving impairment in patients suffering from hypersomnias of central origin as well as in OSAS patients. MWT is an objective measure of daytime sleepiness that appears to be useful in estimating the driving performance in sleepy patients. Copyright © 2013 Elsevier B.V. All rights reserved.

Meningioma patients diagnosed 2007–2009 and the association with use of mobile and cordless phones: a case–control study

PubMed Central

2013-01-01

Background To study the association between use of wireless phones and meningioma. Methods We performed a case–control study on brain tumour cases of both genders aged 18–75 years and diagnosed during 2007–2009. One population-based control matched on gender and age was used to each case. Here we report on meningioma cases including all available controls. Exposures were assessed by a questionnaire. Unconditional logistic regression analysis was performed. Results In total 709 meningioma cases and 1,368 control subjects answered the questionnaire. Mobile phone use in total produced odds ratio (OR) = 1.0, 95% confidence interval (CI) = 0.7-1.4 and cordless phone use gave OR = 1.1, 95% CI = 0.8-1.5. The risk increased statistically significant per 100 h of cumulative use and highest OR was found in the fourth quartile (>2,376 hours) of cumulative use for all studied phone types. There was no statistically significant increased risk for ipsilateral mobile or cordless phone use, for meningioma in the temporal lobe or per year of latency. Tumour volume was not related to latency or cumulative use in hours of wireless phones. Conclusions No conclusive evidence of an association between use of mobile and cordless phones and meningioma was found. An indication of increased risk was seen in the group with highest cumulative use but was not supported by statistically significant increasing risk with latency. Results for even longer latency periods of wireless phone use than in this study are desirable. PMID:23870102

Evaluation of post-traumatic anosmia with MRI and chemosensory ERPs.

PubMed

Miao, Xutao; Yang, Ling; Gu, Hua; Ren, Yuanyuan; Chen, Guowei; Liu, Jia; Wei, Yongxiang

2015-08-01

Magnetic resonance imaging (MRI) and chemosensory event-related potentials (ERPs) are important methods to evaluate olfactory function, but there is lack of study to explore the application of MRI and chemosensory ERPs in the patients with traumatic anosmia. The data of 26 post-traumatic anosmic patients and 21 healthy controls were retrospectively surveyed; olfaction and olfactory pathway of all participants were measured clinically using the T&T olfactometer, the Sniffin' Sticks, chemosensory ERPs and MRI. All patients were anosmic based on complaints and clinical examinations. In five patients, the olfactory bulb volume was significantly lower than control group. In 18 patients, the olfactory sulcus (OS) depth was similar to control group, but all the participants had a deeper right OS (right = 7.79 ± 1.31, left = 7.06 ± 1.44, p < 0.01). Olfactory ERPs (oERPs) could be evoked in 17 patients, but these signals showed longer latencies and lower amplitude than controls in the N1 (latency p < 0.05, amplitude p < 0.01) and P2 (latency p < 0.01, amplitude p < 0.05) waves. Nine traumatic anosmic patients had no identifiable oERPs; most of them had olfactory center injury. Trigeminal ERPs were detected in all anosmic patients and controls; patients had longer latencies for N1 (p < 0.05) and P2 (p < 0.05) waves, while there was no similar change in amplitude. Older subjects had smaller OB volume and OS depth. Closed head injury could induce anosmia; the severity extent, injury site and subsequent consciousness are related to the olfaction. oERP is the gold standard for olfactory subjective examination; MRI could indicate the lesions on the olfactory pathway and reflect the possibility of detectable oERPs.

Latency of Epstein-Barr virus is stabilized by antisense-mediated control of the viral immediate-early gene BZLF-1.

PubMed

Prang, N; Wolf, H; Schwarzmann, F

1999-12-01

The ability of the Epstein-Barr virus (EBV) to avoid lytic replication and to establish a latent infection in B-lymphocytes is fundamental for its lifelong persistence and the pathogenesis of various EBV-associated diseases. The viral immediate-early gene BZLF-1 plays a key role for the induction of lytic replication and its activity is strictly regulated on different levels of gene expression. Recently, it was demonstrated that BZLF-1 is also controlled by a posttranscriptional mechanism. Transient synthesis of a mutated competitor RNA saturated this mechanism and caused both expression of the BZLF-1 protein and the induction of lytic viral replication. Using short overlapping fragments of the competitor, it is shown that this control acts on the unspliced primary transcript. RT-PCR demonstrated unspliced BZLF-1 RNA in latently infected B-lymphocytes in the absence of BZLF-1 protein. Due to the complementarity of the gene BZLF-1 and the latency-associated gene EBNA-1 on the opposite strand of the genome, we propose an antisense-mediated mechanism. RNase protection assays demonstrated transcripts in antisense orientation to the BZLF-1 transcript during latency, which comprise a comparable constellation to other herpesviruses. A combined RNAse protection/RT-PCR assay detected the double-stranded hybrid RNA, consisting of the unspliced BZLF-1 transcript and a noncoding intron of the EBNA-1 gene. Binding of BZLF-1 transcripts is suggested to be an important backup control mechanism in addition to transcriptional regulation, stabilizing latency and preventing inappropriate lytic viral replication in vivo. Copyright 1999 Wiley-Liss, Inc.

Idiopathic normal pressure hydrocephalus: analysis of factors related to cerebrospinal fluid dynamics determining functional prognosis.

PubMed

Bárcena, A; Mestre, C; Cañizal, J M; Rivero, B; Lobato, R D

1997-01-01

This investigation has been undertaken to analyze the findings with both the cerebrospinal fluid (CSF) pressure (Pcsf) and CSF pulse pressure (PP) in order to predict the outcome of patients with the syndrome of idiopathic normal pressure hydrocephalus (NPH). Accordingly, a prospective clinical study was planned in which two groups of patients with NPH, having analogous prevalence of several matched clinical and radiological parameters, were separated on the basis of their positive or negative response to shunting. Both the resting Pcsf and CSF PP profiles were compared in these two groups, and between them and normal controls. CSF PP amplitude and CSF PP latency correlated directly in conditions associated with either normal or high compliance (controls and patients with Alzheimer-like disorders), whereas this correlation was inverse in states of low compliance (NPH). On the other hand, shunt-responders showed a resting Pcsf significantly higher than both non-responders and controls. The following conclusions were obtained: 1) CSF PP is a high-amplitude and relative low-latency wave in NPH when compared with controls: 2) CSF PP amplitude and latency correlate directly in normal subjects and in those with primary cerebral atrophy; 3) a non-reversible stage of NPH could be conceived in contradistinction to the reversible one, in both of which an inverse correlation between the amplitude and the latency takes place, the main difference between them being the resting Pcsf, which is significantly lower in the former than in the latter, depending on the degree of atrophic changes developed.

Auditory event-related potentials in subcortical vascular cognitive impairment and in Alzheimer's disease.

PubMed

Muscoso, E G; Costanzo, E; Daniele, O; Maugeri, D; Natale, E; Caravaglios, G

2006-11-01

Few studies exist on ERPs and patients with subcortical vascular cognitive impairment (SVCI). This latter is a quite homogeneous subtype of vascular dementia whose cognitive profile is quite different from that of Alzheimer disease (AD). The present study aims at comparing the ERPs profile both in patients with SVCI and in patients with AD. ERPs and psychometric tests were collected from 39 healthy elderly controls, 51 patients with SVCI and 43 patients with AD. Subjects mentally count high pitched target tones that were randomly intermixed with low pitched frequent tones. We measured ERPs latencies (N1, P2, N2 and P3), and interpeak latencies (N1-P3, N1-P2, N1-N2). Grand averaged potentials in SVCI showed a significant increase of P3 latency. AD patients showed a prolongation of N1, P2, N2, P3 latencies. As far as interpeak latencies are concerned, SVCI patients showed a significant prolongation of N1-P3, AD patients had a significant increase of N1-N2, and N1-P3 intervals. When all patients were considered as a single group, correlation of neuropsychological tests scores showed a significant negative relationship between P300 latency and, respectively, Mini Mental Status Examination, auditive and visual span forward. In both groups, ERPs latency sensitivity, was low, whilst specificity values were quite high. Our finding suggest that these two dementing diseases have different electrophysiologic features that may be related to their specific underlying pathogenetic mechanism; in particular, we hypothesise that, differently from AD, P300 latency prolongation characterizes the early stage of SVCI. So, this ERPs approach could be helpful to detect early alterations of the attentional/working-memory functions in patients with subcortical ischaemic vascular disease.

Effects of mastication on human somatosensory processing: A study using somatosensory-evoked potentials.

PubMed

Nakata, Hiroki; Aoki, Mai; Sakamoto, Kiwako

2017-04-01

The aim of the present study was to investigate the effects of mastication on somatosensory processing using somatosensory-evoked potentials (SEPs). Fourteen healthy subjects received a median nerve stimulation at the right wrist under two conditions: Mastication and Control. SEPs were recorded in five sessions for approximately seven minutes: Pre, Post 1, 2, 3, and 4. Subjects were asked to chew gum for five minutes after one session in Mastication. Control included the same five sessions. The amplitudes and latencies of P14, N20, P25, N35, P45, and N60 components at C3', frontal N30 component at Fz, and P100 and N140 components at Pz were analyzed. The amplitude of P45-N60 was significantly smaller at Post 1, 2, 3, and 4 than at Pre in Control, but not in Mastication. The latency of P25 was significantly longer at Post 2, 3, and 4 than at Pre in Control, but not in Mastication. The latency of P100 was significantly longer at Post 2 than at Pre in Control, but not in Mastication. These results suggest the significant effects of mastication on the neural activity of human somatosensory processing. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

A Fast MAC-Layer Handover for an IEEE 802.16e-Based WMAN

NASA Astrophysics Data System (ADS)

Ray, Sayan K.; Pawlikowski, Krzysztof; Sirisena, Harsha

We propose a modification of the IEEE 802.16e hard handover (HHO) procedure, which significantly reduces the handover latency constraint of the original HHO procedure in IEEE 802.16e networks. It allows a better handling of the delay-sensitive traffic by avoiding unnecessary time-consuming scanning and synchronization activity as well as simplifies the network re-entry procedure. With the help of the backhaul network, it reduces the number of control messages in the original handover policy, making the handover latency acceptable also for real-time streaming traffic. Preliminary performance evaluation studies show that the modified handover procedure is able to reduce the total handover latency by about 50%.

Energy latency tradeoffs for medium access and sleep scheduling in wireless sensor networks

NASA Astrophysics Data System (ADS)

Gang, Lu

Wireless sensor networks are expected to be used in a wide range of applications from environment monitoring to event detection. The key challenge is to provide energy efficient communication; however, latency remains an important concern for many applications that require fast response. The central thesis of this work is that energy efficient medium access and sleep scheduling mechanisms can be designed without necessarily sacrificing application-specific latency performance. We validate this thesis through results from four case studies that cover various aspects of medium access and sleep scheduling design in wireless sensor networks. Our first effort, DMAC, is to design an adaptive low latency and energy efficient MAC for data gathering to reduce the sleep latency. We propose staggered schedule, duty cycle adaptation, data prediction and the use of more-to-send packets to enable seamless packet forwarding under varying traffic load and channel contentions. Simulation and experimental results show significant energy savings and latency reduction while ensuring high data reliability. The second research effort, DESS, investigates the problem of designing sleep schedules in arbitrary network communication topologies to minimize the worst case end-to-end latency (referred to as delay diameter). We develop a novel graph-theoretical formulation, derive and analyze optimal solutions for the tree and ring topologies and heuristics for arbitrary topologies. The third study addresses the problem of minimum latency joint scheduling and routing (MLSR). By constructing a novel delay graph, the optimal joint scheduling and routing can be solved by M node-disjoint paths algorithm under multiple channel model. We further extended the algorithm to handle dynamic traffic changes and topology changes. A heuristic solution is proposed for MLSR under single channel interference. In the fourth study, EEJSPC, we first formulate a fundamental optimization problem that provides tunable energy-latency-throughput tradeoffs with joint scheduling and power control and present both exponential and polynomial complexity solutions. Then we investigate the problem of minimizing total transmission energy while satisfying transmission requests within a latency bound, and present an iterative approach which converges rapidly to the optimal parameter settings.

Pre-attentive auditory discrimination skill in Indian classical vocal musicians and non-musicians.

PubMed

Sanju, Himanshu Kumar; Kumar, Prawin

2016-09-01

To test for pre-attentive auditory discrimination skills in Indian classical vocal musicians and non-musicians. Mismatch negativity (MMN) was recorded to test for pre-attentive auditory discrimination skills with a pair of stimuli of /1000 Hz/ and /1100 Hz/, with /1000 Hz/ as the frequent stimulus and /1100 Hz/ as the infrequent stimulus. Onset, offset and peak latencies were the considered latency parameters, whereas peak amplitude and area under the curve were considered for amplitude analysis. Exactly 50 participants, out of which the experimental group had 25 adult Indian classical vocal musicians and 25 age-matched non-musicians served as the control group, were included in the study. Experimental group participants had a minimum professional music experience in Indian classic vocal music of 10 years. However, control group participants did not have any formal training in music. Descriptive statistics showed better waveform morphology in the experimental group as compared to the control. MANOVA showed significantly better onset latency, peak amplitude and area under the curve in the experimental group but no significant difference in the offset and peak latencies between the two groups. The present study probably points towards the enhancement of pre-attentive auditory discrimination skills in Indian classical vocal musicians compared to non-musicians. It indicates that Indian classical musical training enhances pre-attentive auditory discrimination skills in musicians, leading to higher peak amplitude and a greater area under the curve compared to non-musicians.

Response Latency Measures for Biographical Inventories

DTIC Science & Technology

1991-03-01

research (Trent et al., 1989). Procedures The ASAP, followed by one or more experimental cognitive tests, was computer administered to groups of...comprehension, and binary " true /false" decision about the item. This last stage, in turn, is divided into two substages: self-referent decision...apply stage) As a first step in partitioning latencies, it would be prudent to control experimentally for item length, as had been done in a few studies

Visual and brainstem auditory evoked potentials in children with obesity.

PubMed

Akın, Onur; Arslan, Mutluay; Akgün, Hakan; Yavuz, Süleyman Tolga; Sarı, Erkan; Taşçılar, Mehmet Emre; Ulaş, Ümit Hıdır; Yeşilkaya, Ediz; Ünay, Bülent

2016-03-01

The aim of our study is to investigate alterations in visual evoked potentials (VEP) and brainstem auditory evoked potentials (BAEP) in children with obesity. A total of 96 children, with a mean age of 12.1±2.0 years (range 9-17 years, 63 obese and 33 age and sex-matched control subjects) were included in the study. Laboratory tests were performed to detect insulin resistance (IR) and dyslipidemia. The latencies and amplitudes of VEP and BAEP were measured in healthy and obese subjects. The VEP P100, BAEP interpeak latency (IPL) I-III and IPL I-V averages of obese children were significantly longer than the control subjects. When the obese group was divided into two subgroups, those with IR and without IR, BAEP wave I, wave III and P100 wave latencies were found to be longer in the group with IR. A statistically significant correlation was observed between BAEP wave I latency, IPL I-V, IPL I-III and the homeostatic model assessment insulin resistance (HOMA IR) index and fasting insulin level. Our findings suggest that VEP and BAEP can be used to determine early subclinical on auditory and visual functions of obese children with insulin resistance. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Laser-evoked potentials in painful radiculopathy.

PubMed

Hüllemann, P; von der Brelie, C; Manthey, G; Düsterhöft, J; Helmers, A K; Synowitz, M; Gierthmühlen, J; Baron, R

2017-11-01

The aims of this exploratory study were (1) to develop a standardized objective electrophysiological technique with laser-evoked potentials to assess dorsal root damage quantitatively and (2) to correlate these LEP measures with clinical parameters and sensory abnormalities (QST) in the affected dermatome. Thirty-eight patients with painful radiculopathy and 20 healthy subjects were investigated with LEP recorded from the affected dermatome and control areas as well as with quantitative sensory testing. Questionnaires evaluating severity and functionality were applied. On average, LEP amplitudes and latencies from the affected dermatomes did not differ from the contralateral control side. In patients with left L5 radiculopathy (more severely affected) the N2 latency was longer and the amplitudes reduced. The N2P2 amplitude correlated with pinprick evoked sensations in QST. The N2 latency from the affected dermatome correlates with pain intensity, chronicity, clinical severity and with a decrease of physical function. An increase in N2-latency indicates a more pronounced nerve root damage, which is associated with a decrease of function and an increase of severity and pain. LEP amplitudes are associated with the functional status of the nociceptive system and may distinguish between degeneration of neuronal systems and central sensitization processes. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Compensation for pitch-shifted auditory feedback during the production of Mandarin tone sequences

NASA Astrophysics Data System (ADS)

Xu, Yi; Larson, Charles R.; Bauer, Jay J.; Hain, Timothy C.

2004-08-01

Recent research has found that while speaking, subjects react to perturbations in pitch of voice auditory feedback by changing their voice fundamental frequency (F0) to compensate for the perceived pitch-shift. The long response latencies (150-200 ms) suggest they may be too slow to assist in on-line control of the local pitch contour patterns associated with lexical tones on a syllable-to-syllable basis. In the present study, we introduced pitch-shifted auditory feedback to native speakers of Mandarin Chinese while they produced disyllabic sequences /ma ma/ with different tonal combinations at a natural speaking rate. Voice F0 response latencies (100-150 ms) to the pitch perturbations were shorter than syllable durations reported elsewhere. Response magnitudes increased from 50 cents during static tone to 85 cents during dynamic tone productions. Response latencies and peak times decreased in phrases involving a dynamic change in F0. The larger response magnitudes and shorter latency and peak times in tasks requiring accurate, dynamic control of F0, indicate this automatic system for regulation of voice F0 may be task-dependent. These findings suggest that auditory feedback may be used to help regulate voice F0 during production of bi-tonal Mandarin phrases.

Primary visual response (M100) delays in adolescents with FASD as measured with MEG.

PubMed

Coffman, Brian A; Kodituwakku, Piyadasa; Kodituwakku, Elizabeth L; Romero, Lucinda; Sharadamma, Nirupama Muniswamy; Stone, David; Stephen, Julia M

2013-11-01

Fetal alcohol spectrum disorders (FASD) are debilitating, with effects of prenatal alcohol exposure persisting into adolescence and adulthood. Complete characterization of FASD is crucial for the development of diagnostic tools and intervention techniques to decrease the high cost to individual families and society of this disorder. In this experiment, we investigated visual system deficits in adolescents (12-21 years) diagnosed with an FASD by measuring the latency of patients' primary visual M100 responses using MEG. We hypothesized that patients with FASD would demonstrate delayed primary visual responses compared to controls. M100 latencies were assessed both for FASD patients and age-matched healthy controls for stimuli presented at the fovea (central stimulus) and at the periphery (peripheral stimuli; left or right of the central stimulus) in a saccade task requiring participants to direct their attention and gaze to these stimuli. Source modeling was performed on visual responses to the central and peripheral stimuli and the latency of the first prominent peak (M100) in the occipital source timecourse was identified. The peak latency of the M100 responses were delayed in FASD patients for both stimulus types (central and peripheral), but the difference in latency of primary visual responses to central vs. peripheral stimuli was significant only in FASD patients, indicating that, while FASD patients' visual systems are impaired in general, this impairment is more pronounced in the periphery. These results suggest that basic sensory deficits in this population may contribute to sensorimotor integration deficits described previously in this disorder. Copyright © 2012 Wiley Periodicals, Inc.

Cerebellar damage diminishes long-latency responses to multijoint perturbations

PubMed Central

Trautman, Paxson; Rasquinha, Russell J.; Bhanpuri, Nasir H.; Scott, Stephen H.; Bastian, Amy J.

2013-01-01

Damage to the cerebellum can cause significant problems in the coordination of voluntary arm movements. One prominent idea is that incoordination stems from an inability to predictively account for the complex mechanical interactions between the arm's several joints. Motivated by growing evidence that corrective feedback control shares important capabilities and neural substrates with feedforward control, we asked whether cerebellar damage impacts feedback stabilization of the multijoint arm appropriate for the arm's intersegmental dynamics. Specifically, we tested whether cerebellar dysfunction impacts the ability of posterior deltoid to incorporate elbow motion in its long-latency response (R2 = 45–75 ms and R3 = 75–100 ms after perturbation) to an unexpected torque perturbation. Healthy and cerebellar-damaged subjects were exposed to a selected pattern of shoulder-elbow displacements to probe the response pattern from this shoulder extensor muscle. The healthy elderly subjects expressed a long-latency response linked to both shoulder and elbow motion, including an increase/decrease in shoulder extensor activity with elbow flexion/extension. Critically, cerebellar-damaged subjects displayed the normal pattern of activity in the R3 period indicating an intact ability to rapidly integrate multijoint motion appropriate to the arm's intersegmental dynamics. However, cerebellar-damaged subjects had a lower magnitude of activity that was specific to the long-latency period (both R2 and R3) and a slightly delayed onset of multijoint sensitivity. Taken together, our results suggest that the basic motor pattern of the long-latency response is housed outside the cerebellum and is scaled by processes within the cerebellum. PMID:23390311

Optimizing latency in Xilinx FPGA implementations of the GBT

NASA Astrophysics Data System (ADS)

Muschter, S.; Baron, S.; Bohm, C.; Cachemiche, J.-P.; Soos, C.

2010-12-01

The GigaBit Transceiver (GBT) [1] system has been developed to replace the Timing, Trigger and Control (TTC) system [2], currently used by LHC, as well as to provide data transmission between on-detector and off-detector components in future sLHC detectors. A VHDL version of the GBT-SERDES, designed for FPGAs, was released in March 2010 as a GBT-FPGA Starter Kit for future GBT users and for off-detector GBT implementation [3]. This code was optimized for resource utilization [4], as the GBT protocol is very demanding. It was not, however, optimized for latency — which will be a critical parameter when used in the trigger path. The GBT-FPGA Starter Kit firmware was first analyzed in terms of latency by looking at the separate components of the VHDL version. Once the parts which contribute most to the latency were identified and modified, two possible optimizations were chosen, resulting in a latency reduced by a factor of three. The modifications were also analyzed in terms of logic utilization. The latency optimization results were compared with measurement results from a Virtex 6 ML605 development board [5] equipped with a XC6VLX240T with speedgrade-1 and the package FF1156. Bit error rate tests were also performed to ensure an error free operation. The two final optimizations were analyzed for utilization and compared with the original code, distributed in the Starter Kit.

Complex regional pain syndrome (CRPS) or continuous unilateral distal experimental pain stimulation in healthy subjects does not bias visual attention towards one hemifield.

PubMed

Filippopulos, Filipp M; Grafenstein, Jessica; Straube, Andreas; Eggert, Thomas

2015-11-01

In natural life pain automatically draws attention towards the painful body part suggesting that it interacts with different attentional mechanisms such as visual attention. Complex regional pain syndrome (CRPS) patients who typically report on chronic distally located pain of one extremity may suffer from so-called neglect-like symptoms, which have also been linked to attentional mechanisms. The purpose of the study was to further evaluate how continuous pain conditions influence visual attention. Saccade latencies were recorded in two experiments using a common visual attention paradigm whereby orientating saccades to cued or uncued lateral visual targets had to be performed. In the first experiment saccade latencies of healthy subjects were measured under two conditions: one in which continuous experimental pain stimulation was applied to the index finger to imitate a continuous pain situation, and one without pain stimulation. In the second experiment saccade latencies of patients suffering from CRPS were compared to controls. The results showed that neither the continuous experimental pain stimulation during the experiment nor the chronic pain in CRPS led to an unilateral increase of saccade latencies or to a unilateral increase of the cue effect on latency. The results show that unilateral, continuously applied pain stimuli or chronic pain have no or only very limited influence on visual attention. Differently from patients with visual neglect, patients with CRPS did not show strong side asymmetries of saccade latencies or of cue effects on saccade latencies. Thus, neglect-like clinical symptoms of CRPS patients do not involve the allocation of visual attention.

Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons

PubMed Central

Pourchet, Aldo; Modrek, Aram S.; Placantonakis, Dimitris G.; Mohr, Ian; Wilson, Angus C.

2017-01-01

Herpes simplex virus 1 (HSV-1) uses latency in peripheral ganglia to persist in its human host, however, recurrent reactivation from this reservoir can cause debilitating and potentially life-threatening disease. Most studies of latency use live-animal infection models, but these are complex, multilayered systems and can be difficult to manipulate. Infection of cultured primary neurons provides a powerful alternative, yielding important insights into host signaling pathways controlling latency. However, small animal models do not recapitulate all aspects of HSV-1 infection in humans and are limited in terms of the available molecular tools. To address this, we have developed a latency model based on human neurons differentiated in culture from an NIH-approved embryonic stem cell line. The resulting neurons are highly permissive for replication of wild-type HSV-1, but establish a non-productive infection state resembling latency when infected at low viral doses in the presence of the antivirals acyclovir and interferon-α. In this state, viral replication and expression of a late viral gene marker are not detected but there is an accumulation of the viral latency-associated transcript (LAT) RNA. After a six-day establishment period, antivirals can be removed and the infected cultures maintained for several weeks. Subsequent treatment with sodium butyrate induces reactivation and production of new infectious virus. Human neurons derived from stem cells provide the appropriate species context to study this exclusively human virus with the potential for more extensive manipulation of the progenitors and access to a wide range of preexisting molecular tools. PMID:28594343

Hoffmann-reflex is delayed during 6 degree head-down tilt with balanced traction

NASA Technical Reports Server (NTRS)

Haruna, Y.; Styf, J. R.; Kahan, N.; Hargens, A. R.

1999-01-01

BACKGROUND: Increased spinal height due to the lack of of axial compression on spinal structures in microgravity may stretch the spinal cord, cauda equina, nerve roots, and paraspinal tissues. HYPOTHESIS: Exposure to simulated microgravity causes dysfunction of nerve roots so that the synaptic portion of the Achilles tendon reflex is delayed. METHODS: Six healthy male subjects were randomly divided into two groups with three in each group. The subjects in the first group underwent horizontal bed rest (HBR) for three days. After a two week interval they underwent bed rest in a position of head-down tilt with balanced traction (HDT). So that each subject could serve as his own control, the second group was treated identically but in opposite order. Bilateral F waves and H-reflexes were measured daily (18:30-20:30) on all subjects placed in a prone position. RESULTS: By means of ANOVA, differences between HDT and HBR were observed only in M-latency and F-ratio, not in F-latency, central latency, and H-latency. Differences during the course of the bed rest were observed in M-latency and H-latency only. Tibial H latency was significantly lengthened in HDT group on day 2 and 3, although no significant difference between HDT and HBR was observed. CONCLUSION: The monosynaptic reflex assessed by H-reflex was delayed during 6 degree HDT with traction. The exact mechanism of this delay and whether the change was due to lengthening of the lower part of the vertebrae remain to be clarified.

Interference resolution in major depression.

PubMed

Joormann, Jutta; Nee, Derek Evan; Berman, Marc G; Jonides, John; Gotlib, Ian H

2010-03-01

In two experiments, we investigated individual differences in the ability to resolve interference in participants diagnosed with major depressive disorder (MDD). Participants were administered the "Ignore/Suppress" task, a short-term memory task composed of two steps. In Step 1 ("ignore"), participants were instructed to memorize a set of stimuli while ignoring simultaneously presented irrelevant material. In Step 2 ("suppress"), participants were instructed to forget a subset of the previously memorized material. The ability to resolve interference was indexed by response latencies on two recognition tasks in which participants decided whether a probe was a member of the target set. In Step 1, we compared response latencies to probes from the to-be-ignored list with response latencies to nonrecently presented items. In Step 2, we compared response latencies to probes from the to-be-suppressed list with response latencies to nonrecently presented items. The results indicate that, compared with control participants, depressed participants exhibited increased interference in the "suppress" but not in the "ignore" step of the task, when the stimuli were negative words. No group differences were obtained when we presented letters instead of emotional words. These findings indicate that depression is associated with difficulty in removing irrelevant negative material from short-term memory.

The amblyopic eye in subjects with anisometropia show increased saccadic latency in the delayed saccade task

PubMed Central

Perdziak, Maciej; Witkowska, Dagmara; Gryncewicz, Wojciech; Przekoracka-Krawczyk, Anna; Ober, Jan

2014-01-01

The term amblyopia is used to describe reduced visual function in one eye (or both eyes, though not so often) which cannot be fully improved by refractive correction and explained by the organic cause observed during regular eye examination. Amblyopia is associated with abnormal visual experience (e.g., anisometropia) during infancy or early childhood. Several studies have shown prolongation of saccadic latency time in amblyopic eye. In our opinion, study of saccadic latency in the context of central vision deficits assessment, should be based on central retina stimulation. For this reason, we proposed saccade delayed task. It requires inhibitory processing for maintaining fixation on the central target until it disappears—what constitutes the GO signal for saccade. The experiment consisted of 100 trials for each eye and was performed under two viewing conditions: monocular amblyopic/non-dominant eye and monocular dominant eye. We examined saccadic latency in 16 subjects (mean age 30 ± 11 years) with anisometropic amblyopia (two subjects had also microtropia) and in 17 control subjects (mean age 28 ± 8 years). Participants were instructed to look at central (fixation) target and when it disappears, to make the saccade toward the periphery (10°) as fast as possible, either left or the right target. The study results have proved the significant difference in saccadic latency between the amblyopic (mean 262 ± 48 ms) and dominant (mean 237 ± 45 ms) eye, in anisometropic group. In the control group, the saccadic latency for dominant (mean 226 ± 32 ms) and non-dominant (mean 230 ± 29 ms) eye was not significantly different. By the use of LATER (Linear Approach to the Threshold with Ergodic Rate) decision model we interpret our findings as a decrease in accumulation of visual information acquired by means of central retina in subjects with anisometropic amblyopia. PMID:25352790

A Herpesvirus Protein Selectively Inhibits Cellular mRNA Nuclear Export.

PubMed

Gong, Danyang; Kim, Yong Hoon; Xiao, Yuchen; Du, Yushen; Xie, Yafang; Lee, Kevin K; Feng, Jun; Farhat, Nisar; Zhao, Dawei; Shu, Sara; Dai, Xinghong; Chanda, Sumit K; Rana, Tariq M; Krogan, Nevan J; Sun, Ren; Wu, Ting-Ting

2016-11-09

Nuclear mRNA export is highly regulated to ensure accurate cellular gene expression. Viral inhibition of cellular mRNA export can enhance viral access to the cellular translation machinery and prevent anti-viral protein production but is generally thought to be nonselective. We report that ORF10 of Kaposi's sarcoma-associated herpesvirus (KSHV), a nuclear DNA virus, inhibits mRNA export in a transcript-selective manner to control cellular gene expression. Nuclear export inhibition by ORF10 requires an interaction with an RNA export factor, Rae1. Genome-wide analysis reveals a subset of cellular mRNAs whose nuclear export is blocked by ORF10 with the 3' UTRs of ORF10-targeted transcripts conferring sensitivity to export inhibition. The ORF10-Rae1 interaction is important for the virus to express viral genes and produce infectious virions. These results suggest that a nuclear DNA virus can selectively interfere with RNA export to restrict host gene expression for optimal replication. Published by Elsevier Inc.

Delayed Compensatory Postural Adjustments After Lateral Perturbations Contribute to the Reduced Ability of Older Adults to Control Body Balance.

PubMed

Claudino, Renato; Dos Santos, Marcio José; Mazo, Giovana Zarpellon

2017-10-01

The goal of this study was to investigate the timing of compensatory postural adjustments in older adults during body perturbations in the mediolateral direction, circumstances that increase their risk of falls. The latencies of leg and trunk muscle activation to body perturbations at the shoulder level and variables of center of pressure excursion, which characterize postural stability, were analyzed in 40 older adults (nonfallers and fallers evenly split) and in 20 young participants. The older adults exhibited longer latencies of muscular activation in eight out of 15 postural muscles as compared with young participants; for three muscles, the latencies were longer for the older fallers than nonfallers. Simultaneously, the time for the center of pressure displacement reached its peak after the perturbation was significant longer in both groups of older adults. The observed delays in compensatory postural adjustments may affect the older adults' ability to prompt control body balance after postural disturbances and predispose them to falls.

Effects of age on cognitive control during semantic categorization.

PubMed

Mudar, Raksha A; Chiang, Hsueh-Sheng; Maguire, Mandy J; Spence, Jeffrey S; Eroh, Justin; Kraut, Michael A; Hart, John

2015-01-01

We used event-related potentials (ERPs) to study age effects of perceptual (basic-level) vs. perceptual-semantic (superordinate-level) categorization on cognitive control using the go/nogo paradigm. Twenty-two younger (11 M; 21 ± 2.2 years) and 22 older adults (9 M; 63 ± 5.8 years) completed two visual go/nogo tasks. In the single-car task (SiC) (basic), go/nogo responses were made based on single exemplars of a car (go) and a dog (nogo). In the object animal task (ObA) (superordinate), responses were based on multiple exemplars of objects (go) and animals (nogo). Each task consisted of 200 trials: 160 (80%) 'go' trials that required a response through button pressing and 40 (20%) 'nogo' trials that required inhibition/withholding of a response. ERP data revealed significantly reduced nogo-N2 and nogo-P3 amplitudes in older compared to younger adults, whereas go-N2 and go-P3 amplitudes were comparable in both groups during both categorization tasks. Although the effects of categorization levels on behavioral data and P3 measures were similar in both groups with longer response times, lower accuracy scores, longer P3 latencies, and lower P3 amplitudes in ObA compared to SiC, N2 latency revealed age group differences moderated by the task. Older adults had longer N2 latency for ObA compared to SiC, in contrast, younger adults showed no N2 latency difference between SiC and ObA. Overall, these findings suggest that age differentially affects neural processing related to cognitive control during semantic categorization. Furthermore, in older adults, unlike in younger adults, levels of categorization modulate neural processing related to cognitive control even at the early stages (N2). Published by Elsevier B.V.

Diagnostic accuracy of eye movements in assessing pedophilia.

PubMed

Fromberger, Peter; Jordan, Kirsten; Steinkrauss, Henrike; von Herder, Jakob; Witzel, Joachim; Stolpmann, Georg; Kröner-Herwig, Birgit; Müller, Jürgen Leo

2012-07-01

Given that recurrent sexual interest in prepubescent children is one of the strongest single predictors for pedosexual offense recidivism, valid and reliable diagnosis of pedophilia is of particular importance. Nevertheless, current assessment methods still fail to fulfill psychometric quality criteria. The aim of the study was to evaluate the diagnostic accuracy of eye-movement parameters in regard to pedophilic sexual preferences. Eye movements were measured while 22 pedophiles (according to ICD-10 F65.4 diagnosis), 8 non-pedophilic forensic controls, and 52 healthy controls simultaneously viewed the picture of a child and the picture of an adult. Fixation latency was assessed as a parameter for automatic attentional processes and relative fixation time to account for controlled attentional processes. Receiver operating characteristic (ROC) analyses, which are based on calculated age-preference indices, were carried out to determine the classifier performance. Cross-validation using the leave-one-out method was used to test the validity of classifiers. Pedophiles showed significantly shorter fixation latencies and significantly longer relative fixation times for child stimuli than either of the control groups. Classifier performance analysis revealed an area under the curve (AUC) = 0.902 for fixation latency and an AUC = 0.828 for relative fixation time. The eye-tracking method based on fixation latency discriminated between pedophiles and non-pedophiles with a sensitivity of 86.4% and a specificity of 90.0%. Cross-validation demonstrated good validity of eye-movement parameters. Despite some methodological limitations, measuring eye movements seems to be a promising approach to assess deviant pedophilic interests. Eye movements, which represent automatic attentional processes, demonstrated high diagnostic accuracy. © 2012 International Society for Sexual Medicine.

Functional and psychological characteristics of belgian men with premature ejaculation and their partners.

PubMed

Kempeneers, Philippe; Andrianne, Robert; Bauwens, Sabrina; Georis, Isabelle; Pairoux, Jean-François; Blairy, Sylvie

2013-01-01

Physiological, behavioral, cognitive, and emotional factors are generally acknowledged to play a role in premature ejaculation (PE). However, the nature and the extent of their etiological impact remain largely imprecise. The present study examined functional and psychometric dynamics at work in a PE population. A total of 461 men with PE and 80 partners completed an online questionnaire. The main outcome measures were self-reported ejaculatory latency time, the feeling of control upon ejaculation, sexual satisfaction, distress related to PE, trait anxiety (STAI-B), sexual cognitions (Sexual Irrationality Questionnaire [SIQ]), social anxiety (Liebowitz's Social Anxiety Scale [LSAS] and Social Interaction Self-Statement Test [SISST]), and personality traits (Temperament and Character Inventory-Revised [TCI-R]). In our sample, the median latency time to ejaculation was between 1 and 2 min. Sexual satisfaction and distress correlated more strongly with the feeling of control than with the self-reported latency time. Men experienced more distress and dissatisfaction related to PE than did their partners, while overestimating their partners' distress and dissatisfaction. PE participants' scores differed significantly, albeit slightly, from STAI-B, SIQ, LSAS, and SISST norms. The differences were negligible on TCI-R. Some differences became stronger when subtypes were considered. Participants combining generalized and lifelong PE with self-reported latency times of <30 s reported lower sexual satisfaction and control, higher distress, higher social anxiety, and harm avoidance (TCI-R/HA) scores. By contrast, the situational subtype of PE was found to be characterized by a higher level of satisfaction, a greater feeling of control, less distress, and higher trait anxiety scores. However, the trends remained statistically discrete.

Anticipatory processing in social anxiety: Investigation using attentional control theory.

PubMed

Sluis, Rachel A; Boschen, Mark J; Neumann, David L; Murphy, Karen

2017-12-01

Cognitive models of social anxiety disorder (SAD) emphasize anticipatory processing as a prominent maintaining factor occurring before social-evaluative events. While anticipatory processing is a maladaptive process, the cognitive mechanisms that underlie ineffective control of attention are still unclear. The present study tested predictions derived from attentional control theory in a sample of undergraduate students high and low on social anxiety symptoms. Participants were randomly assigned to either engage in anticipatory processing prior to a threat of a speech task or a control condition with no social evaluative threat. After completing a series of questionnaires, participants performed pro-saccades and antisaccades in response to peripherally presented facial expressions presented in either single-task or mixed-task blocks. Correct antisaccade latencies were longer than correct pro-saccade latencies in-line with attentional control theory. High socially anxious individuals who anticipated did not exhibit impairment on the inhibition and shifting functions compared to high socially anxious individuals who did not anticipate or low socially anxious individuals in either the anticipatory or control condition. Low socially anxious individuals who anticipated exhibited shorter antisaccade latencies and a switch benefit compared to low socially anxious individuals in the control condition. The study used an analogue sample; however findings from analogue samples are generally consistent with clinical samples. The findings suggest that social threat induced anticipatory processing facilitates executive functioning for low socially anxious individuals when anticipating a social-evaluative situation. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Delayed latency of peroneal reflex to sudden inversion with ankle taping or bracing.

PubMed

Shima, N; Maeda, A; Hirohashi, K

2005-01-01

The purpose of the present study was to examine the effects of ankle taping and bracing based on the peroneal reflex in the hypermobile and normal ankle joints with and without history of ankle injury. Thirty-six ankle joints of 18 collegiate American football athletes with and without previous history of injury were studied. The angle of talar tilt (TT) was measured by stress radiograph for classifying normal (TT5 degrees ) ankles. They were tested with taping, bracing, and without any supports as a control. The latency of peroneus longus muscle was measured by a sudden inversion of 25 degrees using surface EMG signals. The results of the present study show no significant three-way Group (hypermobile or normal ankles) by History (previously injured or uninjured ankles) by Condition (control, taping, or bracing) interaction, while Condition main effect was significant (p<0.05). There were significant differences between control (80.8 ms) and taping (83.8 ms, p<0.01), between control and bracing (83.0 ms, p<0.05), but not between taping and bracing (p>0.05). In conclusion, ankle taping and bracing delayed the peroneal reflex latency not only for hypermobile ankles and/or injured ankle joints but also for intact ankle joints.

Behavioral and electrophysiological auditory processing measures in traumatic brain injury after acoustically controlled auditory training: a long-term study

PubMed Central

Figueiredo, Carolina Calsolari; de Andrade, Adriana Neves; Marangoni-Castan, Andréa Tortosa; Gil, Daniela; Suriano, Italo Capraro

2015-01-01

ABSTRACT Objective To investigate the long-term efficacy of acoustically controlled auditory training in adults after tarumatic brain injury. Methods A total of six audioogically normal individuals aged between 20 and 37 years were studied. They suffered severe traumatic brain injury with diffuse axional lesion and underwent an acoustically controlled auditory training program approximately one year before. The results obtained in the behavioral and electrophysiological evaluation of auditory processing immediately after acoustically controlled auditory training were compared to reassessment findings, one year later. Results Quantitative analysis of auditory brainsteim response showed increased absolute latency of all waves and interpeak intervals, bilaterraly, when comparing both evaluations. Moreover, increased amplitude of all waves, and the wave V amplitude was statistically significant for the right ear, and wave III for the left ear. As to P3, decreased latency and increased amplitude were found for both ears in reassessment. The previous and current behavioral assessment showed similar results, except for the staggered spondaic words in the left ear and the amount of errors on the dichotic consonant-vowel test. Conclusion The acoustically controlled auditory training was effective in the long run, since better latency and amplitude results were observed in the electrophysiological evaluation, in addition to stability of behavioral measures after one-year training. PMID:26676270

On the association between glioma, wireless phones, heredity and ionising radiation.

PubMed

Carlberg, Michael; Hardell, Lennart

2012-09-01

We performed two case-control studies on brain tumours diagnosed during 1 January 1997 to 30 June 2000 and 1 July 2000 to 31 December 2003, respectively. Living cases and controls aged 20-80 years were included. An additional study was performed on deceased cases with a malignant brain tumour using deceased controls. Pooled results for glioma yielded for ipsilateral use of mobile phone odds ratio (OR)=2.9, 95% confidence interval (CI)=1.8-4.7 in the >10 years latency group. The corresponding result for cordless phone was OR=3.8, 95% CI=1.8-8.1. OR increased statistically significant for cumulative use of wireless phones per 100h and per year of latency. For high-grade glioma ipsilateral use of mobile phone gave OR=3.9, 95% CI=2.3-6.6 and cordless phone OR=5.5, 95% CI=2.3-13 in the >10 years latency group. Heredity for brain tumour gave OR=3.4, 95% CI=2.1-5.5 for glioma. There was no interaction with use of wireless phones. X-ray investigation of the head gave overall OR=1.3, 95% CI=1.1-1.7 for glioma without interaction with use of wireless phones or heredity. In conclusion use of mobile and cordless phone increased the risk for glioma with highest OR for ipsilateral use, latency >10 years and third tertile of cumulative use in hours. In total, the risk was highest in the age group <20 years for first use of a wireless phone. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Knockout of NMDA receptors in parvalbumin interneurons recreates autism-like phenotypes.

PubMed

Saunders, John A; Tatard-Leitman, Valerie M; Suh, Jimmy; Billingslea, Eddie N; Roberts, Timothy P; Siegel, Steven J

2013-04-01

Autism is a disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors with few effective treatments. New evidence suggests that autism has reliable electrophysiological endophenotypes and that these measures may be caused by n-methyl-d-aspartic acid receptor (NMDAR) disruption on parvalbumin (PV)-containing interneurons. These findings could be used to create new translational biomarkers. Recent developments have allowed for cell-type selective knockout of NMDARs in order to examine the perturbations caused by disrupting specific circuits. This study examines several electrophysiological and behavioral measures disrupted in autism using a PV-selective reduction in NMDA R1 subunit. Mouse electroencephalograph (EEG) was recorded in response to auditory stimuli. Event-related potential (ERP) component amplitude and latency analysis, social testing, and premating ultrasonic vocalizations (USVs) recordings were performed. Correlations were examined between the ERP latency and behavioral measures. The N1 ERP latency was delayed, sociability was reduced, and mating USVs were impaired in PV-selective NMDA Receptor 1 Knockout (NR1 KO) as compared with wild-type mice. There was a significant correlation between N1 latency and sociability but not between N1 latency and premating USV power or T-maze performance. The increases in N1 latency, impaired sociability, and reduced vocalizations in PV-selective NR1 KO mice mimic similar changes found in autism. Electrophysiological changes correlate to reduced sociability, indicating that the local circuit mechanisms controlling N1 latency may be utilized in social function. Therefore, we propose that behavioral and electrophysiological alterations in PV-selective NR1 KO mice may serve as a useful model for therapeutic development in autism. Autism Res 2013, 6: 69-77. © 2013 International Society for Autism Research, Wiley Periodicals, Inc. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

A new, ultra-low latency data transmission protocol for Earthquake Early Warning Systems

NASA Astrophysics Data System (ADS)

Hill, P.; Hicks, S. P.; McGowan, M.

2016-12-01

One measure used to assess the performance of Earthquake Early Warning Systems (EEWS) is the delay time between earthquake origin and issued alert. EEWS latency is dependent on a number of sources (e.g. P-wave propagation, digitisation, transmission, receiver processing, triggering, event declaration). Many regional seismic networks use the SEEDlink protocol; however, packet size is fixed to 512-byte miniSEED records, resulting in transmission latencies of >0.5 s. Data packetisation is seen as one of the main sources of delays in EEWS (Brown et al., 2011). Optimising data-logger and telemetry configurations is a cost-effective strategy to improve EEWS alert times (Behr et al., 2015). Digitisers with smaller, selectable packets can result in faster alerts (Sokos et al., 2016). We propose a new seismic protocol for regional seismic networks benefiting low-latency applications such as EEWS. The protocol, based on Güralp's existing GDI-link format is an efficient and flexible method to exchange data between seismic stations and data centers for a range of network configurations. The main principle is to stream data sample-by-sample instead of fixed-length packets to minimise transmission latency. Self-adaptive packetisation with compression maximises available telemetry bandwidth. Highly flexible metadata fields within GDI-link are compatible with existing miniSEED definitions. Data is sent as integers or floats, supporting a wide range of data formats, including discrete parameters such as Pd & τC for on-site earthquake early warning. Other advantages include: streaming station state-of-health information, instrument control, support of backfilling and fail-over strategies during telemetry outages. Based on tests carried out on the Güralp Minimus data-logger, we show our new protocol can reduce transmission latency to as low as 1 ms. The low-latency protocol is currently being implemented with common processing packages. The results of these tests will help to highlight latency levels that can be achieved with next-generation EEWS.

Dynamic tumor tracking using the Elekta Agility MLC

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

Fast, Martin F., E-mail: martin.fast@icr.ac.uk; Nill, Simeon, E-mail: simeon.nill@icr.ac.uk; Bedford, James L.

2014-11-01

Purpose: To evaluate the performance of the Elekta Agility multileaf collimator (MLC) for dynamic real-time tumor tracking. Methods: The authors have developed a new control software which interfaces to the Agility MLC to dynamically program the movement of individual leaves, the dynamic leaf guides (DLGs), and the Y collimators (“jaws”) based on the actual target trajectory. A motion platform was used to perform dynamic tracking experiments with sinusoidal trajectories. The actual target positions reported by the motion platform at 20, 30, or 40 Hz were used as shift vectors for the MLC in beams-eye-view. The system latency of the MLCmore » (i.e., the average latency comprising target device reporting latencies and MLC adjustment latency) and the geometric tracking accuracy were extracted from a sequence of MV portal images acquired during irradiation for the following treatment scenarios: leaf-only motion, jaw + leaf motion, and DLG + leaf motion. Results: The portal imager measurements indicated a clear dependence of the system latency on the target position reporting frequency. Deducting the effect of the target frequency, the leaf adjustment latency was measured to be 38 ± 3 ms for a maximum target speed v of 13 mm/s. The jaw + leaf adjustment latency was 53 ± 3 at a similar speed. The system latency at a target position frequency of 30 Hz was in the range of 56–61 ms for the leaves (v ≤ 31 mm/s), 71–78 ms for the jaw + leaf motion (v ≤ 25 mm/s), and 58–72 ms for the DLG + leaf motion (v ≤ 59 mm/s). The tracking accuracy showed a similar dependency on the target position frequency and the maximum target speed. For the leaves, the root-mean-squared error (RMSE) was between 0.6–1.5 mm depending on the maximum target speed. For the jaw + leaf (DLG + leaf) motion, the RMSE was between 0.7–1.5 mm (1.9–3.4 mm). Conclusions: The authors have measured the latency and geometric accuracy of the Agility MLC, facilitating its future use for clinical tracking applications.« less

Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

PubMed Central

2009-01-01

The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only) in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway. PMID:19961595

Normalization of sensorimotor integration by repetitive transcranial magnetic stimulation in cervical dystonia.

PubMed

Zittel, S; Helmich, R C; Demiralay, C; Münchau, A; Bäumer, T

2015-08-01

Previous studies indicated that sensorimotor integration and plasticity of the sensorimotor system are impaired in dystonia patients. We investigated motor evoked potential amplitudes and short latency afferent inhibition to examine corticospinal excitability and cortical sensorimotor integration, before and after inhibitory 1 Hz repetitive transcranial magnetic stimulation over primary sensory and primary motor cortex in patients with cervical dystonia (n = 12). Motor evoked potentials were recorded from the right first dorsal interosseous muscle after application of unconditioned transcranial magnetic test stimuli and after previous conditioning electrical stimulation of the right index finger at short interstimulus intervals of 25, 30 and 40 ms. Results were compared to a group of healthy age-matched controls. At baseline, motor evoked potential amplitudes did not differ between groups. Short latency afferent inhibition was reduced in cervical dystonia patients compared to healthy controls. Inhibitory 1 Hz sensory cortex repetitive transcranial magnetic stimulation but not motor cortex repetitive transcranial magnetic stimulation increased motor evoked potential amplitudes in cervical dystonia patients. Additionally, both 1 Hz repetitive transcranial magnetic stimulation over primary sensory and primary motor cortex normalized short latency afferent inhibition in these patients. In healthy subjects, sensory repetitive transcranial magnetic stimulation had no influence on motor evoked potential amplitudes and short latency afferent inhibition. Plasticity of sensorimotor circuits is altered in cervical dystonia patients.

Effects of gut passage, feces, and seed handling on latency and rate of germination in seeds consumed by capuchins (Cebus capucinus).

PubMed

Valenta, Kim; Fedigan, Linda M

2009-04-01

One of the key measures of the effectiveness of primary seed dispersal by animals is the quality of seed dispersal (Schupp: Plant Ecol 107/108 [1993] 15-29). We present data on quality of seed dispersal by two groups of white-faced capuchins (Cebus capucinus) in Costa Rica to test the hypothesis that capuchin seed handling results in effective primary dispersal for some fruit species they consume. We examined seed handling for 27 plant species, and germination rates of 18 species consumed by capuchins. For five of the most commonly swallowed seed species, we determined germination rates and average time to germination (latency) for seeds ingested and defecated by capuchins and compared these to seeds removed directly from fruit and planted. For the same five species, we compared germination rates and latency for passed seeds planted in capuchin feces to those cleaned of feces and planted in soil. For three of five species, differences in proportion of germinated seeds were significantly higher for gut passed seeds than for controls. For four of five species, germination latency was significantly faster for gut passed seeds than for controls. Feces had either no effect on seed germination rate or precluded germination. Data presented here support the hypothesis that white-faced capuchins are effective primary dispersers.

Anti-Alzheimer activity of isolated karanjin from Pongamia pinnata (L.) pierre and embelin from Embelia ribes Burm.f.

PubMed

Saini, Prachi; Lakshmayya, L; Bisht, Vinod Singh

2017-01-01

The aim of this study is to find out the anti-Alzheimer's activity of isolated karanjin and embelin. Karanjin isolated from Pongamia pinnata (L.) pierre and embelin from Embelia ribes Burm.f. and their purity was confirmed by ultraviolet spectrophotometric and Thin layer chromatography based study. Anti-Alzheimer's activity of isolated compounds were evaluated through elevated plus maze and Morris water maze model on Swiss albino mice. Diazepam (1 mg/kg body weight, intraperitoneally) was used for the induction of Alzheimer's like effects (amnesia) on Swiss albino mice and piracetam (200 mg/kg body weight, oral) used as a standard treatment. In EPM, embelin and karanjin decrease the transfer latency time in dose dependent manner and escape latency time in MWM method. A significant ( P < 0.01) reduction in amnesia with an anti-Alzheimer's effect found when results of isolated compounds were compared with standard and vehicle control. Diazepam (1 mg/kg) treated group showed significant increase in escape latency and transfer latency when compared with vehicle control; which indicates impairment in learning and memory. Both isolated compounds and standard significantly reversed the amnesia induced by diazepam and improved learning and memory of mice in dose and time dependent manner. This study supports the ethnobotanical use of these two plants in India for the management of nerve or brain related problems.

Mid-latency evoked potentials in self-reported impulsive aggression.

PubMed

Houston, R J; Stanford, M S

2001-02-01

The present study was conducted to examine psychophysiological differences in arousability among individuals who display impulsive aggressive outbursts. Amplitude and latency for the mid-latency evoked potentials (P1, N1 and P2) were obtained at scalp electrode sites. The evoking stimuli were three intensities (low, medium, high) of photic stimulation. Compared to non-aggressive controls, impulsive aggressive subjects showed significantly reduced P1 amplitude, which is indicative of an inefficient sensory gating mechanism. In addition, these subjects exhibited significantly larger N1 amplitude implying an enhanced orienting of attention to stimuli. Impulsive aggressive subjects also exhibited shorter P1, N1 and P2 peak latency. These results suggest that impulsive aggressive individuals may display quicker orienting and processing of stimuli in an attempt to compensate for low resting arousal levels. Finally, impulsive aggressive subjects augmented the P1-N1 component more frequently than controls, which is consistent with previous studies examining impulsivity and sensation seeking. Together, these findings extend previous work concerning the underlying physiology of impulsive aggression. It has been suggested that impulsive aggressive individuals may attempt to compensate for low resting arousal levels by engaging in stimulus seeking behaviors. Accordingly, the present findings imply similar physiological compensatory responses as demonstrated by heightened orienting of attention, processing and arousability. In addition, a compromised sensory gating system in impulsive aggressors may exacerbate such circumstances, and lead to later cognitive processing deficits.

Software-defined networking control plane for seamless integration of multiple silicon photonic switches in Datacom networks.

PubMed

Shen, Yiwen; Hattink, Maarten H N; Samadi, Payman; Cheng, Qixiang; Hu, Ziyiz; Gazman, Alexander; Bergman, Keren

2018-04-16

Silicon photonics based switches offer an effective option for the delivery of dynamic bandwidth for future large-scale Datacom systems while maintaining scalable energy efficiency. The integration of a silicon photonics-based optical switching fabric within electronic Datacom architectures requires novel network topologies and arbitration strategies to effectively manage the active elements in the network. We present a scalable software-defined networking control plane to integrate silicon photonic based switches with conventional Ethernet or InfiniBand networks. Our software-defined control plane manages both electronic packet switches and multiple silicon photonic switches for simultaneous packet and circuit switching. We built an experimental Dragonfly network testbed with 16 electronic packet switches and 2 silicon photonic switches to evaluate our control plane. Observed latencies occupied by each step of the switching procedure demonstrate a total of 344 µs control plane latency for data-center and high performance computing platforms.

Case-control study of the association between malignant brain tumours diagnosed between 2007 and 2009 and mobile and cordless phone use.

PubMed

Hardell, Lennart; Carlberg, Michael; Söderqvist, Fredrik; Mild, Kjell Hansson

2013-12-01

Previous studies have shown a consistent association between long-term use of mobile and cordless phones and glioma and acoustic neuroma, but not for meningioma. When used these phones emit radiofrequency electromagnetic fields (RF-EMFs) and the brain is the main target organ for the handheld phone. The International Agency for Research on Cancer (IARC) classified in May, 2011 RF-EMF as a group 2B, i.e. a 'possible' human carcinogen. The aim of this study was to further explore the relationship between especially long-term (>10 years) use of wireless phones and the development of malignant brain tumours. We conducted a new case-control study of brain tumour cases of both genders aged 18-75 years and diagnosed during 2007-2009. One population-based control matched on gender and age (within 5 years) was used to each case. Here, we report on malignant cases including all available controls. Exposures on e.g. use of mobile phones and cordless phones were assessed by a self-administered questionnaire. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index using the whole control sample. Of the cases with a malignant brain tumour, 87% (n=593) participated, and 85% (n=1,368) of controls in the whole study answered the questionnaire. The odds ratio (OR) for mobile phone use of the analogue type was 1.8, 95% confidence interval (CI)=1.04‑3.3, increasing with >25 years of latency (time since first exposure) to an OR=3.3, 95% CI=1.6-6.9. Digital 2G mobile phone use rendered an OR=1.6, 95% CI=0.996-2.7, increasing with latency >15-20 years to an OR=2.1, 95% CI=1.2-3.6. The results for cordless phone use were OR=1.7, 95% CI=1.1-2.9, and, for latency of 15-20 years, the OR=2.1, 95% CI=1.2-3.8. Few participants had used a cordless phone for >20-25 years. Digital type of wireless phones (2G and 3G mobile phones, cordless phones) gave increased risk with latency >1-5 years, then a lower risk in the following latency groups, but again increasing risk with latency >15-20 years. Ipsilateral use resulted in a higher risk than contralateral mobile and cordless phone use. Higher ORs were calculated for tumours in the temporal and overlapping lobes. Using the meningioma cases in the same study as reference entity gave somewhat higher ORs indicating that the results were unlikely to be explained by recall or observational bias. This study confirmed previous results of an association between mobile and cordless phone use and malignant brain tumours. These findings provide support for the hypothesis that RF-EMFs play a role both in the initiation and promotion stages of carcinogenesis.

Cluster detection methods applied to the Upper Cape Cod cancer data.

PubMed

Ozonoff, Al; Webster, Thomas; Vieira, Veronica; Weinberg, Janice; Ozonoff, David; Aschengrau, Ann

2005-09-15

A variety of statistical methods have been suggested to assess the degree and/or the location of spatial clustering of disease cases. However, there is relatively little in the literature devoted to comparison and critique of different methods. Most of the available comparative studies rely on simulated data rather than real data sets. We have chosen three methods currently used for examining spatial disease patterns: the M-statistic of Bonetti and Pagano; the Generalized Additive Model (GAM) method as applied by Webster; and Kulldorff's spatial scan statistic. We apply these statistics to analyze breast cancer data from the Upper Cape Cancer Incidence Study using three different latency assumptions. The three different latency assumptions produced three different spatial patterns of cases and controls. For 20 year latency, all three methods generally concur. However, for 15 year latency and no latency assumptions, the methods produce different results when testing for global clustering. The comparative analyses of real data sets by different statistical methods provides insight into directions for further research. We suggest a research program designed around examining real data sets to guide focused investigation of relevant features using simulated data, for the purpose of understanding how to interpret statistical methods applied to epidemiological data with a spatial component.

Deep Sequencing Reveals Direct Targets of Gammaherpesvirus-Induced mRNA Decay and Suggests That Multiple Mechanisms Govern Cellular Transcript Escape

PubMed Central

Clyde, Karen; Glaunsinger, Britt A.

2011-01-01

One characteristic of lytic infection with gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV) and murine herpesvirus 68 (MHV68), is the dramatic suppression of cellular gene expression in a process known as host shutoff. The alkaline exonuclease proteins (KSHV SOX, MHV-68 muSOX and EBV BGLF5) have been shown to induce shutoff by destabilizing cellular mRNAs. Here we extend previous analyses of cellular mRNA abundance during lytic infection to characterize the effects of SOX and muSOX, in the absence of other viral genes, utilizing deep sequencing technology (RNA-seq). Consistent with previous observations during lytic infection, the majority of transcripts are downregulated in cells expressing either SOX or muSOX, with muSOX acting as a more potent shutoff factor than SOX. Moreover, most cellular messages fall into the same expression class in both SOX- and muSOX-expressing cells, indicating that both factors target similar pools of mRNAs. More abundant mRNAs are more efficiently downregulated, suggesting a concentration effect in transcript targeting. However, even among highly expressed genes there are mRNAs that escape host shutoff. Further characterization of select escapees reveals multiple mechanisms by which cellular genes can evade downregulation. While some mRNAs are directly refractory to SOX, the steady state levels of others remain unchanged, presumably as a consequence of downstream effects on mRNA biogenesis. Collectively, these studies lay the framework for dissecting the mechanisms underlying the susceptibility of mRNA to destruction during lytic gammaherpesvirus infection. PMID:21573023

Epidemiology of virus infection and human cancer.

PubMed

Chen, Chien-Jen; Hsu, Wan-Lun; Yang, Hwai-I; Lee, Mei-Hsuan; Chen, Hui-Chi; Chien, Yin-Chu; You, San-Lin

2014-01-01

The International Agency for Research on Cancer (IARC) has comprehensively assessed the human carcinogenicity of biological agents. Seven viruses including Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), Kaposi's sarcoma herpes virus (KSHV), human immunodeficiency virus, type-1 (HIV-1), human T cell lymphotrophic virus, type-1 (HTLV-1), and human papillomavirus (HPV) have been classified as Group 1 human carcinogens by IARC. The conclusions are based on the findings of epidemiological and mechanistic studies. EBV, HPV, HTLV-1, and KSHV are direct carcinogens; HBV and HCV are indirect carcinogens through chronic inflammation; HIV-1 is an indirect carcinogen through immune suppression. Some viruses may cause more than one cancer, while some cancers may be caused by more than one virus. However, only a proportion of persons infected by these oncogenic viruses will develop specific cancers. A series of studies have been carried out to assess the viral, host, and environmental cofactors of EBV-associated nasopharyngeal carcinoma, HBV/HCV-associated hepatocellular carcinoma, and HPV-associated cervical carcinoma. Persistent infection and high viral load are important risk predictors of these virus-caused cancers. Risk calculators incorporating host and viral factors have also been developed for the prediction of long-term risk of hepatocellular carcinoma. These risk calculators are useful for the triage and clinical management of infected patients. Both clinical trials and national programs of immunization or antiviral therapy have demonstrated a significant reduction in the incidence of cancers caused by HBV, HCV, and HPV. Future researches on gene-gene and gene-environment interaction of oncogenic viruses and human host are in urgent need.

Does Noise From Shipping and Boat Traffic Affect Predator Vigilance in the European Common Hermit Crab?

PubMed

Nousek-McGregor, Anna E; Mei, Francesca Tee Liang

2016-01-01

The effect of noise on predator vigilance in Pagurus bernhardus was explored in this study. Latency of the first response, emergence time, and response type were measured from hermit crabs during continuous and variable vessel noise and two controls. The mean (±SE) response latency was longer for the noise treatments (continuous, 18.19 ± 2.78 s; variable, 11.39 ± 1.48 s) than for the controls (ambient, 7.21 ± 0.82 s; silent, 6.66 ± 0.95 s). Response type and emergence time were not significantly affected but were more variable during the noise treatments than during the controls. Noisy conditions may increase predation risk, suggesting potential fitness consequences for invertebrates.

Latency in Distributed Acquisition and Rendering for Telepresence Systems.

PubMed

Ohl, Stephan; Willert, Malte; Staadt, Oliver

2015-12-01

Telepresence systems use 3D techniques to create a more natural human-centered communication over long distances. This work concentrates on the analysis of latency in telepresence systems where acquisition and rendering are distributed. Keeping latency low is important to immerse users in the virtual environment. To better understand latency problems and to identify the source of such latency, we focus on the decomposition of system latency into sub-latencies. We contribute a model of latency and show how it can be used to estimate latencies in a complex telepresence dataflow network. To compare the estimates with real latencies in our prototype, we modify two common latency measurement methods. This presented methodology enables the developer to optimize the design, find implementation issues and gain deeper knowledge about specific sources of latency.

Pooled analysis of case-control studies on malignant brain tumours and the use of mobile and cordless phones including living and deceased subjects.

PubMed

Hardell, Lennart; Carlberg, Michael; Hansson Mild, Kjell

2011-05-01

We studied the association between use of mobile and cordless phones and malignant brain tumours. Pooled analysis was performed of two case-control studies on patients with malignant brain tumours diagnosed during 1997-2003 and matched controls alive at the time of study inclusion and one case-control study on deceased patients and controls diagnosed during the same time period. Cases and controls or relatives to deceased subjects were interviewed using a structured questionnaire. Replies were obtained for 1,251 (85%) cases and 2,438 (84%) controls. The risk increased with latency period and cumulative use in hours for both mobile and cordless phones. Highest risk was found for the most common type of glioma, astrocytoma, yielding in the >10 year latency group for mobile phone use odds ratio (OR) = 2.7, 95% confidence interval (CI) = 1.9-3.7 and cordless phone use OR = 1.8, 95% CI = 1.2-2.9. In a separate analysis, these phone types were independent risk factors for glioma. The risk for astrocytoma was highest in the group with first use of a wireless phone before the age of 20; mobile phone use OR = 4.9, 95% CI = 2.2-11, cordless phone use OR = 3.9, 95% CI = 1.7-8.7. In conclusion, an increased risk was found for glioma and use of mobile or cordless phone. The risk increased with latency time and cumulative use in hours and was highest in subjects with first use before the age of 20.

Situational Awareness During Mass-Casualty Events: Command and Control

PubMed Central

Demchak, Barry; Chan, Theordore C.; Griswold, William G.; Lenert, Leslie

2006-01-01

In existing Incident Command systems1, situational awareness is achieved manually through paper tracking systems. Such systems often produce high latencies and incomplete data, resulting in inefficient and ineffective resource deployment. The WIISARD2 system collects much more data than a paper-based system, dramatically reducing latency while increasing the kinds and quality of information available to Incident Commanders. The WIISARD Command Center solves the problem of data overload and uncertainty through the careful use of limited screen area and novel visualization techniques. PMID:17238524

Auditory brain stem response and cortical evoked potentials in children with type 1 diabetes mellitus.

PubMed

Radwan, Heba Mohammed; El-Gharib, Amani Mohamed; Erfan, Adel Ali; Emara, Afaf Ahmad

2017-05-01

Delay in ABR and CAEPs wave latencies in children with type 1DM indicates that there is abnormality in the neural conduction in DM patients. The duration of DM has greater effect on auditory function than the control of DM. Diabetes mellitus (DM) is a common endocrine and metabolic disorder. Evoked potentials offer the possibility to perform a functional evaluation of neural pathways in the central nervous system. To investigate the effect of type 1 diabetes mellitus (T1DM) on auditory brain stem response (ABR) and cortical evoked potentials (CAEPs). This study included two groups: a control group (GI), which consisted of 20 healthy children with normal peripheral hearing, and a study group (GII), which consisted of 30 children with type I DM. Basic audiological evaluation, ABR, and CAEPs were done in both groups. Delayed absolute latencies of ABR and CAEPs waves were found. Amplitudes showed no significant difference between both groups. Positive correlation was found between ABR wave latencies and duration of DM. No correlation was found between ABR, CAEPs, and glycated hemoglobin.

Evaluation of central and peripheral neuropathy in patients with chronic obstructive pulmonary disease.

PubMed

Aras, Yeşim Güzey; Aydemir, Yusuf; Güngen, Belma Doğan; Güngen, Adil Can

2018-01-01

The aim of the study was to investigate the frequency and characteristics of peripheral nervous system (PNS) and central nervous system (CNS) involvement in COPD. The study included 41 COPD patients and 41 healthy volunteers. Electrophysiological studies were carried out: electromyography (EMG) and visual evoked potentials (VEPs). The median nerve, ulnar nerve, common peroneal nerve, and tibial nerve were evaluated for latency, amplitude, and conduction velocity. The mean age of patients with COPD was 61.8 years and disease duration 10.3 years. There was no difference between patient and control groups in terms of age, BMI, smoking status, or biochemical parameters. Upon VEP examination, latencies were significantly prolonged and amplitudes shortened in the patient group compared to the control group. In EMG measurements, conduction velocity and amplitudes in all nerves were low in the patient group. Similarly, latencies in all nerves were higher in patients with COPD. Central and peripheral nervous system involvement could develop in patients with moderate-severe COPD, and these patients should be monitored for neuropathic changes in combination with neurological examination.

Anxiety, inhibition, efficiency, and effectiveness. An investigation using antisaccade task.

PubMed

Derakshan, Nazanin; Ansari, Tahereh L; Hansard, Miles; Shoker, Leor; Eysenck, Michael W

2009-01-01

Effects of anxiety on the antisaccade task were assessed. Performance effectiveness on this task (indexed by error rate) reflects a conflict between volitional and reflexive responses resolved by inhibitory processes (Hutton, S. B., & Ettinger, U. (2006). The antisaccade task as a research tool in psychopathology: A critical review. Psychophysiology, 43, 302-313). However, latency of the first correct saccade reflects processing efficiency (relationship between performance effectiveness and use of resources). In two experiments, high-anxious participants had longer correct antisaccade latencies than low-anxious participants and this effect was greater with threatening cues than positive or neutral ones. The high- and low-anxious groups did not differ in terms of error rate in the antisaccade task. No group differences were found in terms of latency or error rate in the prosaccade task. These results indicate that anxiety affects performance efficiency but not performance effectiveness. The findings are interpreted within the context of attentional control theory (Eysenck, M. W., Derakshan, N., Santos, R., & Calvo, M. G. (2007). Anxiety and cognitive performance: Attentional control theory. Emotion, 7 (2), 336-353).

Overview and Evaluation of Bluetooth Low Energy: An Emerging Low-Power Wireless Technology

PubMed Central

Gomez, Carles; Oller, Joaquim; Paradells, Josep

2012-01-01

Bluetooth Low Energy (BLE) is an emerging low-power wireless technology developed for short-range control and monitoring applications that is expected to be incorporated into billions of devices in the next few years. This paper describes the main features of BLE, explores its potential applications, and investigates the impact of various critical parameters on its performance. BLE represents a trade-off between energy consumption, latency, piconet size, and throughput that mainly depends on parameters such as connInterval and connSlaveLatency. According to theoretical results, the lifetime of a BLE device powered by a coin cell battery ranges between 2.0 days and 14.1 years. The number of simultaneous slaves per master ranges between 2 and 5,917. The minimum latency for a master to obtain a sensor reading is 676 μs, although simulation results show that, under high bit error rate, average latency increases by up to three orders of magnitude. The paper provides experimental results that complement the theoretical and simulation findings, and indicates implementation constraints that may reduce BLE performance.

Epstein-Barr virus latency switch in human B-cells: a physico-chemical model.

PubMed

Werner, Maria; Ernberg, Ingemar; Zou, Jiezhi; Almqvist, Jenny; Aurell, Erik

2007-08-31

The Epstein-Barr virus is widespread in all human populations and is strongly associated with human disease, ranging from infectious mononucleosis to cancer. In infected cells the virus can adopt several different latency programs, affecting the cells' behaviour. Experimental results indicate that a specific genetic switch between viral latency programs, reprograms human B-cells between proliferative and resting states. Each of these two latency programs makes use of a different viral promoter, Cp and Qp, respectively. The hypothesis tested in this study is that this genetic switch is controlled by both human and viral transcription factors; Oct-2 and EBNA-1. We build a physico-chemical model to investigate quantitatively the dynamical properties of the promoter regulation and experimentally examine protein level variations between the two latency programs. Our experimental results display significant differences in EBNA-1 and Oct-2 levels between resting and proliferating programs. With the model we identify two stable latency programs, corresponding to a resting and proliferating cell. The two programs differ in robustness and transcriptional activity. The proliferating state is markedly more stable, with a very high transcriptional activity from its viral promoter. We predict the promoter activities to be mutually exclusive in the two different programs, and our relative promoter activities correlate well with experimental data. Transitions between programs can be induced, by affecting the protein levels of our transcription factors. Simulated time scales are in line with experimental results. We show that fundamental properties of the Epstein-Barr virus involvement in latent infection, with implications for tumor biology, can be modelled and understood mathematically. We conclude that EBNA-1 and Oct-2 regulation of Cp and Qp is sufficient to establish mutually exclusive expression patterns. Moreover, the modelled genetic control predict both mono- and bistable behavior and a considerable difference in transition dynamics, based on program stability and promoter activities. Both these phenomena we hope can be further investigated experimentally, to increase the understanding of this important switch. Our results also stress the importance of the little known regulation of human transcription factor Oct-2.

Subjectively measured ejaculation latency time and its association with different sexual activities while controlling for age and relationship length.

PubMed

Jern, Patrick; Santtila, Pekka; Johansson, Ada; Varjonen, Markus; Witting, Katarina; von der Pahlen, Bettina; Sandnabba, Kenneth

2009-09-01

Recently, attempts to formulate valid and suitable definitions for (different subcategories of) premature ejaculation have resulted in substantial progress in the pursuit to gain knowledge about ejaculatory function. However, the association between ejaculatory dysfunction and different types of sexual activities has yet to be thoroughly investigated, and (due to conflicting results between studies) the potential effects of age and relationship length still need to be taken into account. The aim of this study is to investigate the associations of age, relationship length, frequency of different sexual activities, and different modes of achieving ejaculation with self-reported ejaculation latency time. The main outcome is establishing associations between age, relationship length, self-reported ejaculation latency time, and frequency of different kinds of sexual activities and different modes of achieving ejaculation (such as achieving ejaculation through oral or vaginal sex). Statistical analyses of data on age, relationship length, self-reported ejaculation latency time, and frequency of different sexual activities and different modes of achieving ejaculation were conducted on a population-based sample of 3,189 males aged 18-48 years (mean = 29.9 years, standard deviation = 6.94). Age and relationship length were significantly negatively associated with self-reported ejaculation latency time. Frequency of different kinds of sexual behavior generally had a positive association with self-reported ejaculation latency time, as had different modes of achieving ejaculation. The findings highlight the need for more extensive studies on and increased knowledge of different aspects of ejaculatory function before a valid and suitable definition for premature ejaculation can be formulated.

Multifocal visual evoked potential in optic neuritis, ischemic optic neuropathy and compressive optic neuropathy

PubMed Central

Jayaraman, Manju; Gandhi, Rashmin Anilkumar; Ravi, Priya; Sen, Parveen

2014-01-01

Purpose: To investigate the effect of optic neuritis (ON), ischemic optic neuropathy (ION) and compressive optic neuropathy (CON) on multifocal visual evoked potential (mfVEP) amplitudes and latencies, and to compare the parameters among three optic nerve disorders. Materials and Methods: mfVEP was recorded for 71 eyes of controls and 48 eyes of optic nerve disorders with subgroups of optic neuritis (ON, n = 21 eyes), ischemic optic neuropathy (ION, n = 14 eyes), and compressive optic neuropathy (CON, n = 13 eyes). The size of defect in mfVEP amplitude probability plots and relative latency plots were analyzed. The pattern of the defect in amplitude probability plot was classified according to the visual field profile of optic neuritis treatment trail (ONTT). Results: Median of mfVEP amplitude (log SNR) averaged across 60 sectors were reduced in ON (0.17 (0.13-0.33)), ION (0.14 (0.12-0.21)) and CON (0.21 (0.14-0.30)) when compared to controls. The median mfVEP relative latencies compared to controls were significantly prolonged in ON and CON group of 10.53 (2.62-15.50) ms and 5.73 (2.67-14.14) ms respectively compared to ION group (2.06 (-4.09-13.02)). The common mfVEP amplitude defects observed in probability plots were diffuse pattern in ON, inferior altitudinal defect in ION and temporal hemianopia in CON eyes. Conclusions: Optic nerve disorders cause reduction in mfVEP amplitudes. The extent of delayed latency noted in ischemic optic neuropathy was significantly lesser compared to subjects with optic neuritis and compressive optic neuropathy. mfVEP amplitudes can be used to objectively assess the topography of the visual field defect. PMID:24088641

Women’s Sexual Arousal: Effects of High Alcohol Dosages and Self-Control Instructions

PubMed Central

George, William H.; Davis, Kelly Cue; Heiman, Julia R.; Norris, Jeanette; Stoner, Susan A.; Schacht, Rebecca L.; Hendershot, Christian S.; Kajumulo, Kelly F.

2011-01-01

The basic relationship between alcohol and women’s sexual arousal – especially genital arousal –received little research attention for nearly 30 years (e.g. Wilson & Lawson, 1978) until very recently (e.g. George et al., 2009). To investigate hypotheses based on earlier findings and Alcohol Myopia Theory (AMT), two experiments evaluated the effects of high blood alcohol concentrations (BACs) and arousal instructional demands on indices of vaginal responding and self-reported sexual arousal. In Experiment 1, self-control instructions to maximize (versus suppress) arousal increased peak and average Vaginal Pulse Amplitude (VPA) change. Self-control also interacted with a target BAC of .08% (versus .00%) to influence latency to peak arousal onset: Intoxicated women instructed to maximize showed a shorter latency to peak arousal than did intoxicated women instructed to suppress; however, sober women showed the same pattern. Also, in Experiment 1, the target BAC of .08% had no effect on VPA or subjective arousal measures. In Experiment 2, a target BAC of .10% (versus .00%) attenuated peak change and average change in VPA, but this dosage had no effects on latency to peak achieved arousal, or on subjective arousal. Instructions to maximize arousal (versus no instruction) had no effect on any arousal measures. Overall, among young moderate drinking women, alcohol had attenuating effects but only at the higher dosage. Maximize versus suppress instructions about arousal had predicted effects on arousal and interactive effects on latency, but only at the lower dosage. The findings highlight the importance of dosage and contextual factors in alcohol’s impact on the variability of women’s sexual responding. PMID:21439287

Continuous recognition of spatial and nonspatial stimuli in hippocampal-lesioned rats.

PubMed

Jackson-Smith, P; Kesner, R P; Chiba, A A

1993-03-01

The present experiments compared the performance of hippocampal-lesioned rats to control rats on a spatial continuous recognition task and an analogous nonspatial task with similar processing demands. Daily sessions for Experiment 1 involved sequential presentation of individual arms on a 12-arm radial maze. Each arm contained a Froot Loop reinforcement the first time it was presented, and latency to traverse the arm was measured. A subset of the arms were repeated, but did not contain reinforcement. Repeated arms were presented with lags ranging from 0 to 6 (0 to 6 different arm presentations occurred between the first and the repeated presentation). Difference scores were computed by subtracting the latency on first presentations from the latency on repeated presentations, and these scores were high in all rats prior to surgery, with a decreasing function across lag. There were no differences in performance following cortical control or sham surgery. However, there was a total deficit in performance following large electrolytic lesions of the hippocampus. The second experiment employed the same continuous recognition memory procedure, but used three-dimensional visual objects (toys, junk items, etc., in various shapes, sizes, and textures) as stimuli on a flat runway. As in Experiment 1, the stimuli were presented successively and latency to run to and move the object was measured. Objects were repeated with lags ranging from 0 to 4. Performance on this task following surgery did not differ from performance prior to surgery for either the control group or the hippocampal lesion group. These results provide support for Kesner's attribute model of hippocampal function in that the hippocampus is assumed to mediate data-based memory for spatial locations, but not three-dimensional visual objects.

Effect of fibular repositioning taping in adult basketball players with chronic ankle instability: a randomized, placebo-controlled, crossover trial.

PubMed

Alves, Yanina; Ribeiro, Fernando; Silva, Anabela G

2017-07-05

Chronic ankle instability presents a high incidence and prevalence in basketbal players. It's important to develop strategies to reduce the functional and mechanical limitations resulting from this condition. To compare the effect of Mulligan ́s fibular repositioning taping with a placebo taping immediatly after application and after a running test (Yo-Yo IRT). 16 adult basketball players (10 male, 6 female) with chronic ankle instability and mean age 21.50 ± 2.76 years old. Assessment of static postural control (15 seconds of unipedal stance test with eyes closed in a force platform), functional performance (figure 8 hop test and lateral hop test) and neuromuscular control (peroneus longus latency time in sudden inversion) in two conditions: Mulligan and Placebo. No significant effect was found for the intervantion factor in both hop tests (p>0.170), but there was a significant effect for the time factor (p<0.03). For the peroneus longus latency time, there was a significant interaction between factors (p=0.028) and also for time (p=0.042). No significant effect was found for any of the static postural control variables (area, speed and total displacement) (p≥0.10). There was no differences between Mulligan's fibular repositioning taping and Placebo taping in postural control and functional performance in basketball players with chronic ankle instability. However, Mulligan's taping appears to reduce peroneus longus latency time after a running when compared with a placebo taping.

Traffic Adaptive Energy Efficient and Low Latency Medium Access Control for Wireless Sensor Networks

NASA Astrophysics Data System (ADS)

Yadav, Rajesh; Varma, Shirshu; Malaviya, N.

2008-05-01

Medium access control for wireless sensor networks has been a very active research area in the recent years. The traditional wireless medium access control protocol such as IEEE 802.11 is not suitable for the sensor network application because these are battery powered. The recharging of these sensor nodes is expensive and also not possible. The most of the literature in the medium access for the sensor network focuses on the energy efficiency. The proposed MAC protocol solves the energy inefficiency caused by idle listening, control packet overhead and overhearing taking nodes latency into consideration based on the network traffic. Simulation experiments have been performed to demonstrate the effectiveness of the proposed approach. The validation of the simulation results of the proposed MAC has been done by comparing it with the analytical model. This protocol has been simulated in Network Simulator ns-2.

Control of Task Sequences: What is the Role of Language?

PubMed Central

Mayr, Ulrich; Kleffner, Killian; Kikumoto, Atsushi; Redford, Melissa A.

2015-01-01

It is almost a truism that language aids serial-order control through self-cuing of upcoming sequential elements. We measured speech onset latencies as subjects performed hierarchically organized task sequences while "thinking aloud" each task label. Surprisingly, speech onset latencies and response times (RTs) were highly synchronized, a pattern that is not consistent with the hypothesis that speaking aids proactive retrieval of upcoming sequential elements during serial-order control. We also found that when instructed to do so, participants were able to speak task labels prior to presentation of response-relevant stimuli and that this substantially reduced RT signatures of retrieval—however at the cost of more sequencing errors. Thus, while proactive retrieval is possible in principle, in natural situations it seems to be prevented through a strong, "gestalt-like" tendency to synchronize speech and action. We suggest that this tendency may support context updating rather than proactive control. PMID:24274386

Programmable immersive peripheral environmental system (PIPES): a prototype control system for environmental feedback devices

NASA Astrophysics Data System (ADS)

Frend, Chauncey; Boyles, Michael

2015-03-01

This paper describes an environmental feedback device (EFD) control system aimed at simplifying the VR development cycle. Programmable Immersive Peripheral Environmental System (PIPES) affords VR developers a custom approach to programming and controlling EFD behaviors while relaxing the required knowledge and expertise of electronic systems. PIPES has been implemented for the Unity engine and features EFD control using the Arduino integrated development environment. PIPES was installed and tested on two VR systems, a large format CAVE system and an Oculus Rift HMD system. A photocell based end-to-end latency experiment was conducted to measure latency within the system. This work extends previously unpublished prototypes of a similar design. Development and experiments described in this paper are part of the VR community goal to understand and apply environment effects to VEs that ultimately add to users' perceived presence.

EMG responses to maintain stance during multidirectional surface translations

NASA Technical Reports Server (NTRS)

Henry, S. M.; Fung, J.; Horak, F. B.; Peterson, B. W. (Principal Investigator)

1998-01-01

To characterize muscle synergy organization underlying multidirectional control of stance posture, electromyographic activity was recorded from 11 lower limb and trunk muscles of 7 healthy subjects while they were subjected to horizontal surface translations in 12 different, randomly presented directions. The latency and amplitude of muscle responses were quantified for each perturbation direction. Tuning curves for each muscle were examined to relate the amplitude of the muscle response to the direction of surface translation. The latencies of responses for the shank and thigh muscles were constant, regardless of perturbation direction. In contrast, the latencies for another thigh [tensor fascia latae (TFL)] and two trunk muscles [rectus abdominis (RAB) and erector spinae (ESP)] were either early or late, depending on the perturbation direction. These three muscles with direction-specific latencies may play different roles in postural control as prime movers or as stabilizers for different translation directions, depending on the timing of recruitment. Most muscle tuning curves were within one quadrant, having one direction of maximal activity, generally in response to diagonal surface translations. Two trunk muscles (RAB and ESP) and two lower limb muscles (semimembranosus and peroneus longus) had bipolar tuning curves, with two different directions of maximal activity, suggesting that these muscle can play different roles as part of different synergies, depending on translation direction. Muscle tuning curves tended to group into one of three regions in response to 12 different directions of perturbations. Two muscles [rectus femoris (RFM) and TFL] were maximally active in response to lateral surface translations. The remaining muscles clustered into one of two diagonal regions. The diagonal regions corresponded to the two primary directions of active horizontal force vector responses. Two muscles (RFM and adductor longus) were maximally active orthogonal to their predicted direction of maximal activity based on anatomic orientation. Some of the muscles in each of the synergic regions were not anatomic synergists, suggesting a complex central organization for recruitment of muscles. The results suggest that neither a simple reflex mechanism nor a fixed muscle synergy organization is adequate to explain the muscle activation patterns observed in this postural control task. Our results are consistent with a centrally mediated pattern of muscle latencies combined with peripheral influence on muscle magnitude. We suggest that a flexible continuum of muscle synergies that are modifiable in a task-dependent manner be used for equilibrium control in stance.

Aberrant Neuromagnetic Activation in the Motor Cortex in Children with Acute Migraine: A Magnetoencephalography Study

PubMed Central

Guo, Xinyao; Xiang, Jing; Wang, Yingying; O’Brien, Hope; Kabbouche, Marielle; Horn, Paul; Powers, Scott W.; Hershey, Andrew D.

2012-01-01

Migraine attacks have been shown to interfere with normal function in the brain such as motor or sensory function. However, to date, there has been no clinical neurophysiology study focusing on the motor function in children with migraine during headache attacks. To investigate the motor function in children with migraine, twenty-six children with acute migraine, meeting International Classification of Headache Disorders criteria and age- and gender-matched healthy children were studied using a 275-channel magnetoencephalography system. A finger-tapping paradigm was designed to elicit neuromagnetic activation in the motor cortex. Children with migraine showed significantly prolonged latency of movement-evoked magnetic fields (MEF) during finger movement compared with the controls. The correlation coefficient of MEF latency and age in children with migraine was significantly different from that in healthy controls. The spectral power of high gamma (65–150 Hz) oscillations during finger movement in the primary motor cortex is also significantly higher in children with migraine than in controls. The alteration of responding latency and aberrant high gamma oscillations suggest that the developmental trajectory of motor function in children with migraine is impaired during migraine attacks and/or developmentally delayed. This finding indicates that childhood migraine may affect the development of brain function and result in long-term problems. PMID:23185541

Virtual Morris task responses in individuals in an abstinence phase from alcohol.

PubMed

Ceccanti, Mauro; Coriale, Giovanna; Hamilton, Derek A; Carito, Valentina; Coccurello, Roberto; Scalese, Bruna; Ciafrè, Stefania; Codazzo, Claudia; Messina, Marisa Patrizia; Chaldakov, George N; Fiore, Marco

2018-02-01

The present study was aimed at examining spatial learning and memory, in 33 men and 12 women with alcohol use disorder (AUD) undergoing ethanol detoxification, by using a virtual Morris task. As controls, we recruited 29 men and 10 women among episodic drinkers without a history of alcohol addiction or alcohol-related diseases. Elevated latency to the first movement in all trials was observed only in AUD persons; furthermore, control women had longer latencies compared with control men. Increased time spent to reach the hidden platform in the learning phase was found for women of both groups compared with men, in particular during trial 3. As predicted, AUD persons (more evident in men) spent less time in the target quadrant during the probe trial; however, AUD women had longer latencies to reach the platform in the visible condition during trials 6 and 7 that resulted in a greater distance moved. As for the probe trial, men of both groups showed increased virtual locomotion compared with the women of both groups. The present investigation confirms and extends previous studies showing (i) different gender responses in spatial learning tasks, (ii) some alterations due to alcohol addiction in virtual spatial learning, and (iii) differences between AUD men and AUD women in spatial-behaviour-related paradigms.

On-demand tramadol hydrochloride use in premature ejaculation treatment.

PubMed

Kaynar, Mehmet; Kilic, Ozcan; Yurdakul, Talat

2012-01-01

To determine the efficacy of tramadol in premature ejaculation (PE) treatment compared with placebo. A single-blind, placebo-controlled, crossover study was conducted with 60 lifelong (primary) patients with PE. The patients were randomized into 2 groups, each consisting of 30 patients, who took tramadol or placebo on demand. PE was defined as an intravaginal ejaculation latency time of ≤60 seconds in 90% of intercourse episodes. The efficacy of the drugs was assessed using the intravaginal ejaculation latency time, ability of ejaculation control, and sexual satisfaction scores after an 8-week treatment period. All participants completed the study voluntarily. Two groups were similar in terms of the patient demographics. Increases in the intravaginal ejaculation latency time, ability of ejaculation control, and sexual satisfaction score between the placebo and tramadol groups were compared with the baseline values in both groups. At the end of study period, the tramadol group had significantly (P<.001) greater values for all 3 parameters compared with those in the placebo group. On-demand use of low-dose tramadol is effective for lifelong PE. Currently, selective seratonin reuptake inhibitors such as dapoxetine, are a more popular treatment option for PE. However, tramadol might be considered an alternative agent for primary PE treatment. Copyright © 2012 Elsevier Inc. All rights reserved.

Neural correlates of performance monitoring in chronic cannabis users and cannabis-naïve controls

PubMed Central

Fridberg, Daniel J; Skosnik, Patrick D; Hetrick, William P; O’Donnell, Brian F

2014-01-01

Chronic cannabis use is associated with residual negative effects on measures of executive functioning. However, little previous work has focused specifically on executive processes involved in performance monitoring in frequent cannabis users. The present study investigated event-related potential (ERP) correlates of performance monitoring in chronic cannabis users. The error-related negativity (ERN) and error positivity (Pe), ERPs sensitive to performance monitoring, were recorded from 30 frequent cannabis users (mean usage=5.52 days/week) and 32 cannabis-naïve control participants during a speeded stimulus discrimination task. The “oddball” P3 ERP was recorded as well. Users and controls did not differ on the amplitude or latency of the ERN; however, Pe amplitude was larger among users. Users also showed increased amplitude and reduced latency of the P3 in response to infrequent stimuli presented during the task. Among users, urinary cannabinoid metabolite levels at testing were unrelated to ERP outcomes. However, total years of cannabis use correlated negatively with P3 latency and positively with P3 amplitude, and age of first cannabis use correlated negatively with P3 amplitude. The results of this study suggest that chronic cannabis use is associated with alterations in neural activity related to the processing of motivationally-relevant stimuli (P3) and errors (Pe). PMID:23427191

Incentive-related modulation of cognitive control in healthy, anxious, and depressed adolescents: development and psychopathology related differences.

PubMed

Hardin, Michael G; Schroth, Elizabeth; Pine, Daniel S; Ernst, Monique

2007-05-01

Developmental changes in cognitive and affective processes contribute to adolescent risk-taking behavior, emotional intensification, and psychopathology. The current study examined adolescent development of cognitive control processes and their modulation by incentive, in health and psychopathology. Predictions include 1) better cognitive control in adults than adolescents, and in healthy adolescents than anxious and depressed adolescents, and 2) a stronger influence of incentives in adolescents than adults, and in healthy adolescents than their depressed and anxious counterparts. Antisaccadic eye movement parameters, which provide a measure of cognitive control, were collected during a reward antisaccade task that included parameterized incentive levels. Participants were 20 healthy adults, 30 healthy adolescents, 16 adolescents with an anxiety disorder, and 11 adolescents with major depression. Performance accuracy and saccade latency were analyzed to test both developmental and psychopathology hypotheses. Development and psychopathology group differences in cognitive control were found. Specifically, adults performed better than healthy adolescents, and healthy adolescents than anxious and depressed adolescents. Incentive improved accuracy for all groups; however, incremental increases were not sufficiently large to further modulate performance. Incentives also affected saccade latencies, pushing healthy adolescent latencies to adult levels, while being less effective in adolescents with depression or anxiety. This latter effect was partially mediated by anxiety symptom severity. Current findings evidence the modulation of cognitive control processes by incentives. While seen in both healthy adults and healthy adolescents, this modulatory effect was stronger in youth. While anxious and depressed adolescents exhibited improved cognitive control under incentives, this effect was smaller than that in healthy adolescents. These findings suggest differential incentive and/or cognitive control processing in anxiety and depression, and across development. Differences could result from disorder specific, or combined developmental and pathological mechanisms.

Incentive-related modulation of cognitive control in healthy, anxious, and depressed adolescents

PubMed Central

Hardin, Michael G.; Schroth, Elizabeth; Pine, Daniel S.; Ernst, Monique

2009-01-01

Background Developmental changes in cognitive and affective processes contribute to adolescent risk-taking behavior, emotional intensification, and psychopathology. The current study examined adolescent development of cognitive control processes and their modulation by incentive, in health and psychopathology. Predictions include 1) better cognitive control in adults than adolescents, and in healthy adolescents than anxious and depressed adolescents, and 2) a stronger influence of incentives in adolescents than adults, and in healthy adolescents than their depressed and anxious counterparts. Methods Antisaccadic eye movement parameters, which provide a measure of cognitive control, were collected during a reward antisaccade task that included parameterized incentive levels. Participants were 20 healthy adults, 30 healthy adolescents, 16 adolescents with an anxiety disorder, and 11 adolescents with major depression. Performance accuracy and saccade latency were analyzed to test both developmental and psychopathology hypotheses. Results Development and psychopathology group differences in cognitive control were found. Specifically, adults performed better than healthy adolescents, and healthy adolescents than anxious and depressed adolescents. Incentive improved accuracy for all groups; however, incremental increases were not sufficiently large to further modulate performance. Incentives also affected saccade latencies, pushing healthy adolescent latencies to adult levels, while being less effective in adolescents with depression or anxiety. This latter effect was partially mediated by anxiety symptom severity. Conclusions Current findings evidence the modulation of cognitive control processes by incentives. While seen in both healthy adults and healthy adolescents, this modulatory effect was stronger in youth. While anxious and depressed adolescents exhibited improved cognitive control under incentives, this effect was smaller than that in healthy adolescents. These findings suggest differential incentive and/or cognitive control processing in anxiety and depression, and across development. Differences could result from disorder specific, or combined developmental and pathological mechanisms. PMID:17501725

A 2.5-Kilobase Deletion Containing a Cluster of Nine MicroRNAs in the Latency-Associated-Transcript Locus of the Pseudorabies Virus Affects the Host Response of Porcine Trigeminal Ganglia during Established Latency

PubMed Central

Mahjoub, Nada; Dhorne-Pollet, Sophie; Fuchs, Walter; Endale Ahanda, Marie-Laure; Lange, Elke; Klupp, Barbara; Arya, Anoop; Loveland, Jane E.; Lefevre, François; Mettenleiter, Thomas C.

2014-01-01

ABSTRACT The alphaherpesvirus pseudorabies virus (PrV) establishes latency primarily in neurons of trigeminal ganglia when only the transcription of the latency-associated transcript (LAT) locus is detected. Eleven microRNAs (miRNAs) cluster within the LAT, suggesting a role in establishment and/or maintenance of latency. We generated a mutant (M) PrV deleted of nine miRNA genes which displayed properties that were almost identical to those of the parental PrV wild type (WT) during propagation in vitro. Fifteen pigs were experimentally infected with either WT or M virus or were mock infected. Similar levels of virus excretion and host antibody response were observed in all infected animals. At 62 days postinfection, trigeminal ganglia were excised and profiled by deep sequencing and quantitative RT-PCR. Latency was established in all infected animals without evidence of viral reactivation, demonstrating that miRNAs are not essential for this process. Lower levels of the large latency transcript (LLT) were found in ganglia infected by M PrV than in those infected by WT PrV. All PrV miRNAs were expressed, with highest expression observed for prv-miR-LLT1, prv-miR-LLT2 (in WT ganglia), and prv-miR-LLT10 (in both WT and M ganglia). No evidence of differentially expressed porcine miRNAs was found. Fifty-four porcine genes were differentially expressed between WT, M, and control ganglia. Both viruses triggered a strong host immune response, but in M ganglia gene upregulation was prevalent. Pathway analyses indicated that several biofunctions, including those related to cell-mediated immune response and the migration of dendritic cells, were impaired in M ganglia. These findings are consistent with a function of the LAT locus in the modulation of host response for maintaining a latent state. IMPORTANCE This study provides a thorough reference on the establishment of latency by PrV in its natural host, the pig. Our results corroborate the evidence obtained from the study of several LAT mutants of other alphaherpesviruses encoding miRNAs from their LAT regions. Neither PrV miRNA expression nor high LLT expression levels are essential to achieve latency in trigeminal ganglia. Once latency is established by PrV, the only remarkable differences are found in the pattern of host response. This indicates that, as in herpes simplex virus, LAT functions as an immune evasion locus. PMID:25320324

Anti-Alzheimer activity of isolated karanjin from Pongamia pinnata (L.) pierre and embelin from Embelia ribes Burm.f.

PubMed Central

Saini, Prachi; Lakshmayya, L.; Bisht, Vinod Singh

2017-01-01

Aim: The aim of this study is to find out the anti-Alzheimer’s activity of isolated karanjin and embelin. Materials and Methods: Karanjin isolated from Pongamia pinnata (L.) pierre and embelin from Embelia ribes Burm.f. and their purity was confirmed by ultraviolet spectrophotometric and Thin layer chromatography based study. Anti-Alzheimer’s activity of isolated compounds were evaluated through elevated plus maze and Morris water maze model on Swiss albino mice. Diazepam (1 mg/kg body weight, intraperitoneally) was used for the induction of Alzheimer’s like effects (amnesia) on Swiss albino mice and piracetam (200 mg/kg body weight, oral) used as a standard treatment. Results: In EPM, embelin and karanjin decrease the transfer latency time in dose dependent manner and escape latency time in MWM method. A significant (P < 0.01) reduction in amnesia with an anti-Alzheimer’s effect found when results of isolated compounds were compared with standard and vehicle control. Diazepam (1 mg/kg) treated group showed significant increase in escape latency and transfer latency when compared with vehicle control; which indicates impairment in learning and memory. Conclusion: Both isolated compounds and standard significantly reversed the amnesia induced by diazepam and improved learning and memory of mice in dose and time dependent manner. This study supports the ethnobotanical use of these two plants in India for the management of nerve or brain related problems. PMID:29861598

Functional brain development in growth-restricted and constitutionally small fetuses: a fetal magnetoencephalography case-control study.

PubMed

Morin, E C; Schleger, F; Preissl, H; Braendle, J; Eswaran, H; Abele, H; Brucker, S; Kiefer-Schmidt, I

2015-08-01

Fetal magnetoencephalography records fetal brain activity non-invasively. Delayed brain responses were reported for fetuses weighing below the tenth percentile. To investigate whether this delay indicates delayed brain maturation resulting from placental insufficiency, this study distinguished two groups of fetuses below the tenth percentile: growth-restricted fetuses with abnormal umbilical artery Doppler velocity (IUGR) and constitutionally small-for-gestational-age fetuses with normal umbilical artery Doppler findings (SGA) were compared with fetuses of adequate weight for gestational age (AGA), matched for age and behavioural state. A case-control study of matched pairs. Fetal magnetoencephalography-Center at the University Hospital of Tuebingen. Fourteen IUGR fetuses and 23 SGA fetuses were matched for gestational age and fetal behavioural state with 37 healthy, normal-sized fetuses. A 156-channel fetal magentoencephalography system was used to record fetal brain activity. Light flashes as visual stimulation were applied to the fetus. The Student's t-test for paired groups was performed. Latency of fetal visual evoked magnetic responses (VER). The IUGR fetuses showed delayed VERs compared with controls (IUGR, 233.1 ms; controls, 184.6 ms; P = 0.032). SGA fetuses had similar evoked response latencies compared with controls (SGA, 216.1 ms; controls, 219.9 ms; P = 0.828). Behavioural states were similarly distributed. Visual evoked responses are delayed in IUGR fetuses, but not in SGA. Fetal behavioural state as an influencing factor of brain response latency was accounted for in the comparison. This reinforces that delayed brain maturation is the result of placental insufficiency. © 2015 Royal College of Obstetricians and Gynaecologists.

Spatial analysis of lung, colorectal, and breast cancer on Cape Cod: An application of generalized additive models to case-control data

PubMed Central

Vieira, Verónica; Webster, Thomas; Weinberg, Janice; Aschengrau, Ann; Ozonoff, David

2005-01-01

Background The availability of geographic information from cancer and birth defect registries has increased public demands for investigation of perceived disease clusters. Many neighborhood-level cluster investigations are methodologically problematic, while maps made from registry data often ignore latency and many known risk factors. Population-based case-control and cohort studies provide a stronger foundation for spatial epidemiology because potential confounders and disease latency can be addressed. Methods We investigated the association between residence and colorectal, lung, and breast cancer on upper Cape Cod, Massachusetts (USA) using extensive data on covariates and residential history from two case-control studies for 1983–1993. We generated maps using generalized additive models, smoothing on longitude and latitude while adjusting for covariates. The resulting continuous surface estimates disease rates relative to the whole study area. We used permutation tests to examine the overall importance of location in the model and identify areas of increased and decreased risk. Results Maps of colorectal cancer were relatively flat. Assuming 15 years of latency, lung cancer was significantly elevated just northeast of the Massachusetts Military Reservation, although the result did not hold when we restricted to residences of longest duration. Earlier non-spatial epidemiology had found a weak association between lung cancer and proximity to gun and mortar positions on the reservation. Breast cancer hot spots tended to increase in magnitude as we increased latency and adjusted for covariates, indicating that confounders were partly hiding these areas. Significant breast cancer hot spots were located near known groundwater plumes and the Massachusetts Military Reservation. Discussion Spatial epidemiology of population-based case-control studies addresses many methodological criticisms of cluster studies and generates new exposure hypotheses. Our results provide evidence for spatial clustering of breast cancer on upper Cape Cod. The analysis suggests further investigation of the potential association between breast cancer and pollution plumes based on detailed exposure modeling. PMID:15955253

Spatial analysis of lung, colorectal, and breast cancer on Cape Cod: an application of generalized additive models to case-control data.

PubMed

Vieira, Verónica; Webster, Thomas; Weinberg, Janice; Aschengrau, Ann; Ozonoff, David

2005-06-14

The availability of geographic information from cancer and birth defect registries has increased public demands for investigation of perceived disease clusters. Many neighborhood-level cluster investigations are methodologically problematic, while maps made from registry data often ignore latency and many known risk factors. Population-based case-control and cohort studies provide a stronger foundation for spatial epidemiology because potential confounders and disease latency can be addressed. We investigated the association between residence and colorectal, lung, and breast cancer on upper Cape Cod, Massachusetts (USA) using extensive data on covariates and residential history from two case-control studies for 1983-1993. We generated maps using generalized additive models, smoothing on longitude and latitude while adjusting for covariates. The resulting continuous surface estimates disease rates relative to the whole study area. We used permutation tests to examine the overall importance of location in the model and identify areas of increased and decreased risk. Maps of colorectal cancer were relatively flat. Assuming 15 years of latency, lung cancer was significantly elevated just northeast of the Massachusetts Military Reservation, although the result did not hold when we restricted to residences of longest duration. Earlier non-spatial epidemiology had found a weak association between lung cancer and proximity to gun and mortar positions on the reservation. Breast cancer hot spots tended to increase in magnitude as we increased latency and adjusted for covariates, indicating that confounders were partly hiding these areas. Significant breast cancer hot spots were located near known groundwater plumes and the Massachusetts Military Reservation. Spatial epidemiology of population-based case-control studies addresses many methodological criticisms of cluster studies and generates new exposure hypotheses. Our results provide evidence for spatial clustering of breast cancer on upper Cape Cod. The analysis suggests further investigation of the potential association between breast cancer and pollution plumes based on detailed exposure modeling.

Differences in nocturnal and daytime sleep between primary and psychiatric hypersomnia: diagnostic and treatment implications.

PubMed

Vgontzas, A N; Bixler, E O; Kales, A; Criley, C; Vela-Bueno, A

2000-01-01

The differential diagnosis of primary (idiopathic) vs. psychiatric hypersomnia is challenging because of the lack of specific clinical or laboratory criteria differentiating these two disorders and the frequent comorbidity of mental disorders in patients with primary hypersomnia. The aim of this study was to assess whether polysomnography aids in the differential diagnosis of these two disorders. After excluding patients taking medication and those with an additional diagnosis of sleep-disordered breathing, we compared the nocturnal and daytime sleep of 82 consecutive patients with a diagnosis of either primary hypersomnia (N = 59) or psychiatric hypersomnia (N = 23) and normal control subjects (N = 50). During nocturnal sleep, patients with psychiatric hypersomnia showed significantly higher sleep latency, wake time after sleep onset, and total wake time and a significantly lower percentage of sleep time than patients with primary hypersomnia and control subjects (p < .05). In addition, the daytime sleep of patients with psychiatric hypersomnia was significantly higher in terms of sleep latency, total wake time, and percentage of light (stage 1) sleep and lower in terms of percentage of sleep time and stage 2 sleep than in patients with primary hypersomnia and control subjects (p < .05). The daytime sleep of patients with primary hypersomnia as compared with that of control subjects was characterized by lower sleep latency and total wake time and a higher percentage of sleep time (p < .05). Finally, a sleep latency of less than 10 minutes or a sleep time percentage greater than 70% in either of the two daytime naps was associated with a sensitivity of 78.0% and a specificity of 95.7%. Our findings indicate that psychiatric hypersomnia is a disorder of hyperarousal, whereas primary hypersomnia is a disorder of hypoarousal. Polysomnographic measures may provide useful information in the differential diagnosis and treatment of these two disorders.

Falcon: a highly flexible open-source software for closed-loop neuroscience.

PubMed

Ciliberti, Davide; Kloosterman, Fabian

2017-08-01

Closed-loop experiments provide unique insights into brain dynamics and function. To facilitate a wide range of closed-loop experiments, we created an open-source software platform that enables high-performance real-time processing of streaming experimental data. We wrote Falcon, a C++ multi-threaded software in which the user can load and execute an arbitrary processing graph. Each node of a Falcon graph is mapped to a single thread and nodes communicate with each other through thread-safe buffers. The framework allows for easy implementation of new processing nodes and data types. Falcon was tested both on a 32-core and a 4-core workstation. Streaming data was read from either a commercial acquisition system (Neuralynx) or the open-source Open Ephys hardware, while closed-loop TTL pulses were generated with a USB module for digital output. We characterized the round-trip latency of our Falcon-based closed-loop system, as well as the specific latency contribution of the software architecture, by testing processing graphs with up to 32 parallel pipelines and eight serial stages. We finally deployed Falcon in a task of real-time detection of population bursts recorded live from the hippocampus of a freely moving rat. On Neuralynx hardware, round-trip latency was well below 1 ms and stable for at least 1 h, while on Open Ephys hardware latencies were below 15 ms. The latency contribution of the software was below 0.5 ms. Round-trip and software latencies were similar on both 32- and 4-core workstations. Falcon was used successfully to detect population bursts online with ~40 ms average latency. Falcon is a novel open-source software for closed-loop neuroscience. It has sub-millisecond intrinsic latency and gives the experimenter direct control of CPU resources. We envisage Falcon to be a useful tool to the neuroscientific community for implementing a wide variety of closed-loop experiments, including those requiring use of complex data structures and real-time execution of computationally intensive algorithms, such as population neural decoding/encoding from large cell assemblies.

Falcon: a highly flexible open-source software for closed-loop neuroscience

NASA Astrophysics Data System (ADS)

Ciliberti, Davide; Kloosterman, Fabian

2017-08-01

Objective. Closed-loop experiments provide unique insights into brain dynamics and function. To facilitate a wide range of closed-loop experiments, we created an open-source software platform that enables high-performance real-time processing of streaming experimental data. Approach. We wrote Falcon, a C++ multi-threaded software in which the user can load and execute an arbitrary processing graph. Each node of a Falcon graph is mapped to a single thread and nodes communicate with each other through thread-safe buffers. The framework allows for easy implementation of new processing nodes and data types. Falcon was tested both on a 32-core and a 4-core workstation. Streaming data was read from either a commercial acquisition system (Neuralynx) or the open-source Open Ephys hardware, while closed-loop TTL pulses were generated with a USB module for digital output. We characterized the round-trip latency of our Falcon-based closed-loop system, as well as the specific latency contribution of the software architecture, by testing processing graphs with up to 32 parallel pipelines and eight serial stages. We finally deployed Falcon in a task of real-time detection of population bursts recorded live from the hippocampus of a freely moving rat. Main results. On Neuralynx hardware, round-trip latency was well below 1 ms and stable for at least 1 h, while on Open Ephys hardware latencies were below 15 ms. The latency contribution of the software was below 0.5 ms. Round-trip and software latencies were similar on both 32- and 4-core workstations. Falcon was used successfully to detect population bursts online with ~40 ms average latency. Significance. Falcon is a novel open-source software for closed-loop neuroscience. It has sub-millisecond intrinsic latency and gives the experimenter direct control of CPU resources. We envisage Falcon to be a useful tool to the neuroscientific community for implementing a wide variety of closed-loop experiments, including those requiring use of complex data structures and real-time execution of computationally intensive algorithms, such as population neural decoding/encoding from large cell assemblies.

Effects of D-004, a lipid extract of the fruit of the Cuban royal palm (Roystonea regia) or the lipidosterolic extract of saw palmetto (Serenoa repens) on the sexual activity in male rats: A controlled, experimental study.

PubMed

Fernández, Lilia C; Mas, Rosa; Fernández, Julio; Mendoza, Sarahí; Gámez, Rafael; Pardo, Balia

2008-02-01

The etiology of benign prostatic hyperplasia (BPH) is not completely understood, but hormonal changes in aging men seem to be pivotal. Dihydrotestosterone, a potent, active metabolite of testosterone, is formed by the enzymatic action of prostate 5α-reductase and causes cell growth and hyperplasia. Consistent with this action, male sexual dysfunction has been clinically documented to be among the drug-related adverse events associated with 5α-reductase inhibitors. The lipidosterolic extract of saw palmetto (LESP) fruit (Serenoa repens) has been used to treat BPH. D-004, a lipid extract of Roystonea regia Royal palm fruit, has been found to prevent prostatic hyperplasia induced by testoste-rone in rodents and to competitively inhibit prostate 5α-reductase activity in vitro. The purpose of this study was to assess the effects of D-004 and LESP, administered as single or repeated doses, on the sexual activity in male rats. This controlled, experimental study was conducted at the Pharmacology Department, Centre of Natural Products, National Centre for Scientific Research, Havana City, Cuba. Adult male Wistar rats weighing 250 to 300 g were randomized into 5 groups: 2 groups treated orally with D-004 (400 and 800 mg/kg); 2 groups treated orally with LESP (400 and 800 mg/kg); and 1 control group orally administered a water vehicle. Sexual activity behavior (the number of mounts and intromissions, mount latency, and intromission latency) was assessed during 2 observation periods: 90 minutes after the initial dose and at the end of the 30-day treatment. Latency was defined as time elapsed between the first mount and intromission. A total of 50 rats (mean [SD] age, 10 [3] weeks; mean [SD] weight, 295 [10] g) were included in the experiment. There were no significant difterences in the mean number of mounts, intromissions, mount latency, or intromission latency in the groups treated with single or repeated doses of D-004 or LESP (400 and 800 mg/kg) compared with the controls. There was also no between-group difterence in mating behavior among the active treatment groups. All rats survived up to study completion, with normal behavior (weight gain, food intake, daily observations, without any sign of toxicity). There were no observable adverse events during the study. D-004 and LESP administered as a single dose or repeated doses for 30 days did not significantly affect male rat sexual activity behavior compared with a vehicle control group.

Formation Flying for Satellites and UAVs

NASA Technical Reports Server (NTRS)

Merrill, Garrick; Becker, Chris

2015-01-01

A formation monitoring and control system was developed utilizing mesh networking and decentralized control. Highlights of this system include low latency, seamless addition and removal of vehicles, network relay functionality, and the ability to run on a variety of hardware.

Case-control study of the association between malignant brain tumours diagnosed between 2007 and 2009 and mobile and cordless phone use

PubMed Central

HARDELL, LENNART; CARLBERG, MICHAEL; SÖDERQVIST, FREDRIK; MILD, KJELL HANSSON

2013-01-01

Previous studies have shown a consistent association between long-term use of mobile and cordless phones and glioma and acoustic neuroma, but not for meningioma. When used these phones emit radiofrequency electromagnetic fields (RF-EMFs) and the brain is the main target organ for the hand-held phone. The International Agency for Research on Cancer (IARC) classified in May, 2011 RF-EMF as a group 2B, i.e. a ‘possible’ human carcinogen. The aim of this study was to further explore the relationship between especially long-term (>10 years) use of wireless phones and the development of malignant brain tumours. We conducted a new case-control study of brain tumour cases of both genders aged 18–75 years and diagnosed during 2007–2009. One population-based control matched on gender and age (within 5 years) was used to each case. Here, we report on malignant cases including all available controls. Exposures on e.g. use of mobile phones and cordless phones were assessed by a self-administered questionnaire. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index using the whole control sample. Of the cases with a malignant brain tumour, 87% (n=593) participated, and 85% (n=1,368) of controls in the whole study answered the questionnaire. The odds ratio (OR) for mobile phone use of the analogue type was 1.8, 95% confidence interval (CI)=1.04–3.3, increasing with >25 years of latency (time since first exposure) to an OR=3.3, 95% CI=1.6–6.9. Digital 2G mobile phone use rendered an OR=1.6, 95% CI=0.996–2.7, increasing with latency >15–20 years to an OR=2.1, 95% CI=1.2–3.6. The results for cordless phone use were OR=1.7, 95% CI=1.1–2.9, and, for latency of 15–20 years, the OR=2.1, 95% CI=1.2–3.8. Few participants had used a cordless phone for >20–25 years. Digital type of wireless phones (2G and 3G mobile phones, cordless phones) gave increased risk with latency >1–5 years, then a lower risk in the following latency groups, but again increasing risk with latency >15–20 years. Ipsilateral use resulted in a higher risk than contralateral mobile and cordless phone use. Higher ORs were calculated for tumours in the temporal and overlapping lobes. Using the meningioma cases in the same study as reference entity gave somewhat higher ORs indicating that the results were unlikely to be explained by recall or observational bias. This study confirmed previous results of an association between mobile and cordless phone use and malignant brain tumours. These findings provide support for the hypothesis that RF-EMFs play a role both in the initiation and promotion stages of carcinogenesis. PMID:24064953

Distinctive Effect of Donepezil Treatment on P300 and N200 Subcomponents of Auditory Event-Related Evoked Potentials in Alzheimer Disease Patients.

PubMed

Vaitkevičius, Arūnas; Kaubrys, Gintaras; Audronytė, Eglė

2015-07-03

Latency of P300 subcomponent of event-related potentials (ERPs) increases in Alzheimer disease (AD) patients, which correlate well with cognitive impairment. Cholinesterase inhibitors (ChEIs) reduce P300 latency in AD patients with parallel improvement in cognition. It is not known whether N200 response to ChEIs is similar to that of P300. The aim of this study was to evaluate and compare characteristics of P300 and N200 in AD patients, treatment-naïve and on stable donepezil treatment, matched by age, education, sex, and cognitive function. We recruited 22 consecutive treatment-naïve AD patients (AD-N group), 22 AD patients treated with a stable donepezil dose of 10 mg/day for at least 3 months (AD-T group), and 50 healthy controls were recruited. Neuropsychological testing (MMSE, ADAS-Cog, and additional tests) and ERP recording was performed and analyzed. All groups did not differ according to age, duration of education, or sex (p>0.05). AD-N and AD-T groups did not differ according to cognitive function. The AD-T group had longer duration of disease than the AD-N group (p<0.001). The AD-T and AD-N groups did not differ in P300 latencies (p=0.49). N200 latency was longer in the AD-T group (p<0.001). The general linear model showed that significant predictors of P300 latency were age (p=0.019) and AD treatment status (p<0.001). Duration of AD was a significant predictor of N200 latency (p=0.004). The response of N200 latency to donepezil treatment differs from the response of P300. P300 is a better marker of ChEI treatment-dependent cognitive functions. N200 is more dependent on the duration of AD.

Reduced evolutionary rates in HIV-1 reveal extensive latency periods among replicating lineages.

PubMed

Immonen, Taina T; Leitner, Thomas

2014-10-16

HIV-1 can persist for the duration of a patient's life due in part to its ability to hide from the immune system, and from antiretroviral drugs, in long-lived latent reservoirs. Latent forms of HIV-1 may also be disproportionally involved in transmission. Thus, it is important to detect and quantify latency in the HIV-1 life cycle. We developed a novel molecular clock-based phylogenetic tool to investigate the prevalence of HIV-1 lineages that have experienced latency. The method removes alternative sources that may affect evolutionary rates, such as hypermutation, recombination, and selection, to reveal the contribution of generation-time effects caused by latency. Our method was able to recover latent lineages with high specificity and sensitivity, and low false discovery rates, even on relatively short branches on simulated phylogenies. Applying the tool to HIV-1 sequences from 26 patients, we show that the majority of phylogenetic lineages have been affected by generation-time effects in every patient type, whether untreated, elite controller, or under effective or failing treatment. Furthermore, we discovered extensive effects of latency in sequence data (gag, pol, and env) from reservoirs as well as in the replicating plasma population. To better understand our phylogenetic findings, we developed a dynamic model of virus-host interactions to investigate the proportion of lineages in the actively replicating population that have ever been latent. Assuming neutral evolution, our dynamic modeling showed that under most parameter conditions, it is possible for a few activated latent viruses to propagate so that in time, most HIV-1 lineages will have been latent at some time in their past. These results suggest that cycling in and out of latency plays a major role in the evolution of HIV-1. Thus, no aspect of HIV-1 evolution can be fully understood without considering latency - including treatment, drug resistance, immune evasion, transmission, and pathogenesis.

[Mushroom poisoning--the dark side of mycetism].

PubMed

Flammer, René; Schenk-Jäger, Katharina M

2009-05-01

Most mushroom intoxications become evident within 12 hours with vomiting and diarrhea. They can be divided into incidents with a short latency (less than four hours) and incidents with a long latency (longer than four hours). As a rule of thumb amatoxin poisonings must be considered in case of symptoms appearing with a long latency (8-12-18 h), especially after consumption of non-controlled wild mushrooms. Shorter latencies do not exclude amatoxin poisoning. Large meals of mushrooms, which are rich in chitin, mixed meals and individual factors, may shorten latency and disguise amatoxin poisoning. Any vomiting and diarrhea after mushroom consumption is suspicious. Unless the mushrooms are not to be identified within 30 minutes by an expert, specific treatment for amatoxin poisoning must be started. Identification shall be achieved by macroscopic or microscopic means; and urine analysis for amatoxins are crucial. By commencing treatment before analysis, mortality rates may be as low as 5%. Current standards in amatoxin poisoning treatment can be obtained at the Swiss Toxicological Information Centre (Phone 145), where contacts to mycologists are available as well. Emergency mycologists are listed on the website www.vapko.ch. Of the 18 different syndromes we present the most common and most important in Switzerland. In an overview all of them are listed. Early gastrointestinal syndrome with its short latency of less than 4 h and indigestion with a very variable latency are the most common. Psychotropic symptoms after consumptions of fly agaric and panther cap are rare, in case of psilocybin-containing mushrooms, symptoms are frequent, but hardly ever lead to medical treatment. In case of renal failure and rhabdomyolysis of unknown origin, completing a patient's history by questioning nutritional habits might reveal causal relationship with ingestion of orellanin-containing mushrooms or tricholoma equestre respectively. Mushrooms in the backyard are attractive for children. We discuss possible approaches.

Test Operations Procedure (TOP) 02-2-546 Teleoperated Unmanned Ground Vehicle (UGV) Latency Measurements

DTIC Science & Technology

2017-01-11

discrete system components or measurements of latency in autonomous systems. 15. SUBJECT TERMS Unmanned Ground Vehicles, Basic Video Latency, End-to... discrete system components or measurements of latency in autonomous systems. 1.1 Basic Video Latency. Teleoperation latency, or lag, describes

Software-defined networking control plane for seamless integration of multiple silicon photonic switches in Datacom networks

DOE PAGES

Shen, Yiwen; Hattink, Maarten; Samadi, Payman; ...

2018-04-13

Silicon photonics based switches offer an effective option for the delivery of dynamic bandwidth for future large-scale Datacom systems while maintaining scalable energy efficiency. The integration of a silicon photonics-based optical switching fabric within electronic Datacom architectures requires novel network topologies and arbitration strategies to effectively manage the active elements in the network. Here, we present a scalable software-defined networking control plane to integrate silicon photonic based switches with conventional Ethernet or InfiniBand networks. Our software-defined control plane manages both electronic packet switches and multiple silicon photonic switches for simultaneous packet and circuit switching. We built an experimental Dragonfly networkmore » testbed with 16 electronic packet switches and 2 silicon photonic switches to evaluate our control plane. Observed latencies occupied by each step of the switching procedure demonstrate a total of 344 microsecond control plane latency for data-center and high performance computing platforms.« less

Software-defined networking control plane for seamless integration of multiple silicon photonic switches in Datacom networks

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

Shen, Yiwen; Hattink, Maarten; Samadi, Payman

Silicon photonics based switches offer an effective option for the delivery of dynamic bandwidth for future large-scale Datacom systems while maintaining scalable energy efficiency. The integration of a silicon photonics-based optical switching fabric within electronic Datacom architectures requires novel network topologies and arbitration strategies to effectively manage the active elements in the network. Here, we present a scalable software-defined networking control plane to integrate silicon photonic based switches with conventional Ethernet or InfiniBand networks. Our software-defined control plane manages both electronic packet switches and multiple silicon photonic switches for simultaneous packet and circuit switching. We built an experimental Dragonfly networkmore » testbed with 16 electronic packet switches and 2 silicon photonic switches to evaluate our control plane. Observed latencies occupied by each step of the switching procedure demonstrate a total of 344 microsecond control plane latency for data-center and high performance computing platforms.« less

Attention orienting and inhibitory control across the different mood states in bipolar disorder: an emotional antisaccade task.

PubMed

García-Blanco, Ana C; Perea, Manuel; Salmerón, Ladislao

2013-12-01

An antisaccade experiment, using happy, sad, and neutral faces, was conducted to examine the effect of mood-congruent information on inhibitory control (antisaccade task) and attentional orienting (prosaccade task) during the different episodes of bipolar disorder (BD) - manic (n=22), depressive (n=25), and euthymic (n=24). A group of 28 healthy controls was also included. Results revealed that symptomatic patients committed more antisaccade errors than healthy individuals, especially with mood-congruent faces. The manic group committed more antisaccade errors in response to happy faces, while the depressed group tended to commit more antisaccade errors in response to sad faces. Additionally, antisaccade latencies were slower in BD patients than in healthy individuals, whereas prosaccade latencies were slower in symptomatic patients. Taken together, these findings revealed the following: (a) slow inhibitory control in BD patients, regardless of their episode (i.e., a trait), and (b) impaired inhibitory control restricted to symptomatic patients (i.e., a state). Copyright © 2013 Elsevier B.V. All rights reserved.

Sympathetic skin response in multiple sclerosis: a meta-analysis of case-control studies.

PubMed

Margaritella, Nicolò; Mendozzi, Laura; Garegnani, Massimo; Gilardi, Elisabetta; Nemni, Raffaello; Pugnetti, Luigi

2018-01-01

The usefulness of sympathetic skin responses (SSR) in multiple sclerosis (MS) has been advocated by several studies in the last 20 years; however, due to a great heterogeneity of findings, a comprehensive meta-analysis of case-control studies is in order to pinpoint consistencies and investigate the causes of discrepancies. We searched MEDLINE, EMBASE and Cochrane databases for case-control studies comparing SSR absence frequency and latency between patients with MS and healthy controls. Thirteen eligible studies including 415 MS patients and 331 healthy controls were identified. The pooled analysis showed that SSR can be always obtained in healthy controls while 34% of patients had absent SSRs in at least one limb (95% CI 22-47%; p < 0.0001) but with considerable heterogeneity across studies (I 2  = 90.3%). Patients' age explained 22% of the overall variability and positive correlations were found with Expanded Disability Status Scale and disease duration. The pooled mean difference of SSR latency showed a significant increase in patients on both upper (193 ms; 95% CI 120-270 ms) and lower (350 ms; 95% CI 190-510 ms) extremities. We tested the discriminatory value of SSR latency thresholds defined as the 95% confidence interval (CI) upper bound of the healthy controls, and validated the results on a new dataset. The lower limb threshold of 1.964 s produces the best results in terms of sensitivity 0.86, specificity 0.67, positive predicted value 0.75 and negative predicted value 0.80. Despite a considerable heterogeneity of findings, there is evidence that SSR is a useful tool in MS.

Analog Testing of Operations Concepts for Mitigation of Communication Latency During Human Space Exploration

NASA Technical Reports Server (NTRS)

Chappell, Steven P.; Abercromby, Andrew F.; Miller, Matthew J.; Halcon, Christopher; Gernhardt, Michael L.

2016-01-01

OBJECTIVES: NASA Extreme Environment Mission Operations (NEEMO) is an underwater spaceflight analog that allows a true mission-like operational environment and uses buoyancy effects and added weight to simulate different gravity levels. Three missions were undertaken from 2014-2015, NEEMO's 18-20. All missions were performed at the Aquarius undersea research habitat. During each mission, the effects of varying operations concepts and tasks type and complexity on representative communication latencies associated with Mars missions were studied. METHODS: 12 subjects (4 per mission) were weighed out to simulate near-zero or partial gravity extravehicular activity (EVA) and evaluated different operations concepts for integration and management of a simulated Earth-based science backroom team (SBT) to provide input and direction during exploration activities. Exploration traverses were planned in advance based on precursor data collected. Subjects completed science-related tasks including presampling surveys, geologic-based sampling, and marine-based sampling as a portion of their tasks on saturation dives up to 4 hours in duration that were to simulate extravehicular activity (EVA) on Mars or the moons of Mars. One-way communication latencies, 5 and 10 minutes between space and mission control, were simulated throughout the missions. Objective data included task completion times, total EVA times, crew idle time, translation time, SBT assimilation time (defined as time available for SBT to discuss data/imagery after it has been collected, in addition to the time taken to watch imagery streaming over latency). Subjective data included acceptability, simulation quality, capability assessment ratings, and comments. RESULTS: Precursor data can be used effectively to plan and execute exploration traverse EVAs (plans included detailed location of science sites, high-fidelity imagery of the sites, and directions to landmarks of interest within a site). Operations concepts that allow for presampling surveys enable efficient traverse execution and meaningful Mission Control Center (MCC) interaction across long communication latencies and can be done with minimal crew idle time. Imagery and information from the EVA crew that is transmitted real-time to the intravehicular (IV) crewmember(s) can be used to verify that exploration traverse plans are being executed correctly. That same data can be effectively used by MCC (across comm latency) to provide further instructions to the crew from a SBT on sampling priorities, additional tasks, and changes to the plan. Text / data capabilities are preferred over voice capabilities between MCC and IV when executing exploration traverse plans over communication latency. Autonomous crew planning tools can be effective at modifying existing plans if the objectives and constraints are clearly defined.

Thought Control Training as a Treatment for Insomnia.

ERIC Educational Resources Information Center

Ribordy, Sheila C.

College students with difficulty falling asleep were treated with either progressive relaxation, systematic desensitization, or a thought control procedure. All three treatment groups showed significant lower latency to sleep onset times than a waiting-list control group at the end of the three-week treatment period. A three-week followup revealed…

Latency Determination and Compensation in Real-Time Gnss/ins Integrated Navigation Systems

NASA Astrophysics Data System (ADS)

Solomon, P. D.; Wang, J.; Rizos, C.

2011-09-01

Unmanned Aerial Vehicle (UAV) technology is now commonplace in many defence and civilian environments. However, the high cost of owning and operating a sophisticated UAV has slowed their adoption in many commercial markets. Universities and research groups are actively experimenting with UAVs to further develop the technology, particularly for automated flying operations. The two main UAV platforms used are fixed-wing and helicopter. Helicopter-based UAVs offer many attractive features over fixed-wing UAVs, including vertical take-off, the ability to loiter, and highly dynamic flight. However the control and navigation of helicopters are significantly more demanding than those of fixed-wing UAVs and as such require a high bandwidth real-time Position, Velocity, Attitude (PVA) navigation system. In practical Real-Time Navigation Systems (RTNS) there are delays in the processing of the GNSS data prior to the fusion of the GNSS data with the INS measurements. This latency must be compensated for otherwise it degrades the solution of the navigation filter. This paper investigates the effect of latency in the arrival time of the GNSS data in a RTNS. Several test drives and flights were conducted with a low-cost RTNS, and compared with a high quality GNSS/INS solution. A technique for the real-time, automated and accurate estimation of the GNSS latency in low-cost systems was developed and tested. The latency estimates were then verified through cross-correlation with the time-stamped measurements from the reference system. A delayed measurement Extended Kalman Filter was then used to allow for the real-time fusing of the delayed measurements, and then a final system developed for on-the-fly measurement and compensation of GNSS latency in a RTNS.

Pattern Electroretinography and Visual Evoked Potentials Provide Clinical Evidence of CNS Modulation of High- and Low-Contrast VEP Latency in Glaucoma

PubMed Central

Sponsel, William E.; Johnson, Susan L.; Trevino, Rick; Gonzalez, Alberto; Groth, Sylvia L.; Majcher, Carolyn; Fulton, Diane C.; Reilly, Matthew A.

2017-01-01

Purpose Both pattern electroretinography (PERG) and visual evoked potentials (VEP) can be performed using low- (15%; Lc) and high- (85%; Hc) contrast gratings that may preferentially stimulate the magno- and parvocellular pathways. We observed that among glaucomatous patients showing only one VEP latency deficit per eye, there appeared to be a very strong tendency for an Hc delay in one eye and an Lc delay in the other. Methods Diopsys NOVA-LX system was used to measure VEP Hc and Lc latency among a clinical glaucoma population to find all individuals with either a single Hc or Lc latency abnormality in each eye (group 1), or with greater than 0 and less than 4 Hc or Lc VEP latency abnormalities in the two eyes (group 2) to determine whether a significant inverse correlation existed for these values in either group. Hc and Lc PERG data were also evaluated to assess associated retinal ganglion cell responses. Results A strong inverse correlation (P = 0.0000003) was observed between the Hc and Lc VEP latency values among the 64 eyes in group 1. Group 2 provided a comparable result (n = 143; 286 eyes; P = 0.0005). PERG (n = 81; 162 eyes) also showed strong bilateral symmetry for magnitude values (P < 0.0001 for both Lc and Hc in groups 1 and 2). Conclusions Bilateral retention of both low-resolution/high-speed and high-resolution/low-speed function may persist with both eyes open despite symmetrically pathologic retinal ganglion cell PERG waveform asynchrony for Hc and Lc stimuli in the paired eyes. Translational Relevance Clinical electrophysiology strongly suggests binocular compensation for dynamic dysfunction operates under central nervous system (CNS) control in glaucoma. PMID:29134137

Statistical learning methods for aero-optic wavefront prediction and adaptive-optic latency compensation

NASA Astrophysics Data System (ADS)

Burns, W. Robert

Since the early 1970's research in airborne laser systems has been the subject of continued interest. Airborne laser applications depend on being able to propagate a near diffraction-limited laser beam from an airborne platform. Turbulent air flowing over the aircraft produces density fluctuations through which the beam must propagate. Because the index of refraction of the air is directly related to the density, the turbulent flow imposes aberrations on the beam passing through it. This problem is referred to as Aero-Optics. Aero-Optics is recognized as a major technical issue that needs to be solved before airborne optical systems can become routinely fielded. This dissertation research specifically addresses an approach to mitigating the deleterious effects imposed on an airborne optical system by aero-optics. A promising technology is adaptive optics: a feedback control method that measures optical aberrations and imprints the conjugate aberrations onto an outgoing beam. The challenge is that it is a computationally-difficult problem, since aero-optic disturbances are on the order of kilohertz for practical applications. High control loop frequencies and high disturbance frequencies mean that adaptive-optic systems are sensitive to latency in sensors, mirrors, amplifiers, and computation. These latencies build up to result in a dramatic reduction in the system's effective bandwidth. This work presents two variations of an algorithm that uses model reduction and data-driven predictors to estimate the evolution of measured wavefronts over a short temporal horizon and thus compensate for feedback latency. The efficacy of the two methods are compared in this research, and evaluated against similar algorithms that have been previously developed. The best version achieved over 75% disturbance rejection in simulation in the most optically active flow region in the wake of a turret, considerably outperforming conventional approaches. The algorithm is shown to be insensitive to changes in flow condition, and stable in the presence of small latency uncertainty. Consideration is given to practical implementation of the algorithms as well as computational requirement scaling.

Visual event-related potential changes in two subtypes of multiple system atrophy, MSA-C and MSA-P.

PubMed

Kamitani, Toshiaki; Kuroiwa, Yoshiyuki; Wang, Lihong; Li, Mei; Suzuki, Yume; Takahashi, Tatsuya; Ikegami, Tadashi; Matsubara, Sho

2002-08-01

We investigated the visual event-related potentials (ERPs) in two subtypes of multisystem atrophy (MSA) in 15 MSA-C patients, 12 MSA-P patients, and 21 normal control (NC) subjects. We used a visual oddball task to elicit ERPs. No significant changes were seen in N1 or N2 latency, in either MSA-C or MSA-P, compared with the NC group. An early stage of visual information process related to N1 and a visual discrimination process related to N2 might be preserved in both MSA-C and MSA-P. The P3a peak was more frequently undetectable in MSA than in the NC group. Significant P3a amplitude reduction in both MSA-C and MSA-P suggests impairment of the automatic cognitive processing in both MSA-C and MSA-P. Significant difference was found in P3b latency and P3b amplitude only in MSA-C, compared with the NC group. The result suggests the impairment of the controlled cognitive processing after the visual discrimination process in the MSA-C group. We further investigated the correlation between visual ERP changes and magnetic resonance imaging (MRI) data. Quantitative MRI measurements showed reduced size of the pons, cerebellum, perisylvian cerebral area, and deep cerebral gray matter in both MSA-C and MSA-P, and of the corpus callosum only in MSA-P, as compared to NC group. In both MSA-C and MSA-P, P3b latency was significantly correlated with the size on MRI of the pons and the cerebellum. P3b latency in the whole MSA group was also significantly correlated with the size of the pons and the cerebellum. These results indicate that P3b latency changes in parallel with the volume of the pons and the cerebellum in both MSA-C and MSA-P.

A Critical Role of Glutamine and Asparagine γ-Nitrogen in Nucleotide Biosynthesis in Cancer Cells Hijacked by an Oncogenic Virus

PubMed Central

Zhu, Ying; Li, Tingting; Ramos da Silva, Suzane; Lee, Jae-Jin; Lu, Chun; Eoh, Hyungjin; Jung, Jae U.

2017-01-01

ABSTRACT While glutamine is a nonessential amino acid that can be synthesized from glucose, some cancer cells primarily depend on glutamine for their growth, proliferation, and survival. Numerous types of cancer also depend on asparagine for cell proliferation. The underlying mechanisms of the glutamine and asparagine requirement in cancer cells in different contexts remain unclear. In this study, we show that the oncogenic virus Kaposi’s sarcoma-associated herpesvirus (KSHV) accelerates the glutamine metabolism of glucose-independent proliferation of cancer cells by upregulating the expression of numerous critical enzymes, including glutaminase 2 (GLS2), glutamate dehydrogenase 1 (GLUD1), and glutamic-oxaloacetic transaminase 2 (GOT2), to support cell proliferation. Surprisingly, cell crisis is rescued only completely by supplementation with asparagine but minimally by supplementation with α-ketoglutarate, aspartate, or glutamate upon glutamine deprivation, implying an essential role of γ-nitrogen in glutamine and asparagine for cell proliferation. Specifically, glutamine and asparagine provide the critical γ-nitrogen for purine and pyrimidine biosynthesis, as knockdown of four rate-limiting enzymes in the pathways, including carbamoylphosphate synthetase 2 (CAD), phosphoribosyl pyrophosphate amidotransferase (PPAT), and phosphoribosyl pyrophosphate synthetases 1 and 2 (PRPS1 and PRPS2, respectively), suppresses cell proliferation. These findings indicate that glutamine and asparagine are shunted to the biosynthesis of nucleotides and nonessential amino acids from the tricarboxylic acid (TCA) cycle to support the anabolic proliferation of KSHV-transformed cells. Our results illustrate a novel mechanism by which an oncogenic virus hijacks a metabolic pathway for cell proliferation and imply potential therapeutic applications in specific types of cancer that depend on this pathway. PMID:28811348

Thoracic Diseases Associated with HIV Infection in the Era of Antiretroviral Therapy: Clinical and Imaging Findings

PubMed Central

Prabhu, Somnath J.; Crothers, Kristina; Stern, Eric J.; Godwin, J. David; Pipavath, Sudhakar N.

2014-01-01

The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) pandemic has entered its 4th decade. Since the introduction of combination antiretroviral therapy (ART) in 1996, the number of AIDS-related deaths has plateaued worldwide. Today, owing to the effectiveness of ART, the HIV-infected population is aging and HIV infection has become a chronic illness. Non-AIDS comorbidities are increasing, and the spectrum of HIV-related thoracic diseases is evolving. In developed countries, bacterial pneumonia has become more common than Pneumocystis pneumonia. Its imaging appearance depends on the responsible organism, most commonly Streptococcus pneumoniae. Mycobacterium tuberculosis continues to be a major threat. Its imaging patterns vary depending on CD4 count. Primary lung cancer and Hodgkin lymphoma are two important non–AIDS-defining malignancies that are increasingly encountered at chest imaging. Human herpesvirus 8, also known as Kaposi sarcoma–associated herpesvirus (KSHV), is strongly linked to HIV-related diseases, including Kaposi sarcoma, multicentric Castleman disease, KSHV inflammatory cytokine syndrome, and primary effusion lymphoma. Immune reconstitution inflammatory syndrome is a direct complication of ART whose manifestations vary with the underlying disease. Given the high rate of smoking among HIV-infected patients, chronic obstructive pulmonary disease is another important cause of morbidity and mortality. A high degree of suspicion is required for the early diagnosis of pulmonary arterial hypertension and lymphocytic interstitial pneumonia, given their nonspecific manifestations. Finally, multilocular thymic cyst manifests as a cystic anterior mediastinal mass. Recognition of the clinical and radiologic manifestations of these less traditional HIV-related diseases can expedite diagnosis and treatment in the ART era. © RSNA, 2014 PMID:25019430

Kaposi's Sarcoma-Associated Herpesvirus mRNA Accumulation in Nuclear Foci Is Influenced by Viral DNA Replication and Viral Noncoding Polyadenylated Nuclear RNA.

PubMed

Vallery, Tenaya K; Withers, Johanna B; Andoh, Joana A; Steitz, Joan A

2018-07-01

Kaposi's sarcoma-associated herpesvirus (KSHV), like other herpesviruses, replicates within the nuclei of its human cell host and hijacks host machinery for expression of its genes. The activities that culminate in viral DNA synthesis and assembly of viral proteins into capsids physically concentrate in nuclear areas termed viral replication compartments. We sought to better understand the spatiotemporal regulation of viral RNAs during the KSHV lytic phase by examining and quantifying the subcellular localization of select viral transcripts. We found that viral mRNAs, as expected, localized to the cytoplasm throughout the lytic phase. However, dependent on active viral DNA replication, viral transcripts also accumulated in the nucleus, often in foci in and around replication compartments, independent of the host shutoff effect. Our data point to involvement of the viral long noncoding polyadenylated nuclear (PAN) RNA in the localization of an early, intronless viral mRNA encoding ORF59-58 to nuclear foci that are associated with replication compartments. IMPORTANCE Late in the lytic phase, mRNAs from Kaposi's sarcoma-associated herpesvirus accumulate in the host cell nucleus near viral replication compartments, centers of viral DNA synthesis and virion production. This work contributes spatiotemporal data on herpesviral mRNAs within the lytic host cell and suggests a mechanism for viral RNA accumulation. Our findings indicate that the mechanism is independent of the host shutoff effect and splicing but dependent on active viral DNA synthesis and in part on the viral noncoding RNA, PAN RNA. PAN RNA is essential for the viral life cycle, and its contribution to the nuclear accumulation of viral messages may facilitate propagation of the virus. Copyright © 2018 American Society for Microbiology.

Effect of Tai Ji Quan training on self-reported sleep quality in elderly Chinese women with knee osteoarthritis: a randomized controlled trail.

PubMed

Lü, Jiaojiao; Huang, Lingyan; Wu, Xie; Fu, Weijie; Liu, Yu

2017-05-01

The purpose of this study was to explore the effects of a 24-week Tai Ji Quan training program on sleep quality, quality of life, and physical performance among elderly Chinese women with knee osteoarthritis (OA). A 24-week randomized, controlled trial of 46 elderly women with knee OA. Participants were randomly assigned to either a Tai Ji Quan group (n = 23) or a control group (n = 23). Participants in the Tai Ji Quan group completed training sessions three times per week, while those in the control group had bi-weekly educational classes. The primary outcome was total score of the Pittsburgh Sleep Quality of Index (PSQI). Secondary outcomes were: seven subscales of the PSQI; sleep latency; total sleep time; sleep efficiency; physical component summary (PCS) and mental component summary (MCS) of the 36-item Short Form Health Survey (SF-36); Berg Balance Scale (BBS); and Timed Up and Go (TUG). Compared with the control group, participants in the Tai Ji Quan group had significantly improved primary outcome (global PSQI score, p = 0.006) and secondary outcomes, including three PSQI sub-scores (sleep latency, p = 0.031; sleep duration, p = 0.043; daytime dysfunction, p = 0.007), total sleep time (p = 0.033), and SF-36 PCS (p = 0.006). The Tai Ji Quan group also had significant improvements compared with baseline in three PSQI sub-scores (sleep latency, p = 0.031; habitual sleep efficiency, p = 0.049; sleep disturbance, p = 0.016), sleep latency (p = 0.003), BBS (p = 0.001), and TUG (p = 0.006). Tai Ji Quan training is an effective treatment approach to improve sleep quality and quality of life in elderly Chinese women with knee OA. Chinese Clinical Trial Registry (June 16, 2013): ChiCTR-TRC-13003264. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibition deficit in the spatial tendency of the response in multiple-domain amnestic mild cognitive impairment. An event-related potential study

PubMed Central

Cespón, Jesús; Galdo-Álvarez, Santiago; Díaz, Fernando

2015-01-01

Longitudinal studies have shown that a high percentage of people with amnestic mild cognitive impairment (MCI) develop Alzheimer’s disease (AD). Prodromal AD is known to involve deficits in executive control processes. In the present study, we examined such deficits by recording EEG in 13 single-domain amnestic MCI (sdaMCI), 12 multiple-domain amnestic MCI (mdaMCI) and 18 healthy elderly (control group, CG) participants while they performed a Simon task. The Simon task demands deployment of executive processes because participants have to respond to non-spatial features of a lateralized stimulus and inhibit the more automatic spatial tendency of the response. We specifically focused on the negativity central contralateral (N2cc), an event-related potential (ERP) component related to brain activity that prevents the cross-talk between direction of spatial attention and manual response preparation. The reaction time (RT) was not significantly different among the three groups of participants. The percentage of errors (PE) was higher in mdaMCI than in CG and sdaMCI participants. In addition, N2cc latency was delayed in mdaMCI (i.e., delayed implementation of mechanisms for controlling the spatial tendency of the response). The N2cc latency clearly distinguished among mdaMCI and CG/sdaMCI participants (area under curve: 0.91). Longer N2cc was therefore associated with executive control deficits, which suggests that N2cc latency is a correlate of mdaMCI. PMID:25999853

SMAC: A soft MAC to reduce control overhead and latency in CDMA-based AMI networks

DOE PAGES

Garlapati, Shravan; Kuruganti, Teja; Buehrer, Michael R.; ...

2015-10-26

The utilization of state-of-the-art 3G cellular CDMA technologies in a utility owned AMI network results in a large amount of control traffic relative to data traffic, increases the average packet delay and hence are not an appropriate choice for smart grid distribution applications. Like the CDG, we consider a utility owned cellular like CDMA network for smart grid distribution applications and classify the distribution smart grid data as scheduled data and random data. Also, we propose SMAC protocol, which changes its mode of operation based on the type of the data being collected to reduce the data collection latency andmore » control overhead when compared to 3G cellular CDMA2000 MAC. The reduction in the data collection latency and control overhead aids in increasing the number of smart meters served by a base station within the periodic data collection interval, which further reduces the number of base stations needed by a utility or reduces the bandwidth needed to collect data from all the smart meters. The reduction in the number of base stations and/or the reduction in the data transmission bandwidth reduces the CAPital EXpenditure (CAPEX) and OPerational EXpenditure (OPEX) of the AMI network. Finally, the proposed SMAC protocol is analyzed using markov chain, analytical expressions for average throughput and average packet delay are derived, and simulation results are also provided to verify the analysis.« less

The influence of executive capacity on selective attention and subsequent processing

PubMed Central

Daffner, Kirk R.; Tarbi, Elise C.; Haring, Anna E.; Zhuravleva, Tatyana Y.; Sun, Xue; Rentz, Dorene M.; Holcomb, Phillip J.

2012-01-01

Recent investigations that suggest selective attention (SA) is dependent on top-down control mechanisms lead to the expectation that individuals with high executive capacity (EC) would exhibit more robust neural indices of SA. This prediction was tested by using event-related potentials (ERPs) to examine differences in markers of information processing across 25 subjects divided into two groups based on high vs. average EC, as defined by neuropsychological test scores. Subjects performed an experimental task requiring SA to a specified color. In contrast to expectation, individuals with high and average EC did not differ in the size of ERP indices of SA: the anterior Selection Positivity (SP) and posterior Selection Negativity (SN). However, there were substantial differences between groups in markers of subsequent processing, including the anterior N2 (a measure of attentional control) and the P3a (an index of the orienting of attention). EC predicted speed of processing at both early and late attentional stages. Individuals with lower EC exhibited prolonged SN, P3a, and P3b latencies. However, the delays in carrying out SA operations did not account for subsequent delays in decision making, or explain excessive orienting and reduced attentional control mechanisms in response to stimuli that should have been ignored. SN latency, P3 latency, and the size of the anterior N2 made independent contributions to the variance of EC. In summary, our findings suggest that current views regarding the relationship between top-down control mechanisms and SA may need refinement. PMID:22701415

C145 as a short-latency electrophysiological index of cognitive compensation in Alzheimer's disease

PubMed Central

Chapman, Robert M.; Porsteinsson, Anton P.; Gardner, Margaret N.; Mapstone, Mark; McCrary, John W.; Sandoval, Tiffany C.; Guillily, Maria D.; DeGrush, Elizabeth; Reilly, Lindsey A.

2012-01-01

Brain plasticity and cognitive compensation in the elderly are of increasing interest, and Alzheimer's disease (AD) offers an opportunity to elucidate how the brain may overcome damage. We provide neurophysiological evidence of a short-latency ERP component (C145) linked to stimulus relevancy that may reflect cognitive compensation in early-stage Alzheimer's disease (AD). Thirty-six subjects with early-stage, mild AD and 36 like-aged normal elderly (Controls) had their EEG recorded while performing our Number-Letter task, a cognitive/perceptual paradigm that manipulates stimulus relevancies. ERP components, including C145, were extracted from ERPs using Principal Components Analysis. C145 amplitudes and spatial distributions were compared among Controls, AD subjects with high performance on the Number-Letter task, and AD subjects with low performance. Compared to AD subjects, Control subjects showed enhanced C145 processing of visual stimuli in the occipital region where differential processing of relevant stimuli occurred. AD high performers recruited central brain areas in processing task relevancy. Controls and AD low performers did not show a significant task relevancy effect in these areas. We conclude that short-latency ERP components can detect electrophysiological differences in early-stage AD that reflect altered cognition. Differences in C145 amplitudes between AD and normal elderly groups regarding brain locations and types of task effects suggest compensatory mechanisms can occur in the AD brain to overcome loss of normal functionality, and this early compensation may have a profound effect on the cognitive efficiency of AD individuals. PMID:22886016

The parallel programming of voluntary and reflexive saccades.

PubMed

Walker, Robin; McSorley, Eugene

2006-06-01

A novel two-step paradigm was used to investigate the parallel programming of consecutive, stimulus-elicited ('reflexive') and endogenous ('voluntary') saccades. The mean latency of voluntary saccades, made following the first reflexive saccades in two-step conditions, was significantly reduced compared to that of voluntary saccades made in the single-step control trials. The latency of the first reflexive saccades was modulated by the requirement to make a second saccade: first saccade latency increased when a second voluntary saccade was required in the opposite direction to the first saccade, and decreased when a second saccade was required in the same direction as the first reflexive saccade. A second experiment confirmed the basic effect and also showed that a second reflexive saccade may be programmed in parallel with a first voluntary saccade. The results support the view that voluntary and reflexive saccades can be programmed in parallel on a common motor map.

Policy Driven Development: Flexible Policy Insertion for Large Scale Systems.

PubMed

Demchak, Barry; Krüger, Ingolf

2012-07-01

The success of a software system depends critically on how well it reflects and adapts to stakeholder requirements. Traditional development methods often frustrate stakeholders by creating long latencies between requirement articulation and system deployment, especially in large scale systems. One source of latency is the maintenance of policy decisions encoded directly into system workflows at development time, including those involving access control and feature set selection. We created the Policy Driven Development (PDD) methodology to address these development latencies by enabling the flexible injection of decision points into existing workflows at runtime , thus enabling policy composition that integrates requirements furnished by multiple, oblivious stakeholder groups. Using PDD, we designed and implemented a production cyberinfrastructure that demonstrates policy and workflow injection that quickly implements stakeholder requirements, including features not contemplated in the original system design. PDD provides a path to quickly and cost effectively evolve such applications over a long lifetime.

Innovative neurophysiological methods in itch research: long-latency evoked potentials after electrical and thermal stimulation in patients with atopic dermatitis.

PubMed

Yudina, Marina M; Toropina, Galina G; Lvov, Andrey; Gieler, Uwe

2011-10-01

The aim of this study was to examine the findings of innovative neurophysiological methods of itch research. Short-latency and pain-related somatosensory-evoked potentials after electrical stimulation, as well as long-latency evoked potentials after thermal stimulation were studied in 38 patients with atopic dermatitis (AD) and 26 healthy volunteers. Quantitative Sensory Testing of thermal perception was performed in 22 patients with AD from the main AD group and in 15 healthy volunteers. Brain hyperactivity to electrical stimuli, delayed thermal-evoked potentials and elevated thermal thresholds were revealed in patients with AD compared with healthy controls. The data indicate small nerve fibre dysfunction in patients with AD, which may contribute to the pathogenesis of AD and chronic itch. The study demonstrates objective approaches to assess the function of small nerve fibres in patients with chronic itch.

[Value of condensation and rarefaction click evoked action potential latency difference in the diagnosis of Meniere's disease].

PubMed

Wang, Z; Shao, X; Yan, W; Lin, H

2000-06-01

To study the value of condensation and rarefaction clicks evoked action potential (AP) latency difference (LD) in diagnosis of Meniere's disease. AP was recorded with ECochG in controls (50 ears) and patients with Meniere's disease(90 ears) and sensorineural hearing loss(SNHL) of other origins(60 ears). LD was calculated and analyzed. LD in patients with Meniere's disease was (0.30 +/- 0.15) ms, which was significantly larger than that of controls(0.18 +/- 0.07) ms and of patients with SNHL of other origins(0.20 +/- 0.10) ms (P < 0.01). In the group of Meniere's disease, LD in patients with the mild and moderate hearing impairment was larger than those with severe hearing loss(P < 0.01) and LD in patients with low tone or high tone auditory sensation curve was larger than those with flat auditory sensation curve(P < 0.01). Positive rate was 4/60(6.7%) in other SNHL patients and 58/90(64.0%) in Meniere's disease group respectively. The increase in condensation and rarefaction click evoked AP latency difference can be an objective parameter in diagnosis of Meniere's disease.

Selectivity of N170 for visual words in the right hemisphere: Evidence from single-trial analysis.

PubMed

Yang, Hang; Zhao, Jing; Gaspar, Carl M; Chen, Wei; Tan, Yufei; Weng, Xuchu

2017-08-01

Neuroimaging and neuropsychological studies have identified the involvement of the right posterior region in the processing of visual words. Interestingly, in contrast, ERP studies of the N170 typically demonstrate selectivity for words more strikingly over the left hemisphere. Why is right hemisphere selectivity for words during the N170 epoch typically not observed, despite the clear involvement of this region in word processing? One possibility is that amplitude differences measured on averaged ERPs in previous studies may have been obscured by variation in peak latency across trials. This study examined this possibility by using single-trial analysis. Results show that words evoked greater single-trial N170s than control stimuli in the right hemisphere. Additionally, we observed larger trial-to-trial variability on N170 peak latency for words as compared to control stimuli over the right hemisphere. Results demonstrate that, in contrast to much of the prior literature, the N170 can be selective to words over the right hemisphere. This discrepancy is explained in terms of variability in trial-to-trial peak latency for responses to words over the right hemisphere. © 2017 Society for Psychophysiological Research.

Human herpesvirus-8 (HHV-8) sero-detection and HIV association in Kaposi's sarcoma (KS), non-KS tumors and non-neoplastic conditions

PubMed Central

Mwakigonja, Amos R; Pyakurel, Pawan; Kokhaei, Parviz; Pak, Fatemeh; Lema, Leonard K; Kaaya, Ephata E; Biberfeld, Peter

2008-01-01

Background The association of the human herpesvirus-8/Kaposi's sarcoma (KS)-associated herpesvirus (HHV-8/KSHV) serology with various malignancies in Tanzania is not currently well established while previous studies were based on either PCR or immunofluorescence assays [IFA] but not with a sensitive enzyme-linked immunosorbent assay (ELISA). Selected archival diagnostic biopsies (n = 184) and sera from indigenous patients with KS (n = 120), non-KS tumors (n = 24) and non-neoplastic lesions (n = 40) at Muhimbili National Hospital (MNH), Tanzania, were evaluated by diagnostic histopathology, immunohistology [anti-HHV-8 latency-associated nuclear antigen (LANA)] and serology for HIV (ELISA) and HHV-8 (IFA and ELISA). Results About 66.3% (n = 122) cases including AIDS-associated Kaposi's sarcoma (AKS) (n = 93), reactive conditions (n = 28) and only one non-KS tumour were HIV positive. Endemic KS (EKS) patients were mostly males (96.3%, 26/27) who were less (69.9%, 65/93) predominant in AIDS-associated (AKS). A high (89%) percentage of patients with anti-HHV-8 antibodies was found in the cohort including the HIV positive (92%) cases, males (81.2%), KS patients (93%), non-KS tumors (92%), and reactive conditions (75%). All HHV-8 seronegative KS cases were nodular stage whereas both sera and corresponding biopsies from early stage KS were HHV-8+. Assay sensitivity, positive predictive value (PPV) and specificity were 98.6%, 93.5% and 16.7% for IFA and 93.5%, 98.6% and 50.0% for ELISA respectively. Conclusion HHV-8 seroprevalence at MNH appears high as expected among AKS cases and males but also in non-KS patients. ELISA showed a combination of high HHV-8 sensitivity as well as higher PPV and specificity than IFA which however, showed higher sensitivity. The apparent stage-dependent, inverted serum HHV-8 immunoreactivity supports a notion of viral immune-segregation during KS development. Routine HHV-8 screening should be considered particularly in patients at risk of KS and for selection of blood/organ donations. PMID:18590556

An M2 Rather than a TH2 Response Contributes to Better Protection against Latency Reactivation following Ocular Infection of Naive Mice with a Recombinant Herpes Simplex Virus 1 Expressing Murine Interleukin-4.

PubMed

Lee, Dhong Hyun; Ghiasi, Homayon

2018-05-15

We found previously that altering macrophage polarization toward M2 responses by injection of colony-stimulating factor 1 (CSF-1) was more effective in reducing both primary and latent infections in mice ocularly infected with herpes simplex virus 1 (HSV-1) than M1 polarization by gamma interferon (IFN-γ) injection. Cytokines can coordinately regulate macrophage and T helper (T H ) responses, with interleukin-4 (IL-4) inducing type 2 T H (T H 2) as well as M2 responses and IFN-γ inducing T H 1 as well as M1 responses. We have now differentiated the contributions of these immune compartments to protection against latency reactivation and corneal scarring by comparing the effects of infection with recombinant HSV-1 in which the latency-associated transcript (LAT) gene was replaced with either the IL-4 (HSV-IL-4) or IFN-γ (HSV-IFN-γ) gene using infection with the parental (LAT-negative) virus as a control. Analysis of peritoneal macrophages in vitro established that the replacement of LAT with the IL-4 or IFN-γ gene did not affect virus infectivity and promoted polarization appropriately. Protection against corneal scarring was significantly higher in mice ocularly infected with HSV-IL-4 than in those infected with HSV-IFN-γ or parental virus. Levels of primary virus replication in the eyes and trigeminal ganglia (TG) were similar in the three groups of mice, but the numbers of gC + cells were lower on day 5 postinfection in the eyes of HSV-IL-4-infected mice than in those infected with HSV-IFN-γ or parental virus. Latency and explant reactivation were lower in both HSV-IL-4- and HSV-IFN-γ-infected mice than in those infected with parental virus, with the lowest level of latency being associated with HSV-IL-4 infection. Higher latency correlated with higher levels of CD8, PD-1, and IFN-γ mRNA, while reduced latency and T-cell exhaustion correlated with lower gC + expression in the TG. Depletion of macrophages increased the levels of latency in all ocularly infected mice compared with their undepleted counterparts, with macrophage depletion increasing latency in the HSV-IL-4 group greater than 3,000-fold. Our results suggest that shifting the innate macrophage immune responses toward M2, rather than M1, responses in HSV-1 infection would improve protection against establishment of latency, reactivation, and eye disease. IMPORTANCE Ocular HSV-1 infections are among the most frequent serious viral eye infections in the United States and a major cause of virus-induced blindness. As establishment of a latent infection in the trigeminal ganglia results in recurrent infection and is associated with corneal scarring, prevention of latency reactivation is a major therapeutic goal. It is well established that absence of latency-associated transcripts (LATs) reduces latency reactivation. Here we demonstrate that recombinant HSV-1 expressing IL-4 (an inducer of T H 2/M2 responses) or IFN-γ (an inducer of T H 1/M1 responses) in place of LAT further reduced latency, with HSV-IL-4 showing the highest overall protective efficacy. In naive mice, this higher protective efficacy was mediated by innate rather than adaptive immune responses. Although both M1 and M2 macrophage responses were protective, shifting macrophages toward an M2 response through expression of IL-4 was more effective in curtailing ocular HSV-1 latency reactivation. Copyright © 2018 American Society for Microbiology.

The value of P300 event related potentials in the assessment of cognitive function in subclinical hypothyroidism.

PubMed

Dejanović, Mirjana; Ivetić, Vesna; Nestorović, Vojkan; Milanović, Zvezdan; Erić, Mirela

2017-03-01

Mild hypothyroidism (thyroid stimulating hormone [TSH] less than 10 mIU/L) induces reversible cognitive dysfunction, which can be evaluated by event related potentials (ERP). So far, only little is known about the impact of subclinical hypothyroidism on ERP as electrophysiological markers of cognitive activity. The aim of this study was to follow-up P300 latencies and amplitudes in patients with subclinical hypothyroidism and to evaluate the influence of thyroxine treatment which led to the normalization of TSH level in serum. We recorded the P300 wave using an auditory oddball paradigm in 60 patients (mean age 51.1±6.2 years, range 40-62 years), with subclinical hypothyroidism (normal mean value of FT4, with elevated TSH levels) at baseline, after 3 months, after 6 months and in 30 healthy control subjects. 30 patients treated six months with L-thyroxine until the normalization of TSH and 30 patients received placebo. The P300 latencies in patients with subclinical hypothyroidism were significantly longer, and the P300 amplitudes were significantly smaller than those of the control group. In the thyroxine treated patients P300 latency continuously decreased over the observation period with a significant difference after 6 months compared to baseline (P<0.01). The amplitude P300 showed no significant changes over time. Our results show the importance of P300 event related potentials in the detection of cognitive changes in patients with hypothyroidism. The P300 latency stands out as a marker for cognitive function recovery during treatment with thyroxine.

Evaluation of multifocal visual evoked potentials in patients with Graves' orbitopathy and subclinical optic nerve involvement.

PubMed

Pérez-Rico, Consuelo; Rodríguez-González, Natividad; Arévalo-Serrano, Juan; Blanco, Román

2012-08-01

Dysthyroid optic neuropathy is the most serious, although infrequent (8-10 %) complication in Graves' orbitopathy (GO). It is known that early stages of compressive optic neuropathy may produce reversible visual field defects, suggesting axoplasmic stasis rather than ganglion cell death. This observational, cross-sectional, case-control study assessed 34 consecutive patients (65 eyes) with Graves' hyperthyroidism and longstanding GO and 31 age-matched control subjects. The patients' multifocal visual evoked potentials (mfVEP) were compared to their clinical and psychophysical (standard automated perimetry [SAP]) and structural (optic coherence tomography [OCT]) diagnostic test data. Abnormal cluster defects were found in 12.3 % and 3.1 % of eyes on the interocular and monocular amplitude analysis mfVEP probability plots, respectively. As well, mfVEP latencies delays were found in 13.8 and 20 % of eyes on the interocular and monocular analysis probability plots, respectively. Interestingly, 19 % of patients with GO had ocular hypertension, and a strong correlation between intraocular pressure measured at upgaze and mfVEP latency was found. MfVEP amplitudes and visual acuity were significantly related to each other (P < 0.05), but not with the latencies delays. However, relationships between the interocular or monocular mfVEP amplitudes and latencies analysis and SAP indices or OCT data were not statistically significant. One-third of our patients with GO showed changes in the mfVEP, indicating significant subclinical optic nerve dysfunction. In this sense, the mfVEP may be a useful diagnostic tool in the clinic for early diagnosis and monitoring of optic nerve function abnormalities in patients with GO.

Altered cortical excitability in anorexia nervosa.

PubMed

Khedr, E M; El Fetoh, N A; El Bieh, E; Ali, A M; Karim, A A

2014-09-01

Recent EEG and positron emission tomography (PET) studies have reported hyperactivation of the right hemisphere in anorexia nervosa (AN). The aim of the present study was to test this notion by examining cortical excitability in subjects with AN using transcranial magnetic stimulation (TMS). We investigated thirteen patients meeting the DSM IV diagnostic criteria for AN and 14 controls age and sex matched. Each subject was assessed clinically using the Eating Disorder Inventory (EDI), the Eating Attitude Test (EAT) and Beck's Depression Inventory (BDI-II). TMS measures involved resting and active motor thresholds (RMT, AMT) as well as motor evoked potentials (MEP), cortical silent period duration (CSP), transcallosal inhibition (TCI), and short latency intracortical inhibition (SICI) of the first dorsal interosseous muscle (FDI) were assessed. Cortical esophageal MEP latencies (CL) were also recorded. The RMT and MEP onset latency of the FDI and the esophagus as well as duration of the TCI were significantly reduced in anorexic patients compared to the control group. There were no significant differences neither in AMT nor CSP between patients and controls. Moreover, we found significant negative correlations between the EAT scores and RMT, and TCI duration. Although anorexic patients had significantly higher BDI score, there was no correlation between it and cortical excitability. Anorexic individuals are characterized by pathologically increased motor and esophageal cortical excitability that significantly correlates with clinical symptoms of anorexia nervosa. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Cerebellar Structure and Function in Male Wistar-Kyoto Hyperactive Rats

PubMed Central

Thanellou, Alexandra; Green, John T.

2014-01-01

Previous research has suggested that the Wistar-Kyoto Hyperactive (WKHA) rat strain may model some of the behavioral features associated with attention-deficit/hyperactivity disorder (ADHD). We have shown that, in cerebellar-dependent eyeblink conditioning, WKHA emit eyeblink CRs with shortened onset latencies. To further characterize the shortened CR onset latencies seen in WKHA rats, we examined 750-ms delay conditioning with either a tone CS or a light CS, we extended acquisition training, and we included Wistar rats as an additional, outbred control strain. Our results indicated that WKHAs learned more quickly and showed a shortened CR onset latency to a tone CS compared to both Wistar-Kyoto Hypertensive (WKHT) and Wistars. WKHAs and Wistars show a lengthening of CR onset latency over conditioning with a tone CS and an increasing confinement of CRs to the later part of the tone CS (inhibition of delay). WKHAs learned more quickly to a light CS only in comparison to WKHTs and showed a shortened CR onset latency only in comparison to Wistars. Wistars showed an increasing confinement of CRs to the late part of the light CS over conditioning. We used unbiased stereology to estimate the number of Purkinje and granule cells in the cerebellar cortex of the three strains. Our results indicated that WKHAs have more granule cells than Wistars and WKHTs and more Purkinje cells than Wistars. Results are discussed in terms of CS processing and cerebellar cortical contributions to EBC. PMID:23398437

Decreased reactivation of a herpes simplex virus type 1 (HSV-1) latency associated transcript (LAT) mutant using the in vivo mouse UV-B model of induced reactivation

PubMed Central

BenMohamed, Lbachir; Osorio, Nelson; Srivastava, Ruchi; Khan, Arif A.; Simpson, Jennifer L.; Wechsler, Steven L.

2015-01-01

Blinding ocular herpetic disease in humans is due to herpes simplex virus type 1 (HSV-1) reactivations from latency, rather than to primary acute infection. The cellular and molecular mechanisms that control the HSV-1 latency-reactivation cycle remain to be fully elucidated. The aim of this study was to determine if reactivation of the HSV-1 latency associated transcript (LAT) deletion mutant (dLAT2903) was impaired in this model, as it is in the rabbit model of induced and spontaneous reactivation and in the explant TG induced reactivation model in mice. The eyes of mice latently infected with wild type HSV-1 strain McKrae (LAT(+) virus) or dLAT2903 (LAT(−) virus) were irradiated with UV-B and reactivation was determined. We found that compared to LAT(−) virus, LAT(+) virus reactivated at a higher rate as determined by shedding of virus in tears on days 3 to 7 after UV-B treatment. Thus, the UV-B induced reactivation model of HSV-1 appears to be a useful small animal model for studying the mechanisms involved in how LAT enhances the HSV-1 reactivation phenotype. The utility of the model for investigating the immune evasion mechanisms regulating the HSV-1 latency/reactivation cycle and for testing the protective efficacy of candidate therapeutic vaccines and drugs are discussed. PMID:26002839

Auditory middle latency response in children with learning difficulties.

PubMed

Frizzo, Ana Claudia Figueiredo; Issac, Myriam Lima; Pontes-Fernandes, Angela Cristina; Menezes, Pedro de Lemos; Funayama, Carolina Araújo Rodrigues

2012-07-01

 This is an objective laboratory assessment of the central auditory systems of children with learning disabilities.  To examine and determine the properties of the components of the Auditory Middle Latency Response in a sample of children with learning disabilities.  This was a prospective, cross-sectional cohort study with quantitative, descriptive, and exploratory outcomes. We included 50 children aged 8-13 years of both genders with and without learning disorders. Those with disorders of known organic, environmental, or genetic causes were excluded.  The Na, Pa, and Nb waves were identified in all subjects. The ranges of the latency component values were as follows: Na = 9.8-32.3 ms, Pa = 19.0-51.4 ms, Nb = 30.0-64.3 ms (learning disorders group) and Na = 13.2-29.6 ms, Pa = 21.8-42.8 ms, Nb = 28.4-65.8 ms (healthy group). The values of the Na-Pa amplitude ranged from 0.3 to 6.8 ìV (learning disorders group) or 0.2-3.6 ìV (learning disorders group). Upon analysis, the functional characteristics of the groups were distinct: the left hemisphere Nb latency was longer in the study group than in the control group. Peculiarities of the electrophysiological measures were observed in the children with learning disorders. This study has provided information on the Auditory Middle Latency Response and can serve as a reference for other clinical and experimental studies in children with these disorders.

Electrophysiological analysis of pathways connecting the medial preoptic area with the mesencephalic central grey matter in rats.

PubMed

MacLeod, N K; Mayer, M L

1980-01-01

1. An electrophysiological study of ascending and descending connexions between the dorsal raphe region of the mesencephalic periaqueductal grey matter and the medial preoptic area has been performed in dioestrous female rats anaesthetized with urethane. 2. Extracellular action potentials recorded from 208 neurones in the medial preoptic area were analysed for a change in excitability following stimulation of the periaqueductal grey matter. 174 neurones were also tested for changes in excitability following stimulation of the mediobasal hypothalamus. 3. Stimulation of the periaqueductal grey matter at 1 Hz was rarely effective, but short trains of pulses (three at 100 Hz) usually caused an initial inhibition (62.5% of 208) of both projection identified and adjacent neurones of the medial preoptic area, at latencies of 5--90 msec (mean 34.1 +/- 1.4 msec). Inhibition following stimulation of the mediobasal hypothalamus occurred less frequently (34%) and at shorter latency (mean 12.0 +/- 1.8 msec; n = 48). 4. Less frequently (10.6%) periaqueductal grey matter stimulation caused an initial excitation of preoptic neurones at latencies of 15--180 msec, (mean 35.3 +/- 7.2). Initial excitation following mediobasal hypothalamus stimulation was stronger, occurred more frequently (29%) and at shorter latencies (range 3--60 msec, mean 13.1 +/- 1.5). Following such initial excitation, inhibition of spontaneous or ionophoretically evoked activity occurred more frequently following mediobasal hypothalamic stimulation, than after periaqueductal grey matter stimulation. 5. Twenty-four neurones displayed antidromic invasion following periaqueductal grey matter stimulation. Latencies for invasion ranged from 13 to 50 msec (mean 25.5 +/- 2.0 msec) and are suggestive of an unmyelinated projection. Occasionally an abrupt decrease in latency followed an increase in stimulus intensity. Antidromic invasion from mediobasal hypothalamus was characterized by a shorter latency (mean 12.5 +/- 0.7 msec; n = 43). A period of reduced excitability lasting 40--100 msec followed antidromic invasion from either site. 6. Antidromic responses to paired mediobasal hypothalamic or periaqueductal grey matter stimuli at 5 msec intervals revealed an increased latency of invasion of the second response, due to the partial refractory period of the neurone. Five cells showed a decreased latency of invasion at stimulus separations of 10--150 msec, interpreted as evidence of a supranormal period. Changes in conduction velocity during the supranormal period may give rise to a variable latency of invasion of spontaneously active cells. 7. These results provide evidence for direct, reciprocal connexions between the midbrain central grey and the medial preoptic area. These circuits may play a role in controlling neuroendocrine and behavioural aspects of reproductive functions.

NEEMO 18-20: Analog Testing for Mitigation of Communication Latency During Human Space Exploration

NASA Technical Reports Server (NTRS)

Chappell, Steven P.; Beaton, Kara H.; Miller, Matthew J.; Graff, Trevor G.; Abercromby, Andrew F. J.; Gernhardt, Michael L.; Halcon, Christopher

2016-01-01

NASA Extreme Environment Mission Operations (NEEMO) is an underwater spaceflight analog that allows a true mission-like operational environment and uses buoyancy effects and added weight to simulate different gravity levels. Three missions were undertaken from 2014-2015, NEEMO's 18-20. All missions were performed at the Aquarius undersea research habitat. During each mission, the effects of communication latencies on operations concepts, timelines, and tasks were studied. METHODS: Twelve subjects (4 per mission) were weighed out to simulate near-zero or partial gravity extravehicular activity (EVA) and evaluated different operations concepts for integration and management of a simulated Earth-based science team (ST) to provide input and direction during exploration activities. Exploration traverses were preplanned based on precursor data. Subjects completed science-related tasks including pre-sampling surveys, geologic-based sampling, and marine-based sampling as a portion of their tasks on saturation dives up to 4 hours in duration that were designed to simulate extravehicular activity (EVA) on Mars or the moons of Mars. One-way communication latencies, 5 and 10 minutes between space and mission control, were simulated throughout the missions. Objective data included task completion times, total EVA times, crew idle time, translation time, ST assimilation time (defined as time available for ST to discuss data/imagery after data acquisition). Subjective data included acceptability, simulation quality, capability assessment ratings, and comments. RESULTS: Precursor data can be used effectively to plan and execute exploration traverse EVAs (plans included detailed location of science sites, high-fidelity imagery of the sites, and directions to landmarks of interest within a site). Operations concepts that allow for pre-sampling surveys enable efficient traverse execution and meaningful Mission Control Center (MCC) interaction across communication latencies and can be done with minimal crew idle time. Imagery and contextual information from the EVA crew that is transmitted real-time to the intravehicular (IV) crewmember(s) can be used to verify that exploration traverse plans are being executed correctly. That same data can be effectively used by MCC (across comm latency) to provide meaningful feedback and instruction to the crew regarding sampling priorities, additional tasks, and changes to the EVA timeline. Text / data capabilities are preferred over voice capabilities between MCC and IV when executing exploration traverse plans over communication latency.

Auditory Brainstem and Middle Latency Responses Measured Pre- and Posttreatment for Hyperacusic Hearing-Impaired Persons Successfully Treated to Improve Sound Tolerance and to Expand the Dynamic Range for Loudness: Case Evidence.

PubMed

Formby, Craig; Korczak, Peggy; Sherlock, LaGuinn P; Hawley, Monica L; Gold, Susan

2017-02-01

In this report of three cases, we consider electrophysiologic measures from three hyperacusic hearing-impaired individuals who, prior to treatment to expand their dynamic ranges for loudness, were problematic hearing aid candidates because of their diminished sound tolerance and reduced dynamic ranges. Two of these individuals were treated with structured counseling combined with low-level broadband sound therapy from bilateral sound generators and the third case received structured counseling in combination with a short-acting placebo sound therapy. Each individual was highly responsive to his or her assigned treatment as revealed by expansion of the dynamic range by at least 20 dB at one or more frequencies posttreatment. Of specific interest in this report are their latency and amplitude measures taken from tone burst-evoked auditory brainstem response (ABR) and cortically derived middle latency response (MLR) recordings, measured as a function of increasing loudness at 500 and 2,000 Hz pre- and posttreatment. The resulting ABR and MLR latency and amplitude measures for each case are considered here in terms of pre- and posttreatment predictions. The respective pre- and posttreatment predictions anticipated larger pretreatment response amplitudes and shorter pretreatment response latencies relative to typical normal control values and smaller normative-like posttreatment response amplitudes and longer posttreatment response latencies relative to the corresponding pretreatment values for each individual. From these results and predictions, we conjecture about the neural origins of the hyperacusis conditions (i.e., brainstem versus cortical) and the neuronal sites responsive to treatment. The only consistent finding in support of the pre- and posttreatment predictions and, thus, the strongest index of hyperacusis and positive treatment-related effects was measured for MLR latency responses for wave Pa at 2,000 Hz. Other response indices, including ABR wave V latency and wave V-V' amplitude and MLR wave Na-Pa amplitude for 500 and 2,000 Hz, appear either ambiguous across and/or within these individuals. Notwithstanding significant challenges for interpreting these findings, including associated confounding effects of their sensorineural hearing losses and differences in the presentation levels of the toneburst stimuli used to collect these measures for each individual, our limited analyses of three cases suggest measures of MLR wave Pa latency at 2,000 Hz (reflecting cortical contributions) may be a promising objective indicator of hyperacusis and dynamic range expansion treatment effects.

Disrupted Executive Function and Aggression in Individuals With a History of Adverse Childhood Experiences: An Event-Related Potential Study.

PubMed

Xue, Jiao-Mei; Lin, Ping-Zhen; Sun, Ji-Wei; Cao, Feng-Lin

2017-12-01

Here, we explored the functional and neural mechanisms underlying aggression related to adverse childhood experiences. We assessed behavioral performance and event-related potentials during a go/no-go and N-back paradigm. The participants were 15 individuals with adverse childhood experiences and high aggression (ACE + HA), 13 individuals with high aggression (HA), and 14 individuals with low aggression and no adverse childhood experiences (control group). The P2 latency (initial perceptual processing) was longer in the ACE + HA group for the go trials. The HA group had a larger N2 (response inhibition) than controls for the no-go trials. Error-related negativity (error processing) in the ACE + HA and HA groups was smaller than that of controls for false alarm go trials. Lastly, the ACE + HA group had shorter error-related negativity latencies than controls for false alarm trials. Overall, our results reveal the neural correlates of executive function in aggressive individuals with ACEs.

Validation of a Behavioral Approach for Measuring Saccades in Parkinson's Disease.

PubMed

Turner, Travis H; Renfroe, Jenna B; Duppstadt-Delambo, Amy; Hinson, Vanessa K

2017-01-01

Speed and control of saccades are related to disease progression and cognitive functioning in Parkinson's disease (PD). Traditional eye-tracking complexities encumber application for individual evaluations and clinical trials. The authors examined psychometric properties of standalone tasks for reflexive prosaccade latency, volitional saccade initiation, and saccade inhibition (antisaccade) in a heterogeneous sample of 65 PD patients. Demographics had minimal impact on task performance. Thirty-day test-retest reliability estimates for behavioral tasks were acceptable and similar to traditional eye tracking. Behavioral tasks demonstrated concurrent validity with traditional eye-tracking measures; discriminant validity was less clear. Saccade initiation and inhibition discriminated PD patients with cognitive impairment. The present findings support further development and use of the behavioral tasks for assessing latency and control of saccades in PD.

Consistent latencies of vestibular evoked myogenic potentials.

PubMed

Wang, Shou-Jen; Yeh, Te-Huei; Chang, Chun-Hsiang; Young, Yi-Ho

2008-12-01

This study investigated the association between neck length and vestibular evoked myogenic potential (VEMP) latencies in healthy children, adolescents, and adults to elucidate when VEMP latencies reach consistent levels. Findings of VEMP tests in 14 healthy children, seven healthy adolescents, and 14 healthy adults were analyzed for correlations with neck length, which was measured as the distance of a line dropping vertically from the mastoid tip to the horizontal plane passing through the clavicle. All healthy children, adolescents, and adults exhibited present VEMP responses. Children, adolescents, and adults significantly differed in p13 latency, n23 latency, and p13-n23 interval. According to receiver operating characteristic curve analysis, the optimal cutoff values of p13 and n23 latencies between children and adults were 12.6 and 19.8 msec, respectively. Because the odds ratio of p13 latency was less than that of n23 latency, n23 latency was used to discriminate VEMP latencies between children and adults. Accordingly, a cutoff value of 15.3 cm for neck length was proposed as a criterion for predicting VEMP latency within the adult range. Consequently, a positive correlation between neck length and VEMP latency was observed when neck length was <15.3 cm, while above which level one need not account for neck length in evaluating VEMP latency. The intra-subject variability of norms can be enhanced if the normative data for VEMP characteristic parameters take structural variance into account. This study suggests that the adult range of VEMP latencies can be anticipated if neck length is >15.3 cm.

Effects of D-004, a lipid extract of the fruit of the Cuban royal palm (Roystonea regia) or the lipidosterolic extract of saw palmetto (Serenoa repens) on the sexual activity in male rats: A controlled, experimental study

PubMed Central

Fernández, Lilia C.; Mas, Rosa; Fernández, Julio; Mendoza, Sarahí; Gámez, Rafael; Pardo, Balia

2008-01-01

Background: The etiology of benign prostatic hyperplasia (BPH) is not completely understood, but hormonal changes in aging men seem to be pivotal. Dihydrotestosterone, a potent, active metabolite of testosterone, is formed by the enzymatic action of prostate 5α-reductase and causes cell growth and hyperplasia. Consistent with this action, male sexual dysfunction has been clinically documented to be among the drug-related adverse events associated with 5α-reductase inhibitors. The lipidosterolic extract of saw palmetto (LESP) fruit (Serenoa repens) has been used to treat BPH. D-004, a lipid extract of Roystonea regia Royal palm fruit, has been found to prevent prostatic hyperplasia induced by testoste-rone in rodents and to competitively inhibit prostate 5α-reductase activity in vitro. Objective: The purpose of this study was to assess the effects of D-004 and LESP, administered as single or repeated doses, on the sexual activity in male rats. Methods: This controlled, experimental study was conducted at the Pharmacology Department, Centre of Natural Products, National Centre for Scientific Research, Havana City, Cuba. Adult male Wistar rats weighing 250 to 300 g were randomized into 5 groups: 2 groups treated orally with D-004 (400 and 800 mg/kg); 2 groups treated orally with LESP (400 and 800 mg/kg); and 1 control group orally administered a water vehicle. Sexual activity behavior (the number of mounts and intromissions, mount latency, and intromission latency) was assessed during 2 observation periods: 90 minutes after the initial dose and at the end of the 30-day treatment. Latency was defined as time elapsed between the first mount and intromission. Results: A total of 50 rats (mean [SD] age, 10 [3] weeks; mean [SD] weight, 295 [10] g) were included in the experiment. There were no significant difterences in the mean number of mounts, intromissions, mount latency, or intromission latency in the groups treated with single or repeated doses of D-004 or LESP (400 and 800 mg/kg) compared with the controls. There was also no between-group difterence in mating behavior among the active treatment groups. All rats survived up to study completion, with normal behavior (weight gain, food intake, daily observations, without any sign of toxicity). There were no observable adverse events during the study. Conclusions: D-004 and LESP administered as a single dose or repeated doses for 30 days did not significantly affect male rat sexual activity behavior compared with a vehicle control group. PMID:24692784

LCTS on ALPHASAT and Sentinel 1a: in orbit status of the LEO to geo data relay system

NASA Astrophysics Data System (ADS)

Zech, H.; Heine, F.; Troendle, D.; Pimentel, P. M.; Panzlaff, K.; Motzigemba, M.; Meyer, R.; Philipp-May, S.

2017-11-01

The performance of sensors for Earth Observation Missions is constantly improving. This drives the need for a reliable, high-speed data transfer capability from a Low Earth Orbit (LEO) spacecraft (S/C) to ground. In addition, for the transfer of time-critical data to ground, a low latency between data generation in orbit and data reception at the respective mission control center is of high importance. Laser communication between Satellites for high data transmission in combination with a GEO data relay system for reducing the latency time addresses these requirements.

Reflex muscle contraction in anterior shoulder instability.

PubMed

Wallace, D A; Beard, D J; Gill, R H; Eng, B; Carr, A J

1997-01-01

Reduced proprioception may contribute to recurrent anterior shoulder instability. Twelve patients with unilateral shoulder instability were investigated for evidence of deficient proprioception with an activated pneumatic cylinder and surface electromyography electrodes; the contralateral normal shoulder was used as a control. The latency between onset of movement and the detection of muscle contraction was used as an index of proprioception. No significant difference in muscle contraction latency was detected between the stable and unstable shoulders, suggesting that there was no significant defect in muscular reflex activity. This study does not support the use proprioception-enhancing physiotherapy in the treatment of posttraumatic anterior shoulder instability.

Topography of sound level representation in the FM sweep selective region of the pallid bat auditory cortex.

PubMed

Measor, Kevin; Yarrow, Stuart; Razak, Khaleel A

2018-05-26

Sound level processing is a fundamental function of the auditory system. To determine how the cortex represents sound level, it is important to quantify how changes in level alter the spatiotemporal structure of cortical ensemble activity. This is particularly true for echolocating bats that have control over, and often rapidly adjust, call level to actively change echo level. To understand how cortical activity may change with sound level, here we mapped response rate and latency changes with sound level in the auditory cortex of the pallid bat. The pallid bat uses a 60-30 kHz downward frequency modulated (FM) sweep for echolocation. Neurons tuned to frequencies between 30 and 70 kHz in the auditory cortex are selective for the properties of FM sweeps used in echolocation forming the FM sweep selective region (FMSR). The FMSR is strongly selective for sound level between 30 and 50 dB SPL. Here we mapped the topography of level selectivity in the FMSR using downward FM sweeps and show that neurons with more monotonic rate level functions are located in caudomedial regions of the FMSR overlapping with high frequency (50-60 kHz) neurons. Non-monotonic neurons dominate the FMSR, and are distributed across the entire region, but there is no evidence for amplitopy. We also examined how first spike latency of FMSR neurons change with sound level. The majority of FMSR neurons exhibit paradoxical latency shift wherein the latency increases with sound level. Moreover, neurons with paradoxical latency shifts are more strongly level selective and are tuned to lower sound level than neurons in which latencies decrease with level. These data indicate a clustered arrangement of neurons according to monotonicity, with no strong evidence for finer scale topography, in the FMSR. The latency analysis suggests mechanisms for strong level selectivity that is based on relative timing of excitatory and inhibitory inputs. Taken together, these data suggest how the spatiotemporal spread of cortical activity may represent sound level. Copyright © 2018. Published by Elsevier B.V.

Latent iron deficiency at birth influences auditory neural maturation in late preterm and term infants.

PubMed

Choudhury, Vivek; Amin, Sanjiv B; Agarwal, Asha; Srivastava, L M; Soni, Arun; Saluja, Satish

2015-11-01

In utero latent iron deficiency has been associated with abnormal neurodevelopmental outcomes during childhood. Its concomitant effect on auditory neural maturation has not been well studied in late preterm and term infants. The objective was to determine whether in utero iron status is associated with auditory neural maturation in late preterm and term infants. This prospective cohort study was performed at Sir Ganga Ram Hospital, New Delhi, India. Infants with a gestational age ≥34 wk were eligible unless they met the exclusion criteria: craniofacial anomalies, chromosomal disorders, hemolytic disease, multiple gestation, third-trimester maternal infection, chorioamnionitis, toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex virus infections (TORCH), Apgar score <5 at 5 min, sepsis, cord blood not collected, or auditory evaluation unable to be performed. Sixty consecutive infants with risk factors for iron deficiency, such as small for gestational age and maternal diabetes, and 30 without risk factors for iron deficiency were enrolled. Absolute wave latencies and interpeak latencies, evaluated by auditory brainstem response within 48 h after birth, were measured and compared between infants with latent iron deficiency (serum ferritin ≤75 ng/mL) and infants with normal iron status (serum ferritin >75 ng/mL) at birth. Twenty-three infants had latent iron deficiency. Infants with latent iron deficiency had significantly prolonged wave V latencies (7.10 ± 0.68 compared with 6.60 ± 0.66), III-V interpeak latencies (2.37 ± 0.64 compared with 2.07 ± 0.33), and I-V interpeak latencies (5.10 ± 0.57 compared with 4.72 ± 0.56) compared with infants with normal iron status (P < 0.05). This difference remained significant on regression analyses after control for confounders. No difference was noted between latencies I and III and interpeak latencies I-III. Latent iron deficiency is associated with abnormal auditory neural maturation in infants at ≥34 wk gestational age. This trial was registered at clinicaltrials.gov as NCT02503397. © 2015 American Society for Nutrition.

Perceived ejaculatory latency and pleasure in different outlets.

PubMed

Corty, Eric W

2008-11-01

Ejaculatory latencies have been studied in coitus and with masturbation, but not with oral or manual stimulation by a partner. The present study extended research on ejaculatory latency to these outlets, and investigated the effect of perceived pleasure on self-reported ejaculatory latency. A convenience sample of male college students, not selected for sexual dysfunction, completed questionnaires assessing the outcome measures. Self-report measures of latency to ejaculation in, and perceived pleasure associated with, four different outlets (vaginal intercourse, oral intercourse, manual stimulation by a partner, and masturbation). Ejaculatory latencies in partnered activities were predictive of each other. Masturbatory latencies were predictive of coital latencies but not oral or manual stimulation latencies; all the partnered activities were predictive of each other. There was no difference in time to ejaculation among any of the partnered outlets, although ejaculation occurred more quickly with masturbation than with coitus or manual stimulation. In terms of pleasure associated with the outlets, vaginal and oral intercourse were perceived as equally pleasurable, and both were rated as more pleasurable than manual stimulation or masturbation, which did not differ from each other. These results suggest that rapidity of ejaculation is consistent across outlets for the partnered sexual activities, and that there is little unique-in terms of ejaculatory latency--about vaginal intercourse compared with oral or manual stimulation by a partner. Masturbation, however, does differ from the partnered activities. Although the average correlation, for individuals, between latency and pleasure for the different outlets is near zero, there are subgroups of men who have (i) a negative relation, (ii) a positive relation, or (iii) no relation. Results show that men, for whom greater pleasure is associated with shorter latency, are more likely to be dissatisfied with their intravaginal ejaculatory latencies, regardless of actual latency.

Group II muscle afferents probably contribute to the medium latency soleus stretch reflex during walking in humans

PubMed Central

Grey, Michael J; Ladouceur, Michel; Andersen, Jacob B; Nielsen, Jens Bo; Sinkjær, Thomas

2001-01-01

The objective of this study was to determine which afferents contribute to the medium latency response of the soleus stretch reflex resulting from an unexpected perturbation during human walking. Fourteen healthy subjects walked on a treadmill at approximately 3.5 km h−1 with the left ankle attached to a portable stretching device. The soleus stretch reflex was elicited by applying small amplitude (∼8 deg) dorsiflexion perturbations 200 ms after heel contact. Short and medium latency responses were observed with latencies of 55 ± 5 and 78 ± 6 ms, respectively. The short latency response was velocity sensitive (P < 0.001), while the medium latency response was not (P = 0.725). Nerve cooling increased the delay of the medium latency component to a greater extent than that of the short latency component (P < 0.005). Ischaemia strongly decreased the short latency component (P = 0.004), whereas the medium latency component was unchanged (P = 0.437). Two hours after the ingestion of tizanidine, an α2-adrenergic receptor agonist known to selectively depress the transmission in the group II afferent pathway, the medium latency reflex was strongly depressed (P = 0.007), whereas the short latency component was unchanged (P = 0.653). An ankle block with lidocaine hydrochloride was performed to suppress the cutaneous afferents of the foot and ankle. Neither the short (P = 0.453) nor medium (P = 0.310) latency reflexes were changed. Our results support the hypothesis that, during walking the medium latency component of the stretch reflex resulting from an unexpected perturbation is contributed to by group II muscle afferents. PMID:11483721

Arm Dominance Affects Feedforward Strategy more than Feedback Sensitivity during a Postural Task

PubMed Central

Walker, Elise H. E.; Perreault, Eric J.

2015-01-01

Handedness is a feature of human motor control that is still not fully understood. Recent work has demonstrated that the dominant and nondominant arm each excel at different behaviors, and has proposed that this behavioral asymmetry arises from lateralization in the cerebral cortex: the dominant side specializes in predictive trajectory control, while the nondominant side is specialized for impedance control. Long-latency stretch reflexes are an automatic mechanism for regulating posture, and have been shown to contribute to limb impedance. To determine whether long-latency reflexes also contribute to asymmetric motor behavior in the upper limbs, we investigated the effect of arm dominance on stretch reflexes during a postural task that required varying degrees of impedance control. Our results demonstrated slightly but significantly larger reflex responses in the biarticular muscles of the nondominant arm, as would be consistent with increased impedance control. These differences were attributed solely to higher levels of voluntary background activity in the nondominant biarticular muscles, indicating that feedforward strategies for postural stability may differ between arms. Reflex sensitivity, which was defined as the magnitude of the reflex response for matched levels of background activity, was not significantly different between arms for a broad subject population ranging from 23–51 years of age. These results indicate that inter-arm differences in feedforward strategies are more influential during posture than differences in feedback sensitivity, in a broad subject population. Interestingly, restricting our analysis to subjects under 40 years of age revealed a small increase in long-latency reflex sensitivity in the nondominant arm relative to the dominant arm. Though our subject numbers were small for this secondary analysis, it suggests that further studies may be required to assess the influence of reflex lateralization throughout development. PMID:25850407

Postural control strategies related to anticipatory perturbation and quick perturbation in adolescent idiopathic scoliosis.

PubMed

Kuo, Fang-Chuan; Hong, Chang-Zern; Lai, Chung-Liang; Tan, Shih-Hsin

2011-05-01

Cross-sectional study. To investigate the automatic balance correction related to anticipatory perturbation (AP) and quick backward perturbation in adolescent idiopathic scoliosis (AIS). Most previous studies on AIS patients focused on posture sway and lacked analysis of muscle activated patterns in dynamic standing control. Thirty-two AIS patients and 23 age-matched normal subjects received perturbation balance tests on an unstable platform. The tilting angle of the platform and the muscle activity of the bilateral lumbar multifidi, gluteus medii, and gastrocnemii muscles were recorded. Electromyographic (EMG) amplitude, onset latencies, and duration were calculated with software accompanied with machine. The AIS group had less posture tilting but higher muscle activities than normal subjects under both perturbation conditions (P < 0.05). Under the AP test, AIS showed earlier onset and prolonged activation of left multifidus and right gastrocnemius compared with normal subjects (P < 0.05). The latency of the multifidus on the lumbar convex side occurred earlier than on the concave side. However, the asymmetric onset timing of the gastrocnemius was the opposite of the multifidi in the AIS group (P < 0.05). In contrast to the AP condition, bilateral leg and trunk muscles activated at similar latencies and durations in the AIS group (P < 0.05). Under the quick backward perturbation test, the control group had longer active duration of right multifidus and bilateral gastrocnemii than AIS to cope with larger platform tilting. In addition, asymmetric onset of gluteus medii and duration of multifidi was observed in the control group (P < 0.05). There were significant differences in posture control patterns between AIS and normal subjects. AIS subjects have asymmetric habitual muscle activities for AP, whereas when coping with sudden balance threats, they react with synchronized recruitment of bilateral postural muscles.

Arm dominance affects feedforward strategy more than feedback sensitivity during a postural task.

PubMed

Walker, Elise H E; Perreault, Eric J

2015-07-01

Handedness is a feature of human motor control that is still not fully understood. Recent work has demonstrated that the dominant and nondominant arm each excel at different behaviors and has proposed that this behavioral asymmetry arises from lateralization in the cerebral cortex: the dominant side specializes in predictive trajectory control, while the nondominant side is specialized for impedance control. Long-latency stretch reflexes are an automatic mechanism for regulating posture and have been shown to contribute to limb impedance. To determine whether long-latency reflexes also contribute to asymmetric motor behavior in the upper limbs, we investigated the effect of arm dominance on stretch reflexes during a postural task that required varying degrees of impedance control. Our results demonstrated slightly but significantly larger reflex responses in the biarticular muscles of the nondominant arm, as would be consistent with increased impedance control. These differences were attributed solely to higher levels of voluntary background activity in the nondominant biarticular muscles, indicating that feedforward strategies for postural stability may differ between arms. Reflex sensitivity, which was defined as the magnitude of the reflex response for matched levels of background activity, was not significantly different between arms for a broad subject population ranging from 23 to 51 years of age. These results indicate that inter-arm differences in feedforward strategies are more influential during posture than differences in feedback sensitivity, in a broad subject population. Interestingly, restricting our analysis to subjects under 40 years of age revealed a small increase in long-latency reflex sensitivity in the nondominant arm relative to the dominant arm. Though our subject numbers were small for this secondary analysis, it suggests that further studies may be required to assess the influence of reflex lateralization throughout development.

Avoiding and tolerating latency in large-scale next-generation shared-memory multiprocessors

NASA Technical Reports Server (NTRS)

Probst, David K.

1993-01-01

A scalable solution to the memory-latency problem is necessary to prevent the large latencies of synchronization and memory operations inherent in large-scale shared-memory multiprocessors from reducing high performance. We distinguish latency avoidance and latency tolerance. Latency is avoided when data is brought to nearby locales for future reference. Latency is tolerated when references are overlapped with other computation. Latency-avoiding locales include: processor registers, data caches used temporally, and nearby memory modules. Tolerating communication latency requires parallelism, allowing the overlap of communication and computation. Latency-tolerating techniques include: vector pipelining, data caches used spatially, prefetching in various forms, and multithreading in various forms. Relaxing the consistency model permits increased use of avoidance and tolerance techniques. Each model is a mapping from the program text to sets of partial orders on program operations; it is a convention about which temporal precedences among program operations are necessary. Information about temporal locality and parallelism constrains the use of avoidance and tolerance techniques. Suitable architectural primitives and compiler technology are required to exploit the increased freedom to reorder and overlap operations in relaxed models.

Handling of Adolescent Rats Improves Learning and Memory and Decreases Anxiety

PubMed Central

Costa, Rafaela; Tamascia, Mariana L; Nogueira, Marie D; Casarini, Dulce E; Marcondes, Fernanda K

2012-01-01

Some environmental interventions can result in physiologic and behavioral changes in laboratory animals. In this context, the handling of adolescent or adult rodents has been reported to influence exploratory behavior and emotionality. Here we examined the effects of handling on memory and anxiety levels of adolescent rats. Male Sprague–Dawley rats (age, 60 d) were divided into a control group and a handled group, which were handled for 5 min daily, 5 d per week, for 6 wk. During handling bouts, the rat was removed from its cage, placed in the experimenter's lap or on the top of a table, and had its neck and back gently stroked by the experimenter's fingers. During week 6, each rat's anxiety level was evaluated in the elevated plus-maze (EPM) test. Learning and memory were evaluated 48 h later, by measuring escape latency in the elevated plus-maze test. Plasma corticosterone and catecholamine levels were measured also. Norepinephrine levels were lower in the handled rats compared with control animals, with no differences in epinephrine and corticosterone. As compared with the control rats, the handled rats showed increases in the percentage of time spent in the open arms of the test apparatus, percentage of entries into open arms, and number of visits to the end of the open arms and decreases in the latency of the first open arm entry. Escape latency was lower in the handled rats compared with control rats in both the first and second trials. The data obtained suggest that handling decreases anxiety levels and improves learning skills and memory in rats. PMID:23312082

Dexmedetomidine ameliorates nocifensive behavior in humanized sickle cell mice

PubMed Central

Calhoun, Gabriela; Wang, Li; Almeida, Luis E.F.; Kenyon, Nicholas; Afsar, Nina; Nouraie, Mehdi; Finkel, Julia C.; Quezado, Zenaide M.N.

2015-01-01

Patients with sickle cell disease (SCD) can have recurrent episodes of vaso-occlusive crises, which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients, increasing opioid use results in continued and increasing pain. Many believe that this phenomenon results from opioid-induced tolerance or hyperalgesia or that SCD pain involves non-opioid-responsive mechanisms. Dexmedetomidine, a specific α2-adrenoreceptor agonist, which has sedative and analgesic properties, reduces opioid requirements, and can facilitate opioid withdrawal in clinical settings. We hypothesized that dexmedetomidine would ameliorate the nociception phenotype of SCD mice. Townes and BERK SCD mice, strains known to have altered nociception phenotypes, were used in a crossover preclinical trial that measured nocifensive behavior before and after treatment with dexmedetomidine or vehicle. In a linear dose-effect relationship, over 60-min, dexmedetomidine, compared with vehicle, significantly increased hot plate latency in Townes and BERK mice (P≤0.006). In sickling, but not control mice, dexmedetomidine improved grip force, an indicator of muscle pain (P=0.002). As expected, dexmedetomidine had a sedative effect in sickling and control mice as it decreased wakefulness scores compared with vehicle (all P<0.001). Interestingly, the effects of dexmedetomidine on hot plate latency and wakefulness scores were different in sickling and control mice, i.e., dexmedetomidine-related increases in hotplate latency and decreases in wakefulness scores were significantly smaller in Townes sickling compared to control mice. In conclusion, these findings of beneficial effects of dexmedetomidine on the nociception phenotype in SCD mice might support the conduct of studies of dexmedetomidine in SCD patients. PMID:25724786

Static and Dynamic Measurements of Accommodation in Individuals with Down Syndrome

PubMed Central

Manny, Ruth E.; Glasser, Adrian; Stuebing, Karla K.

2011-01-01

Purpose. To identify whether static and dynamic aspects of accommodation other than accuracy are deficient in individuals with Down syndrome (DS) and whether poor accommodation is related to sensory or motor pathway deficits. Methods. Static aspects of accommodation (maximum accommodative response and lag) were measured with an autorefractor for both proximal and minus lens demands. Dynamic aspects of accommodation (latency, peak velocity, microfluctuations) were recorded at 30 Hz with a custom-built photorefractor as subjects viewed a movie switching between 11 m and 50, 33, 25, or 20 cm. Thirty-six subjects with DS were recruited (age 3 to 39 years), and 24 (67%) had useable responses for at least one study measurement for comparison with 140 controls (3 to 40 years) from a previously published cohort. Results. DS subjects had lower maximum accommodative responses (mean = 2.52 ± 1.66 D) and higher lags (1.81 ± 1.30 D for 33 cm demand) than controls for both proximal and minus lens stimuli. DS subjects had greater microfluctuations (one-way ANCOVA, P < 0.001), and a small percentage of the total number of latency measurements (17% accommodative and 16% disaccommodative) were longer than controls. Peak velocities of accommodation and disaccommodation were not different between groups (one-way ANCOVA, P = 0.143). Conclusions. Peak velocities of accommodation and disaccommodation (primarily motor aspects) did not differ between controls and DS subjects; however, latencies (primarily sensory) and microfluctuations (combined motor and sensory) were poorer in DS subjects. These results suggest that poor accommodative accuracy in individuals with DS may be predominantly related to sensory deficits. PMID:20739471

Interval timing under a behavioral microscope: Dissociating motivational and timing processes in fixed-interval performance.

PubMed

Daniels, Carter W; Sanabria, Federico

2017-03-01

The distribution of latencies and interresponse times (IRTs) of rats was compared between two fixed-interval (FI) schedules of food reinforcement (FI 30 s and FI 90 s), and between two levels of food deprivation. Computational modeling revealed that latencies and IRTs were well described by mixture probability distributions embodying two-state Markov chains. Analysis of these models revealed that only a subset of latencies is sensitive to the periodicity of reinforcement, and prefeeding only reduces the size of this subset. The distribution of IRTs suggests that behavior in FI schedules is organized in bouts that lengthen and ramp up in frequency with proximity to reinforcement. Prefeeding slowed down the lengthening of bouts and increased the time between bouts. When concatenated, latency and IRT models adequately reproduced sigmoidal FI response functions. These findings suggest that behavior in FI schedules fluctuates in and out of schedule control; an account of such fluctuation suggests that timing and motivation are dissociable components of FI performance. These mixture-distribution models also provide novel insights on the motivational, associative, and timing processes expressed in FI performance. These processes may be obscured, however, when performance in timing tasks is analyzed in terms of mean response rates.

Increased seizure latency and decreased severity of pentylenetetrazol-induced seizures in mice after essential oil administration.

PubMed

Koutroumanidou, Eleni; Kimbaris, Athanasios; Kortsaris, Alexandros; Bezirtzoglou, Eugenia; Polissiou, Moschos; Charalabopoulos, Konstantinos; Pagonopoulou, Olga

2013-01-01

The effect of pretreatment with essential oils (EOs) from eight aromatic plants on the seizure latency and severity of pentylenetetrazol- (PTZ-) induced seizures in mice was evaluated. Weight-dependent doses of Rosmarinus officinalis, Ocimum basilicum, Mentha spicata, Mentha pulegium, Lavandula angustifolia, Mentha piperita, Origanum dictamnus, and Origanum vulgare, isolated from the respective aromatic plants from NE Greece, were administered 60 minutes prior to intraperitoneal (i.p.) injection of a lethal dose of PTZ to eight respective groups of Balb-c mice. Control group received only one i.p. PTZ injection. Motor and behavioral activity of the animals after EOs administration, development of tonic-clonic seizures, seizure latency and severity, and percentage of survival after PTZ administration were determined for each group. All groups of mice treated with the EOs showed reduced activity and stability after the administration of the oil, except for those treated with O. vulgare (100% mortality after the administration of the oil). After PTZ administration, mice from the different groups showed increased latency and reduced severity of seizures (ranging from simple twitches to complete seizures). Mice who had received M. piperita demonstrated no seizures and 100% survival. The different drastic component and its concentration could account for the diversity of anticonvulsant effects.

Abnormal auditory synchronization in stuttering: A magnetoencephalographic study.

PubMed

Kikuchi, Yoshikazu; Okamoto, Tsuyoshi; Ogata, Katsuya; Hagiwara, Koichi; Umezaki, Toshiro; Kenjo, Masamutsu; Nakagawa, Takashi; Tobimatsu, Shozo

2017-02-01

In a previous magnetoencephalographic study, we showed both functional and structural reorganization of the right auditory cortex and impaired left auditory cortex function in people who stutter (PWS). In the present work, we reevaluated the same dataset to further investigate how the right and left auditory cortices interact to compensate for stuttering. We evaluated bilateral N100m latencies as well as indices of local and inter-hemispheric phase synchronization of the auditory cortices. The left N100m latency was significantly prolonged relative to the right N100m latency in PWS, while healthy control participants did not show any inter-hemispheric differences in latency. A phase-locking factor (PLF) analysis, which indicates the degree of local phase synchronization, demonstrated enhanced alpha-band synchrony in the right auditory area of PWS. A phase-locking value (PLV) analysis of inter-hemispheric synchronization demonstrated significant elevations in the beta band between the right and left auditory cortices in PWS. In addition, right PLF and PLVs were positively correlated with stuttering frequency in PWS. Taken together, our data suggest that increased right hemispheric local phase synchronization and increased inter-hemispheric phase synchronization are electrophysiological correlates of a compensatory mechanism for impaired left auditory processing in PWS. Published by Elsevier B.V.

Latency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection

PubMed Central

Krishna, Benjamin A.; Poole, Emma L.; Smit, Martine J.; Wills, Mark R.

2017-01-01

ABSTRACT Reactivation of human cytomegalovirus (HCMV) latent infection from early myeloid lineage cells constitutes a threat to immunocompromised or immune-suppressed individuals. Consequently, understanding the control of latency and reactivation to allow targeting and killing of latently infected cells could have far-reaching clinical benefits. US28 is one of the few viral genes that is expressed during latency and encodes a cell surface G protein-coupled receptor (GPCR), which, during lytic infection, is a constitutive cell-signaling activator. Here we now show that in monocytes, which are recognized sites of HCMV latency in vivo, US28 attenuates multiple cell signaling pathways, including mitogen-activated protein (MAP) kinase and NF-κB, and that this is required to establish a latent infection; viruses deleted for US28 initiate a lytic infection in infected monocytes. We also show that these monocytes then become potent targets for the HCMV-specific host immune response and that latently infected cells treated with an inverse agonist of US28 also reactivate lytic infection and similarly become immune targets. Consequently, we suggest that the use of inhibitors of US28 could be a novel immunotherapeutic strategy to reactivate the latent viral reservoir, allowing it to be targeted by preexisting HCMV-specific T cells. PMID:29208743

Functional impairment of the auditory pathway after perinatal asphyxia and the short-term effect of perinatal propofol anesthesia in lambs.

PubMed

Smit, Adriana L; Seehase, Matthias; Stokroos, Robert J; Jellema, Reint K; Felipe, Lilian; Chenault, Michelene N; Anteunis, Lucien J C; Kremer, Bernd; Kramer, Boris W

2013-07-01

Sensorineural hearing loss (SNHL) is a common feature in the postasphyxial syndrome in newborns. Several anesthetic drugs have been proposed to attenuate secondary neuronal injury elicited by hypoxia-ischemia. We hypothesized that propofol anesthesia reduces auditory impairment after perinatal asphyxia in comparison with isoflurane. Twenty-three pregnant ewes were randomized to propofol or isoflurane anesthesia and sedation. The lambs underwent in utero umbilical cord occlusion (isoflurane n = 5; propofol n = 7) and were compared with sham-treated animals (isoflurane n = 5; propofol n = 6) at a gestational age of 133 d. For 8 h after delivery by cesarean section, repeated auditory brainstem responses (ABRs) were recorded to obtain hearing thresholds, peak amplitudes, latencies, and interpeak latencies. Significantly elevated mean thresholds, diminished amplitudes, and elevated latencies were observed in the asphyxia group relative to the control group through the observation period. Comparison of anesthetic treatment in the asphyxia group revealed a significantly lower elevation in threshold and less impairment in the ABR amplitudes and latencies during propofol anesthesia as compared with isoflurane anesthesia. Our results support the hypothesis that anesthesia with propofol has a preventive effect on the functional changes to the auditory pathway in the event of perinatal asphyxia.

GPUbased, Microsecond Latency, HectoChannel MIMO Feedback Control of Magnetically Confined Plasmas

NASA Astrophysics Data System (ADS)

Rath, Nikolaus

Feedback control has become a crucial tool in the research on magnetic confinement of plasmas for achieving controlled nuclear fusion. This thesis presents a novel plasma feedback control system that, for the first time, employs a Graphics Processing Unit (GPU) for microsecond-latency, real-time control computations. This novel application area for GPU computing is opened up by a new system architecture that is optimized for low-latency computations on less than kilobyte sized data samples as they occur in typical plasma control algorithms. In contrast to traditional GPU computing approaches that target complex, high-throughput computations with massive amounts of data, the architecture presented in this thesis uses the GPU as the primary processing unit rather than as an auxiliary of the CPU, and data is transferred from A-D/D-A converters directly into GPU memory using peer-to-peer PCI Express transfers. The described design has been implemented in a new, GPU-based control system for the High-Beta Tokamak - Extended Pulse (HBT-EP) device. The system is built from commodity hardware and uses an NVIDIA GeForce GPU and D-TACQ A-D/D-A converters providing a total of 96 input and 64 output channels. The system is able to run with sampling periods down to 4 μs and latencies down to 8 μs. The GPU provides a total processing power of 1.5 x 1012 floating point operations per second. To illustrate the performance and versatility of both the general architecture and concrete implementation, a new control algorithm has been developed. The algorithm is designed for the control of multiple rotating magnetic perturbations in situations where the plasma equilibrium is not known exactly and features an adaptive system model: instead of requiring the rotation frequencies and growth rates embedded in the system model to be set a priori, the adaptive algorithm derives these parameters from the evolution of the perturbation amplitudes themselves. This results in non-linear control computations with high computational demands, but is handled easily by the GPU based system. Both digital processing latency and an arbitrary multi-pole response of amplifiers and control coils is fully taken into account for the generation of control signals. To separate sensor signals into perturbed and equilibrium components without knowledge of the equilibrium fields, a new separation method based on biorthogonal decomposition is introduced and used to derive a filter that performs the separation in real-time. The control algorithm has been implemented and tested on the new, GPU-based feedback control system of the HBT-EP tokamak. In this instance, the algorithm was set up to control four rotating n = 1 perturbations at different poloidal angles. The perturbations were treated as coupled in frequency but independent in amplitude and phase, so that the system effectively controls a helical n = 1 perturbation with unknown poloidal spectrum. Depending on the plasma's edge safety factor and rotation frequency, the control system is shown to be able to suppress the amplitude of the dominant 8 kHz mode by up to 60% or amplify the saturated amplitude by a factor of up to two. Intermediate feedback phases combine suppression and amplification with a speed up or slow down of the mode rotation frequency. Increasing feedback gain results in the excitation of an additional, slowly rotating 1.4 kHz mode without further effects on the 8 kHz mode. The feedback performance is found to exceed previous results obtained with an FPGA- and Kalman-filter based control system without requiring any tuning of system model parameters. Experimental results are compared with simulations based on a combination of the Boozer surface current model and the Fitzpatrick-Aydemir model. Within the subset of phenomena that can be represented by the model as well as determined experimentally, qualitative agreement is found.

Monitoring auditory cortical plasticity in hearing aid users with long latency auditory evoked potentials: a longitudinal study.

PubMed

Leite, Renata Aparecida; Magliaro, Fernanda Cristina Leite; Raimundo, Jeziela Cristina; Bento, Ricardo Ferreira; Matas, Carla Gentile

2018-02-19

The objective of this study was to compare long-latency auditory evoked potentials before and after hearing aid fittings in children with sensorineural hearing loss compared with age-matched children with normal hearing. Thirty-two subjects of both genders aged 7 to 12 years participated in this study and were divided into two groups as follows: 14 children with normal hearing were assigned to the control group (mean age 9 years and 8 months), and 18 children with mild to moderate symmetrical bilateral sensorineural hearing loss were assigned to the study group (mean age 9 years and 2 months). The children underwent tympanometry, pure tone and speech audiometry and long-latency auditory evoked potential testing with speech and tone burst stimuli. The groups were assessed at three time points. The study group had a lower percentage of positive responses, lower P1-N1 and P2-N2 amplitudes (speech and tone burst), and increased latencies for the P1 and P300 components following the tone burst stimuli. They also showed improvements in long-latency auditory evoked potentials (with regard to both the amplitude and presence of responses) after hearing aid use. Alterations in the central auditory pathways can be identified using P1-N1 and P2-N2 amplitude components, and the presence of these components increases after a short period of auditory stimulation (hearing aid use). These findings emphasize the importance of using these amplitude components to monitor the neuroplasticity of the central auditory nervous system in hearing aid users.

Monitoring auditory cortical plasticity in hearing aid users with long latency auditory evoked potentials: a longitudinal study

PubMed Central

Leite, Renata Aparecida; Magliaro, Fernanda Cristina Leite; Raimundo, Jeziela Cristina; Bento, Ricardo Ferreira; Matas, Carla Gentile

2018-01-01

OBJECTIVE: The objective of this study was to compare long-latency auditory evoked potentials before and after hearing aid fittings in children with sensorineural hearing loss compared with age-matched children with normal hearing. METHODS: Thirty-two subjects of both genders aged 7 to 12 years participated in this study and were divided into two groups as follows: 14 children with normal hearing were assigned to the control group (mean age 9 years and 8 months), and 18 children with mild to moderate symmetrical bilateral sensorineural hearing loss were assigned to the study group (mean age 9 years and 2 months). The children underwent tympanometry, pure tone and speech audiometry and long-latency auditory evoked potential testing with speech and tone burst stimuli. The groups were assessed at three time points. RESULTS: The study group had a lower percentage of positive responses, lower P1-N1 and P2-N2 amplitudes (speech and tone burst), and increased latencies for the P1 and P300 components following the tone burst stimuli. They also showed improvements in long-latency auditory evoked potentials (with regard to both the amplitude and presence of responses) after hearing aid use. CONCLUSIONS: Alterations in the central auditory pathways can be identified using P1-N1 and P2-N2 amplitude components, and the presence of these components increases after a short period of auditory stimulation (hearing aid use). These findings emphasize the importance of using these amplitude components to monitor the neuroplasticity of the central auditory nervous system in hearing aid users. PMID:29466495

The minimal unit of phonological encoding: prosodic or lexical word.

PubMed

Wheeldon, Linda R; Lahiri, Aditi

2002-09-01

Wheeldon and Lahiri (Journal of Memory and Language 37 (1997) 356) used a prepared speech production task (Sternberg, S., Monsell, S., Knoll, R. L., & Wright, C. E. (1978). The latency and duration of rapid movement sequences: comparisons of speech and typewriting. In G. E. Stelmach (Ed.), Information processing in motor control and learning (pp. 117-152). New York: Academic Press; Sternberg, S., Wright, C. E., Knoll, R. L., & Monsell, S. (1980). Motor programs in rapid speech: additional evidence. In R. A. Cole (Ed.), The perception and production of fluent speech (pp. 507-534). Hillsdale, NJ: Erlbaum) to demonstrate that the latency to articulate a sentence is a function of the number of phonological words it comprises. Latencies for the sentence [Ik zoek het] [water] 'I seek the water' were shorter than latencies for sentences like [Ik zoek] [vers] [water] 'I seek fresh water'. We extend this research by examining the prepared production of utterances containing phonological words that are less than a lexical word in length. Dutch compounds (e.g. ooglid 'eyelid') form a single morphosyntactic word and a phonological word, which in turn includes two phonological words. We compare their prepared production latencies to those syntactic phrases consisting of an adjective and a noun (e.g. oud lid 'old member') which comprise two morphosyntactic and two phonological words, and to morphologically simple words (e.g. orgel 'organ') which comprise one morphosyntactic and one phonological word. Our findings demonstrate that the effect is limited to phrasal level phonological words, suggesting that production models need to make a distinction between lexical and phrasal phonology.

Enhanced Fine-Form Perception Does Not Contribute to Gestalt Face Perception in Autism Spectrum Disorder

PubMed Central

Maekawa, Toshihiko; Miyanaga, Yuka; Takahashi, Kenji; Takamiya, Naomi; Ogata, Katsuya; Tobimatsu, Shozo

2017-01-01

Individuals with autism spectrum disorder (ASD) show superior performance in processing fine detail, but often exhibit impaired gestalt face perception. The ventral visual stream from the primary visual cortex (V1) to the fusiform gyrus (V4) plays an important role in form (including faces) and color perception. The aim of this study was to investigate how the ventral stream is functionally altered in ASD. Visual evoked potentials were recorded in high-functioning ASD adults (n = 14) and typically developing (TD) adults (n = 14). We used three types of visual stimuli as follows: isoluminant chromatic (red/green, RG) gratings, high-contrast achromatic (black/white, BW) gratings with high spatial frequency (HSF, 5.3 cycles/degree), and face (neutral, happy, and angry faces) stimuli. Compared with TD controls, ASD adults exhibited longer N1 latency for RG, shorter N1 latency for BW, and shorter P1 latency, but prolonged N170 latency, for face stimuli. Moreover, a greater difference in latency between P1 and N170, or between N1 for BW and N170 (i.e., the prolongation of cortico-cortical conduction time between V1 and V4) was observed in ASD adults. These findings indicate that ASD adults have enhanced fine-form (local HSF) processing, but impaired color processing at V1. In addition, they exhibit impaired gestalt face processing due to deficits in integration of multiple local HSF facial information at V4. Thus, altered ventral stream function may contribute to abnormal social processing in ASD. PMID:28146575

Meta-analysis of long-term mobile phone use and the association with brain tumours.

PubMed

Hardell, Lennart; Carlberg, Michael; Söderqvist, Fredrik; Hansson Mild, Kjell

2008-05-01

We evaluated long-term use of mobile phones and the risk for brain tumours in case-control studies published so far on this issue. We identified ten studies on glioma and meta-analysis yielded OR = 0.9, 95% CI = 0.8-1.1. Latency period of > or =10-years gave OR = 1.2, 95% CI = 0.8-1.9 based on six studies, for ipsilateral use (same side as tumour) OR = 2.0, 95% CI = 1.2-3.4 (four studies), but contralateral use did not increase the risk significantly, OR = 1.1, 95% CI = 0.6-2.0. Meta-analysis of nine studies on acoustic neuroma gave OR = 0.9, 95% CI = 0.7-1.1 increasing to OR = 1.3, 95% CI = 0.6-2.8 using > or =10-years latency period (four studies). Ipsilateral use gave OR = 2.4, 95% CI = 1.1-5.3 and contra-lateral OR = 1.2, 95% CI = 0.7-2.2 in the > or =10-years latency period group (three studies). Seven studies gave results for meningioma yielding overall OR = 0.8, 95% CI = 0.7-0.99. Using > or =10-years latency period OR = 1.3, 95% CI = 0.9-1.8 was calculated (four studies) increasing to OR = 1.7, 95% CI = 0.99-3.1 for ipsilateral use and OR = 1.0, 95% CI = 0.3-3.1 for contralateral use (two studies). We conclude that this meta-analysis gave a consistent pattern of an association between mobile phone use and ipsilateral glioma and acoustic neuroma using > or =10-years latency period.

Lateral step initiation behavior in older adults.

PubMed

Sparto, Patrick J; Jennings, J Richard; Furman, Joseph M; Redfern, Mark S

2014-02-01

Older adults have varied postural responses during induced and voluntary lateral stepping. The purpose of the research was to quantify the occurrence of different stepping strategies during lateral step initiation in older adults and to relate the stepping responses to retrospective history of falls. Seventy community-ambulating older adults (mean age 76 y, range 70-94 y) performed voluntary lateral steps as quickly as possible to the right or left in response to a visual cue, in a blocked design. Vertical ground reaction forces were measured using a forceplate, and the number and latency of postural adjustments were quantified. Subjects were assigned to groups based on their stepping strategy. The frequency of trials with one or two postural adjustments was compared with data from 20 younger adults (mean age 38 y, range 21-58 y). Logistic regression was used to relate presence of a fall in the previous year with the number and latency of postural adjustments. In comparison with younger adults, who almost always demonstrated one postural adjustment when stepping laterally, older adults constituted a continuous distribution in the percentage of step trials made with one postural adjustment (from 0% to 100% of trials). Latencies of the initial postural adjustment and foot liftoff varied depending on the number of postural adjustments made. A history of falls was associated a larger percentage of two postural adjustments, and a longer latency of foot liftoff. In conclusion, the number and latency of postural adjustments made during voluntary lateral stepping provides additional evidence that lateral control of posture may be a critical indicator of aging. Copyright © 2013 Elsevier B.V. All rights reserved.

Contribution of the Major ND10 Proteins PML, hDaxx and Sp100 to the Regulation of Human Cytomegalovirus Latency and Lytic Replication in the Monocytic Cell Line THP-1

PubMed Central

Wagenknecht, Nadine; Reuter, Nina; Scherer, Myriam; Reichel, Anna; Müller, Regina; Stamminger, Thomas

2015-01-01

Promyelocytic leukemia nuclear bodies, also termed nuclear domain 10 (ND10), have emerged as nuclear protein accumulations mediating an intrinsic cellular defense against viral infections via chromatin-based mechanisms, however, their contribution to the control of herpesviral latency is still controversial. In this study, we utilized the monocytic cell line THP-1 as an in vitro latency model for human cytomegalovirus infection (HCMV). Characterization of THP-1 cells by immunofluorescence and Western blot analysis confirmed the expression of all major ND10 components. THP-1 cells with a stable, individual knockdown of PML, hDaxx or Sp100 were generated. Importantly, depletion of the major ND10 proteins did not prevent the terminal cellular differentiation of THP-1 monocytes. After construction of a recombinant, endotheliotropic human cytomegalovirus expressing IE2-EYFP, we investigated whether the depletion of ND10 proteins affects the onset of viral IE gene expression. While after infection of differentiated, THP-1-derived macrophages as well as during differentiation-induced reactivation from latency an increase in the number of IE-expressing cells was readily detectable in the absence of the major ND10 proteins, no effect was observed in non-differentiated monocytes. We conclude that PML, hDaxx and Sp100 primarily act as cellular restriction factors during lytic HCMV replication and during the dynamic process of reactivation but do not serve as key determinants for the establishment of HCMV latency. PMID:26057166

Auditory middle latency response in children with learning difficulties

PubMed Central

Frizzo, Ana Claudia Figueiredo; Issac, Myriam Lima; Pontes-Fernandes, Angela Cristina; Menezes, Pedro de Lemos; Funayama, Carolina Araújo Rodrigues

2012-01-01

Summary Introduction: This is an objective laboratory assessment of the central auditory systems of children with learning disabilities. Aim: To examine and determine the properties of the components of the Auditory Middle Latency Response in a sample of children with learning disabilities. Methods: This was a prospective, cross-sectional cohort study with quantitative, descriptive, and exploratory outcomes. We included 50 children aged 8–13 years of both genders with and without learning disorders. Those with disorders of known organic, environmental, or genetic causes were excluded. Results and Conclusions: The Na, Pa, and Nb waves were identified in all subjects. The ranges of the latency component values were as follows: Na = 9.8–32.3 ms, Pa = 19.0–51.4 ms, Nb = 30.0–64.3 ms (learning disorders group) and Na = 13.2–29.6 ms, Pa = 21.8–42.8 ms, Nb = 28.4–65.8 ms (healthy group). The values of the Na-Pa amplitude ranged from 0.3 to 6.8 ìV (learning disorders group) or 0.2–3.6 ìV (learning disorders group). Upon analysis, the functional characteristics of the groups were distinct: the left hemisphere Nb latency was longer in the study group than in the control group. Peculiarities of the electrophysiological measures were observed in the children with learning disorders. This study has provided information on the Auditory Middle Latency Response and can serve as a reference for other clinical and experimental studies in children with these disorders. PMID:25991954

Lateral step initiation behavior in older adults

PubMed Central

Sparto, Patrick J; Jennings, J Richard; Furman, Joseph M; Redfern, Mark S

2013-01-01

Older adults have varied postural responses during induced and voluntary lateral stepping. The purpose of the research was to quantify the occurrence of different stepping strategies during lateral step initiation in older adults and to relate the stepping responses to retrospective history of falls. Seventy community-ambulating older adults (mean age 76 y, range 70–94 y) performed voluntary lateral steps as quickly as possible to the right or left in response to a visual cue, in a blocked design. Vertical ground reaction forces were measured using a forceplate, and the number and latency of postural adjustments were quantified. Subjects were assigned to groups based on their stepping strategy. The frequency of trials with one or two postural adjustments was compared with data from 20 younger adults (mean age 38 y, range 21–58 y). Logistic regression was used to relate presence of a fall in the previous year with the number and latency of postural adjustments. In comparison with younger adults, who almost always demonstrated one postural adjustment when stepping laterally, older adults constituted a continuous distribution in the percentage of step trials made with one postural adjustment (from 0% to 100% of trials). Latencies of the initial postural adjustment and foot liftoff varied depending on the number of postural adjustments made. A history of falls was associated a larger percentage of two postural adjustments, and a longer latency of foot liftoff. In conclusion, the number and latency of postural adjustments made during voluntary lateral stepping provides additional evidence that lateral control of posture may be a critical indicator of aging. PMID:24295896

Kinesthetic information facilitates saccades towards proprioceptive-tactile targets.

PubMed

Voudouris, Dimitris; Goettker, Alexander; Mueller, Stefanie; Fiehler, Katja

2016-05-01

Saccades to somatosensory targets have longer latencies and are less accurate and precise than saccades to visual targets. Here we examined how different somatosensory information influences the planning and control of saccadic eye movements. Participants fixated a central cross and initiated a saccade as fast as possible in response to a tactile stimulus that was presented to either the index or the middle fingertip of their unseen left hand. In a static condition, the hand remained at a target location for the entire block of trials and the stimulus was presented at a fixed time after an auditory tone. Therefore, the target location was derived only from proprioceptive and tactile information. In a moving condition, the hand was first actively moved to the same target location and the stimulus was then presented immediately. Thus, in the moving condition additional kinesthetic information about the target location was available. We found shorter saccade latencies in the moving compared to the static condition, but no differences in accuracy or precision of saccadic endpoints. In a second experiment, we introduced variable delays after the auditory tone (static condition) or after the end of the hand movement (moving condition) in order to reduce the predictability of the moment of the stimulation and to allow more time to process the kinesthetic information. Again, we found shorter latencies in the moving compared to the static condition but no improvement in saccade accuracy or precision. In a third experiment, we showed that the shorter saccade latencies in the moving condition cannot be explained by the temporal proximity between the relevant event (auditory tone or end of hand movement) and the moment of the stimulation. Our findings suggest that kinesthetic information facilitates planning, but not control, of saccadic eye movements to proprioceptive-tactile targets. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inferring the 1985-2014 impact of mobile phone use on selected brain cancer subtypes using Bayesian structural time series and synthetic controls.

PubMed

de Vocht, Frank

2016-12-01

Mobile phone use has been increasing rapidly in the past decades and, in parallel, so has the annual incidence of certain types of brain cancers. However, it remains unclear whether this correlation is coincidental or whether use of mobile phones may cause the development, promotion or progression of specific cancers. The 1985-2014 incidence of selected brain cancer subtypes in England were analyzed and compared to counterfactual 'synthetic control' timeseries. Annual 1985-2014 incidence of malignant glioma, glioblastoma multiforme, and malignant neoplasms of the temporal and parietal lobes in England were modelled based on population-level covariates using Bayesian structural time series models assuming 5,10 and 15year minimal latency periods. Post-latency counterfactual 'synthetic England' timeseries were nowcast based on covariate trends. The impact of mobile phone use was inferred from differences between measured and modelled time series. There is no evidence of an increase in malignant glioma, glioblastoma multiforme, or malignant neoplasms of the parietal lobe not predicted in the 'synthetic England' time series. Malignant neoplasms of the temporal lobe however, have increased faster than expected. A latency period of 10years reflected the earliest latency period when this was measurable and related to mobile phone penetration rates, and indicated an additional increase of 35% (95% Credible Interval 9%:59%) during 2005-2014; corresponding to an additional 188 (95%CI 48-324) cases annually. A causal factor, of which mobile phone use (and possibly other wireless equipment) is in agreement with the hypothesized temporal association, is related to an increased risk of developing malignant neoplasms in the temporal lobe. Copyright © 2016 The Author. Published by Elsevier Ltd.. All rights reserved.

Delayed Latency of Postural Muscles of Individuals with Intellectual Disabilities.

PubMed

Tolentino-Castro, J Walter; Mühlbeier, Andreas; Mochizuki, Luis; Wagner, Heiko

2018-01-01

Individuals with intellectual disabilities (ID) (50 < IQ < 79) show impaired motor and postural control, these impairments are highly related to falls and injuries. Recent studies demonstrated these impairments are related with fine and gross motor development, which are more strongly associated with cognition, and consequently language for individuals with ID than for without ID. Despite these studies, little is known about the structure and functioning of this population's spinal cord, which is highly involved in postural control. The aim of our study was to assess the latency of the reflex responses in postural muscles after unexpected lateral external perturbations, in individuals with intellectual disabilities compared to typically developed participants. We assessed 16 participants with intellectual disabilities, 9 males and 7 females (aged 24.06 ± 8.66 years) and 20 typical developed participants (CG), 11 females, 9 males, (aged 21.20±1.96 years). While the participants were in an upright standing position electromyography was used to collect data from M. obliquus externus abdominis (OE) muscles, which were activated by unpredictable perturbations applied by a servomotor on a hand-held grip, following the lateral external perturbation to the trunk. The intellectual disabilities group presented contralateral OE muscles latency of 85.71±27.24 ms, and CG group presented 68.62±10.25 ms, no differences was found. Ipsilateral OE muscles latency also did not differs between the groups, ID group showed 96.60±30.20 ms and CG group showed 95.57±33.53 ms. Our study furthers the knowledge about the muscular activity of individuals with intellectual disabilities. The present experimental results may suggest unique spinal cord processing of individuals with intellectual disabilities when they are faced with unexpected lateral external perturbations.

Sedative music facilitates deep sleep in young adults.

PubMed

Chen, Chih-Kuang; Pei, Yu-Cheng; Chen, Ning-Hung; Huang, Li-Ting; Chou, Shih-Wei; Wu, Katie P; Ko, Pei-Chih; Wong, Alice M K; Wu, Chih-Kuan

2014-04-01

To investigate the effect of sedative music on the different stages of the sleep cycle in young adults with various sleep latencies by using polysomnography (PSG). Prospective, randomized, controlled, crossover study. Sleep center of a teaching hospital. Young adults with different sleep latencies. Poor sleepers (Pittsburgh Sleep Quality Index score ≥5) were excluded. Each participant stayed one night in the sleep center for adaptation and on each of the following two nights was assigned to (1) music and (2) control (without music) conditions in random order. In the music condition, sedative music composed by certified music therapists was played on a compact disc player for the first hour the participant was in bed. Sleep measures recorded with PSG, including sleep latency and durations of sleep stages. Twenty-four young adults (mean±standard deviation, 24.5±2.6 years) participated. They were classified into the short sleep latency (SL) group if the baseline SL of the adaptation night was shorter than 10 minutes or into the long SL group if the baseline SL was 10 minutes or longer. Sedative music did not alter the SL in either group. Sedative music reduced stage II sleep in both SL groups (main effect of music, p=0.03; interaction effect, p=0.87) but increased the duration of deep sleep (stages III and IV) only in the long SL group (main effect of music, p=0.15; interaction effect, p=0.02). In participants with long SL, sedative music improved the quality of sleep by prolonging the duration of deep sleep. This effect provides an alternative and noninvasive way to improve sleep in selected persons experiencing sleep problems.

Melatonin improves sleep in children with epilepsy: randomized, double-blind cross-over study

PubMed Central

Jain, Sejal V; Horn, Paul S; Simakajornboon, Narong; Beebe, Dean W; Holland, Katherine; Byars, Anna W; Glauser, Tracy A

2015-01-01

Objective Insomnia, especially maintenance insomnia is widely prevalent in epilepsy. Although melatonin is commonly used, limited data address its efficacy. We performed a randomized, double-blind, placebo-controlled, cross-over study to identify the effects of melatonin on sleep and seizure control in children with epilepsy. Methods Eleven pre-pubertal, developmentally normal children aged 6–11 years with epilepsy were randomized by software algorithm to receive placebo or 9 mg sustained release melatonin for 4 weeks, followed by a 1-week washout and 4-week crossover condition. The pharmacy performed blinding; patients, parents and study staff other than a statistician were blinded. Primary outcomes were sleep onset latency and wakefulness after sleep onset (WASO) measured on polysomnography. Secondary outcomes included seizure frequency, epileptiform spike density per hour of sleep on EEG and reaction time measures on psychomotor vigilance task. Statistical tests appropriate for cross-over designs were used for analysis. Results Data were analyzed from ten subjects who completed the study. Melatonin decreased sleep latency (Mean difference (MD): 11.4 min, p= 0.02) and WASO (MD 22 min, p=0.04) as compared to placebo. No worsening of spike density or seizure frequency was seen. Additionally, Slow-wave sleep duration and REM latency were increased with melatonin and REM sleep duration was decreased. These changes were statistically significant. Worsening of headache was noted in one subject with migraine on melatonin. Conclusion Sustained-release melatonin resulted in statistically significant decreases in sleep latency and WASO. No clear effects on seizures were observed but the study was too small to allow any conclusions to be drawn in this regard. PMID:25862116

Carbon dioxide field flooding reduces neurologic impairment after open heart surgery.

PubMed

Martens, Sven; Neumann, Katrin; Sodemann, Christian; Deschka, Heinz; Wimmer-Greinecker, Gerhard; Moritz, Anton

2008-02-01

Air emboli released from incompletely deaired cardiac chambers may cause neurocognitive decline after open heart surgery. Carbon dioxide (CO2) field flooding is reported to reduce residual intracavital air during cardiac surgery. A protective effect of carbon dioxide insufflation on postoperative brain function remains unproven in clinical trials. Eighty patients undergoing heart valve operations by median sternotomy were randomly assigned to either CO2 insufflation (group I, n = 39) or unprotected controls (group II, n = 41). Preoperative evaluation included neurocognitive test batteries consisting of six different tests, and objective measurements of brain function by means of P300 wave auditory-evoked potentials (peak latencies, ms). Neurocognitive testing and P300 measurements were repeated on postoperative day 5. Neurocognitive deficit (ND) was defined as a 20% decrement in two or more tests. Preoperatively, P300 peak latencies did not differ between groups (374 +/- 75 vs 366 +/- 72 ms, not significant [n.s.]). Five days after surgery, P300 peak latencies were significantly shorter with CO2 protection as compared with the unprotected control group (group I: 390 +/- 68 ms, group II: 429 +/- 75 ms, p = 0.02). Clinical outcome was comparable as for mortality (group I: 1 patient; group II: 2 patients) and cerebrovascular events or confusional syndromes (group I: 5 patients; group II: 4 patients) or other clinical variables as intubation time or hospital stay. Neurocognitive test batteries did not reveal differences between groups. Shorter P300 peak latencies after surgery indicate less brain damage in patients who underwent heart valve operations with CO2 flooding of the thoracic cavity. Even if these findings were not supported by clinical results or neurocognitive test batteries in our cohort, carbon dioxide field flooding has proven efficiency and should be advocated for all patients undergoing open heart surgery.

Clinical significance of vestibular evoked myogenic potentials in benign paroxysmal positional vertigo.

PubMed

Yang, Won Sun; Kim, Sung Huhn; Lee, Jong Dae; Lee, Won-Sang

2008-12-01

To investigate the vestibular evoked myogenic potentials (VEMPs) resulting in benign paroxysmal positional vertigo (BPPV) patients and to verify its clinical applications in BPPV. A prospective study. Tertiary referral dizziness center. Forty-one patients with diagnosis of BPPV and 92 healthy volunteers who underwent VEMP testing. Patients were treated by canalith repositioning maneuvers according to the affected canal, and testing of VEMP was performed at diagnosis and after treatment. Testing of VEMP was performed in BPPV patients and in the control group. The number of times the canalith repositioning maneuver was repeated until the patient's report of relief from vertigo and findings of negative positioning test were recorded to find out the relationship between VEMP results and the progress of disease. Vestibular evoked myogenic potential results of BPPV patients showed prolonged p13 and n23 latencies compared with those of the control group, and we could not find any significant difference in VEMP latencies between patients with posterior and horizontal canal type of BPPV. The number of times that the maneuver was repeated did not correlate with the degree of latency prolongation, but in the "no response" group, the number of times was considerably greater than that in the "response" group. We found that VEMP latencies are increased in BPPV patients, which may signify neuronal degenerative changes in the macula of the saccule. When an extensive neuronal damage was suspected by VEMP results such as "no response" in VEMP, the disease progress showed a chronic and resistive course. Therefore, we propose that VEMP could be a useful method to determine a clinical prognosis of patients with BPPV.

The Clinical Utility of Vestibular Evoked Myogenic Potentials in Patients of Benign Paroxysmal Positional Vertigo.

PubMed

Sreenivasan, Anuprasad; Sivaraman, Ganesan; Parida, Pradiptata Kumar; Alexander, Arun; Saxena, Sunil Kumar; Suria, Gopalakrishnan

2015-06-01

Vestibular Evoked Myogenic Potentials (VEMP) is an emerging tool to diagnose Benign Paroxysmal Positional Vertigo (BPPV). The clinical utility of VEMP has been reported only in small accord in Indian literature. To study the latency and amplitude of VEMP in patients with BPPV and compare it with that of normal subjects. The study included two groups. Group one (control group) were 18 normal subjects. Group two (test group) were 15 subjects with unilateral BPPV. Those subjects who fulfilled the selection criteria based on case history and audiological assessment were taken for the VEMP recording. The VEMP response consist of positive and negative successive waves (pI-nI), with latency values in adults about 13 and 23 milliseconds respectively. Data was analysed using Statistical Package for Social Sciences (SPSS) version 12 (Chicago, IL, USA). Unpaired t-test was employed to measure the statistical difference between control group and test group. The difference in n23 and the peak to peak amplitude between the ipsilateral and contralateral ears of the test group were statistically significant, whereas such a difference in the p13 latency turned out to be statistically insignificant. It should be noted that, out of 15 patients in the test group, five patients showed only artifact tracer recordings in both the ears which is considered as no response. The heterogeneity of the results extended from absence of VEMP to prolongation of both p13, n23; prolongation of p13 alone; and even side to side variations. Absent response from the ipsilateral ear, prolonged latency of n23 and decreased peak to peak amplitude (p13, n23), indicates the disease pathology. However, large sample size is required to draw further conclusions and to consolidate the usage of VEMP in the diagnosis of BPPV.

Linguistic processing in idiopathic generalized epilepsy: an auditory event-related potential study.

PubMed

Henkin, Yael; Kishon-Rabin, Liat; Pratt, Hillel; Kivity, Sara; Sadeh, Michelle; Gadoth, Natan

2003-09-01

Auditory processing of increasing acoustic and linguistic complexity was assessed in children with idiopathic generalized epilepsy (IGE) by using auditory event-related potentials (AERPs) as well as reaction time and performance accuracy. Twenty-four children with IGE [12 with generalized tonic-clonic seizures (GTCSs), and 12 with absence seizures (ASs)] with average intelligence and age-appropriate scholastic skills, uniformly medicated with valproic acid (VPA), and 20 healthy controls, performed oddball discrimination tasks that consisted of the following stimuli: (a) pure tones; (b) nonmeaningful monosyllables that differed by their phonetic features (i.e., phonetic stimuli); and (c) meaningful monosyllabic words from two semantic categories (i.e., semantic stimuli). AERPs elicited by nonlinguistic stimuli were similar in healthy and epilepsy children, whereas those elicited by linguistic stimuli (i.e., phonetic and semantic) differed significantly in latency, amplitude, and scalp distribution. In children with GTCSs, phonetic and semantic processing were characterized by slower processing time, manifested by prolonged N2 and P3 latencies during phonetic processing, and prolongation of all AERPs latencies during semantic processing. In children with ASs, phonetic and semantic processing were characterized by increased allocation of attentional resources, manifested by enhanced N2 amplitudes. Semantic processing also was characterized by prolonged P3 latency. In both patient groups, processing of linguistic stimuli resulted in different patterns of brain-activity lateralization compared with that in healthy controls. Reaction time and performance accuracy did not differ among the study groups. AERPs exposed linguistic-processing deficits related to seizure type in children with IGE. Neurologic follow-up should therefore include evaluation of linguistic functions, and remedial intervention should be provided, accordingly.

Resident T Cells are Unable to Control HSV-1 Activity in the Brain Ependymal Region During Latency1

PubMed Central

Menendez, Chandra M.; Jinkins, Jeremy K.; Carr, Daniel J.J.

2016-01-01

Herpes simplex virus type 1 (HSV-1) is one of the leading etiologies of sporadic viral encephalitis. Early anti-viral intervention is crucial to the survival of herpes simplex encephalitis patients; however, many survivors suffer from long-term neurological deficits. It is currently understood that HSV-1 establishes a latent infection within sensory peripheral neurons throughout the life of the host. However, the tissue residence of latent virus, other than in sensory neurons, and the potential pathogenic consequences of latency remain enigmatic. In the present study, we characterized the lytic and latent infection of HSV-1 in the central nervous system in comparison to the peripheral nervous system following ocular infection in mice. We utilized RT-PCR to detect latency associated transcripts and HSV-1 lytic cycle genes within the brain stem, the ependyma (EP), containing the limbic and cortical areas which also harbor neural progenitor cells, in comparison to the trigeminal ganglia. Unexpectedly, HSV-1 lytic genes, usually identified during acute infection, are uniquely expressed in the EP 60 days post infection when animals are no longer suffering from encephalitis. An inflammatory response was also mounted in the EP by the maintenance of resident memory T cells. However, EP T cells were incapable of controlling HSV-1 infection ex-vivo and secreted less IFN-γ which correlated with expression of a variety of exhaustion-related inhibitory markers. Collectively our data suggest that the persistent viral lytic gene expression during latency is the cause of the chronic inflammatory response leading to the exhaustion of the resident T cells in the EP. PMID:27357149

Deficits in Lower Limb Muscle Reflex Contraction Latency and Peak Force Are Associated With Impairments in Postural Control and Gross Motor Skills of Children With Developmental Coordination Disorder: A Cross-Sectional Study.

PubMed

Fong, Shirley S M; Ng, Shamay S M; Guo, X; Wang, Yuling; Chung, Raymond C K; Stat, Grad; Ki, W Y; Macfarlane, Duncan J

2015-10-01

This cross-sectional, exploratory study aimed to compare neuromuscular performance, balance and motor skills proficiencies of typically developing children and those with developmental coordination disorder (DCD) and to determine associations of these neuromuscular factors with balance and motor skills performances in children with DCD.One hundred thirty children with DCD and 117 typically developing children participated in the study. Medial hamstring and gastrocnemius muscle activation onset latencies in response to an unexpected posterior-to-anterior trunk perturbation were assessed by electromyography and accelerometer. Hamstring and gastrocnemius muscle peak force and time to peak force were quantified by dynamometer, and balance and motor skills performances were evaluated with the Movement Assessment Battery for Children (MABC).Independent t tests revealed that children with DCD had longer hamstring and gastrocnemius muscle activation onset latencies (P < 0.001) and lower isometric peak forces (P < 0.001), but not times to peak forces (P > 0.025), than the controls. Multiple regression analysis accounting for basic demographics showed that gastrocnemius peak force was independently associated with the MABC balance subscore and ball skills subscore, accounting for 5.7% (P = 0.003) and 8.5% (P = 0.001) of the variance, respectively. Gastrocnemius muscle activation onset latency also explained 11.4% (P < 0.001) of the variance in the MABC ball skills subscore.Children with DCD had delayed leg muscle activation onset times and lower isometric peak forces. Gastrocnemius peak force was associated with balance and ball skills performances, whereas timing of gastrocnemius muscle activation was a determinant of ball skill performance in the DCD population.

Noisy anthropogenic infrastructure interferes with alarm responses in Savannah sparrows (Passerculus sandwichensis)

PubMed Central

Koper, Nicola

2018-01-01

Many birds rely on anti-predator communication to protect their nests; however, anthropogenic noise from industrial activities such as oil and gas development may disrupt acoustic communication. Here, we conducted acoustic playback experiments to determine whether Savannah sparrows (Passerculus sandwichensis) responded to conspecific alarm calls by delaying feeding visits, and whether this response was impaired by noise-producing natural gas compressor stations, generator- or grid-powered screw pump oil wells, and noise amplitude. We played alarm calls, and, as a control, western meadowlark songs, to Savannah sparrows as they approached their nests to feed their nestlings, and measured feeding latency. The greatest impacts on behaviour were detected at the noisiest treatment, compressor stations; feeding latency was shortened here compared with control sites, which may expose nests to greater predation risk. As noise amplitudes increased, Savannah sparrows took longer to feed following meadowlark playbacks, perhaps because noise interfered with interpretation of acoustic cues. The effects of compressor stations on anti-predator behaviour may be best explained by the distracting effects of anthropogenic noise, while increases in feeding latency following meadowlark playbacks may be explained by a heightened response threshold caused by acoustic masking. Industrial infrastructure can influence the reproductive success of wildlife through its impact on perception and interpretation of conspecific signals, but these effects are complex. PMID:29892404

Effect of LED light stimulation on sleep latency in night shift people

NASA Astrophysics Data System (ADS)

Wu, Jih-Huah; Chang, Yang-Chyuan; Chiu, Hui-Ling; Fang, Wei; Shan, Yi-Chia; Chen, Ming-Jie; Chang, Yu-Ting

2014-05-01

Sleep problems are getting worse and worse in modern world. They have a severe impact on psychological and physical health, as well as social performances. From our previous study, the brainwave α rhythm, θ wave and β wave were affected by radiating the palm of the subjects with low-level laser array. In addition, from other study, the LED array stimulator (LEDAS) also has the similar effects. In the present study, LED light was used to radiate the left palm of the subjects too, and the effects were assessed with the multiple sleep latency test (MSLT) and heart-rate variability (HRV) analysis. The results revealed that it doesn't have significant meaning between these two groups. However, the tendency of the sleep latency (SL) in the LED group was shorter than that in the control group. In addition, the autonomic nervous system (ANS) analysis showed that the sympathetic nervous system was getting larger in the LED group than that in the control group, and total ANS activity were mainly getting larger in the LED group. We infer that this LED stimulation could reduce SL and balance ANS activity of the night-shift people. In the future, the further study will be conducted on normal subjects.

Auditory evoked potentials in children and adolescents with Down syndrome.

PubMed

Gregory, Letícia; Rosa, Rafael F M; Zen, Paulo R G; Sleifer, Pricila

2018-01-01

Down syndrome, or trisomy 21, is the most common genetic alteration in humans. The syndrome presents with several features, including hearing loss and changes in the central nervous system, which may affect language development in children and lead to school difficulties. The present study aimed to investigate group differences in the central auditory system by long-latency auditory evoked potentials and cognitive potential. An assessment of 23 children and adolescents with Down syndrome was performed, and a control group composed of 43 children and adolescents without genetic and/or neurological changes was used for comparison. All children underwent evaluation with pure tone and vocal audiometry, acoustic immitance measures, long-latency auditory evoked potentials, and cognitive potential. Longer latencies of the waves were found in the Down syndrome group than the control group, without significant differences in amplitude, suggesting that individuals with Down syndrome have difficulty in discrimination and auditory memory. It is, therefore, important to stimulate and monitor these children in order to enable adequate development and improve their life quality. We also emphasize the importance of the application of auditory evoked potentials in clinical practice, in order to contribute to the early diagnosis of hearing alterations and the development of more research in this area. © 2017 Wiley Periodicals, Inc.

Attention in essential tremor: evidence from event-related potentials.

PubMed

Pauletti, C; Mannarelli, D; Locuratolo, N; Vanacore, N; De Lucia, M C; Mina, C; Fattapposta, F

2013-07-01

Clinically subtle executive dysfunctions have recently been described in essential tremor (ET), though the presence of attentional deficits is still unclear. We investigated the psychophysiological aspects of attention in ET, using event-related potentials (ERPs). Twenty-one non-demented patients with ET and 21 age- and sex-matched healthy controls underwent a psychophysiological evaluation. P300 components and the Contingent Negative Variation (CNV) were recorded. The latencies and amplitudes of the P3a and P3b subcomponents and CNV areas were evaluated. Possible correlations between clinical parameters and ERP data were investigated. P3a latency was significantly longer in the ET group (p < 0.05), while no differences emerged between patients and controls in P3b latency. No differences were observed between the two groups in the CNV parameters. ET patients display a difficulty in the response to novelty and in the recruitment of prefrontal attentive circuits, while the memory context-updating process appears to be spared. This selective cognitive dysfunction does not appear to interfere with the attentional set linked to the expectancy evaluated during a complex choice-reaction time task, which is preserved in ET. This multitask psychophysiological approach reveals the presence of a peculiar attentional deficit in patients with ET, thus expanding the clinical features of this disease.

Interhemispheric transfer time in patients with auditory hallucinations: an auditory event-related potential study.

PubMed

Henshall, Katherine R; Sergejew, Alex A; McKay, Colette M; Rance, Gary; Shea, Tracey L; Hayden, Melissa J; Innes-Brown, Hamish; Copolov, David L

2012-05-01

Central auditory processing in schizophrenia patients with a history of auditory hallucinations has been reported to be impaired, and abnormalities of interhemispheric transfer have been implicated in these patients. This study examined interhemispheric functional connectivity between auditory cortical regions, using temporal information obtained from latency measures of the auditory N1 evoked potential. Interhemispheric Transfer Times (IHTTs) were compared across 3 subject groups: schizophrenia patients who had experienced auditory hallucinations, schizophrenia patients without a history of auditory hallucinations, and normal controls. Pure tones and single-syllable words were presented monaurally to each ear, while EEG was recorded continuously. IHTT was calculated for each stimulus type by comparing the latencies of the auditory N1 evoked potential recorded contralaterally and ipsilaterally to the ear of stimulation. The IHTTs for pure tones did not differ between groups. For word stimuli, the IHTT was significantly different across the 3 groups: the IHTT was close to zero in normal controls, was highest in the AH group, and was negative (shorter latencies ipsilaterally) in the nonAH group. Differences in IHTTs may be attributed to transcallosal dysfunction in the AH group, but altered or reversed cerebral lateralization in nonAH participants is also possible. Copyright © 2012 Elsevier B.V. All rights reserved.

Stress-induced changes in brain serotonergic activity, plasma cortisol and aggressive behavior in Arctic charr (Salvelinus alpinus) is counteracted by L-DOPA.

PubMed

Höglund, E; Kolm, N; Winberg, S

2001-10-01

Arctic charr (Salvelinus alpinus) were tested for aggressive behavior using intruder tests, before and after 2 days of dyadic social interaction. Following social interaction, half of the dominant and half of the subordinate fish were given L-DOPA (10 mg/kg, orally), whereas the remaining dominant and subordinate fish were given vehicle. One hour following drug treatment, the fish were tested for aggressive behavior again in a third and final intruder test, after which blood plasma and brain tissue were sampled for analysis of plasma cortisol concentrations and brain levels of monoamines and monoamine metabolites. Subordinate fish showed a reduction in the number of attacks launched against the intruder, as well as an increase in attack latency, as compared to prior to dyadic social interactions. Social subordination also resulted in an elevation of brain serotonergic activity. Fish receiving L-DOPA prior to the final intruder test showed shorter attack latency than vehicle controls. Drug treatment was a stressful experience and vehicle controls showed elevated plasma cortisol levels and longer attack latency as compared to before treatment. L-DOPA-treated fish showed lower plasma levels of cortisol and lower serotonergic activity in certain brain areas than vehicle controls. These results suggest that L-DOPA counteracts the stress-induced inhibition of aggressive behavior, and at the same time inhibits stress-induced effects on brain serotonergic activity and plasma cortisol concentrations.

Functional Assessment of Corticospinal System Excitability in Karate Athletes.

PubMed

Moscatelli, Fiorenzo; Messina, Giovanni; Valenzano, Anna; Monda, Vincenzo; Viggiano, Andrea; Messina, Antonietta; Petito, Annamaria; Triggiani, Antonio Ivano; Ciliberti, Michela Anna Pia; Monda, Marcellino; Capranica, Laura; Cibelli, Giuseppe

2016-01-01

To investigate the involvement of the primary motor cortex (M1) in the coordination performance of karate athletes through transcranial magnetic stimulation (TMS). Thirteen right-handed male karate athletes (25.0±5.0 years) and 13 matched non-athlete controls (26.7±6.2 years) were enrolled. A single-pulse TMS was applied using a figure-eight coil stimulator. Resting motor threshold (rMT) was determined. Surface electromyography was recorded from the first dorsal interosseous muscle. Motor evoked potential (MEP) latencies and amplitudes at rMT, 110%, and 120% of rMT were considered. Functional assessment of the coordination performance was assessed by in-phase (IP) and anti-phase (AP) homolateral hand and foot coordination tasks performed at 80, 120, and 180 bpm. Compared to controls, athletes showed lower rMT (p<0.01), shorter MEP latency (p<0.01) and higher MEP amplitude (p<0.01), with a significant correlation (r = 0.50, p<0.01) between rMT and MEP latency. Coordination decreased with increasing velocity, and better IP performances emerged compared to AP ones (p<0.001). In general, a high correlation between rMT and coordination tasks was found for both IP and AP conditions. With respect to controls, karate athletes present a higher corticospinal excitability indicating the presence of an activity-dependent alteration in the balance and interactions between inhibitory and facilitatory circuits determining the final output from the M1. Furthermore, the high correlation between corticospinal excitability and coordination performance could support sport-specific neurophysiological arrangements.

Specialised use of working memory by Portia africana, a spider-eating salticid.

PubMed

Cross, Fiona R; Jackson, Robert R

2014-03-01

Using expectancy-violation methods, we investigated the role of working memory in the predatory strategy of Portia africana, a salticid spider from Kenya that preys by preference on other spiders. One of this predator's tactics is to launch opportunistic leaping attacks on to other spiders in their webs. Focussing on this particular tactic, our experiments began with a test spider on a ramp facing a lure (dead prey spider mounted on a cork disc) that could be reached by leaping. After the test spider faced the lure for 30 s, we blocked the test spider's view of the lure by lowering an opaque shutter before the spider leapt. When the shutter was raised 90 s later, either the same lure came into view again (control) or a different lure came into view (experimental: different prey type in same orientation or same prey type in different orientation). We recorded attack frequency (number of test spiders that leapt at the lure) and attack latency (time elapsing between shutter being raised and spiders initiating a leap). Attack latencies in control trials were not significantly different from attack latencies in experimental trials, regardless of whether it was prey type or prey orientation that changed in the experimental trials. However, compared with test spiders in the no-change control trials, significantly fewer test spiders leapt when prey type changed. There was no significant effect on attack frequency when prey orientation changed. These findings suggest that this predator represents prey type independently of prey orientation.

Abnormal reflex activation of hamstring muscles in dogs with cranial cruciate ligament rupture.

PubMed

Hayes, Graham M; Granger, Nicolas; Langley-Hobbs, Sorrel J; Jeffery, Nick D

2013-06-01

The mechanisms underlying cranial cruciate ligament rupture (CCLR) in dogs are poorly understood. In this study hamstring muscle reflexes in response to cranial tibial translation were analysed to determine whether these active stabilisers of the stifle joint are differently activated in dogs with CCLR compared to control dogs. In a prospective clinical study reflex muscle activity from the lateral and medial hamstring muscles (biceps femoris and semimembranosus) was recorded using surface electrodes in control dogs (n=21) and dogs with CCLR (n=22). These electromyographic recordings were analysed using an algorithm previously validated in humans. The hamstring reflex was reliably and reproducibly recorded in normal dogs. Both a short latency response (SLR, 17.6±2.1ms) and a medium latency response (MLR, 37.7±2.7ms) could be identified. In dogs with unilateral CCLR, the SLR and MLR were not significantly different between the affected and the unaffected limbs, but the MLR latency of both affected and unaffected limbs in CCLR dogs were significantly prolonged compared to controls. In conclusion, the hamstring reflex can be recorded in dogs and the MLR is prolonged in dogs with CCLR. Since both affected and unaffected limbs exhibit prolonged MLR, it is possible that abnormal hamstring reflex activation is a mechanism by which progressive CCL damage may occur. The methodology allows for further investigation of the relationship between neuromuscular imbalance and CCLR or limitations in functional recovery following surgical intervention. Copyright © 2012 Elsevier Ltd. All rights reserved.

Bias to negative emotions: a depression state-dependent marker in adolescent major depressive disorder.

PubMed

Maalouf, Fadi T; Clark, Luke; Tavitian, Lucy; Sahakian, Barbara J; Brent, David; Phillips, Mary L

2012-06-30

The aim of the current research was to examine for the first time the extent to which bias to negative emotions in an inhibitory control paradigm is a state or trait marker in major depressive disorder (MDD) in adolescents. We administered the affective go/no go task which measures the ability to switch attention to or away from positive or negative emotional stimuli to 40 adolescents with MDD (20 in acute episode (MDDa) and 20 in remission (MDDr)) and 17 healthy controls (HC). MDDa were significantly faster on the shift to negative target blocks as compared to shift to positive target blocks while HC and MDDr displayed the opposite pattern as measured by an "emotional bias index" (EBI=latency (shift to negative targets)-latency (shift to positive targets)). There was also a trend for an effect of group on commission errors, suggesting more impulsive responding by MDDa than both MDDr and HC independently of stimulus valence throughout the task. Negative bias was not associated with depression severity or medication status. In conclusion, bias to negative emotional stimuli appears to be present in the acute stage of MDD and absent in remission suggesting that it is a depression state-specific marker of MDD in adolescents. Latency emerges as a better proxy of negative bias than commission errors and accuracy on this inhibitory control task in adolescents with MDD. Copyright © 2012 Elsevier Ltd. All rights reserved.

Multifocal blue-on-yellow visual evoked potentials in early glaucoma.

PubMed

Klistorner, Alexander; Graham, Stuart L; Martins, Alessandra; Grigg, John R; Arvind, Hemamalini; Kumar, Rajesh S; James, Andrew C; Billson, Francis A

2007-09-01

To determine the sensitivity and specificity of blue-on-yellow multifocal visual evoked potentials (mfVEPs) in early glaucoma. Cross-sectional study. Fifty patients with a confirmed diagnosis of early glaucoma and 60 normal participants. Black-and-white mfVEPs and blue-on-yellow mfVEPs were recorded using the Accumap version 2.0 (ObjectiVision Pty. Ltd., Sydney, Australia). All patients also underwent achromatic standard automated perimetry (SAP). Multifocal VEP amplitude and latency values in glaucoma patients were analyzed and compared with those of the normal controls. Based on the definition of visual field defect, in the group of glaucomatous eyes with SAP defects, amplitude of blue-on-yellow mfVEP was abnormal in all 64 cases (100% sensitivity), whereas black-and-white mfVEP missed 5 cases (92.2% sensitivity). Generally, larger scotomata were noted on blue-on-yellow mfVEP compared with black-and-white mfVEP for the same eyes. There was high topographic correspondence between SAP and amplitude of blue-on-yellow mfVEP and significant (P<0.0001) correlation between them (correlation coefficient, 0.73). Abnormal amplitude was detected in 3 of 60 eyes of control subjects (95% specificity). There was, however, no correlation between visual field defect and latency delay in glaucoma patients. Although there was a significant difference between averaged latency of control and glaucoma eyes, values considerably overlapped. The blue-on-yellow mfVEP is a sensitive and specific tool for detecting early glaucoma based on amplitude analysis.

Potential effects of reward and loss avoidance in overweight adolescents.

PubMed

Reyes, Sussanne; Peirano, Patricio; Luna, Beatriz; Lozoff, Betsy; Algarín, Cecilia

2015-08-01

Reward system and inhibitory control are brain functions that exert an influence on eating behavior regulation. We studied the differences in inhibitory control and sensitivity to reward and loss avoidance between overweight/obese and normal-weight adolescents. We assessed 51 overweight/obese and 52 normal-weight 15-y-old Chilean adolescents. The groups were similar regarding sex and intelligence quotient. Using Antisaccade and Incentive tasks, we evaluated inhibitory control and the effect of incentive trials (neutral, loss avoidance, and reward) on generating correct and incorrect responses (latency and error rate). Compared to normal-weight group participants, overweight/obese adolescents showed shorter latency for incorrect antisaccade responses (186.0 (95% CI: 176.8-195.2) vs. 201.3 ms (95% CI: 191.2-211.5), P < 0.05) and better performance reflected by lower error rate in incentive trials (43.6 (95% CI: 37.8-49.4) vs. 53.4% (95% CI: 46.8-60.0), P < 0.05). Overweight/obese adolescents were more accurate on loss avoidance (40.9 (95% CI: 33.5-47.7) vs. 49.8% (95% CI: 43.0-55.1), P < 0.05) and reward (41.0 (95% CI: 34.5-47.5) vs. 49.8% (95% CI: 43.0-55.1), P < 0.05) compared to neutral trials. Overweight/obese adolescents showed shorter latency for incorrect responses and greater accuracy in reward and loss avoidance trials. These findings could suggest that an imbalance of inhibition and reward systems influence their eating behavior.

Optogenetic stimulation of cortex to map evoked whisker movements in awake head-restrained mice.

PubMed

Auffret, Matthieu; Ravano, Veronica L; Rossi, Giulia M C; Hankov, Nicolas; Petersen, Merissa F A; Petersen, Carl C H

2018-01-01

Whisker movements are used by rodents to touch objects in order to extract spatial and textural tactile information about their immediate surroundings. To understand the mechanisms of such active sensorimotor processing it is important to investigate whisker motor control. The activity of neurons in the neocortex affects whisker movements, but many aspects of the organization of cortical whisker motor control remain unknown. Here, we filmed whisker movements evoked by sequential optogenetic stimulation of different locations across the left dorsal sensorimotor cortex of awake head-restrained mice. Whisker movements were evoked by optogenetic stimulation of many regions in the dorsal sensorimotor cortex. Optogenetic stimulation of whisker sensory barrel cortex evoked retraction of the contralateral whisker after a short latency, and a delayed rhythmic protraction of the ipsilateral whisker. Optogenetic stimulation of frontal cortex evoked rhythmic bilateral whisker protraction with a longer latency compared to stimulation of sensory cortex. Compared to frontal cortex stimulation, larger amplitude bilateral rhythmic whisking in a less protracted position was evoked at a similar latency by stimulating a cortical region posterior to Bregma and close to the midline. These data suggest that whisker motor control might be broadly distributed across the dorsal mouse sensorimotor cortex. Future experiments must investigate the complex neuronal circuits connecting specific cell-types in various cortical regions with the whisker motor neurons located in the facial nucleus. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Controlling Brownian motion of single protein molecules and single fluorophores in aqueous buffer.

PubMed

Cohen, Adam E; Moerner, W E

2008-05-12

We present an Anti-Brownian Electrokinetic trap (ABEL trap) capable of trapping individual fluorescently labeled protein molecules in aqueous buffer. The ABEL trap operates by tracking the Brownian motion of a single fluorescent particle in solution, and applying a time-dependent electric field designed to induce an electrokinetic drift that cancels the Brownian motion. The trapping strength of the ABEL trap is limited by the latency of the feedback loop. In previous versions of the trap, this latency was set by the finite frame rate of the camera used for video-tracking. In the present system, the motion of the particle is tracked entirely in hardware (without a camera or image-processing software) using a rapidly rotating laser focus and lock-in detection. The feedback latency is set by the finite rate of arrival of photons. We demonstrate trapping of individual molecules of the protein GroEL in buffer, and we show confinement of single fluorophores of the dye Cy3 in water.

De-optical-line-terminal hybrid access-aggregation optical network for time-sensitive services based on software-defined networking orchestration

NASA Astrophysics Data System (ADS)

Bai, Wei; Yang, Hui; Xiao, Hongyun; Yu, Ao; He, Linkuan; Zhang, Jie; Li, Zhen; Du, Yi

2017-11-01

With the increase in varieties of services in network, time-sensitive services (TSSs) appear and bring forward an impending need for delay performance. Ultralow-latency communication has become one of the important development goals for many scenarios in the coming 5G era (e.g., robotics and driverless cars). However, the conventional methods, which decrease delay by promoting the available resources and the network transmission speed, have limited effect; a new breakthrough for ultralow-latency communication is necessary. We propose a de-optical-line-terminal (De-OLT) hybrid access-aggregation optical network (DAON) for TSS based on software-defined networking (SDN) orchestration. In this network, low-latency all-optical communication based on optical burst switching can be achieved by removing OLT. For supporting this network and guaranteeing the quality of service for TSSs, we design SDN-driven control method and service provision method. Numerical results demonstrate the proposed DAON promotes network service efficiency and avoids traffic congestion.

ScreenMasker: An Open-source Gaze-contingent Screen Masking Environment.

PubMed

Orlov, Pavel A; Bednarik, Roman

2016-09-01

The moving-window paradigm, based on gazecontingent technic, traditionally used in a studies of the visual perceptual span. There is a strong demand for new environments that could be employed by non-technical researchers. We have developed an easy-to-use tool with a graphical user interface (GUI) allowing both execution and control of visual gaze-contingency studies. This work describes ScreenMasker, an environment that allows create gaze-contingent textured displays used together with stimuli presentation software. ScreenMasker has an architecture that meets the requirements of low-latency real-time eye-movement experiments. It also provides a variety of settings and functions. Effective rendering times and performance are ensured by means of GPU processing under CUDA technology. Performance tests show ScreenMasker's latency to be 67-74 ms on a typical office computer, and high-end 144-Hz screen latencies of about 25-28 ms. ScreenMasker is an open-source system distributed under the GNU Lesser General Public License and is available at https://github.com/PaulOrlov/ScreenMasker .

Low-Latency Telerobotics from Mars Orbit: The Case for Synergy Between Science and Human Exploration

NASA Technical Reports Server (NTRS)

Valinia, A.; Garvin, J. B.; Vondrak, R.; Thronson, H.; Lester, D.; Schmidt, G.; Fong, T.; Wilcox, B.; Sellers, P.; White, N.

2012-01-01

Initial, science-directed human exploration of Mars will benefit from capabilities in which human explorers remain in orbit to control telerobotic systems on the surface (Figure 1). Low-latency, high-bandwidth telerobotics (LLT) from Mars orbit offers opportunities for what the terrestrial robotics community considers to be high-quality telepresence. Such telepresence would provide high quality sensory perception and situation awareness, and even capabilities for dexterous manipulation as required for adaptive, informed selection of scientific samples [1]. Astronauts on orbit in close communication proximity to a surface exploration site (in order to minimize communication latency) represent a capability that would extend human cognition to Mars (and potentially for other bodies such as asteroids, Venus, the Moon, etc.) without the challenges, expense, and risk of putting those humans on hazardous surfaces or within deep gravity wells. Such a strategy may be consistent with goals for a human space flight program that, are currently being developed within NASA.

Soleus muscle H-reflex monitoring in endoscopic surgery under general anesthesia percutaneous interlaminar approach.

PubMed

Wang, Huixue; Gao, Yingji; Ji, Lixin; Bai, Wanshan

2018-05-01

The clinical value of soleus muscle H-reflex monitoring in general anesthesia percutaneous interlaminar approach was investigated. A total of 80 cases with unilateral L5-S1 disc herniation between January 2015 and October 2016 were randomly divided into control group (without soleus muscle H-reflex monitoring, n=40) and observation group (with soleus muscle H-reflex monitoring, n=40). Results showed that the operation time of the observation group was shorter than that of the control group (P<0.05), and the blood loss during the operation was less than that of the control group (P<0.05). The length of postoperative hospital stay was shorter than that of the control group (P<0.05). At 24 h after operation, the amplitude of H-reflex in diseased side soleus muscle was significantly lower than that in healthy side (P<0.05). The preoperative, postoperative and 24 h postoperatively, the latency of H-reflex in diseased side soleus muscle was shorter than that of healthy side (P<0.05). The latency and amplitude of H-reflex latency in soleus muscle were significantly lower (P<0.05), and the height of intervertebral space in observation group was significantly higher than that in control group (P<0.05). The total percentage of postsurgical sensory dysfunction, dyskinesia, post-root canal stenosis, disc herniation and cerebrospinal fluid leakage was lower than that of the control group (P<0.05). Japanese Orthopaedic Association score of the observation group was significantly higher at 1 month, and 1 year after operation lower than the control group (P<0.05). Taken together, soleus muscle H-reflex monitoring can effectively reduce the damage to the nerve roots under percutaneous endoscopic intervertebral endoscopic surgery under general anesthesia, improve the accuracy of surgery, reduce the complications, shorten the operation time and reduce the surgical bleeding, which is more beneficial to patients smooth recovery.

[Origin of acoustically evoked short latency negative response in guinea pigs].

PubMed

Huang, Wen-qin; Qin, Huan-hua; Nong, Dong-xiao; Tang, An-zhou; Li, Zhi-mei; Yang, Tian

2011-04-01

To establish a model of acoustically evoked short latency negative response (ASNR) in guinea pigs, a model of profound hearing loss with normal saccular functions, and verify the correlation between ASNR and vestibular evoked myogenic potential (VEMP). Thirty-two healthy guinea pigs were employed in the experiment, which were randomly divided into control group (16 subjects) and deafened group (16 subjects). Each animal experienced auditory and vestibular tests including auditory brainstem response (ABR), VEMP and caloric test. A quick treatment was employed for deafened group consisting of a subcutaneous injection of kanamycin at a dose of 400 mg/kg followed by a jugular vein injection of ethacrynic acid at a dose of 40 mg/kg one hour later. The animals were received ABR, VEMP and caloric test 7 - 10 days following the drug administration. The deafened group was further divided into ASNR group and non-ASNR group, based on the presence of ASNR. In deafened group, five subjects died postoperatively, 11 subjects (22 ears) provided full data, ASNR was elicited in eight ears (36.4%), the threshold was 120 - 130 dB SPL with mean of (124.4 ± 4.96) dB SPL. Its latency range was 1.75 - 2.60 ms with mean of (2.15 ± 0.27) ms. The mean latency of threshold was (2.34 ± 0.18) ms. All eight ASNR ears presented with VEMP. The VEMP threshold, positive and negative potential latencies proved no statistical difference (P > 0.05) between ASNR group and control group. Significant difference was detected between the VEMP presence of ASNR group and non-ASNR group (P = 0.002). There was no statistically significant correlation between VEMP and caloric test neither between ASNR and caloric test in deafened group. This study evoked ASNR in an ototoxicity guinea pig model which has profound hearing loss with normal saccular functions. The presence of ASNR correlated with VEMP, however, not correlated with caloric test, suggesting that ASNR and VEMP are both originated from the saccule.

Varicella zoster virus latency

PubMed Central

Eshleman, Emily; Shahzad, Aamir; Cohrs, Randall J

2011-01-01

Primary infection by varicella zoster virus (VZV) typically results in childhood chickenpox, at which time latency is established in the neurons of the cranial nerve, dorsal root and autonomic ganglia along the entire neuraxis. During latency, the histone-associated virus genome assumes a circular episomal configuration from which transcription is epigenetically regulated. The lack of an animal model in which VZV latency and reactivation can be studied, along with the difficulty in obtaining high-titer cell-free virus, has limited much of our understanding of VZV latency to descriptive studies of ganglia removed at autopsy and analogy to HSV-1, the prototype alphaherpesvirus. However, the lack of miRNA, detectable latency-associated transcript and T-cell surveillance during VZV latency highlight basic differences between the two neurotropic herpesviruses. This article focuses on VZV latency: establishment, maintenance and reactivation. Comparisons are made with HSV-1, with specific attention to differences that make these viruses unique human pathogens. PMID:21695042

EXPERIMENTAL ANALYSIS OF THE CONTROL OF SPEECH PRODUCTION AND PERCEPTION. PROGRESS REPORT NO. I, FEBRUARY 1--SEPTEMBER 1, 1961.

ERIC Educational Resources Information Center

LANE, HARLAN; AND OTHERS

THIS DOCUMENT IS THE FIRST IN A SERIES REPORTING ON PROGRESS OF AN EXPERIMENTAL RESEARCH PROGRAM IN SPEECH CONTROL. THE TOPICS DISCUSSED ARE--(1) THE DISCONTINUITY OF AUDITORY DISCRIMINATION LEARNING IN HUMAN ADULTS, (2) DISCRIMINATIVE CONTROL OF CONCURRENT RESPONSES--THE RELATIONS AMONG RESPONSE FREQUENCY, LATENCY, AND TOPOGRAPHY IN AUDITORY…

Short- and long-latency auditory evoked potentials in individuals with vestibular dysfunction.

PubMed

Santos Filha, Valdete Alves Valentins Dos; Bruckmann, Mirtes; Garcia, Michele Vargas

2018-01-01

Purpose Evaluate the auditory pathway at the brainstem and cortical levels in individuals with peripheral vestibular dysfunction. Methods The study sample was composed 19 individuals aged 20-80 years that presented exam results suggestive of Peripheral Vestibular Disorder (PVD) or Vestibular Dysfunction (VD). Participants underwent evaluation of the auditory pathway through Brainstem Auditory Evoked Potentials (BAEP) (short latency) and P1, N1, P2, N2, and P300 cortical potentials (long latency). Results Nine individuals presented diagnosis of VD and 10 participants were diagnosed with PVD. The overall average of the long latency potentials of the participants was within the normal range, whereas an increased mean was observed in the short latency of waves III and V of the left ear, as well as in the I - III interpeak interval of both ears. Association of the auditory potentials with VD and PVD showed statistically significant correlation only in the III - V interpeak interval of the right ear for short latency. Comparison between the long and short latencies in the groups showed differences between VD and PVD, but without statistical significance. Conclusion No statistically significant correlation was observed between VD/PVD and the auditory evoked potentials; however, for the long latency potentials, individuals with VD presented higher latency in P1, N1, P2, and N2, where as participants with PVD showed higher latency in P300. In the short latency potentials, there was an increase in the absolute latencies in the VD group and in the interpeak intervals in the PVD group.

FPGA cluster for high-performance AO real-time control system

NASA Astrophysics Data System (ADS)

Geng, Deli; Goodsell, Stephen J.; Basden, Alastair G.; Dipper, Nigel A.; Myers, Richard M.; Saunter, Chris D.

2006-06-01

Whilst the high throughput and low latency requirements for the next generation AO real-time control systems have posed a significant challenge to von Neumann architecture processor systems, the Field Programmable Gate Array (FPGA) has emerged as a long term solution with high performance on throughput and excellent predictability on latency. Moreover, FPGA devices have highly capable programmable interfacing, which lead to more highly integrated system. Nevertheless, a single FPGA is still not enough: multiple FPGA devices need to be clustered to perform the required subaperture processing and the reconstruction computation. In an AO real-time control system, the memory bandwidth is often the bottleneck of the system, simply because a vast amount of supporting data, e.g. pixel calibration maps and the reconstruction matrix, need to be accessed within a short period. The cluster, as a general computing architecture, has excellent scalability in processing throughput, memory bandwidth, memory capacity, and communication bandwidth. Problems, such as task distribution, node communication, system verification, are discussed.

Visual search and spatial attention: ERPs in focussed and divided attention conditions.

PubMed

Wijers, A A; Okita, T; Mulder, G; Mulder, L J; Lorist, M M; Poiesz, R; Scheffers, M K

1987-08-01

ERPs and performance were measured in divided and focussed attention visual search tasks. In focussed attention tasks, to-be-attended and to-be-ignored letters were presented simultaneously. We varied display load, mapping conditions and display size. RT, P3b-latency and negativity in the ERP associated with controlled search all increased with display load. Each of these measures showed selectivity of controlled search, in that they decreased with focussing of attention. An occipital N230, on the other hand, was not sensitive to focussing of attention, but was primarily affected by display load. ERPs to both attended and unattended targets in focussed attention conditions showed and N2 compared to nontargets, suggesting that both automatic and controlled letter classifications are possible. These effects were not affected by display size. Consistent mapping resulted in shorter RT and P3b-latency in divided attention conditions, compared to varied mapping conditions, but had no effect in focussed attention conditions.

INFLUENCE OF AGE ON NEUROMUSCULAR CONTROL DURING A DYNAMIC WEIGHT BEARING TASK

PubMed Central

Madhavan, Sangeetha; Burkart, Sarah; Baggett, Gail; Nelson, Katie; Teckenburg, Trina; Zwanziger, Mike; Shields, Richard K.

2009-01-01

Neuromuscular control strategies may change with age and predispose elderly to knee joint injury. The purposes of this study were to determine if long latency responses (LLR), muscle activation patterns, and movement accuracy differs between the young and elderly during a novel single limb squat (SLS) task. Ten young and ten elderly subjects performed a series of resistive SLS (~0–30 degrees) while matching a computer-generated sinusoidal target. The SLS device provided a 16% body weight resistance to knee movement. Both young and elderly showed significant overshoot error when the knee was perturbed (p < 0.05). Accuracy of the tracking task was similar between the young and elderly (p=0.34), but the elderly required more muscle activity compared to the younger subjects (p < 0.05). The elderly group had larger long latency responses (LLRs) than the younger group (p < 0.05). These results support that neuromuscular control of the knee changes with age, and may contribute to injury. PMID:19799103

CSMA Versus Prioritized CSMA for Air-Traffic-Control Improvement

NASA Technical Reports Server (NTRS)

Robinson, Daryl C.

2001-01-01

OPNET version 7.0 simulations are presented involving an important application of the Aeronautical Telecommunications Network (ATN), Controller Pilot Data Link Communications (CPDLC) over the Very High Frequency Data Link, Mode 2 (VDL-2). Communication is modeled for essentially all incoming and outgoing nonstop air-traffic for just three United States cities: Cleveland, Cincinnati, and Detroit. There are 32 airports in the simulation, 29 of which are either sources or destinations for the air-traffic of the aforementioned three airports. The simulation involves 111 Air Traffic Control (ATC) ground stations, and 1,235 equally equipped aircraft-taking off, flying realistic free-flight trajectories, and landing in a 24-hr period. Collisionless, Prioritized Carrier Sense Multiple Access (CSMA) is successfully tested and compared with the traditional CSMA typically associated with VDL-2. The performance measures include latency, throughput, and packet loss. As expected, Prioritized CSMA is much quicker and more efficient than traditional CSMA. These simulation results show the potency of Prioritized CSMA for implementing low latency, high throughput, and efficient connectivity.

The effect of optokinetic stimulation on daytime sleepiness

NASA Technical Reports Server (NTRS)

Leslie, K. R.; Stickgold, R.; Dizio, P.; Lackner, J. R.; Hobson, J. A.

1997-01-01

This study examined the effect of optokinetic stimulation on objective sleepiness, as measured by the Multiple Sleep Latency Test (MSLT). The Nightcap, a portable sleep monitor, was used in a novel way to perform MSLTs, as well as record sleep in the home. Subjects wore the Nightcap for seven consecutive nights. On days 3 and 5 of the protocol, subjects came into the lab for an MSLT. On the experimental day, subjects underwent 10 minutes optokinetic stimulation (OKS), resulting in moderate motion sickness prior to each MSLT trial. Although subjects in the OKS condition reported significantly more drowsiness than controls, this did not result in significantly reduced sleep latencies.

Telecare and Social Link Solution for Ambient Assisted Living Using a Robot Companion with Visiophony

NASA Astrophysics Data System (ADS)

Varène, Thibaut; Hillereau, Paul; Simonnet, Thierry

An increasing number of people are in need of help at home (elderly, isolated and/or disabled persons; people with mild cognitive impairment). Several solutions can be considered to maintain a social link while providing tele-care to these people. Many proposals suggest the use of a robot acting as a companion. In this paper we will look at an environment constrained solution, its drawbacks (such as latency) and its advantages (flexibility, integration…). A key design choice is to control the robot using a unified Voice over Internet Protocol (VoIP) solution, while addressing bandwidth limitations, providing good communication quality and reducing transmission latency

Increased Attentional Focus Modulates Eye Movements in a Mixed Antisaccade Task for Younger and Older Adults

PubMed Central

Wang, Jingxin; Tian, Jing; Wang, Rong; Benson, Valerie

2013-01-01

We examined performance in the antisaccade task for younger and older adults by comparing latencies and errors in what we defined as high attentional focus (mixed antisaccades and prosaccades in the same block) and low attentional focus (antisaccades and prosaccades in separate blocks) conditions. Shorter saccade latencies for correctly executed eye movements were observed for both groups in mixed, compared to blocked, antisaccade tasks, but antisaccade error rates were higher for older participants across both conditions. The results are discussed in relation to the inhibitory hypothesis, the goal neglect theory and attentional control theory. PMID:23620767

The Influence of Non-Nociceptive Factors on Hot Plate Latency in Rats

PubMed Central

Gunn, Amanda; Bobeck, Erin N.; Weber, Ceri; Morgan, Michael M.

2010-01-01

The hot plate is a widely used test to assess nociception. The effect of non-nociceptive factors (weight, sex, activity, habituation, and repeated testing) on hot plate latency was examined. Comparison of body weight and hot plate latency revealed a small but significant inverse correlation (light rats had longer latencies). Habituating rats to the test room for 1 hr prior to testing did not decrease hot plate latency except for female rats tested on Days 2 - 4. Hot plate latency decreased with repeated daily testing, but this was not caused by a decrease in locomotor activity or learning to respond. Activity on the hot plate was consistent across all four trials, and prior exposure to a room temperature plate caused a similar decrease in latency as rats tested repeatedly on the hot plate. Despite this decrease in baseline hot plate latency, there was no difference in morphine antinociceptive potency. The present study shows that weight, habituation to the test room, and repeated testing can alter baseline hot plate latency, but these effects are small and have relatively little impact on morphine antinociception. PMID:20797920

Performance and evaluation of real-time multicomputer control systems

NASA Technical Reports Server (NTRS)

Shin, K. G.

1985-01-01

Three experiments on fault tolerant multiprocessors (FTMP) were begun. They are: (1) measurement of fault latency in FTMP; (2) validation and analysis of FTMP synchronization protocols; and investigation of error propagation in FTMP.

An Anatomically Constrained, Stochastic Model of Eye Movement Control in Reading

ERIC Educational Resources Information Center

McDonald, Scott A.; Carpenter, R. H. S.; Shillcock, Richard C.

2005-01-01

This article presents SERIF, a new model of eye movement control in reading that integrates an established stochastic model of saccade latencies (LATER; R. H. S. Carpenter, 1981) with a fundamental anatomical constraint on reading: the vertically split fovea and the initial projection of information in either visual field to the contralateral…

Interactions between neurons in the frontal cortex and hippocampus in cats trained to select reinforcements of different value in conditions of cholinergic deficiency.

PubMed

Dolbakyan, E E; Merzhanova, G Kh

2007-09-01

An operant food-related conditioned reflex was developed in six cats by the "active choice" protocol: short-latency pedal presses were followed by presentation of low-quality reinforcement (bread-meat mix), while long-latency pedal presses were followed by presentation of high-quality reinforcement (meat). Animals differed in terms of their food-procuring strategies, displaying "self-control," "ambivalence," or "impulsivity." Multineuron activity was recorded from the frontal cortex and hippocampus (field CA3). Cross-correlation analysis of interneuronal interactions within (local networks) and between (distributed networks) study structures showed that the numbers of interneuronal interactions in both local and distributed networks were maximal in animals with "self-control." On the background of systemic administration of the muscarinic cholinoreceptor blockers scopolamine and trihexyphenidyl, the numbers of interneuronal interactions decreased, while "common source" influences increased. This correlated with impairment of the reproduction of the selected strategy, primarily affecting the animals' self-controlled behavior. These results show that the "self-control" strategy is determined by the organization of local and distributed networks in the frontal cortex and hippocampus.

Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

PubMed Central

Allen, Sariah J.; Rhode-Kurnow, Antje; Mott, Kevin R.; Jiang, Xianzhi; Carpenter, Dale; Rodriguez-Barbosa, J. Ignacio; Jones, Clinton; Wechsler, Steven L.; Ware, Carl F.

2014-01-01

Herpesvirus entry mediator (HVEM) is one of several cell surface proteins herpes simplex virus (HSV) uses for attachment/entry. HVEM regulates cellular immune responses and can also increase cell survival. Interestingly, latency-associated transcript (LAT), the only viral gene consistently expressed during neuronal latency, enhances latency and reactivation by promoting cell survival and by helping the virus evade the host immune response. However, the mechanisms of these LAT activities are not well understood. We show here for the first time that one mechanism by which LAT enhances latency and reactivation appears to be by upregulating HVEM expression. HSV-1 latency/reactivation was significantly reduced in Hvem−/− mice, indicating that HVEM plays a significant role in HSV-1 latency/reactivation. Furthermore, LAT upregulated HVEM expression during latency in vivo and also when expressed in vitro in the absence of other viral factors. This study suggests a mechanism whereby LAT upregulates HVEM expression potentially through binding of two LAT small noncoding RNAs to the HVEM promoter and that the increased HVEM then leads to downregulation of immune responses in the latent microenvironment and increased survival of latently infected cells. Thus, one of the mechanisms by which LAT enhances latency/reactivation appears to be through increasing expression of HVEM. PMID:24307582

Mental body transformation deficits in patients with chronic balance disorders.

PubMed

Allum, J H J; Langewitz, W; Sleptsova, M; Welge-Luessen, A; Honegger, F; Schatz, T H; Biner, C L; Maguire, C; Schmid, D A

2017-01-01

Movements may be generated consistent with imagining one's own body transformed or "disembodied" to a new position. Based on this concept we hypothesized that patients with objective balance deficits (obj-BD) would have altered neural transformation processes executing own body transformation (OBT) with functional consequences on balance control. Also we examined whether feeling unstable due to dizziness only (DO), without an obj-BD, also lead to an impaired OBT. 32 patients with chronic dizziness were tested: 16 patients with obj-BD as determined by balance control during a sequence of stance and gait tasks, 16 patients with dizziness only (DO). Patients and 9 healthy controls (HCs) were asked to replicate roll trunk movements of an instructor in a life size video: first, with spontaneously copied (SPO) or "embodied" egocentric movements (lean when the instructor leans); second, with "disembodied" or "transformed" movements (OBT) with exact replication - lean left when the instructor leans left. Onset latency of trunk roll, rise time to peak roll angle (interval), roll velocity, and amplitude were measured. SPO movements were always mirror-imaged. OBT task latencies were significantly longer and intervals shorter than for SPO tasks (p < 0.03) for all groups. Obj-BD but not DO patients had more errors for the OBT task and, compared to HCs, had longer onset latencies (p < 0.05) and smaller velocities (p < 0.003) and amplitudes (p < 0.001) in both the SPO and OBT tasks. Measures of DO patients were not significantly different from those of HCs. Mental transformation (OBT) and SPO copying abilities are impaired in subjects with obj-BD and dizziness, but not with dizziness only. We conclude that processing the neuropsychological representation of the human body (body schema) slows when balance control is deficient.

Beneficial effects of garlic on learning and memory deficits and brain tissue damages induced by lead exposure during juvenile rat growth is comparable to the effect of ascorbic acid.

PubMed

Ghasemi, Simagol; Hosseini, Mahmoud; Feizpour, Azadeh; Alipour, Fatemeh; Sadeghi, Akram; Vafaee, Farzaneh; Mohammadpour, Toktam; Soukhtanloo, Mohammad; Ebrahimzadeh Bideskan, Alireza; Beheshti, Farimah

2017-04-01

The neuroprotective effects of both garlic and ascorbic acid (AA) have been documented. In this study the effects of garlic and ascorbic acid on memory deficits and brain tissue oxidative damages induced by lead exposure was investigated. The juvenile rats were divided and treated: (1) Control, (2) Lead (lead acetate in drinking water, 8 weeks), (3) Lead - Ascorbic Acid (Lead-AA), (4)  Lead - Garlic (100 mg/kg, daily, gavage) (Lead-Gar). In Morris water maze (MWM), the escape latency and traveled path in the Lead group were significantly higher while, the time spent in the target quadrant (Q1) was lower than Control. Both Lead-Gar and Lead-AA groups spent more times in Q1than to lead group. There were no significant differences in swimming speed between the groups. In passive avoidance (PA) test, the time latency for entering the dark compartment by Lead group was lower than Control. Treatment of the animals by AA and garlic significantly increased the time latency. In Lead group, the total thiol concentration in brain tissues was significantly lower while, MDA was higher than Control. Treatment by both garlic and AA increased total thiol concentrations and decreased MDA. Both garlic and AA decreased the lead content of brain tissues. It is suggested that treatment with garlic attenuates the learning and memory impairments due to lead exposure during juvenile rat growth which is comparable to AA. The possible mechanism may be due to its protective effects against brain tissues oxidative damage as well the lowering effects of brain lead content.

CTCF Binding Sites in the Herpes Simplex Virus 1 Genome Display Site-Specific CTCF Occupation, Protein Recruitment, and Insulator Function.

PubMed

Washington, Shannan D; Musarrat, Farhana; Ertel, Monica K; Backes, Gregory L; Neumann, Donna M

2018-04-15

There are seven conserved CTCF binding domains in the herpes simplex virus 1 (HSV-1) genome. These binding sites individually flank the latency-associated transcript (LAT) and the immediate early (IE) gene regions, suggesting that CTCF insulators differentially control transcriptional domains in HSV-1 latency. In this work, we show that two CTCF binding motifs in HSV-1 display enhancer blocking in a cell-type-specific manner. We found that CTCF binding to the latent HSV-1 genome was LAT dependent and that the quantity of bound CTCF was site specific. Following reactivation, CTCF eviction was dynamic, suggesting that each CTCF site was independently regulated. We explored whether CTCF sites recruit the polycomb-repressive complex 2 (PRC2) to establish repressive domains through a CTCF-Suz12 interaction and found that Suz12 colocalized to the CTCF insulators flanking the ICP0 and ICP4 regions and, conversely, was removed at early times postreactivation. Collectively, these data support the idea that CTCF sites in HSV-1 are independently regulated and may contribute to lytic-latent HSV-1 control in a site-specific manner. IMPORTANCE The role of chromatin insulators in DNA viruses is an area of interest. It has been shown in several beta- and gammaherpesviruses that insulators likely control the lytic transcriptional profile through protein recruitment and through the formation of three-dimensional (3D) chromatin loops. The ability of insulators to regulate alphaherpesviruses has been understudied to date. The alphaherpesvirus HSV-1 has seven conserved insulator binding motifs that flank regions of the genome known to contribute to the establishment of latency. Our work presented here contributes to the understanding of how insulators control transcription of HSV-1. Copyright © 2018 American Society for Microbiology.

Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial.

PubMed

Cortesi, Flavia; Giannotti, Flavia; Sebastiani, Teresa; Panunzi, Sara; Valente, Donatella

2012-12-01

Although melatonin and cognitive-behavioural therapy have shown efficacy in treating sleep disorders in children with autism spectrum disorders, little is known about their relative or combined efficacy. One hundred and sixty children with autism spectrum disorders, aged 4-10 years, suffering from sleep onset insomnia and impaired sleep maintenance, were assigned randomly to either (1) combination of controlled-release melatonin and cognitive-behavioural therapy; (2) controlled-release melatonin; (3) four sessions of cognitive-behavioural therapy; or (4) placebo drug treatment condition for 12 weeks in a 1 : 1 : 1 : 1 ratio. Children were studied at baseline and after 12 weeks of treatment. Treatment response was assessed with 1-week actigraphic monitoring, sleep diary and sleep questionnaire. Main outcome measures, derived actigraphically, were sleep latency, total sleep time, wake after sleep onset and number of awakenings. The active treatment groups all resulted in improvements across all outcome measures, with moderate-to-large effect sizes from baseline to a 12-week assessment. Melatonin treatment was mainly effective in reducing insomnia symptoms, while cognitive-behavioural therapy had a light positive impact mainly on sleep latency, suggesting that some behavioural aspects might play a role in determining initial insomnia. The combination treatment group showed a trend to outperform other active treatment groups, with fewer dropouts and a greater proportion of treatment responders achieving clinically significant changes (63.38% normative sleep efficiency criterion of >85% and 84.62%, sleep onset latency <30 min). This study demonstrates that adding behavioural intervention to melatonin treatment seems to result in a better treatment response, at least in the short term. © 2012 European Sleep Research Society.

Lexical selection in the semantically blocked cyclic naming task: the role of cognitive control and learning

PubMed Central

Crowther, Jason E.; Martin, Randi C.

2014-01-01

Studies of semantic interference in language production have provided evidence for a role of cognitive control mechanisms in regulating the activation of semantic competitors during naming. The present study investigated the relationship between individual differences in cognitive control abilities, for both younger and older adults, and the degree of semantic interference in a blocked cyclic naming task. We predicted that individuals with lower working memory capacity (as measured by word span), lesser ability to inhibit distracting responses (as measured by Stroop interference), and a lesser ability to resolve proactive interference (as measured by a recent negatives task) would show a greater increase in semantic interference in naming, with effects being larger for older adults. Instead, measures of cognitive control were found to relate to specific indices of semantic interference in the naming task, rather than overall degree of semantic interference, and few interactions with age were found, with younger and older adults performing similarly. The increase in naming latencies across naming trials within a cycle was negatively correlated with word span for both related and unrelated conditions, suggesting a strategy of narrowing response alternatives based upon memory for the set of item names. Evidence for a role of inhibition in response selection was obtained, as Stroop interference correlated positively with the change in naming latencies across cycles for the related, but not unrelated, condition. In contrast, recent negatives interference correlated negatively with the change in naming latencies across unrelated cycles, suggesting that individual differences in this tap the degree of strengthening of links in a lexical network based upon prior exposure. Results are discussed in terms of current models of lexical selection and consequences for word retrieval in more naturalistic production. PMID:24478675

Inhibition of highly pathogenic avian influenza (HPAI) virus by a peptide derived from vFLIP through its direct destabilization of viruses.

PubMed

Moon, Ho-Jin; Nikapitiya, Chamilani; Lee, Hyun-Cheol; Park, Min-Eun; Kim, Jae-Hoon; Kim, Tae-Hwan; Yoon, Ji-Eun; Cho, Won-Kyung; Ma, Jin Yeul; Kim, Chul-Joong; Jung, Jae U; Lee, Jong-Soo

2017-07-07

The antiviral activities of synthesized Kα2-helix peptide, which was derived from the viral FLICE-like inhibitor protein (vFLIP) of Kaposi's sarcoma-associated herpesvirus (KSHV), against influenza A virus (IAV) were investigated in vitro and in vivo, and mechanisms of action were suggested. In addition to the robust autophagy activity of the Kα2-helix peptide, the present study showed that treatment with the Kα2 peptide fused with the TAT peptide significantly inhibited IAV replication and transmission. Moreover, TAT-Kα2 peptide protected the mice, that were challenged with lethal doses of highly pathogenic influenza A H5N1 or H1N1 viruses. Mechanistically, we found that TAT-Kα2 peptide destabilized the viral membranes, depending on their lipid composition of the viral envelop. In addition to IAV, the Kα2 peptide inhibited infections with enveloped viruses, such as Vesicular Stomatitis Virus (VSV) and Respiratory Syncytial Virus (RSV), without cytotoxicity. These results suggest that TAT-Kα2 peptide is a potential antiviral agent for controlling emerging or re-emerging enveloped viruses, particularly diverse subtypes of IAVs.

Is the relationship between race and continuous positive airway pressure adherence mediated by sleep duration?

PubMed

Billings, Martha E; Rosen, Carol L; Wang, Rui; Auckley, Dennis; Benca, Ruth; Foldvary-Schaefer, Nancy; Iber, Conrad; Zee, Phyllis; Redline, Susan; Kapur, Vishesh K

2013-02-01

Black race has been associated with decreased continuous positive airway pressure (CPAP) adherence. Short sleep duration, long sleep latency, and insomnia complaints may affect CPAP adherence as they affect sleep and opportunity to use CPAP. We assessed whether self-reported sleep measures were associated with CPAP adherence and if racial variations in these sleep characteristics may explain racial differences in CPAP adherence. Analysis of data from a randomized controlled trial (HomePAP), which investigated home versus laboratory-based diagnosis and treatment of obstructive sleep apnea. Seven American Academy of Sleep Medicine-accredited sleep centers in five cities in the United States. Enrolled subjects (n = 191) with apnea-hypopnea index ≥ 15 and sleepiness (Epworth Sleepiness Scale > 12). N/A. Multivariable regression was used to assess if subjective sleep measures and symptoms predicted 3-mo CPAP use. Mediation analysis was used to assess if sleep measures mediated the association of race with CPAP adherence. Black participants reported shorter sleep duration and longer sleep latency at baseline than white and Hispanic participants. Shorter sleep duration and longer sleep latency predicted worse CPAP adherence. Sleep duration mediated the association of black race with lower CPAP adherence. However, insomnia symptoms were not associated with race or CPAP adherence. Among subjects with similar severity of obstructive sleep apnea and sleepiness, baseline self-reported sleep duration and latency, but not perceived insomnia, predicted CPAP adherence over 3 mo. Sleep duration explains some of the observed differences in CPAP use by race. Sleep duration and latency should be considered when evaluating poor CPAP adherence. PORTABLE MONITORING FOR DIAGNOSIS AND MANAGEMENT OF SLEEP APNEA (HOMEPAP) URL: http://clinicaltrials.gov/show/NCT00642486. NIH clinical trials registry number: NCT00642486.

Relationship between parent knowledge of child sleep, and child sleep practices and problems: A pilot study in a children's hospital cohort.

PubMed

McDowall, Philippa S; Elder, Dawn E; Campbell, Angela J

2017-08-01

To describe parent reports of sleep practices, and examine associations with parent knowledge of child sleep, and whether children's sleep practices differ between parents who underestimated, overestimated or accurately estimated children's sleep needs. Parents of children aged 2-12 years (n = 115) attending hospital inpatient or day wards were approached and asked to report child sleep routines, sleep problems, parent education, household income and parent knowledge of child sleep via questionnaire. Younger age was associated with earlier bedtimes and wake times, shorter sleep latencies, longer sleep durations and greater sleep problems (P < 0.05). Parents from higher income homes reported earlier bedtimes and wake times, shorter sleep latencies and fewer sleep problems (P < 0.05). Parents with higher education reported shorter sleep latencies (P < 0.05). Parents with greater knowledge about child sleep reported earlier weekday and weekend bedtimes (r s  ≥ 0.26) and wake times (r s  ≥ 0.21) and greater consistency between their child's weekend and weekday sleep routines (P < 0.05). In comparison with parents who correctly estimated their child's sleep needs: parents who underestimated reported later weekday bedtimes (on average, 46 min), and longer sleep latencies (17 min); parents who overestimated reported longer sleep latencies (22 min). These findings remained significant when controlling for child age (P < 0.05). Parents with increased sleep knowledge, higher incomes and higher levels of education were more likely to report earlier bedtimes, wake times and more consistent sleep routines for their children. © 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

Probable neuro sexual mode of action of Casimiroa edulis seed extract versus [correction of verses] sildenafil citrate (Viagra(tm)) on mating behavior in normal male rats.

PubMed

Ali, Syed Tabrez; Rakkah, Nabeeh I

2008-01-01

The present study deals with the aphrodisiac actions of the aqueous extract of the seeds of the hypotensive plant Casimiroa edulis on the sexual behavior of normal male rats. In this investigation 30 healthy male Wister strain white albino rats showing the brisk sexual activity age 15 weeks, weighing 400-450 grams were included. Female rats were artificially brought into estrous by hormonal treatment. Receptivity was checked by exposing them to the male rats and the most receptive females were selected for the stud The mating responses including Mounting Frequency (MF), Intromission Frequency (IF), Mounting Latency (ML), Intromission Latency (IL), Ejaculatory Latency in first and second series (EL1 and EL2) and Post Ejaculatory Interval (PEI) were recorded after treating the animals with 250 mg/kg casimiroa edulis extract (test reference) and 5 mg/kg sildenafil citrate (standard reference) respectively orally per day for 7 days. Both the groups exhibited a significant increase in Mounting Frequency, Intromission Frequency, and first and second ejaculatory latencies, where as Mounting and Intromission latencies and the Post Ejaculatory Interval showed a significant reduction than the controls. Although a similar pattern of mating behavior was observed among the test and the standard groups, however in all the cases as expected, sildenafil produced greater activity than the casimiroa edulis extract. These results suggest the possibility of a similar mode of action of casimiroa edulis and sildenafil citrate on mating behavior in these animals. Our work reported in this research thus provide preliminary evidence that the aqueous seed extract of casimiroa edulis possesses alphrodisiac activity and may be used as an alternative drug therapy to restore sexual functions probably via a neurogenic mode of action.

Posttraining intraamygdala infusions of oxotremorine and propranolol modulate storage of memory for reductions in reward magnitude.

PubMed

Salinas, J A; Introini-Collison, I B; Dalmaz, C; McGaugh, J L

1997-07-01

These experiments examined the effects of posttraining intraamygdala administration of the muscarinic agonist, oxotremorine, and the beta-noradrenergic antagonist, propranolol, on memory for reduction in reward magnitude. Male Sprague-Dawley rats (175-200 g) implanted with bilateral intraamygdala cannulae were food deprived (maintained at 80% of body weight) and trained to run a straight alley (six trials/day) for either ten 45-mg food pellets (high reward) or one 45-mg food pellet (low reward) for 10 days. In Experiment One, the animals in the high-reward group were than shifted to a one-pellet reward and immediately given intraamygdala infusions (0.5 microliter/side) of either oxotremorine (10 ng) or phosphate buffer. Shifted training continued for 4 more days and no further injections were given. Shifted animals given the buffer solution displayed an increase in runway latencies but returned to preshift latencies by the fifth day of shifted training. In contrast, animals given oxotremorine exhibited increased latencies through the fifth day. In Experiment Two, rats were trained as in Experiment. One but immediately following the shift received intraamygdala infusions of oxotremorine (10 ng), propranolol (0.3 microgram), both, or phosphate buffer. Shifted vehicle-injected rats returned to preshift performance by the fifth day of shifted training. Shifted propranolol rats returned to preshift latencies by the third day of shifted training. In contrast, the shifted oxotremorine and the shifted oxotremorine/propranolol rats displayed longer latencies than unshifted controls through 5 days of shifted training. The findings indicate that the muscarinic cholinergic and beta-noradrenergic systems within the amygdala interact in regulating memory and support the view that noradrenergic influences are mediated through cholinergic activation.