What's all the talk about? Topic modelling in a mental health Internet support group.

PubMed

Carron-Arthur, Bradley; Reynolds, Julia; Bennett, Kylie; Bennett, Anthony; Griffiths, Kathleen M

2016-10-28

The majority of content in an Internet Support Group (ISG) is contributed by 1 % of the users ('super users'). Computational methods, such as topic modelling, can provide a large-scale quantitative objective description of this content. Such methods may provide a new perspective on the nature of engagement on ISGs including the role of super users and their possible effect on other users. A topic model was computed for all posts (N = 131,004) in the ISG BlueBoard using Latent Dirichlet Allocation. A model containing 25 topics was selected on the basis of intelligibility as determined by diagnostic metrics and qualitative investigation. This model yielded 21 substantive topics for further analysis. Two chi-square tests were conducted separately for each topic to ascertain: (i) if the odds of super users' and other users' posting differed for each topic; and (ii) if for super users the odds of posting differed depending on whether the response was to a super user or to another user. The 21 substantive topics covered a range of issues related to mental health and peer-support. There were significantly higher odds that super users wrote content on 13 topics, with the greatest effects being for Parenting Role (OR [95%CI] = 7.97 [7.85-8.10]), Co-created Fiction (4.22 [4.17-4.27]), Mental Illness (3.13 [3.11-3.16]) and Positive Change (2.82 [2.79-2.84]). There were significantly lower odds for super users on 7 topics, with the greatest effects being for the topics Depression (OR = 0.27 [0.27-0.28]), Medication (0.36 [0.36-0.37]), Therapy (0.55 [0.54-0.55]) and Anxiety (0.55 [0.55-0.55]). However, super users were significantly more likely to write content on 5 out of these 7 topics when responding to other users than when responding to fellow super users. The findings suggest that super users serve the role of emotionally supportive companions with a focus on topics broadly resembling the consumer/carer model of recovery. Other users engage in topics with a greater focus on experiential knowledge, disclosure and informational support, a pattern resembling the clinical symptom-focussed approach to recovery. However, super users modify their content in response to other users in a manner consistent with being 'active help providers'.

Identification and characterization of a novel ISG15-ubiquitin mixed chain and its role in regulating protein homeostasis

PubMed Central

Fan, Jun-Bao; Arimoto, Kei-lchiro; Motamedchaboki, Khatereh; Yan, Ming; Wolf, Dieter A.; Zhang, Dong-Er

2015-01-01

As a ubiquitin-like modifier, ISG15 is conjugated to many cellular proteins in a process termed protein ISGylation. However, the crosstalk between protein ISGylation and the ubiquitin proteasome system is not fully understood. Here, we report that cellular ubiquitin is a substrate of ISG15 and Lys 29 on ubiquitin is the major ISG15 acceptor site. Using a model substrate, we demonstrate that ISG15 can modify ubiquitin, which is immobilized on its substrate, to form ISG15-ubiquitin mixed chains. Furthermore, our results indicate that ISG15-ubiquitin mixed chains do not serve as degradation signals for a ubiquitin fusion degradation substrate. Accordingly, an ISG15-ubiquitin fusion protein, which mimics an ISG15-ubiquitin mixed chain, negatively regulates cellular turnover of ubiquitylated proteins. In addition, ISG15-ubiquitin mixed chains, which are detectable on endogenously ubiquitylated proteins, dampen cellular turnover of these proteins. Thus, our studies unveil an unanticipated interplay between two protein modification systems and highlight its role in coordinating protein homeostasis. PMID:26226047

Addressing Fission Product Validation in MCNP Burnup Credit Criticality Calculations

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

Mueller, Don; Bowen, Douglas G; Marshall, William BJ J

2015-01-01

The US Nuclear Regulatory Commission (NRC) Division of Spent Fuel Storage and Transportation issued Interim Staff Guidance (ISG) 8, Revision 3 in September 2012. This ISG provides guidance for NRC staff members’ review of burnup credit (BUC) analyses supporting transport and dry storage of pressurized water reactor spent nuclear fuel (SNF) in casks. The ISG includes guidance for addressing validation of criticality (k eff) calculations crediting the presence of a limited set of fission products and minor actinides (FP&MAs). Based on previous work documented in NRC Regulatory Guide (NUREG) Contractor Report (CR)-7109, the ISG recommends that NRC staff members acceptmore » the use of either 1.5 or 3% of the FP&MA worth—in addition to bias and bias uncertainty resulting from validation of k eff calculations for the major actinides in SNF—to conservatively account for the bias and bias uncertainty associated with the specified unvalidated FP&MAs. The ISG recommends (1) use of 1.5% of the FP&MA worth if a modern version of SCALE and its nuclear data are used and (2) 3% of the FP&MA worth for well qualified, industry standard code systems other than SCALE with the Evaluated Nuclear Data Files, Part B (ENDF/B),-V, ENDF/B-VI, or ENDF/B-VII cross sections libraries. The work presented in this paper provides a basis for extending the use of the 1.5% of the FP&MA worth bias to BUC criticality calculations performed using the Monte Carlo N-Particle (MCNP) code. The extended use of the 1.5% FP&MA worth bias is shown to be acceptable by comparison of FP&MA worths calculated using SCALE and MCNP with ENDF/B-V, -VI, and -VII–based nuclear data. The comparison supports use of the 1.5% FP&MA worth bias when the MCNP code is used for criticality calculations, provided that the cask design is similar to the hypothetical generic BUC-32 cask model and that the credited FP&MA worth is no more than 0.1 Δk eff (ISG-8, Rev. 3, Recommendation 4).« less

IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses

PubMed Central

Lenschow, Deborah J.; Lai, Caroline; Frias-Staheli, Natalia; Giannakopoulos, Nadia V.; Lutz, Andrew; Wolff, Thorsten; Osiak, Anna; Levine, Beth; Schmidt, Robert E.; García-Sastre, Adolfo; Leib, David A.; Pekosz, Andrew; Knobeloch, Klaus-Peter; Horak, Ivan; Virgin, Herbert Whiting

2007-01-01

Type I interferons (IFNs) play an essential role in the host response to viral infection through the induction of numerous IFN-stimulated genes (ISGs), including important antiviral molecules such as PKR, RNase L, Mx, and iNOS. Yet, additional antiviral ISGs likely exist. IFN-stimulated gene 15 (ISG15) is a ubiquitin homolog that is rapidly up-regulated after viral infection, and it conjugates to a wide array of host proteins. Although it has been hypothesized that ISG15 functions as an antiviral molecule, the initial evaluation of ISG15-deficient mice revealed no defects in their responses to vesicular stomatitis virus or lymphocytic choriomeningitis virus, leaving open the important question of whether ISG15 is an antiviral molecule in vivo. Here we demonstrate that ISG15 is critical for the host response to viral infection. ISG15−/− mice are more susceptible to influenza A/WSN/33 and influenza B/Lee/40 virus infections. ISG15−/− mice also exhibited increased susceptibility to both herpes simplex virus type 1 and murine gammaherpesvirus 68 infection and to Sindbis virus infection. The increased susceptibility of ISG15−/− mice to Sindbis virus infection was rescued by expressing wild-type ISG15, but not a mutant form of ISG15 that cannot form conjugates, from the Sindbis virus genome. The demonstration of ISG15 as a novel antiviral molecule with activity against both RNA and DNA viruses provides a target for the development of therapies against important human pathogens. PMID:17227866

Silencing of IFN-stimulated gene transcription is regulated by histone H1 and its chaperone TAF-I

PubMed Central

Kadota, Shinichi; Nagata, Kyosuke

2014-01-01

Chromatin structure and its alteration play critical roles in the regulation of transcription. However, the transcriptional silencing mechanism with regard to the chromatin structure at an unstimulated state of the interferon (IFN)-stimulated gene (ISG) remains unclear. Here we investigated the role of template activating factor-I (TAF-I, also known as SET) in ISG transcription. Knockdown (KD) of TAF-I increased ISG transcript and simultaneously reduced the histone H1 level on the ISG promoters during the early stages of transcription after IFN stimulation from the unstimulated state. The transcription factor levels on the ISG promoters were increased in TAF-I KD cells only during the early stages of transcription. Furthermore, histone H1 KD also increased ISG transcript. TAF-I and histone H1 double KD did not show the additive effect in ISG transcription, suggesting that TAF-I and histone H1 may act on the same regulatory pathway to control ISG transcription. In addition, TAF-I KD and histone H1 KD affected the chromatin structure near the ISG promoters. On the basis of these findings, we propose that TAF-I and its target histone H1 are key regulators of the chromatin structure at the ISG promoter to maintain the silent state of ISG transcription. PMID:24878923

Human rhinovirus-induced ISG15 selectively modulates epithelial antiviral immunity

PubMed Central

Zaheer, R S; Wiehler, S; Hudy, M H; Traves, S L; Pelikan, J B; Leigh, R; Proud, D

2014-01-01

Human rhinovirus (HRV) infections trigger exacerbations of lower airway diseases. HRV infects human airway epithelial cells and induces proinflammatory and antiviral molecules that regulate the response to HRV infection. Interferon (IFN)-stimulated gene of 15 kDa (ISG15) has been shown to regulate other viruses. We now show that HRV-16 infection induces both intracellular epithelial ISG15 expression and ISG15 secretion in vitro. Moreover, ISG15 protein levels increased in nasal secretions of subjects with symptomatic HRV infections. HRV-16-induced ISG15 expression is transcriptionally regulated via an IFN regulatory factor pathway. ISG15 does not directly alter HRV replication but does modulate immune signaling via the viral sensor protein RIG-I to impact production of CXCL10, which has been linked to innate immunity to viruses. Extracellular ISG15 also alters CXCL10 production. We conclude that ISG15 has a complex role in host defense against HRV infection, and that additional studies are needed to clarify the role of this molecule. PMID:24448099

ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response.

PubMed

Malakhova, Oxana A; Zhang, Dong-Er

2008-04-04

Interferons regulate diverse immune functions through the transcriptional activation of hundreds of genes involved in anti-viral responses. The interferon-inducible ubiquitin-like protein ISG15 is expressed in cells in response to a variety of stress conditions like viral or bacterial infection and is present in its free form or is conjugated to cellular proteins. In addition, protein ubiquitination plays a regulatory role in the immune system. Many viruses modulate the ubiquitin (Ub) pathway to alter cellular signaling and the antiviral response. Ubiquitination of retroviral group-specific antigen precursors and matrix proteins of the Ebola, vesicular stomatitis, and rabies viruses by Nedd4 family HECT domain E3 ligases is an important step in facilitating viral release. We found that Nedd4 is negatively regulated by ISG15. Free ISG15 specifically bound to Nedd4 and blocked its interaction with Ub-E2 molecules, thus preventing further Ub transfer from E2 to E3. Furthermore, overexpression of ISG15 diminished the ability of Nedd4 to ubiquitinate viral matrix proteins and led to a decrease in the release of Ebola VP40 virus-like particles from the cells. These results point to a mechanistically novel function of ISG15 in the enhancement of the innate anti-viral response through specific inhibition of Nedd4 Ub-E3 activity. To our knowledge, this is the first example of a Ub-like protein with the ability to interfere with Ub-E2 and E3 interaction to inhibit protein ubiquitination.

Estimated protective effectiveness of intramuscular immune serum globulin post-exposure prophylaxis during a measles outbreak in British Columbia, Canada, 2014.

PubMed

Bigham, Mark; Murti, Michelle; Fung, Christina; Hemming, Felicity; Loadman, Susan; Stam, Robert; Van Buynder, Paul; Lem, Marcus

2017-05-09

Intramuscular Immune Serum Globulin (IM ISG) is recommended as post-measles exposure prophylaxis (PEP) when administered within 6days of initial exposure, with variable effectiveness in preventing measles disease. Effectiveness of IM ISG PEP in preventing clinical measles was assessed during a 2014 measles outbreak among a religious-affiliated community in British Columbia, Canada. Fifty-five self-reporting measles susceptible contacts were offered exclusively IM ISG PEP within an eligibility period best surmised to be within 6days of initial measles case exposure. Clinical outcome of IM ISG PEP recipients was determined by selective active surveillance and case self-reporting. IM ISG PEP failure was defined as onset of a measles-like rash 8-21days post-IM ISG PEP. Post-IM ISG PEP measles IgG antibody level was tested in 8 recipients. Factors associated with measles disease were analyzed. Seventeen of 55 IM ISG PEP recipients developed clinically consistent measles in the following 8-21days, corresponding to an estimated crude protective effectiveness of 69%. In school aged children 5-18years, among whom potential exposure intensity and immune status confounders were considered less likely, estimated IM ISG PEP protective effectiveness was 50%. Age <25years was significantly associated with breakthrough clinical measles in bivariate analysis (p=0.0217). Among 8 tested contacts of 17 considered IM ISG PEP failures, post-IM ISG PEP measles IgG antibody levels (mean 16.3days (range 16-17days) post-PEP) were all <150mIU/ml. The estimated crude IM ISG PEP protective effectiveness against measles disease within 8-21days post-ISG administration was 69%. Accuracy of this estimated protective effectiveness is vulnerable to assumptions and uncertainties in ascertaining exposure details and pre-exposure immune status. Increasing the Canadian recommended measles IM ISG PEP dose from 0.25 to 0.5ml/kg (up to 15ml maximum volume) may increase protective effectiveness. Copyright © 2017 Elsevier Ltd. All rights reserved.

Silencing of IFN-stimulated gene transcription is regulated by histone H1 and its chaperone TAF-I.

PubMed

Kadota, Shinichi; Nagata, Kyosuke

2014-07-01

Chromatin structure and its alteration play critical roles in the regulation of transcription. However, the transcriptional silencing mechanism with regard to the chromatin structure at an unstimulated state of the interferon (IFN)-stimulated gene (ISG) remains unclear. Here we investigated the role of template activating factor-I (TAF-I, also known as SET) in ISG transcription. Knockdown (KD) of TAF-I increased ISG transcript and simultaneously reduced the histone H1 level on the ISG promoters during the early stages of transcription after IFN stimulation from the unstimulated state. The transcription factor levels on the ISG promoters were increased in TAF-I KD cells only during the early stages of transcription. Furthermore, histone H1 KD also increased ISG transcript. TAF-I and histone H1 double KD did not show the additive effect in ISG transcription, suggesting that TAF-I and histone H1 may act on the same regulatory pathway to control ISG transcription. In addition, TAF-I KD and histone H1 KD affected the chromatin structure near the ISG promoters. On the basis of these findings, we propose that TAF-I and its target histone H1 are key regulators of the chromatin structure at the ISG promoter to maintain the silent state of ISG transcription. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

ISG15 in the tumorigenesis and treatment of cancer: An emerging role in malignancies of the digestive system

PubMed Central

Zuo, Chaohui; Sheng, Xinyi; Ma, Min; Xia, Man; Ouyang, Linda

2016-01-01

The interferon-stimulated gene 15 ubiquitin-like modifier (ISG15) encodes an IFN-inducible, ubiquitin-like protein. The ISG15 protein forms conjugates with numerous cellular proteins that are involved in a multitude of cellular functions, including interferon-induced immune responses and the regulation of cellular protein turnover. The expression of ISG15 and ISG15-mediated conjugation has been implicated in a wide range of human tumors and cancer cell lines, but the roles of ISG15 in tumorigenesis and responses to anticancer treatments remain largely unknown. In this review, we discuss the findings of recent studies with regard to the role of ISG15 pathways in cancers of the digestive system. PMID:27626310

ISG15 in the tumorigenesis and treatment of cancer: An emerging role in malignancies of the digestive system.

PubMed

Zuo, Chaohui; Sheng, Xinyi; Ma, Min; Xia, Man; Ouyang, Linda

2016-11-08

The interferon-stimulated gene 15 ubiquitin-like modifier (ISG15) encodes an IFN-inducible, ubiquitin-like protein. The ISG15 protein forms conjugates with numerous cellular proteins that are involved in a multitude of cellular functions, including interferon-induced immune responses and the regulation of cellular protein turnover. The expression of ISG15 and ISG15-mediated conjugation has been implicated in a wide range of human tumors and cancer cell lines, but the roles of ISG15 in tumorigenesis and responses to anticancer treatments remain largely unknown. In this review, we discuss the findings of recent studies with regard to the role of ISG15 pathways in cancers of the digestive system.

ISG15 Functions as an Interferon-Mediated Antiviral Effector Early in the Murine Norovirus Life Cycle

PubMed Central

Rodriguez, Marisela R.; Monte, Kristen; Thackray, Larissa B.

2014-01-01

ABSTRACT Human noroviruses (HuNoV) are the leading cause of nonbacterial gastroenteritis worldwide. Similar to HuNoV, murine noroviruses (MNV) are enteric pathogens spread via the fecal-oral route and have been isolated from numerous mouse facilities worldwide. Type I and type II interferons (IFN) restrict MNV-1 replication; however, the antiviral effectors impacting MNV-1 downstream of IFN signaling are largely unknown. Studies using dendritic cells, macrophages, and mice deficient in free and conjugated forms of interferon-stimulated gene 15 (ISG15) revealed that ISG15 conjugation contributes to protection against MNV-1 both in vitro and in vivo. ISG15 inhibited a step early in the viral life cycle upstream of viral genome transcription. Directly transfecting MNV-1 RNA into IFN-stimulated mouse embryonic fibroblasts (MEFs) and bone marrow-derived dendritic cells (BMDC) lacking ISG15 conjugates bypassed the antiviral activity of ISG15, further suggesting that ISG15 conjugates restrict the MNV-1 life cycle at the viral entry/uncoating step. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection both in vitro and in vivo and for the first time implicate the ISG15 pathway in the regulation of early stages of MNV-1 replication. IMPORTANCE Type I IFNs are important in controlling murine norovirus 1 (MNV-1) infections; however, the proteins induced by IFNs that restrict viral growth are largely unknown. This report reveals that interferon-stimulated gene 15 (ISG15) mitigates MNV-1 replication both in vitro and in vivo. In addition, it shows that ISG15 inhibits MNV-1 replication by targeting an early step in the viral life cycle, MNV-1 entry and/or uncoating. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection both in vitro and in vivo and for the first time implicate the ISG15 pathway in the regulation of viral entry/uncoating. PMID:24899198

Expression Analysis of Interferon-Stimulated Gene 15 in the Rock Bream Oplegnathus fasciatus against Rock Bream Iridovirus (RSIV) Challenge.

PubMed

Kim, Kyung-Hee; Yang, In Jung; Kim, Woo-Jin; Park, Choul-Ji; Park, Jong-Won; Noh, Gyeong Eon; Lee, Seunghyung; Lee, Young Mee; Hwang, Hyung Kyu; Kim, Hyun Chul

2017-12-01

Interferon-stimulated gene 15 (ISG15) is known to interfere with viral replication and infection by limiting the viral infection of cells. Interferon-stimulated gene 15 (ISG15) interferes with viral replication and infectivity by limiting viral infection in cells. It also plays an important role in the immune response. In this study, tissue-specific expression of ISG15 in healthy rock bream samples and spatial and temporal expression analysis of rock bream ISG15 (RbISG15) were performed following rock bream iridovirus (RSIV) infection. RbISG15 expression was significantly higher in the eye, gill, intestine, kidney, liver, muscle, spleen, and stomach, but low in the brain. There were particularly high levels of expression in the liver and muscle. RbISG15 expression was also examined in several tissues and at various times following RSIV infection. ISG15 expression increased within 3 h in the whole body and decreased at 24 h after infection. In addition, temporal expression of several tissues following RSIV infection showed a similar pattern in the muscle, kidney, and spleen, increasing at 3 h and decreasing at 72 h. These results suggest that ISG15 plays an important role in the immune response of rock bream. Overall, this study characterizes the response of RbISG15 following RSIV infection.

Inspiratory muscle training with threshold or incentive spirometry: Which is the most effective?

PubMed

Paiva, Dulciane Nunes; Assmann, Laíse Bender; Bordin, Diogo Fanfa; Gass, Ricardo; Jost, Renan Trevisan; Bernardo-Filho, Mario; França, Rodrigo Alves; Cardoso, Dannuey Machado

2015-01-01

Inspiratory muscular training (IMT) increases the respiratory muscle strength, however, there is no data demonstrating its superiority over the incentive spirometry (IS) in doing so. Values of muscle strength after IMT (Threshold IMT(®)) and by the IS (Voldyne(®)) in healthy females was compared. Subjects (n=40) were randomly divided into control group (CG, n=14), IS group (ISG, n=13) and threshold group (TG, n=13). PImax was measured before (pre-IMT), at 15 and 30 days of IMT. There was an increase in PImax of the TG at 15 days (p<0.001) and 30 days of IMT (p<0.001). The same occurred with the ISG, which increased the PImax at 15 days (p<0.001) and 30 days of training (p<0.001). After 30 days of IMT, the TG presented a PImax which was significantly higher than ISG and the CG (p=0.045 and p<0.001, respectively). It can be concluded that IMT by threshold was more effective in increasing muscle strength than the Voldyne. Copyright © 2014 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.

ISG15 counteracts Listeria monocytogenes infection

PubMed Central

Radoshevich, Lilliana; Impens, Francis; Ribet, David; Quereda, Juan J; Nam Tham, To; Nahori, Marie-Anne; Bierne, Hélène; Dussurget, Olivier; Pizarro-Cerdá, Javier; Knobeloch, Klaus-Peter; Cossart, Pascale

2015-01-01

ISG15 is an interferon-stimulated, linear di-ubiquitin-like protein, with anti-viral activity. The role of ISG15 during bacterial infection remains elusive. We show that ISG15 expression in nonphagocytic cells is dramatically induced upon Listeria infection. Surprisingly this induction can be type I interferon independent and depends on the cytosolic surveillance pathway, which senses bacterial DNA and signals through STING, TBK1, IRF3 and IRF7. Most importantly, we observed that ISG15 expression restricts Listeria infection in vitro and in vivo. We made use of stable isotope labeling in tissue culture (SILAC) to identify ISGylated proteins that could be responsible for the protective effect. Strikingly, infection or overexpression of ISG15 leads to ISGylation of ER and Golgi proteins, which correlates with increased secretion of cytokines known to counteract infection. Together, our data reveal a previously uncharacterized ISG15-dependent restriction of Listeria infection, reinforcing the view that ISG15 is a key component of the innate immune response. DOI: http://dx.doi.org/10.7554/eLife.06848.001 PMID:26259872

Diagnosis/Classification Criteria for Behcet's Disease

PubMed Central

Davatchi, Fereydoun

2012-01-01

Historical Background. The ISG criteria for Behcet's, created in 1990, have excellent specificity, but lack sensitivity. The International Criteria for Behcet's Disease (ICBD) was created in 2006, as replacement to ISG. The aim of this study was to compare their performance. ISG and ICBD Criteria. For ISG oral aphthosis is mandatory. The presence of any two of the following (genital aphthosis, skin lesions, eye lesions, and positive pathergy test) will diagnose/classify the patient as BD. For ICBD, vascular lesions were added, while oral aphthosis is no more mandatory. Getting 3 or more points diagnose/classify the patient as BD (genital aphthosis 2 points, eye lesions 2 points, and the remaining each one point). Performance and Comparison of ISG and ICBD. Their sensitivity, specificity, and accuracy (percent agreement), were tested in three independent cohort of patients from Far-East (China), Middle-East (Iran), and Europe (Germany). The sensitivity for ISG was respectively 65.4%, 78.1%, 83.7% and for ICBD 87%, 98.2%, and 96.5%. The specificity for ISG was 99.2%, 98.8%, 89.5% and for ICBD 94.1%, 95.6%, and 73.7%. The accuracy for ISG was 74.2%, 85.5%, 85.5% and for ICBD 88.9%, 97.3%, and 89.5%. Conclusion. ICBD has better sensitivity, and accuracy than ISG. PMID:21961081

Hepatic expression of proteasome subunit alpha type-6 is upregulated during viral hepatitis and putatively regulates the expression of ISG15 ubiquitin-like modifier, a proviral host gene in hepatitis C virus infection.

PubMed

Broering, R; Trippler, M; Werner, M; Real, C I; Megger, D A; Bracht, T; Schweinsberg, V; Sitek, B; Eisenacher, M; Meyer, H E; Baba, H A; Weber, F; Hoffmann, A-C; Gerken, G; Schlaak, J F

2016-05-01

The interferon-stimulated gene 15 (ISG15) plays an important role in the pathogenesis of hepatitis C virus (HCV) infection. ISG15-regulated proteins have previously been identified that putatively affect this proviral interaction. The present observational study aimed to elucidate the relation between ISG15 and these host factors during HCV infection. Transcriptomic and proteomic analyses were performed using liver samples of HCV-infected (n = 54) and uninfected (n = 10) or HBV-infected controls (n = 23). Primary human hepatocytes (PHH) were treated with Toll-like receptor ligands, interferons and kinase inhibitors. Expression of ISG15 and proteasome subunit alpha type-6 (PSMA6) was suppressed in subgenomic HCV replicon cell lines using specific siRNAs. Comparison of hepatic expression patterns revealed significantly increased signals for ISG15, IFIT1, HNRNPK and PSMA6 on the protein level as well as ISG15, IFIT1 and PSMA6 on the mRNA level in HCV-infected patients. In contrast to interferon-stimulated genes, PSMA6 expression occurred independent of HCV load and genotype. In PHH, the expression of ISG15 and PSMA6 was distinctly induced by poly(I:C), depending on IRF3 activation or PI3K/AKT signalling, respectively. Suppression of PSMA6 in HCV replicon cells led to significant induction of ISG15 expression, thus combined knock-down of both genes abrogated the antiviral effect induced by the separate suppression of ISG15. These data indicate that hepatic expression of PSMA6, which is upregulated during viral hepatitis, likely depends on TLR3 activation. PSMA6 affects the expression of immunoregulatory ISG15, a proviral factor in the pathogenesis of HCV infection. Therefore, the proteasome might be involved in the enigmatic interaction between ISG15 and HCV. © 2016 John Wiley & Sons Ltd.

Biochemical and Structural Insights into the Preference of Nairoviral DeISGylases for Interferon-Stimulated Gene Product 15 Originating from Certain Species

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

Deaton, M. K.; Dzimianski, J. V.; Daczkowski, C. M.

ABSTRACT The regulation of the interferon type I (IFN-I) response has been shown to rely on posttranslational modification by ubiquitin (Ub) and Ub-like interferon-stimulated gene product 15 (ISG15) to stabilize, or activate, a variety of IFN-I signaling and downstream effector proteins. Unlike Ub, which is almost perfectly conserved among eukaryotes, ISG15 is highly divergent, even among mammals. Since zoonotic viruses rely on viral proteins to recognize, or cleave, ISG15 conjugates in order to evade, or suppress, innate immunity, the impact of ISG15 biodiversity on deISGylating proteases of the ovarian tumor family (vOTU) from nairoviruses was evaluated. The enzymatic activities ofmore » vOTUs originating from the Crimean-Congo hemorrhagic fever virus, Erve virus, and Nairobi sheep disease virus were tested against ISG15s from humans, mice, shrews, sheep, bats, and camels, which are mammalian species known to be infected by nairoviruses. This along with investigation of binding by isothermal titration calorimetry illustrated significant differences in the abilities of nairovirus deISGylases to accommodate certain species of ISG15. To investigate the molecular underpinnings of species preferences of these vOTUs, a structure was determined to 2.5 Å for a complex of Erve virus vOTU protease and a mouse ISG15 domain. This structure revealed the molecular basis of Erve virus vOTU's preference for ISG15 over Ub and the first structural insight into a nonhuman ISG15. This structure also revealed key interactions, or lack thereof, surrounding three amino acids that may drive a viral deISgylase to prefer an ISG15 from one species over that of another. IMPORTANCEViral ovarian tumor domain proteases (vOTUs) are one of the two principal classes of viral proteases observed to reverse posttranslational modification of host proteins by ubiquitin and interferon-stimulated gene product 15 (ISG15), subsequently facilitating downregulation of IFN-I signaling pathways. Unlike the case with ubiquitin, the amino acid sequences of ISG15s from various species are notably divergent. We illustrate that vOTUs have clear preferences for ISG15s from certain species. In addition, these observations are related to the molecular insights acquired via the first X-ray structure of the vOTU from the Erve nairovirus in complex with the first structurally resolved nonhuman ISG15. This information implicates certain amino acids that drive the preference of vOTUs for ISG15s from certain species.« less

76 FR 60937 - Draft License Renewal Interim Staff Guidance LR-ISG-2011-02; Aging Management Program for Steam...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-30

...-2011-02; Aging Management Program for Steam Generators AGENCY: Nuclear Regulatory Commission. ACTION... License Renewal Interim Staff Guidance (LR-ISG), LR-ISG-2011-02, ``Aging Management Program for Steam... using Revision 3 of NEI 97-06 to manage steam generator aging. The Draft LR-ISG revises the NRC staff's...

Fluorescence-Activated Cell Sorting-Based Analysis Reveals an Asymmetric Induction of Interferon-Stimulated Genes in Response to Seasonal Influenza A Virus

PubMed Central

von Recum-Knepper, Jessica; Sadewasser, Anne; Weinheimer, Viola K.

2015-01-01

ABSTRACT Influenza A virus (IAV) infection provokes an antiviral response involving the expression of type I and III interferons (IFN) and IFN-stimulated genes (ISGs) in infected cell cultures. However, the spatiotemporal dynamics of the IFN reaction are incompletely understood, as previous studies investigated mainly the population responses of virus-infected cultures, although substantial cell-to-cell variability has been documented. We devised a fluorescence-activated cell sorting-based assay to simultaneously quantify expression of viral antigens and ISGs, such as ISG15, MxA, and IFIT1, in IAV-infected cell cultures at the single-cell level. This approach revealed that seasonal IAV triggers an unexpected asymmetric response, as the major cell populations expressed either viral antigen or ISG, but rarely both. Further investigations identified a role of the viral NS1 protein in blocking ISG expression in infected cells, which surprisingly did not reduce paracrine IFN signaling to noninfected cells. Interestingly, viral ISG control was impaired in cultures infected with avian-origin IAV, including the H7N9 virus from eastern China. This phenotype was traced back to polymorphic NS1 amino acids known to be important for stable binding of the polyadenylation factor CPSF30 and concomitant suppression of host cell gene expression. Most significantly, mutation of two amino acids within the CPSF30 attachment site of NS1 from seasonal IAV diminished the strict control of ISG expression in infected cells and substantially attenuated virus replication. In conclusion, our approach revealed an asymmetric, NS1-dependent ISG induction in cultures infected with seasonal IAV, which appears to be essential for efficient virus propagation. IMPORTANCE Interferons are expressed by infected cells in response to IAV infection and play important roles in the antiviral immune response by inducing hundreds of interferon-stimulated genes (ISGs). Unlike many previous studies, we investigated the ISG response at the single-cell level, enabling novel insights into this virus-host interaction. Hence, cell cultures infected with seasonal IAV displayed an asymmetric ISG induction that was confined almost exclusively to noninfected cells. In comparison, ISG expression was observed in larger cell populations infected with avian-origin IAV, suggesting a more resolute antiviral response to these strains. Strict control of ISG expression by seasonal IAV was explained by the binding of the viral NS1 protein to the polyadenylation factor CPSF30, which reduces host cell gene expression. Mutational disruption of CPSF30 binding within NS1 concomitantly attenuated ISG control and replication of seasonal IAV, illustrating the importance of maintaining an asymmetric ISG response for efficient virus propagation. PMID:25903337

Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease.

PubMed

Scholte, Florine E M; Zivcec, Marko; Dzimianski, John V; Deaton, Michelle K; Spengler, Jessica R; Welch, Stephen R; Nichol, Stuart T; Pegan, Scott D; Spiropoulou, Christina F; Bergeron, Éric

2017-09-05

Antiviral responses are regulated by conjugation of ubiquitin (Ub) and interferon-stimulated gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights into viral OTU functions and support the development of therapeutics and vaccines. Published by Elsevier Inc.

Characterization of Phospholipids in Insulin Secretory Granules and Mitochondria in Pancreatic Beta Cells and Their Changes with Glucose Stimulation*

PubMed Central

MacDonald, Michael J.; Ade, Lacmbouh; Ntambi, James M.; Ansari, Israr-Ul H.; Stoker, Scott W.

2015-01-01

The lipid composition of insulin secretory granules (ISG) has never previously been thoroughly characterized. We characterized the phospholipid composition of ISG and mitochondria in pancreatic beta cells without and with glucose stimulation. The phospholipid/protein ratios of most phospholipids containing unsaturated fatty acids were higher in ISG than in whole cells and in mitochondria. The concentrations of negatively charged phospholipids, phosphatidylserine, and phosphatidylinositol in ISG were 5-fold higher than in the whole cell. In ISG phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, and sphingomyelin, fatty acids 12:0 and 14:0 were high, as were phosphatidylserine and phosphatidylinositol containing 18-carbon unsaturated FA. With glucose stimulation, the concentration of many ISG phosphatidylserines and phosphatidylinositols increased; unsaturated fatty acids in phosphatidylserine increased; and most phosphatidylethanolamines, phosphatidylcholines, sphingomyelins, and lysophosphatidylcholines were unchanged. Unsaturation and shorter fatty acid length in phospholipids facilitate curvature and fluidity of membranes, which favors fusion of membranes. Recent evidence suggests that negatively charged phospholipids, such as phosphatidylserine, act as coupling factors enhancing the interaction of positively charged regions in SNARE proteins in synaptic or secretory vesicle membrane lipid bilayers with positively charged regions in SNARE proteins in the plasma membrane lipid bilayer to facilitate docking of vesicles to the plasma membrane during exocytosis. The results indicate that ISG phospholipids are in a dynamic state and are consistent with the idea that changes in ISG phospholipids facilitate fusion of ISG with the plasma membrane-enhancing glucose-stimulated insulin exocytosis. PMID:25762724

The antiviral activities of ISG15.

PubMed

Morales, David J; Lenschow, Deborah J

2013-12-13

Post-translational protein modification is an important strategy for the regulation of the cell proteome independent of the need for new gene expression. Ubiquitin and ubiquitin-like modifiers mediate the regulation of protein levels, signaling pathways, vesicular trafficking, and many other cellular processes through their covalent conjugation to proteins. Interferon stimulated gene 15 (ISG15) is a ubiquitin-like modifier induced by type I interferon. In addition to conjugating to potentially hundreds of target proteins, ISG15 can be found in an unconjugated form both inside of the cell and released from interferon stimulated cells into the extracellular environment. Due to its robust expression after type I interferon stimulation and the broad panel of proteins that it targets, ISG15 has drawn much attention as a potential regulator of the immune response and has been shown to mediate protection in a number of different viral infection models. Here we will review the current state of the field of ISG15, the viruses against which ISG15 mediates protection, and the mechanisms by which ISG15 exerts antiviral activity. © 2013.

Characterization of phospholipids in insulin secretory granules and mitochondria in pancreatic beta cells and their changes with glucose stimulation.

PubMed

MacDonald, Michael J; Ade, Lacmbouh; Ntambi, James M; Ansari, Israr-Ul H; Stoker, Scott W

2015-04-24

The lipid composition of insulin secretory granules (ISG) has never previously been thoroughly characterized. We characterized the phospholipid composition of ISG and mitochondria in pancreatic beta cells without and with glucose stimulation. The phospholipid/protein ratios of most phospholipids containing unsaturated fatty acids were higher in ISG than in whole cells and in mitochondria. The concentrations of negatively charged phospholipids, phosphatidylserine, and phosphatidylinositol in ISG were 5-fold higher than in the whole cell. In ISG phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, and sphingomyelin, fatty acids 12:0 and 14:0 were high, as were phosphatidylserine and phosphatidylinositol containing 18-carbon unsaturated FA. With glucose stimulation, the concentration of many ISG phosphatidylserines and phosphatidylinositols increased; unsaturated fatty acids in phosphatidylserine increased; and most phosphatidylethanolamines, phosphatidylcholines, sphingomyelins, and lysophosphatidylcholines were unchanged. Unsaturation and shorter fatty acid length in phospholipids facilitate curvature and fluidity of membranes, which favors fusion of membranes. Recent evidence suggests that negatively charged phospholipids, such as phosphatidylserine, act as coupling factors enhancing the interaction of positively charged regions in SNARE proteins in synaptic or secretory vesicle membrane lipid bilayers with positively charged regions in SNARE proteins in the plasma membrane lipid bilayer to facilitate docking of vesicles to the plasma membrane during exocytosis. The results indicate that ISG phospholipids are in a dynamic state and are consistent with the idea that changes in ISG phospholipids facilitate fusion of ISG with the plasma membrane-enhancing glucose-stimulated insulin exocytosis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Pathogenic Influenza Viruses and Coronaviruses Utilize Similar and Contrasting Approaches To Control Interferon-Stimulated Gene Responses

PubMed Central

Menachery, Vineet D.; Eisfeld, Amie J.; Schäfer, Alexandra; Josset, Laurence; Sims, Amy C.; Proll, Sean; Fan, Shufang; Li, Chengjun; Neumann, Gabriele; Tilton, Susan C.; Chang, Jean; Gralinski, Lisa E.; Long, Casey; Green, Richard; Williams, Christopher M.; Weiss, Jeffrey; Matzke, Melissa M.; Webb-Robertson, Bobbie-Jo; Schepmoes, Athena A.; Shukla, Anil K.; Metz, Thomas O.; Smith, Richard D.; Waters, Katrina M.; Katze, Michael G.; Kawaoka, Yoshihiro

2014-01-01

ABSTRACT The broad range and diversity of interferon-stimulated genes (ISGs) function to induce an antiviral state within the host, impeding viral pathogenesis. While successful respiratory viruses overcome individual ISG effectors, analysis of the global ISG response and subsequent viral antagonism has yet to be examined. Employing models of the human airway, transcriptomics and proteomics datasets were used to compare ISG response patterns following highly pathogenic H5N1 avian influenza (HPAI) A virus, 2009 pandemic H1N1, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome CoV (MERS-CoV) infection. The results illustrated distinct approaches utilized by each virus to antagonize the global ISG response. In addition, the data revealed that highly virulent HPAI virus and MERS-CoV induce repressive histone modifications, which downregulate expression of ISG subsets. Notably, influenza A virus NS1 appears to play a central role in this histone-mediated downregulation in highly pathogenic influenza strains. Together, the work demonstrates the existence of unique and common viral strategies for controlling the global ISG response and provides a novel avenue for viral antagonism via altered histone modifications. PMID:24846384

An online intervention for reducing depressive symptoms: secondary benefits for self-esteem, empowerment and quality of life.

PubMed

Crisp, Dimity; Griffiths, Kathleen; Mackinnon, Andrew; Bennett, Kylie; Christensen, Helen

2014-04-30

Internet-based interventions are increasingly recognized as effective for the treatment and prevention of depression; however, there is a paucity of research investigating potential secondary benefits. From a consumer perspective, improvements in indicators of wellbeing such as perceived quality of life may represent the most important outcomes for evaluating the effectiveness of an intervention. This study investigated the 'secondary' benefits for self-esteem, empowerment, quality of life and perceived social support of two 12-week online depression interventions when delivered alone and in combination. Participants comprised 298 adults displaying elevated psychological distress. Participants were randomised to receive: an Internet Support Group (ISG); an automated Internet psycho-educational training program for depression; a combination of these conditions; or a control website. Analyses were performed on an intent-to-treat basis. Following the automated training program immediate improvements were shown in participants׳ self-esteem and empowerment relative to control participants. Improvements in perceived quality of life were reported 6-months following the completion of the intervention when combined with an ISG. These findings provide initial evidence for the effectiveness of this online intervention for improving individual wellbeing beyond the primary aim of the treatment. However, further research is required to investigate the mechanisms underlying improvement in these secondary outcomes. Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.

Development and Preliminary In vitro Evaluation of Nanomicelles Laden In situ Gel of Dexamethasone for Ophthalmic Delivery

NASA Astrophysics Data System (ADS)

Chowdhury, Pallabita

In our previous work we developed and characterized 0.1% dexamethasone mixed nanomicelles (DMN). DMN were prepared using surfactants polyoxyl 40 stearate (P40S) and polysorbate 80 (P80), which are approved by the FDA for ocular use. The present study builds on the previous work by developing and evaluating nanomicelles laden in situ gel of 0.1% dexamethasone (DMN-ISG) with potential for treating anterior segment eye inflammations. DMN-ISG was prepared by mixing the basic 2X formulation of DMN with appropriate concentrations of gellan gum, mannitol, benzododecinium bromide and tromethamine. DMN-ISG was characterized for gelation, viscosity, transparency, morphology using Transmission Electron Microscopy (TEM), thermoanalysis using Differential Scanning Calorimetry (DSC), in vitro drug release and sterility. DMN prepared with an optimized composition of P40S/P80=7/3 by weight were used in the preparation of DMN-ISG. TEM image of DMN-ISG showed the presence of dexamethasone nanomicelles in the size range between 20-40 nm entrapped in the gel structure. More than 50% of the drug was released from DMN-ISG in the first few hours and the remaining drug was released in a sustained manner for up to 30 h. Aseptically prepared DMN-ISG formulation remained sterile for up to 14 days. The preliminary findings of our investigation suggest that DMN-ISG has the potential for use in treating anterior segment eye inflammations. Further in vivo evaluation is warranted.

Innate immune responses against rock bream iridovirus (RBIV) infection in rock bream (Oplegnathus fasciatus) following poly (I:C) administration.

PubMed

Jung, Myung-Hwa; Jung, Sung-Ju

2017-12-01

Poly (I:C) showed promise as an immunoprotective agents in rock bream against rock bream iridovirus (RBIV) infection. In this study, we evaluated the time-dependent virus replication pattern and antiviral immune responses in RBIV-infected rock bream with and without poly (I:C) administration. In the poly (I:C)+virus-injected group, virus copy numbers were more than 18.9-, 24.0- and 479.2-fold lower than in the virus only injected group at 4 (4.73 × 10 4 and 8.95 × 10 5 /μl, respectively), 7 (3.67 × 10 5 and 8.81 × 10 6 /μl, respectively) and 10 days post infection (dpi) (1.26 × 10 5 and 6.02 × 10 7 /μl, respectively). Moreover, significantly high expression levels of TLR3 (8.6- and 7.7-fold, at 4 and 7 dpi, respectively) and IL1β (3.6-fold at 2 dpi) were observed in the poly (I:C)+virus-injected group, but the expression levels were not significantly in the virus-injected group. However, IL8 and TNFα expression levels showed no statistical significance in both groups. Mx, ISG15 and PKR were significantly highly expressed from 4 to 10 dpi in the virus-injected group. Nevertheless, in the poly (I:C)+virus-injected group, Mx and ISG15 expression were significantly expressed from 2 dpi. In summary, poly (I:C) administration in rock bream induces TLR3, IL1β, Mx and ISG15-mediated immune responses, which could be a critical factor for inhibition of virus replication. Copyright © 2017 Elsevier Ltd. All rights reserved.

77 FR 55230 - Japan Lessons-Learned Project Directorate Interim Staff Guidance JLD-ISG-2012-01; Compliance With...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-07

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0068] Japan Lessons-Learned Project Directorate Interim... Commission (NRC). ACTION: Japan Lessons-Learned Project Directorate interim staff guidance; issuance. SUMMARY...-Learned Project Directorate Interim Staff Guidance (JLD-ISG), JLD-ISG-2012-01, ``Compliance with Order EA...

Newly translated proteins are substrates for ubiquitin, ISG15, and FAT10.

PubMed

Spinnenhirn, Valentina; Bitzer, Annegret; Aichem, Annette; Groettrup, Marcus

2017-01-01

The ubiquitin-like modifier, FAT10, is involved in proteasomal degradation and antigen processing. As ubiquitin and the ubiquitin-like modifier, ISG15, cotranslationally modify proteins, we investigated whether FAT10 could also be conjugated to newly synthesized proteins. Indeed, we found that nascent proteins are modified with FAT10, but not with the same preference for newly synthesized proteins as observed for ISG15. Our data show that puromycin-labeled polypeptides are strongly modified by ISG15 and less intensely by ubiquitin and FAT10. Nevertheless, conjugates of all three modifiers copurify with ribosomes. Taken together, we show that unlike ISG15, ubiquitin and FAT10 are conjugated to a similar degree to newly translated and pre-existing proteins. © 2016 Federation of European Biochemical Societies.

The Next Linear Collider Program

Science.gov Websites

text only International Study Group (ISG) Meetings NLC Home Page NLC Technical SLAC Eleventh Linear Collider International Study Group at KEK, December 16 - 19, 2003 Tenth (X) Linear Collider International Study Group at SLAC, June, 2003 Nineth Linear Collider ,International Study Group at KEK, December 10-13

The International Service for the Geoid and its products

NASA Astrophysics Data System (ADS)

Reguzzoni, Mirko; Sona, Giovanna; Barzaghi, Riccardo; Sansò, Fernando; Albertella, Alberta; Carrion, Daniela; Iapige De Gaetani, Carlo; Rossi, Lorenzo

2017-04-01

The International Service for the Geoid (ISG) was established in 1992 and it is currently an official service of the International Association of Geodesy (IAG). Its activities are coordinated by the International Gravity Field Service (IGFS) and they are also related to those of the IAG Commission 2 on Gravity Field. ISG is hosted by Politecnico di Milano in Italy. The main task of ISG is to collect, analyze and redistribute local, regional and even continental geoid models, which are therefore the main products of the service. In this work the geoid repository is described, specifying the information provided for the models, the unified ASCII format used for their storing and the possible policy rules for their redistribution. Moreover, the current state-of-art of the repository is presented, in particular analyzing the geographical distribution of the available models and their years of computation. Note that not only the latest released geoid models are collected in the ISG repository, but also less recent ones, with the aim of keeping memory of the progress done in this research field during the years. Software for estimating and handling geoid models is provided too. Apart from distributing geoid models and software, the service has also educational and research purposes. From this perspective, additional products are the international schools on geoid computation that have been organized by ISG since 1994, basically every 2-3 years. A historical overview of the schools, with emphasis on the school program and its evolution in time, is here presented. As for the research activities, apart from participating to international projects and working groups, the main ISG product was the publication of the IGeS Bulletin in the past and the Newton's Bulletin nowadays, in cooperation with the International Gravimetric Bureau (BGI). The Newton's Bulletin has a technical and applied nature and it has been recently selected by the geodetic community for publications on the assessment of EGM2008 and GOCE global gravity models. Finally a short presentation of the service website as the main platform for the product distribution and advertising is here provided.

UBE2L6/UBCH8 and ISG15 attenuate autophagy in esophageal cancer cells

PubMed Central

Falvey, Chloe M.; O'Donovan, Tracey R.; El-Mashed, Shereen; Nyhan, Michelle J.; O'Reilly, Seamus; McKenna, Sharon L.

2017-01-01

Esophageal cancer remains a poor prognosis cancer due to advanced stage of presentation and drug resistant disease. To understand the molecular mechanisms influencing response to chemotherapy, we examined genes that are differentially expressed between drug sensitive, apoptosis competent esophageal cancer cells (OE21, OE33, FLO-1) and those which are more resistant and do not exhibit apoptosis (KYSE450 and OE19). Members of the ISG15 (ubiquitin-like) protein modification pathway, including UBE2L6 and ISG15, were found to be more highly expressed in the drug sensitive cell lines. In this study, we evaluated the contribution of these proteins to the response of drug sensitive cells. Depletion of UBE2L6 or ISG15 with siRNA did not influence caspase-3 activation or nuclear fragmentation following treatment with 5-fluorouracil (5-FU). We assessed autophagy by analysis of LC3II expression and Cyto-ID staining. Depletion of either ISG15 or UBE2L6 resulted in enhanced endogenous autophagic flux. An increase in autophagic flux was also observed following treatment with cytotoxic drugs (5-FU, rapamycin). In ISG15 depleted cells, this increase in autophagy was associated with improved recovery of drug treated cells. In contrast, UBE2L6 depleted cells, did not show enhanced recovery. UBE2L6 may therefore influence additional targets that limit the pro-survival effect of ISG15 depletion. These data identify UBE2L6 and ISG15 as novel inhibitors of autophagy, with the potential to influence chemosensitivity in esophageal cancer cells. PMID:28186990

A Method for Evaluating Information Security Governance (ISG) Components in Banking Environment

NASA Astrophysics Data System (ADS)

Ula, M.; Ula, M.; Fuadi, W.

2017-02-01

As modern banking increasingly relies on the internet and computer technologies to operate their businesses and market interactions, the threats and security breaches have highly increased in recent years. Insider and outsider attacks have caused global businesses lost trillions of Dollars a year. Therefore, that is a need for a proper framework to govern the information security in the banking system. The aim of this research is to propose and design an enhanced method to evaluate information security governance (ISG) implementation in banking environment. This research examines and compares the elements from the commonly used information security governance frameworks, standards and best practices. Their strength and weakness are considered in its approaches. The initial framework for governing the information security in banking system was constructed from document review. The framework was categorized into three levels which are Governance level, Managerial level, and technical level. The study further conducts an online survey for banking security professionals to get their professional judgment about the ISG most critical components and the importance for each ISG component that should be implemented in banking environment. Data from the survey was used to construct a mathematical model for ISG evaluation, component importance data used as weighting coefficient for the related component in the mathematical model. The research further develops a method for evaluating ISG implementation in banking based on the mathematical model. The proposed method was tested through real bank case study in an Indonesian local bank. The study evidently proves that the proposed method has sufficient coverage of ISG in banking environment and effectively evaluates the ISG implementation in banking environment.

77 FR 15818 - License Renewal Interim Staff Guidance LR-ISG-2011-05: Ongoing Review of Operating Experience

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-16

...-05: Ongoing Review of Operating Experience AGENCY: Nuclear Regulatory Commission. ACTION: Interim... License Renewal Interim Staff Guidance (LR-ISG), LR-ISG-2011-05, ``Ongoing Review of Operating Experience... industry-wide operating experience as an attribute of aging management programs used at nuclear power...

76 FR 17160 - Office of New Reactors; Final Interim Staff Guidance on the Review of Nuclear Power Plant Designs...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-28

...The NRC staff is issuing its Final Interim Staff Guidance (ISG) DC/COL-ISG-021 titled ``Interim Staff Guidance on the Review of Nuclear Power Plant Designs Using a Gas Turbine Driven Standby Emergency Alternating Current Power System,'' Agencywide Documents Access and Management System (ADAMS) Accession No. ML102510119 for DC/ COL-ISG-021 and ADAMS Accession No. ML102510164 for Attachment 1 to DC/ COL-ISG-021. This ISG provides new guidance for applicants submitting a combined license (COL) or design certification (DC) application for new nuclear power reactors under Title 10 of the Code of Federal Regulations, part 52. In addition, it supplements the guidance provided to the NRC staff in NUREG-0800, ``Standard Review Plan for the Review of Safety Analysis Reports for Nuclear Power Plants,'' March 2007, Standard Review Plan (SRP), Section 8.3.1 and Sections 9.5.4 through 9.5.8. The NRC staff issues DC/COL-ISGs to facilitate activities associated with NRC review of applications for DCs and COLs. The NRC staff intends to incorporate DC/COL-ISG-021 into the next revision of SRP Section 8.3.1 and Sections 9.5.4 through 9.5.8 and Regulatory Guide 1.206, ``Combined License Applications for Nuclear Power Plants (LWR Edition),'' June 2007. Disposition: On February 3, 2010, the NRC staff issued proposed DC/ COL-ISG-021 on ``Review of Nuclear Power Plant Designs Using a Gas Turbine Driven Standby Emergency Alternating Current Power System,'' ADAMS Accession No. ML092640035. The NRC staff received comments on the proposed guidance. This final issuance resolves the majority of the comments. The NRC staff responses to these comments can be found in ADAMS Accession No. ML102510176.

Nasal delivery of analgesic ketorolac tromethamine thermo- and ion-sensitive in situ hydrogels.

PubMed

Li, Xin; Du, Lina; Chen, Xu; Ge, Pingju; Wang, Yu; Fu, Yangmu; Sun, Haiyan; Jiang, Qingwei; Jin, Yiguang

2015-07-15

Ketorolac tromethamine (KT) was potent to treat moderate to moderately severe pains. However, KT solutions for nasal delivery lost quickly from the nasal route. Thermo- and ion-sensitive in-situ hydrogels (ISGs) are appropriate for nasal drug delivery because the intranasal temperature maintains ∼37 °C and nasal fluids consist of plentiful cations. In this study, a novel nasal thermo- and ion-sensitive ISG of KT was prepared with thermo-sensitive poloxamer 407 (P407) and ion-sensitive deacetylated gellan gum (DGG). The optimal formulation of the KT ISG consisted of 3% (w/v) DGG and 18% (w/v) P407 and its viscosity was up to 7.63 Pas at 37 °C. Furthermore, penetration enhancers and bacterial inhibitors were added and their fractions in the ISG were optimized based on transmucosal efficiencies and toxicity on toad pili. Sulfobutyl ether-β-cyclodextrin of 2.5% (w/v) and chlorobutanol of 0.5% (w/v) were chosen as the penetration enhancer and the bacterial inhibitor, respectively. The Fick's diffusion and dissolution of KT could drive it continuous release from the dually sensitive ISG according to the in vitro investigation. Two methods, writhing frequencies induced by acetic acid and latency time of tails retracting from hot water, were used to evaluate the pharmacodynamics of the KT ISG on the mouse models. The writhing frequencies significantly decreased and the latency time of tail retracting was obviously prolonged (p<0.05) for the KT ISG compared to the control. The thermo- and ion-sensitive KT ISG had appropriate gelation temperature, sustained drug release, improved intranasal absorption, obvious pharmacodynamic effect, and negligible nasal ciliotoxicity. It is a promising intranasal analgesic formulation. Copyright © 2015. Published by Elsevier B.V.

Assessing the risk of laparoscopic morcellation of occult uterine sarcomas during hysterectomy and myomectomy: Literature review and the ISGE recommendations.

PubMed

Sizzi, Ornella; Manganaro, Lucia; Rossetti, Alfonso; Saldari, Matteo; Florio, Giuseppe; Loddo, Alessandro; Zurawin, Robert; van Herendael, Bruno; Djokovic, Dusan

2018-01-01

This project of the International Society for Gynecologic Endoscopy (ISGE) had the objective to review the literature and provide recommendations on the occult sarcoma risk assessment in patients who are candidates for minimally invasive gynecological surgery involving intra-abdominal electromechanical tissue morcellation. The ISGE Task Force for Estimation of the Risk in Endoscopic Morcellation initially defined key topics and clinical questions which may guide a comprehensive preoperative patient assessment. A literature search within the Medline/PubMed and Cochrane Database was carried out using keywords "morcellation", "uterine fibroids", "uterine sarcoma", "myomectomy" and "hysterectomy". Relevant publications (original studies, meta-analyses and previous reviews), written in English and published until May 30th, 2017, were selected and analyzed. Previously emitted statements of 12 recognized professional societies or government institutions and their supporting literature were also studied. For each topic/clinical question, the available information was graded by the level of evidence. The ISGE recommendations were established in accordance with the evidence quality. In the light of available information, 9 recommendations on preoperative clinical, laboratorial and imaging evaluation of the candidates for intracorporeal uterus/leiomyoma morcellation were formulated, mainly based on consensus and expert opinions. There is a lack of high-quality evidence, which does not allow the establishment of strong recommendations. Electromechanical tissue morcellation may be used in gynecological patients who are considered "low risk" upon appropriate preoperative evaluation; however, further studies and prospective data collection are greatly needed to improve sarcoma risk assessment in women with presumed uterine leiomyomas. Copyright © 2017 Elsevier B.V. All rights reserved.

The European S and F intersterility groups of Heterobasidion annosum may represent sympatric protospecies

Treesearch

Matteo Garbelotto; William J. Otrosina; Fields W. Cobb; Thomas D Bruns

1998-01-01

In those regions of Europe where they coexist, the F and S intersterility groups (ISGs) of Heterobasidion annosum (Fr.) Bref. are primarily found on Abies spp. and Picea abies (L.) Karst., respectively. Eighty-three isolates of H. annosum were collected from Abies...

CDK9-Dependent Transcriptional Elongation in the Innate Interferon-Stimulated Gene Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells

PubMed Central

Tian, Bing; Zhao, Yingxin; Kalita, Mridul; Edeh, Chukwudi B.; Paessler, Slobodan; Casola, Antonella; Teng, Michael N.; Garofalo, Roberto P.

2013-01-01

Respiratory syncytial virus (RSV) is a negative-sense single-stranded RNA virus responsible for lower respiratory tract infections. During infection, the presence of double-stranded RNA (dsRNA) activates the interferon (IFN) regulatory factor 3 (IRF3) transcription factor, an event triggering expression of immediate early, IFN-stimulated genes (ISGs). We examine the role of transcriptional elongation in control of IRF3-dependent ISG expression. RSV infection induces ISG54, ISG56, and CIG5 gene expression in an IRF3-dependent manner demonstrated by IRF3 small interfering RNA (siRNA) silencing in both A549 epithelial cells and IRF3−/− MEFs. ISG expression was mediated by the recruitment of IRF3, CDK9, polymerase II (Pol II), and phospho-Ser2 carboxy-terminal domain (CTD) Pol II to the IFN-stimulated response element (ISRE) binding sites of the IRF3-dependent ISG promoters in native chromatin. We find that RSV infection enhances the activated fraction of cyclin-dependent kinase 9 (CDK9) by promoting its association with bromodomain 4 (BRD4) and disrupting its association with the inhibitory 7SK small nuclear RNA. The requirement of CDK9 activity for ISG expression was shown by siRNA-mediated silencing of CDK9 and by a selective CDK9 inhibitor in A549 cells. In contrast, RSV-induced beta interferon (IFN-β) expression is not influenced by CDK9 inhibition. Using transcript-selective quantitative real-time reverse transcription-PCR (Q-RT-PCR) assays for the ISG54 gene, we observed that RSV induces transition from short to fully spliced mRNA transcripts and that this transition is blocked by CDK9 inhibition in both A549 and primary human small airway epithelial cells. These data indicate that transcription elongation plays a major role in RSV-induced ISG expression and is mediated by IRF3-dependent recruitment of activated CDK9. CDK9 activity may be a target for immunomodulation in RSV-induced lung disease. PMID:23596302

Ovarian Tumor (OTU)-domain Containing Viral Proteases Evade Ubiquitin- and ISG15-dependent Innate Immune Responses

PubMed Central

Frias-Staheli, Natalia; Giannakopoulos, Nadia V.; Kikkert, Marjolein; Taylor, Shannon L.; Bridgen, Anne; Paragas, Jason J.; Richt, Juergen A.; Rowland, Raymond R.; Schmaljohn, Connie S.; Lenschow, Deborah J.; Snijder, Eric J.; García-Sastre, Adolfo; Virgin, Herbert Whiting

2007-01-01

Summary Ubiquitin (Ub) and interferon stimulated gene product 15 (ISG15) reversibly conjugate to proteins via a conserved LRLRGG C-terminal motif, mediating important innate antiviral responses. The ovarian tumor (OTU) domain represents a superfamily of predicted proteases found in eukaryotic, bacterial and viral proteins, some of which have Ub-deconjugating activity. We show that the OTU domain-containing proteases of nairoviruses and arteriviruses hydrolyze Ub and ISG15 from cellular target proteins. This broad activity contrasts with the target specificity of known mammalian OTU domain-containing proteins. The biological significance of this activity of viral OTU domain-containing proteases was evidenced by their capacity to inhibit NF-κB dependent signaling and to antagonize the antiviral effects of ISG15 during Sindbis virus infection in vivo. The deconjugating activity of viral OTU proteases represents a novel viral immune evasion mechanism that inhibits Ub-and ISG15-dependent antiviral pathways. PMID:18078692

Identification of five interferon-induced cellular proteins that inhibit west nile virus and dengue virus infections.

PubMed

Jiang, Dong; Weidner, Jessica M; Qing, Min; Pan, Xiao-Ben; Guo, Haitao; Xu, Chunxiao; Zhang, Xianchao; Birk, Alex; Chang, Jinhong; Shi, Pei-Yong; Block, Timothy M; Guo, Ju-Tao

2010-08-01

Interferons (IFNs) are key mediators of the host innate antiviral immune response. To identify IFN-stimulated genes (ISGs) that instigate an antiviral state against two medically important flaviviruses, West Nile virus (WNV) and dengue virus (DENV), we tested 36 ISGs that are commonly induced by IFN-alpha for antiviral activity against the two viruses. We discovered that five ISGs efficiently suppressed WNV and/or DENV infection when they were individually expressed in HEK293 cells. Mechanistic analyses revealed that two structurally related cell plasma membrane proteins, IFITM2 and IFITM3, disrupted early steps (entry and/or uncoating) of the viral infection. In contrast, three IFN-induced cellular enzymes, viperin, ISG20, and double-stranded-RNA-activated protein kinase, inhibited steps in viral proteins and/or RNA biosynthesis. Our results thus imply that the antiviral activity of IFN-alpha is collectively mediated by a panel of ISGs that disrupt multiple steps of the DENV and WNV life cycles.

76 FR 75771 - Emergency Planning Guidance for Nuclear Power Plants

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-05

... Guidance for Nuclear Power Plants AGENCY: Nuclear Regulatory Commission. ACTION: Issuance of NUREG... Support of Nuclear Power Plants;'' NSIR/DPR-ISG-01, ``Interim Staff Guidance Emergency Planning for Nuclear Power Plants;'' and NUREG/CR-7002, ``Criteria for Development of Evacuation Time Estimate Studies...

Influence of low concentration V and Co oxide doping on the dissolution behaviors of simplified nuclear waste glasses

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

Lu, Xiaonan; Neeway, James J.; Ryan, Joseph V.

Transition metal oxides are commonly present in nuclear waste and they can alter the structure, property and especially dissolution behaviors of the glasses used for waste immobilization. In this paper, we investigated vanadium and cobalt oxide induced structural and properties changes, especially dissolution behaviors, of International Simple Glass (ISG), a model nuclear waste glass system. Static chemical durability tests were performed at 90 °C with a pH value of 7 and a surface-area-to-solution-volume of 200 m-1 for 112 days on three glasses: ISG, ISG doped with 0.5 mol% Co2O3, and ISG doped with 2.0 mol% V2O5. ICP-MS was used tomore » analyze the dissolved ion concentrations. It was found that doping with vanadium and cobalt oxide, even at the low doping concentration, significantly reduced the extent of the ISG glass dissolution. Differential Scanning Calorimetry (DSC) analysis showed that vanadium oxide doping reduced the glass transition temperature (Tg) while cobalt oxide did not significantly change the Tg of ISG. X-ray diffraction (XRD), Raman spectrometry and scanning electron microscopy (SEM) were used to analyze the glass samples before and after corrosion to understand the phase and microstructure changes.« less

Cell-Specific IRF-3 Responses Protect against West Nile Virus Infection by Interferon-Dependent and -Independent Mechanisms

PubMed Central

Daffis, Stephane; Samuel, Melanie A; Keller, Brian C; Gale, Michael; Diamond, Michael S

2007-01-01

Interferon regulatory factor (IRF)-3 is a master transcription factor that activates host antiviral defense programs. Although cell culture studies suggest that IRF-3 promotes antiviral control by inducing interferon (IFN)-β, near normal levels of IFN-α and IFN-β were observed in IRF-3−/− mice after infection by several RNA and DNA viruses. Thus, the specific mechanisms by which IRF-3 modulates viral infection remain controversial. Some of this disparity could reflect direct IRF-3-dependent antiviral responses in specific cell types to control infection. To address this and determine how IRF-3 coordinates an antiviral response, we infected IRF-3−/− mice and two primary cells relevant for West Nile virus (WNV) pathogenesis, macrophages and cortical neurons. IRF-3−/− mice were uniformly vulnerable to infection and developed elevated WNV burdens in peripheral and central nervous system tissues, though peripheral IFN responses were largely normal. Whereas wild-type macrophages basally expressed key host defense molecules, including RIG-I, MDA5, ISG54, and ISG56, and restricted WNV infection, IRF-3−/− macrophages lacked basal expression of these host defense genes and supported increased WNV infection and IFN-α and IFN-β production. In contrast, wild-type cortical neurons were highly permissive to WNV and did not basally express RIG-I, MDA5, ISG54, and ISG56. IRF-3−/− neurons lacked induction of host defense genes and had blunted IFN-α and IFN-β production, yet exhibited only modestly increased viral titers. Collectively, our data suggest that cell-specific IRF-3 responses protect against WNV infection through both IFN-dependent and -independent programs. PMID:17676997

The IFN Response in Bats Displays Distinctive IFN-Stimulated Gene Expression Kinetics with Atypical RNASEL Induction.

PubMed

De La Cruz-Rivera, Pamela C; Kanchwala, Mohammed; Liang, Hanquan; Kumar, Ashwani; Wang, Lin-Fa; Xing, Chao; Schoggins, John W

2018-01-01

Bats host a large number of zoonotic viruses, including several viruses that are highly pathogenic to other mammals. The mechanisms underlying this rich viral diversity are unknown, but they may be linked to unique immunological features that allow bats to act as asymptomatic viral reservoirs. Vertebrates respond to viral infection by inducing IFNs, which trigger antiviral defenses through IFN-stimulated gene (ISG) expression. Although the IFN system of several bats is characterized at the genomic level, less is known about bat IFN-mediated transcriptional responses. In this article, we show that IFN signaling in bat cells from the black flying fox ( Pteropus alecto ) consists of conserved and unique ISG expression profiles. In IFN-stimulated cells, bat ISGs comprise two unique temporal subclusters with similar early induction kinetics but distinct late-phase declines. In contrast, human ISGs lack this decline phase and remained elevated for longer periods. Notably, in unstimulated cells, bat ISGs were expressed more highly than their human counterparts. We also found that the antiviral effector 2-5A-dependent endoribonuclease, which is not an ISG in humans, is highly IFN inducible in black flying fox cells and contributes to cell-intrinsic control of viral infection. These studies reveal distinctive innate immune features that may underlie a unique virus-host relationship in bats. Copyright © 2017 by The American Association of Immunologists, Inc.

Network Analysis Identifies Proinflammatory Plasma Cell Polarization for Secretion of ISG15 in Human Autoimmunity

PubMed Central

Care, Matthew A.; Stephenson, Sophie J.; Barnes, Nicholas A.; Fan, Im; Zougman, Alexandre; El-Sherbiny, Yasser M.; Vital, Edward M.; Westhead, David R.; Tooze, Reuben M.

2016-01-01

Plasma cells (PCs) as effectors of humoral immunity produce Igs to match pathogenic insult. Emerging data suggest more diverse roles exist for PCs as regulators of immune and inflammatory responses via secretion of factors other than Igs. The extent to which such responses are preprogrammed in B-lineage cells or can be induced in PCs by the microenvironment is unknown. In this study, we dissect the impact of IFNs on the regulatory networks of human PCs. We show that core PC programs are unaffected, whereas PCs respond to IFNs with distinctive transcriptional responses. The IFN-stimulated gene 15 (ISG15) system emerges as a major transcriptional output induced in a sustained fashion by IFN-α in PCs and linked both to intracellular conjugation and ISG15 secretion. This leads to the identification of ISG15-secreting plasmablasts/PCs in patients with active systemic lupus erythematosus. Thus, ISG15-secreting PCs represent a distinct proinflammatory PC subset providing an Ig-independent mechanism of PC action in human autoimmunity. PMID:27357150

Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response

PubMed Central

Arnaud, Noëlla; Dabo, Stéphanie; Akazawa, Daisuke; Fukasawa, Masayoshi; Shinkai-Ouchi, Fumiko; Hugon, Jacques; Wakita, Takaji; Meurs, Eliane F.

2011-01-01

Recognition of viral RNA structures by the intracytosolic RNA helicase RIG-I triggers induction of innate immunity. Efficient induction requires RIG-I ubiquitination by the E3 ligase TRIM25, its interaction with the mitochondria-bound MAVS protein, recruitment of TRAF3, IRF3- and NF-κB-kinases and transcription of Interferon (IFN). In addition, IRF3 alone induces some of the Interferon-Stimulated Genes (ISGs), referred to as early ISGs. Infection of hepatocytes with Hepatitis C virus (HCV) results in poor production of IFN despite recognition of the viral RNA by RIG-I but can lead to induction of early ISGs. HCV was shown to inhibit IFN production by cleaving MAVS through its NS3/4A protease and by controlling cellular translation through activation of PKR, an eIF2α-kinase containing dsRNA-binding domains (DRBD). Here, we have identified a third mode of control of IFN induction by HCV. Using HCVcc and the Huh7.25.CD81 cells, we found that HCV controls RIG-I ubiquitination through the di-ubiquitine-like protein ISG15, one of the early ISGs. A transcriptome analysis performed on Huh7.25.CD81 cells silenced or not for PKR and infected with JFH1 revealed that HCV infection leads to induction of 49 PKR-dependent genes, including ISG15 and several early ISGs. Silencing experiments revealed that this novel PKR-dependent pathway involves MAVS, TRAF3 and IRF3 but not RIG-I, and that it does not induce IFN. Use of PKR inhibitors showed that this pathway requires the DRBD but not the kinase activity of PKR. We then demonstrated that PKR interacts with HCV RNA and MAVS prior to RIG-I. In conclusion, HCV recruits PKR early in infection as a sensor to trigger induction of several IRF3-dependent genes. Among those, ISG15 acts to negatively control the RIG-I/MAVS pathway, at the level of RIG-I ubiquitination.These data give novel insights in the machinery involved in the early events of innate immune response. PMID:22022264

The International Criteria for Behçet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria.

PubMed

2014-03-01

Behçet's disease (BD) is a chronic, relapsing, inflammatory vascular disease with no pathognomonic test. Low sensitivity of the currently applied International Study Group (ISG) clinical diagnostic criteria led to their reassessment. An International Team for the Revision of the International Criteria for BD (from 27 countries) submitted data from 2556 clinically diagnosed BD patients and 1163 controls with BD-mimicking diseases or presenting at least one major BD sign. These were randomly divided into training and validation sets. Logistic regression, 'leave-one-country-out' cross-validation and clinical judgement were employed to develop new International Criteria for BD (ICBD) with the training data. Existing and new criteria were tested for their performance in the validation set. For the ICBD, ocular lesions, oral aphthosis and genital aphthosis are each assigned 2 points, while skin lesions, central nervous system involvement and vascular manifestations 1 point each. The pathergy test, when used, was assigned 1 point. A patient scoring ≥4 points is classified as having BD. In the training set, 93.9% sensitivity and 92.1% specificity were assessed compared with 81.2% sensitivity and 95.9% specificity for the ISG criteria. In the validation set, ICBD demonstrated an unbiased estimate of sensitivity of 94.8% (95% CI: 93.4-95.9%), considerably higher than that of the ISG criteria (85.0%). Specificity (90.5%, 95% CI: 87.9-92.8%) was lower than that of the ISG-criteria (96.0%), yet still reasonably high. For countries with at least 90%-of-cases and controls having a pathergy test, adding 1 point for pathergy test increased the estimate of sensitivity from 95.5% to 98.5%, while barely reducing specificity from 92.1% to 91.6%. The new proposed criteria derived from multinational data exhibits much improved sensitivity over the ISG criteria while maintaining reasonable specificity. It is proposed that the ICBD criteria to be adopted both as a guide for diagnosis and classification of BD. © 2013 The Authors Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology.

Negative regulation of protein phosphatase 2Cbeta by ISG15 conjugation.

PubMed

Takeuchi, Tomoharu; Kobayashi, Takayasu; Tamura, Shinri; Yokosawa, Hideyoshi

2006-08-07

ISG15, an interferon-upregulated ubiquitin-like protein, is covalently conjugated to various cellular proteins (ISGylation). In this study, we found that protein phosphatase 2Cbeta (PP2Cbeta), which functions in the nuclear factor kappaB (NF-kappaB) pathway via dephosphorylation of TGF-beta-activated kinase, was ISGylated, and analysis by NF-kappaB luciferase reporter assay revealed that PP2Cbeta activity was suppressed by co-expression of ISG15, UBE1L, and UbcH8. We determined the ISGylation sites of PP2Cbeta and constructed its ISGylation-resistant mutant. In contrast to the wild type, this mutant suppressed the NF-kappaB pathway even in the presence of ISG15, UBE1L, and UbcH8. Thus, we propose that ISGylation negatively regulates PP2Cbeta activity.

Behçet's disease in the United States: A single center descriptive and comparative study.

PubMed

Kilian, Nathan C; Sawalha, Amr H

2017-12-01

Behçet's disease is heterogeneous with clinical variability across ethnicities and geographic locations. The goal of this study was to analyze the clinical characteristics of our multi-ethnic Behçet's disease cohort at the University of Michigan. A detailed patient characterization was performed. Differences in disease characteristics between men and women, and between patients fulfilling the International Criteria for Behçet's Disease (ICBD) and the International Study Group criteria (ISG) were determined in our cohort. A total of 114 patients with a male to female ratio of ~ 1:4 were included. All patients met the ICBD criteria, including 76 who also met the ISG criteria. Over 95% of patients had recurrent genital ulcers, which is higher than generally reported. Retinitis was 5.3 times more likely in men than in women (p=0.009), and arthralgia was 3.3 times more likely in women than men (p=0.048). When comparing cohorts derived from the two different criteria, the ISG cohort had more skin manifestations (OR=3.3, p=0.0006). Acneiform lesions were associated with ~8 times higher odds of developing retinitis in our patients (p=0.0008), and superficial thrombophlebitis was associated with a trend for higher odds of developing uveitis (OR=4.1, p=0.057). Using the ICBD criteria, 38 additional patients were identified compared to only using the ISG criteria. Of these patients, 28 presented with only mucosal ulceration with or without joint involvement. We characterize Behçet's disease in a multi-ethnic cohort from North America. Using ICBD criteria in the United States significantly increases the likelihood of identifying Behçet's disease, particularly in patients with isolated mucosal involvement who constitute a substantial subset of patients in this region.

Type 1 IFN-independent activation of a subset of interferon stimulated genes in West Nile virus Eg101-infected mouse cells

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

Pulit-Penaloza, Joanna A.; Scherbik, Svetlana V.; Brinton, Margo A., E-mail: mbrinton@gsu.edu

2012-04-10

Although infection of mouse embryofibroblasts (MEFs) with WNV Eg101 induced interferon (IFN) beta production and STAT1 and STAT2 phosphorylation, these transcription factors (TFs) were not detected in the nucleus or on the promoters of four IRF-3-independent interferon stimulated genes (ISGs): Oas1a and Irf7 (previously characterized as IFN/ISGF3-dependent), Oas1b and Irf1. These ISGs were upregulated in WNV Eg101-infected STAT1-/-, STAT2-/-, and IFN alpha/beta receptor -/- MEFs. Although either IRF-3 or IRF-7 could amplify/sustain Oas1a and Oas1b upregulation at later times after infection, these factors were not required for the initial gene activation. The lack of upregulation of these ISGs in WNVmore » Eg101-infected IRF-3/9-/- MEFs suggested the involvement of IRF-9. Activation of Irf1 in infected MEFs did not depend on any of these IRFs. The data indicate that additional alternative activation mechanisms exist for subsets of ISGs when a virus infection has blocked ISG activation by the canonical IFN-mediated pathway.« less

78 FR 31614 - Implementation of Regulatory Guide 1.221 on Design-Basis Hurricane and Hurricane Missiles

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-24

... for Nuclear Power Plants,'' in support of NRC reviews of early site permit (ESP), standard design... NUREG-0800, ``Standard Review Plan for the Review of Safety Analysis Reports for Nuclear Power Plants... License Applications for Nuclear Power Plants, (LWR Edition)'' (ML070630003) In addition, this ISG...

Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating Activity of SARS-CoV Papain-Like Protease

PubMed Central

Ratia, Kiira; Kilianski, Andrew; Baez-Santos, Yahira M.; Baker, Susan C.; Mesecar, Andrew

2014-01-01

Severe acute respiratory syndrome coronavirus (SARS-CoV) encodes a papain-like protease (PLpro) with both deubiquitinating (DUB) and deISGylating activities that are proposed to counteract the post-translational modification of signaling molecules that activate the innate immune response. Here we examine the structural basis for PLpro's ubiquitin chain and interferon stimulated gene 15 (ISG15) specificity. We present the X-ray crystal structure of PLpro in complex with ubiquitin-aldehyde and model the interaction of PLpro with other ubiquitin-chain and ISG15 substrates. We show that PLpro greatly prefers K48- to K63-linked ubiquitin chains, and ISG15-based substrates to those that are mono-ubiquitinated. We propose that PLpro's higher affinity for K48-linked ubiquitin chains and ISG15 stems from a bivalent mechanism of binding, where two ubiquitin-like domains prefer to bind in the palm domain of PLpro with the most distal ubiquitin domain interacting with a “ridge” region of the thumb domain. Mutagenesis of residues within this ridge region revealed that these mutants retain viral protease activity and the ability to catalyze hydrolysis of mono-ubiquitin. However, a select number of these mutants have a significantly reduced ability to hydrolyze the substrate ISG15-AMC, or be inhibited by K48-linked diubuiquitin. For these latter residues, we found that PLpro antagonism of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) signaling pathway is abrogated. This identification of key and unique sites in PLpro required for recognition and processing of diubiquitin and ISG15 versus mono-ubiquitin and protease activity provides new insight into ubiquitin-chain and ISG15 recognition and highlights a role for PLpro DUB and deISGylase activity in antagonism of the innate immune response. PMID:24854014

75 FR 66138 - George Mathew, M.D.; Denial of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-27

... Services Group (CHS/ISG) of Arlington, Texas, which used numerous pharmacies owned by ``sham corporations... dispensing controlled substances) and four (Respondent's compliance with State and Federal laws related to... that since the initiation of the proceedings, ``Respondent has had approximately four years to handle...

Different Expression of Interferon-Stimulated Genes in Response to HIV-1 Infection in Dendritic Cells Based on Their Maturation State

PubMed Central

Calonge, Esther; Bermejo, Mercedes; Diez-Fuertes, Francisco; Mangeot, Isabelle; González, Nuria; Coiras, Mayte; Jiménez Tormo, Laura; García-Perez, Javier; Dereuddre-Bosquet, Nathalie; Le Grand, Roger

2017-01-01

ABSTRACT Dendritic cells (DCs) are professional antigen-presenting cells whose functions are dependent on their degree of differentiation. In their immature state, DCs capture pathogens and migrate to the lymph nodes. During this process, DCs become resident mature cells specialized in antigen presentation. DCs are characterized by a highly limiting environment for human immunodeficiency virus type 1 (HIV-1) replication due to the expression of restriction factors such as SAMHD1 and APOBEC3G. However, uninfected DCs capture and transfer viral particles to CD4 lymphocytes through a trans-enhancement mechanism in which chemokines are involved. We analyzed changes in gene expression with whole-genome microarrays when immature DCs (IDCs) or mature DCs (MDCs) were productively infected using Vpx-loaded HIV-1 particles. Whereas productive HIV infection of IDCs induced expression of interferon-stimulated genes (ISGs), such induction was not produced in MDCs, in which a sharp decrease in ISG- and CXCR3-binding chemokines was observed, lessening trans-infection of CD4 lymphocytes. Similar patterns of gene expression were found when DCs were infected with HIV-2 that naturally expresses Vpx. Differences were also observed under conditions of restrictive HIV-1 infection, in the absence of Vpx. ISG expression was not modified in IDCs, whereas an increase of ISG- and CXCR3-binding chemokines was observed in MDCs. Overall these results suggest that sensing and restriction of HIV-1 infection are different in IDCs and MDCs. We propose that restrictive infection results in increased virulence through different mechanisms. In IDCs avoidance of sensing and induction of ISGs, whereas in MDCs increased production of CXCR3-binding chemokines, would result in lymphocyte attraction and enhanced infection at the immune synapse. IMPORTANCE In this work we describe for the first time the activation of a different genetic program during HIV-1 infection depending on the state of maturation of DCs. This represents a breakthrough in the understanding of the restriction to HIV-1 infection of DCs. The results show that infection of DCs by HIV-1 reprograms their gene expression pattern. In immature cells, productive HIV-1 infection activates interferon-related genes involved in the control of viral replication, thus inducing an antiviral state in surrounding cells. Paradoxically, restriction of HIV-1 by SAMHD1 would result in lack of sensing and IFN activation, thus favoring initial HIV-1 escape from the innate immune response. In mature DCs, restrictive infection results in HIV-1 sensing and induction of ISGs, in particular CXCR3-binding chemokines, which could favor the transmission of HIV to lymphocytes. Our data support the hypothesis that genetic DC reprograming by HIV-1 infection favors viral escape and dissemination, thus increasing HIV-1 virulence. PMID:28148784

Distinct Molecular Events during Secretory Granule Biogenesis Revealed by Sensitivities to Brefeldin A

PubMed Central

Fernandez, Carlos J.; Haugwitz, Michael; Eaton, Benjamin; Moore, Hsiao-Ping H.

1997-01-01

The biogenesis of peptide hormone secretory granules involves a series of sorting, modification, and trafficking steps that initiate in the trans-Golgi and trans-Golgi network (TGN). To investigate their temporal order and interrelationships, we have developed a pulse–chase protocol that follows the synthesis and packaging of a sulfated hormone, pro-opiomelanocortin (POMC). In AtT-20 cells, sulfate is incorporated into POMC predominantly on N-linked endoglycosidase H-resistant oligosaccharides. Subcellular fractionation and pharmacological studies confirm that this sulfation occurs at the trans-Golgi/TGN. Subsequent to sulfation, POMC undergoes a number of molecular events before final storage in dense-core granules. The first step involves the transfer of POMC from the sulfation compartment to a processing compartment (immature secretory granules, ISGs): Inhibiting export of pulse-labeled POMC by brefeldin A (BFA) or a 20°C block prevents its proteolytic conversion to mature adrenocorticotropic hormone. Proteolytic cleavage products were found in vesicular fractions corresponding to ISGs, suggesting that the processing machinery is not appreciably activated until POMC exits the sulfation compartment. A large portion of the labeled hormone is secreted from ISGs as incompletely processed intermediates. This unregulated secretory process occurs only during a limited time window: Granules that have matured for 2 to 3 h exhibit very little unregulated release, as evidenced by the efficient storage of the 15-kDa N-terminal fragment that is generated by a relatively late cleavage event within the maturing granule. The second step of granule biogenesis thus involves two maturation events: proteolytic activation of POMC in ISGs and a transition of the organelle from a state of high unregulated release to one that favors intracellular storage. By using BFA, we show that the two processes occurring in ISGs may be uncoupled: although the unregulated secretion from ISGs is impaired by BFA, proteolytic processing of POMC within this organelle proceeds unaffected. The finding that BFA impairs constitutive secretion from both the TGN and ISGs also suggests that these secretory processes may be related in mechanism. Finally, our data indicate that the unusually high levels of unregulated secretion often associated with endocrine tumors may result, at least in part, from inefficient storage of secretory products at the level of ISGs. PMID:9362061

Distinct molecular events during secretory granule biogenesis revealed by sensitivities to brefeldin A.

PubMed

Fernandez, C J; Haugwitz, M; Eaton, B; Moore, H P

1997-11-01

The biogenesis of peptide hormone secretory granules involves a series of sorting, modification, and trafficking steps that initiate in the trans-Golgi and trans-Golgi network (TGN). To investigate their temporal order and interrelationships, we have developed a pulse-chase protocol that follows the synthesis and packaging of a sulfated hormone, pro-opiomelanocortin (POMC). In AtT-20 cells, sulfate is incorporated into POMC predominantly on N-linked endoglycosidase H-resistant oligosaccharides. Subcellular fractionation and pharmacological studies confirm that this sulfation occurs at the trans-Golgi/TGN. Subsequent to sulfation, POMC undergoes a number of molecular events before final storage in dense-core granules. The first step involves the transfer of POMC from the sulfation compartment to a processing compartment (immature secretory granules, ISGs): Inhibiting export of pulse-labeled POMC by brefeldin A (BFA) or a 20 degrees C block prevents its proteolytic conversion to mature adrenocorticotropic hormone. Proteolytic cleavage products were found in vesicular fractions corresponding to ISGs, suggesting that the processing machinery is not appreciably activated until POMC exits the sulfation compartment. A large portion of the labeled hormone is secreted from ISGs as incompletely processed intermediates. This unregulated secretory process occurs only during a limited time window: Granules that have matured for 2 to 3 h exhibit very little unregulated release, as evidenced by the efficient storage of the 15-kDa N-terminal fragment that is generated by a relatively late cleavage event within the maturing granule. The second step of granule biogenesis thus involves two maturation events: proteolytic activation of POMC in ISGs and a transition of the organelle from a state of high unregulated release to one that favors intracellular storage. By using BFA, we show that the two processes occurring in ISGs may be uncoupled: although the unregulated secretion from ISGs is impaired by BFA, proteolytic processing of POMC within this organelle proceeds unaffected. The finding that BFA impairs constitutive secretion from both the TGN and ISGs also suggests that these secretory processes may be related in mechanism. Finally, our data indicate that the unusually high levels of unregulated secretion often associated with endocrine tumors may result, at least in part, from inefficient storage of secretory products at the level of ISGs.

78 FR 39399 - Self-Regulatory Organizations; NYSE Arca, Inc.; Notice of Filing of Proposed Rule Change...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-01

... Custodian's custody, subject to certain limitations based on events beyond the Gold Custodian's control... Securities Commission, Autorite des marches financiers, New Brunswick Securities Commission, Nova Scotia... are members of the Intermarket Surveillance Group (``ISG''), and FINRA, on behalf of the Exchange, may...

Detection and analysis of protein ISGylation.

PubMed

Takeuchi, Tomoharu; Yokosawa, Hideyoshi

2008-01-01

ISG15 is a ubiquitin-like modifi er that is conjugated to target proteins by a sequential reaction catalyzed by E1/E2/E3 enzymes (protein ISGylation). ISG15 and protein ISGylation are upregulated by interferon stimuli. ISG15 functions as an antiviral protein against Sindbis virus and HIV-1, but the molecular mechanism remains unknown. Here we describe in detail methods for detecting and analyzing protein ISGylation. The methods consist of plasmid transfection and affi nity purifi cation of ISGylated proteins. In addition, we describe a method for detecting ISGylation of a target protein, Ubc13.

Interferon-Induced Ifit2/ISG54 Protects Mice from Lethal VSV Neuropathogenesis

PubMed Central

Fensterl, Volker; Wetzel, Jaime L.; Ramachandran, Srividya; Ogino, Tomoaki; Stohlman, Stephen A.; Bergmann, Cornelia C.; Diamond, Michael S.; Virgin, Herbert W.; Sen, Ganes C.

2012-01-01

Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, Ifit1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or Ifit1. We observed that in Ifit2 knockout (Ifit2 −/−) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and Ifit1 −/− mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2−/− mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2 −/− mice and induced interferon-β. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2 −/− mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2 −/− mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2−/− mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2 −/− mice. Our study provides a clear demonstration of tissue-, virus- and ISG-specific antiviral action of interferon. PMID:22615570

77 FR 23513 - Updated Aging Management Criteria for Reactor Vessel Internal Components of Pressurized Water...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-19

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0070] Updated Aging Management Criteria for Reactor Vessel Internal Components of Pressurized Water Reactors AGENCY: Nuclear Regulatory Commission. ACTION: Draft...-ISG), LR-ISG-2011-04, ``Updated Aging Management Criteria for PWR Reactor Vessel Internal Components...

Studies on the ecology and genetics of hybridization in Heterobasdion

Treesearch

M.M. Garbelotto; William J. Otrosina; I.H. Chapela; P. Gonthier

2001-01-01

The Heterobasidion taxonomic complex comprises two of the most important hngal tree pathogens in North America (Okosina 1989), and includes at least three other taxa in Eurasia (Niemela 1998). These taxa were initially identified as intersterility groups (ISGs) (Korhonen 1978) within the species H. annosum, but the current trend is...

Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase activity of parkin

PubMed Central

Im, Eunju; Yoo, Lang; Hyun, Minju; Shin, Woo Hyun

2016-01-01

Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the pars compacta of the substantia nigra and accumulation of ubiquitinated proteins in aggregates called Lewy bodies. Several mutated genes have been found in familial PD patients, including SNCA (α-synuclein), PARK2 (parkin), PINK1, PARK7 (DJ-1), LRRK2 and ATP13A2. Many pathogenic mutations of PARK2, which encodes the ubiquitin E3 ligase parkin, result in loss of function, leading to accumulation of parkin substrates and consequently contributing to dopaminergic cell death. ISG15 is a member of the ubiquitin-like modifier family and is induced by stimulation with type I interferons. Similar to ubiquitin and ubiquitination, covalent conjugation of ISG15 to target proteins (ISGylation) regulates their biochemical properties. In this study, we identified parkin as a novel target of ISGylation specifically mediated by the ISG15-E3 ligase HERC5. In addition, we identified two ISGylation sites, Lys-349 and Lys-369, in the in-between-ring domain of parkin. ISGylation of these sites promotes parkin's ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation and increases its cytoprotective effect. In conclusion, covalent ISG15 conjugation is a novel mode of modulating parkin activity, and alteration in this pathway may be associated with PD pathogenesis. PMID:27534820

Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase activity of parkin.

PubMed

Im, Eunju; Yoo, Lang; Hyun, Minju; Shin, Woo Hyun; Chung, Kwang Chul

2016-08-01

Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the pars compacta of the substantia nigra and accumulation of ubiquitinated proteins in aggregates called Lewy bodies. Several mutated genes have been found in familial PD patients, including SNCA (α-synuclein), PARK2 (parkin), PINK1, PARK7 (DJ-1), LRRK2 and ATP13A2 Many pathogenic mutations of PARK2, which encodes the ubiquitin E3 ligase parkin, result in loss of function, leading to accumulation of parkin substrates and consequently contributing to dopaminergic cell death. ISG15 is a member of the ubiquitin-like modifier family and is induced by stimulation with type I interferons. Similar to ubiquitin and ubiquitination, covalent conjugation of ISG15 to target proteins (ISGylation) regulates their biochemical properties. In this study, we identified parkin as a novel target of ISGylation specifically mediated by the ISG15-E3 ligase HERC5. In addition, we identified two ISGylation sites, Lys-349 and Lys-369, in the in-between-ring domain of parkin. ISGylation of these sites promotes parkin's ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation and increases its cytoprotective effect. In conclusion, covalent ISG15 conjugation is a novel mode of modulating parkin activity, and alteration in this pathway may be associated with PD pathogenesis. © 2016 The Authors.

Conceptus-derived prostaglandins regulate gene expression in the endometrium prior to pregnancy recognition in ruminants

PubMed Central

Spencer, Thomas E.; Forde, Niamh; Dorniak, Piotr; Hansen, Thomas R.; Romero, Jared J.; Lonergan, Patrick

2013-01-01

In cattle, the blastocyst hatches from the zona pellucida on days 8 to 9 and then forms a conceptus that grows and elongates into an ovoid and then filamentous shape between days 9 and 16. The growing conceptus synthesizes and secretes prostaglandins and interferon tau. Our hypothesis was that the ovoid conceptus exerts a local effect on the endometrium prior to maternal recognition of pregnancy on day 16 in cattle. In Study One, synchronized cyclic heifers received nothing or 20 in vitro produced blastocysts on day 7, and uteri were collected on day 13. Interferon tau was not detected by radioimmunoassay in the uterine flush of pregnant heifers containing multiple ovoid conceptuses; however, total prostaglandin levels were higher in the uterine lumen of pregnant as compared to cyclic heifers. Microarray analysis revealed that 44 genes were increased in the endometrium of day 13 pregnant as compared to cyclic heifers, and many of those genes were classical Type I IFN-stimulated genes (ISGs). Studies Two and Three determined effects of infusing prostaglandins at the levels produced by the elongating day 14 conceptus into the uterine lumen of cyclic ewes on ISG expression in the endometrium. Results indicated that prostaglandin infusion increased the abundance of several ISGs in the endometrium. These studies support the hypothesis that the day 13 conceptus secretes prostaglandins that act locally in a paracrine manner to alter gene expression in the endometrium prior to pregnancy recognition in cattle. PMID:23966582

IFN-gamma priming up-regulates IFN-stimulated gene factor 3 (ISGF3) components, augmenting responsiveness of IFN-resistant melanoma cells to type I IFNs.

PubMed

Wong, L H; Hatzinisiriou, I; Devenish, R J; Ralph, S J

1998-06-01

IFN-stimulated gene factor 3 (ISGF3) mediates transcriptional activation of IFN-sensitive genes (ISGs). The component subunits of ISGF3, STAT1alphabeta, STAT2, and p48-ISGF3gamma, are tyrosine phosphorylated before their assembly into a complex. Subsequently, the ISGF3 complex is translocated to the nucleus. We have recently established that the responsiveness of human melanoma cell lines to type I IFNs correlates directly with their intracellular levels of ISGF3 components, particularly STAT1. In the present study, we show that pretreating IFN-resistant melanoma cell lines with IFN-gamma (IFN-gamma priming) before stimulation with type I IFN also results in increased levels of ISGF3 components and enhanced DNA-binding activation of ISGF3. In addition, IFN-gamma priming of IFN-resistant melanoma cell lines increased expression of type I IFN-induced ISG products, including ISG54, 2'-5'-oligoadenylate synthase, HLA class I, B7-1, and ICAM-1 Ags. Furthermore, IFN-gamma priming enhanced the antiviral effect of IFN-beta on the IFN-resistant melanoma cell line, MM96. These results support a role for IFN-gamma priming in up-regulating ISGF3, thereby augmenting the responsiveness of IFN-resistant melanoma cell lines to type I IFN and providing a molecular basis and justification for using sequential IFN therapy, as proposed by others, to enhance the use of IFNs in the treatment of melanoma.

77 FR 27815 - Aging Management of Stainless Steel Structures and Components in Treated Borated Water

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-11

... NUCLEAR REGULATORY COMMISSION [NRC-2011-0256] Aging Management of Stainless Steel Structures and... Guidance (LR-ISG), LR-ISG-2011-01, ``Aging Management of Stainless Steel Structures and Components in...) Report for the aging management of stainless steel structures and components exposed to treated borated...

75 FR 62610 - Advisory Committee on Reactor Safeguards (ACRS); Meeting of the ACRS Subcommittee on Plant...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-12

...: Draft Regulatory Guide DG-1237, ``Guidance on Making Changes to Emergency Plans for Nuclear Power Reactors,'' Interim Staff Guidance (ISG) NSIR/DPR-ISG-01, ``Emergency Planning for Nuclear Power Plants... NUCLEAR REGULATORY COMMISSION Advisory Committee on Reactor Safeguards (ACRS); Meeting of the ACRS...

75 FR 36715 - Advisory Committee on Reactor Safeguards; Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-28

... Seismic Input for Site Response and Soil Structure Interaction Analyses'' (Open)--The Committee will hold... Seismic Input for Site Response and Soil Structure Interaction Analyses.'' 9:30 a.m.-10:30 a.m.: Interim Staff Guidance (ISG) DC/COL-ISG-020, ``Implementation of Seismic Margin Analysis for New Reactors Based...

Resistance to Rhabdoviridae Infection and Subversion of Antiviral Responses.

PubMed

Blondel, Danielle; Maarifi, Ghizlane; Nisole, Sébastien; Chelbi-Alix, Mounira K

2015-07-07

Interferon (IFN) treatment induces the expression of hundreds of IFN-stimulated genes (ISGs). However, only a selection of their products have been demonstrated to be responsible for the inhibition of rhabdovirus replication in cultured cells; and only a few have been shown to play a role in mediating the antiviral response in vivo using gene knockout mouse models. IFNs inhibit rhabdovirus replication at different stages via the induction of a variety of ISGs. This review will discuss how individual ISG products confer resistance to rhabdoviruses by blocking viral entry, degrading single stranded viral RNA, inhibiting viral translation or preventing release of virions from the cell. Furthermore, this review will highlight how these viruses counteract the host IFN system.

75 FR 35510 - License Renewal Interim Staff Guidance Process, Revision 2 Notice of Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-22

... Related Regulatory Functions.'' An electronic copy of the revised LR-ISG process is available in the NRC's Agencywide Documents Access and Management System (ADAMS) under Accession No. ML100920158. The revised LR-ISG... interim changes to certain NRC license renewal guidance documents. These guidance documents facilitate the...

78 FR 21980 - Aging Management of Internal Surfaces, Service Level III and Other Coatings, Atmospheric Storage...

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2013-04-12

... NUCLEAR REGULATORY COMMISSION [NRC-2013-0068] Aging Management of Internal Surfaces, Service Level... Interim Staff Guidance (LR-ISG), LR-ISG-2012-02, ``Aging Management of Internal Surfaces, Service Level... proposes to revise NRC staff-recommended aging management programs (AMP) and aging management review (AMR...

76 FR 58311 - Draft License Renewal Interim Staff Guidance LR-ISG-2011-05; Ongoing Review of Operating Experience

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... nuclear power plants. In response to a request from the Nuclear Energy Institute (NEI), the NRC is... NUCLEAR REGULATORY COMMISSION [NRC-2011-0191] Draft License Renewal Interim Staff Guidance LR-ISG-2011-05; Ongoing Review of Operating Experience AGENCY: Nuclear Regulatory Commission. ACTION: Draft...

75 FR 42797 - Self-Regulatory Organizations; NASDAQ OMX PHLX, Inc.; Notice of Filing and Immediate...

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2010-07-22

... pursuant to an industry-wide initiative, under the auspices of the Intermarket Surveillance Group (``ISG... equivalent of the net delta'' of a hedged equity option position is subject to the position limits under... purposes of the Exemption. \\8\\ The term ``options contract equivalent of the net delta'' is defined in...

77 FR 30341 - Self-Regulatory Organizations; NYSE Arca, Inc.; Order Granting Approval of Proposed Rule Change...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-22

... procedures designed to prevent the use and dissemination of material non-public information regarding such... Intermarket Surveillance Group (``ISG''), which includes all U.S. national securities exchanges and certain... throughout the world. Global shares are the actual (ordinary) shares of a non-U.S. company which trade both...

miR-370 regulates ISG15 expression and influences IFN-α sensitivity in hepatocellular carcinoma cells.

PubMed

Liu, Zhuo; Ma, Min; Yan, Lei; Chen, Shilin; Li, Sha; Yang, Darong; Wang, Xiaohong; Xiao, Hua; Deng, Hongyu; Zhu, Haizhen; Zuo, Chaohui; Xia, Man

2018-05-05

Interferon-α (IFN-α) is an adjuvant to chemotherapy and radiotherapy for hepatocellular carcinoma (HCC), but some HCC patients do not respond to treatment with IFN-α. We performed loss-of-function and gain-of-function experiments to examine the role of ISG15 in the IFN-α sensitivity of LH86, HLCZ01, SMMC7721, and Huh7 cell lines and tumor samples. The overexpression of ISG15 reduced apoptosis in Huh7 and LH86 cells in the presence of IFN-α, whereas the shRNA-mediated knock down of ISG15 expression increased apoptosis in both Huh7 and LH86 cells. We identified a putative miR-370 target site in the 3'-UTR in the ISG15 mRNA, and the level of miR-370 expression in HCC cell lines reflected the level of IFN-α-induced apoptosis exhibited by each. Both HCC cell lines and tumor samples had significantly lower levels of miR-370 than the control cells and tissues (P< 0.05). The overexpression of miR-370 in IFN-α-treated LH86 and Huh7 cells increased apoptosis and reduced the volume of LH86- and Huh7-derived xenograft tumors in mice treated with IFN-α compared with the control tumors. Our findings suggest that miR-370 functions as an HCC tumor suppressor and regulator of IFN-α sensitivity and that miR-370 might be a useful prognostic marker for HCC patients.

Evidence for the Deregulation of Protein Turnover Pathways in Atm-Deficient Mouse Cerebellum: An Organotypic Study.

PubMed

Kim, Catherine D; Reed, Ryan E; Juncker, Meredith A; Fang, Zhide; Desai, Shyamal D

2017-07-01

Interferon-stimulated gene 15 (ISG15), an antagonist of the ubiquitin pathway, is elevated in cells and brain tissues obtained from ataxia telangiectasia (A-T) patients. Previous studies reveal that an elevated ISG15 pathway inhibits ubiquitin-dependent protein degradation, leading to activation of basal autophagy as a compensatory mechanism for protein turnover in A-T cells. Also, genotoxic stress (ultraviolet [UV] radiation) deregulates autophagy and induces aberrant degradation of ubiquitylated proteins in A-T cells. In the current study, we show that, as in A-T cells, ISG15 protein expression is elevated in cerebellums and various other tissues obtained from Atm-compromised mice in an Atm-allele-dependent manner (Atm+/+ < Atm+/- < Atm-/-). Notably, in cerebellums, the brain part primarily affected in A-T, levels of ISG15 were significantly greater (3-fold higher) than cerebrums obtained from the same set of mice. Moreover, as in A-T cell culture, UV induces aberrant degradation of ubiquitylated proteins and autophagy in Atm-deficient, but not in Atm-proficient, cerebellar brain slices grown in culture. Thus, the ex vivo organotypic A-T mouse brain culture model mimics that of an A-T human cell culture model and could be useful for studying the role of ISG15-dependent proteinopathy in cerebellar neurodegeneration, a hallmark of A-T in humans. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3.

PubMed

Rabbani, M A G; Ribaudo, Michael; Guo, Ju-Tao; Barik, Sailen

2016-12-15

A major arm of cellular innate immunity is type I interferon (IFN), represented by IFN-α and IFN-β. Type I IFN transcriptionally induces a large number of cellular genes, collectively known as IFN-stimulated gene (ISG) proteins, which act as antivirals. The IFIT (interferon-induced proteins with tetratricopeptide repeats) family proteins constitute a major subclass of ISG proteins and are characterized by multiple tetratricopeptide repeats (TPRs). In this study, we have interrogated IFIT proteins for the ability to inhibit the growth of human parainfluenza virus type 3 (PIV3), a nonsegmented negative-strand RNA virus of the Paramyxoviridae family and a major cause of respiratory disease in children. We found that IFIT1 significantly inhibited PIV3, whereas IFIT2, IFIT3, and IFIT5 were less effective or not at all. In further screening a set of ISG proteins we discovered that several other such proteins also inhibited PIV3, including IFITM1, IDO (indoleamine 2,3-dioxygenase), PKR (protein kinase, RNA activated), and viperin (virus inhibitory protein, endoplasmic reticulum associated, interferon inducible)/Cig5. The antiviral effect of IDO, the enzyme that catalyzes the first step of tryptophan degradation, could be counteracted by tryptophan. These results advance our knowledge of diverse ISG proteins functioning as antivirals and may provide novel approaches against PIV3. The innate immunity of the host, typified by interferon (IFN), is a major antiviral defense. IFN inhibits virus growth by inducing a large number of IFN-stimulated gene (ISG) proteins, several of which have been shown to have specific antiviral functions. Parainfluenza virus type 3 (PIV3) is major pathogen of children, and no reliable vaccine or specific antiviral against it currently exists. In this article, we report several ISG proteins that strongly inhibit PIV3 growth, the use of which may allow a better antiviral regimen targeting PIV3. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

PubMed Central

Rabbani, M. A. G.; Ribaudo, Michael; Guo, Ju-Tao

2016-01-01

ABSTRACT A major arm of cellular innate immunity is type I interferon (IFN), represented by IFN-α and IFN-β. Type I IFN transcriptionally induces a large number of cellular genes, collectively known as IFN-stimulated gene (ISG) proteins, which act as antivirals. The IFIT (interferon-induced proteins with tetratricopeptide repeats) family proteins constitute a major subclass of ISG proteins and are characterized by multiple tetratricopeptide repeats (TPRs). In this study, we have interrogated IFIT proteins for the ability to inhibit the growth of human parainfluenza virus type 3 (PIV3), a nonsegmented negative-strand RNA virus of the Paramyxoviridae family and a major cause of respiratory disease in children. We found that IFIT1 significantly inhibited PIV3, whereas IFIT2, IFIT3, and IFIT5 were less effective or not at all. In further screening a set of ISG proteins we discovered that several other such proteins also inhibited PIV3, including IFITM1, IDO (indoleamine 2,3-dioxygenase), PKR (protein kinase, RNA activated), and viperin (virus inhibitory protein, endoplasmic reticulum associated, interferon inducible)/Cig5. The antiviral effect of IDO, the enzyme that catalyzes the first step of tryptophan degradation, could be counteracted by tryptophan. These results advance our knowledge of diverse ISG proteins functioning as antivirals and may provide novel approaches against PIV3. IMPORTANCE The innate immunity of the host, typified by interferon (IFN), is a major antiviral defense. IFN inhibits virus growth by inducing a large number of IFN-stimulated gene (ISG) proteins, several of which have been shown to have specific antiviral functions. Parainfluenza virus type 3 (PIV3) is major pathogen of children, and no reliable vaccine or specific antiviral against it currently exists. In this article, we report several ISG proteins that strongly inhibit PIV3 growth, the use of which may allow a better antiviral regimen targeting PIV3. PMID:27707917

Bias estimates used in lieu of validation of fission products and minor actinides in MCNP K eff calculations for PWR burnup credit casks

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

Mueller, Don E.; Marshall, William J.; Wagner, John C.

The U.S. Nuclear Regulatory Commission (NRC) Division of Spent Fuel Storage and Transportation recently issued Interim Staff Guidance (ISG) 8, Revision 3. This ISG provides guidance for burnup credit (BUC) analyses supporting transport and storage of PWR pressurized water reactor (PWR) fuel in casks. Revision 3 includes guidance for addressing validation of criticality (k eff) calculations crediting the presence of a limited set of fission products and minor actinides (FP&MA). Based on previous work documented in NUREG/CR-7109, recommendation 4 of ISG-8, Rev. 3, includes a recommendation to use 1.5 or 3% of the FP&MA worth to conservatively cover the biasmore » due to the specified FP&MAs. This bias is supplementary to the bias and bias uncertainty resulting from validation of k eff calculations for the major actinides in SNF and does not address extension to actinides and fission products beyond those identified herein. The work described in this report involves comparison of FP&MA worths calculated using SCALE and MCNP with ENDF/B-V, -VI, and -VII based nuclear data and supports use of the 1.5% FP&MA worth bias when either SCALE or MCNP codes are used for criticality calculations, provided the other conditions of the recommendation 4 are met. The method used in this report may also be applied to demonstrate the applicability of the 1.5% FP&MA worth bias to other codes using ENDF/B V, VI or VII based nuclear data. The method involves use of the applicant s computational method to generate FP&MA worths for a reference SNF cask model using specified spent fuel compositions. The applicant s FP&MA worths are then compared to reference values provided in this report. The applicants FP&MA worths should not exceed the reference results by more than 1.5% of the reference FP&MA worths.« less

76 FR 72725 - Draft License Renewal Interim Staff Guidance LR-ISG-2011-05: Ongoing Review of Operating Experience

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-25

... Experience.'' This LR-ISG provides guidance and clarification concerning ongoing review of plant-specific and... plants. As noticed on September 20, 2011 (76 FR 58311), the public comment period was extended and, as of... to communicate insights and lessons learned and to address emergent issues not covered in license...

78 FR 25487 - Final License Renewal Interim Staff Guidance LR-ISG-2012-01: Wall Thinning Due to Erosion Mechanisms

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-01

....'' This LR-ISG revises an NRC staff-recommended aging management program (AMP) in NUREG-1801, Revision 2, ``Generic Aging Lessons Learned (GALL) Report,'' and the NRC staff's aging management review procedure and... for piping and components within the scope of the Requirements for Renewal of Operating Licenses for...

Resistance to Rhabdoviridae Infection and Subversion of Antiviral Responses

PubMed Central

Blondel, Danielle; Maarifi, Ghizlane; Nisole, Sébastien; Chelbi-Alix, Mounira K.

2015-01-01

Interferon (IFN) treatment induces the expression of hundreds of IFN-stimulated genes (ISGs). However, only a selection of their products have been demonstrated to be responsible for the inhibition of rhabdovirus replication in cultured cells; and only a few have been shown to play a role in mediating the antiviral response in vivo using gene knockout mouse models. IFNs inhibit rhabdovirus  replication at different stages via the induction of a variety of ISGs. This review will discuss how individual ISG products confer resistance to rhabdoviruses by blocking viral entry, degrading single stranded viral RNA, inhibiting viral translation or preventing release of virions from the cell. Furthermore, this review will highlight how these viruses counteract the host IFN system. PMID:26198243

Inhibition of interferon induction and action by the nairovirus Nairobi sheep disease virus/Ganjam virus.

PubMed

Holzer, Barbara; Bakshi, Siddharth; Bridgen, Anne; Baron, Michael D

2011-01-01

The Nairoviruses are an important group of tick-borne viruses that includes pathogens of man (Crimean Congo hemorrhagic fever virus) and livestock animals (Dugbe virus, Nairobi sheep disease virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.

Ebola virus-like particles stimulate type I interferons and proinflammatory cytokine expression through the toll-like receptor and interferon signaling pathways.

PubMed

Ayithan, Natarajan; Bradfute, Steven B; Anthony, Scott M; Stuthman, Kelly S; Dye, John M; Bavari, Sina; Bray, Mike; Ozato, Keiko

2014-02-01

Ebola viruses (EBOV) can cause severe hemorrhagic disease with high case fatality rates. Currently, no vaccines or therapeutics are approved for use in humans. Ebola virus-like particles (eVLP) comprising of virus protein (VP40), glycoprotein, and nucleoprotein protect rodents and nonhuman primates from lethal EBOV infection, representing as a candidate vaccine for EBOV infection. Previous reports have shown that eVLP stimulate the expression of proinflammatory cytokines in dendritic cells (DCs) and macrophages (MΦs) in vitro. However, the molecular mechanisms and signaling pathways through which eVLP induce innate immune responses remain obscure. In this study, we show that eVLP stimulate not only the expression of proinflammatory cytokines but also the expression of type I interferons (IFNs) and IFN-stimulated genes (ISGs) in murine bone marrow-derived DCs (BMDCs) and MΦs. Our data indicate that eVLP trigger host responses through toll-like receptor (TLR) pathway utilizing 2 distinct adaptors, MyD88 and TRIF. More interestingly, eVLP activated the IFN signaling pathway by inducing a set of potent antiviral ISGs. Last, eVLP and synthetic adjuvants, Poly I:C and CpG DNA, cooperatively increased the expression of cytokines and ISGs. Further supporting this synergy, eVLP when administered together with Poly I:C conferred mice enhanced protection against EBOV infection. These results indicate that eVLP stimulate early innate immune responses through TLR and type I IFN signaling pathways to protect the host from EBOV infection.

Annotated Gene and Proteome Data Support Recognition of Interconnections Between the Results of Different Experiments in Space Research

NASA Astrophysics Data System (ADS)

Bauer, Johann; Wehland, Markus; Pietsch, Jessica; Sickmann, Albert; Weber, Gerhard; Grimm, Daniela

2016-06-01

In a series of studies, human thyroid and endothelial cells exposed to real or simulated microgravity were analyzed in terms of changes in gene expression patterns or protein content. Due to the limitation of available cells in many space research experiments, comparative and control experiments had to be done in a serial manner. Therefore, detected genes or proteins were annotated with gene names and SwissProt numbers, in order to allow searches for interconnections between results obtained in different experiments by different methods. A crosscheck of several studies on the behavior of cytoskeletal genes and proteins suggested that clusters of cytoskeletal components change differently under the influence of microgravity and/or vibration in different cell types. The result that LOX and ISG15 gene expression were clearly altered during the Shenzhou-8 spaceflight mission could be estimated by comparison with the results of other experiments. The more than 100-fold down-regulation of LOX supports our hypothesis that the amount and stability of extracellular matrix have a great influence on the formation of three-dimensional aggregates under microgravity. The approximately 40-fold up-regulation of ISG15 cannot yet be explained in detail, but strongly suggests that ISGylation, an alternative form of posttranslational modification, plays a role in longterm cultures.

75 FR 23821 - Final License Renewal Interim Staff Guidance LR-ISG-2009-01: Aging Management of Spent Fuel Pool...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-04

... approach acceptable to the NRC staff for meeting the requirements of 10 CFR part 54. On December 1, 2009... nuclear power plant spent fuel pool neutron-absorbing materials for compliance with part 54... Regulations (10 CFR part 54). The final LR-ISG revises the NRC staff's aging management recommendations...

76 FR 58846 - Final Interim Staff Guidance: Review of Evaluation To Address Gas Accumulation Issues in Safety...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-22

... of the comments. A document comparing the version of the ISG that went out for public comment and the final version of the ISG can be found under ADAMS Accession No. ML111170302. ADDRESSES: Publicly... its issued staff guidance in the agency external web page ( http://www.nrc.gov/reading-rm/doc...

75 FR 5632 - Office of New Reactors; Interim Staff Guidance on the Review of Nuclear Power Plant Designs Using...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-03

....8 and Regulatory Guide 1.206, ``Combined License Applications for Nuclear Power Plants (LWR Edition... Management System (ADAMS) Accession No. ML092640035). This ISG provides new guidance information for... (SRP), Section 8.3.1 and Sections 9.5.4 through 9.5.8. The NRC staff issues DC/COL-ISGs to facilitate...

The Adenovirus E1A C Terminus Suppresses a Delayed Antiviral Response and Modulates RAS Signaling.

PubMed

Zemke, Nathan R; Berk, Arnold J

2017-12-13

The N-terminal half of adenovirus e1a assembles multimeric complexes with host proteins that repress innate immune responses and force host cells into S-phase. In contrast, the functions of e1a's C-terminal interactions with FOXK, DCAF7, and CtBP are unknown. We found that these interactions modulate RAS signaling, and that a single e1a molecule must bind all three of these host proteins to suppress activation of a subset of IFN-stimulated genes (ISGs). These ISGs were otherwise induced in primary respiratory epithelial cells at 12 hr p.i. This delayed activation of ISGs required IRF3 and coincided with an ∼10-fold increase in IRF3 from protein stabilization. The induced IRF3 bound to chromatin and localized to the promoters of activated ISGs. While IRF3, STAT1/2, and IRF9 all greatly increased in concentration, there were no corresponding mRNA increases, suggesting that e1a regulates the stabilities of these key activators of innate immune responses, as shown directly for IRF3. Copyright © 2017 Elsevier Inc. All rights reserved.

Teaching multidisciplinary environmental science in a wetland setting

USGS Publications Warehouse

Panno, S.V.; Hackley, Keith C.; Nuzzo, V.A.

1998-01-01

High-school students from across the country came to the Illinois State Geological Survey (ISGS) to assist in field research for two weeks in July, 1994, as part of The Johns Hopkins University Center for Talented Youth Summer Experience Program. During the research project at the ISGS, students were exposed to a multidisciplinary scientific investigation where geology, hydrogeology, ground-water chemistry, and plant biology could be directly observed and used to study the potentially destructive effects of nearby road and house construction on a fen-wetland complex. Experienced researchers provided classroom and field instruction to the students prior to leading the field investigations. Following field work, the students returned to the ISGS laboratories where they assisted with the chemical analysis of ground-water samples and compiled and interpreted their data. The students wrote up their results in standard scientific report format and gave oral presentations covering various aspects of the project to an audience of ISGS scientists and guests. The results of their work, which showed changes in the wetland's plant biodiversity resulting from urban development within the watershed, will provide data needed for the preservation of biodiversity in these and other wetlands.

Standardization of quantum key distribution and the ETSI standardization initiative ISG-QKD

NASA Astrophysics Data System (ADS)

Länger, Thomas; Lenhart, Gaby

2009-05-01

In recent years, quantum key distribution (QKD) has been the object of intensive research activities and of rapid progress, and it is now developing into a competitive industry with commercial products. Once QKD systems are transferred from the controlled environment of physical laboratories into a real-world environment for practical use, a number of practical security, compatibility and connectivity issues need to be resolved. In particular, comprehensive security evaluation and watertight security proofs need to be addressed to increase trust in QKD. System interoperability with existing infrastructures and applications as well as conformance with specific user requirements have to be assured. Finding common solutions to these problems involving all actors can provide an advantage for the commercialization of QKD as well as for further technological development. The ETSI industry specification group for QKD (ISG-QKD) offers a forum for creating such universally accepted standards and will promote significant leverage effects on coordination, cooperation and convergence in research, technical development and business application of QKD.

Development of fetal and placental innate immune responses during establishment of persistent infection with bovine viral diarrhea virus.

PubMed

Smirnova, Natalia P; Webb, Brett T; Bielefeldt-Ohmann, Helle; Van Campen, Hana; Antoniazzi, Alfredo Q; Morarie, Susan E; Hansen, Thomas R

2012-08-01

Transplacental viral infections are dependent upon complex interactions between feto-placental and maternal immune responses and the stage of fetal development at which the infection occurs. Bovine viral diarrhea virus (BVDV) has the ability to cross the placenta and infect the fetus. Infection early in gestation with non-cytopathic (ncp) BVDV leads to persistent infection. Establishment of fetal persistent infection results in life-long viremia, virus-specific immunotolerance, and may have detrimental developmental consequences. We have previously shown that heifers infected experimentally with ncp BVDV type 2 on d. 75 of gestation had transient robust up-regulation of the type I interferon (IFN) stimulated genes (ISGs) 3-15 days after viral inoculation. Blood from persistently infected (PI) fetuses, collected 115 days post maternal infection, demonstrated moderate chronic up-regulation of ISGs. This infection model was used to delineate timing of the development of innate immune responses in the fetus and placenta during establishment of persistent infection. It was hypothesized that: (i) chronic stimulation of innate immune responses occurs following infection of the fetus and (ii) placental production of the type I IFN contributes to up-regulation of ISGs in PI fetuses. PI fetuses, generated by intranasal inoculation of pregnant heifers with ncp BVDV, and control fetuses from uninfected heifers, were collected via Cesarean sections on d. 82, 89, 97, 192, and 245 of gestation. Fetal viremia was confirmed starting on d. 89. Significant up-regulation of mRNA encoding cytosolic dsRNA sensors -RIG-I and MDA5 - was detected on d. 82-192. Detection of viral dsRNA by cytosolic sensors leads to the stimulation of ISGs, which was reflected in significant up-regulation of ISG15 mRNA in fetal blood on d. 89, 97, and 192. No difference in IFN-α and IFN-β mRNA concentration was found in fetal blood or caruncular tissue, while a significant increase in both IFN-α and IFN-β mRNA was seen in cotyledons from PI fetuses on d. 192. It is concluded that fetuses respond to early gestational ncp BVDV infection by induction of the type I IFN pathway, resulting in chronic up-regulation of ISGs. Cotyledonary tissue contributes to up-regulation of ISGs by increased production of IFNs. The innate immune response might partially curtail viral replication in PI fetuses, but is not able to eliminate the virus in the absence of a virus-specific adaptive immune response. Copyright © 2012 Elsevier B.V. All rights reserved.

76 FR 52995 - Draft License Renewal Interim Staff Guidance LR-ISG-2011-05: Ongoing Review of Operating...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-24

...- 2011-0191. Address questions about NRC dockets to Carol Gallagher, telephone: 301-492-3668; e-mail...): Publicly available documents created or received at the NRC are available online in the NRC Library at http...-800-397-4209, 301-415-4737, or by e-mail to [email protected] . The draft LR-ISG proposes to revise...

Pegylated interferons Lambda-1a and alfa-2a display different gene induction and cytokine and chemokine release profiles in whole blood, human hepatocytes and peripheral blood mononuclear cells.

PubMed

Freeman, J; Baglino, S; Friborg, J; Kraft, Z; Gray, T; Hill, M; McPhee, F; Hillson, J; Lopez-Talavera, J C; Wind-Rotolo, M

2014-06-01

Pegylated interferon-lambda-1a (Lambda), a type III interferon (IFN) in clinical development for the treatment of chronic HCV infection, has shown comparable efficacy and an improved safety profile to a regimen based on pegylated IFN alfa-2a (alfa). To establish a mechanistic context for this improved profile, we investigated the ex vivo effects of Lambda and alfa on cytokine and chemokine release, and on expression of IFN-stimulated genes (ISGs) in primary human hepatocytes and peripheral blood mononuclear cells (PBMCs) from healthy subjects. Our findings were further compared with changes observed in blood analysed from HCV-infected patients treated with Lambda or alfa in clinical studies. mRNA transcript and protein expression of the IFN-λ-limiting receptor subunit was lower compared with IFN-α receptor subunits in all cell types. Upon stimulation, alfa and Lambda induced ISG expression in hepatocytes and PBMCs, although in PBMCs Lambda-induced ISG expression was modest. Furthermore, alfa and Lambda induced release of cytokines and chemokines from hepatocytes and PBMCs, although differences in their kinetics of induction were observed. In HCV-infected patients, alfa treatment induced ISG expression in whole blood after single and repeat dosing. Lambda treatment induced modest ISG expression after single dosing and showed no induction after repeat dosing. Alfa and Lambda treatment increased IP-10, iTAC, IL-6, MCP-1 and MIP-1β levels in serum, with alfa inducing higher levels of all mediators compared with Lambda. Overall, ex vivo and in vivo induction profiles reported in this analysis strongly correlate with clinical observations of fewer related adverse events for Lambda vs those typically associated with alfa. © 2014 John Wiley & Sons Ltd.

IFN regulatory factor 1 restricts hepatitis E virus replication by activating STAT1 to induce antiviral IFN-stimulated genes.

PubMed

Xu, Lei; Zhou, Xinying; Wang, Wenshi; Wang, Yijin; Yin, Yuebang; Laan, Luc J W van der; Sprengers, Dave; Metselaar, Herold J; Peppelenbosch, Maikel P; Pan, Qiuwei

2016-10-01

IFN regulatory factor 1 (IRF1) is one of the most important IFN-stimulated genes (ISGs) in cellular antiviral immunity. Although hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide, how ISGs counteract HEV infection is largely unknown. This study was conducted to investigate the effect of IRF1 on HEV replication. Multiple cell lines were used in 2 models that harbor HEV. In different HEV cell culture systems, IRF1 effectively inhibited HEV replication. IRF1 did not trigger IFN production, and chromatin immunoprecipitation sequencing data analysis revealed that IRF1 bound to the promoter region of signal transducers and activators of transcription 1 (STAT1). Functional assay confirmed that IRF1 could drive the transcription of STAT1, resulting in elevation of total and phosphorylated STAT1 proteins and further activating the transcription of a panel of downstream antiviral ISGs. By pharmacological inhibitors and RNAi-mediated gene-silencing approaches, we revealed that antiviral function of IRF1 is dependent on the JAK-STAT cascade. Furthermore, induction of ISGs and the anti-HEV effect of IRF1 overlapped that of IFNα, but was potentiated by ribavirin. We demonstrated that IRF1 effectively inhibits HEV replication through the activation of the JAK-STAT pathway, and the subsequent transcription of antiviral ISGs, but independent of IFN production.-Xu, L., Zhou, X., Wang, W., Wang, Y., Yin, Y., van der Laan, L. J. W., Sprengers, D., Metselaar, H. J., Peppelenbosch, M. P., Pan, Q. IFN regulatory factor 1 restricts hepatitis E virus replication by activating STAT1 to induce antiviral IFN-stimulated genes. © FASEB.

Inhibition of Interferon Induction and Action by the Nairovirus Nairobi Sheep Disease Virus/Ganjam Virus

PubMed Central

Holzer, Barbara; Bakshi, Siddharth; Bridgen, Anne; Baron, Michael D.

2011-01-01

The Nairoviruses are an important group of tick-borne viruses that includes pathogens of man (Crimean Congo hemorrhagic fever virus) and livestock animals (Dugbe virus, Nairobi sheep disease virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU. PMID:22163042

Gene expression profile of endoscopically active and inactive ulcerative colitis: preliminary data.

PubMed

Ţieranu, Cristian George; Dobre, Maria; Mănuc, Teodora Ecaterina; Milanesi, Elena; Pleşea, Iancu Emil; Popa, Caterina; Mănuc, Mircea; Ţieranu, Ioana; Preda, Carmen Monica; Diculescu, Mihai Mircea; Ionescu, Elena Mirela; Becheanu, Gabriel

2017-01-01

Multiple cytokines and chemokines related to immune response, apoptosis and inflammation have been identified as molecules implicated in ulcerative colitis (UC) pathogenesis. The aim of this study was to identify the differences at gene expression level of a panel of candidate genes in mucosa from patients with active UC (UCA), patients in remission (UCR), and normal controls. Eleven individuals were enrolled in the study: eight UC patients (four with active lesions, four with mucosal healing) and three controls without inflammatory bowel disease (IBD) seen on endoscopy. All the individuals underwent mucosal biopsy during colonoscopy. Gene expression profile was evaluated by polymerase chain reaction (PCR) array, investigating 84 genes implicated in apoptosis, inflammation, immune response, cellular adhesion, tissue remodeling and mucous secretion. Seventeen and three genes out of 84 were found significantly differentially expressed in UCA and UCR compared to controls, respectively. In particular, REG1A and CHI3L1 genes reported an up-regulation in UCA with a fold difference above 200. In UCR patients, the levels of CASP1, LYZ and ISG15 were different compared to controls. However, since a significant up-regulation of both CASP1 and LYZ was observed also in the UCA group, only ISG15 levels remained associated to the remission state. ISG15, that plays a key role in the innate immune response, seemed to be specifically associated to the UC remission state. These preliminary data represent a starting point for defining the gene profile of UC in different stages in Romanian population. Identification of genes implicated in UC pathogenesis could be useful to select new therapeutic targets.

Severe fever with thrombocytopenia syndrome virus inhibits exogenous Type I IFN signaling pathway through its NSs invitro.

PubMed

Chen, Xu; Ye, Haiyan; Li, Shilin; Jiao, Baihai; Wu, Jianqin; Zeng, Peibin; Chen, Limin

2017-01-01

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus (SFTS virus, SFTSV). At present there is still no specific antiviral treatment for SFTSV; To understand which cells support SFTSV life cycle and whether SFTSV infection activates host innate immunity, four different cell lines (Vero, Hela, Huh7.5.1, and Huh7.0) were infected with SFTSV. Intracellular/extracellular viral RNA and expression of IFNα, and IFNß were detected by real-time RT- PCR following infection. To confirm the role of non-structural protein (NSs) of SFTSV in exogenous IFNα-induced Jak/STAT signaling, p-STAT1 (Western Blot), ISRE activity (Luciferase assay) and ISG expression (real-time PCR) were examined following IFNα stimulation in the presence or absence of over-expression of NSs in Hela cells. Our study showed that all the four cell lines supported SFTSV life cycle and SFTSV activated host innate immunity to produce type I IFNs in Hela cells but not in Huh7.0, Huh7.5.1 or Vero cells. NSs inhibited exogenous IFNα-induced Jak/STAT signaling as shown by decreased p-STAT1 level, suppressed ISRE activity and down-regulated ISG expression. Suppression of the exogenous Type I IFN-induced Jak/STAT signaling by NSs might be one of the mechanisms of SFTSV to evade host immune surveillance.

An Online, Moderated Peer-to-Peer Support Bulletin Board for Depression: User-Perceived Advantages and Disadvantages

PubMed Central

Reynolds, Julia; Vassallo, Sara

2015-01-01

Background Online, peer-to-peer support groups for depression are common on the World Wide Web and there is some evidence of their effectiveness. However, little is known about the mechanisms by which Internet support groups (ISGs) might work. Objective This study aimed to investigate consumer perceptions of the benefits and disadvantages of online peer-to-peer support by undertaking a content analysis of the spontaneous posts on BlueBoard, a well-established, moderated, online depression bulletin board. Methods The research set comprised all posts on the board (n=3645) for each of 3 months selected at 4 monthly intervals over 2011. The data were analyzed using content analysis and multiple coders. Results A total of 586 relevant posts were identified, 453 (77.3%) reporting advantages and 133 (22.7%) reporting disadvantages. Positive personal change (335/453, 74.0%) and valued social interactions and support (296/453, 65.3%) emerged as perceived advantages. Other identified benefits were valued opportunities to disclose/express feelings or views (29/453, 6.4%) and advantages of the BlueBoard environment (45/453, 9.9%). Disadvantages were negative personal change (50/133, 37.6%), perceived disadvantages of board rules/moderation (42/133, 31.6%), unhelpful social interactions/contact with other members (40/133, 30.1%), and technical obstacles to using the board (14/133, 10.5%). Conclusions Consumers value the opportunity to participate in an online mutual support group for mental health concerns. Further research is required to better understand how and if these perceived advantages translate into positive outcomes for consumers, and whether the perceived disadvantages of such boards can be addressed without compromising the safety and positive outcomes of the board. PMID:26543919

An Online, Moderated Peer-to-Peer Support Bulletin Board for Depression: User-Perceived Advantages and Disadvantages.

PubMed

Griffiths, Kathleen Margaret; Reynolds, Julia; Vassallo, Sara

2015-01-01

Online, peer-to-peer support groups for depression are common on the World Wide Web and there is some evidence of their effectiveness. However, little is known about the mechanisms by which Internet support groups (ISGs) might work. This study aimed to investigate consumer perceptions of the benefits and disadvantages of online peer-to-peer support by undertaking a content analysis of the spontaneous posts on BlueBoard, a well-established, moderated, online depression bulletin board. The research set comprised all posts on the board (n=3645) for each of 3 months selected at 4 monthly intervals over 2011. The data were analyzed using content analysis and multiple coders. A total of 586 relevant posts were identified, 453 (77.3%) reporting advantages and 133 (22.7%) reporting disadvantages. Positive personal change (335/453, 74.0%) and valued social interactions and support (296/453, 65.3%) emerged as perceived advantages. Other identified benefits were valued opportunities to disclose/express feelings or views (29/453, 6.4%) and advantages of the BlueBoard environment (45/453, 9.9%). Disadvantages were negative personal change (50/133, 37.6%), perceived disadvantages of board rules/moderation (42/133, 31.6%), unhelpful social interactions/contact with other members (40/133, 30.1%), and technical obstacles to using the board (14/133, 10.5%). Consumers value the opportunity to participate in an online mutual support group for mental health concerns. Further research is required to better understand how and if these perceived advantages translate into positive outcomes for consumers, and whether the perceived disadvantages of such boards can be addressed without compromising the safety and positive outcomes of the board.

A shot in the rear, not a shot in the dark: application of a mass clinic framework in a public health emergency.

PubMed

Erwin, Paul Campbell; Sheeler, Lorinda; Lott, John M

2009-01-01

An outbreak of foodborne hepatitis A infection compelled two regional health departments in eastern Tennessee to implement an emergency mass clinic for providing hepatitis immune serum globulin (ISG) to several thousand potentially exposed people. For the mass clinic framework, we utilized the smallpox post-event clinic plans of the Centers for Disease Control and Prevention (CDC), although the plans had only been exercised for smallpox. Following CDC's guidelines for staffing and organizing the mass clinic, we provided 5,038 doses of ISG during a total of 24 hours of clinic operation, using 3,467 person-hours, or 1.45 ISG doses per person-hour-very close to the 1.58 doses per person-hour targeted in CDC's smallpox post-event clinic plans. The mass clinic showed that CDC's smallpox post-event clinic guidelines were feasible, practical, and adaptable to other mass clinic situations.

Early innate immune responses to Sin Nombre hantavirus occur independently of IFN regulatory factor 3, characterized pattern recognition receptors, and viral entry.

PubMed

Prescott, Joseph B; Hall, Pamela R; Bondu-Hawkins, Virginie S; Ye, Chunyan; Hjelle, Brian

2007-08-01

Sin Nombre virus (SNV) is a highly pathogenic New World virus and etiologic agent of hantavirus cardiopulmonary syndrome. We have previously shown that replication-defective virus particles are able to induce a strong IFN-stimulated gene (ISG) response in human primary cells. RNA viruses often stimulate the innate immune response by interactions between viral nucleic acids, acting as a pathogen-associated molecular pattern, and cellular pattern-recognition receptors (PRRs). Ligand binding to PRRs activates transcription factors which regulate the expression of antiviral genes, and in all systems examined thus far, IFN regulatory factor 3 (IRF3) has been described as an essential intermediate for induction of ISG expression. However, we now describe a model in which IRF3 is dispensable for the induction of ISG transcription in response to viral particles. IRF3-independent ISG transcription in human hepatoma cell lines is initiated early after exposure to SNV virus particles in an entry- and replication-independent fashion. Furthermore, using gene knockdown, we discovered that this activation is independent of the best-characterized RNA- and protein-sensing PRRs including the cytoplasmic caspase recruitment domain-containing RNA helicases and the TLRs. SNV particles engage a heretofore unrecognized PRR, likely located at the cell surface, and engage a novel IRF3-independent pathway that activates the innate immune response.

Antitumor Effects of Epidrug/IFNα Combination Driven by Modulated Gene Signatures in Both Colorectal Cancer and Dendritic Cells.

PubMed

Fragale, Alessandra; Romagnoli, Giulia; Licursi, Valerio; Buoncervello, Maria; Del Vecchio, Giorgia; Giuliani, Caterina; Parlato, Stefania; Leone, Celeste; De Angelis, Marta; Canini, Irene; Toschi, Elena; Belardelli, Filippo; Negri, Rodolfo; Capone, Imerio; Presutti, Carlo; Gabriele, Lucia

2017-07-01

Colorectal cancer results from the progressive accumulation of genetic and epigenetic alterations. IFN signaling defects play an important role in the carcinogenesis process, in which the inability of IFN transcription regulatory factors (IRF) to access regulatory sequences in IFN-stimulated genes (ISG) in tumors and in immune cells may be pivotal. We reported that low-dose combination of two FDA-approved epidrugs, azacytidine (A) and romidepsin (R), with IFNα2 (ARI) hampers the aggressiveness of both colorectal cancer metastatic and stem cells in vivo and triggers immunogenic cell death signals that stimulate dendritic cell (DC) function. Here, we investigated the molecular signals induced by ARI treatment and found that this drug combination increased the accessibility to regulatory sequences of ISGs and IRFs that were epigenetically silenced in both colorectal cancer cells and DCs. Likewise, specific ARI-induced histone methylation and acetylation changes marked epigenetically affected ISG promoters in both metastatic cancer cells and DCs. Analysis by ChIP-seq confirmed such ARI-induced epigenetically regulated IFN signature. The activation of this signal endowed DCs with a marked migratory capability. Our results establish a direct correlation between reexpression of silenced ISGs by epigenetic control and ARI anticancer activity and provide new knowledge for the development of innovative combined therapeutic strategies for colorectal cancer. Cancer Immunol Res; 5(7); 604-16. ©2017 AACR . ©2017 American Association for Cancer Research.

Imaging of the small intestine in Crohn's disease: Joint position statement of the Indian Society of Gastroenterology and Indian Radiological and Imaging Association.

PubMed

Kedia, Saurabh; Sharma, Raju; Makharia, Govind K; Ahuja, Vineet; Desai, Devendra; Kandasamy, Devasenathipathy; Eapen, Anu; Ganesan, Karthik; Ghoshal, Uday C; Kalra, Naveen; Karthikeyan, D; Madhusudhan, Kumble Seetharama; Philip, Mathew; Puri, Amarender Singh; Puri, Sunil; Sinha, Saroj K; Banerjee, Rupa; Bhatia, Shobna; Bhat, Naresh; Dadhich, Sunil; Dhali, G K; Goswami, B D; Issar, S K; Jayanthi, V; Misra, S P; Nijhawan, Sandeep; Puri, Pankaj; Sarkar, Avik; Singh, S P; Srivastava, Anshu; Abraham, Philip; Ramakrishna, B S

2017-11-01

The Indian Society of Gastroenterology (ISG) Task Force on Inflammatory Bowel Disease and the Indian Radiological and Imaging Association (IRIA) developed combined ISG-IRIA evidence-based best-practice guidelines for imaging of the small intestine in patients with suspected or known Crohn's disease. These 29 position statements, developed through a modified Delphi process, are intended to serve as reference for teaching, clinical practice, and research.

Induction of Interferon-Stimulated Genes by Simian Virus 40 T Antigens

PubMed Central

Rathi, Abhilasha V.; Cantalupo, Paul G.; Sarkar, Saumendra N.; Pipas, James M.

2010-01-01

Simian virus 40 (SV40) large T antigen (TAg) is a multifunctional oncoprotein essential for productive viral infection and for cellular transformation. We have used microarray analysis to examine the global changes in cellular gene expression induced by wild-type T antigen (TAgwt) and TAg-mutants in mouse embryo fibroblasts (MEFs). The expression profile of approximately 800 cellular genes was altered by TAgwt and a truncated TAg (TAgN136), including many genes that influence cell cycle, DNA-replication, transcription, chromatin structure and DNA repair. Unexpectedly, we found a significant number of immune response genes upregulated by TAgwt including many interferon stimulated genes (ISGs) such as ISG56, OAS, Rsad2, Ifi27 and Mx1. Additionally, we also observed activation of STAT1 by TAgwt. Our genetic studies using several TAg mutants reveal an unexplored function of TAg and indicate that the LXCXE motif and p53 binding are required for the upregulation of ISGs. PMID:20692676

Amplified RLR signaling activation through an interferon-stimulated gene-endoplasmic reticulum stress-mitochondrial calcium uniporter protein loop

PubMed Central

Cheng, Jinbo; Liao, Yajin; Zhou, Lujun; Peng, Shengyi; Chen, Hong; Yuan, Zengqiang

2016-01-01

Type I interferon (IFN-I) is critical for a host against viral and bacterial infections via induction of hundreds of interferon-stimulated genes (ISGs), but the mechanism underlying the regulation of IFN-I remains largely unknown. In this study, we first demonstrate that ISG expression is required for optimal IFN-β levels, an effect that is further enhanced by endoplasmic reticulum (ER) stress. Furthermore, we identify mitochondrial calcium uniporter protein (MCU) as a mitochondrial antiviral signaling protein (MAVS)-interacting protein that is important for ER stress induction and amplified MAVS signaling activation. In addition, by performing an ectopic expression assay to screen a library of 117 human ISGs for effects on IFN-β levels, we found that tumor necrosis factor receptor 1 (TNFR1) significantly increases IFN-β levels independent of ER stress. Altogether, our findings suggest that MCU and TNFR1 are involved in the regulation of RIG-I-like receptors (RLR) signaling. PMID:26892273

PARP12 suppresses Zika virus infection through PARP-dependent degradation of NS1 and NS3 viral proteins.

PubMed

Li, Lili; Zhao, Hui; Liu, Ping; Li, Chunfeng; Quanquin, Natalie; Ji, Xue; Sun, Nina; Du, Peishuang; Qin, Cheng-Feng; Lu, Ning; Cheng, Genhong

2018-06-19

Zika virus infection stimulates a type I interferon (IFN) response in host cells, which suppresses viral replication. Type I IFNs exert antiviral effects by inducing the expression of hundreds of IFN-stimulated genes (ISGs). To screen for antiviral ISGs that restricted Zika virus replication, we individually knocked out 21 ISGs in A549 lung cancer cells and identified PARP12 as a strong inhibitor of Zika virus replication. Our findings suggest that PARP12 mediated the ADP-ribosylation of NS1 and NS3, nonstructural viral proteins that are involved in viral replication and modulating host defense responses. This modification of NS1 and NS3 triggered their proteasome-mediated degradation. These data increase our understanding of the antiviral activity of PARP12 and suggest a molecular basis for the potential development of therapeutics against Zika virus. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

A Serpin Shapes the Extracellular Environment to Prevent Influenza A Virus Maturation

PubMed Central

Dittmann, Meike; Hoffmann, Hans-Heinrich; Scull, Margaret A.; Gilmore, Rachel H.; Bell, Kierstin L.; Ciancanelli, Michael; Wilson, Sam J.; Crotta, Stefania; Yu, Yingpu; Flatley, Brenna; Xiao, Jing W.; Casanova, Jean-Laurent; Wack, Andreas; Bieniasz, Paul D.; Rice, Charles M.

2015-01-01

Summary Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPINE1, conferred increased susceptibility to IAV in vitro. Together, our findings reveal that manipulating the extracellular environment to inhibit the last step in a virus life cycle is an important mechanism of the antiviral response. PMID:25679759

A new mechanism of interferon's antiviral action: Induction of autophagy, essential for paramyxovirus replication, is inhibited by the interferon stimulated gene, TDRD7.

PubMed

Subramanian, Gayatri; Kuzmanovic, Teodora; Zhang, Ying; Peter, Cara Beate; Veleeparambil, Manoj; Chakravarti, Ritu; Sen, Ganes C; Chattopadhyay, Saurabh

2018-01-01

The interferon (IFN) system represents the first line of defense against a wide range of viruses. Virus infection rapidly triggers the transcriptional induction of IFN-β and IFN Stimulated Genes (ISGs), whose protein products act as viral restriction factors by interfering with specific stages of virus life cycle, such as entry, transcription, translation, genome replication, assembly and egress. Here, we report a new mode of action of an ISG, IFN-induced TDRD7 (tudor domain containing 7) inhibited paramyxovirus replication by inhibiting autophagy. TDRD7 was identified as an antiviral gene by a high throughput screen of an ISG shRNA library for blocking IFN's protective effect against Sendai virus (SeV) replication. The antiviral activity of TDRD7 against SeV, human parainfluenza virus 3 and respiratory syncytial virus was confirmed by its genetic ablation or ectopic expression in several types of mouse and human cells. TDRD7's antiviral action was mediated by its ability to inhibit autophagy, a cellular catabolic process which was robustly induced by SeV infection and required for its replication. Mechanistic investigation revealed that TDRD7 interfered with the activation of AMP-dependent kinase (AMPK), an enzyme required for initiating autophagy. AMPK activity was required for efficient replication of several paramyxoviruses, as demonstrated by its genetic ablation or inhibition of its activity by TDRD7 or chemical inhibitors. Therefore, our study has identified a new antiviral ISG with a new mode of action.

The Value of Harmonizing Multiple Improvement Technologies: A Process Improvement Professional’s View

DTIC Science & Technology

2008-03-01

maturity models and ISO standards, specifically CMMI, CMMI-ACQ and ISO 12207 . Also, the improvement group supplemented their selection of these...compliant with the technologies and standards that are important to the business. Lockheed Martin IS&GS has integrated CMMI, EIA 632, ISO 12207 , and Six...geographically dispersed organization. [Siviy 07-1] Northrop Grumman Mission Systems has integrated CMMI, ISO 9001, AS9100, and Six Sigma, as well as a

Inpatient Psychiatric Admission Rates in a U.S. Air Force Basic Military Training Population

DTIC Science & Technology

2017-05-20

PRESENTATION. 18 . AUTHOR’S PRINTED NAME, RANK, GRADE 19. AUTHOR’S SIGNATURE Joseph A . Mansfield, CPT, 0-3 f.W4SFIELD JOSEPH AU>H 1050007,,.0...7141 for email instructions. 30 March 2017 17187 26. DATE REVIEWED 27. DATE FORWARDED TO 502 ISG/JAC A pril 18 , 2017 28. AUTHOR CONTACTED FOR...1086667270 ::.!!:: .. ~ -"’"’ -· A pril 18 , 2017 2nd ENDORSEMENT 1502 ISG/JAC Use Only) 33. DATE RECEIVED 34. DATE FORWARDED TO 59 MOW/PA 35

Radiation-induced refraction artifacts in the optical CT readout of polymer gel dosimeters

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

Campbell, Warren G.; Jirasek, Andrew, E-mail: jirasek@uvic.ca; Wells, Derek M.

2014-11-01

Purpose: The objective of this work is to demonstrate imaging artifacts that can occur during the optical computed tomography (CT) scanning of polymer gel dosimeters due to radiation-induced refractive index (RI) changes in polyacrylamide gels. Methods: A 1 L cylindrical polyacrylamide gel dosimeter was irradiated with 3 × 3 cm{sup 2} square beams of 6 MV photons. A prototype fan-beam optical CT scanner was used to image the dosimeter. Investigative optical CT scans were performed to examine two types of rayline bending: (i) bending within the plane of the fan-beam and (ii) bending out the plane of the fan-beam. Tomore » address structured errors, an iterative Savitzky–Golay (ISG) filtering routine was designed to filter 2D projections in sinogram space. For comparison, 2D projections were alternatively filtered using an adaptive-mean (AM) filter. Results: In-plane rayline bending was most notably observed in optical CT projections where rays of the fan-beam confronted a sustained dose gradient that was perpendicular to their trajectory but within the fan-beam plane. These errors caused distinct streaking artifacts in image reconstructions due to the refraction of higher intensity rays toward more opaque regions of the dosimeter. Out-of-plane rayline bending was observed in slices of the dosimeter that featured dose gradients perpendicular to the plane of the fan-beam. These errors caused widespread, severe overestimations of dose in image reconstructions due to the higher-than-actual opacity that is perceived by the scanner when light is bent off of the detector array. The ISG filtering routine outperformed AM filtering for both in-plane and out-of-plane rayline errors caused by radiation-induced RI changes. For in-plane rayline errors, streaks in an irradiated region (>7 Gy) were as high as 49% for unfiltered data, 14% for AM, and 6% for ISG. For out-of-plane rayline errors, overestimations of dose in a low-dose region (∼50 cGy) were as high as 13 Gy for unfiltered data, 10 Gy for AM, and 3.1 Gy for ISG. The ISG routine also addressed unrelated artifacts that previously needed to be manually removed in sinogram space. However, the ISG routine blurred reconstructions, causing losses in spatial resolution of ∼5 mm in the plane of the fan-beam and ∼8 mm perpendicular to the fan-beam. Conclusions: This paper reveals a new category of imaging artifacts that can affect the optical CT readout of polyacrylamide gel dosimeters. Investigative scans show that radiation-induced RI changes can cause significant rayline errors when rays confront a prolonged dose gradient that runs perpendicular to their trajectory. In fan-beam optical CT, these errors manifested in two ways: (1) distinct streaking artifacts caused by in-plane rayline bending and (2) severe overestimations of opacity caused by rays bending out of the fan-beam plane and missing the detector array. Although the ISG filtering routine mitigated these errors better than an adaptive-mean filtering routine, it caused unacceptable losses in spatial resolution.« less

Radiation-induced refraction artifacts in the optical CT readout of polymer gel dosimeters.

PubMed

Campbell, Warren G; Wells, Derek M; Jirasek, Andrew

2014-11-01

The objective of this work is to demonstrate imaging artifacts that can occur during the optical computed tomography (CT) scanning of polymer gel dosimeters due to radiation-induced refractive index (RI) changes in polyacrylamide gels. A 1 L cylindrical polyacrylamide gel dosimeter was irradiated with 3 × 3 cm(2) square beams of 6 MV photons. A prototype fan-beam optical CT scanner was used to image the dosimeter. Investigative optical CT scans were performed to examine two types of rayline bending: (i) bending within the plane of the fan-beam and (ii) bending out the plane of the fan-beam. To address structured errors, an iterative Savitzky-Golay (ISG) filtering routine was designed to filter 2D projections in sinogram space. For comparison, 2D projections were alternatively filtered using an adaptive-mean (AM) filter. In-plane rayline bending was most notably observed in optical CT projections where rays of the fan-beam confronted a sustained dose gradient that was perpendicular to their trajectory but within the fan-beam plane. These errors caused distinct streaking artifacts in image reconstructions due to the refraction of higher intensity rays toward more opaque regions of the dosimeter. Out-of-plane rayline bending was observed in slices of the dosimeter that featured dose gradients perpendicular to the plane of the fan-beam. These errors caused widespread, severe overestimations of dose in image reconstructions due to the higher-than-actual opacity that is perceived by the scanner when light is bent off of the detector array. The ISG filtering routine outperformed AM filtering for both in-plane and out-of-plane rayline errors caused by radiation-induced RI changes. For in-plane rayline errors, streaks in an irradiated region (>7 Gy) were as high as 49% for unfiltered data, 14% for AM, and 6% for ISG. For out-of-plane rayline errors, overestimations of dose in a low-dose region (∼50 cGy) were as high as 13 Gy for unfiltered data, 10 Gy for AM, and 3.1 Gy for ISG. The ISG routine also addressed unrelated artifacts that previously needed to be manually removed in sinogram space. However, the ISG routine blurred reconstructions, causing losses in spatial resolution of ∼5 mm in the plane of the fan-beam and ∼8 mm perpendicular to the fan-beam. This paper reveals a new category of imaging artifacts that can affect the optical CT readout of polyacrylamide gel dosimeters. Investigative scans show that radiation-induced RI changes can cause significant rayline errors when rays confront a prolonged dose gradient that runs perpendicular to their trajectory. In fan-beam optical CT, these errors manifested in two ways: (1) distinct streaking artifacts caused by in-plane rayline bending and (2) severe overestimations of opacity caused by rays bending out of the fan-beam plane and missing the detector array. Although the ISG filtering routine mitigated these errors better than an adaptive-mean filtering routine, it caused unacceptable losses in spatial resolution.

Interferon-lambda (IFN-λ) induces signal transduction and gene expression in human hepatocytes, but not in lymphocytes or monocytes

PubMed Central

Dickensheets, Harold; Sheikh, Faruk; Park, Ogyi; Gao, Bin; Donnelly, Raymond P.

2013-01-01

This study compared the ability of IFN-α and IFN-λ to induce signal transduction and gene expression in primary human hepatocytes, PBLs, and monocytes. IFN-α drug products are widely used to treat chronic HCV infection; however, IFN-α therapy often induces hematologic toxicities as a result of the broad expression of IFNARs on many cell types, including most leukocytes. rIFN-λ1 is currently being tested as a potential alternative to IFN-α for treating chronic HCV. Although IFN-λ has been shown to be active on hepatoma cell lines, such as HepG2 and Huh-7, its ability to induce responses in primary human hepatocytes or leukocytes has not been examined. We found that IFN-λ induces activation of Jak/STAT signaling in mouse and human hepatocytes, and the ability of IFN-λ to induce STAT activation correlates with induction of numerous ISGs. Although the magnitude of ISG expression induced by IFN-λ in hepatocytes was generally lower than that induced by IFN-α, the repertoire of regulated genes was quite similar. Our findings demonstrate that although IFN-α and IFN-λ signal through distinct receptors, they induce expression of a common set of ISGs in hepatocytes. However, unlike IFN-α, IFN-λ did not induce STAT activation or ISG expression by purified lymphocytes or monocytes. This important functional difference may provide a clinical advantage for IFN-λ as a treatment for chronic HCV infection, as it is less likely to induce the leukopenias that are often associated with IFN-α therapy. PMID:23258595

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

Zhang, Jiandong; Neeway, James J.; Zhang, Yanyan

Glass particles with dimensions typically ranging from tens to hundreds of microns are often used in glass corrosion research in order to accelerate testing. Two-dimensional and three-dimensional nanoscale imaging techniques are badly needed to characterize the alteration layers at the surfaces of these corroded glass particles. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) can provide a lateral resolution as low as ~100 nm, and, compared to other imaging techniques, is sensitive to elements lighter than carbon. Here, we used ToF-SIMS to characterize the alteration layers of corroded international simple glass (ISG) particles. At most particle surfaces, we observed inhomogeneous or nomore » alteration layers, indicating that the thickness of the alterations layers may be too thin to be observable by ToF-SIMS imaging. Relatively thick (e.g., 1–10 µm) alteration layers were inhomogeneously distributed at a small portion of surfaces.Interestingly, some large-size (tens of microns) glass particles were fully altered. Above observations suggest that weak attachment and the defects on ISG particle surfaces play an important role in ISG glass corrosion.« less

Behçet's disease departs the 'Silk Road': a case report and brief review of literature with geographical comparison.

PubMed

Ahmed, Zohair; Rossi, Maria L; Yong, Sherri; Martin, Daniel K; Walayat, Saqib; Cashman, Michael; Tsoraides, Steven; Dhillon, Sonu

2016-01-01

Behçet's disease (BD) is a chronic multisystem inflammatory disease most prevalent in Eastern Asia and along the Mediterranean basin, an area referred to as the 'Silk Road'. The diagnosis of BD is largely based on the International Study Group (ISG) criteria, which are more specific than sensitive. ISG criteria do not include intestinal manifestations, a feature more commonly seen in the West. Intestinal BD is one of several findings that are not typically seen along the 'Silk Road'. Herein we report a rare case of intestinal BD and compare Western versus traditional BD. A 25-year-old male with a history of painful oral aphthous ulcers, pericarditis, and diffuse papulopustular rash presented to the emergency department with two terminal ileal perforations. Pathology demonstrated mucosal necrosis with active inflammation and no chronic inflammatory changes. Post-surgical laboratory studies showed an elevated c-reactive protein of 35.57 mg/dL, erythrocyte sedimentation rate of 82 mm/h, and a positive anti-Saccharomyces cerevisiae antibody. Rheumatological workup including ANA, RF, PR3 antibody, MPO antibody, ANCA, SSA and SSB, Smith antibody, SCL-70, and anti-Jo-1 antibodies were all negative. His pericarditis symptoms improved with colchicine and prednisone prior to discharge. Our patient did not meet the current ISG criteria for traditional BD; however, he clearly showed findings typically seen in Western patients with BD, which include intestinal manifestations, cardiac involvement, and lack of pathergy reaction and ocular changes. Our investigation demonstrates that the clinical manifestations common to this disorder vary among geographic and ethnic populations. Commonly used criteria for the diagnosis of BD may not be sensitive for some populations, such as Western BD, potentially leading to underdiagnoses and mismanagement. Recognition and select inclusion of these differences may be one way to assist with diagnosing Western BD in the future. As our knowledge of BD continues to evolve, so must the population-specific criteria used to define BD.

Validation of the classification criteria commonly used in Korea and a modified set of preliminary criteria for Behçet's disease: a multi-center study.

PubMed

Chang, H K; Lee, S S; Bai, H J; Lee, Y W; Yoon, B Y; Lee, C H; Lee, Y H; Song, G G; Chung, W T; Lee, S W; Choe, J Y; Kim, C G; Chang, D K

2004-01-01

Recently we have proposed a modified set of criteria to settle the questions raised regarding the International Study Group (ISG) criteria for Behçet's disease (BD). The aim of the present study was to validate the two pre-existing criteria sets commonly used in Korea, the ISG criteria and the criteria of the Behçet's Disease Research Committee of Japan (Japanese criteria), as well as the proposed modified criteria. The study population included 155 consecutive patients with BD and 170 controls with non-Behçet's rheumatic diseases. Detailed data for all of the subjects were recorded prospectively by the participating physicians on a standard form that listed the clinical features of BD. The sensitivity, specificity, and accuracy of each set of the criteria were measured. Of the three criteria sets employed, the modified criteria were the most accurate, with an accuracy of 96.3%. The ISG criteria often failed to classify the following patients with BD: patients with only oral and genital ulcerations, certain patients with intestinal ulcerations, patients who did not manifest oral ulcerations, and patients with acute disease but fewer than three recurrent oral ulceration relapses in a 1-year period. The Japanese criteria also failed to categorize the following patients with BD: patients with oral and genital ulcerations, and patients with oral ulcerations, skin lesions, and a positive pathergy reaction. In addition, the Japanese criteria misclassified some of the control subjects with non-Behçet's uveitis as having BD. The results of this study suggest that there are some points that need to be reconsidered in the clinical application of the two pre-existing sets of criteria. Although the modified criteria were the most accurate, further validation studies will be required in other ethnic populations.

Subcellular localization and functional characterization of a fish IRF9 from crucian carp Carassius auratus.

PubMed

Shi, Jun; Zhang, Yi-Bing; Liu, Ting-Kai; Sun, Fan; Gui, Jian-Fang

2012-08-01

Mammalian interferon (IFN) regulatory factor 9 (IRF-9) has long been recognized as the DNA sequence recognition subunit of IFN-stimulated gene factor 3 (ISGF3) complex, which is critical for type I IFN to induce the expression of IFN-stimulated genes (ISGs) against viral infection. Recent studies have shown that fish IFN exerts antiviral effects by induction of a number of ISGs and also of itself; however, little is known about the role of fish IRF9 in IFN signaling. Here we identify a fish IRF9 orthologue (CaIRF9) from IFN-producing cell line, crucian carp Carassius auratus blastulae embryonic (CAB) cells. Analysis of subcellular distribution of CaIRF9-green fluorescent protein indicates that CaIRF9 is constitutively present in the nucleus, which is driven by two nuclear localization signals (NLS), one locating within DNA-binding domain (DBD) of CaIRF9 and the other immediately behind DBD, although human IRF9 contains only one NLS analogous to the former of CaIRF9. Overexpression of CaIRF9 together with CaSTAT2 not only activates ISRE-containing promoter but also upregulates the expression of fish ISGs. Strikingly, CaIRF9 together with CaSTAT2 also exhibits an ability to activate crucian carp IFN promoter, and blockade of cellular CaIRF9 attenuates IFN itself-induced activation of crucian carp IFN promoter. Taken together, these data suggest that crucian carp IFN induces the expression of ISGs and also of itself possibly by the JAK-STAT signaling pathway that is conserved from fish to mammals. Copyright © 2012 Elsevier Ltd. All rights reserved.

Transcriptional expression of type-I interferon response genes and stability of housekeeping genes in the human endometrium and endometriosis.

PubMed

Vestergaard, Anna L; Knudsen, Ulla B; Munk, Torben; Rosbach, Hanne; Martensen, Pia M

2011-04-01

Endometriosis is a painful chronic female disease defined by the presence of endometrial tissue implants in ectopic (Ec) locations. The pathogenesis is much debated, and type-I interferons (IFNs) could be involved. The expression of genes of the type-I IFN response were profiled by a specific PCR array of RNA obtained from Ec and eutopic (Eu) endometrium collected from nine endometriosis patients and nine healthy control women. Transcriptional expression levels of selected IFN-regulated and housekeeping genes (HKGs) were investigated by real-time quantitative reverse transcriptase PCR (qRT-PCR). Stably expressed HKGs for valid normalization of transcriptional studies of endometrium and endometriosis have not yet been published. Here, seven HKGs were evaluated for stability using the GeNorm and NormFinder software. A normalization factor based on HMBS, TBP and YWHAZ expression was suitable for normalization of qRT-PCR studies of Eu versus Ec endometrium. In the endometrial cell lines HEC1A, HEC1B, Ishikawa and RL95-2, HMBS and HPRT1 were the most stably expressed. The IFN-specific PCR array indicated significantly different expression of the genes BST2, COL16A1, HOXB2 and ISG20 between the endometrial tissue types. However, by correctly normalized qRT-PCR, levels of BST2, COL16A1 and the highly type-I IFN-stimulated genes ISG12A and 6-16 displayed insignificant variations. Conversely, HOXB2 and ISG20 transcriptions were significantly reduced in endometriosis lesions compared with endometrium from endometriosis patients and healthy controls. In conclusion, appropriate HKGs for normalization of qRT-PCR studies of endometrium and endometriosis have been identified here. Abolished expression of ISG20 and HOX genes could be important in endometriosis.

An Analysis of Context-Aware Data Models for Smart Cities: Towards Fiware and Etsi Cim Emerging Data Model

NASA Astrophysics Data System (ADS)

Jara, A. J.; Bocchi, Y.; Fernandez, D.; Molina, G.; Gomez, A.

2017-09-01

Smart Cities requires the support of context-aware and enriched semantic descriptions to support a scalable and cross-domain development of smart applications. For example, nowadays general purpose sensors such as crowd monitoring (counting people in an area), environmental information (pollution, air quality, temperature, humidity, noise) etc. can be used in multiple solutions with different objectives. For that reason, a data model that offers advanced capabilities for the description of context is required. This paper presents an overview of the available technologies for this purpose and how it is being addressed by the Open and Agile Smart Cities principles and FIWARE platform through the data models defined by the ETSI ISG Context Information Management (ETSI CIM).

Nanoscale imaging of alteration layers of corroded international simple glass particles using ToF-SIMS

DOE PAGES

Zhang, Jiandong; Neeway, James J.; Zhang, Yanyan; ...

2017-02-24

Glass particles with dimensions typically ranging from tens to hundreds of microns are often used in glass corrosion research in order to accelerate testing. Two-dimensional and three-dimensional nanoscale imaging techniques are badly needed to characterize the alteration layers at the surfaces of these corroded glass particles. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) can provide a lateral resolution as low as ~100 nm, and, compared to other imaging techniques, is sensitive to elements lighter than carbon. Here, we used ToF-SIMS to characterize the alteration layers of corroded international simple glass (ISG) particles. At most particle surfaces, we observed inhomogeneous or nomore » alteration layers, indicating that the thickness of the alterations layers may be too thin to be observable by ToF-SIMS imaging. Relatively thick (e.g., 1–10 µm) alteration layers were inhomogeneously distributed at a small portion of surfaces.Interestingly, some large-size (tens of microns) glass particles were fully altered. Above observations suggest that weak attachment and the defects on ISG particle surfaces play an important role in ISG glass corrosion.« less

Discovery of a Broad-Spectrum Antiviral Compound That Inhibits Pyrimidine Biosynthesis and Establishes a Type 1 Interferon-Independent Antiviral State

PubMed Central

Adcock, Robert S.; Schroeder, Chad E.; Chu, Yong-Kyu; Sotsky, Julie B.; Cramer, Daniel E.; Chilton, Paula M.; Song, Chisu; Anantpadma, Manu; Davey, Robert A.; Prodhan, Aminul I.; Yin, Xinmin; Zhang, Xiang

2016-01-01

Viral emergence and reemergence underscore the importance of developing efficacious, broad-spectrum antivirals. Here, we report the discovery of tetrahydrobenzothiazole-based compound 1, a novel, broad-spectrum antiviral lead that was optimized from a hit compound derived from a cytopathic effect (CPE)-based antiviral screen using Venezuelan equine encephalitis virus. Compound 1 showed antiviral activity against a broad range of RNA viruses, including alphaviruses, flaviviruses, influenza virus, and ebolavirus. Mechanism-of-action studies with metabolomics and molecular approaches revealed that the compound inhibits host pyrimidine synthesis and establishes an antiviral state by inducing a variety of interferon-stimulated genes (ISGs). Notably, the induction of the ISGs by compound 1 was independent of the production of type 1 interferons. The antiviral activity of compound 1 was cell type dependent with a robust effect observed in human cell lines and no observed antiviral effect in mouse cell lines. Herein, we disclose tetrahydrobenzothiazole compound 1 as a novel lead for the development of a broad-spectrum, antiviral therapeutic and as a molecular probe to study the mechanism of the induction of ISGs that are independent of type 1 interferons. PMID:27185801

Nanoscale imaging of alteration layers of corroded international simple glass particles using ToF-SIMS

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

Zhang, Jiandong; Neeway, James J.; Zhang, Yanyan

Glass particles with dimensions typically ranging from tens to hundreds of microns are often used in glass corrosion research in order to accelerate testing. Two-dimensional and three-dimensional nanoscale imaging techniques are badly needed to characterize the alteration layers at the surfaces of these corroded glass particles. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) can provide a lateral resolution as low as ~100 nm, and, compared to other imaging techniques, is sensitive to elements lighter than carbon. In this work, we used ToF-SIMS to characterize the alteration layers of corroded international simple glass (ISG) particles. At most particle surfaces, inhomogeneous or nomore » alteration layers were observed, indicating that the thickness of the alterations layers may be too thin to be observable by ToF-SIMS imaging. Relatively thick (e.g., 1-10 microns) alteration layers were inhomogeneously distributed at a small portion of surfaces. More interestingly, some large-size (tens of microns) glass particles were fully altered. Above observations suggest that weak attachment and the defects on ISG particle surfaces play an important role in ISG glass corrosion.« less

High prevalence of Behçet's disease in southern Italy.

PubMed

Olivieri, Ignazio; Leccese, Pietro; Padula, Angela; Nigro, Angelo; Palazzi, Carlo; Gilio, Michele; D'Angelo, Salvatore

2013-01-01

This paper aims to estimate the prevalence of Behçet's disease (BD) in the city of Potenza, the regional capital of Basilicata (or Lucania) Region, in southern Italy. Patients with BD living in Potenza for at least 12 months prior to diagnosis were identified through the following sources: general practitioners, community-based specialists, San Carlo Hospital specialists, the Basilicata centralised index and the Basilicata database for rare diseases. All identified patients were contacted by phone and were recalled to our outpatient clinic for re-evaluation. Patients were classified as having complete BD if they met the International Study Group (ISG) criteria for BD. By surveying a population of 69.060 subjects, 13 patients with a diagnosis of BD were identified. All were white and Italian by descendent. Eleven out of these satisfied the ISG criteria and allowed us to obtain a prevalence rate of 15.9 per 100.000 (95%CI 8.9-28.5), which is the highest ever found value in Europe. This cross-sectional population-based study suggests that BD is more frequent in the southern part than in the northern part of Italy and confirms that the prevalence of the disease increases in a north-to-south manner within the European continent.

HIV-1 activation of innate immunity depends strongly on the intracellular level of TREX1 and sensing of incomplete reverse transcription products.

PubMed

Kumar, Swati; Morrison, James H; Dingli, David; Poeschla, Eric

2018-05-16

TREX1 has been reported to degrade cytosolic immune-stimulatory DNA, including viral DNA generated during HIV-1 infection, but the dynamic range of its capacity to suppress innate immune stimulation is unknown and its full role in the viral life cycle remains unclear. A main purpose of our study was to determine how the intracellular level of TREX1 affects HIV-1 activation and avoidance of innate immunity. Using stable over-expression and CRISPR-mediated gene disruption, we engineered a range of TREX1 levels in human THP-1 monocytes. Increasing the level of TREX1 dramatically suppressed HIV-1 induction of interferon-stimulated genes (ISGs). Productive infection and integrated proviruses were equal to increased. Knocking out TREX1 impaired viral infectivity, increased early viral cDNA and caused ten-fold or greater increases in HIV-1 ISG induction. Knockout of cyclic GMP-AMP synthase (cGAS) abrogated all ISG induction. Moreover, cGAS knockout produced no increase in single cycle infection, establishing that HIV-1 DNA-triggered signaling is not rapid enough to impair the initial ISG-triggering infection cycle. Disruption of the HIV-1 capsid by PF74 also induced ISGs and this was TREX1 level-dependent, required reverse transcriptase catalysis, and was eliminated by cGAS gene knockout. Thus, the intracellular level of TREX1 pivotally modulates innate immune induction by HIV-1. Partial HIV-1 genomes are the TREX1 target and are sensed by cGAS. The nearly complete lack of innate immune induction despite equal to increased viral integration observed when the TREX1 protein level is experimentally elevated indicates that integration-competent genomes are shielded from cytosolic sensor-effectors during uncoating and transit to the nucleus. IMPORTANCE Much remains unknown about how TREX1 influences HIV-1 replication, whether it targets full-length viral DNA versus partial intermediates, how intracellular TREX1 protein levels correlate with ISG induction, and whether TREX1 digestion of cytoplasmic DNA and subsequent cGAS pathway activation affects both initial and subsequent cycles of infection. To answer these questions, we experimentally varied the intracellular level of TREX1 and show that this strongly determines the innate immunogenicity of HIV-1. In addition, several lines of evidence including time of addition experiments with drugs that impair reverse transcription or capsid integrity showed that the pathogen-associated molecular patterns sensed after viral entry contain DNA, are TREX1 and cGAS substrates, and are derived from incomplete RT products. In contrast, the experiments demonstrate that full-length integration competent viral DNA is immune to TREX1. Treatment approaches that reduce TREX1 levels or facilitate release of DNA intermediates may advantageously combine enhanced innate immunity with antiviral effects. Copyright © 2018 American Society for Microbiology.

Interferometric step gauge for CMM verification

NASA Astrophysics Data System (ADS)

Hemming, B.; Esala, V.-P.; Laukkanen, P.; Rantanen, A.; Viitala, R.; Widmaier, T.; Kuosmanen, P.; Lassila, A.

2018-07-01

The verification of the measurement capability of coordinate measuring machines (CMM) is usually performed using gauge blocks or step gauges as reference standards. Gauge blocks and step gauges are robust and easy to use, but have some limitations such as finite lengths and uncertainty of thermal expansion. This paper describes the development, testing and uncertainty evaluation of an interferometric step gauge (ISG) for CMM verification. The idea of the ISG is to move a carriage bearing a gauge block along a rail and to measure the position with an interferometer. For a displacement of 1 m the standard uncertainty of the position of the gauge block is 0.2 µm. A short range periodic error of CMM can also be detected.

The nonstructural proteins of Pneumoviruses are remarkably distinct in substrate diversity and specificity.

PubMed

Ribaudo, Michael; Barik, Sailen

2017-11-06

Interferon (IFN) inhibits viruses by inducing several hundred cellular genes, aptly named 'interferon (IFN)-stimulated genes' (ISGs). The only two RNA viruses of the Pneumovirus genus of the Paramyxoviridae family, namely Respiratory Syncytial Virus (RSV) and Pneumonia Virus of Mice (PVM), each encode two nonstructural (NS) proteins that share no sequence similarity but yet suppress IFN. Since suppression of IFN underlies the ability of these viruses to replicate in the host cells, the mechanism of such suppression has become an important area of research. This Short Report is an important extension of our previous efforts in defining this mechanism. We show that, like their PVM counterparts, the RSV NS proteins also target multiple members of the ISG family. While significantly extending the substrate repertoire of the RSV NS proteins, these results, unexpectedly, also reveal that the target preferences of the NS proteins of the two viruses are entirely different. This is surprising since the two Pneumoviruses are phylogenetically close with similar genome organization and gene function, and the NS proteins of both also serve as suppressors of host IFN response. The finding that the NS proteins of the two highly similar viruses suppress entirely different members of the ISG family raises intriguing questions of pneumoviral NS evolution and mechanism of action.

Functional Characterization of Canine Interferon-Lambda

PubMed Central

Fan, Wenhui; Xu, Lei; Ren, Liqian; Qu, Hongren; Li, Jing; Liang, Jingjing; Liu, Wenjun

2014-01-01

In this study, we provide the first comprehensive annotation of canine interferon-λ (CaIFN-λ, type III IFN). Phylogenetic analysis based on genomic sequences indicated that CaIFN-λ is located in the same branch with Swine IFN-λ1 (SwIFN-λ), Bat IFN-λ1 (BaIFN-λ), and human IFN-λ1 (HuIFN-λ1). CaIFN-λ was cloned, expressed in Escherichia coli, and purified to further investigate the biological activity in vitro. The recombinant CaIFN-λ (rCaIFN-λ) displayed potent antiviral activity on both homologous and heterologous animal cells in terms of inhibiting the replication of the New Jersey serotype of vesicular stomatitis virus (VSV), canine parvovirus, and influenza virus A/WSN/33 (H1N1), respectively. In addition, we also found that rCaIFN-λ exhibits a significant antiproliferative response against A72 canine tumor cells and MDCK cells in a dose-dependent manner. Furthermore, CaIFN-λ activated the JAK-STAT signaling pathway. To evaluate the expression of CaIFN-λ induced by virus and the expression of IFN-stimulated genes (ISGs) induced by rCaIFN-λ in the MDCK cells, we measured the relative mRNA level of CaIFN-λ and ISGs (ISG15, Mx1, and 2′5′-OAS) by quantitative real-time PCR and found that the mRNA level of CaIFN-λ and the ISGs significantly increased after treating the MDCK cells with viruses and rCaIFN-λ protein, respectively. Finally, to evaluate the binding activity of rCaIFN-λ to its receptor, we expressed the extracellular domain of the canine IFN-λ receptor 1 (CaIFN-λR1-EC) and determined the binding activity via ELISA. Our results demonstrated that rCaIFN-λ bound tightly to recombinant CaIFN-λR1-EC (rCaIFN-λR1-EC). PMID:24950142

Endogenous Retrovirus ev21 Dose Not Recombine with ALV-J and Induces the Expression of ISGs in the Host.

PubMed

Feng, Min; Tan, Yan; Dai, Manman; Li, Yuanfang; Xie, Tingting; Li, Hongmei; Shi, Meiqing; Zhang, Xiquan

2016-01-01

Avian leukosis virus subgroup J (ALV-J) infection can cause tumors and immunosuppression. Endogenous viruses integrate into host genomes and can recombine with exogenous avian leukosis virus (ALV). In this study, we analyzed the interaction of endogenous retrovirus 21 ( ev21 ) with the ALV-J in late-feathering Chinese yellow chicken. Two ALV-J strains M180 and K243 were isolated from late-feathering and fast-feathering Chinese yellow chicken flocks, respectively. The env gene of the two strains showed 94.2-94.8% nucleotide identity with reference ALV-J strains. Compared with the env gene and the LTR of ev21 and M180, the nucleotide identity of LTR was 69.7% and env gene was 58.4%, respectively, especially the amino acid identity of env gene as low as 14.2%. Phylogenetic analysis of the nucleotide sequence of the env gene and the 3'LTR showed that M180 was closely related to ALV-J, and was located in a distinct group with ev21 in the phylogenetic tree. Using co-immunoprecipitation (co-IP), we next demonstrate that the envelope protein of ev21 does not interact with the M180 envelope protein. We further show that the envelope protein of ev21 cannot activate ALV-J LTR promoter activity using luciferase-reporter assays. qPCR and western blot analysis revealed that envelope protein of endogenous ev21 can facilitate the expression of PKR at 6h post ALV-J infection (hpi) and facilitate the expression of ISG12 and CH25H at 24 hpi. However, the expression of the env gene of M180 strain was not significantly at 6 and 24 hpi. We conclude that there is no evidence of recombination between endogenous retrovirus ev21 and ALV-J strain M180 in late-feathering Chinese yellow chicken, and envelope protein of ev21 can affect the expression of host ISGs, but appears not to influence the replication of ALV-J strain M180. This is the first report of interaction among the endogenous retrovirus ev21, ALV-J and the late-feathering chicken.

The path to a successful one-million tonne demonstration of geological sequestration: Characterization, cooperation, and collaboration

USGS Publications Warehouse

Finley, R.J.; Greenberg, S.E.; Frailey, S.M.; Krapac, I.G.; Leetaru, H.E.; Marsteller, S.

2011-01-01

The development of the Illinois Basin-Decatur USA test site for a 1 million tonne injection of CO2 into the Mount Simon Sandstone saline reservoir beginning in 2011 has been a multiphase process requiring a wide array of personnel and resources that began in 2003. The process of regional characterization took two years as part of a Phase I effort focused on the entire Illinois Basin, located in Illinois, Indiana, and Kentucky, USA. Seeking the cooperation of an industrial source of CO2 and site selection within the Basin took place during Phase II while most of the concurrent research emphasis was on a set of small-scale tests of Enhanced Oil Recovery (EOR) and CO2 injection into a coal seam. Phase III began the commitment to the 1 million-tonne test site development through the collaboration of the Archer Daniels Midland Company (ADM) who is providing a site, the CO2, and developing a compression facility, of Schlumberger Carbon Services who is providing expertise for operations, drilling, geophysics, risk assessment, and reservoir modelling, and of the Illinois State Geological Survey (ISGS) whose geologists and engineers lead the Midwest Geological Sequestration Consortium (MGSC). Communications and outreach has been a collaborative effort of ADM, ISGS and Schlumberger Carbon Services. The Consortium is one of the seven Regional Carbon Sequestration Partnerships, a carbon sequestration research program supported by the National Energy Technology Laboratory of the U.S. Department of Energy. ?? 2011 Published by Elsevier Ltd.

Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease.

PubMed

Giles, E M; Sanders, T J; McCarthy, N E; Lung, J; Pathak, M; MacDonald, T T; Lindsay, J O; Stagg, A J

2017-01-01

Type 1 interferon (IFN-1) promotes regulatory T-cell function to suppress inflammation in the mouse intestine, but little is known about IFN-1 in the human gut. We therefore assessed the influence of IFN-1 on CD4+ T-cells isolated from human colon tissue obtained from healthy controls or patients with inflammatory bowel disease (IBD). Immunofluorescent imaging revealed constitutive expression of IFNβ in human intestinal tissue, and colonic T-cells were responsive to exogenous IFN-1 as assessed by phosphorylation of signal transduction and activator of transcription 1 (pSTAT1) and induction of interferon stimulated genes (ISGs). Unlike their blood counterparts, intestinal T-cells from non-inflamed regions of IBD colon displayed enhanced responsiveness to IFN-1, increased frequency of pSTAT1+ cells, and greater induction of ISGs upon IFN-1 exposure in vitro. In healthy tissue, antibody neutralization of IFNβ selectively reduced T-cell production of the pro-regulatory cytokine interleukin-10 (IL-10) and increased IFNγ synthesis. In contrast, neutralization of IFNβ in IBD tissue cultures increased the frequency of T-cells producing inflammatory cytokines but did not alter IL-10 expression. These data support a role for endogenous IFN-1 as a context-dependent modulator of T-cell function that promotes regulatory activity in healthy human intestine, but indicate that the IFN-1/STAT1 pathway is dysregulated in inflammatory bowel disease.

STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-λ but not by interferon-α.

PubMed

Yamauchi, Shota; Takeuchi, Kenji; Chihara, Kazuyasu; Honjoh, Chisato; Kato, Yuji; Yoshiki, Hatsumi; Hotta, Hak; Sada, Kiyonao

2016-12-08

Interferon-α (IFN-α) and IFN-λ are structurally distinct cytokines that bind to different receptors, but induce expression of similar sets of genes through Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. The difference between IFN-α and IFN-λ signaling remains poorly understood. Here, using the CRISPR/Cas9 system, we examine the role of STAT1 and STAT2 in the inhibition of hepatitis C virus (HCV) replication by IFN-α and IFN-λ. Treatment with IFN-α increases expression of IFN-stimulated genes (ISGs) such as double-stranded RNA-activated protein kinase (PKR) and decreases viral RNA and protein levels in HCV-infected Huh-7.5 human hepatoma cells. These responses are only partially attenuated by knockout of STAT1 but are abolished by knockout of STAT2. In contrast, the inhibition of HCV replication by IFN-λ is abolished by knockout of STAT1 or STAT2. Microarray analysis reveals that IFN-α but not IFN-λ can induce expression of the majority of ISGs in STAT1 knockout cells. These findings suggest that IFN-α can inhibit HCV replication through a STAT2-dependent but STAT1-independent pathway, whereas IFN-λ induces ISG expression and inhibits HCV replication exclusively through a STAT1- and STAT2-dependent pathway.

STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-λ but not by interferon-α

PubMed Central

Yamauchi, Shota; Takeuchi, Kenji; Chihara, Kazuyasu; Honjoh, Chisato; Kato, Yuji; Yoshiki, Hatsumi; Hotta, Hak; Sada, Kiyonao

2016-01-01

Interferon-α (IFN-α) and IFN-λ are structurally distinct cytokines that bind to different receptors, but induce expression of similar sets of genes through Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. The difference between IFN-α and IFN-λ signaling remains poorly understood. Here, using the CRISPR/Cas9 system, we examine the role of STAT1 and STAT2 in the inhibition of hepatitis C virus (HCV) replication by IFN-α and IFN-λ. Treatment with IFN-α increases expression of IFN-stimulated genes (ISGs) such as double-stranded RNA-activated protein kinase (PKR) and decreases viral RNA and protein levels in HCV-infected Huh-7.5 human hepatoma cells. These responses are only partially attenuated by knockout of STAT1 but are abolished by knockout of STAT2. In contrast, the inhibition of HCV replication by IFN-λ is abolished by knockout of STAT1 or STAT2. Microarray analysis reveals that IFN-α but not IFN-λ can induce expression of the majority of ISGs in STAT1 knockout cells. These findings suggest that IFN-α can inhibit HCV replication through a STAT2-dependent but STAT1-independent pathway, whereas IFN-λ induces ISG expression and inhibits HCV replication exclusively through a STAT1- and STAT2-dependent pathway. PMID:27929099

Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats

PubMed Central

Izquierdo-Bouldstridge, Andrea; Bustillos, Alberto; Bonet-Costa, Carles; Aribau-Miralbés, Patricia; García-Gomis, Daniel; Dabad, Marc; Esteve-Codina, Anna; Pascual-Reguant, Laura; Peiró, Sandra; Esteller, Manel; Murtha, Matthew; Millán-Ariño, Lluís

2017-01-01

Abstract Histone H1 has seven variants in human somatic cells and contributes to chromatin compaction and transcriptional regulation. Knock-down (KD) of each H1 variant in breast cancer cells results in altered gene expression and proliferation differently in a variant specific manner with H1.2 and H1.4 KDs being most deleterious. Here we show combined depletion of H1.2 and H1.4 has a strong deleterious effect resulting in a strong interferon (IFN) response, as evidenced by an up-regulation of many IFN-stimulated genes (ISGs) not seen in individual nor in other combinations of H1 variant KDs. Although H1 participates to repress ISG promoters, IFN activation upon H1.2 and H1.4 KD is mainly generated through the activation of the IFN response by cytosolic nucleic acid receptors and IFN synthesis, and without changes in histone modifications at induced ISG promoters. H1.2 and H1.4 co-KD also promotes the appearance of accessibility sites genome wide and, particularly, at satellites and other repeats. The IFN response may be triggered by the expression of noncoding RNA generated from heterochromatic repeats or endogenous retroviruses upon H1 KD. In conclusion, redundant H1-mediated silencing of heterochromatin is important to maintain cell homeostasis and to avoid an unspecific IFN response. PMID:28977426

Life-Cycle Assessment Harmonization and Soil Science Ranking Results on Food-Waste Management Methods.

PubMed

Morris, Jeffrey; Brown, Sally; Cotton, Matthew; Matthews, H Scott

2017-05-16

This study reviewed 147 life cycle studies, with 28 found suitable for harmonizing food waste management methods' climate and energy impacts. A total of 80 scientific soil productivity studies were assessed to rank management method soil benefits. Harmonized climate impacts per kilogram of food waste range from -0.20 kg of carbon dioxide equivalents (CO 2 e) for anaerobic digestion (AD) to 0.38 kg of CO 2 e for landfill gas-to-energy (LFGTE). Aerobic composting (AC) emits -0.10 kg of CO 2 e. In-sink grinding (ISG) via a food-waste disposer and flushing for management with other sewage at a wastewater treatment plant emits 0.10 kg of CO 2 e. Harmonization reduced climate emissions versus nonharmonized averages. Harmonized energy impacts range from -0.32 MJ for ISG to 1.14 MJ for AC. AD at 0.27 MJ and LFGTE at 0.40 MJ fall in between. Rankings based on soil studies show AC first for carbon storage and water conservation, with AD second. AD first for fertilizer replacement, with AC second, and AC and AD tied for first for plant yield increase. ISG ranks third and LFGTE fourth on all four soil-quality and productivity indicators. Suggestions for further research include developing soil benefits measurement methods and resolving inconsistencies in the results between life-cycle assessments and soil science studies.

Soybean-derived Bowman-Birk Inhibitor (BBI) Inhibits HIV Replication in Macrophages.

PubMed

Ma, Tong-Cui; Zhou, Run-Hong; Wang, Xu; Li, Jie-Liang; Sang, Ming; Zhou, Li; Zhuang, Ke; Hou, Wei; Guo, De-Yin; Ho, Wen-Zhe

2016-10-13

The Bowman-Birk inhibitor (BBI), a soybean-derived protease inhibitor, is known to have anti-inflammatory effect in both in vitro and in vivo systems. Macrophages play a key role in inflammation and immune activation, which is implicated in HIV disease progression. Here, we investigated the effect of BBI on HIV infection of peripheral blood monocyte-derived macrophages. We demonstrated that BBI could potently inhibit HIV replication in macrophages without cytotoxicity. Investigation of the mechanism(s) of BBI action on HIV showed that BBI induced the expression of IFN-β and multiple IFN stimulated genes (ISGs), including Myxovirus resistance protein 2 (Mx2), 2',5'-oligoadenylate synthetase (OAS-1), Virus inhibitory protein (viperin), ISG15 and ISG56. BBI treatment of macrophages also increased the expression of several known HIV restriction factors, including APOBEC3F, APOBEC3G and tetherin. Furthermore, BBI enhanced the phosphorylation of IRF3, a key regulator of IFN-β. The inhibition of IFN-β pathway by the neutralization antibody to type I IFN receptor (Anti-IFNAR) abolished BBI-mediated induction of the anti-HIV factors and inhibition of HIV in macrophages. These findings that BBI could activate IFN-β-mediated signaling pathway, initialize the intracellular innate immunity in macrophages and potently inhibit HIV at multiple steps of viral replication cycle indicate the necessity to further investigate BBI as an alternative and cost-effective anti-HIV natural product.

CpG ODN 1668 induce innate and adaptive immune responses in rock bream (Oplegnathus fasciatus) against rock bream iridovirus (RBIV) infection.

PubMed

Jung, Myung-Hwa; Jung, Sung-Ju

2017-10-01

Rock bream iridovirus (RBIV) causes severe mass mortalities in rock bream in Korea. CpG ODN 1668 showed promise as immunoprotective agents against RBIV infection in rock bream. In this study, we assessed innate/adaptive-related gene expression patterns in RBIV-infected rock bream with and without CpG ODN 1668 administration to determine important immune defense related factors that may affect fish survival. In the CpG ODN 1668+virus-injected group, virus copies were more than 7.4- to 790591-fold lower than in the virus-injected group at 4 d (8.79 × 10 4 and 6.58 × 10 5 /μl, respectively), 7 d (5.30 × 10 2 and 2.29 × 10 7 /μl, respectively) and 10 dpi (7.79 × 10 1 and 6.16 × 10 7 /μl, respectively). Furthermore, in the CpG ODN 1668+virus-injected group, significantly higher levels of MyD88 (6 h, 1 d, 4 d and 7 dpi), IL1β (1 d, 2 d and 7 dpi) and perforin/granzyme (1 dpi) expression were observed, whereas these genes were not significantly expressed in the virus-injected group at that time points. Mx, ISG15 and PKR were significantly highly expressed at 4 d and 7 dpi and reduced when low viral loads at 10 dpi in the CpG ODN 1668+virus-injected group. Conversely, in the virus-injected group, Mx, ISG15 and PKR expression were significantly higher than the control group until 10 dpi. However, MHC class I, CD8, Fas, Fas ligand and caspases (3, 8 and 9) expression levels showed no statistically significant differences between virus- and CpG ODN 1668+virus-injected group. In summary, CpG ODN 1668 administration in fish induces innate immune response or cell death pathway, which could be a major contributing factor to effective fish control over viral transcription on 4 d to 10 dpi. Expression of MyD88, IL1β, perforin and granzyme-related immune gene response is critical factor for inhibition of RBIV replication. Copyright © 2017 Elsevier Ltd. All rights reserved.

Orally administered live attenuated Salmonella Typhimurium protects mice against lethal infection with H1N1 influenza virus.

PubMed

Kamble, Nitin Machindra; Hajam, Irshad Ahmed; Lee, John Hwa

2017-03-01

Pre-stimulation of toll-like receptors (TLRs) by agonists has been shown to increase protection against influenza virus infection. In this study, we evaluated the protective response generated against influenza A/Puerto Rico/8/1934 (PR8; H1N1) virus by oral and nasal administration of live attenuated Salmonella enterica serovar Typhimurium, JOL911 strain, in mice. Oral and nasal inoculation of JOL911 significantly increased the mRNA copy number of TLR-2, TLR4 and TLR5, and downstream type I interferon (IFN) molecules, IFN-α and IFN-β, both in peripheral blood mononuclear cells (PBMCs) and in lung tissue. Similarly, the mRNA copy number of interferon-inducible genes (ISGs), Mx and ISG15, were significantly increased in both the orally and the nasally inoculated mice. Post PR8 virus lethal challenge, the nasal JOL911 and the PBS control group mice showed significant loss of body weight with 70% and 100% mortality, respectively, compared to only 30% mortality in the oral JOL911 group mice. Post sub-lethal challenge, the significant reduction in PR8 virus copy number in lung tissue was observed in oral [on day 4 and 6 post-challenge (dpc)] and nasal (on 4dpc) than the PBS control group mice. The lethal and sub-lethal challenge showed that the generated stimulated innate resistance (StIR) in JOL911 inoculated mice conferred resistance to acute and initial influenza infection but might not be sufficient to prevent the PR8 virus invasion and replication in the lung. Overall, the present study indicates that oral administration of attenuated S. Typhimurium can pre-stimulate multiple TLR pathways in mice to provide immediate early StIR against a lethal H1N1 virus challenge. Copyright © 2017 Elsevier B.V. All rights reserved.

Antagonist-mediated down-regulation of toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus

PubMed Central

2012-01-01

Introduction Prevalence of an abnormal Papanicolaou smear was significantly increased in lupus patients in cross-sectional studies, associated with a higher prevalence of high-risk human papillomavirus (HPV) infection. The nucleic acid-specific Toll-like receptors (TLRs) locate at the endolysosomal compartments and trigger the induction of cytokines for the innate immune response. This study evaluated whether abnormal host innate immune response in lupus patients may enhance HPV persistence. Methods Protein levels of TLRs 3, 7, 8 and 9 in cervical epithelial cells of lupus patients and controls with or without HPV infection were assessed using flow cytometry. Characteristics associated with the differential expression of TLRs in systemic lupus erythematosus (SLE) were elucidated. The effect and interferon-stimulated genes (ISGs) (ISG15 and Mx-1) gene expressions were then measured in oncogenic HeLa (HPV18), CaSki (HPV) and C33A (HPV negative) cell lines using flow cytometry and quantitative real-time PCR. Ex vivo productions of cytokines and interferon-gamma (IFN-γ) upon TLR ligands stimulations were subsequently measured using cytometric bead array and ELISA. Results For subjects with HPV infection, levels of TLR3 and TLR7 were significantly lower in lupus patients compared with controls. Significantly decreased TLRs 7, 8 and 9 levels were observed in HPV-negative SLE compared to healthy controls. For SLE with and without HPV infection, TLR7 and 9 levels were significantly lower in infected SLE than those in HPV-negative patients. Independent explanatory variables associated with down-regulation of TLR7 level included HPV infection and a higher cumulative dose of prednisolone; while a higher cumulative dose of hydroxychloroquine and HPV infection were associated with down-regulation of TLR9 level. In cervical cell lines, TLRs 3, 7, 8, 9 protein levels and antiviral ISG15 and Mx-1 gene expressions were inhibited in two oncogenic HPV types. Functional data showed that the induction of pro-inflammatory cytokines by TLR ligands (R837, ssRNA and ODN2395) was greatly impaired in CaSki and HeLa than C33A cells. Conclusions In conclusion, prednisolone and TLR antagonist (hydroxychloroquine) may down-regulate protein levels of TLR7 and TLR9 in lupus patients, thereby decreasing the innate immune response against HPV infection. Upon infection, HPV further down-regulate TLR7 and 9 levels for viral persistence. Furthermore, reduction of nucleic acid-sensing TLRs 7, 8 and 9 in carcinogenic HPVs ensures that the expression of inducible pro-inflammatory cytokines is minimized to prevent the expression of antiviral ISGs (ISG15 and Mx-1) on a biologically relevant antiviral response. PMID:22513098

Induction of Interferon-Stimulated Genes by IRF3 Promotes Replication of Toxoplasma gondii

PubMed Central

Majumdar, Tanmay; Chattopadhyay, Saurabh; Ozhegov, Evgeny; Dhar, Jayeeta; Goswami, Ramansu; Sen, Ganes C.; Barik, Sailen

2015-01-01

Innate immunity is the first line of defense against microbial insult. The transcription factor, IRF3, is needed by mammalian cells to mount innate immune responses against many microbes, especially viruses. IRF3 remains inactive in the cytoplasm of uninfected cells; upon virus infection, it gets phosphorylated and then translocates to the nucleus, where it binds to the promoters of antiviral genes and induces their expression. Such genes include type I interferons (IFNs) as well as Interferon Stimulated Genes (ISGs). IRF3-/- cells support enhanced replication of many viruses and therefore, the corresponding mice are highly susceptible to viral pathogenesis. Here, we provide evidence for an unexpected pro-microbial role of IRF3: the replication of the protozoan parasite, Toxoplasma gondii, was significantly impaired in IRF3-/- cells. In exploring whether the transcriptional activity of IRF3 was important for its pro-parasitic function, we found that ISGs induced by parasite-activated IRF3 were indeed essential, whereas type I interferons were not important. To delineate the signaling pathway that activates IRF3 in response to parasite infection, we used genetically modified human and mouse cells. The pro-parasitic signaling pathway, which we termed PISA (Parasite-IRF3 Signaling Activation), activated IRF3 without any involvement of the Toll-like receptor or RIG-I-like receptor pathways, thereby ruling out a role of parasite-derived RNA species in activating PISA. Instead, PISA needed the presence of cGAS, STING, TBK1 and IRF3, indicating the necessity of DNA-triggered signaling. To evaluate the physiological significance of our in vitro findings, IRF3-/- mice were challenged with parasite infection and their morbidity and mortality were measured. Unlike WT mice, the IRF3-/- mice did not support replication of the parasite and were resistant to pathogenesis caused by it. Our results revealed a new paradigm in which the antiviral host factor, IRF3, plays a cell-intrinsic pro-parasitic role. PMID:25811886

Induction of interferon-stimulated genes by IRF3 promotes replication of Toxoplasma gondii.

PubMed

Majumdar, Tanmay; Chattopadhyay, Saurabh; Ozhegov, Evgeny; Dhar, Jayeeta; Goswami, Ramansu; Sen, Ganes C; Barik, Sailen

2015-03-01

Innate immunity is the first line of defense against microbial insult. The transcription factor, IRF3, is needed by mammalian cells to mount innate immune responses against many microbes, especially viruses. IRF3 remains inactive in the cytoplasm of uninfected cells; upon virus infection, it gets phosphorylated and then translocates to the nucleus, where it binds to the promoters of antiviral genes and induces their expression. Such genes include type I interferons (IFNs) as well as Interferon Stimulated Genes (ISGs). IRF3-/- cells support enhanced replication of many viruses and therefore, the corresponding mice are highly susceptible to viral pathogenesis. Here, we provide evidence for an unexpected pro-microbial role of IRF3: the replication of the protozoan parasite, Toxoplasma gondii, was significantly impaired in IRF3-/- cells. In exploring whether the transcriptional activity of IRF3 was important for its pro-parasitic function, we found that ISGs induced by parasite-activated IRF3 were indeed essential, whereas type I interferons were not important. To delineate the signaling pathway that activates IRF3 in response to parasite infection, we used genetically modified human and mouse cells. The pro-parasitic signaling pathway, which we termed PISA (Parasite-IRF3 Signaling Activation), activated IRF3 without any involvement of the Toll-like receptor or RIG-I-like receptor pathways, thereby ruling out a role of parasite-derived RNA species in activating PISA. Instead, PISA needed the presence of cGAS, STING, TBK1 and IRF3, indicating the necessity of DNA-triggered signaling. To evaluate the physiological significance of our in vitro findings, IRF3-/- mice were challenged with parasite infection and their morbidity and mortality were measured. Unlike WT mice, the IRF3-/- mice did not support replication of the parasite and were resistant to pathogenesis caused by it. Our results revealed a new paradigm in which the antiviral host factor, IRF3, plays a cell-intrinsic pro-parasitic role.

IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function.

PubMed

Broggi, Achille; Tan, Yunhao; Granucci, Francesca; Zanoni, Ivan

2017-10-01

Interferon-λ (IFN-λ) is a central regulator of mucosal immunity; however, its signaling specificity relative to that of type I interferons is poorly defined. IFN-λ can induce antiviral interferon-stimulated genes (ISGs) in epithelia, while the effect of IFN-λ in non-epithelial cells remains unclear. Here we report that neutrophils responded to IFN-λ. We found that in addition to inducing ISG transcription, IFN-λ (but not IFN-β) specifically activated a translation-independent signaling pathway that diminished the production of reactive oxygen species and degranulation in neutrophils. In mice, IFN-λ was elicited by enteric viruses and acted on neutrophils to decrease oxidative stress and intestinal damage. Thus, IFN-λ acted as a unique immunomodulatory agent by modifying transcriptional and non-translational neutrophil responses, which might permit a controlled development of the inflammatory process.

Hepatitis C virus and antiviral innate immunity: who wins at tug-of-war?

PubMed

Yang, Da-Rong; Zhu, Hai-Zhen

2015-04-07

Hepatitis C virus (HCV) is a major human pathogen of chronic hepatitis and related liver diseases. Innate immunity is the first line of defense against invading foreign pathogens, and its activation is dependent on the recognition of these pathogens by several key sensors. The interferon (IFN) system plays an essential role in the restriction of HCV infection via the induction of hundreds of IFN-stimulated genes (ISGs) that inhibit viral replication and spread. However, numerous factors that trigger immune dysregulation, including viral factors and host genetic factors, can help HCV to escape host immune response, facilitating viral persistence. In this review, we aim to summarize recent advances in understanding the innate immune response to HCV infection and the mechanisms of ISGs to suppress viral survival, as well as the immune evasion strategies for chronic HCV infection.

Optimal Charge-to-Spin Conversion in Graphene on Transition-Metal Dichalcogenides

NASA Astrophysics Data System (ADS)

Offidani, Manuel; Milletarı, Mirco; Raimondi, Roberto; Ferreira, Aires

2017-11-01

When graphene is placed on a monolayer of semiconducting transition metal dichalcogenide (TMD) its band structure develops rich spin textures due to proximity spin-orbital effects with interfacial breaking of inversion symmetry. In this work, we show that the characteristic spin winding of low-energy states in graphene on a TMD monolayer enables current-driven spin polarization, a phenomenon known as the inverse spin galvanic effect (ISGE). By introducing a proper figure of merit, we quantify the efficiency of charge-to-spin conversion and show it is close to unity when the Fermi level approaches the spin minority band. Remarkably, at high electronic density, even though subbands with opposite spin helicities are occupied, the efficiency decays only algebraically. The giant ISGE predicted for graphene on TMD monolayers is robust against disorder and remains large at room temperature.

Interferon lambda 1-3 expression in infants hospitalized for RSV or HRV associated bronchiolitis.

PubMed

Selvaggi, Carla; Pierangeli, Alessandra; Fabiani, Marco; Spano, Lucia; Nicolai, Ambra; Papoff, Paola; Moretti, Corrado; Midulla, Fabio; Antonelli, Guido; Scagnolari, Carolina

2014-05-01

The airway expression of type III interferons (IFNs) was evaluated in infants hospitalized for respiratory syncytial virus (RSV) or rhinovirus (HRV) bronchiolitis. As an additional objective we sought to determine whether a different expression of IFN lambda 1-3 was associated with different harboring viruses, the clinical course of bronchiolitis or with the levels of well established IFN stimulated genes (ISGs), such as mixovirus resistance A (MxA) and ISG56. The analysis was undertaken in 118 infants with RSV or HRV bronchiolitis. Nasopharyngeal washes were collected for virological studies and molecular analysis of type III IFN responses. RSV elicited higher levels of IFN lambda subtypes when compared with HRV. A similar expression of type III IFN was found in RSVA or RSVB infected infants and in those infected with HRVA or HRVC viruses. Results also indicate that IFN lambda 1 and IFN lambda 2-3 levels were correlated with each other and with MxA and ISG56-mRNAs. In addition, a positive correlation exists between the IFN lambda1 levels and the clinical score index during RSV infection. In particular, higher IFN lambda 1 levels are associated to an increase of respiratory rate. These findings show that differences in the IFN lambda 1-3 levels in infants with RSV or HRV infections are present and that the expression of IFN lambda 1 correlates with the severity of RSV bronchiolitis. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Covalent ISG15 conjugation to CHIP promotes its ubiquitin E3 ligase activity and inhibits lung cancer cell growth in response to type I interferon.

PubMed

Yoo, Lang; Yoon, A-Rum; Yun, Chae-Ok; Chung, Kwang Chul

2018-01-24

The carboxyl terminus of Hsp70-interacting protein (CHIP) acts as a ubiquitin E3 ligase and a link between the chaperones Hsp70/90 and the proteasome system, playing a vital role in maintaining protein homeostasis. CHIP regulates a number of proteins involved in a myriad of physiological and pathological processes, but the underlying mechanism of action via posttranslational modification has not been extensively explored. In this study, we investigated a novel modulatory mode of CHIP and its effect on CHIP enzymatic activity. ISG15, an ubiquitin-like modifier, is induced by type I interferon (IFN) stimulation and can be conjugated to target proteins (ISGylation). Here we demonstrated that CHIP may be a novel target of ISGylation in HEK293 cells stimulated with type I IFN. We also found that Lys143/144/145 and Lys287 residues in CHIP are important for and target residues of ISGylation. Moreover, ISGylation promotes the E3 ubiquitin ligase activity of CHIP, subsequently causing a decrease in levels of oncogenic c-Myc, one of its many ubiquitination targets, in A549 lung cancer cells and inhibiting A549 cell and tumor growth. In conclusion, the present study demonstrates that covalent ISG15 conjugation produces a novel CHIP regulatory mode that enhances the tumor-suppressive activity of CHIP, thereby contributing to the antitumor effect of type I IFN.

77 FR 61275 - Privacy Act of 1974: Implementation

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-09

... (FBI) Privacy Act system of records titled FBI Data Warehouse System, JUSTICE/FBI- 022. This system is...)(G), (H), and (I), (5), and (8); (f); and (g) of the Privacy Act: (1) FBI Data Warehouse System...

Reciprocal inhibition between intracellular antiviral signaling and the RNAi machinery in mammalian cells

PubMed Central

Seo, Gil Ju; Kincaid, Rodney P.; Phanaksri, Teva; Burke, James M.; Pare, Justin M.; Cox, Jennifer E.; Hsiang, Tien-Ying; Krug, Robert M.; Sullivan, Christopher S.

2013-01-01

SUMMARY RNA interference (RNAi) is an established antiviral defense mechanism in plants and invertebrates. Whether RNAi serves a similar function in mammalian cells remains unresolved. We find that in some cell types, mammalian RNAi activity is reduced shortly after viral infection via poly ADP-ribosylation of the RNA induced silencing complex (RISC), a core component of RNAi. Well-established antiviral signaling pathways, including RIG-I/MAVS and RNAseL, contribute to inhibition of RISC. In the absence of virus infection, microRNAs repress interferon-stimulated genes (ISGs) associated with cell death and proliferation, thus maintaining homeostasis. Upon detection of intracellular pathogen-associated molecular patterns, RISC activity decreases, contributing to increased expression of ISGs. Our results suggest that unlike in lower eukaryotes, mammalian RISC is not antiviral in some contexts, but rather, RISC has been co-opted to negatively regulate toxic host antiviral effectors via microRNAs. PMID:24075860

ISG hybrid powertrain: a rule-based driver model incorporating look-ahead information

NASA Astrophysics Data System (ADS)

Shen, Shuiwen; Zhang, Junzhi; Chen, Xiaojiang; Zhong, Qing-Chang; Thornton, Roger

2010-03-01

According to European regulations, if the amount of regenerative braking is determined by the travel of the brake pedal, more stringent standards must be applied, otherwise it may adversely affect the existing vehicle safety system. The use of engine or vehicle speed to derive regenerative braking is one way to avoid strict design standards, but this introduces discontinuity in powertrain torque when the driver releases the acceleration pedal or applies the brake pedal. This is shown to cause oscillations in the pedal input and powertrain torque when a conventional driver model is adopted. Look-ahead information, together with other predicted vehicle states, are adopted to control the vehicle speed, in particular, during deceleration, and to improve the driver model so that oscillations can be avoided. The improved driver model makes analysis and validation of the control strategy for an integrated starter generator (ISG) hybrid powertrain possible.

Interferon sensitivity-determining region of hepatitis C virus influences virus production and interferon signaling

PubMed Central

Sugiyama, Ryuichi; Murayama, Asako; Nitta, Sayuri; Yamada, Norie; Tasaka-Fujita, Megumi; Masaki, Takahiro; Aly, Hussein Hassan; Shiina, Masaaki; Ryo, Akihide; Ishii, Koji; Wakita, Takaji; Kato, Takanobu

2018-01-01

The number of amino acid substitutions in the interferon (IFN) sensitivity-determining region (ISDR) of hepatitis C virus (HCV) NS5A is a strong predictor for the outcome of IFN-based treatment. To assess the involvement of ISDR in the HCV life cycle and to clarify the molecular mechanisms influencing IFN susceptibility, we used recombinant JFH-1 viruses with NS5A of the genotype 1b Con1 strain (JFH1/5ACon1) and with NS5A ISDR containing 7 amino acid substitutions (JFH1/5ACon1/i-7mut), and compared the virus propagation and the induction of interferon-stimulated genes (ISGs). By transfecting RNAs of these strains into HuH-7-derived cells, we found that the efficiency of infectious virus production of JFH1/5ACon1/i-7mut was attenuated compared with JFH1/5ACon1. After transfecting full-length HCV RNA into HepaRG cells, the mRNA expression of ISGs was sufficiently induced by IFN treatment in JFH1/5ACon1/i-7mut-transfected but not in JFH1/5ACon1-transfected cells. These data suggested that the NS5A-mediated inhibition of ISG induction was deteriorated by amino acid substitutions in the ISDR. In conclusion, using recombinant JFH-1 viruses, we demonstrated that HCV NS5A is associated with infectious virus production and the inhibition of IFN signaling, and amino acid substitutions in the NS5A ISDR deteriorate these functions. These observations explain the strain-specific evasion of IFN signaling by HCV. PMID:29464023

Comparative analysis of selected innate immune-related genes following infection of immortal DF-1 cells with highly pathogenic (H5N1) and low pathogenic (H9N2) avian influenza viruses.

PubMed

Liu, Ai-Ling; Li, Yu-Feng; Qi, Wenbao; Ma, Xiu-Li; Yu, Ke-Xiang; Huang, Bing; Liao, Ming; Li, Feng; Pan, Jie; Song, Min-Xun

2015-04-01

H5N1 and H9N2 viruses are important causes of avian influenza in China. H5N1 is typically associated with severe to fatal disease in poultry, while H9N2 is usually associated with mild disease. Differences in viral virulence prompted us to investigate whether innate immune responses would be differentially regulated following infection by H5N1 and H9N2 viruses. To address this hypothesis, expression of a panel of innate immune-related genes including IFN-α, IFN-β, Mx1, OASL, ISG12, IFIT5, IRF7, USP18, SST, and KHSRP in immortal DF-1 cells following H5N1 and H9N2 infection was analyzed and compared by real-time quantitative RT-PCR. Cells infected by either virus overall exhibited a similar expression profile for four ISGs (Mx1, OASL, ISG12, and IFIT5), IFN-α, IFN-β, and SST gene. However, two immune-regulatory genes (IRF7 and KHSRP) were not responsive to highly pathogenic H5N1 infection but were strongly up-regulated in DF-1 cells infected with low pathogenic H9N2 infection. The subtype-dependent host response observed in this study offers new insights into the potential roles of IRF7 and KHSRP in control and modulation of the replication and virulence of different subtypes or strains of avian influenza A virus.

Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease.

PubMed

Rice, Gillian I; Melki, Isabelle; Frémond, Marie-Louise; Briggs, Tracy A; Rodero, Mathieu P; Kitabayashi, Naoki; Oojageer, Anthony; Bader-Meunier, Brigitte; Belot, Alexandre; Bodemer, Christine; Quartier, Pierre; Crow, Yanick J

2017-02-01

Increased type I interferon is considered relevant to the pathology of a number of monogenic and complex disorders spanning pediatric rheumatology, neurology, and dermatology. However, no test exists in routine clinical practice to identify enhanced interferon signaling, thus limiting the ability to diagnose and monitor treatment of these diseases. Here, we set out to investigate the use of an assay measuring the expression of a panel of interferon-stimulated genes (ISGs) in children affected by a range of inflammatory diseases. A cohort study was conducted between 2011 and 2016 at the University of Manchester, UK, and the Institut Imagine, Paris, France. RNA PAXgene blood samples and clinical data were collected from controls and symptomatic patients with a genetically confirmed or clinically well-defined inflammatory phenotype. The expression of six ISGs was measured by quantitative polymerase chain reaction, and the median fold change was used to calculate an interferon score (IS) for each subject compared to a previously derived panel of 29 controls (where +2 SD of the control data, an IS of >2.466, is considered as abnormal). Results were correlated with genetic and clinical data. Nine hundred ninety-two samples were analyzed from 630 individuals comprising symptomatic patients across 24 inflammatory genotypes/phenotypes, unaffected heterozygous carriers, and controls. A consistent upregulation of ISG expression was seen in 13 monogenic conditions (455 samples, 265 patients; median IS 10.73, interquartile range (IQR) 5.90-18.41), juvenile systemic lupus erythematosus (78 samples, 55 patients; median IS 10.60, IQR 3.99-17.27), and juvenile dermatomyositis (101 samples, 59 patients; median IS 9.02, IQR 2.51-21.73) compared to controls (78 samples, 65 subjects; median IS 0.688, IQR 0.427-1.196), heterozygous mutation carriers (89 samples, 76 subjects; median IS 0.862, IQR 0.493-1.942), and individuals with non-molecularly defined autoinflammation (89 samples, 69 patients; median IS 1.07, IQR 0.491-3.74). An assessment of six ISGs can be used to define a spectrum of inflammatory diseases related to enhanced type I interferon signaling. If future studies demonstrate that the IS is a reactive biomarker, this measure may prove useful both in the diagnosis and the assessment of treatment efficacy.

Distinct Dictation of Japanese Encephalitis Virus-Induced Neuroinflammation and Lethality via Triggering TLR3 and TLR4 Signal Pathways

PubMed Central

Uyangaa, Erdenebelig; Kim, Seong Bum; Kim, Jin Hyoung; Kim, Bum Seok; Kim, Koanhoi; Eo, Seong Kug

2014-01-01

Japanese encephalitis (JE) is major emerging neurologic disease caused by JE virus. To date, the impact of TLR molecules on JE progression has not been addressed. Here, we determined whether each TLR modulates JE, using several TLR-deficient mouse strains (TLR2, TLR3, TLR4, TLR7, TLR9). Surprisingly, among the tested TLR-deficient mice there were contrasting results in TLR3−/− and TLR4−/− mice, i.e. TLR3−/− mice were highly susceptible to JE, whereas TLR4−/− mice showed enhanced resistance to JE. TLR3 ablation induced severe CNS inflammation characterized by early infiltration of inflammatory CD11b+Ly-6Chigh monocytes along with profoundly increased viral burden, proinflammatory cytokine/chemokine expression as well as BBB permeability. In contrast, TLR4−/− mice showed mild CNS inflammation manifested by reduced viral burden, leukocyte infiltration and proinflammatory cytokine expression. Interestingly, TLR4 ablation provided potent in vivo systemic type I IFN innate response, as well as ex vivo type I IFN production associated with strong induction of antiviral PRRs (RIG-I, MDA5), transcription factors (IRF-3, IRF-7), and IFN-dependent (PKR, Oas1, Mx) and independent ISGs (ISG49, ISG54, ISG56) by alternative activation of IRF3 and NF-κB in myeloid-derived DCs and macrophages, as compared to TLR3−/− myeloid-derived cells which were more permissive to viral replication through impaired type I IFN innate response. TLR4 ablation also appeared to mount an enhanced type I IFN innate and humoral, CD4+ and CD8+ T cell responses, which were mediated by altered immune cell populations (increased number of plasmacytoid DCs and NK cells, reduced CD11b+Ly-6Chigh monocytes) and CD4+Foxp3+ Treg number in lymphoid tissue. Thus, potent type I IFN innate and adaptive immune responses in the absence of TLR4 were closely coupled with reduced JE lethality. Collectively, these results suggest that a balanced triggering of TLR signal array by viral components during JE progression could be responsible for determining disease outcome through regulating negative and positive factors. PMID:25188232

Peripheral inflammation is associated with remote global gene expression changes in the brain

PubMed Central

2014-01-01

Background Although the central nervous system (CNS) was once considered an immunologically privileged site, in recent years it has become increasingly evident that cross talk between the immune system and the CNS does occur. As a result, patients with chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease or psoriasis, are often further burdened with neuropsychiatric symptoms, such as depression, anxiety and fatigue. Despite the recent advances in our understanding of neuroimmune communication pathways, the precise effect of peripheral immune activation on neural circuitry remains unclear. Utilizing transcriptomics in a well-characterized murine model of systemic inflammation, we have started to investigate the molecular mechanisms by which inflammation originating in the periphery can induce transcriptional modulation in the brain. Methods Several different systemic and tissue-specific models of peripheral toll-like-receptor-(TLR)-driven (lipopolysaccharide (LPS), lipoteichoic acid and Imiquimod) and sterile (tumour necrosis factor (TNF) and 12-O-tetradecanoylphorbol-13-acetate (TPA)) inflammation were induced in C57BL/6 mice. Whole brain transcriptional profiles were assessed and compared 48 hours after intraperitoneal injection of lipopolysaccharide or vehicle, using Affymetrix GeneChip microarrays. Target gene induction, identified by microarray analysis, was validated independently using qPCR. Expression of the same panel of target genes was then investigated in a number of sterile and other TLR-dependent models of peripheral inflammation. Results Microarray analysis of whole brains collected 48 hr after LPS challenge revealed increased transcription of a range of interferon-stimulated genes (ISGs) in the brain. In addition to acute LPS challenge, ISGs were induced in the brain following both chronic LPS-induced systemic inflammation and Imiquimod-induced skin inflammation. Unique to the brain, this transcriptional response is indicative of peripherally triggered, interferon-mediated CNS inflammation. Similar models of sterile inflammation and lipoteichoic-acid-induced systemic inflammation did not share the capacity to trigger ISG induction in the brain. Conclusions These data highlight ISG induction in the brain as being a consequence of a TLR-induced type I interferon response. As considerable evidence links type I interferons to psychiatric disorders, we hypothesize that interferon production in the brain could represent an important mechanism, linking peripheral TLR-induced inflammation with behavioural changes. PMID:24708794

Activation of Type I and III Interferon Signalling Pathways Occurs in Lung Epithelial Cells Infected with Low Pathogenic Avian Influenza Viruses

PubMed Central

Sutejo, Richard; Yeo, Dawn S.; Myaing, Myint Zu; Hui, Chen; Xia, Jiajia; Ko, Debbie; Cheung, Peter C. F.; Tan, Boon-Huan; Sugrue, Richard J.

2012-01-01

The host response to the low pathogenic avian influenza (LPAI) H5N2, H5N3 and H9N2 viruses were examined in A549, MDCK, and CEF cells using a systems-based approach. The H5N2 and H5N3 viruses replicated efficiently in A549 and MDCK cells, while the H9N2 virus replicated least efficiently in these cell types. However, all LPAI viruses exhibited similar and higher replication efficiencies in CEF cells. A comparison of the host responses of these viruses and the H1N1/WSN virus and low passage pH1N1 clinical isolates was performed in A549 cells. The H9N2 and H5N2 virus subtypes exhibited a robust induction of Type I and Type III interferon (IFN) expression, sustained STAT1 activation from between 3 and 6 hpi, which correlated with large increases in IFN-stimulated gene (ISG) expression by 10 hpi. In contrast, cells infected with the pH1N1 or H1N1/WSN virus showed only small increases in Type III IFN signalling, low levels of ISG expression, and down-regulated expression of the IFN type I receptor. JNK activation and increased expression of the pro-apoptotic XAF1 protein was observed in A549 cells infected with all viruses except the H1N1/WSN virus, while MAPK p38 activation was only observed in cells infected with the pH1N1 and the H5 virus subtypes. No IFN expression and low ISG expression levels were generally observed in CEF cells infected with either AIV, while increased IFN and ISG expression was observed in response to the H1N1/WSN infection. These data suggest differences in the replication characteristics and antivirus signalling responses both among the different LPAI viruses, and between these viruses and the H1N1 viruses examined. These virus-specific differences in host cell signalling highlight the importance of examining the host response to avian influenza viruses that have not been extensively adapted to mammalian tissue culture. PMID:22470468

Standardization of quantum technologies and QKD activities within ETSI (Conference Presentation)

NASA Astrophysics Data System (ADS)

Lenhart, Gaby

2016-04-01

In order to establish new ICT technologies successfully on the market it is essential to build trust within any potential users. This is especially true for technologies which are based upon paradigms that are not yet familiar to these users, such as quantum technologies. Technical standards are an excellent means to offer a certain degree of legal reliability and technical interoperability that is required by industry for commercial take up. While such standards on the one hand must be clear enough to provide strict rules for implementers, on the other hand they also must remain flexible enough to not restrict progress in further research and development on the standardized technology. Hence such standards have to be produced by a wide variety of stakeholders taking into account all their different needs. The paper will provide some insight into the general mechanisms of standardization and their relation to quantum technologies. Alongside with the relevance of standardization as an enabler for certification of quantum based technologies it will explain its potential for securing intellectual property. In its first part paper will concentrate on the advantages of standardization and discuss fears some of the stakeholders share, in detail. The second part will focus on the technical work going on in ETSI in relation to quantum technologies. In 2008 ETSI created a standards work group on Quantum Key Distribution, the ETSI ISG QKD and more recently a group on Quantum-Safe Cryptography, the ETSI ISG QSC. A significant part of the technical work of these groups has already been published and will be introduced in the following. However a big share of work is still ongoing and lot more is planned for the future, as are continuous revisions and updates of the published specifications. This standardization work covers several levels: It starts of by problem statements in the form of use cases, from which technical requirements can be derived. These requirements then form the base upon which a reference architecture is created. Various different specifications describe in detail components, protocols and interfaces. An ontology is developed in order to guarantee common understanding of the technical terms used in standardization for quantum technologies. Special emphasis is provided to security proofs.

Technical Standards for the ATCCIS Architecture. ATCCIS Working Paper 25

DTIC Science & Technology

1990-08-01

doubling every 144 UNCLASSIFIED UNCLASSIFIED insurance, tourism , construction). EDIFACT was developed by the UN working party on Facilitation of...EXPERTS mwe"aBetio -- SEIO CIVIL-ClDRETRAES~ EME GENCY -(MUCWGCOM G4Wp (ISG ,,* -- * PLANINWOCOMMITTEE (SCEPC) PLANNING AND PANGCOMIE ; OMMUNICATIONS

Application of thermal analysis techniques in activated carbon production

USGS Publications Warehouse

Donnals, G.L.; DeBarr, J.A.; Rostam-Abadi, M.; Lizzio, A.A.; Brady, T.A.

1996-01-01

Thermal analysis techniques have been used at the ISGS as an aid in the development and characterization of carbon adsorbents. Promising adsorbents from fly ash, tires, and Illinois coals have been produced for various applications. Process conditions determined in the preparation of gram quantities of carbons were used as guides in the preparation of larger samples. TG techniques developed to characterize the carbon adsorbents included the measurement of the kinetics of SO2 adsorption, the performance of rapid proximate analyses, and the determination of equilibrium methane adsorption capacities. Thermal regeneration of carbons was assessed by TG to predict the life cycle of carbon adsorbents in different applications. TPD was used to determine the nature of surface functional groups and their effect on a carbon's adsorption properties.

A tetrapod-like repertoire of innate immune receptors and effectors for coelacanths

USGS Publications Warehouse

Boudinot, Pierre; Zou, Jun; Ota, Tatsuya; Buonocore, Francesco; Scapigliati, Giuseppe; Canapa, Adriana; Cannon, John; Litman, Gary; Hansen, John D.

2014-01-01

The recent availability of both robust transcriptome and genome resources for coelacanth (Latimeria chalumnae) has led to unique discoveries for coelacanth immunity such as the lack of IgM, a central component of adaptive immunity. This study was designed to more precisely address the origins and evolution of gene families involved in the initial recognition and response to microbial pathogens, which effect innate immunity. Several multigene families involved in innate immunity are addressed, including: Toll-like receptors (TLRs), retinoic acid inducible gene 1 (RIG1)-like receptors (RLRs), the nucleotide-binding domain and leucine-rich repeat containing proteins (NLRs), diverse immunoglobulin domain-containing proteins (DICP) and modular domain immune-type receptors (MDIRs). Our analyses also include the tripartite motif-containing proteins (TRIM), which are involved in pathogen recognition as well as the positive regulation of antiviral immunity. Finally, this study addressed some of the downstream effectors of the antimicrobial response including IL-1 family members, type I and II interferons (IFN) and IFN-stimulated effectors (ISGs). Collectively, the genes and gene families in coelacanth that effect innate immune functions share characteristics both in content, structure and arrangement with those found in tetrapods but not in teleosts. The findings support the sister group relationship of coelacanth fish with tetrapods.

Interferon lambda inhibits dengue virus replication in epithelial cells.

PubMed

Palma-Ocampo, Helen K; Flores-Alonso, Juan C; Vallejo-Ruiz, Verónica; Reyes-Leyva, Julio; Flores-Mendoza, Lilian; Herrera-Camacho, Irma; Rosas-Murrieta, Nora H; Santos-López, Gerardo

2015-09-28

In viral disease, infection is controlled at the cellular level by type I interferon (IFN-I), but dengue virus (DENV) has the ability to inhibit this response. Type III interferon, also known as lambda IFN (IFN-III or IFN-λ), is a complementary pathway to the antiviral response by IFN-I. This work analyzed the IFN-λ (IFN-III) mediated antiviral response against DENV serotype 2 (DENV-2) infection. Dengue fever patients were sampled to determine their IFN-λ levels by ELISA. To study the IFN-λ response during DENV infection we selected the epithelial cell line C33-A, and we demonstrated that it is permissive to DENV-2 infection. The effect of IFN-λ on virus replication was determined in these cells, in parallel to the expression of IFN-stimulated genes (ISGs), and Suppressor of Cytokine Signaling (SOCS), genes measured by RT-qPCR. We found increased (~1.8 times) serological IFN-λ in dengue fever patients compared to healthy blood donors. IFN-λ inhibited DENV-2 replication in a dose-dependent manner in vitro. The reduction of viral titer corresponded with increased ISG mRNA levels (MX1 and OAS1), with the highest inhibition occurring at ISG's peak expression. Presence of IFN-negative regulators, SOCS1 and SOCS3, during DENV-2 infection was associated with reduced IFN-λ1 expression. Evidence described here suggests that IFN-λ is a good candidate inhibitor of viral replication in dengue infection. Mechanisms for the cellular and organismal interplay between DENV and IFN- λ need to be further studied as they could provide insights into strategies to treat this disease. Furthermore, we report a novel epithelial model to study dengue infection in vitro.

Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells.

PubMed

Foxman, Ellen F; Storer, James A; Fitzgerald, Megan E; Wasik, Bethany R; Hou, Lin; Zhao, Hongyu; Turner, Paul E; Pyle, Anna Marie; Iwasaki, Akiko

2015-01-20

Most isolates of human rhinovirus, the common cold virus, replicate more robustly at the cool temperatures found in the nasal cavity (33-35 °C) than at core body temperature (37 °C). To gain insight into the mechanism of temperature-dependent growth, we compared the transcriptional response of primary mouse airway epithelial cells infected with rhinovirus at 33 °C vs. 37 °C. Mouse airway cells infected with mouse-adapted rhinovirus 1B exhibited a striking enrichment in expression of antiviral defense response genes at 37 °C relative to 33 °C, which correlated with significantly higher expression levels of type I and type III IFN genes and IFN-stimulated genes (ISGs) at 37 °C. Temperature-dependent IFN induction in response to rhinovirus was dependent on the MAVS protein, a key signaling adaptor of the RIG-I-like receptors (RLRs). Stimulation of primary airway cells with the synthetic RLR ligand poly I:C led to greater IFN induction at 37 °C relative to 33 °C at early time points poststimulation and to a sustained increase in the induction of ISGs at 37 °C relative to 33 °C. Recombinant type I IFN also stimulated more robust induction of ISGs at 37 °C than at 33 °C. Genetic deficiency of MAVS or the type I IFN receptor in infected airway cells permitted higher levels of viral replication, particularly at 37 °C, and partially rescued the temperature-dependent growth phenotype. These findings demonstrate that in mouse airway cells, rhinovirus replicates preferentially at nasal cavity temperature due, in part, to a less efficient antiviral defense response of infected cells at cool temperature.

The Superiority of IFN-λ as a Therapeutic Candidate to Control Acute Influenza Viral Lung Infection.

PubMed

Kim, Sujin; Kim, Min-Ji; Kim, Chang-Hoon; Kang, Ju Wan; Shin, Ha Kyung; Kim, Dong-Young; Won, Tae-Bin; Han, Doo Hee; Rhee, Chae Seo; Yoon, Joo-Heon; Kim, Hyun Jik

2017-02-01

Here, we studied the IFN-regulated innate immune response against influenza A virus (IAV) infection in the mouse lung and the therapeutic effect of IFN-λ2/3 in acute IAV lung infection. For viral infections, IAV (WS/33, H1N1, PR8 H1N1, H5N1) were inoculated into wild-type mice by intranasal delivery, and IAV mRNA level and viral titer were measured. To compare the antiviral effect of IFNs in vivo in the lung, neutralizing antibodies and recombinant IFNs were used. After intranasal inoculation of IAV into mice, viral infection peaked at 7 days postinfection, and the IAV titer also reached its peak at this time. We found that IFN-β and IFN-λ2/3 were preferentially induced after IAV infection and the IFN-λ2/3-mediated innate immune response was specifically required for the induction of IFN-stimulated genes (ISGs) transcription in the mouse respiratory tract. Neutralization of secreted IFN-λ2/3 aggravated acute IAV lung infection in mice with intact IFN-β induction; consistent with this finding, the transcription of ISGs was significantly reduced. Intranasal administration of IFN-λ2/3 significantly suppressed various strains of IAV infection, including WS/33 (H1N1), PR (H1N1), and H5N1 in the mouse lung, and was accompanied by greater up-regulation of ISGs. Taken together, our data indicate that the IFN-λ2/3-mediated innate immune response is necessary to protect the lungs from IAV infection, and intranasally delivered IFN-λ2/3 has the potential to be a useful therapeutic strategy for treating acute IAV lung infection.

Transient and Prolonged Response of Chicken Cecum Mucosa to Colonization with Different Gut Microbiota

PubMed Central

Volf, Jiri; Polansky, Ondrej; Varmuzova, Karolina; Gerzova, Lenka; Sekelova, Zuzana; Faldynova, Marcela; Babak, Vladimir; Medvecky, Matej; Smith, Adrian L.; Kaspers, Bernd; Velge, Philippe; Rychlik, Ivan

2016-01-01

In this study we determined protein and gene expression in the caeca of newly hatched chickens inoculated with cecal contents sourced from hens of different ages. Over 250 proteins exhibited modified expression levels in response to microbiota inoculation. The most significant inductions were observed for ISG12-2, OASL, ES1, LYG2, DMBT1-L, CDD, ANGPTL6, B2M, CUZD1, IgM and Ig lambda chain. Of these, ISG12-2, ES1 and both immunoglobulins were expressed at lower levels in germ-free chickens compared to conventional chickens. In contrast, CELA2A, BRT-2, ALDH1A1, ADH1C, AKR1B1L, HEXB, ALDH2, ALDOB, CALB1 and TTR were expressed at lower levels following inoculation of microbiota. When chicks were given microbiota preparations from different age donors, the recipients mounted differential responses to the inoculation which also differed from the response profile in naturally colonised birds. For example, B2M, CUZD1 and CELA2A responded differently to the inoculation with microbiota of 4- or 40-week-old hens. The increased or decreased gene expression could be recorded 6 weeks after the inoculation of newly hatched chickens. To characterise the proteins that may directly interact with the microbiota we characterised chicken proteins that co-purified with the microbiota and identified a range of host proteins including CDD, ANGPTL6, DMBT1-L, MEP1A and Ig lambda. We propose that induction of ISG12-2 results in reduced apoptosis of host cells exposed to the colonizing commensal microbiota and that CDD, ANGPTL6, DMBT1-L, MEP1A and Ig lambda reduce contact of luminal microbiota with the gut epithelium thereby reducing the inflammatory response. PMID:27685470

SARS hCoV papain-like protease is a unique Lys48 linkage-specific di-distributive deubiquitinating enzyme

PubMed Central

Békés, Miklós; Rut, Wioletta; Kasperkiewicz, Paulina; Mulder, Monique P. C.; Ovaa, Huib; Drag, Marcin; Lima, Christopher D.; Huang, Tony T.

2015-01-01

Ubiquitin (Ub) and the ubiquitin-like modifier interferon stimulated gene 15 (ISG15) participate in the host defense of viral infections. Viruses, including the Severe Acute Respiratory Syndrome human coronavirus (SARS hCoV), have co-opted Ub/ISG15-conjugation pathways for their own advantage or have evolved effector proteins to counter pro-inflammatory properties of Ub/ISG15-conjugated host proteins. Here, we compare substrate specificities of the papain-like protease (PLpro) from the recently emerged Middle Eastern Respiratory Syndrome (MERS) hCoV to the related protease from SARS, SARS PLpro. Through biochemical assays, we show that similar to SARS PLpro, MERS PLpro is both a deubiquitinating and a deISGylating enzyme. Further analysis of the intrinsic deubiquitinating enzyme (DUB) activity of these viral proteases revealed unique differences between the recognition and cleavage specificities of polyUb chains. First, MERS PLpro shows broad linkage specificity for the cleavage of polyUb chains, while SARS PLpro prefers to cleave Lys48-linked polyUb chains. Second, MERS PLpro cleaves polyUb chains in a “mono-distributive” manner (one Ub at a time), and SARS PLpro prefers to cleave K48-linked poly-Ub chains by sensing a di-Ub moiety as a minimal recognition element using a “di-distributive” cleavage mechanism. The di-distributive cleavage mechanism for SARS PLpro appears to be uncommon among USP-family DUBs, as related USP family members from humans do not display such a mechanism. We propose that these intrinsic enzymatic differences between SARS and MERS PLpro will help identify pro-inflammatory substrates of these viral DUBs and can guide in the design of therapeutics to combat infection by coronaviruses. PMID:25764917

SARS hCoV papain-like protease is a unique Lys48 linkage-specific di-distributive deubiquitinating enzyme.

PubMed

Békés, Miklós; Rut, Wioletta; Kasperkiewicz, Paulina; Mulder, Monique P C; Ovaa, Huib; Drag, Marcin; Lima, Christopher D; Huang, Tony T

2015-06-01

Ubiquitin (Ub) and the Ub-like (Ubl) modifier interferon-stimulated gene 15 (ISG15) participate in the host defence of viral infections. Viruses, including the severe acute respiratory syndrome human coronavirus (SARS hCoV), have co-opted Ub-ISG15 conjugation pathways for their own advantage or have evolved effector proteins to counter pro-inflammatory properties of Ub-ISG15-conjugated host proteins. In the present study, we compare substrate specificities of the papain-like protease (PLpro) from the recently emerged Middle East respiratory syndrome (MERS) hCoV to the related protease from SARS, SARS PLpro. Through biochemical assays, we show that, similar to SARS PLpro, MERS PLpro is both a deubiquitinating (DUB) and a deISGylating enzyme. Further analysis of the intrinsic DUB activity of these viral proteases revealed unique differences between the recognition and cleavage specificities of polyUb chains. First, MERS PLpro shows broad linkage specificity for the cleavage of polyUb chains, whereas SARS PLpro prefers to cleave Lys48-linked polyUb chains. Secondly, MERS PLpro cleaves polyUb chains in a 'mono-distributive' manner (one Ub at a time) and SARS PLpro prefers to cleave Lys48-linked polyUb chains by sensing a di-Ub moiety as a minimal recognition element using a 'di-distributive' cleavage mechanism. The di-distributive cleavage mechanism for SARS PLpro appears to be uncommon among USP (Ub-specific protease)-family DUBs, as related USP family members from humans do not display such a mechanism. We propose that these intrinsic enzymatic differences between SARS and MERS PLpro will help to identify pro-inflammatory substrates of these viral DUBs and can guide in the design of therapeutics to combat infection by coronaviruses.

Energy Optimization for a Weak Hybrid Power System of an Automobile Exhaust Thermoelectric Generator

NASA Astrophysics Data System (ADS)

Fang, Wei; Quan, Shuhai; Xie, Changjun; Tang, Xinfeng; Ran, Bin; Jiao, Yatian

2017-11-01

An integrated starter generator (ISG)-type hybrid electric vehicle (HEV) scheme is proposed based on the automobile exhaust thermoelectric generator (AETEG). An eddy current dynamometer is used to simulate the vehicle's dynamic cycle. A weak ISG hybrid bench test system is constructed to test the 48 V output from the power supply system, which is based on engine exhaust-based heat power generation. The thermoelectric power generation-based system must ultimately be tested when integrated into the ISG weak hybrid mixed power system. The test process is divided into two steps: comprehensive simulation and vehicle-based testing. The system's dynamic process is simulated for both conventional and thermoelectric powers, and the dynamic running process comprises four stages: starting, acceleration, cruising and braking. The quantity of fuel available and battery pack energy, which are used as target vehicle energy functions for comparison with conventional systems, are simplified into a single energy target function, and the battery pack's output current is used as the control variable in the thermoelectric hybrid energy optimization model. The system's optimal battery pack output current function is resolved when its dynamic operating process is considered as part of the hybrid thermoelectric power generation system. In the experiments, the system bench is tested using conventional power and hybrid thermoelectric power for the four dynamic operation stages. The optimal battery pack curve is calculated by functional analysis. In the vehicle, a power control unit is used to control the battery pack's output current and minimize energy consumption. Data analysis shows that the fuel economy of the hybrid power system under European Driving Cycle conditions is improved by 14.7% when compared with conventional systems.

77 FR 71019 - Japan Lessons-Learned Project Directorate Interim Staff Guidance JLD-ISG-2012-04; Guidance on...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-28

... Insights from the Fukushima Dai-ichi Accident,'' dated March 12, 2012 (ADAMS Accession No. ML12053A340... resulting nuclear accident, at the Fukushima Dai-ichi nuclear power plant in March 2011. Enclosure 1 to the...

Death-domain associated protein-6 (DAXX) mediated apoptosis in hantavirus infection is counter-balanced by activation of interferon-stimulated nuclear transcription factors

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

Khaiboullina, Svetlana F., E-mail: sv.khaiboullina@gmail.com; Morzunov, Sergey P.; Boichuk, Sergei V.

2013-09-01

Hantaviruses are negative strand RNA species that replicate predominantly in the cytoplasm. They also activate numerous cellular responses, but their involvement in nuclear processes is yet to be established. Using human umbilical vein endothelial cells (HUVECs), this study investigates the molecular finger-print of nuclear transcription factors during hantavirus infection. The viral-replication-dependent activation of pro-myelocytic leukemia protein (PML) was followed by subsequent localization in nuclear bodies (NBs). PML was also found in close proximity to activated Sp100 nuclear antigen and interferon-stimulated gene 20 kDa protein (ISG-20), but co-localization with death-domain associated protein-6 (DAXX) was not observed. These data demonstrate that hantavirusmore » triggers PML activation and localization in NBs in the absence of DAXX-PLM-NB co-localization. The results suggest that viral infection interferes with DAXX-mediated apoptosis, and expression of interferon-activated Sp100 and ISG-20 proteins may indicate intracellular intrinsic antiviral attempts.« less

Antibody-dependent enhancement of dengue virus infection inhibits RLR-mediated Type-I IFN-independent signalling through upregulation of cellular autophagy

PubMed Central

Huang, Xinwei; Yue, Yaofei; Li, Duo; Zhao, Yujiao; Qiu, Lijuan; Chen, Junying; Pan, Yue; Xi, Juemin; Wang, Xiaodan; Sun, Qiangming; Li, Qihan

2016-01-01

Antibody dependent enhancement (ADE) of dengue virus (DENV) infection is identified as the main risk factor of severe Dengue diseases. Through opsonization by subneutralizing or non-neutralizing antibodies, DENV infection suppresses innate cell immunity to facilitate viral replication. However, it is largely unknown whether suppression of type-I IFN is necessary for a successful ADE infection. Here, we report that both DENV and DENV-ADE infection induce an early ISG (NOS2) expression through RLR-MAVS signalling axis independent of the IFNs signaling. Besides, DENV-ADE suppress this early antiviral response through increased autophagy formation rather than induction of IL-10 secretion. The early induced autophagic proteins ATG5-ATG12 participate in suppression of MAVS mediated ISGs induction. Our findings suggest a mechanism for DENV to evade the early antiviral response before IFN signalling activation. Altogether, these results add knowledge about the complexity of ADE infection and contribute further to research on therapeutic strategies. PMID:26923481

How Does Vaccinia Virus Interfere With Interferon?

PubMed

Smith, Geoffrey L; Talbot-Cooper, Callum; Lu, Yongxu

2018-01-01

Interferons (IFNs) are secreted glycoproteins that are produced by cells in response to virus infection and other stimuli and induce an antiviral state in cells bearing IFN receptors. In this way, IFNs restrict virus replication and spread before an adaptive immune response is developed. Viruses are very sensitive to the effects of IFNs and consequently have evolved many strategies to interfere with interferon. This is particularly well illustrated by poxviruses, which have large dsDNA genomes and encode hundreds of proteins. Vaccinia virus is the prototypic poxvirus and expresses many proteins that interfere with IFN and are considered in this review. These proteins act either inside or outside the cell and within the cytoplasm or nucleus. They function by restricting the production of IFN by blocking the signaling pathways leading to transcription of IFN genes, stopping IFNs binding to their receptors, blocking IFN-induced signal transduction leading to expression of interferon-stimulated genes (ISGs), or inhibiting the antiviral activity of ISG products. © 2018 Elsevier Inc. All rights reserved.

Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling

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

Johnson, Karen E.; Song, Byeongwoon; Knipe, David M.

2008-05-10

Host cells respond to viral infection by many mechanisms, including the production of type I interferons which act in a paracrine and autocrine manner to induce the expression of antiviral interferon-stimulated genes (ISGs). Viruses have evolved means to inhibit interferon signaling to avoid induction of the innate immune response. Herpes simplex virus 1 (HSV-1) has several mechanisms to inhibit type I interferon production, the activities of ISGs, and the interferon signaling pathway itself. We report that the inhibition of the Jak/STAT pathway by HSV-1 requires viral gene expression and that viral immediate-early protein ICP27 plays a role in downregulating STAT-1more » phosphorylation and in preventing the accumulation of STAT-1 in the nucleus. We also show that expression of ICP27 by transfection causes an inhibition of IFN-induced STAT-1 nuclear accumulation. Therefore, ICP27 is necessary and sufficient for at least some of the effects of HSV infection on STAT-1.« less

Variation in interferon sensitivity and induction between Usutu and West Nile (lineages 1 and 2) viruses.

PubMed

Cacciotti, Giulia; Caputo, Beniamino; Selvaggi, Carla; la Sala, Andrea; Vitiello, Laura; Diallo, Diawo; Ceianu, Cornelia; Antonelli, Guido; Nowotny, Norbert; Scagnolari, Carolina

2015-11-01

Given the pivotal role of monocyte-derived dendritic cells (DCs) in determining the magnitude of the antiviral innate immune response, we sought to determine whether Usutu virus (USUV) and West Nile virus (WNV) lineages (L)1 and L2 can infect DCs and affect the rate of type I interferon (IFN) activation. The sensitivity of these viruses to types I and III IFNs was also compared. We found that USUV can infect DCs, induce higher antiviral activities, IFN alpha subtypes and the IFN stimulated gene (ISG)15 pathway, and is more sensitive to types I and III IFNs than WNVs. In contrast, we confirmed that IFN alpha/beta subtypes were more effective against WNV L2 than WNV L1. However, the replication kinetics, induction of IFN alpha subtypes and ISGs in DCs and the sensitivity to IFN lambda 1-3 did not differ between WNV L1 and L2. Copyright © 2015 Elsevier Inc. All rights reserved.

Understanding the molecular mechanism(s) of hepatitis C virus (HCV) induced interferon resistance.

PubMed

Qashqari, Hanadi; Al-Mars, Amany; Chaudhary, Adeel; Abuzenadah, Adel; Damanhouri, Ghazi; Alqahtani, Mohammed; Mahmoud, Maged; El Sayed Zaki, Maysaa; Fatima, Kaneez; Qadri, Ishtiaq

2013-10-01

Hepatitis C virus (HCV) is one of the foremost causes of chronic liver disease affecting over 300 million globally. HCV contains a positive-stranded RNA of ~9600 nt and is surrounded by the 5' and 3'untranslated regions (UTR). The only successful treatment regimen includes interferon (IFN) and ribavirin. Like many other viruses, HCV has also evolved various mechanisms to circumvent the IFN response by blocking (1) downstream signaling actions via STAT1, STAT2, IRF9 and JAK-STAT pathways and (2) repertoire of IFN Stimulatory Genes (ISGs). Several studies have identified complex host demographic and genetic factors as well as viral genetic heterogeneity associated with outcomes of IFN therapy. The genetic predispositions of over 2000 ISGS may render the patients to become resistant, thus identification of such parameters within a subset of population are necessary for management corollary. The ability of various HCV genotypes to diminish IFN antiviral responses plays critical role in the establishment of chronic infection at the acute stage of infection, thus highlighting importance of the resistance in HCV treated groups. The recently defined role of viral protein such as C, E2, NS3/NS4 and NS5A proteins in inducing the IFN resistance are discussed in this article. How the viral and host genetic composition and epistatic connectivity among polymorphic genomic sites synchronizes the evolutionary IFN resistance trend remains under investigation. However, these signals may have the potential to be employed for accurate prediction of therapeutic outcomes. In this review article, we accentuate the significance of host and viral components in IFN resistance with the aim to determine the successful outcome in patients. Copyright © 2013 Elsevier B.V. All rights reserved.

Shoulder biomechanics and the success of translational research.

PubMed

Cutti, Andrea Giovanni; Chadwick, Edward K

2014-03-01

In 2009, the International Shoulder Group (ISG) had the opportunity to propose to the readers of Medical and Biological Engineering and Computing a Special Issue on shoulder biomechanics. At that time, we pointed out that the field was evolving to include more applied research. After 4 years, we can confirm that impression: 10 out of 12 papers included in this second Special Issue deal with clinical related questions, through theoretical and experimental methodologies. This demonstrates that the translational research at the base of ISG foundation in 1989 is effective. We think that the papers of this issue will have an impact on clinics in general and on the treatment of work-related injuries and diseases in particular. Based on the statistics of the Italian Workers' Compensation Authority (INAIL), injuries at the shoulder are first in terms of average duration of "temporary total disability to work". Moreover, occupational diseases at the shoulder in the industrial and services sector represented 16 % of all occupational diseases in 2012, i.e., 46 % of those related to the upper limb. These data stress the need for specific interventions, with the contribution of both researchers and policy makers. Starting from the papers included here, we would encourage additional efforts on: (1) quantitative analysis of shoulder loading during tasks associated with musculoskeletal injuries, and ways to reduce that loading, (2) simple and effective tools to improve the diagnosis and outcome assessment of motion-related shoulder diseases, and (3) the development of rehabilitation treatments focused on occupational tasks, taking advantage of state-of-the-art biofeedback technologies, and exploiting the power of biomechanical models for muscle force prediction.

77 FR 16270 - Updated Aging Management Criteria for Reactor Vessel Internal Components of Pressurized Water...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-20

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0070] Updated Aging Management Criteria for Reactor Vessel Internal Components of Pressurized Water Reactors AGENCY: Nuclear Regulatory Commission. ACTION: Draft..., ``Updated Aging Management Criteria for PWR Reactor Vessel Internal Components.'' This draft LR-ISG revises...

NLC Injector Systems

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text only NLC Home Page NLC Technical SLAC Sources Damping Rings S & L Band Linacs Engineering ; Presentations Injector System Documentation Talks and Presentations The NLC ZDR ISG Reports Sources Lasers Photocathodes Electron Source Laser Maintenance Facility Positron Source Sources Technical Notes Sources Meeting

78 FR 13097 - Electric Power Research Institute; Seismic Evaluation Guidance

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-26

... outcrop motion for which the soil layers above the foundation elevation have been removed. Updating the... performing soil-structure interaction analyses. Consistent with guidance described in DC/COL-ISG-017, ``Ensuring Hazard-Consistent Seismic Input for Site Response and Soil Structure Interaction Analyses,'' the...

76 FR 69292 - Aging Management of Stainless Steel Structures and Components in Treated Borated Water

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-08

... NUCLEAR REGULATORY COMMISSION [NRC-2011-0256] Aging Management of Stainless Steel Structures and... Stainless Steel Structures and Components in Treated Borated Water.'' This LR-ISG revises the guidance in...) and Generic Aging Lessons Learned (GALL) Report for the aging management of stainless steel structures...

76 FR 9381 - Notice of Availability of Interim Staff Guidance Documents for Spent Fuel Storage Casks

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-17

.... FOR FURTHER INFORMATION CONTACT: Matthew Gordon, Structural Mechanics and Materials Branch, Division... a fee. Comments and questions on ISG-23 should be directed to Matthew Gordon, Structural Mechanics..., 2011. For the U.S. Nuclear Regulatory Commission. Michele Sampson, Acting Chief, Structural Mechanics...

77 FR 64564 - Implementation of Regulatory Guide 1.221 on Design-Basis Hurricane and Hurricane Missiles

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-22

...-Basis Hurricane and Hurricane Missiles AGENCY: Nuclear Regulatory Commission. ACTION: Proposed interim...-ISG-024, ``Implementation of Regulatory Guide 1.221 on Design-Basis Hurricane and Hurricane Missiles....221, ``Design-Basis Hurricane and Hurricane Missiles for Nuclear Power Plants.'' DATES: Submit...

77 FR 55232 - Japan Lessons-Learned Project Directorate Interim Staff Guidance JLD-ISG-2012-03; Compliance With...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-07

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0067] Japan Lessons-Learned Project Directorate Interim...-Learned Project Directorate Interim Staff Guidance; issuance. SUMMARY: The U.S. Nuclear Regulatory Commission (NRC or the Commission) is issuing the Final Japan Lessons-Learned Project Directorate (JLD...

77 FR 55231 - Japan Lessons-Learned Project Directorate Interim Staff Guidance JLD-ISG-2012-02; Compliance With...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-07

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0069] Japan Lessons-Learned Project Directorate Interim...-Learned Project Directorate interim staff guidance; issuance. SUMMARY: The U.S. Nuclear Regulatory Commission (NRC or the Commission) is issuing the Final Japan Lessons-Learned Project Directorate Interim...

78 FR 40199 - Draft Spent Fuel Storage and Transportation Interim Staff Guidance

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-03

... NUCLEAR REGULATORY COMMISSION [NRC-2013-0140] Draft Spent Fuel Storage and Transportation Interim... Spent Fuel Storage and Transportation Interim Staff Guidance No. 24 (SFST-ISG-24), Revision 0, ``The Use of a Demonstration Program as Confirmation of Integrity for Continued Storage of High Burnup Fuel...

75 FR 45678 - Notice of Availability of Interim Staff Guidance Document for Fuel Cycle Facilities

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-03

... Document for Fuel Cycle Facilities AGENCY: Nuclear Regulatory Commission. ACTION: Notice of availability..., Division of Fuel Cycle Safety and Safeguards, Office of Nuclear Material Safety and Safeguards, U.S... Commission (NRC) prepares and issues Interim Staff Guidance (ISG) documents for fuel cycle facilities. These...

77 FR 74883 - Aging Management of Stainless Steel Structures and Components in Treated Borated Water; Revision 1

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-18

... NUCLEAR REGULATORY COMMISSION [NRC-2011-0256] Aging Management of Stainless Steel Structures and..., ``Aging Management of Stainless Steel Structures and Components in Treated Borated Water,'' which was... Staff Guidance LR-ISG-2011-01, ``Aging Management of Stainless Steel Structures and Components in...

Zika Virus Persistently Infects and Is Basolaterally Released from Primary Human Brain Microvascular Endothelial Cells.

PubMed

Mladinich, Megan C; Schwedes, John; Mackow, Erich R

2017-07-11

Zika virus (ZIKV) is a mosquito-borne Flavivirus that has emerged as the cause of encephalitis and fetal microencephaly in the Americas. ZIKV uniquely persists in human bodily fluids for up to 6 months, is sexually transmitted, and traverses the placenta and the blood-brain barrier (BBB) to damage neurons. Cells that support persistent ZIKV replication and mechanisms by which ZIKV establishes persistence remain enigmatic but central to ZIKV entry into protected neuronal compartments. The endothelial cell (EC) lining of capillaries normally constrains transplacental transmission and forms the BBB, which selectively restricts access of blood constituents to neurons. We found that ZIKV (strain PRVABC59) persistently infects and continuously replicates in primary human brain microvascular ECs (hBMECs), without cytopathology, for >9 days and following hBMEC passage. ZIKV did not permeabilize hBMECs but was released basolaterally from polarized hBMECs, suggesting a direct mechanism for ZIKV to cross the BBB. ZIKV-infected hBMECs were rapidly resistant to alpha interferon (IFN-α) and transiently induced, but failed to secrete, IFN-β and IFN-λ. Global transcriptome analysis determined that ZIKV constitutively induced IFN regulatory factor 7 (IRF7), IRF9, and IFN-stimulated genes (ISGs) 1 to 9 days postinfection, despite persistently replicating in hBMECs. ZIKV constitutively induced ISG15, HERC5, and USP18, which are linked to hepatitis C virus (HCV) persistence and IFN regulation, chemokine CCL5, which is associated with immunopathogenesis, as well as cell survival factors. Our results reveal that hBMECs act as a reservoir of persistent ZIKV replication, suggest routes for ZIKV to cross hBMECs into neuronal compartments, and define novel mechanisms of ZIKV persistence that can be targeted to restrict ZIKV spread. IMPORTANCE ZIKV persists in patients, crossing placental and neuronal barriers, damaging neurons, and causing fetal microencephaly. We found that ZIKV persistently infects brain endothelial cells that normally protect neurons from viral exposure. hBMECs are not damaged by ZIKV infection and, analogous to persistent HCV infection, ZIKV constitutively induces and evades antiviral ISG and IFN responses to continuously replicate in hBMECs. As a result, hBMECs provide a protective niche for systemic ZIKV spread and a viral reservoir localized in the normally protective blood-brain barrier. Consistent with the spread of ZIKV into neuronal compartments, ZIKV was released basolaterally from hBMECs. Our findings define hBMEC responses that contribute to persistent ZIKV infection and potential targets for clearing ZIKV infections from hBMECs. These results further suggest roles for additional ZIKV-infected ECs to facilitate viral spread and persistence in the protected placental, retinal, and testicular compartments. Copyright © 2017 Mladinich et al.

Innate Immune Responses in ALV-J Infected Chicks and Chickens with Hemangioma In Vivo.

PubMed

Feng, Min; Dai, Manman; Xie, Tingting; Li, Zhenhui; Shi, Meiqing; Zhang, Xiquan

2016-01-01

Avian leukosis virus subgroup J (ALV-J) infection can cause tumors and immunosuppression. Since the precise mechanism of the innate immune response induced by ALV-J is unknown, we investigated the antiviral innate immune responses induced by ALV-J in chicks and chickens that had developed tumors. Spleen levels of interleukin-6 (IL-6), IL-10, IL-1β, and interferon-β (IFN-β) were not significantly different between the infected chick groups and the control groups from 1 day post hatch to 7 days post hatch. However, IL-6, IL-1β, and IFN-β protein levels in the three clinical samples with hemangiomas were dramatically increased compared to the healthy samples. In addition, the anti-inflammatory cytokine IL-10 increased sharply in two of three clinical samples. We also found a more than 20-fold up-regulation of ISG12-1 mRNA at 1 day post infection (d.p.i.) and a twofold up-regulation of ZC3HAV1 mRNA at 4 d.p.i. However, there were no statistical differences in ISG12-1 and ZC3HAV1 mRNA expression levels in the tumorigenesis phase. ALV-J infection induced a significant increase of Toll-like receptor 7 (TLR-7) at 1 d.p.i. and dramatically increased the mRNA levels of melanoma differentiation-associated gene 5 (MDA5) in the tumorigenesis phase. Moreover, the protein levels of interferon regulatory factor 1 (IRF-1) and signal transducer and activator of transcription 1 (STAT1) were decreased in chickens with tumors. These results suggest that ALV-J was primarily recognized by chicken TLR7 and MDA5 at early and late in vivo infection stages, respectively. ALV-J strain SCAU-HN06 did not induce any significant antiviral innate immune response in 1 week old chicks. However, interferon-stimulated genes were not induced normally during the late phase of ALV-J infection due to a reduction of IRF1 and STAT1 expression.

78 FR 56750 - Interim Staff Guidance on Environmental Issues Associated With New Reactors

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-13

..., greenhouse gas and climate change, socioeconomics, environmental justice, need for power, alternatives..., Attachment 1--Staff Guidance for Greenhouse Gas and Climate Change Impacts. ML12326A895 ISG-026, Attachment 2... NRC regulatory approval in the form of licensing. Changes in internal staff guidance are not matters...

77 FR 60479 - Burnup Credit in the Criticality Safety Analyses of Pressurized Water Reactor Spent Fuel in...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-03

... Pressurized Water Reactor Spent Fuel in Transportation and Storage Casks AGENCY: Nuclear Regulatory Commission... 3, entitled, ``Burnup Credit in the Criticality Safety Analyses of PWR [Pressurized Water Reactor... water reactor spent nuclear fuel (SNF) in transportation packages and storage casks. SFST-ISG-8...

76 FR 17159 - Office of New Reactors; Final Interim Staff Guidance on Standard Review Plan, Section 17.4...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-28

... Interim Staff Guidance on Standard Review Plan, Section 17.4, ``Reliability Assurance Program'' AGENCY... design reliability assurance program (RAP). This ISG updates the guidance provided to the staff in Standard Review Plan (SRP), Section 17.4, ``Reliability Assurance Program,'' of NUREG-0800, ``Standard...

75 FR 13610 - Office of New Reactors; Interim Staff Guidance on Implementation of a Seismic Margin Analysis for...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-22

... Staff Guidance on Implementation of a Seismic Margin Analysis for New Reactors Based on Probabilistic... Seismic Margin Analysis for New Reactors Based on Probabilistic Risk Assessment,'' (Agencywide Documents.../COL-ISG-020 ``Implementation of a Seismic Margin Analysis for New Reactors Based on Probabilistic Risk...

78 FR 33120 - Final Interim Staff Guidance LR-ISG-2011-04; Updated Aging Management Criteria for Reactor Vessel...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-03

..., ``Generic Aging Lessons Learned Report'' (GALL Report), for the aging management of Pressurized Water... communicate insights and lessons learned and to address emergent issues not covered in license renewal... ensure that PWR license renewal applicants will adequately address age-related degradation and aging...

78 FR 49782 - Interim Staff Guidance on Changes During Construction

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-15

... seven comments on the Draft ISG from the Nuclear Energy Institute (NEI) (ADAMS Accession No. ML12089A019... construction impacts evaluation and the 10 CFR 50.59- like review (including applicability determination..., the construction impacts evaluation and the 10 CFR 50.59 and 10 CFR 50-59-like evaluation (including...

Surveillance Snapshot: Respiratory Infections Resulting in Hospitalization, U.S. Air Force Recruits, October 2009 - February 2017

DTIC Science & Technology

2017-05-01

simultaneously to the 502 ISG/JAC legal office and PAO for review to help reduce tum-around time. If you have any questions regarding legal reviews...oral penicillin to intramuscular bicillin (January 2012). Although causality should not be assumed, these interventions appear to be inversely

Interferon-λ: immune functions at barrier surfaces and beyond

PubMed Central

Lazear, Helen M.; Nice, Timothy J.; Diamond, Michael S.

2015-01-01

SUMMARY When type III interferon (IFN-λ; also known as interleukin-28 (IL-28) and IL-29) was discovered in 2003, its antiviral function was expected to be analogous to the type I IFNs (IFN-α and IFN-β), via the induction of IFN-stimulated genes (ISGs). While IFN-λ stimulates expression of antiviral ISGs preferentially in cells of epithelial origin, recent studies have defined additional antiviral mechanisms in other cell types and tissues. Models of viral infection using mice lacking IFN-λ signaling and single nucleotide polymorphism (SNP) associations with human disease have expanded our understanding of the contribution of IFN-λ to the antiviral response at anatomic barriers and the immune response beyond these barriers. In this review, we highlight recent insights into the functions of IFN-λ, including its ability to restrict virus spread into the brain and to clear chronic viral infections in the gastrointestinal tract. We also discuss how IFN-λ modulates innate and adaptive immunity, autoimmunity, and tumor progression and its possible therapeutic applications in human disease. PMID:26200010

TRIM79α, an interferon-stimulated gene product, restricts tick-borne encephalitis virus replication by degrading the viral RNA polymerase

PubMed Central

Taylor, R. Travis; Lubick, Kirk J.; Robertson, Shelly J.; Broughton, James P.; Bloom, Marshall E.; Bresnahan, Wade A.; Best, Sonja M.

2011-01-01

In response to virus infection, type I interferons (IFNs) induce several genes, most of whose functions are largely unknown. Here we show that the tripartite motif (TRIM) protein, TRIM79α, is an IFN-stimulated gene (ISG) product that specifically targets tick-borne encephalitis virus (TBEV), a Flavivirus that causes encephalitides in humans. TRIM79α restricts TBEV replication by mediating lysosome-dependent degradation of the flavivirus NS5 protein, an RNA-dependent RNA polymerase essential for virus replication. NS5 degradation was specific to tick-borne flaviviruses as TRIM79α did not recognize NS5 from West Nile virus (WNV) or inhibit WNV replication. In the absence of TRIM79α, IFN-β was less effective in inhibiting tick-borne flavivirus infection of mouse macrophages, highlighting the importance of a single virus-specific ISG in establishing an antiviral state. The specificity of TRIM79α for TBEV reveals a remarkable ability of the innate IFN response to discriminate between closely related flaviviruses. PMID:21925107

Genomic Circuitry Underlying Immunological Response to Pediatric Acute Respiratory Infection.

PubMed

Henrickson, Sarah E; Manne, Sasikanth; Dolfi, Douglas V; Mansfield, Kathleen D; Parkhouse, Kaela; Mistry, Rakesh D; Alpern, Elizabeth R; Hensley, Scott E; Sullivan, Kathleen E; Coffin, Susan E; Wherry, E John

2018-01-09

Acute respiratory tract viral infections (ARTIs) cause significant morbidity and mortality. CD8 T cells are fundamental to host responses, but transcriptional alterations underlying anti-viral mechanisms and links to clinical characteristics remain unclear. CD8 T cell transcriptional circuitry in acutely ill pediatric patients with influenza-like illness was distinct for different viral pathogens. Although changes included expected upregulation of interferon-stimulated genes (ISGs), transcriptional downregulation was prominent upon exposure to innate immune signals in early IFV infection. Network analysis linked changes to severity of infection, asthma, sex, and age. An influenza pediatric signature (IPS) distinguished acute influenza from other ARTIs and outperformed other influenza prediction gene lists. The IPS allowed a deeper investigation of the connection between transcriptional alterations and clinical characteristics of acute illness, including age-based differences in circuits connecting the STAT1/2 pathway to ISGs. A CD8 T cell-focused systems immunology approach in pediatrics identified age-based alterations in ARTI host response pathways. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Genome-wide expression profiling analysis to identify key genes in the anti-HIV mechanism of CD4+ and CD8+ T cells.

PubMed

Gao, Lijie; Wang, Yunqi; Li, Yi; Dong, Ya; Yang, Aimin; Zhang, Jie; Li, Fengying; Zhang, Rongqiang

2018-07-01

Comprehensive bioinformatics analyses were performed to explore the key biomarkers in response to HIV infection of CD4 + and CD8 + T cells. The numbers of CD4 + and CD8 + T cells of HIV infected individuals were analyzed and the GEO database (GSE6740) was screened for differentially expressed genes (DEGs) in HIV infected CD4 + and CD8 + T cells. Gene Ontology enrichment, KEGG pathway analyses, and protein-protein interaction (PPI) network were performed to identify the key pathway and core proteins in anti-HIV virus process of CD4 + and CD8 + T cells. Finally, we analyzed the expressions of key proteins in HIV-infected T cells (GSE6740 dataset) and peripheral blood mononuclear cells(PBMCs) (GSE511 dataset). 1) CD4 + T cells counts and ratio of CD4 + /CD8 + T cells decreased while CD8 + T cells counts increased in HIV positive individuals; 2) 517 DEGs were found in HIV infected CD4 + and CD8 + T cells at acute and chronic stage with the criterial of P-value <0.05 and fold change (FC) ≥2; 3) In acute HIV infection, type 1 interferon (IFN-1) pathway might played a critical role in response to HIV infection of T cells. The main biological processes of the DEGs were response to virus and defense response to virus. At chronic stage, ISG15 protein, in conjunction with IFN-1 pathway might play key roles in anti-HIV responses of CD4 + T cells; and 4) The expression of ISG15 increased in both T cells and PBMCs after HIV infection. Gene expression profile of CD4 + and CD8 + T cells changed significantly in HIV infection, in which ISG15 gene may play a central role in activating the natural antiviral process of immune cells. © 2018 Wiley Periodicals, Inc.

Bovine embryo induces an anti-inflammatory response in uterine epithelial cells and immune cells in vitro: possible involvement of interferon tau as an intermediator

PubMed Central

TALUKDER, Anup K.; YOUSEF, Mohamed S.; RASHID, Mohammad B.; AWAI, Kensuke; ACOSTA, Tomas J.; SHIMIZU, Takashi; OKUDA, Kiyoshi; SHIMADA, Masayuki; IMAKAWA, Kazuhiko; MIYAMOTO, Akio

2017-01-01

Recent observations suggest that the bovine uterus starts to react to the early embryo immediately after its arrival from the oviduct. The present study aimed to investigate the effect of the early developing embryo on the immune-related gene profile in bovine uterine epithelial cells (BUECs) in vitro, and to further examine the impact of conditioned media (CM), either from embryo-BUEC co-culture or embryo culture alone, on gene expression in peripheral blood mononuclear cells (PBMCs). First, BUECs were co-cultured with morulae (n = 10) for D5-D9 (D0 = IVF), and gene expression in BUECs was analyzed. Subsequently, PBMCs were cultured in CM from embryo-BUEC co-culture or D5-D9 embryo culture, and gene expression was evaluated. In BUECs, the embryo induced interferon (IFN)-stimulated genes (ISGs: ISG15, OAS1, and MX2), a key factor for IFN-signaling (STAT1), and type-1 IFN receptors (IFNAR1 and IFNAR2), with suppression of NFkB2, NFkBIA and pro-inflammatory cytokines (TNFA and IL1B). The embryo also stimulated PTGES and PGE2 secretion in BUECs. In PBMCs, both CM from embryo-BUEC co-culture and embryo culture alone induced ISGs, STAT1 and TGFB1, while suppressing TNFA and IL17. Similarly, interferon tau (IFNT) at 100 pg/ml suppressed NFkB2, TNFA and IL1B in BUECs, and also stimulated TGFB1 and suppressed TNFA in PBMCs. Our findings suggest that the bovine embryo, in the first four days in the uterus (D5-D9), starts to induce an anti-inflammatory response in epithelial cells and in immune cells. IFNT is likely to act as one of the intermediators for induction of the anti-inflammatory response in the bovine uterus. PMID:28603222

Transgene Expression and Host Cell Responses to Replication-Defective, Single-Cycle, and Replication-Competent Adenovirus Vectors.

PubMed

Crosby, Catherine M; Barry, Michael A

2017-02-18

Most adenovirus (Ad) vectors are E1 gene deleted replication defective (RD-Ad) vectors that deliver one transgene to the cell and all expression is based on that one gene. In contrast, E1-intact replication-competent Ad (RC-Ad) vectors replicate their DNA and their transgenes up to 10,000-fold, amplifying transgene expression markedly higher than RD-Ad vectors. While RC-Ad are more potent, they run the real risk of causing adenovirus infections in vector recipients and those that administer them. To gain the benefits of transgene amplification, but avoid the risk of Ad infections, we developed "single cycle" Ad (SC-Ad) vectors. SC-Ads amplify transgene expression and generated markedly stronger and more persistent immune responses than RD-Ad as expected. However, they also unexpectedly generated stronger immune responses than RC-Ad vectors. To explore the basis of this potency here, we compared gene expression and the cellular responses to infection to these vectors in vitro and in vivo. In vitro, in primary human lung epithelial cells, SC- and RC-Ad amplified their genomes more than 400-fold relative to RD-Ad with higher replication by SC-Ad. This replication translated into higher green fluorescent protein (GFP) expression for 48 h by SC- and RC-Ad than by RD-Ad. In vitro, in the absence of an immune system, RD-Ad expression became higher by 72 h coincident with cell death mediated by SC- and RC-Ad and release of transgene product from the dying cells. When the vectors were compared in human THP-1 Lucia- interferon-stimulated gene (ISG) cells, which are a human monocyte cell line that have been modified to quantify ISG activity, RC-Ad6 provoked significantly stronger ISG responses than RD- or SC-Ad. In mice, intravenous or intranasal injection produced up to 100-fold genome replication. Under these in vivo conditions in the presence of the immune system, luciferase expression by RC and SC-Ad was markedly higher than that by RD-Ad. In immunodeficient mice, SC-Ad drove stronger luciferase expression than RC- or RD-Ad. These data demonstrate better transgene expression by SC- and RC-Ad in vitro and in vivo than RD-Ad. This higher expression by the replicating vectors results in a peak of expression within 1 to 2 days followed by cell death of infected cells and release of transgene products. While SC- and RC-Ad expression were similar in mice and in Syrian hamsters, RC-Ad provoked much stronger ISG induction which may explain in part SC-Ad's ability to generate stronger and more persistent immune responses than RC-Ad in Ad permissive hamsters.

Tumoral immune-infiltrate (IF), PD-L1 expression and role of CD8/TIA-1 lymphocytes in localized osteosarcoma patients treated within protocol ISG-OS1.

PubMed

Palmerini, Emanuela; Agostinelli, Claudio; Picci, Piero; Pileri, Stefano; Marafioti, Teresa; Lollini, Pier-Luigi; Scotlandi, Katia; Longhi, Alessandra; Benassi, Maria Serena; Ferrari, Stefano

2017-12-19

We hypothesized that immune-infiltrates were associated with superior survival, and examined a primary osteosarcoma tissue microarrays (TMAs) to test this hypothesis. 129 patients (pts) with localized osteosarcoma treated within protocol ISG-OS1 were included in the study. Clinical characteristics, expression of CD8, CD3, FOXP3, CD20, CD68/CD163 (tumor associated macrophage, TAM), Tia-1 (cytotoxic T cell), CD303 (plasmacytoid dendritic cells: pDC), Arginase-1 (myeloid derived suppressor cells: MDSC), PD-1 on immune-cells (IC), and PD-L1 on tumoral cells (TC) and IC were analysed and correlated with outcome. Most of the cases presented tumor infiltrating lymphocytes (TILs) (CD3+ 90%; CD8+ 86%). Tia-1 was detected in 73% of the samples. PD-L1 expression was found in 14% patients in IC and 0% in TC; 22% showed PD-1 expression in IC.With a median follow-up of 8 years (range 1-13), the 5-year overall survival (5-year OS) was 74% (95% CI 64-85). Univariate analysis showed better 5-year OS for: a) pts with a good histologic response to neoadjuvant chemotherapy (p = 0.0001); b) pts with CD8/Tia1 tumoral infiltrates (p = 0.002); c) pts with normal alkaline phosphatas (sALP) (p = 0.04). After multivariate analysis, histologic response (p = 0.007) and CD8/Tia1 infiltration (p = 0.01) were independently correlated with survival. In the subset of pts with CD8+ infiltrate, worse (p 0.02) OS was observed for PD-L1(IC)+ cases. Our findings support the hypothesis that CD8/Tia1 infiltrate in tumor microenvironment at diagnosis confers superior survival for pts with localized osteosarcoma, while PD-L1 expression is associated with worse survival.

75 FR 53353 - Notice of Availability of Final Interim Staff Guidance Document No. 25 “Pressure and Helium...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-31

... Guidance Document No. 25 ``Pressure and Helium Leakage Testing of the Confinement Boundary of Spent Fuel...: The Division of Spent Fuel Storage and Transportation (SFST) of the Office of Nuclear Materials Safety... Helium Leakage Testing of the Confinement Boundary of Spent Fuel Dry Storage Systems.'' This ISG...

77 FR 33777 - Interim Staff Guidance JLD-ISG-2012-02; Compliance With Order EA-12-050, Order Modifying Licenses...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-07

... feet) in height that inundated the Fukushima Dai-ichi nuclear power plant site. The earthquake and... infrastructure and industry in the northeastern coastal areas of Japan. When the earthquake occurred, Fukushima... earthquake appears to have been normal. Following the events at the Fukushima Dai-ichi nuclear power plant...

77 FR 73057 - Japan Lessons-Learned Project Directorate Interim Staff Guidance JLD-ISG-2012-05; Performance of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-07

... height that inundated the Fukushima Dai-ichi nuclear power plant site. The earthquake and tsunami... industry in the northeastern coastal areas of Japan. When the earthquake occurred, Fukushima Dai-ichi Units... loss of cooling capabilities. Following the events at the Fukushima Dai-ichi nuclear power plant, the...

75 FR 5356 - Office of New Reactors; Final Interim Staff Guidance on Post-Combined License Commitments

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-02

... the guidance provided to the NRC staff in Section 1.0, ``Introduction and Interfaces,'' of NUREG-0800... (COL) applications. In addition, this ISG supplements the guidance provided in Section C.III.4 of... Accession No. ML091671355) to solicit public and industry comment. The NRC staff received comments (ADAMS...

77 FR 14446 - Changes to the Generic Aging Lessons Learned (GALL) Report Revision 2 AMP XI.M41, “Buried and...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-09

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0055] Changes to the Generic Aging Lessons Learned (GALL... Aging Lessons Learned (GALL) Report,'' and the NRC staff's aging management review procedure and... into ADAMS. II. Background The NRC issues LR-ISGs to communicate insights and lessons learned and to...

78 FR 19148 - Shielding and Radiation Protection Review Effort and Licensing Conditions for Dry Storage...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-29

... learned and to address emergent issues not covered in SFST Standard Review Plans (SRPs). In this way, the... a formal SRP revision. The NRC has developed draft SFST-ISG-26A, Revision 0 to (1) enhance the... implementation of such guidance in the context of applications does not result in backfitting or non-compliance...

Protein ISG15 Modification in the Development and the Treatment of Chronic Myeloid Leukemia

DTIC Science & Technology

2007-06-01

lysosomal path- way, dephosphorylation of JAKs and the receptor by SHP-1 and SHP-2, dephosphorylation of STATs by TC45 and PTP1B , inhibition of STAT1...like other known negative regulators of signal transduction, such as phosphatases (SHP-1, SHP-2, TC45, and PTP1B ), SOCS and PIAS proteins, Ubp43

76 FR 63676 - Final Division of Safety Systems Interim Staff Guidance DSS-ISG-2010-01: Staff Guidance Regarding...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-13

... learned based on recent submittals. FOR FURTHER INFORMATION CONTACT: Mr. Kent Wood, Division of Safety...-0001; telephone: 301-415-4120; or e- mail: [email protected] . ADDRESSES: You can access publicly... are available online in the NRC Library at http://www.nrc.gov/reading-rm/adams.html . From this page...

77 FR 46127 - Interim Staff Guidance on Changes to the Generic Aging Lessons Learned (GALL) Report Revision 2...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-02

... Aging Lessons Learned (GALL) Report Revision 2 AMP XI.M41, ``Buried and Underground Piping and Tanks... AMPs in NUREG-1801, Revision 2, ``Generic Aging Lessons Learned (GALL) Report,'' and the NRC staff's... issues LR-ISG to communicate insights and lessons learned and to address emergent issues not covered in...

78 FR 48201 - Japan Lessons-Learned Project Directorate Interim Staff Guidance JLD-ISG-2013-01; Guidance for...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-07

... following the earthquake and shutdown of the operating units, however, the first large tsunami wave inundated the site, followed by additional waves. The tsunami caused extensive damage to site facilities and..., and after some period of time at the other units. Unit 6 retained the function of one air-cooled EDG...

78 FR 3039 - Japan Lessons-Learned Project Directorate Interim Staff Guidance JLD-ISG-2012-06; Performing a...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-15

... following the earthquake and shutdown of the operating units, however, the first large tsunami wave inundated the site, followed by additional waves. The tsunami caused extensive damage to site facilities and..., and after some period of time at the other units. Unit 6 retained the function of one air-cooled EDG...

MicroRNA Profiling of Sendai Virus-Infected A549 Cells Identifies miR-203 as an Interferon-Inducible Regulator of IFIT1/ISG56

PubMed Central

Buggele, William A.

2013-01-01

The mammalian type I interferon (IFN) response is a primary barrier for virus infection and is essential for complete innate and adaptive immunity. Both IFN production and IFN-mediated antiviral signaling are the result of differential cellular gene expression, a process that is tightly controlled at transcriptional and translational levels. To determine the potential for microRNA (miRNA)-mediated regulation of the antiviral response, small-RNA profiling was used to analyze the miRNA content of human A549 cells at steady state and following infection with the Cantell strain of Sendai virus, a potent inducer of IFN and cellular antiviral responses. While the miRNA content of the cells was largely unaltered by infection, specific changes in miRNA abundance were identified during Sendai virus infection. One miRNA, miR-203, was found to accumulate in infected cells and in response to IFN treatment. Results indicate that miR-203 is an IFN-inducible miRNA that can negatively regulate a number of cellular mRNAs, including an IFN-stimulated gene target, IFIT1/ISG56, by destabilizing its mRNA transcript. PMID:23785202

Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11

PubMed Central

Li, Manqing; Kao, Elaine; Gao, Xia; Sandig, Hilary; Limmer, Kirsten; Pavon-Eternod, Mariana; Jones, Thomas E.; Landry, Sebastien; Pan, Tao; Weitzman, Matthew D.; David, Michael

2013-01-01

In mammals, one of the most pronounced consequences of viral infection is the induction of type I interferons, cytokines with potent antiviral activity. Schlafen (Slfn) genes are a subset of interferon-stimulated early response genes (ISGs) that are also induced directly by pathogens via the interferon regulatory factor 3 (IRF3) pathway1. However, many ISGs are of unknown or incompletely understood function. Here we show that human SLFN11 potently and specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1). Our study revealed that SLFN11 has no effect on the early steps of the retroviral infection cycle, including reverse transcription, integration and transcription. Rather, SLFN11 acts at the late stage of virus production by selectively inhibiting the expression of viral proteins in a codon-usage-dependent manner. We further find that SLFN11 binds transfer RNA, and counteracts changes in the tRNA pool elicited by the presence of HIV. Our studies identified a novel antiviral mechanism within the innate immune response, in which SLFN11 selectively inhibits viral protein synthesis in HIV-infected cells by means of codon-bias discrimination. PMID:23000900

Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11.

PubMed

Li, Manqing; Kao, Elaine; Gao, Xia; Sandig, Hilary; Limmer, Kirsten; Pavon-Eternod, Mariana; Jones, Thomas E; Landry, Sebastien; Pan, Tao; Weitzman, Matthew D; David, Michael

2012-11-01

In mammals, one of the most pronounced consequences of viral infection is the induction of type I interferons, cytokines with potent antiviral activity. Schlafen (Slfn) genes are a subset of interferon-stimulated early response genes (ISGs) that are also induced directly by pathogens via the interferon regulatory factor 3 (IRF3) pathway. However, many ISGs are of unknown or incompletely understood function. Here we show that human SLFN11 potently and specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1). Our study revealed that SLFN11 has no effect on the early steps of the retroviral infection cycle, including reverse transcription, integration and transcription. Rather, SLFN11 acts at the late stage of virus production by selectively inhibiting the expression of viral proteins in a codon-usage-dependent manner. We further find that SLFN11 binds transfer RNA, and counteracts changes in the tRNA pool elicited by the presence of HIV. Our studies identified a novel antiviral mechanism within the innate immune response, in which SLFN11 selectively inhibits viral protein synthesis in HIV-infected cells by means of codon-bias discrimination.

Inherent dynamics within the Crimean-Congo Hemorrhagic fever virus protease are localized to the same region as substrate interactions

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

Eisenmesser, Elan Z.; Capodagli, Glenn; Armstrong, Geoffrey S.

Crimean-Congo Hemorrhagic fever virus (CCHFV) is one of several lethal viruses that encodes for a viral ovarian tumor domain (vOTU), which serves to cleave and remove multiple proteins involved in cellular signaling such as ubiquitin (Ub) and interferon stimulated gene produce 15 (ISG15). Such manipulation of the host cell machinery serves to downregulate the host response and, therefore, complete characterization of these proteases is important. While several structures of the CCHFV vOTU protease have been solved, both free and bound to Ub and ISG15, few structural differences have been found and little insight has been gained as to the dynamicmore » plasticity of this protease. Therefore, we have used NMR relaxation experiments to probe the dynamics of CCHV vOTU, both alone and in complex with Ub, thereby discovering a highly dynamic protease that exhibits conformational exchange within the same regions found to engage its Ub substrate. These experiments reveal a structural plasticity around the N-terminal regions of CCHV vOTU, which are unique to vOTUs, and provide a rationale for engaging multiple substrates with the same binding site.« less

TRIM56 Is an Essential Component of the TLR3 Antiviral Signaling Pathway*

PubMed Central

Shen, Yang; Li, Nan L.; Wang, Jie; Liu, Baoming; Lester, Sandra; Li, Kui

2012-01-01

Members of the tripartite motif (TRIM) proteins are being recognized as important regulators of host innate immunity. However, specific TRIMs that contribute to TLR3-mediated antiviral defense have not been identified. We show here that TRIM56 is a positive regulator of TLR3 signaling. Overexpression of TRIM56 substantially potentiated extracellular dsRNA-induced expression of interferon (IFN)-β and interferon-stimulated genes (ISGs), while knockdown of TRIM56 greatly impaired activation of IRF3, induction of IFN-β and ISGs, and establishment of an antiviral state by TLR3 ligand and severely compromised TLR3-mediated chemokine induction following infection by hepatitis C virus. The ability to promote TLR3 signaling was independent of the E3 ubiquitin ligase activity of TRIM56. Rather, it correlated with a physical interaction between TRIM56 and TRIF. Deletion of the C-terminal portion of TRIM56 abrogated the TRIM56-TRIF interaction as well as the augmentation of TLR3-mediated IFN response. Together, our data demonstrate TRIM56 is an essential component of the TLR3 antiviral signaling pathway and reveal a novel role for TRIM56 in innate antiviral immunity. PMID:22948160

Vaccination with UV-inactivated nodavirus partly protects European sea bass against infection, while inducing few changes in immunity.

PubMed

Valero, Yulema; Mokrani, Djamal; Chaves-Pozo, Elena; Arizcun, Marta; Oumouna, Mustapha; Meseguer, José; Esteban, M Ángeles; Cuesta, Alberto

2018-05-15

Developing viral vaccines through the ultraviolet (UV) inactivation of virus is promising technique since it is straightforward and economically affordable, while the resulting viruses are capable of eliciting an adequate antiviral immune response. Nodavirus (NNV) is a devastating virus that mainly affects European sea bass juveniles and larvae, causing serious economic losses in Mediterranean aquaculture. In this work, a potential vaccine consisting on UV-inactivated NNV (iNNV) was generated and administered to healthy juveniles of European sea bass to elucidate whether it triggers the immune response and improves their survival upon challenge. First, iNNV failed to replicate in cell cultures and its intraperitoneal administration to sea bass juveniles also failed to produce fish mortality and induction of the type I interferon (IFN) pathway, indicating that the NNV was efficiently inactivated. By contrast, iNNV administration induced significant serum non-specific antimicrobial activity as well as a specific antiviral activity and immunoglobulin M (IgM) titres against NNV. Interestingly, few changes were observed at transcriptional level in genes related to either innate or adaptive immunity, suggesting that iNNV could be modulating the immune response at protein or functional level. In addition, the iNNV vaccinated group showed improved survival, reaching a relative survival percentage of 57.9%. Moreover, challenged fish that had been vaccinated presented increased serum antibacterial, antiviral and IgM titres, as well as the higher transcription of mhc1a, ifn, isg15 and cd8a genes in brain, while in the head-kidney the transcription of mhc1a, mhc2b and cd8a was down-regulated and mx, isg15 and tcrb was up-regulated. Although the UV-inactivated vaccine against NNV showed promising results, more effort should be addressed to improving this prophylactic method by increasing our understanding of its action mechanisms, thus enabling the mortality rate of NNV to be further reduced. Copyright © 2018 Elsevier Ltd. All rights reserved.

Infectious haematopoietic necrosis virus genogroup-specific virulence mechanisms in sockeye salmon, Oncorhynchus nerka (Walbaum), from Redfish Lake, Idaho

USGS Publications Warehouse

Purcell, M.K.; Garver, K.A.; Conway, C.; Elliott, D.G.; Kurath, G.

2009-01-01

Characterization of infectious haematopoietic necrosis virus (IHNV) field isolates from North America has established three main genogroups (U, M and L) that differ in host-specific virulence. In sockeye salmon, Oncorhynchus nerka, the U genogroup is highly virulent, whereas the M genogroup is nearly non-pathogenic. In this study, we sought to characterize the virus-host dynamics that contribute to genogroup-specific virulence in a captive stock of sockeye salmon from Redfish Lake in Idaho. Juvenile sockeye salmon were challenged by immersion and injection with either a representative U or M viral strain and sampled periodically until 14 days post-infection (p.i.). Fish challenged with each strain had positive viral titre by day 3, regardless of challenge route, but the fish exposed to the M genogroup virus had significantly lower virus titres than fish exposed to the U genogroup virus. Gene expression analysis by quantitative reverse transcriptase PCR was used to simultaneously assess viral load and host interferon (IFN) response in the anterior kidney. Viral load was significantly higher in the U-challenged fish relative to M-challenged fish. Both viruses induced expression of the IFN-stimulated genes (ISGs), but expression was usually significantly lower in the M-challenged group, particularly at later time points (7 and 14 days p.i.). However, ISG expression was comparable with 3 days post-immersion challenge despite a significant difference in viral load. Our data indicated that the M genogroup virus entered the host, replicated and spread in the sockeye salmon tissues, but to a lesser extent than the U genogroup. Both virus types induced a host IFN response, but the high virulence strain (U) continued to replicate in the presence of this response, whereas the low virulence strain (M) was cleared below detectable levels. We hypothesize that high virulence is associated with early in vivo replication allowing the virus to achieve a threshold level, which the host innate immune system cannot control. ?? 2009 Blackwell Publishing Ltd.

Infectious haematopoietic necrosis virus genogroup-specific virulence mechanisms in sockeye salmon, Oncorhynchus nerka (Walbaum), from Redfish Lake, Idaho.

PubMed

Purcell, M K; Garver, K A; Conway, C; Elliott, D G; Kurath, G

2009-07-01

Characterization of infectious haematopoietic necrosis virus (IHNV) field isolates from North America has established three main genogroups (U, M and L) that differ in host-specific virulence. In sockeye salmon, Oncorhynchus nerka, the U genogroup is highly virulent, whereas the M genogroup is nearly non-pathogenic. In this study, we sought to characterize the virus-host dynamics that contribute to genogroup-specific virulence in a captive stock of sockeye salmon from Redfish Lake in Idaho. Juvenile sockeye salmon were challenged by immersion and injection with either a representative U or M viral strain and sampled periodically until 14 days post-infection (p.i.). Fish challenged with each strain had positive viral titre by day 3, regardless of challenge route, but the fish exposed to the M genogroup virus had significantly lower virus titres than fish exposed to the U genogroup virus. Gene expression analysis by quantitative reverse transcriptase PCR was used to simultaneously assess viral load and host interferon (IFN) response in the anterior kidney. Viral load was significantly higher in the U-challenged fish relative to M-challenged fish. Both viruses induced expression of the IFN-stimulated genes (ISGs), but expression was usually significantly lower in the M-challenged group, particularly at later time points (7 and 14 days p.i.). However, ISG expression was comparable with 3 days post-immersion challenge despite a significant difference in viral load. Our data indicated that the M genogroup virus entered the host, replicated and spread in the sockeye salmon tissues, but to a lesser extent than the U genogroup. Both virus types induced a host IFN response, but the high virulence strain (U) continued to replicate in the presence of this response, whereas the low virulence strain (M) was cleared below detectable levels. We hypothesize that high virulence is associated with early in vivo replication allowing the virus to achieve a threshold level, which the host innate immune system cannot control.

77 FR 33780 - Interim Staff Guidance JLD-ISG-2012-03; Compliance with Order EA-12-051, Order Modifying Licenses...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-07

... Fukushima Dai-ichi nuclear power plant in March 2011. Order EA-12-051 requires all licensees and... complying with Order EA-12-051. Following the events at the Fukushima Dai-ichi nuclear power plant, the NRC... agency should make additional improvements to these programs in light of the events at Fukushima Dai-ichi...

77 FR 33779 - Interim Staff Guidance JLD-ISG-2012-01; Compliance With Order EA-12-049, Order Modifying Licenses...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-07

..., estimated to have exceeded 14 meters (45 feet) in height that inundated the Fukushima Dai-ichi nuclear power... earthquake occurred, Fukushima Dai-ichi Units 1, 2, and 3, were in operation and Units 4, 5, and 6, were shut... facility response to the earthquake appears to have been normal. Following the events at the Fukushima Dai...

Image Understanding Research

DTIC Science & Technology

1983-10-19

knowledge -based symbolic reasoning, it nonetheless remains de- pendent on the lower levels of iconic processing for its raw information . Both sorts of...priori knowledge of where any particular line might go, and therefore no information regarding the extent of memory access required for the local...IC FILE COPY ,. c 4/t/7 ISG Report 104 IMAGE UNDERSTANDING RESEARCH Final Technical Report Covering Research Activity During the Period October 1

Identification of orange-spotted grouper (Epinephelus coioides) interferon regulatory factor 3 involved in antiviral immune response against fish RNA virus.

PubMed

Huang, Youhua; Huang, Xiaohong; Cai, Jia; OuYang, Zhengliang; Wei, Shina; Wei, Jingguang; Qin, Qiwei

2015-02-01

Interferon regulatory factor 3 (IRF3) is an important transcription factor which regulates the expression of interferon (IFN) and IFN-stimulated genes (ISGs) following virus recognition. In this study, a novel IRF3 gene was cloned from grouper Epinephelus coioides (EcIRF3) and its effects against Singapore grouper iridovirus (SGIV) and red spotted grouper nervous necrosis virus (RGNNV) was investigated. The full-length of EcIRF3 cDNA was composed of 2513 bp and encoded a polypeptide of 458 amino acids which shared 82% identity with European seabass (Dicentrarchus labrax). EcIRF3 contained three conserved domains including a DNA-binding domain (DBD), an IRF associated domain (IAD) and a serine-rich domain. Expression profile analysis revealed that EcIRF3 was abundant in head kidney, kidney, spleen and gill. Upon different stimuli in vitro, the transcript of EcIRF3 was significantly up-regulated after RGNNV infection or treatment with polyinosin-polycytidylic acid (poly I:C). During SGIV infection, the increase of the EcIRF3 transcription was only detected at the late stage, suggesting that EcIRF3 was differently regulated by different stimuli. Immune fluorescence assay indicated that the fluorescence signal of EcIRF3 was increased significantly after infection with RGNNV or treatment with poly I:C, but moderately at the late stage of SGIV infection. Reporter gene assay showed that EcIRF3 activated zebrafish type I IFN and type III IFN promoter in vitro. The viral gene transcription and virus production of RGNNV were significantly decreased in EcIRF3 overexpressing cells. However, the ectopic expression of EcIRF3 did not affect the gene transcription and virus production of SGIV. Moreover, the mRNA expression levels of type I IFN and IFN-inducible genes (MxI, ISG15 and ISG56) were increased in RGNNV infected EcIRF3 overexpressing cells compared to empty vector transfected cells. Together, our results demonstrated that IFN immune response mediated by grouper IRF3 was exerted crucial roles for fish RNA virus, but not for DNA virus replication. Copyright © 2014 Elsevier Ltd. All rights reserved.

Distinct temporal roles for the promyelocytic leukaemia (PML) protein in the sequential regulation of intracellular host immunity to HSV-1 infection

PubMed Central

Alandijany, Thamir; Conn, Kristen L.; McFarlane, Steven; Orr, Anne

2018-01-01

Detection of viral nucleic acids plays a critical role in the induction of intracellular host immune defences. However, the temporal recruitment of immune regulators to infecting viral genomes remains poorly defined due to the technical difficulties associated with low genome copy-number detection. Here we utilize 5-Ethynyl-2’-deoxyuridine (EdU) labelling of herpes simplex virus 1 (HSV-1) DNA in combination with click chemistry to examine the sequential recruitment of host immune regulators to infecting viral genomes under low multiplicity of infection conditions. Following viral genome entry into the nucleus, PML-nuclear bodies (PML-NBs) rapidly entrapped viral DNA (vDNA) leading to a block in viral replication in the absence of the viral PML-NB antagonist ICP0. This pre-existing intrinsic host defence to infection occurred independently of the vDNA pathogen sensor IFI16 (Interferon Gamma Inducible Protein 16) and the induction of interferon stimulated gene (ISG) expression, demonstrating that vDNA entry into the nucleus alone is not sufficient to induce a robust innate immune response. Saturation of this pre-existing intrinsic host defence during HSV-1 ICP0-null mutant infection led to the stable recruitment of PML and IFI16 into vDNA complexes associated with ICP4, and led to the induction of ISG expression. This induced innate immune response occurred in a PML-, IFI16-, and Janus-Associated Kinase (JAK)-dependent manner and was restricted by phosphonoacetic acid, demonstrating that vDNA polymerase activity is required for the robust induction of ISG expression during HSV-1 infection. Our data identifies dual roles for PML in the sequential regulation of intrinsic and innate immunity to HSV-1 infection that are dependent on viral genome delivery to the nucleus and the onset of vDNA replication, respectively. These intracellular host defences are counteracted by ICP0, which targets PML for degradation from the outset of nuclear infection to promote vDNA release from PML-NBs and the onset of HSV-1 lytic replication. PMID:29309427

Interferon-Inducible Oligoadenylate Synthetase-Like Protein Acts as an Antiviral Effector against Classical Swine Fever Virus via the MDA5-Mediated Type I Interferon-Signaling Pathway.

PubMed

Li, Lian-Feng; Yu, Jiahui; Zhang, Yuexiu; Yang, Qian; Li, Yongfeng; Zhang, Lingkai; Wang, Jinghan; Li, Su; Luo, Yuzi; Sun, Yuan; Qiu, Hua-Ji

2017-06-01

Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), which poses a serious threat to the global pig industry. Interferons (IFNs) and IFN-stimulated genes (ISGs) play a key role in host antiviral defense. We have previously screened the porcine 2'-5'-oligoadenylate synthetase-like protein (pOASL) as a potential anti-CSFV ISG using a reporter CSFV. This study aimed to clarify the underlying antiviral mechanism of pOASL against CSFV. We confirmed that CSFV replication was significantly suppressed in lentivirus-delivered, pOASL-overexpressing PK-15 cells, whereas silencing the expression of endogenous pOASL by small interfering RNAs markedly enhanced CSFV growth. In addition, the transcriptional level of pOASL was upregulated both in vitro and in vivo upon CSFV infection. Interestingly, the anti-CSFV effects of pOASL are independent of the canonical RNase L pathway but depend on the activation of the type I IFN response. Glutathione S -transferase pulldown and coimmunoprecipitation assays revealed that pOASL interacts with MDA5, a double-stranded RNA sensor, and further enhances MDA5-mediated type I IFN signaling. Moreover, we showed that pOASL exerts anti-CSFV effects in an MDA5-dependent manner. In conclusion, pOASL suppresses CSFV replication via the MDA5-mediated type I IFN-signaling pathway. IMPORTANCE The host innate immune response plays an important role in mounting the initial resistance to viral infection. Here, we identify the porcine 2'-5'-oligoadenylate synthetase-like protein (pOASL) as an interferon (IFN)-stimulated gene (ISG) against classical swine fever virus (CSFV). We demonstrate that the anti-CSFV effects of pOASL depend on the activation of type I IFN response. In addition, we show that pOASL, as an MDA5-interacting protein, is a coactivator of MDA5-mediated IFN induction to exert anti-CSFV actions. This work will be beneficial to the development of novel anti-CSFV strategies by targeting pOASL. Copyright © 2017 Li et al.

Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication.

PubMed

Sun, Xiaoming; Hua, Stephane; Chen, Hsiao-Rong; Ouyang, Zhengyu; Einkauf, Kevin; Tse, Samantha; Ard, Kevin; Ciaranello, Andrea; Yawetz, Sigal; Sax, Paul; Rosenberg, Eric S; Lichterfeld, Mathias; Yu, Xu G

2017-12-19

Although dendritic cells are among the human cell population best equipped for cell-intrinsic antiviral immune defense, they seem highly susceptible to infection with the Zika virus (ZIKV). Using highly purified myeloid dendritic cells isolated from individuals with naturally acquired acute infection, we here show that ZIKV induces profound perturbations of transcriptional signatures relative to healthy donors. Interestingly, we noted a remarkable downregulation of antiviral interferon-stimulated genes and innate immune sensors, suggesting that ZIKV can actively suppress interferon-dependent immune responses. In contrast, several host factors known to support ZIKV infection were strongly upregulated during natural ZIKV infection; these transcripts included AXL, the main entry receptor for ZIKV; SOCS3, a negative regulator of ISG expression; and IDO-1, a recognized inducer of regulatory T cell responses. Thus, during in vivo infection, ZIKV can transform the transcriptome of dendritic cells in favor of the virus to render these cells highly conducive to ZIKV infection. Published by Elsevier Inc.

Prolonged activation of innate antiviral gene signature after childbirth is determined by IFNL3 genotype.

PubMed

Price, Aryn A; Tedesco, Dana; Prasad, Mona R; Workowski, Kimberly A; Walker, Christopher M; Suthar, Mehul S; Honegger, Jonathan R; Grakoui, Arash

2016-09-20

Maternal innate and adaptive immune responses are modulated during pregnancy to concurrently defend against infection and tolerate the semiallogeneic fetus. The restoration of these systems after childbirth is poorly understood. We reasoned that enhanced innate immune activation may extend beyond gestation while adaptive immunity recovers. To test this hypothesis, the transcriptional profiles of total peripheral blood mononuclear cells following delivery in healthy women were compared with those of nonpregnant control subjects. Interestingly, interferon-stimulated genes (ISGs) encoding proteins such as IFIT1, IFIT2, and IFIT3, as well as signaling proteins such as STAT1, STAT2, and MAVS, were enriched postpartum. Antiviral genes were primarily expressed in CD14(+) cells and could be stratified according to genetic variation at the interferon-λ3 gene (IFNL3, also named IL28B) SNP rs12979860. Antiviral gene expression was sustained beyond 6 mo following delivery in mothers with a CT or TT genotype, but resembled baseline nonpregnant control levels following delivery in mothers with a CC genotype. CT and TT IFNL3 genotypes have been associated with persistent elevated ISG expression in individuals chronically infected with hepatitis C virus. Together, these data suggest that postpartum, the normalization of the physiological rheostat controlling IFN signaling depends on IFNL3 genotype.

Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease.

PubMed

Békés, Miklós; van der Heden van Noort, Gerbrand J; Ekkebus, Reggy; Ovaa, Huib; Huang, Tony T; Lima, Christopher D

2016-05-19

Deubiquitinating enzymes (DUBs) recognize and cleave linkage-specific polyubiquitin (polyUb) chains, but mechanisms underlying specificity remain elusive in many cases. The severe acute respiratory syndrome (SARS) coronavirus papain-like protease (PLpro) is a DUB that cleaves ISG15, a two-domain Ub-like protein, and Lys48-linked polyUb chains, releasing diUb(Lys48) products. To elucidate this specificity, we report the 2.85 Å crystal structure of SARS PLpro bound to a diUb(Lys48) activity-based probe. SARS PLpro binds diUb(Lys48) in an extended conformation via two contact sites, S1 and S2, which are proximal and distal to the active site, respectively. We show that specificity for polyUb(Lys48) chains is predicated on contacts in the S2 site and enhanced by an S1-S1' preference for a Lys48 linkage across the active site. In contrast, ISG15 specificity is dominated by contacts in the S1 site. Determinants revealed for polyUb(Lys48) specificity should prove useful in understanding PLpro deubiquitinating activities in coronavirus infections. Copyright © 2016 Elsevier Inc. All rights reserved.

Theory of in-plane current induced spin torque in metal/ferromagnet bilayers

NASA Astrophysics Data System (ADS)

Sakanashi, Kohei; Sigrist, Manfred; Chen, Wei

2018-05-01

Using a semiclassical approach that simultaneously incorporates the spin Hall effect (SHE), spin diffusion, quantum well states, and interface spin–orbit coupling (SOC), we address the interplay of these mechanisms as the origin of the spin–orbit torque (SOT) induced by in-plane currents, as observed in the normal metal/ferromagnetic metal bilayer thin films. Focusing on the bilayers with a ferromagnet much thinner than its spin diffusion length, such as Pt/Co with  ∼10 nm thickness, our approach addresses simultaneously the two contributions to the SOT, namely the spin-transfer torque (SHE-STT) due to SHE-induced spin injection, and the inverse spin Galvanic effect spin–orbit torque (ISGE-SOT) due to SOC-induced spin accumulation. The SOC produces an effective magnetic field at the interface, hence it modifies the angular momentum conservation expected for the SHE-STT. The SHE-induced spin voltage and the interface spin current are mutually dependent and, hence, are solved in a self-consistent manner. The result suggests that the SHE-STT and ISGE-SOT are of the same order of magnitude, and the spin transport mediated by the quantum well states may be an important mechanism for the experimentally observed rapid variation of the SOT with respect to the thickness of the ferromagnet.

Peromyscus leucopus mouse brain transcriptome response to Powassan virus infection.

PubMed

Mlera, Luwanika; Meade-White, Kimberly; Dahlstrom, Eric; Baur, Rachel; Kanakabandi, Kishore; Virtaneva, Kimmo; Porcella, Stephen F; Bloom, Marshall E

2018-02-01

Powassan virus (POWV) is a tick-borne Flavivirus responsible for life-threatening encephalitis in North America and some regions of Russia. The ticks that have been reported to transmit the virus belong to the Ixodes species, and they feed on small-to-medium-sized mammals, such as Peromyscus leucopus mice, skunks, and woodchucks. We previously developed a P. leucopus mouse model of POWV infection, and the model is characterized by a lack of clinical signs of disease following intraperitoneal or intracranial inoculation. However, intracranial inoculation results in mild subclinical encephalitis from 5 days post infection (dpi), but the encephalitis resolves by 28 dpi. We used RNA sequencing to profile the P. leucopus mouse brain transcriptome at different time points after intracranial challenge with POWV. At 24 h post infection, 42 genes were significantly differentially expressed and the number peaked to 232 at 7 dpi before declining to 31 at 28 dpi. Using Ingenuity Pathway Analysis, we determined that the genes that were significantly expressed from 1 to 15 dpi were mainly associated with interferon signaling. As a result, many interferon-stimulated genes (ISGs) were upregulated. Some of the ISGs include an array of TRIMs (genes encoding tripartite motif proteins). These results will be useful for the identification of POWV restriction factors.

Type I Interferon Responses by HIV-1 Infection: Association with Disease Progression and Control.

PubMed

Soper, Andrew; Kimura, Izumi; Nagaoka, Shumpei; Konno, Yoriyuki; Yamamoto, Keisuke; Koyanagi, Yoshio; Sato, Kei

2017-01-01

Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome and its infection leads to the onset of several disorders such as the depletion of peripheral CD4 + T cells and immune activation. HIV-1 is recognized by innate immune sensors that then trigger the production of type I interferons (IFN-Is). IFN-Is are well-known cytokines eliciting broad anti-viral effects by inducing the expression of anti-viral genes called interferon-stimulated genes (ISGs). Extensive in vitro studies using cell culture systems have elucidated that certain ISGs such as APOBEC3G, tetherin, SAM domain and HD domain-containing protein 1, MX dynamin-like GTPase 2, guanylate-binding protein 5, and schlafen 11 exert robust anti-HIV-1 activity, suggesting that IFN-I responses triggered by HIV-1 infection are detrimental for viral replication and spread. However, recent studies using animal models have demonstrated that at both the acute and chronic phase of infection, the role of IFN-Is produced by HIV or SIV infection in viral replication, spread, and pathogenesis, may not be that straightforward. In this review, we describe the pluses and minuses of HIV-1 infection stimulated IFN-I responses on viral replication and pathogenesis, and further discuss the possibility for therapeutic approaches.

Allergic Bronchopulmonary Mycosis Caused by Cladosporidium

DTIC Science & Technology

2017-05-23

request form to clinical investigations, S02 ISG/JAC ( Ethics Review) and Public Affairs (S9 MOW/PA) for review and then forward you a final letter of...Presentation and Publication of Medical and Technical Papers. for additional information. 11 . The Joint Ethics Regulation (JER) DoD SS00.07-R...Standards of Conduct, provides standards of ethical conduct for all OoO personnel and their interactions with other non-DoD entities, organizations

Author Correction: New activities for old antibiotics.

PubMed

Cohen, Jeffrey I

2018-06-19

In the version of this News and Views originally published, the author made an incorrect reference to 'mice deficient in Mx1'. This has now been corrected so that the text instead refers to 'mice congenic for Mx1'. The full corrected sentence reads as "Pretreatment of mice congenic for Mx1, an ISG that is critical for protection of animals from influenza, with intranasal neomycin significantly improved survival; however, about 50% of the mice died."

Microphysics of Air-Sea Exchanges

DTIC Science & Technology

2003-09-30

intensities of the three color components at each point of the image . The ISG imaged an area of the water surface of up to 45 cm (downwind) x 30 cm...notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not...satellite-derived sea-surface temperature (SST) fields into meaningful climatologies and to more physically-based applications of satellite data to studies

Seismic Monitoring at the Decatur, IL, Geologic Carbon Dioxide Sequestration Site

NASA Astrophysics Data System (ADS)

Hickman, S. H.; Kaven, J. O.; McGarr, A.; Walter, S. R.; Ellsworth, W. L.; Svitek, J. F.; Burke, L. A.

2014-12-01

The viability of carbon capture and storage (CCS) depends on safely sequestering large quantities of carbon dioxide over geologic time scales. One concern is the potential for induced seismicity. We report on seismic monitoring by the U.S. Geological Survey (USGS) at a CCS demonstration site in Decatur, IL. This is the first (and to date only) CCS project in the U.S. to inject large volumes of CO2 into an extensive undisturbed saline reservoir, and thus serves as an important test for future industrial-scale CCS projects. At Decatur, supercritical CO2 is injected at 2.1 km depth into the Mt. Simon Sandstone, which directly overlies granitic basement. The primary sealing cap is the Eau Claire Shale at a depth of about 1.5 km. The Illinois State Geological Survey (ISGS) manages the ongoing Illinois Basin - Decatur Project, a three-year project beginning in November 2011 during which CO2 is injected at an average rate of 1000 metric tons/day. Archer Daniels Midland (ADM) manages the nearby Illinois Industrial Carbon Capture and Storage project, which, pending permit approval, plans to inject 3000 metric tons/day for five years. The USGS seismic network was installed starting in July 2013 and consists of 12 stations, three of which include borehole sensors at depths of 150 m. The aperture of this network is roughly 8 km, centered on the injection well. A one-dimensional velocity model was derived from a vertical seismic profile survey acquired by ADM and the ISGS to a depth of 2.2 km, tied into acoustic logs from a deep observation well and the USGS borehole stations. This model was used together with absolute and double-difference techniques to locate seismic events. These events group into two clusters: 0.4 to 1.0 km NE and 1.8 to 2.6 km WNW from the injection well, with moment magnitudes ranging from -0.8 to 1.1. Most of these events are in the granitic basement, well below the cap rock, and are unlikely to have compromised the integrity of the seal.

Military Children’s Perceptions of Parents’ Frequent Missile Base Deployments

DTIC Science & Technology

2017-04-26

investigations, 502 ISG/JAC ( Ethics Review) and Public Affairs (59 MOW/PA) for review and then forward you a final letter of approval or disapproval. 9. Once...Medical and Technical Papers, for additional information. 11 . The Joint Ethics Regulation (JER) DoD 5500.07-R, Standards of Conduct, provides...standards of ethical conduct for all DoD personnel and their interactions with other non-DoD entities, organizations, societies, conferences, etc. Part of

Extra Sinus Pathologies on the Routine CT Sinus Study: What the Radiologist Cannot Afford to Miss

DTIC Science & Technology

2017-04-30

assistance. 8. The 59 CRD/Publications and Presentations Section will route the request form to clinical investigations. 502 ISG/JAC ( Ethics Review) and...additional information. 11 . The Joint Ethics Regulation (JER) DoO 5500.07 -R. Standards of Conduct, provides standards of ethical conduct for all DoD...includes a legal ethics review to address any potential conmcts related to DoD personnel participating in non-OoD sponsored conferences

Plasma Exchange for Refractory MDA5 Myositis and ILD

DTIC Science & Technology

2017-04-26

investigations. S02 ISG/JAC ( Ethics Review) and Public Affa irs (S9 MOW/PA) for review and then forward you a final letter of approval or disapproval. 9...Medical and Technical Papers, for additional information. 11 . The Joint Ethics Regulation (JER) DoD SS00.07 -R, Standards of Conduct. provides...standards of ethical conduct for all DoD personnel and their interactions with other non-DoD entities. organizations, societies. conferences, etc. Part of

Incremental Drag due to Grooves and Threads for KE (Kinetic Energy) Projectiles

DTIC Science & Technology

1989-03-01

RFI • CTsB TF * - MF (3a) q L where TF1 is the Thread Factor defined as: TF 0.84 + 0.117 P - o (3b) where p is the groove pitch in inches, MF1 is...g2) MF RF CD (4) where TF11 and TF1 2 are the thread factors for the threads of pitch p, and P2, respectively. 5 One can notice the large

Development of loteprednol etabonate-loaded cationic nanoemulsified in-situ ophthalmic gel for sustained delivery and enhanced ocular bioavailability.

PubMed

Patel, Nirav; Nakrani, Happy; Raval, Mihir; Sheth, Navin

2016-11-01

A novel cationic nanoemulsified in-situ ophthalmic gel of loteprednol etabonate (LE) was developed to improve the permeability and retention time of formulations for overall improvement of drug's ocular bioavability. Capryol 90 (oil phase), tween 80 (surfactant) and transcutol P (cosurfactant) was selected as formulation excipients to construct pseudoternary phase diagrams and nanoemulsion region was recognized from diagrams. Spontaneous emulsification method was used to manufacture LE nanoemulsion and it was optimized using 3 2 factorial design by considering the amount of oil and the ratio of surfactant to cosurfactant (S mix ) as independent variables and evaluated for various physicochemical properties. Optimized NE was dispersed in Poloxamer 407 and 188 solution to form nanoemulsified sols that were predictable to transform into in-situ gels at corneal temperature. Drug pharmacokinetics of sterilized optimized in situ NE gel, NE-ISG2 [0.69% w/w Capryol 90, 0.99%w/w S mix (3:1), 13% Poloxamer 407, 4% w/w Poloxamer 188] and marketed formulation were assessed in rabbit aqueous humor. The in-situ gels were clear, shear thinning in nature and displayed zero-order drug release kinetics. NE-ISG2 showed the minimum ocular irritation potential and significantly (p < 0.01) higher C max and AUC (0-10 h) , delayed T max , extended mean residence time and improved (2.54-fold times) bioavailability compared to marketed formulation.

Cloning of a gene (RIG-G) associated with retinoic acid-induced differentiation of acute promyelocytic leukemia cells and representing a new member of a family of interferon-stimulated genes

PubMed Central

Yu, Man; Tong, Jian-Hua; Mao, Mao; Kan, Li-Xin; Liu, Meng-Min; Sun, Yi-Wu; Fu, Gang; Jing, Yong-Kui; Yu, Long; Lepaslier, Denis; Lanotte, Michel; Wang, Zhen-Yi; Chen, Zhu; Waxman, Samuel; Wang, Ya-Xin; Tan, Jia-Zhen; Chen, Sai-Juan

1997-01-01

In a cell line (NB4) derived from a patient with acute promyelocytic leukemia, all-trans-retinoic acid (ATRA) and interferon (IFN) induce the expression of a novel gene we call RIG-G (for retinoic acid-induced gene G). This gene codes for a 58-kDa protein containing 490 amino acids with several potential sites for post-translational modification. In untreated NB4 cells, the expression of RIG-G is undetectable. ATRA treatment induces the transcriptional expression of RIG-G relatively late (12–24 hr) in a protein synthesis-dependent manner, whereas IFN-α induces its expression early (30 min to 3 hr). Database search has revealed a high-level homology between RIG-G and several IFN-stimulated genes in human (ISG54K, ISG56K, and IFN-inducible and retinoic acid-inducible 58K gene) and some other species, defining a well conserved gene family. The gene is composed of two exons and has been mapped by fluorescence in situ hybridization to chromosome 10q24, where two other human IFN-stimulated gene members are localized. A synergistic induction of RIG-G expression in NB4 cells by combined treatment with ATRA and IFNs suggests that a collaboration exists between their respective signaling pathways. PMID:9207104

Antiviral Responses by Swine Primary Bronchoepithelial Cells Are Limited Compared to Human Bronchoepithelial Cells Following Influenza Virus Infection

PubMed Central

Hauser, Mary J.; Dlugolenski, Daniel; Culhane, Marie R.; Wentworth, David E.; Tompkins, S. Mark; Tripp, Ralph A.

2013-01-01

Swine generate reassortant influenza viruses because they can be simultaneously infected with avian and human influenza; however, the features that restrict influenza reassortment in swine and human hosts are not fully understood. Type I and III interferons (IFNs) act as the first line of defense against influenza virus infection of respiratory epithelium. To determine if human and swine have different capacities to mount an antiviral response the expression of IFN and IFN-stimulated genes (ISG) in normal human bronchial epithelial (NHBE) cells and normal swine bronchial epithelial (NSBE) cells was evaluated following infection with human (H3N2), swine (H1N1), and avian (H5N3, H5N2, H5N1) influenza A viruses. Expression of IFNλ and ISGs were substantially higher in NHBE cells compared to NSBE cells following H5 avian influenza virus infection compared to human or swine influenza virus infection. This effect was associated with reduced H5 avian influenza virus replication in human cells at late times post infection. Further, RIG-I expression was lower in NSBE cells compared to NHBE cells suggesting reduced virus sensing. Together, these studies identify key differences in the antiviral response between human and swine respiratory epithelium alluding to differences that may govern influenza reassortment. PMID:23875024

Enterovirus Exposure Uniquely Discriminates Type 1 Diabetes Patients with a Homozygous from a Heterozygous Melanoma Differentiation-Associated Protein 5/Interferon Induced with Helicase C Domain 1 A946T Genotype.

PubMed

Schulte, Barbara M; Gielen, Paul R; Kers-Rebel, Esther D; Prosser, Amy C; Lind, Katharina; Flodström-Tullberg, Malin; Tack, Cees J; Elving, Lammy D; Adema, Gosse J

2016-09-01

In children at risk for type 1 diabetes, innate immune activity is detected before seroconversion. Enterovirus infections have been linked to diabetes development, and a polymorphism (A946T) in the innate immune sensor recognizing enterovirus RNA, interferon-induced with helicase C domain 1/melanoma differentiation-associated protein 5, predisposes to disease. We hypothesized that the strength of innate antienteroviral responses is affected in autoimmune type 1 diabetes patients and linked to the A946T polymorphism. We compared induction of interferon-stimulated genes (ISGs) in peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs) in healthy individuals and diabetes patients upon stimulation with enterovirus, enterovirus-antibody complexes, or ligands mimicking infection in relation to the A946T polymorphism. Overall, PBMCs of diabetes patients and healthy donors showed comparable ISG induction upon stimulation. No differences were observed in DCs. Interestingly, the data imply that the magnitude of responses to enterovirus and enterovirus-antibody complexes in PBMCs is critically influenced by the A946T polymorphism and elevated in heterozygotes compared to TT homozygous individuals in autoimmune diabetes patients, but not healthy controls. These data imply an intrinsic difference in the responses to enterovirus and enterovirus-antibody complexes in diabetes patients carrying a TT risk genotype compared to heterozygotes that may influence control of enterovirus clearance.

Using remotely sensed imagery and GIS to monitor and research salmon spawning: A case study of the Hanford Reach fall chinook (Oncorhynchus Tshawytscha)

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

RH Visser

2000-03-16

The alteration of ecological systems has greatly reduced salmon populations in the Pacific Northwest. The Hanford Reach of the Columbia River, for example, is a component of the last ecosystem in eastern Washington State that supports a relatively healthy population of fall chinook salmon ([Oncorhynchus tshawytscha], Huntington et al. 1996). This population of fall chinook may function as a metapopulation for the Mid-Columbia region (ISG 1996). Metapopulations can seed or re-colonize unused habitat through the mechanism of straying (spawning in non-natal areas) and may be critical to the salmon recovery process if lost or degraded habitat is restored (i.e., themore » Snake, Upper Columbia, and Yakima rivers). For these reasons, the Hanford Reach fall chinook salmon population is extremely important for preservation of the species in the Columbia River Basin. Because this population is important to the region, non-intrusive techniques of analysis are essential for researching and monitoring population trends and spawning activities.« less

A Case Analysis of Energy Savings Performance Contract Projects and Photovoltaic Energy at Fort Bliss, El Paso, Texas

DTIC Science & Technology

2006-06-01

PHOTOVOLTAIC ENERGY AND FORT BLISS CASE BACKGROUND A. PHOTOVOLTAIC ENERGY The use of photovoltaic power systems is nothing new in the Department...against the Outback MPPT charge controller . This test will be done over a one month timeframe. The Arizona Power ISG test plan is contained in...cost-benefit analysis of conventional power versus emerging photovoltaic energy for the Army’s Fort Bliss in El Paso, TX. The project will also analyze

Structure of the top of the Karnak Limestone Member (Ste. Genevieve) in Illinois

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

Bristol, H.M.; Howard, R.H.

1976-01-01

To facilitate petroleum exploration in Illinois, the Illinois State Geological Survey presents a structure map (for most of southern Illinois) of the Karnak Limestone Member--a relatively pure persistent limestone unit (generally 10 to 35 ft thick) in the Ste. Genevieve Limestone of Genevievian age. All available electric logs and selected studies of well cuttings were used in constructing the map. Oil and gas development maps containing Karnak-structure contours are on open file at the ISGS.

The Average Change in Facial Height Following Bilateral Sagittal Split Osteotomy Advancement in Class II Patients

DTIC Science & Technology

2017-04-21

The S9 CRD/Publications and Presentations Section will route the request form to clinical investigations. 502 ISG/JAC ( Ethics Review) and Public...information. 11 . The Joint Ethics Regulation (JER) DoD S500.07-R. Standards of Conduct. provides standards of ethical conduct for all DoD personnel and...a legal ethics review to address any potential conflicts related to DoD personnel participating in non-DoD sponsored conferences, professional

Who is Distressed Applying the Diabetes Related Distress Scale in a Diabetes Clinic

DTIC Science & Technology

2017-06-09

Presentations Section will route the request form to clinical investigations, S02 ISG/JAC ( Ethics Review) and Public Affairs (59 MOW/PA) for review and then...DITC). See S9 MDWI 41-108, Presentation and Publication of Medical and Technical Papers. for additional information. 11. The Joint Ethics Regulation...JER) DoO 5500.07-R, Standards of Conduct. provides standards of ethical conduct for all DoD personnel and their interactions with other non-OoO

Isolation of Breast Tumor Suppressor Genes from Chromosome 11p.

DTIC Science & Technology

1998-09-01

tumors . Figure 7b shows the SSCA pattern of exon 2 amplified from paired normal/ tumor samples from four different Wilms tumor patients. Sample 1 is...G., Chaussain, J.L., Junien, C. Tumor specific loss of IIp 15.5 alleles in del 1 lp 13 Wilms tumor and in familial adrenocortical carcinoma. Proc...Chilton-MacNeill,S., Campbell, C.E., Weksberg, R., Yeger, H., Reeve, A.E. and Williams, B.R.G. Loss of heterozygosity mapping in Wilms tumor

59th Medical Wing Clinical Research Division Clinical Investigations Program Posters (Count: 2)

DTIC Science & Technology

2017-05-08

Calcote, Joshua - Contractor , 59 MDW/ SGVU DYES (gJ NO N I A 5. PROTOCOL TITLE: (NOTE: For each new release of medical research or technical information...Corresponding Author Joshua C. Calcote Contractor 59 MDW/ SGVU b. c. d. e. 17. IS A 502 ISG/JAC ETHICS REVIEW REQUIRED (JER DOD 5500.07-R)? DYES 181...PRESENTATION. 18. AUTHOR’S PRINTED NAME, RANK. GRADE 19. AUTHOR’S SIGNATURE Dr. Joshua C. Calcote, Contractor ~~~:.7.:.:.-:::.---=::~- -- -·--- ~- 21

Sol gel-derived hydroxyapatite films over porous calcium polyphosphate substrates for improved tissue engineering of osteochondral-like constructs.

PubMed

Lee, Whitaik David; Gawri, Rahul; Pilliar, Robert M; Stanford, William L; Kandel, Rita A

2017-10-15

Integration of in vitro-formed cartilage on a suitable substrate to form tissue-engineered implants for osteochondral defect repair is a considerable challenge. In healthy cartilage, a zone of calcified cartilage (ZCC) acts as an intermediary for mechanical force transfer from soft to hard tissue, as well as an effective interlocking structure to better resist interfacial shear forces. We have developed biphasic constructs that consist of scaffold-free cartilage tissue grown in vitro on, and interdigitated with, porous calcium polyphosphate (CPP) substrates. However, as CPP degrades, it releases inorganic polyphosphates (polyP) that can inhibit local mineralization, thereby preventing the formation of a ZCC at the interface. Thus, we hypothesize that coating CPP substrate with a layer of hydroxyapatite (HA) might prevent or limit this polyP release. To investigate this we tested both inorganic or organic sol-gel processing methods, asa barrier coating on CPP substrate to inhibit polyP release. Both types of coating supported the formation of ZCC in direct contact with the substrate, however the ZCC appeared more continuous in the tissue formed on the organic HA sol gel coated CPP. Tissues formed on coated substrates accumulated comparable quantities of extracellular matrix and mineral, but tissues formed on organic sol-gel (OSG)-coated substrates accumulated less polyP than tissues formed on inorganic sol-gel (ISG)-coated substrates. Constructs formed with OSG-coated CPP substrates had greater interfacial shear strength than those formed with ISG-coated and non-coated substrates. These results suggest that the OSG coating method can modify the location and distribution of ZCC and can be used to improve the mechanical integrity of tissue-engineered constructs formed on porous CPP substrates. Articular cartilage interfaces with bone through a zone of calcified cartilage. This study describes a method to generate an "osteochondral-like" implant that mimics this organization using isolated deep zone cartilage cells and a sol-gel hydroxyapatite coated bone substitute material composed of calcium polyphosphate (CPP). Developing a layer of calcified cartilage at the interface should contribute to enhancing the success of this "osteochondral-like" construct following implantation to repair cartilage defects. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP)

PubMed Central

Lau, Zerlina; Cheung, Pamela; Schneider, William M.; Bozzacco, Leonia; Buehler, Eugen; Takaoka, Akinori; Rice, Charles M.; Felsenfeld, Dan P.; MacDonald, Margaret R.

2017-01-01

The host factor and interferon (IFN)-stimulated gene (ISG) product, zinc-finger antiviral protein (ZAP), inhibits a number of diverse viruses by usurping and intersecting with multiple cellular pathways. To elucidate its antiviral mechanism, we perform a loss-of-function genome-wide RNAi screen to identify cellular cofactors required for ZAP antiviral activity against the prototype alphavirus, Sindbis virus (SINV). In order to exclude off-target effects, we carry out stringent confirmatory assays to verify the top hits. Important ZAP-liaising partners identified include proteins involved in membrane ion permeability, type I IFN signaling, and post-translational protein modification. The factor contributing most to the antiviral function of ZAP is TRIM25, an E3 ubiquitin and ISG15 ligase. We demonstrate here that TRIM25 interacts with ZAP through the SPRY domain, and TRIM25 mutants lacking the RING or coiled coil domain fail to stimulate ZAP’s antiviral activity, suggesting that both TRIM25 ligase activity and its ability to form oligomers are critical for its cofactor function. TRIM25 increases the modification of both the short and long ZAP isoforms by K48- and K63-linked polyubiquitin, although ubiquitination of ZAP does not directly affect its antiviral activity. However, TRIM25 is critical for ZAP’s ability to inhibit translation of the incoming SINV genome. Taken together, these data uncover TRIM25 as a bona fide ZAP cofactor that leads to increased ZAP modification enhancing its translational inhibition activity. PMID:28060952

TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP).

PubMed

Li, Melody M H; Lau, Zerlina; Cheung, Pamela; Aguilar, Eduardo G; Schneider, William M; Bozzacco, Leonia; Molina, Henrik; Buehler, Eugen; Takaoka, Akinori; Rice, Charles M; Felsenfeld, Dan P; MacDonald, Margaret R

2017-01-01

The host factor and interferon (IFN)-stimulated gene (ISG) product, zinc-finger antiviral protein (ZAP), inhibits a number of diverse viruses by usurping and intersecting with multiple cellular pathways. To elucidate its antiviral mechanism, we perform a loss-of-function genome-wide RNAi screen to identify cellular cofactors required for ZAP antiviral activity against the prototype alphavirus, Sindbis virus (SINV). In order to exclude off-target effects, we carry out stringent confirmatory assays to verify the top hits. Important ZAP-liaising partners identified include proteins involved in membrane ion permeability, type I IFN signaling, and post-translational protein modification. The factor contributing most to the antiviral function of ZAP is TRIM25, an E3 ubiquitin and ISG15 ligase. We demonstrate here that TRIM25 interacts with ZAP through the SPRY domain, and TRIM25 mutants lacking the RING or coiled coil domain fail to stimulate ZAP's antiviral activity, suggesting that both TRIM25 ligase activity and its ability to form oligomers are critical for its cofactor function. TRIM25 increases the modification of both the short and long ZAP isoforms by K48- and K63-linked polyubiquitin, although ubiquitination of ZAP does not directly affect its antiviral activity. However, TRIM25 is critical for ZAP's ability to inhibit translation of the incoming SINV genome. Taken together, these data uncover TRIM25 as a bona fide ZAP cofactor that leads to increased ZAP modification enhancing its translational inhibition activity.

Type I IFN augments IL-27-dependent TRIM25 expression to inhibit HBV replication.

PubMed

Tan, Guangyun; Xiao, Qingfei; Song, Hongxiao; Ma, Feng; Xu, Fengchao; Peng, Di; Li, Na; Wang, Xiaosong; Niu, Junqi; Gao, Pujun; Qin, F Xiao-Feng; Cheng, Genhong

2018-03-01

Hepatitis B virus (HBV) can cause chronic hepatitis B, which may lead to cirrhosis and liver cancer. Type I interferon (IFN) is an approved drug for the treatment of chronic hepatitis B. However, the fundamental mechanisms of antiviral action by type I IFN and the downstream signaling pathway are unclear. TRIM25 is an IFN-stimulated gene (ISG) that has an important role in RIG-I ubiquitination and activation. Whether TRIM25 is induced in liver cells by type I IFN to mediate anti-HBV function remains unclear. Here we report that interleukin-27 (IL-27) has a critical role in IFN-induced TRIM25 upregulation. TRIM25 induction requires both STAT1 and STAT3. In TRIM25 knockout HepG2 cells, type I IFN production was consistently attenuated and HBV replication was increased, whereas overexpression of TRIM25 in HepG2 cells resulted in elevated IFN production and reduced HBV replication. More interestingly, we found that TRIM25 expression was downregulated in HBV patients and the addition of serum samples from HBV patients could inhibit TRIM25 expression in HepG2 cells, suggesting that HBV might have involved a mechanism to inhibit antiviral ISG expression and induce IFN resistance. Collectively, our results demonstrate that type I IFN -induced TRIM25 is an important factor in inhibiting HBV replication, and the IFN-IL-27-TRIM25 axis may represent a new target for treating HBV infection.

Evidence that interferon-tau secreted from Day-7 embryo in vivo generates anti-inflammatory immune response in the bovine uterus.

PubMed

Rashid, Mohammad B; Talukder, Anup K; Kusama, Kazuya; Haneda, Shingo; Takedomi, Toshiro; Yoshino, Hitomi; Moriyasu, Satoru; Matsui, Motozumi; Shimada, Masayuki; Imakawa, Kazuhiko; Miyamoto, Akio

2018-06-12

Recent studies suggest that Day-7 bovine embryo starts to communicate with the uterine epithelium through interferon-tau (IFNT) signaling. However, immune modulatory role of IFNT in the uterus just after the embryo moves from the oviduct is unclear. We aimed to examine the hypothesis that Day-7 bovine embryo secretes IFNT in the uterus, which induces anti-inflammatory response in immune cells. The uterine flush (UF) with multiple embryos was collected from Day-7 donor pregnant cows and peripheral blood mononuclear cells (PBMCs) were then cultured in UF. Transcripts detected in PBMCs revealed that UF from pregnant cows down-regulated pro-inflammatory cytokines (TNFA, IL1B) and up-regulated anti-inflammatory cytokine (IL10) expression, with activation of interferon-stimulated genes (ISGs; ISG15, OAS1) as compared with UF from non-pregnant cows. An addition of specific anti-IFNT antibody to the UF inhibited the effect on PBMCs, indicating that IFNT is a major factor for such immune modulation. The observation that conditioned media from bovine uterine epithelial cells both stimulated with IFNT in vitro and supplemented with fresh IFNT induced similar PBMCs gene expression, confirming that IFNT directly acts on this immune crosstalk. This study shows that IFNT secreted from Day-7 embryo in vivo generates anti-inflammatory response in immune cells, which may provide immunological tolerance to accept the embryo. Copyright © 2018 Elsevier Inc. All rights reserved.

Hepatitis E virus persists in the presence of a type III interferon response.

PubMed

Yin, Xin; Li, Xinlei; Ambardekar, Charuta; Hu, Zhimin; Lhomme, Sébastien; Feng, Zongdi

2017-05-01

The RIG-I-like RNA helicase (RLR)-mediated interferon (IFN) response plays a pivotal role in the hepatic antiviral immunity. The hepatitis A virus (HAV) and the hepatitis C virus (HCV) counter this response by encoding a viral protease that cleaves the mitochondria antiviral signaling protein (MAVS), a common signaling adaptor for RLRs. However, a third hepatotropic RNA virus, the hepatitis E virus (HEV), does not appear to encode a functional protease yet persists in infected cells. We investigated HEV-induced IFN responses in human hepatoma cells and primary human hepatocytes. HEV infection resulted in persistent virus replication despite poor spread. This was companied by a type III IFN response that upregulated multiple IFN-stimulated genes (ISGs), but type I IFNs were barely detected. Blocking type III IFN production or signaling resulted in reduced ISG expression and enhanced HEV replication. Unlike HAV and HCV, HEV did not cleave MAVS; MAVS protein size, mitochondrial localization, and function remained unaltered in HEV-replicating cells. Depletion of MAVS or MDA5, and to a less extent RIG-I, also diminished IFN production and increased HEV replication. Furthermore, persistent activation of the JAK/STAT signaling rendered infected cells refractory to exogenous IFN treatment, and depletion of MAVS or the receptor for type III IFNs restored the IFN responsiveness. Collectively, these results indicate that unlike other hepatotropic RNA viruses, HEV does not target MAVS and its persistence is associated with continuous production of type III IFNs.

Development and Validation of a Novel Dual Luciferase Reporter Gene Assay to Quantify Ebola Virus VP24 Inhibition of IFN Signaling

PubMed Central

Frau, Aldo; Sgarbanti, Marco; Orsatti, Roberto

2018-01-01

The interferon (IFN) system is the first line of defense against viral infections. Evasion of IFN signaling by Ebola viral protein 24 (VP24) is a critical event in the pathogenesis of the infection and, hence, VP24 is a potential target for drug development. Since no drugs target VP24, the identification of molecules able to inhibit VP24, restoring and possibly enhancing the IFN response, is a goal of concern. Accordingly, we developed a dual signal firefly and Renilla luciferase cell-based drug screening assay able to quantify IFN-mediated induction of Interferon Stimulated Genes (ISGs) and its inhibition by VP24. Human Embryonic Kidney 293T (HEK293T) cells were transiently transfected with a luciferase reporter gene construct driven by the promoter of ISGs, Interferon-Stimulated Response Element (ISRE). Stimulation of cells with IFN-α activated the IFN cascade leading to the expression of ISRE. Cotransfection of cells with a plasmid expressing VP24 cloned from a virus isolated during the last 2014 outbreak led to the inhibition of ISRE transcription, quantified by a luminescent signal. To adapt this system to test a large number of compounds, we performed it in 96-well plates; optimized the assay analyzing different parameters; and validated the system by calculating the Z′- and Z-factor, which showed values of 0.62 and 0.53 for IFN-α stimulation assay and VP24 inhibition assay, respectively, indicative of robust assay performance. PMID:29495311

Development and Validation of a Novel Dual Luciferase Reporter Gene Assay to Quantify Ebola Virus VP24 Inhibition of IFN Signaling.

PubMed

Fanunza, Elisa; Frau, Aldo; Sgarbanti, Marco; Orsatti, Roberto; Corona, Angela; Tramontano, Enzo

2018-02-24

The interferon (IFN) system is the first line of defense against viral infections. Evasion of IFN signaling by Ebola viral protein 24 (VP24) is a critical event in the pathogenesis of the infection and, hence, VP24 is a potential target for drug development. Since no drugs target VP24, the identification of molecules able to inhibit VP24, restoring and possibly enhancing the IFN response, is a goal of concern. Accordingly, we developed a dual signal firefly and Renilla luciferase cell-based drug screening assay able to quantify IFN-mediated induction of Interferon Stimulated Genes (ISGs) and its inhibition by VP24. Human Embryonic Kidney 293T (HEK293T) cells were transiently transfected with a luciferase reporter gene construct driven by the promoter of ISGs, Interferon-Stimulated Response Element (ISRE). Stimulation of cells with IFN-α activated the IFN cascade leading to the expression of ISRE. Cotransfection of cells with a plasmid expressing VP24 cloned from a virus isolated during the last 2014 outbreak led to the inhibition of ISRE transcription, quantified by a luminescent signal. To adapt this system to test a large number of compounds, we performed it in 96-well plates; optimized the assay analyzing different parameters; and validated the system by calculating the Z'- and Z-factor, which showed values of 0.62 and 0.53 for IFN-α stimulation assay and VP24 inhibition assay, respectively, indicative of robust assay performance.

Structural Analysis of a Viral Ovarian Tumor Domain Protease from the Crimean-Congo Hemorrhagic Fever Virus in Complex with Covalently Bonded Ubiquitin

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

Capodagli, Glenn C.; McKercher, Marissa A.; Baker, Erica A.

Crimean-Congo hemorrhagic fever (CCHF) virus is a tick-borne, negative-sense, single-stranded RNA [ssRNA(-)] nairovirus that produces fever, prostration, and severe hemorrhages in humans. With fatality rates for CCHF ranging up to 70% based on several factors, CCHF is considered a dangerous emerging disease. Originally identified in the former Soviet Union and the Congo, CCHF has rapidly spread across large sections of Europe, Asia, and Africa. Recent reports have identified a viral homologue of the ovarian tumor protease superfamily (vOTU) within its L protein. This protease has subsequently been implicated in downregulation of the type I interferon immune response through cleavage ofmore » posttranslational modifying proteins ubiquitin (Ub) and the Ub-like interferon-simulated gene 15 (ISG15). Additionally, homologues of vOTU have been suggested to perform similar roles in the positive-sense, single-stranded RNA [ssRNA(+)] arteriviruses. By utilizing X-ray crystallographic techniques, the structure of vOTU covalently bound to ubiquitin propylamine, a suicide substrate of the enzyme, was elucidated to 1.7 {angstrom}, revealing unique structural elements that define this new subclass of the OTU superfamily. In addition, kinetic studies were carried out with aminomethylcoumarin (AMC) conjugates of monomeric Ub, ISG15, and NEDD8 (neural precursor cell expressed, developmentally downregulated 8) substrates in order to provide quantitative insights into vOTU's preference for Ub and Ub-like substrates.« less

STAT3-Activated GM-CSFRα Translocates to the Nucleus and Protects CLL Cells from Apoptosis

PubMed Central

Li, Ping; Harris, David; Liu, Zhiming; Rozovski, Uri; Ferrajoli, Alessandra; Wang, Yongtao; Bueso-Ramos, Carlos; Hazan-Halevy, Inbal; Grgurevic, Srdana; Wierda, William; Burger, Jan; O'Brien, Susan; Faderl, Stefan; Keating, Michael; Estrov, Zeev

2014-01-01

Here it was determined that Chronic Lymphocytic Leukemia (CLL) cells express the α-subunit but not the β-subunit of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR/CSF3R). GM-CSFRα was detected on the surface, in the cytosol, and the nucleus of CLL cells via confocal microscopy, cell fractionation, and GM-CSFRα antibody epitope mapping. Because STAT3 is frequently activated in CLL and the GM-CSFRα promoter harbors putative STAT3 consensus binding sites, MM1 cells were transfected with truncated forms of the GM-CSFRα promoter, then stimulated with IL-6 to activate STAT3 to identify STAT3 binding sites. Chromatin immunoprecipitation (ChIP) and an electoromobility shift assay (EMSA) confirmed STAT3 occupancy to those promoter regions in both IL-6 stimulated MM1 and CLL cells. Transfection of MM1 cells with STAT3 siRNA or CLL cells with STAT3 shRNA significantly down-regulated GM-CSFRα mRNA and protein levels. RNA transcripts, involved in regulating cell-survival pathways, and the proteins KAP1 (TRIM28) and ISG15 co-immunoprecipitated with GM-CSFRα. GM-CSFRα-bound KAP1 enhanced the transcriptional activity of STAT3, whereas ISG15 inhibited the NF-κB pathway. Nevertheless, overexpression of GM-CSFRα protected MM1 cells from dexamethasone-induced apoptosis, and GM-CSFRα knockdown induced apoptosis in CLL cells, suggesting that GM-CSFRα provides a ligand-independent survival advantage. PMID:24836891

Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey.

PubMed

Briggs, Tracy A; Rice, Gillian I; Adib, Navid; Ades, Lesley; Barete, Stephane; Baskar, Kannan; Baudouin, Veronique; Cebeci, Ayse N; Clapuyt, Philippe; Coman, David; De Somer, Lien; Finezilber, Yael; Frydman, Moshe; Guven, Ayla; Heritier, Sébastien; Karall, Daniela; Kulkarni, Muralidhar L; Lebon, Pierre; Levitt, David; Le Merrer, Martine; Linglart, Agnes; Livingston, John H; Navarro, Vincent; Okenfuss, Ericka; Puel, Anne; Revencu, Nicole; Scholl-Bürgi, Sabine; Vivarelli, Marina; Wouters, Carine; Bader-Meunier, Brigitte; Crow, Yanick J

2016-04-01

Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.

Computer-assisted stereotactic neurological surgery: pre-planning and on-site real-time operating control and simulation system

NASA Astrophysics Data System (ADS)

Zamorano, Lucia J.; Jiang, Charlie Z. W.

1993-09-01

In this decade the concept and development of computer assisted stereotactic neurological surgery has improved dramatically. First, the computer network replaced the tape as the data transportation media. Second, newer systems include multi-modality image correlation and frameless stereotactics as an integral part of their functionality, and offer extensive assistance to the neurosurgeon from the preplanning stages to and throughout the operation itself. These are very important changes, and have spurred the development of many interesting techniques. Successful systems include the ISG and NSPS-3.0.

Applying CASE Tools for On-Board Software Development

NASA Astrophysics Data System (ADS)

Brammer, U.; Hönle, A.

For many space projects the software development is facing great pressure with respect to quality, costs and schedule. One way to cope with these challenges is the application of CASE tools for automatic generation of code and documentation. This paper describes two CASE tools: Rhapsody (I-Logix) featuring UML and ISG (BSSE) that provides modeling of finite state machines. Both tools have been used at Kayser-Threde in different space projects for the development of on-board software. The tools are discussed with regard to the full software development cycle.

Microphysics of Air-Sea Exchanges

DTIC Science & Technology

2006-06-30

these variables: S- rMss g A co Figure 3 shows the correlation between It and the measured F at 6cm depth: e = 9.3 x 10-5 (mssgA(o0) 75 The Imaging ...camera to directly observe the water surface slope through the relative intensities of the three color components at each point of the image . The ISG...law,no peraon shall be subject any penalty for fling to comply wit a collection of information if it do" n&T display a cur, eniy valid OMB control

Pedometer-Based Internet-Mediated Intervention For Adults With Chronic Low Back Pain: Randomized Controlled Trial

PubMed Central

Kadri, Reema; Hughes, Maria; Kerr, Eve A; Piette, John D; Holleman, Rob; Kim, Hyungjin Myra; Richardson, Caroline R

2013-01-01

Background Chronic pain, especially back pain, is a prevalent condition that is associated with disability, poor health status, anxiety and depression, decreased quality of life, and increased health services use and costs. Current evidence suggests that exercise is an effective strategy for managing chronic pain. However, there are few clinical programs that use generally available tools and a relatively low-cost approach to help patients with chronic back pain initiate and maintain an exercise program. Objective The objective of the study was to determine whether a pedometer-based, Internet-mediated intervention can reduce chronic back pain-related disability. Methods A parallel group randomized controlled trial was conducted with 1:1 allocation to the intervention or usual care group. 229 veterans with nonspecific chronic back pain were recruited from one Department of Veterans Affairs (VA) health care system. Participants randomized to the intervention received an uploading pedometer and had access to a website that provided automated walking goals, feedback, motivational messages, and social support through an e-community (n=111). Usual care participants (n=118) also received the uploading pedometer but did not receive the automated feedback or have access to the website. The primary outcome was measured using the Roland Morris Disability Questionnaire (RDQ) at 6 months (secondary) and 12 months (primary) with a difference in mean scores of at least 2 considered clinically meaningful. Both a complete case and all case analysis, using linear mixed effects models, were conducted to assess differences between study groups at both time points. Results Baseline mean RDQ scores were greater than 9 in both groups. Primary outcome data were provided by approximately 90% of intervention and usual care participants at both 6 and 12 months. At 6 months, average RDQ scores were 7.2 for intervention participants compared to 9.2 for usual care, an adjusted difference of 1.6 (95% CI 0.3-2.8, P=.02) for the complete case analysis and 1.2 (95% CI -0.09 to 2.5, P=.07) for the all case analysis. A post hoc analysis of patients with baseline RDQ scores ≥4 revealed even larger adjusted differences between groups at 6 months but at 12 months the differences were no longer statistically significant. Conclusions Intervention participants, compared with those receiving usual care, reported a greater decrease in back pain-related disability in the 6 months following study enrollment. Between-group differences were especially prominent for patients reporting greater baseline levels of disability but did not persist over 12 months. Primarily, automated interventions may be an efficient way to assist patients with managing chronic back pain; additional support may be needed to ensure continuing improvements. Trial Registration ClinicalTrials.gov NCT00694018; http://clinicaltrials.gov/ct2/show/NCT00694018 (Archived by WebCite at http://www.webcitation.org/6IsG4Y90E). PMID:23969029

The influence of temperature on viral replication and antiviral-related genes response in hirame rhabdovirus-infected flounder (Paralichthys olivaceus).

PubMed

Zhang, Jialin; Tang, Xiaoqian; Sheng, Xiuzhen; Xing, Jing; Zhan, Wenbin

2017-09-01

Hirame rhabdovirus (HIRRV) is a rhabdovirus that causes severe disease in fish. The mortality due to HIRRV infection occurs at temperatures below 15 °C, but no mortality is observed over 20 °C. In this study, Japanese flounder (Paralichthys olivaceus) was artificially infected with the HIRRV CNPo2015 strain at 10 °C or 20 °C. Absolute quantitative real-time PCR was employed to examine the viral replication in spleens after HIRRV infection. Expression profiles of four interferon-related genes (type I IFN, Mx, ISG15, MDA5) and two proinflammatory genes (TNF-α and IL-1β) were also investigated by quantitative real-time PCR. Results showed that viral copies in spleens increased gradually over time and peaked at 72 h post infection (hpi) in the 10 °C group, while viral copies in the 20 °C group increased within 24 hpi, but afterwards decreased to very low levels. Moreover, the expressions of IFNs in the 10 °C group reached the highest levels at 72 hpi, whereas their peak levels appeared much earlier in the 20 °C group, at 12 hpi. The expression levels of TNF-α and IL-1β in the 10 °C group peaked at 12 hpi and then quickly declined. However, the two genes were highly expressed during 6-24 hpi in the 20 °C group. Based on these findings, we concluded that HIRRV infection induced an efficient antiviral immune response at 20 °C, which might inhibit the viral transcription at early stages and finally prevent HIRRV infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

Recovery Act: Understanding the Impact of CO 2 Injection on the Subsurface Microbial Community in an Illinois Basin CCS Reservoir: Integrated Student Training in Geoscience and Geomicrobiology

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

Fouke, Bruce

An integrated research and teaching program was developed to provide cross--disciplinary training opportunities in the emerging field of carbon capture and storage (CCS) for geobiology students attending the University of Illinois Urbana-­Champaign (UIUC). Students from across the UIUC campus participated, including those from the departments of Geology, Microbiology, Biochemistry, Civil and Environmental Engineering, Animal Sciences and the Institute for Genomic Biology. The project took advantage of the unique opportunity provided by the drilling and sampling of the large-­scale Phase III CCS demonstration Illinois Basin - Decatur Project (IBDP) in the central Illinois Basin at nearby Decatur, Illinois. The IBPD ismore » under the direction of the Illinois State Geological Survey (ISGS, located on the UIUC campus) and the Midwest Geological Sequestration Consortium (MGSC). The research component of this project focused on the subsurface sampling and identification of microbes inhabiting the subsurface Cambrian-­age Mt. Simon Sandstone. In addition to formation water collected from the injection and monitoring wells, sidewall rock cores were collected and analyzed to characterize the cements and diagenetic features of the host Mt. Simon Sandstone. This established a dynamic geobiological framework, as well as a comparative baseline, for future studies of how CO 2 injection might affect the deep microbial biosphere at other CCS sites. Three manuscripts have been prepared as a result of these activities, which are now being finalized for submission to top-­tier international peer-­reviewed research journals. The training component of this project was structured to ensure that a broad group of UIUC students, faculty and staff gained insight into CCS issues. An essential part of this training was that the UIUC faculty mentored and involved undergraduate and graduate students, as well as postdocs and research scientists, at all stages of the project in order to develop CCS-­focused classroom and field courses, as well as seminars. This program provided an excellent opportunity for participants to develop the background necessary to establish longer-­term research in CCS-­related geology and microbial ecology. Further, the program provided an ongoing dynamic platform to foster long-term collaboration with the regional ISGS and MGSC sequestration partnership, while offering hands-­on, applied learning experiences.« less

Using reverse genetics to manipulate the NSs gene of the Rift Valley fever virus MP-12 strain to improve vaccine safety and efficacy.

PubMed

Kalveram, Birte; Lihoradova, Olga; Indran, Sabarish V; Ikegami, Tetsuro

2011-11-01

Rift Valley fever virus (RVFV), which causes hemorrhagic fever, neurological disorders or blindness in humans, and a high rate abortion and fetal malformation in ruminants, has been classified as a HHS/USDA overlap select agent and a risk group 3 pathogen. It belongs to the genus Phlebovirus in the family Bunyaviridae and is one of the most virulent members of this family. Several reverse genetics systems for the RVFV MP-12 vaccine strain as well as wild-type RVFV strains, including ZH548 and ZH501, have been developed since 2006. The MP-12 strain (which is a risk group 2 pathogen and a non-select agent) is highly attenuated by several mutations in its M- and L-segments, but still carries virulent S-segment RNA, which encodes a functional virulence factor, NSs. The rMP12-C13type (C13type) carrying 69% in-frame deletion of NSs ORF lacks all the known NSs functions, while it replicates as efficient as does MP-12 in VeroE6 cells lacking type-I IFN. NSs induces a shut-off of host transcription including interferon (IFN)-beta mRNA and promotes degradation of double-stranded RNA-dependent protein kinase (PKR) at the post-translational level. IFN-beta is transcriptionally upregulated by interferon regulatory factor 3 (IRF-3), NF-kB and activator protein-1 (AP-1), and the binding of IFN-beta to IFN-alpha/beta receptor (IFNAR) stimulates the transcription of IFN-alpha genes or other interferon stimulated genes (ISGs), which induces host antiviral activities, whereas host transcription suppression including IFN-beta gene by NSs prevents the gene upregulations of those ISGs in response to viral replication although IRF-3, NF-kB and activator protein-1 (AP-1) can be activated by RVFV7. Thus, NSs is an excellent target to further attenuate MP-12, and to enhance host innate immune responses by abolishing the IFN-beta suppression function. Here, we describe a protocol for generating a recombinant MP-12 encoding mutated NSs, and provide an example of a screening method to identify NSs mutants lacking the function to suppress IFN-beta mRNA synthesis. In addition to its essential role in innate immunity, type-I IFN is important for the maturation of dendritic cells and the induction of an adaptive immune response. Thus, NSs mutants inducing type-I IFN are further attenuated, but at the same time are more efficient at stimulating host immune responses than wild-type MP-12, which makes them ideal candidates for vaccination approaches.

Immune Cell Profiling of IFN-λ Response Shows pDCs Express Highest Level of IFN-λR1 and Are Directly Responsive via the JAK-STAT Pathway.

PubMed

Kelly, Aoife; Robinson, Mark W; Roche, Gerard; Biron, Christine A; O'Farrelly, Cliona; Ryan, Elizabeth J

2016-12-01

The interferon lambda (IFN-λ) cytokines have well-known antiviral properties, yet their contribution to immune regulation is not well understood. Epithelial cells represent the major target cell of IFN-λ; peripheral blood mononuclear cells are generally considered nonresponsive, with the exception of plasmacytoid dendritic cells (pDCs). In this study we aimed to define the potential for discrete subpopulations of cells to directly respond to IFN-λ. Analysis of peripheral blood leukocytes reveals that, while pDCs uniformly express the highest levels of IFN-λ receptor, a small proportion of B cells and monocytes also express the receptor. Nevertheless, B cells and monocytes respond poorly to IFN-λ stimulation in vitro, with minimal STAT phosphorylation and interferon-stimulated gene (ISG) induction observed. We confirm that pDCs respond to IFN-λ in vitro, upregulating their expression of pSTAT1, pSTAT3, and pSTAT5. However, we found that pDCs do not upregulate pSTAT6 in response to IFN-λ treatment. Our results highlight unique aspects of the response to IFN-λ and confirm that while the IFN-λ receptor is expressed by a small proportion of several different circulating immune cell lineages, under normal conditions only pDCs respond to IFN-λ stimulation with robust STAT phosphorylation and ISG induction. The difference in STAT6 responsiveness of pDCs to type I and type III interferons may help explain the divergence in their biological activities.

Expression of Interferon Lambda 4 Is Associated with Reduced Proliferation and Increased Cell Death in Human Hepatic Cells

PubMed Central

Onabajo, Olusegun O.; Porter-Gill, Patricia; Paquin, Ashley; Rao, Nina; Liu, Luyang; Tang, Wei; Brand, Nathan

2015-01-01

Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be generated only in individuals carrying a ΔG frame-shift allele of an exonic genetic variant (rs368234815-ΔG/TT). The rs368234815-ΔG allele is strongly associated with decreased clearance of hepatitis C virus (HCV) infection. Here, we further explored the biological function of IFN-λ4 expressed in human hepatic cells—a hepatoma cell line HepG2 and fresh primary human hepatocytes (PHHs). We performed live confocal imaging, cell death and proliferation assays, mRNA expression profiling, protein detection, and antibody blocking assays using transient and inducible stable in vitro systems. Not only did we observe significant intracellular retention of IFN-λ4 but also detected secreted IFN-λ4 in the culture media of expressing cells. Secreted IFN-λ4 induced strong activation of the interferon-stimulated genes (ISGs) in IFN-λ4-expressing and surrounding cells in transwell assays. Specifically, in PHHs, secreted IFN-λ4 induced expression of the CXCL10 transcript and a corresponding pro-inflammatory chemokine, IP-10. In IFN-λ4-expressing HepG2 cells, we also observed decreased proliferation and increased cell death. All IFN-λ4-induced phenotypes—activation of ISGs, decreased proliferation, and increased cell death—could be inhibited by an anti-IFN-λ4-specific antibody. Our study offers new insights into biology of IFN-λ4 and its possible role in HCV clearance. PMID:26134097

A recombinant adenovirus bicistronically expressing porcine interferon-α and interferon-γ enhances antiviral effects against foot-and-mouth disease virus.

PubMed

Kim, Su-Mi; Kim, Se-Kyung; Park, Jong-Hyeon; Lee, Kwang-Nyeong; Ko, Young-Joon; Lee, Hyang-Sim; Seo, Min-Goo; Shin, Yeun-Kyung; Kim, Byounghan

2014-04-01

Foot-and-mouth disease (FMD) is a virulent and economically costly disease in domestic livestock. Since the current vaccine available against FMD provides no protection until 7days postvaccination, the only alternative method to halt the spread of the FMD virus (FMDV) during outbreaks is by the application of anti-viral agents. The combination of recombinant adenovirus expressing type I interferon (IFN-α) and adenovirus expressing type II IFN (IFN-γ) has been reported to be an effective anti-viral treatment strategy against FMDV. Nevertheless, the recombinant adenovirus mixture may be inefficient because of the low anti-viral efficiency of IFN-γ compared to that of IFN-α. In this study, we generated a recombinant adenovirus co-expressing porcine IFN-α and IFN-γ in tandem using an FMDV 2A sequence to mediate effective cleavage of the two proteins (referred to as Ad-porcine IFN-αγ). We demonstrated that both recombinant porcine IFN-α and IFN-γ were expressed and interferon stimulated gene (ISG)s related with IFN-α and IFN-γ were induced in porcine kidney (IBRS-2) cells infected with Ad-porcine IFN-αγ. Additionally, the anti-viral effects of Ad-porcine IFN-αγ against FMDV were enhanced both in IBRS-2 cells and in CD-1 (ICR) suckling mice compared to that of adenovirus expressing only a single protein. We propose that Ad-porcine IFN-αγ could be a rapid, highly efficient, convenient anti-viral agent against FMDV. Copyright © 2014 Elsevier B.V. All rights reserved.

The role of the PI(3,5)P2 kinase TbFab1 in endo/lysosomal trafficking in Trypanosoma brucei.

PubMed

Gilden, Julia K; Umaer, Khan; Kruzel, Emilia K; Hecht, Oliver; Correa, Renan O; Mansfield, John M; Bangs, James D

2017-06-01

Protein trafficking through endo/lysosomal compartments is critically important to the biology of the protozoan parasite Trypanosoma brucei, but the routes material may take to the lysosome, as well as the molecular factors regulating those routes, remain incompletely understood. Phosphoinositides are signaling phospholipids that regulate many trafficking events by recruiting specific effector proteins to discrete membrane subdomains. In this study, we investigate the role of one phosphoinositide, PI(3,5)P 2 in T. brucei. We find a low steady state level of PI(3,5)P 2 in bloodstream form parasites comparable to that of other organisms. RNAi knockdown of the putative PI(3)P-5 kinase TbFab1 decreases the PI(3,5)P 2 pool leading to rapid cell death. TbFab1 and PI(3,5)P 2 both localize strongly to late endo/lysosomes. While most trafficking functions were intact in TbFab1 deficient cells, including both endocytic and biosynthetic trafficking to the lysosome, lysosomal turnover of an endogenous ubiquitinylated membrane protein, ISG65, was completely blocked suggesting that TbFab1 plays a role in the ESCRT-mediated late endosomal/multivesicular body degradative pathways. Knockdown of a second component of PI(3,5)P 2 metabolism, the PI(3,5)P 2 phosphatase TbFig4, also resulted in delayed turnover of ISG65. Together, these results demonstrate an essential role for PI(3,5)P 2 in the turnover of ubiquitinylated membrane proteins and in trypanosome endomembrane biology. Copyright © 2017 Elsevier B.V. All rights reserved.

Understanding of the mechanical and structural changes induced by alpha particles and heavy ions in the French simulated nuclear waste glass

NASA Astrophysics Data System (ADS)

Karakurt, G.; Abdelouas, A.; Guin, J.-P.; Nivard, M.; Sauvage, T.; Paris, M.; Bardeau, J.-F.

2016-07-01

Borosilicate glasses are considered for the long-term confinement of high-level nuclear wastes. External irradiations with 1 MeV He+ ions and 7 MeV Au5+ ions were performed to simulate effects produced by alpha particles and by recoil nuclei in the simulated SON68 nuclear waste glass. To better understand the structural modifications, irradiations were also carried out on a 6-oxides borosilicate glass, a simplified version of the SON68 glass (ISG glass). The mechanical and macroscopic properties of the glasses were studied as function of the deposited electronic and nuclear energies. Alpha particles and gold ions induced a volume change up to -0.7% and -2.7%, respectively, depending on the glass composition. Nano-indentations tests were used to determine the mechanical properties of the irradiated glasses. A decrease of about -22% to -38% of the hardness and a decrease of the reduced Young's modulus by -8% were measured after irradiations. The evolution of the glass structure was studied by Raman spectroscopy, and also 11B and 27Al Nuclear Magnetic Resonance (MAS-NMR) on a 20 MeV Kr irradiated ISG glass powder. A decrease of the silica network connectivity after irradiation with alpha particles and gold ions is deduced from the structural changes observations. NMR spectra revealed a partial conversion of BO4 to BO3 units but also a formation of AlO5 and AlO6 species after irradiation with Kr ions. The relationships between the mechanical and structural changes are also discussed.

Inhibition of alpha interferon (IFN-α)-induced microRNA-122 negatively affects the anti-hepatitis B virus efficiency of IFN-α.

PubMed

Hao, Junli; Jin, Wensong; Li, Xinghui; Wang, Saifeng; Zhang, Xiaojun; Fan, Hongxia; Li, Changfei; Chen, Lizhao; Gao, Bin; Liu, Guangze; Meng, Songdong

2013-01-01

Alpha interferon (IFN-α)-based therapy can effectively treat chronic hepatitis B virus (HBV) infection, which causes life-threatening complications. Responses to IFN-α therapy vary greatly in chronic hepatitis B (CHB) patients, but underlying mechanisms are almost unknown. In this study, we found that IFN-α treatment induced a marked decrease of microRNA-122 (miR-122) expression in hepatocytes. We next showed that IFN-α-induced miR-122 downregulation was only partly due to transcriptional suppression. One IFN-stimulated gene (ISG), NT5C3, which was identified as a miR-122 target, efficiently inhibited miR-122 by binding and sequestering miR-122 with its mRNA 3'-untranslated region (3'-UTR), indicating that this ISG is involved in IFN-α-mediated miR-122 suppression. Notably, the inhibitory effect of IFN-α on miR-122 was completely abolished by blocking IFN-α-induced upregulation of NT5C3 mRNA expression by RNA interference (RNAi). Meanwhile, we observed that miR-122 dramatically inhibited HBV expression and replication. Finally, we showed that IFN-α-mediated HBV-inhibitory effects could be enhanced significantly by blocking IFN-α-induced downregulation of miR-122. We therefore concluded that IFN-α-induced inhibition of miR-122 may negatively affect the anti-HBV function of IFN-α. These data provide valuable insights for a better understanding of the antiviral mechanism of IFN-α and raise further potential interest in enhancing its anti-HBV efficacy.

Inhibition of Alpha Interferon (IFN-α)-Induced MicroRNA-122 Negatively Affects the Anti-Hepatitis B Virus Efficiency of IFN-α

PubMed Central

Hao, Junli; Jin, Wensong; Li, Xinghui; Wang, Saifeng; Zhang, Xiaojun; Fan, Hongxia; Li, Changfei; Chen, Lizhao; Gao, Bin

2013-01-01

Alpha interferon (IFN-α)-based therapy can effectively treat chronic hepatitis B virus (HBV) infection, which causes life-threatening complications. Responses to IFN-α therapy vary greatly in chronic hepatitis B (CHB) patients, but underlying mechanisms are almost unknown. In this study, we found that IFN-α treatment induced a marked decrease of microRNA-122 (miR-122) expression in hepatocytes. We next showed that IFN-α-induced miR-122 downregulation was only partly due to transcriptional suppression. One IFN-stimulated gene (ISG), NT5C3, which was identified as a miR-122 target, efficiently inhibited miR-122 by binding and sequestering miR-122 with its mRNA 3′-untranslated region (3′-UTR), indicating that this ISG is involved in IFN-α-mediated miR-122 suppression. Notably, the inhibitory effect of IFN-α on miR-122 was completely abolished by blocking IFN-α-induced upregulation of NT5C3 mRNA expression by RNA interference (RNAi). Meanwhile, we observed that miR-122 dramatically inhibited HBV expression and replication. Finally, we showed that IFN-α-mediated HBV-inhibitory effects could be enhanced significantly by blocking IFN-α-induced downregulation of miR-122. We therefore concluded that IFN-α-induced inhibition of miR-122 may negatively affect the anti-HBV function of IFN-α. These data provide valuable insights for a better understanding of the antiviral mechanism of IFN-α and raise further potential interest in enhancing its anti-HBV efficacy. PMID:23055569

Cell-Based Screen Identifies Human Interferon-Stimulated Regulators of Listeria monocytogenes Infection

PubMed Central

Eitson, Jennifer L.; Chen, Didi; Jimenez, Alyssa; Mettlen, Marcel; Schoggins, John W.; Alto, Neal M.

2016-01-01

The type I interferon (IFN) activated transcriptional response is a critical antiviral defense mechanism, yet its role in bacterial pathogenesis remains less well characterized. Using an intracellular pathogen Listeria monocytogenes (Lm) as a model bacterial pathogen, we sought to identify the roles of individual interferon-stimulated genes (ISGs) in context of bacterial infection. Previously, IFN has been implicated in both restricting and promoting Lm growth and immune stimulatory functions in vivo. Here we adapted a gain-of-function flow cytometry based approach to screen a library of more than 350 human ISGs for inhibitors and enhancers of Lm infection. We identify 6 genes, including UNC93B1, MYD88, AQP9, and TRIM14 that potently inhibit Lm infection. These inhibitors act through both transcription-mediated (MYD88) and non-transcriptional mechanisms (TRIM14). Further, we identify and characterize the human high affinity immunoglobulin receptor FcγRIa as an enhancer of Lm internalization. Our results reveal that FcγRIa promotes Lm uptake in the absence of known host Lm internalization receptors (E-cadherin and c-Met) as well as bacterial surface internalins (InlA and InlB). Additionally, FcγRIa-mediated uptake occurs independently of Lm opsonization or canonical FcγRIa signaling. Finally, we established the contribution of FcγRIa to Lm infection in phagocytic cells, thus potentially linking the IFN response to a novel bacterial uptake pathway. Together, these studies provide an experimental and conceptual basis for deciphering the role of IFN in bacterial defense and virulence at single-gene resolution. PMID:28002492

Tip-of-the-tongue phenomena: an introductory phenomenological analysis.

PubMed

Brown, S R

2000-12-01

The issue of meaningful yet unexpressed background-to language and to our experiences of the body-is one whose exploration is still in its infancy. There are various aspects of "invisible," implicit, or background experiences which have been investigated from the viewpoints of phenomenology, cognitive psychology, and linguistics. I will argue that James's concept of the phenomenon of fringes, as explicated by Gurwitsch, provides a structural framework from which to investigate and better understand ideas and concepts that are indeterminate, particularly those experienced in the sense of being sought-after. Johnson's conception of the image-schematic gestalt (ISG) provides an approach to bridging the descriptive gap between phenomenology and cognitive psychology. Starting from an analysis of the fringes, I will turn to a consideration of the tip-of-tongue (TOT) state, as a kind of feeling-of-knowing (FOK) state, from a variety of approaches, focusing mainly on cognitive psychology and phenomenology. I will then integrate a phenomenological analysis of these experiences, from the James/Gurwitsch structural viewpoint, with a cognitive/phenomenological analysis in terms of ISGs, and further integrate that with a cognitive/functional analysis of the relation between consciousness and retrieval, employing Anderson et al's theory of inhibitory mechanisms in cognition. This synthesis of these viewpoints will be employed to explore the thesis that the TOT state and similar experiences may relate to the gestalt nature of schemas, and that figure/ground and other contrast-enhancing structures may be both explanatory and descriptive characterizations of the field of consciousness. Copyright 2000 Academic Press.

Autophagy diminishes the early interferon-β response to influenza A virus resulting in differential expression of interferon-stimulated genes.

PubMed

Perot, Brieuc P; Boussier, Jeremy; Yatim, Nader; Rossman, Jeremy S; Ingersoll, Molly A; Albert, Matthew L

2018-05-10

Influenza A virus (IAV) infection perturbs metabolic pathways such as autophagy, a stress-induced catabolic pathway that crosstalks with cellular inflammatory responses. However, the impact of autophagy perturbation on IAV gene expression or host cell responses remains disputed. Discrepant results may be a reflection of in vivo studies using cell-specific autophagy-related (Atg) gene-deficient mouse strains, which do not delineate modification of developmental programmes from more proximal effects on inflammatory response. In vitro experiments can be confounded by gene expression divergence in wild-type cultivated cell lines, as compared to those experiencing long-term absence of autophagy. With the goal to investigate cellular processes within cells that are competent or incompetent for autophagy, we generated a novel experimental cell line in which autophagy can be restored by ATG5 protein stabilization in an otherwise Atg5-deficient background. We confirmed that IAV induced autophagosome formation and p62 accumulation in infected cells and demonstrated that perturbation of autophagy did not impact viral infection or replication in ATG5-stablized cells. Notably, the induction of interferon-stimulated genes (ISGs) by IAV was diminished when cells were autophagy competent. We further demonstrated that, in the absence of ATG5, IAV-induced interferon-β (IFN-β) expression was increased as compared to levels in autophagy-competent lines, a mechanism that was independent of IAV non-structural protein 1. In sum, we report that induction of autophagy by IAV infection reduces ISG expression in infected cells by limiting IFN-β expression, which may benefit viral replication and spread.

A high throughput screening for TLR3-IRF3 signaling pathway modulators identifies several antipsychotic drugs as TLR inhibitors1

PubMed Central

Zhu, Jianzhong; Smith, Kevin; Hsieh, Paishiun N.; Mburu, Yvonne K.; Chattopadhyay, Saurabh; Sen, Ganes C.; Sarkar, Saumendra N.

2010-01-01

Toll-like Receptor 3 (TLR3) is one of the major innate immune sensors of double stranded RNA (dsRNA). The signal transduction pathway activated by TLR3, upon binding to dsRNA, leads to the activation of two major transcription factors: NF-κB and IRF3. In an effort to identify specific chemical modulators of TLR3-IRF3 signal transduction pathway we developed a cell-based read out system. Using the interferon stimulated gene 56 (ISG56) promoter driven firefly luciferase gene stably integrated in a TLR3 expressing HEK293 cell line, we were able to generate a cell line where treatment with dsRNA resulted in a dose dependent induction of luciferase activity. A screen of two pharmacologically active compound libraries using this system, identified a number of TLR3-IRF3 signaling pathway modulators. Among them we focused on a subset of inhibitors and characterized their mode of action. Several antipsychotic drugs, such as Sertraline, Trifluoperazine and Fluphenazine were found to be direct inhibitors of the innate immune signaling pathway. These inhibitors also showed the ability to inhibit ISG56 induction mediated by TLR4 and TLR7/8 pathways. Interestingly, they did not show significant effect on TLR3, TLR7 and TLR8 mediated NF-κB activation. Detailed analysis of the signaling pathway indicated that these drugs may be exerting their inhibitory effects on IRF3 via PI3K signaling pathway. The data presented here provides mechanistic explanation of possible anti-inflammatory roles of some antipsychotic drugs. PMID:20382888

A three-dimensional culture system using alginate hydrogel prolongs hatched cattle embryo development in vitro.

PubMed

Zhao, Shuan; Liu, Zhen-Xing; Gao, Hui; Wu, Yi; Fang, Yuan; Wu, Shuai-Shuai; Li, Ming-Jie; Bai, Jia-Hua; Liu, Yan; Evans, Alexander; Zeng, Shen-Ming

2015-07-15

No successful method exists to maintain the three-dimensional architecture of hatched embryos in vitro. Alginate, a linear polysaccharide derived from brown algae, has characteristics that make it an ideal material as a three-dimensional (3D) extracellular matrix for in vitro cell, tissue, or embryo culture. In this study, alginate hydrogel was used for IVC of posthatched bovine embryos to observe their development under the 3D system. In vitro-fertilized and parthenogenetically activated posthatched bovine blastocysts were cultured in an alginate encapsulation culture system (AECS), an alginate overlay culture system (AOCS), or control culture system. After 18 days of culture, the survival rate of embryos cultured in AECS was higher than that in the control group (P < 0.05), and the embryos were expanded and elongated in AECS with the maximal length of 1.125 mm. When the AECS shrinking embryos were taken out of the alginate beads on Day 18 and cultured in the normal culture system, 9.09% of them attached to the bottoms of the plastic wells and grew rapidly, with the largest area of an attached embryo being 66.00 mm(2) on Day 32. The embryos cultured in AOCS developed monovesicular or multivesicular morphologies. Total cell number of the embryos cultured in AECS on Day 19 was significantly higher than that of embryos on Day 8. Additionally, AECS and AOCS supported differentiation of the embryonic cells. Binuclear cells were visible in Day-26 adherent embryos, and the messenger RNA expression patterns of Cdx2 and Oct4 in AOCS-cultured embryos were similar to those in vivo embryos, whereas IFNT and ISG15 messenger RNA were still expressed in Day-26 and Day-32 prolong-cultured embryos. In conclusion, AECS and AOCS did support cell proliferation, elongation, and differentiation of hatched bovine embryos during prolonged IVC. The culture system will be useful to further investigate the molecular mechanisms controlling ruminant embryo elongation and implantation. Copyright © 2015 Elsevier Inc. All rights reserved.

Lineage mapper: A versatile cell and particle tracker

NASA Astrophysics Data System (ADS)

Chalfoun, Joe; Majurski, Michael; Dima, Alden; Halter, Michael; Bhadriraju, Kiran; Brady, Mary

2016-11-01

The ability to accurately track cells and particles from images is critical to many biomedical problems. To address this, we developed Lineage Mapper, an open-source tracker for time-lapse images of biological cells, colonies, and particles. Lineage Mapper tracks objects independently of the segmentation method, detects mitosis in confluence, separates cell clumps mistakenly segmented as a single cell, provides accuracy and scalability even on terabyte-sized datasets, and creates division and/or fusion lineages. Lineage Mapper has been tested and validated on multiple biological and simulated problems. The software is available in ImageJ and Matlab at isg.nist.gov.

Report on the Second Catalog Interoperability Workshop

NASA Technical Reports Server (NTRS)

Thieman, James R.; James, Mary E.

1988-01-01

The events, resolutions, and recommendations of the Second Catalog Interoperability Workshop, held at JPL in January, 1988, are discussed. This workshop dealt with the issues of standardization and communication among directories, catalogs, and inventories in the earth and space science data management environment. The Directory Interchange Format, being constructed as a standard for the exchange of directory information among participating data systems, is discussed. Involvement in the Interoperability effort by NASA, NOAA, ISGS, and NSF is described, and plans for future interoperability considered. The NASA Master Directory prototype is presented and critiqued and options for additional capabilities debated.

DDX60L Is an Interferon-Stimulated Gene Product Restricting Hepatitis C Virus Replication in Cell Culture

PubMed Central

Grünvogel, Oliver; Esser-Nobis, Katharina; Reustle, Anna; Schult, Philipp; Müller, Birthe; Metz, Philippe; Trippler, Martin; Windisch, Marc P.; Frese, Michael; Binder, Marco; Fackler, Oliver; Bartenschlager, Ralf; Ruggieri, Alessia

2015-01-01

ABSTRACT All major types of interferon (IFN) efficiently inhibit hepatitis C virus (HCV) replication in vitro and in vivo. Remarkably, HCV replication is not sensitive to IFN-γ in the hepatoma cell line Huh6, despite an intact signaling pathway. We performed transcriptome analyses between Huh6 and Huh-7 cells to identify effector genes of the IFN-γ response and thereby identified the DExD/H box helicase DEAD box polypeptide 60-like (DDX60L) as a restriction factor of HCV replication. DDX60L and its homolog DEAD box polypeptide 60 (DDX60) were both induced upon viral infection and IFN treatment in primary human hepatocytes. However, exclusively DDX60L knockdown increased HCV replication in Huh-7 cells and rescued HCV replication from type II IFN as well as type I and III IFN treatment, suggesting that DDX60L is an important effector protein of the innate immune response against HCV. In contrast, we found no impact of DDX60L on replication of hepatitis A virus. DDX60L protein was detectable only upon strong ectopic overexpression, displayed a broad cytoplasmic distribution, but caused cytopathic effects under these conditions. DDX60L knockdown did not alter interferon-stimulated gene (ISG) induction after IFN treatment but inhibited HCV replication upon ectopic expression, suggesting that it is a direct effector of the innate immune response. It most likely inhibits viral RNA replication, since we found neither impact of DDX60L on translation or stability of HCV subgenomic replicons nor additional impact on assembly of infectious virus. Similar to DDX60, DDX60L had a moderate impact on RIG-I dependent activation of innate immunity, suggesting additional functions in the sensing of viral RNA. IMPORTANCE Interferons induce a plethora of interferon-stimulated genes (ISGs), which are our first line of defense against viral infections. In addition, IFNs have been used in antiviral therapy, in particular against the human pathogen hepatitis C virus (HCV); still, their mechanism of action is not well understood, since diverse, overlapping sets of antagonistic effector ISGs target viruses with different biologies. Our work identifies DDX60L as a novel factor that inhibits replication of HCV. DDX60L expression is regulated similarly to that of its homolog DDX60, but our data suggest that it has distinct functions, since we found no contribution of DDX60 in combatting HCV replication. The identification of novel components of the innate immune response contributes to a comprehensive understanding of the complex mechanisms governing antiviral defense. PMID:26269178

The Interferon-Stimulated Gene Ifitm3 Restricts West Nile Virus Infection and Pathogenesis.

PubMed

Gorman, Matthew J; Poddar, Subhajit; Farzan, Michael; Diamond, Michael S

2016-09-15

The interferon-induced transmembrane protein (IFITM) family of proteins inhibit infection of several different enveloped viruses in cell culture by virtue of their ability to restrict entry and fusion from late endosomes. As few studies have evaluated the importance of Ifitm3 in vivo in restricting viral pathogenesis, we investigated its significance as an antiviral gene against West Nile virus (WNV), an encephalitic flavivirus, in cells and mice. Ifitm3(-/-) mice were more vulnerable to lethal WNV infection, and this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. As no difference in viral burden in the brain or spinal cord was observed after direct intracranial inoculation, Ifitm3 likely functions as an antiviral protein in nonneuronal cells. Consistent with this, Ifitm3(-/-) fibroblasts but not dendritic cells resulted in higher yields of WNV in multistep growth analyses. Moreover, transcomplementation experiments showed that Ifitm3 inhibited WNV infection independently of Ifitm1, Ifitm2, Ifitm5, and Ifitm6. Beyond a direct effect on viral infection in cells, analysis of the immune response in WNV-infected Ifitm3(-/-) mice showed decreases in the total number of B cells, CD4(+) T cells, and antigen-specific CD8(+) T cells. Finally, bone marrow chimera experiments demonstrated that Ifitm3 functioned in both radioresistant and radiosensitive cells, as higher levels of WNV were observed in the brain only when Ifitm3 was absent from both compartments. Our analyses suggest that Ifitm3 restricts WNV pathogenesis likely through multiple mechanisms, including the direct control of infection in subsets of cells. As part of the mammalian host response to viral infections, hundreds of interferon-stimulated genes (ISGs) are induced. The inhibitory activity of individual ISGs varies depending on the specific cell type and viral pathogen. Among ISGs, the genes encoding interferon-induced transmembrane protein (IFITM) have been reported to inhibit multiple families of viruses in cell culture. However, few reports have evaluated the impact of IFITM genes on viral pathogenesis in vivo In this study, we characterized the antiviral activity of Ifitm3 against West Nile virus (WNV), an encephalitic flavivirus, using mice with a targeted gene deletion of Ifitm3 Based on extensive virological and immunological analyses, we determined that Ifitm3 protects mice from WNV-induced mortality by restricting virus accumulation in peripheral organs and, subsequently, in central nervous system tissues. Our data suggest that Ifitm3 restricts WNV pathogenesis by multiple mechanisms and functions in part by controlling infection in different cell types. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

tRNADB-CE: tRNA gene database well-timed in the era of big sequence data.

PubMed

Abe, Takashi; Inokuchi, Hachiro; Yamada, Yuko; Muto, Akira; Iwasaki, Yuki; Ikemura, Toshimichi

2014-01-01

The tRNA gene data base curated by experts "tRNADB-CE" (http://trna.ie.niigata-u.ac.jp) was constructed by analyzing 1,966 complete and 5,272 draft genomes of prokaryotes, 171 viruses', 121 chloroplasts', and 12 eukaryotes' genomes plus fragment sequences obtained by metagenome studies of environmental samples. 595,115 tRNA genes in total, and thus two times of genes compiled previously, have been registered, for which sequence, clover-leaf structure, and results of sequence-similarity and oligonucleotide-pattern searches can be browsed. To provide collective knowledge with help from experts in tRNA researches, we added a column for enregistering comments to each tRNA. By grouping bacterial tRNAs with an identical sequence, we have found high phylogenetic preservation of tRNA sequences, especially at the phylum level. Since many species-unknown tRNAs from metagenomic sequences have sequences identical to those found in species-known prokaryotes, the identical sequence group (ISG) can provide phylogenetic markers to investigate the microbial community in an environmental ecosystem. This strategy can be applied to a huge amount of short sequences obtained from next-generation sequencers, as showing that tRNADB-CE is a well-timed database in the era of big sequence data. It is also discussed that batch-learning self-organizing-map with oligonucleotide composition is useful for efficient knowledge discovery from big sequence data.

Induction of interferon-λ contributes to TLR3 and RIG-I activation-mediated inhibition of herpes simplex virus type 2 replication in human cervical epithelial cells.

PubMed

Zhou, Li; Li, Jie-Liang; Zhou, Yu; Liu, Jin-Biao; Zhuang, Ke; Gao, Jian-Feng; Liu, Shi; Sang, Ming; Wu, Jian-Guo; Ho, Wen-Zhe

2015-12-01

Is it possible to immunologically activate human cervical epithelial cells to produce antiviral factors that inhibit herpes simplex virus type 2 (HSV-2) replication? Our results indicate that human cervical epithelial cells possess a functional TLR3/RIG-I signaling system, the activation of which can mount an Interferon-λ (IFN-λ)-mediated anti-HSV-2 response. There is limited information about the role of cervical epithelial cells in genital innate immunity against HSV-2 infection. We examined the expression of toll-like receptors (TLRs) and retinoic acid-inducible I (RIG-I) in End1/E6E7 cells by real-time PCR. The IFN-λ induced by TLR3 and RIG-I activation of End1/E6E7 cells was also examined by real-time PCR and ELISA. HSV-2 infection of End1/E6E7 cells was evaluated by the real-time PCR detection of HSV-2 gD expression. The antibody to IL-10Rβ was used to determine whether IFN-λ contributes to TLR3/RIG-I mediated HSV-2 inhibition. Expression of interferon regulatory factor 3 (IRF3), IRF7, IFN-stimulated gene 56 (ISG56), 2'-5'-oligoadenylate synthetase I (OAS-1) and myxovirus resistance A (MxA) were determined by the real-time PCR and western blot. End1/E6E7 cells were transfected with shRNA to knockdown the IRF3, IRF7 or RIG-I expression. Student's t-test and post Newman-Keuls test were used to analyze stabilized differences in the immunological parameters above between TLR3/RIG-I-activated cells and control cells. Human cervical epithelial cells expressed functional TLR3 and RIG-I, which could be activated by poly I:C and 5'ppp double-strand RNAs (5'ppp dsRNA), resulting in the induction of endogenous interferon lambda (IFN-λ). The induced IFN-λ contributed to TLR3/RIG-I-mediated inhibition of HSV-2 replication in human cervical epithelial cells, as an antibody to IL-10Rβ, an IFN-λ receptor subunit, could compromise TLR3/RIG-I-mediated inhibition of HSV-2. Further studies showed that TLR3/RIG-I signaling in the cervical epithelial cells by dsRNA induced the expression of the IFN-stimulated genes (ISGs), ISG56, 2'-5'-oligoadenylate synthetase I (OAS-1) and myxovirus resistance A (MxA), the key antiviral elements in the IFN signaling pathway. In addition, we observed that the topical treatment of genital mucosa with poly I:C could protect mice from genital HSV-2 infection. Future prospective studies with primary cells and suitable animal models are needed in order to confirm these outcomes. The findings provide direct and compelling evidence that there is intracellular expression and regulation of IFN-λ in human cervical epithelial cells, which may have a key role in the innate genital protection against viral infections. Not applicable. This work was supported by the National Natural Science Foundation of China (81301428 to L.Z. and 81271334 to W.-Z.H.), the Fundamental Research Funds for the Central Universities (2042015kf0188 to L.Z.), the China Postdoctoral Science Foundation (2013M531745 to L.Z.), the Development Program of China ('973', 2012CB518900 to W.-Z.H.) from the Ministry of Science and Technology of the People's Republic of China, grants (DA12815 and DA022177 to W.-Z.H.) from the National Institute on Drug Abuse (NIDA) and the open project of Hubei Key Laboratory of Wudang Local Chinese Medicine Research (WDCM005 to M.S.). The authors declare no competing financial interests. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Brief Report: Blockade of TANK-Binding Kinase 1/IKKɛ Inhibits Mutant Stimulator of Interferon Genes (STING)-Mediated Inflammatory Responses in Human Peripheral Blood Mononuclear Cells.

PubMed

Frémond, Marie-Louise; Uggenti, Carolina; Van Eyck, Lien; Melki, Isabelle; Bondet, Vincent; Kitabayashi, Naoki; Hertel, Christina; Hayday, Adrian; Neven, Bénédicte; Rose, Yoann; Duffy, Darragh; Crow, Yanick J; Rodero, Mathieu P

2017-07-01

Gain-of-function mutations in TMEM173, encoding the stimulator of interferon (IFN) genes (STING) protein, underlie a novel type I interferonopathy that is minimally responsive to conventional immunosuppressive therapies and associated with high frequency of childhood morbidity and mortality. STING gain-of-function causes constitutive oversecretion of IFN. This study was undertaken to determine the effects of a TANK-binding kinase 1 (TBK-1)/IKKɛ inhibitor (BX795) on secretion and signaling of IFN in primary peripheral blood mononuclear cells (PBMCs) from patients with mutations in STING. PBMCs from 4 patients with STING-associated disease were treated with BX795. The effect of BX795 on IFN pathways was assessed by Western blotting and an IFNβ reporter assay, as well as by quantification of IFNα in cell lysates, staining for STAT-1 phosphorylation, and measurement of IFN-stimulated gene (ISG) messenger RNA (mRNA) expression. Treatment of PBMCs with BX795 inhibited the phosphorylation of IFN regulatory factor 3 and IFNβ promoter activity induced in HEK 293T cells by cyclic GMP-AMP or by genetic activation of STING. In vitro exposure to BX795 inhibited IFNα production in PBMCs of patients with STING-associated disease without affecting cell survival. In addition, BX795 decreased STAT-1 phosphorylation and ISG mRNA expression independent of IFNα blockade. These findings demonstrate the effect of BX795 on reducing type I IFN production and IFN signaling in cells from patients with gain-of-function mutations in STING. A combined inhibition of TBK-1 and IKKɛ therefore holds potential for the treatment of patients carrying STING mutations, and may also be relevant in other type I interferonopathies. © 2017, American College of Rheumatology.

Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis.

PubMed

Beyer, Ulrike; Brand, Frank; Martens, Helge; Weder, Julia; Christians, Arne; Elyan, Natalie; Hentschel, Bettina; Westphal, Manfred; Schackert, Gabriele; Pietsch, Torsten; Hong, Bujung; Krauss, Joachim K; Samii, Amir; Raab, Peter; Das, Anibh; Dumitru, Claudia A; Sandalcioglu, I Erol; Hakenberg, Oliver W; Erbersdobler, Andreas; Lehmann, Ulrich; Reifenberger, Guido; Weller, Michael; Reijns, Martin A M; Preller, Matthias; Wiese, Bettina; Hartmann, Christian; Weber, Ruthild G

2017-12-01

In search of novel germline alterations predisposing to tumors, in particular to gliomas, we studied a family with two brothers affected by anaplastic gliomas, and their father and paternal great-uncle diagnosed with prostate carcinoma. In this family, whole-exome sequencing yielded rare, simultaneously heterozygous variants in the Aicardi-Goutières syndrome (AGS) genes ADAR and RNASEH2B co-segregating with the tumor phenotype. AGS is a genetically induced inflammatory disease particularly of the brain, which has not been associated with a consistently increased cancer risk to date. By targeted sequencing, we identified novel ADAR and RNASEH2B variants, and a 3- to 17-fold frequency increase of the AGS mutations ADAR,c.577C>G;p.(P193A) and RNASEH2B,c.529G>A;p.(A177T) in the germline of familial glioma patients as well as in test and validation cohorts of glioblastomas and prostate carcinomas versus ethnicity-matched controls, whereby rare RNASEH2B variants were significantly more frequent in familial glioma patients. Tumors with ADAR or RNASEH2B variants recapitulated features of AGS, such as calcification and increased type I interferon expression. Patients carrying ADAR or RNASEH2B variants showed upregulation of interferon-stimulated gene (ISG) transcripts in peripheral blood as seen in AGS. An increased ISG expression was also induced by ADAR and RNASEH2B variants in tumor cells and was blocked by the JAK inhibitor Ruxolitinib. Our data implicate rare variants in the AGS genes ADAR and RNASEH2B and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis, consistent with a genetic basis underlying inflammation-driven malignant transformation in glioma and prostate carcinoma development.

ALV-J strain SCAU-HN06 induces innate immune responses in chicken primary monocyte-derived macrophages.

PubMed

Feng, Min; Dai, Manman; Cao, Weisheng; Tan, Yan; Li, Zhenhui; Shi, Meiqing; Zhang, Xiquan

2017-01-01

Avian leucosis virus subgroup J (ALV-J) can cause lifelong infection and can escape from the host immune defenses in chickens. Since macrophages act as the important defense line against invading pathogens in host innate immunity, we investigated the function and innate immune responses of chicken primary monocyte-derived macrophages (MDM) after ALV-J infection in this study. Our results indicated that ALV-J was stably maintained in MDM cells but that the viral growth rate was significantly lower than that in DF-1 cells. We also found that ALV-J infection significantly increased nitric oxide (NO) production, but had no effect on MDM phagocytic capacity. Interestingly, infection with ALV-J rapidly promoted the expression levels of Myxovirus resistance 1 (Mx) (3 h, 6 h), ISG12 (6 h), and interleukin-1β (IL-1β) (3 h, 12 h) at an early infection stage, whereas it sharply decreased the expression of Mx (24 h, 36 h), ISG12 (36 h), and made little change on IL-1β (24 h, 36 h) production at a late infection stage in MDM cells. Moreover, the protein levels of interferon-β (IFN-β) and interleukin-6 (IL-6) had sharply increased in infected MDM cells from 3 to 36 h post infection (hpi) of ALV-J. And, the protein level of interleukin-10 (IL-10) was dramatically decreased at 36 hpi in MDM cells infected with ALV-J. These results demonstrate that ALV-J can induce host innate immune responses and we hypothesize that macrophages play an important role in host innate immune attack and ALV-J immune escape. © The Author 2016. Published by Oxford University Press on behalf of Poultry Science Association.

Systematic identification of anti-interferon function on hepatitis C virus genome reveals p7 as an immune evasion protein.

PubMed

Qi, Hangfei; Chu, Virginia; Wu, Nicholas C; Chen, Zugen; Truong, Shawna; Brar, Gurpreet; Su, Sheng-Yao; Du, Yushen; Arumugaswami, Vaithilingaraja; Olson, C Anders; Chen, Shu-Hua; Lin, Chung-Yen; Wu, Ting-Ting; Sun, Ren

2017-02-21

Hepatitis C virus (HCV) encodes mechanisms to evade the multilayered antiviral actions of the host immune system. Great progress has been made in elucidating the strategies HCV employs to down-regulate interferon (IFN) production, impede IFN signaling transduction, and impair IFN-stimulated gene (ISG) expression. However, there is a limited understanding of the mechanisms governing how viral proteins counteract the antiviral functions of downstream IFN effectors due to the lack of an efficient approach to identify such interactions systematically. To study the mechanisms by which HCV antagonizes the IFN responses, we have developed a high-throughput profiling platform that enables mapping of HCV sequences critical for anti-IFN function at high resolution. Genome-wide profiling performed with a 15-nt insertion mutant library of HCV showed that mutations in the p7 region conferred high levels of IFN sensitivity, which could be alleviated by the expression of WT p7 protein. This finding suggests that p7 protein of HCV has an immune evasion function. By screening a liver-specific ISG library, we identified that IFI6-16 significantly inhibits the replication of p7 mutant viruses without affecting WT virus replication. In contrast, knockout of IFI6-16 reversed the IFN hypersensitivity of p7 mutant virus. In addition, p7 was found to be coimmunoprecipitated with IFI6-16 and to counteract the function of IFI6-16 by depolarizing the mitochondria potential. Our data suggest that p7 is a critical immune evasion protein that suppresses the antiviral IFN function by counteracting the function of IFI6-16.

Oral administration of pentachlorophenol induces interferon signaling mRNAs in C57BL/6 male mouse liver.

PubMed

Kanno, Jun; Aisaki, Ken-ichi; Igarashi, Katsuhide; Kitajima, Satoshi; Matsuda, Nae; Morita, Koichi; Tsuji, Masaki; Moriyama, Noriko; Furukawa, Yusuke; Otsuka, Maki; Tachihara, Erika; Nakatsu, Noriyuki; Kodama, Yukio

2013-01-01

Pentachlorophenol (PCP) was monitored for transcriptome responses in adult mouse liver at 2, 4, 8 and 24 hr after a single oral administration at four dose levels, 0, 10, 30 and 100 mg/kg. The expression data obtained using Affymetrix GeneChip MOE430 2.0 were absolutized by the Percellome method and expressed as three dimensional (3D) surface graphs with axes of time, dose and copy numbers of mRNA per cell. We developed the programs RSort, for comprehensive screening of the 3D surface data and PercellomeExploror for cross-referencing and confirmed the significant responses by visual inspection. In the first 8 hr, approximately 100 probe sets (PSs) related to PXR/SXR and Cyp2a4 and other metabolic enzymes were induced whereas Fos and JunB were suppressed. At 24 hr, about 1,200 PSs were strongly induced. We cross-referenced the Percellome database consisting of 111 chemicals on the liver transcriptome and found that about half of the PSs belonged to the metabolic pathways including Nrf2-mediated oxidative stress response networks shared with some of the 111 chemicals. The other half of the induced genes were interferon signaling network genes (ISG) and their induction was unique to PCP. Toll like receptors and other pattern recognition receptors, interferon regulatory factors and interferon alpha itself were included but inflammatory cytokines were not induced. In summary, these data indicated that functional symptoms of PCP treatment, such as hyperthermia and profuse sweating might be mediated by the ISG rather than the previously documented mitochondrial uncoupling mechanism. PCP might become a hint for developing low molecular weight orally available interferon mimetic drugs following imiquimod and RO4948191 as agonists of toll-like receptor and interferon receptor.

Suppression of type I interferon production by porcine epidemic diarrhea virus and degradation of CREB-binding protein by nsp1

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

Zhang, Qingzhan; Shi, Kaichuang; Yoo, Dongwan, E-mail: dyoo@illinois.edu

Type I interferons (IFN-α/β) are the major components of the innate immune response of hosts, and in turn many viruses have evolved to modulate the host response during infection. We found that the IFN-β production was significantly suppressed during PEDV infection in cells. To identify viral IFN antagonists and to study their suppressive function, viral coding sequences for the entire structural and nonstructural proteins were cloned and expressed. Of 16 PEDV nonstructural proteins (nsps), nsp1, nsp3, nsp7, nsp14, nsp15 and nsp16 were found to inhibit the IFN-β and IRF3 promoter activities. The sole accessory protein ORF3, structure protein envelope (E),more » membrane (M), and nucleocapsid (N) protein were also shown to inhibit such activities. PEDV nsp1 did not interfere the IRF3 phosphorylation and nuclear translocation but interrupted the enhanceosome assembly of IRF3 and CREB-binding protein (CBP) by degrading CBP. A further study showed that the CBP degradation by nsp1 was proteasome-dependent. Our data demonstrate that PEDV modulates the host innate immune responses by degrading CBP and suppressing ISGs expression. - Highlights: • PEDV modulates the host innate immune system by suppressing the type I interferon production and ISGs expression. • Ten viral proteins were identified as IFN antagonists, and nsp1 was the most potent viral IFN antagonist. • PEDV nsp1 did not interfere the IRF3 phosphorylation and nuclear translocation but interrupted the enhanceosome assembly of IRF3 and CREB-binding protein (CBP). • PEDV nsp1 caused the CBP degradation in the nucleus, which may be the key mechanism for PEDV-mediated IFN downregulation.« less

Interplay between Janus Kinase/Signal Transducer and Activator of Transcription Signaling Activated by Type I Interferons and Viral Antagonism

PubMed Central

Nan, Yuchen; Wu, Chunyan; Zhang, Yan-Jin

2017-01-01

Interferons (IFNs), which were discovered a half century ago, are a group of secreted proteins that play key roles in innate immunity against viral infection. The major signaling pathway activated by IFNs is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which leads to the expression of IFN-stimulated genes (ISGs), including many antiviral effectors. Viruses have evolved various strategies with which to antagonize the JAK/STAT pathway to influence viral virulence and pathogenesis. In recent years, notable progress has been made to better understand the JAK/STAT pathway activated by IFNs and antagonized by viruses. In this review, recent progress in research of the JAK/STAT pathway activated by type I IFNs, non-canonical STAT activation, viral antagonism of the JAK/STAT pathway, removing of the JAK/STAT antagonist from viral genome for attenuation, and the potential pathogenesis roles of tyrosine phosphorylation-independent non-canonical STATs activation during virus infection are discussed in detail. We expect that this review will provide new insight into the understanding the complexity of the interplay between JAK/STAT signaling and viral antagonism. PMID:29312301

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

Hurrell, James W.

In fiscal year 2011, the Community Earth System Model (CESM) tutorial was taught at NCAR from 1-5 August 2011. This project hosted 79 full participants (1 accepted participant from China couldn't get a visa) selected from 180 applications. The tutorial was advertised through emails to CESM mailing lists. NCAR staff and long-term visitors (who were not eligible to attend) were also invited to 'audit' the climate and practical lectures and to work on the practical sessions on their own. 15 NCAR staff and long-term visitors took advantage of this opportunity. The majority of the students were graduate students, but severalmore » post-docs, faculty, and other research scientists also attended. Additionally, many people are using the on-line lessons and practical sessions. As of August 18, 2011, 407 people had registered to access and use the tutorial from 33 countries all over the world, but a majority from US universities. In fiscal year 2011, the Climate and Global Dynamics Division Information Systems Group (CGD/ISG) built and operated a temporary computer laboratory in a meeting room. This project was made possible through funding from the National Science Foundation Directorate of Geosciences, and the Department of Energy Office of Science.« less

Geochemical Modeling of Carbon Sequestration, MMV, and EOR in the Illinois Basin

USGS Publications Warehouse

Berger, P.M.; Roy, W.R.; Mehnert, E.

2009-01-01

The Illinois State Geologic Survey is conducting several ongoing CO2 sequestration projects that require geochemical models to gain an understanding of the processes occurring in the subsurface. The ISGS has collected brine and freshwater samples associated with an enhanced oil recovery project in the Loudon oil field. Geochemical modeling allows us to understand reactions with carbonate and silicate minerals in the reservoir, and the effects they have had on brine composition. For the Illinois Basin Decatur project, geochemical models should allow predictions of the reactions that will take place before CO2 injection begins. ?? 2009 Elsevier Ltd. All rights reserved.

Replication and Oncolytic Activity of an Avian Orthoreovirus in Human Hepatocellular Carcinoma Cells

PubMed Central

Kozak, Robert A.; Hattin, Larissa; Biondi, Mia J.; Corredor, Juan C.; Walsh, Scott; Xue-Zhong, Max; Manuel, Justin; McGilvray, Ian D.; Morgenstern, Jason; Lusty, Evan; Cherepanov, Vera; McBey, Betty-Anne; Leishman, David; Feld, Jordan J.; Bridle, Byram; Nagy, Éva

2017-01-01

Oncolytic viruses are cancer therapeutics with promising outcomes in pre-clinical and clinical settings. Animal viruses have the possibility to avoid pre-existing immunity in humans, while being safe and immunostimulatory. We isolated an avian orthoreovirus (ARV-PB1), and tested it against a panel of hepatocellular carcinoma cells. We found that ARV-PB1 replicated well and induced strong cytopathic effects. It was determined that one mechanism of cell death was through syncytia formation, resulting in apoptosis and induction of interferon stimulated genes (ISGs). As hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma worldwide, we investigated the effect of ARV-PB1 against cells already infected with this virus. Both HCV replicon-containing and infected cells supported ARV-PB1 replication and underwent cytolysis. Finally, we generated in silico models to compare the structures of human reovirus- and ARV-PB1-derived S1 proteins, which are the primary targets of neutralizing antibodies. Tertiary alignments confirmed that ARV-PB1 differs from its human homolog, suggesting that immunity to human reoviruses would not be a barrier to its use. Therefore, ARV-PB1 can potentially expand the repertoire of oncolytic viruses for treatment of human hepatocellular carcinoma and other malignancies. PMID:28441762

Sequestering ADM ethanol plant carbon dioxide

USGS Publications Warehouse

Finley, R.J.; Riddle, D.

2008-01-01

Archer Daniels Midland Co. (ADM) and the Illinois State Geological Survey (ISGS) are collaborating on a project in confirming that a rock formation can store carbon dioxide from the plant in its pores. The project aimed to sequester the gas underground permanently to minimize release of the greenhouse gas into the atmosphere. It is also designed to store one million tons of carbon dioxide over a three-year period. The project is worth $84.3M, funded by $66.7M from the US Department Energy, supplemented by co-funding from ADM and other corporate and state resources. The project will start drilling of wells to an expected depth over 6500 feet into the Mount Simon Sandstone formation.

Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice

PubMed Central

Li, Guangming; Cheng, Menglan; Nunoya, Jun-ichi; Cheng, Liang; Guo, Haitao; Yu, Haisheng; Liu, Yong-jun; Su, Lishan; Zhang, Liguo

2014-01-01

The role of plasmacytoid dendritic cells (pDC) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis remains unclear. HIV-1 infection in the humanized mouse model leads to persistent HIV-1 infection and immunopathogenesis, including type I interferons (IFN-I) induction, immune-activation and depletion of human leukocytes, including CD4 T cells. We developed a monoclonal antibody that specifically depletes human pDC in all lymphoid organs in humanized mice. When pDC were depleted prior to HIV-1 infection, the induction of IFN-I and interferon-stimulated genes (ISGs) were abolished during acute HIV-1 infection with either a highly pathogenic CCR5/CXCR4-dual tropic HIV-1 or a standard CCR5-tropic HIV-1 isolate. Consistent with the anti-viral role of IFN-I, HIV-1 replication was significantly up-regulated in pDC-depleted mice. Interestingly, the cell death induced by the highly pathogenic HIV-1 isolate was severely reduced in pDC-depleted mice. During chronic HIV-1 infection, depletion of pDC also severely reduced the induction of IFN-I and ISGs, associated with elevated HIV-1 replication. Surprisingly, HIV-1 induced depletion of human immune cells including T cells in lymphoid organs, but not the blood, was reduced in spite of the increased viral replication. The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells. We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis. These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment. PMID:25077616

Maternal recognition of pregnancy and implantation are not associated with an interferon response of the endometrium to the presence of the conceptus in dromedary camel.

PubMed

Abdoon, Ahmed Sabry; Giraud-Delville, Corrine; Kandil, Omaima Mohamed; Kerboeuf-Giraud, Annelye; Eozénou, Caroline; Carvalho, Anais Vitorino; Julian, Skidmore; Sandra, Olivier

2017-03-01

Maternal recognition of pregnancy (MRP) and implantation involve appropriate interactions between the elongating conceptus and the receptive endometrium that will condition development of the feto-placental unit to term. Molecular mechanisms that take place at the conceptus-endometrium interface during early pregnancy have been extensively investigated in domestic ungulates but they are still poorly understood in camelids including the dromedary camel (Camelus dromedarius), a domestic species with important economic and social roles in arid and semi-arid areas. In order to better understand how MRP and implantation take place in the left horn of this species, we investigated expression levels of genes encoding steroid hormones (PGR, ESR1), transcription factors (STAT1, FOXL2), interferon stimulated genes (MX1, MX2, OAS1, RSAD2) including SOCS genes (SOCS1, SOCS2, SOCS3 and CISH), previously identified as conceptus regulated genes in the endometrium of other domestic animals. Using endometrial tissue collected from left and right uterine horns of dromedary camel females that were non pregnant or early pregnant, gene expression of these genes was detected and our results provided first insights on their regulation, showing that (i) conceptus implantation is not associated with an IFN response in the pregnant uterine horn (ii) when regulation of classical interferon-stimulated genes (ISG) occurs, it takes place during the formation of the feto-placental unit, and (iii) gene expression can differ between the left and right uterine horns during implantation and early placentation phase. Additional experiments will be required in dromedary camels to understand the unusual regulation of ISG during implantation as well as to determine the molecular processes that drive the systematic implantation of the elongating conceptus in the left uterine horn. Copyright © 2017 Elsevier Inc. All rights reserved.

Severe combined immunodeficiency in Sting V154M/WT mice.

PubMed

Bouis, Delphine; Kirstetter, Peggy; Arbogast, Florent; Lamon, Delphine; Delgado, Virginia; Jung, Sophie; Ebel, Claudine; Jacobs, Hugues; Knapp, Anne-Marie; Jeremiah, Nadia; Belot, Alexandre; Martin, Thierry; Crow, Yanick J; André-Schmutz, Isabelle; Korganow, Anne-Sophie; Rieux-Laucat, Frédéric; Soulas-Sprauel, Pauline

2018-05-23

Autosomal dominant gain-of-function (GOF) mutations in human STING (Stimulator of Interferon Genes) lead to a severe autoinflammatory disease called SAVI (STING Associated Vasculopathy with onset in Infancy), associated with enhanced expression of interferon (IFN) stimulated gene (ISG) transcripts. The goal of this study was to analyze the phenotype of a new mouse model of Sting hyperactivation, and the role of type I IFN in this system. We generated a knock-in model carrying an amino acid substitution (V154M) in mouse Sting, corresponding to a recurrent mutation seen in human patients with SAVI. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. Sting V154M/WT mice were crossed to IFNAR (IFNα/β Receptor) knock-out mice in order to evaluate the type I IFN-dependence of the mutant Sting phenotype recorded. In Sting V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T and NK cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B and T cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Whilst the V154M/WT mutant demonstrated increased expression of ISGs, the SCID phenotype was not reversed in Sting V154M/WT IFNAR knock-out mice. However, the anti-proliferative defect in T cells was partially rescued by IFNAR deficiency. Sting GOF mice developed an IFN-independent SCID phenotype with a T, B and NK cell developmental defect and hypogammaglobulinemia, associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was, partially, IFN-dependent. Copyright © 2018. Published by Elsevier Inc.

Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression.

PubMed

Bolen, Christopher R; Ding, Siyuan; Robek, Michael D; Kleinstein, Steven H

2014-04-01

Despite activating similar signaling cascades, the type I and type III interferons (IFNs) differ in their ability to antagonize virus replication. However, it is not clear whether these cytokines induce unique antiviral states, particularly in the liver, where the clinically important hepatitis B and C viruses cause persistent infection. Here, clustering and promoter analyses of microarray-based gene expression profiling were combined with mechanistic studies of signaling pathways to dynamically characterize the transcriptional responses induced by these cytokines in Huh7 hepatoma cells and primary human hepatocytes. Type I and III IFNs differed greatly in their level of interferon-stimulated gene (ISG) induction with a clearly detectable hierarchy (IFN-β > IFN-α > IFN-λ3 > IFN-λ1 > IFN-λ2). Notably, although the hierarchy identified varying numbers of differentially expressed genes when quantified using common statistical thresholds, further analysis of gene expression over multiple timepoints indicated that the individual IFNs do not in fact regulate unique sets of genes. The kinetic profiles of IFN-induced gene expression were also qualitatively similar with the important exception of IFN-α. While stimulation with either IFN-β or IFN-λs resulted in a similar long-lasting ISG induction, IFN-α signaling peaked early after stimulation then declined due to a negative feedback mechanism. The quantitative expression hierarchy and unique kinetics of IFN-α reveal potential specific roles for individual IFNs in the immune response, and elucidate the mechanism behind previously observed differences in IFN antiviral activity. While current clinical trials are focused on IFN-λ1 as a potential antiviral therapy, the finding that IFN-λ3 invariably possesses the highest activity among type III IFNs suggests that this cytokine may have superior clinical activity. © 2014 by the American Association for the Study of Liver Diseases.

Comparison of sitagliptin with nateglinide on postprandial glucose and related hormones in drug-naïve Japanese patients with type 2 diabetes mellitus: A pilot study

PubMed Central

Tanimoto, Masumi; Kanazawa, Akio; Hirose, Takahisa; Yoshihara, Tomoaki; Kobayashi-Kimura, Saeko; Nakanishi, Risa; Tosaka, Yuka; Sasaki-Omote, Ruri; Kudo-Fujimaki, Kyoko; Komiya, Koji; Ikeda, Fuki; Someya, Yuki; Mita, Tomoya; Fujitani, Yoshio; Watada, Hirotaka

2015-01-01

Aims/Introduction Dipeptidyl peptidase-4 inhibitors and glinides are effective in reducing postprandial hyperglycemia. However, little information is available on the comparative effects of the two drugs on the levels of postprandial glucose. The aim of the present study was to compare the effects of sitagliptin and nateglinide on meal tolerance tests in drug-naïve patients with type 2 diabetes mellitus. Materials and Methods The study participants were 19 patients with type 2 diabetes mellitus, which was inadequately controlled by diet and exercise. An open-label, prospective, cross-over trial was carried out to compare the effects of single-dose sitagliptin and nateglinide on the postprandial glucose level and its related hormones during meal tests. Results The change in area under the curve (AUC) of glucose from 0 to 180 min (AUC0–180 min) during the meal test by nateglinide was similar to that by sitagliptin. As expected, the change in active glucagon like peptide-1 was significantly higher after a single-dose of sitagliptin than nateglinide. Then, insulin secretion relative to glucose elevation (ISG) (ΔISG0–180 min: ΔAUC0–180 min insulin/AUC0–180 min glucose) was significantly enhanced by nateglinide compared with sitagliptin. Conversely, glucagon level (ΔAUC0–180 min glucagon) was increased by administration of nateglinide, whereas the glucagon level was reduced by administration of sitagliptin. Conclusions The effects of sitagliptin on postprandial glucose levels were similar to those of nateglinide in drug-naïve type 2 diabetes patients. However, the induced changes in insulin, active glucagon-like peptide-1 and glucagon during meal loading suggest that reduction of postprandial hyperglycemia was achieved by the unique effect of each drug. PMID:26417414

The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription.

PubMed

Chan, Baca; Gonçalves Magalhães, Vladimir; Lemmermann, Niels A W; Juranić Lisnić, Vanda; Stempel, Markus; Bussey, Kendra A; Reimer, Elisa; Podlech, Jürgen; Lienenklaus, Stefan; Reddehase, Matthias J; Jonjić, Stipan; Brinkmann, Melanie M

2017-05-01

The type I interferon (IFN) response is imperative for the establishment of the early antiviral immune response. Here we report the identification of the first type I IFN antagonist encoded by murine cytomegalovirus (MCMV) that shuts down signaling following pattern recognition receptor (PRR) sensing. Screening of an MCMV open reading frame (ORF) library identified M35 as a novel and strong negative modulator of IFNβ promoter induction following activation of both RNA and DNA cytoplasmic PRR. Additionally, M35 inhibits the proinflammatory cytokine response downstream of Toll-like receptors (TLR). Using a series of luciferase-based reporters with specific transcription factor binding sites, we determined that M35 targets NF-κB-, but not IRF-mediated, transcription. Expression of M35 upon retroviral transduction of immortalized bone marrow-derived macrophages (iBMDM) led to reduced IFNβ transcription and secretion upon activation of stimulator of IFN genes (STING)-dependent signaling. On the other hand, M35 does not antagonize interferon-stimulated gene (ISG) 56 promoter induction or ISG transcription upon exogenous stimulation of the type I IFN receptor (IFNAR). M35 is present in the viral particle and, upon MCMV infection of fibroblasts, is immediately shuttled to the nucleus where it exerts its immunomodulatory effects. Deletion of M35 from the MCMV genome and hence from the viral particle resulted in elevated type I IFN transcription and secretion in vitro and in vivo. In the absence of M35, lower viral titers are observed during acute infection of the host, and productive infection in the salivary glands was not detected. In conclusion, the M35 protein is released by MCMV immediately upon infection in order to deftly inhibit the antiviral type I IFN response by targeting NF-κB-mediated transcription. The identification of this novel viral protein reinforces the importance of timely countermeasures in the complex relationship between virus and host.

BRCA1 Mutation Status and Follicular Fluid Exposure Alters NFκB Signaling and ISGylation in Human Fallopian Tube Epithelial Cells.

PubMed

Hollingsworth, Julia; Lau, Angela; Tone, Alicia; Kollara, Alexandra; Allen, Lisa; Colgan, Terence J; Dube, Valerie; Rosen, Barry; Murphy, K Joan; Greenblatt, Ellen M; Feigenberg, Tomer; Virtanen, Carl; Brown, Theodore J

2018-05-28

Germline BRCA1 or BRCA2 mutations (mtBRCA1 and mtBRCA2) increase risk for high-grade serous ovarian cancer (HGSOC), the most commonly diagnosed epithelial ovarian cancer histotype. Other identified risk factors for this cancer, which originates primarily in the distal fallopian tube epithelium (FTE), implicate ovulation, during which the FTE cells become transiently exposed to follicular fluid (FF). To test whether mtBRCA1 or mtBRCA2 nonmalignant FTE cells respond differently to periovulatory FF exposure than control patient FTE cells, gene expression profiles from primary FTE cultures derived from BRCA1 or BRCA2 mutation carriers or control patients were compared at baseline, 24 hours after FF exposure, and 24 hours after FF replacement with culture medium. Hierarchical clustering revealed both FF exposure and BRCA mutation status affect gene expression, with BRCA1 mutation having the greatest impact. Gene set enrichment analysis revealed increased NFκB and EGFR signaling at baseline in mtBRCA1 samples, with increased interferon target gene expression, including members of the ISGylation pathway, observed after recovery from FF exposure. Gene set enrichment analysis did not identify altered pathway signaling in mtBRCA2 samples. An inverse relationship between EGFR signaling and ISGylation with BRCA1 protein levels was verified in an immortalized FTE cell line, OE-E6/E7, stably transfected with BRCA1 cDNA. Suppression of ISG15 and ISGylated protein levels by increased BRCA1 expression was found to be mediated by decreased NFκB signaling. These studies indicate that increased NFκB signaling associated with decreased BRCA1 expression results in increased ISG15 and protein ISGylation following FF exposure, which may be involved in predisposition to HGSOC. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

NOTCH3 variants and risk of ischemic stroke.

PubMed

Ross, Owen A; Soto-Ortolaza, Alexandra I; Heckman, Michael G; Verbeeck, Christophe; Serie, Daniel J; Rayaprolu, Sruti; Rich, Stephen S; Nalls, Michael A; Singleton, Andrew; Guerreiro, Rita; Kinsella, Emma; Wszolek, Zbigniew K; Brott, Thomas G; Brown, Robert D; Worrall, Bradford B; Meschia, James F

2013-01-01

Mutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved. All 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS). Sequencing of the 269 SWISS probands identified one (0.4%) with small vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series. Cysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study.

Proteomic profiling of the human T-cell nucleolus.

PubMed

Jarboui, Mohamed Ali; Wynne, Kieran; Elia, Giuliano; Hall, William W; Gautier, Virginie W

2011-12-01

The nucleolus, site of ribosome biogenesis, is a dynamic subnuclear organelle involved in diverse cellular functions. The size, number and organisation of nucleoli are cell-specific and while it remains to be established, the nucleolar protein composition would be expected to reflect lineage-specific transcriptional regulation of rDNA genes and have cell-type functional components. Here, we describe the first characterisation of the human T-cell nucleolar proteome. Using the Jurkat T-cell line and a reproducible organellar proteomic approach, we identified 872 nucleolar proteins. In addition to ribosome biogenesis and RNA processing networks, network modeling and topological analysis of nucleolar proteome revealed distinct macromolecular complexes known to orchestrate chromatin structure and to contribute to the regulation of gene expression, replication, recombination and repair, and chromosome segregation. Furthermore, among our dataset, we identified proteins known to functionally participate in T-cell biology, including RUNX1, ILF3, ILF2, STAT3, LSH, TCF-1, SATB1, CTCF, HMGB3, BCLAF1, FX4L1, ZAP70, TIAM1, RAC2, THEMIS, LCP1, RPL22, TOPK, RETN, IFI-16, MCT-1, ISG15, and 14-3-3τ, which support cell-specific composition of the Jurkat nucleolus. Subsequently, the nucleolar localisation of RUNX1, ILF3, STAT3, ZAP70 and RAC2 was further validated by Western Blot analysis and immunofluorescence microscopy. Overall, our T-cell nucleolar proteome dataset not only further expands the existing repertoire of the human nucleolar proteome but support a cell type-specific composition of the nucleolus in T cell and highlights the potential roles of the nucleoli in lymphocyte biology. Copyright © 2011 Elsevier Ltd. All rights reserved.

Catalytic Function and Substrate Specificity of the Papain-Like Protease Domain of nsp3 from the Middle East Respiratory Syndrome Coronavirus

PubMed Central

Báez-Santos, Yahira M.; Mielech, Anna M.; Deng, Xufang; Baker, Susan

2014-01-01

ABSTRACT The papain-like protease (PLpro) domain from the deadly Middle East respiratory syndrome coronavirus (MERS-CoV) was overexpressed and purified. MERS-CoV PLpro constructs with and without the putative ubiquitin-like (UBL) domain at the N terminus were found to possess protease, deubiquitinating, deISGylating, and interferon antagonism activities in transfected HEK293T cells. The quaternary structure and substrate preferences of MERS-CoV PLpro were determined and compared to those of severe acute respiratory syndrome coronavirus (SARS-CoV) PLpro, revealing prominent differences between these closely related enzymes. Steady-state kinetic analyses of purified MERS-CoV and SARS-CoV PLpros uncovered significant differences in their rates of hydrolysis of 5-aminomethyl coumarin (AMC) from C-terminally labeled peptide, ubiquitin, and ISG15 substrates, as well as in their rates of isopeptide bond cleavage of K48- and K63-linked polyubiquitin chains. MERS-CoV PLpro was found to have 8-fold and 3,500-fold higher catalytic efficiencies for hydrolysis of ISG15-AMC than for hydrolysis of the Ub-AMC and Z-RLRGG-AMC substrates, respectively. A similar trend was observed for SARS-CoV PLpro, although it was much more efficient than MERS-CoV PLpro toward ISG15-AMC and peptide-AMC substrates. MERS-CoV PLpro was found to process K48- and K63-linked polyubiquitin chains at similar rates and with similar debranching patterns, producing monoubiquitin species. However, SARS-CoV PLpro much preferred K48-linked polyubiquitin chains to K63-linked chains, and it rapidly produced di-ubiquitin molecules from K48-linked chains. Finally, potent inhibitors of SARS-CoV PLpro were found to have no effect on MERS-CoV PLpro. A homology model of the MERS-CoV PLpro structure was generated and compared to the X-ray structure of SARS-CoV PLpro to provide plausible explanations for differences in substrate and inhibitor recognition. IMPORTANCE Unlocking the secrets of how coronavirus (CoV) papain-like proteases (PLpros) perform their multifunctional roles during viral replication entails a complete mechanistic understanding of their substrate recognition and enzymatic activities. We show that the PLpro domains from the MERS and SARS coronaviruses can recognize and process the same substrates, but with different catalytic efficiencies. The differences in substrate recognition between these closely related PLpros suggest that neither enzyme can be used as a generalized model to explain the kinetic behavior of all CoV PLpros. As a consequence, decoding the mechanisms of PLpro-mediated antagonism of the host innate immune response and the development of anti-CoV PLpro enzyme inhibitors will be a challenging undertaking. The results from this study provide valuable information for understanding how MERS-CoV PLpro-mediated antagonism of the host innate immune response is orchestrated, as well as insight into the design of inhibitors against MERS-CoV PLpro. PMID:25142582

Nonlinear relationship between the Product Consistency Test (PCT) response and the Al/B ratio in a soda-lime aluminoborosilicate glass

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

Farooqi, Rahmat Ullah; Hrma, Pavel

2016-06-01

We have investigated the effect of A1/B ratio on the Product Consistency Test (PCT) response. In an aluminoborosilicate soda-lime glass based on a modified International Simple Glass, ISG-3, the A1/B ratio varied from 0 to 0.55 (in mole fractions). In agreement with various models of the PCT response as a function of glass composition, we observed a monotonic increase of B and Na releases with decreasing A1/B mole ratio, but only when the ratio was higher than 0.05. Below this value (A1/B < 0.05), we observed a sharp decrease that we attribute to B in tetrahedral coordination.

Fleet Mooring Leg Design Program Documentation. Volume 7. Source Listings: Table and Graphs.

DTIC Science & Technology

1982-12-01

cop3b ,wgt3. asgt3b, a s)lip,fr ict , cImp3, & scopi, Wgtl, 6 n&sep, & plx,plzpld, N 00 & p2x ,p2z ,P2d, & p3x p3z ,p3d, & hioad~hdir, & rbuoy ,xbuoy...XP-XPOINTl I( YP-YPOINT (Ii IF(JSW ED 1) GO TO 12S DELWX-WXU-WXL DELWY-WYU-WYL XP-(XPNT(I 1*OELWXI)/_,iLVX YP-(YPNT(I 3SOELWYJ/OELVY N’ 12S XF- ICT *XP...0) xcoord-xa a gym -S wrifelul .8) xcoord,hsym,isyn ws- 1 Soo continue * gYM -0 if (isg eq k) isym-S if (k ne 11 goto S0 xcoord-xm an gala 900 continue

Functional, signalling and transcriptional differences of three distinct type I IFNs in a perciform fish, the mandarin fish Siniperca chuatsi.

PubMed

Laghari, Zubair Ahmed; Chen, Shan Nan; Li, Li; Huang, Bei; Gan, Zhen; Zhou, Ying; Huo, Hui Jun; Hou, Jing; Nie, Pin

2018-07-01

Teleost fish are unique in having type I and type II interferons (IFNs) only, and the type I IFNs are classified into Group one and Group two based on the presence of two or four cysteines respectively, and are further classified into seven subgroups. In the present study, three distinct type I IFNs, IFNc, IFNd and IFNh, have been identified in the genome sequences of a perciform fish, the mandarin fish Siniperca chuatsi. These IFNs are induced following the stimulation of Polyinosinic polycytidylic acid (poly(I:C)) and Resiquimod (R848) either in vivo or in vitro. But, the infectious spleen and kidney necrosis virus (ISKNV) infection caused a delayed response of IFNs, which may be resulted from the viral inhibition of type I IFN production and related signalling. The three receptor subunits, cytokine receptor family B 1 (CRFB1), CRFB2 and CRFB5 are also expressed in a similar manner as observed for the IFNs, and IFNc, IFNd and IFNh use preferentially the receptor complex, CRFB2 and CRFB5, CRFB1 and CRFB5, CRFB1 and CRFB5 respectively for their effective signalling in the induction of IFN-stimulated genes (ISGs). Moreover, the IFNs are able to induce their own expression, and also the IRF3 and IRF7 expression, leading to the amplification of IFN cascade. It is further revealed that these three IFNs are transcribed differently by IRF7 and IRF3. The composition, function, signalling and transcription of type I IFNs have been investigated in detail in a teleost fish. Copyright © 2018 Elsevier Ltd. All rights reserved.

Global analysis of ubiquitome in PRRSV-infected pulmonary alveolar macrophages.

PubMed

Zhang, Huan; Fang, Liurong; Zhu, Xinyu; Wang, Dang; Xiao, Shaobo

2018-06-18

Protein lysine ubiquitination is a dynamic reversible post-translational modification that plays key roles in modulating different cellular processes. Porcine reproductive and respiratory syndrome virus (PRRSV) is a notorious pathogen, causing tremendous economic losses for the global swine industry. The possible involvement of ubiquitination in PRRSV infection is unclear. So anti-ubiquitination-based enrichment and LC-MS were performed to investigate the global ubiquitination events triggered by PRRSV infection in pulmonary alveolar macrophages. We totally identified 4044 lysine ubiquitination sites on 1580 cellular proteins, of which 983 sites on 717 proteins were significantly altered at 36 h postinfection. A systematic, intensive bioinformatic analysis of the ubiquitome data suggested that PRRSV suppresses the host immune responses by manipulating the ubiquitination of important adaptors and effectors, including TRAF6, JAK1, STAT1, and ISGs. Ubiquitination was also observed on 15 PRRSV proteins, including important virus proteases and structural proteins that function in virus infectivity and neutralizing antibody elicitation. The efficient replication of PRRSV requires an intact ubiquitin-proteasome system. Our study is the first to analyze the global ubiquitination events in pulmonary alveolar macrophages during PRRSV infection. It provides insight into the molecular mechanisms of PRRSV pathogenesis, promoting the development of antiviral drugs. PRRSV is a notorious pathogen which has been resulting in huge economic losses in the swine industry since the first outbreak. Therefore, more in-depth knowledge of the PRRSV immunoregulatory mechanisms and valid control methods to combat the virus are urgently needed. Ubiquitination is an important post-translational modification regulating various cellular processes. However, information about the possible involvement of ubiquitination responses to PRRSV infection is limited. In this study, a quantitative proteomic approach was first used to analyze ubiquitination level alteration in PRRSV-infected PAMs. We demonstrate that PRRSV can suppresses the host immune responses by manipulating the ubiquitination of important effectors that include TRAF6, JAK1, STAT1, and ISGs. Furthermore, 15 PRRSV proteins undergo ubiquitination and efficient replication of PRRSV requires an intact ubiquitin-proteasome system. Our study will significantly expand our knowledge about the molecular mechanisms of PRRSV pathogenesis and provides novel insights into the development of antiviral drugs. Copyright © 2018. Published by Elsevier B.V.

Endothelial Cell Proteomic Response to Rickettsia conorii Infection Reveals Activation of the Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT)-Inferferon Stimulated Gene (ISG)15 Pathway and Reprogramming Plasma Membrane Integrin/Cadherin Signaling.

PubMed

Zhao, Yingxin; Valbuena, Gustavo; Walker, David H; Gazi, Michal; Hidalgo, Marylin; DeSousa, Rita; Oteo, Jose Antonio; Goez, Yenny; Brasier, Allan R

2016-01-01

Rickettsia conorii is the etiologic agent of Mediterranean spotted fever, a re-emerging infectious disease with significant mortality. This Gram-negative, obligately intracellular pathogen is transmitted via tick bites, resulting in disseminated vascular endothelial cell infection with vascular leakage. In the infected human, Rickettsia conorii infects endothelial cells, stimulating expression of cytokines and pro-coagulant factors. However, the integrated proteomic response of human endothelial cells to R. conorii infection is not known. In this study, we performed quantitative proteomic profiling of primary human umbilical vein endothelial cells (HUVECs) with established R conorii infection versus those stimulated with endotoxin (LPS) alone. We observed differential expression of 55 proteins in HUVEC whole cell lysates. Of these, we observed induction of signal transducer and activator of transcription (STAT)1, MX dynamin-like GTPase (MX1), and ISG15 ubiquitin-like modifier, indicating activation of the JAK-STAT signaling pathway occurs in R. conorii-infected HUVECs. The down-regulated proteins included those involved in the pyrimidine and arginine biosynthetic pathways. A highly specific biotinylated cross-linking enrichment protocol was performed to identify dysregulation of 11 integral plasma membrane proteins that included up-regulated expression of a sodium/potassium transporter and down-regulation of α-actin 1. Analysis of Golgi and soluble Golgi fractions identified up-regulated proteins involved in platelet-endothelial adhesion, phospholipase activity, and IFN activity. Thirty four rickettsial proteins were identified with high confidence in the Golgi, plasma membrane, or secreted protein fractions. The host proteins associated with rickettsial infections indicate activation of interferon-STAT signaling pathways; the disruption of cellular adhesion and alteration of antigen presentation pathways in response to rickettsial infections are distinct from those produced by nonspecific LPS stimulation. These patterns of differentially expressed proteins suggest mechanisms of pathogenesis as well as methods for diagnosis and monitoring Rickettsia infections. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

The Impact of Operating Parameters and Correlated Parameters for Extended BWR Burnup Credit

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

Ade, Brian J.; Marshall, William B. J.; Ilas, Germina

Applicants for certificates of compliance for spent nuclear fuel (SNF) transportation and dry storage systems perform analyses to demonstrate that these systems are adequately subcritical per the requirements of Title 10 of the Code of Federal Regulations (10 CFR) Parts 71 and 72. For pressurized water reactor (PWR) SNF, these analyses may credit the reduction in assembly reactivity caused by depletion of fissile nuclides and buildup of neutron-absorbing nuclides during power operation. This credit for reactivity reduction during depletion is commonly referred to as burnup credit (BUC). US Nuclear Regulatory Commission (NRC) staff review BUC analyses according to the guidancemore » in the Division of Spent Fuel Storage and Transportation Interim Staff Guidance (ISG) 8, Revision 3, Burnup Credit in the Criticality Safety Analyses of PWR Spent Fuel in Transportation and Storage Casks.« less

Flotillin proteins recruit sphingosine to membranes and maintain cellular sphingosine-1-phosphate levels

PubMed Central

Riento, Kirsi; Zhang, Qifeng; Clark, Jonathan; Begum, Farida; Stephens, Elaine; Wakelam, Michael J.

2018-01-01

Sphingosine-1-phosphate (S1P) is an important lipid signalling molecule. S1P is produced via intracellular phosphorylation of sphingosine (Sph). As a lipid with a single fatty alkyl chain, Sph may diffuse rapidly between cellular membranes and through the aqueous phase. Here, we show that the absence of microdomains generated by multimeric assemblies of flotillin proteins results in reduced S1P levels. Cellular phenotypes of flotillin knockout mice, including changes in histone acetylation and expression of Isg15, are recapitulated when S1P synthesis is perturbed. Flotillins bind to Sph in vitro and increase recruitment of Sph to membranes in cells. Ectopic re-localisation of flotillins within the cell causes concomitant redistribution of Sph. The data suggest that flotillins may directly or indirectly regulate cellular sphingolipid distribution and signalling. PMID:29787576

Identification and Herc5-mediated ISGylation of novel target proteins.

PubMed

Takeuchi, Tomoharu; Inoue, Satoshi; Yokosawa, Hideyoshi

2006-09-22

ISG15, a protein containing two ubiquitin-like domains, is an interferon-stimulated gene product that functions in antiviral response and is conjugated to various cellular proteins (ISGylation) upon interferon stimulation. ISGylation occurs via a pathway similar to the pathway for ubiquitination that requires the sequential action of E1/E2/E3: the E1 (UBE1L), E2 (UbcH8), and E3 (Efp/Herc5) enzymes for ISGylation have been hitherto identified. In this study, we identified six novel candidate target proteins for ISGylation by a proteomic approach. Four candidate target proteins were demonstrated to be ISGylated in UBE1L- and UbcH8-dependent manners, and ISGylation of the respective target proteins was stimulated by Herc5. In addition, Herc5 was capable of binding with the respective target proteins. Thus, these results suggest that Herc5 functions as a general E3 ligase for protein ISGylation.

Long non-coding RNA GAS5 is induced by interferons and plays an antitumor role in esophageal squamous cell carcinoma.

PubMed

Huang, Jianbing; Li, Yuan; Lu, Zhiliang; Che, Yun; Sun, Shouguo; Mao, Shuangshuang; Lei, Yuanyuan; Zang, Ruochuan; Li, Ning; Sun, Nan; He, Jie

2018-05-09

The long non-coding RNA GAS5 has been reported as a tumor suppressor in many cancers. However, its functions and mechanisms remain largely unknown in esophageal squamous cell carcinoma (ESCC). In this study, we found that GAS5 was over-expressed in ESCC tissue compared with that in normal esophageal tissue in a public database. Functional studies showed that GAS5 could inhibit ESCC cell proliferation, migration and invasion in vitro. Further analysis revealed that GAS5 was regulated by interferon (IFN) responses via the JAK-STAT pathway. Moreover, as an IFN-stimulated gene (ISG), GAS5 was a positive regulator of IFN responses. The feedback loop between GAS5 and the IFN signaling pathway plays an important antitumor role in ESCC, thus providing novel potential therapeutic targets. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Enabling Interactive Measurements from Large Coverage Microscopy

PubMed Central

Bajcsy, Peter; Vandecreme, Antoine; Amelot, Julien; Chalfoun, Joe; Majurski, Michael; Brady, Mary

2017-01-01

Microscopy could be an important tool for characterizing stem cell products if quantitative measurements could be collected over multiple spatial and temporal scales. With the cells changing states over time and being several orders of magnitude smaller than cell products, modern microscopes are already capable of imaging large spatial areas, repeat imaging over time, and acquiring images over several spectra. However, characterizing stem cell products from such large image collections is challenging because of data size, required computations, and lack of interactive quantitative measurements needed to determine release criteria. We present a measurement web system consisting of available algorithms, extensions to a client-server framework using Deep Zoom, and the configuration know-how to provide the information needed for inspecting the quality of a cell product. The cell and other data sets are accessible via the prototype web-based system at http://isg.nist.gov/deepzoomweb. PMID:28663600

IFN-λ Inhibits MiR-122 Transcription through a Stat3-HNF4α Inflammatory Feedback Loop in an IFN-α Resistant HCV Cell Culture System

PubMed Central

Aboulnasr, Fatma; Hazari, Sidhartha; Nayak, Satyam; Chandra, Partha K.; Panigrahi, Rajesh; Ferraris, Pauline; Chava, Srinivas; Kurt, Ramazan; Song, Kyongsub; Dash, Asha; Balart, Luis A.; Garry, Robert F.; Wu, Tong; Dash, Srikanta

2015-01-01

Background HCV replication in persistently infected cell culture remains resistant to IFN-α/RBV combination treatment, whereas IFN-λ1 induces viral clearance. The antiviral mechanisms by which IFN-λ1 induces sustained HCV clearance have not been determined. Aim To investigate the mechanisms by which IFN-λ clears HCV replication in an HCV cell culture model. Methods IFN-α sensitive (S3-GFP) and resistant (R4-GFP) cells were treated with equivalent concentrations of either IFN-α or IFN-λ. The relative antiviral effects of IFN-α and IFN-λ1 were compared by measuring the HCV replication, quantification of HCV-GFP expression by flow cytometry, and viral RNA levels by real time RT-PCR. Activation of Jak-Stat signaling, interferon stimulated gene (ISG) expression, and miRNA-122 transcription in S3-GFP and R4-GFP cells were examined. Results We have shown that IFN-λ1 induces HCV clearance in IFN-α resistant and sensitive replicon cell lines in a dose dependent manner through Jak-Stat signaling, and induces STAT 1 and STAT 2 activation, ISRE-luciferase promoter activation and ISG expression. Stat 3 activation is also involved in IFN-λ1 induced antiviral activity in HCV cell culture. IFN-λ1 induced Stat 3 phosphorylation reduces the expression of hepatocyte nuclear factor 4 alpha (HNF4α) through miR-24 in R4-GFP cells. Reduced expression of HNF4α is associated with decreased expression of miR-122 resulting in an anti-HCV effect. Northern blot analysis confirms that IFN-λ1 reduces miR-122 levels in R4-GFP cells. Our results indicate that IFN-λ1 activates the Stat 3-HNF4α feedback inflammatory loop to inhibit miR-122 transcription in HCV cell culture. Conclusions In addition to the classical Jak–Stat antiviral signaling pathway, IFN-λ1 inhibits HCV replication through the suppression of miRNA-122 transcription via an inflammatory Stat 3–HNF4α feedback loop. Inflammatory feedback circuits activated by IFNs during chronic inflammation expose non-responders to the risk of hepatocellular carcinoma. PMID:26657215

Induction of interferon-gamma and downstream pathways during establishment of fetal persistent infection with bovine viral diarrhea virus.

PubMed

Smirnova, Natalia P; Webb, Brett T; McGill, Jodi L; Schaut, Robert G; Bielefeldt-Ohmann, Helle; Van Campen, Hana; Sacco, Randy E; Hansen, Thomas R

2014-04-01

Development of transplacental infection depends on the ability of the virus to cross the placenta and replicate within the fetus while counteracting maternal and fetal immune responses. Unfortunately, little is known about this complex process. Non-cytopathic (ncp) strains of bovine viral diarrhea virus (BVDV), a pestivirus in the Flaviviridae family, cause persistent infection in early gestational fetuses (<150 days; persistently infected, PI), but are cleared by immunocompetent animals and late gestational fetuses (>150 days; transiently infected, TI). Evasion of innate immune response and development of immunotolerance to ncp BVDV have been suggested as possible mechanisms for the establishment of the persistent infection. Previously we have observed a robust temporal induction of interferon (IFN) type I (innate immune response) and upregulation of IFN stimulated genes (ISGs) in BVDV TI fetuses. Modest chronic upregulation of ISGs in PI fetuses and calves reflects a stimulated innate immune response during persistent BVDV infection. We hypothesized that establishing persistent fetal BVDV infection is also accompanied by the induction of IFN-gamma (IFN-γ). The aims of the present study were to determine IFN-γ concentration in blood and amniotic fluid from control, TI and PI fetuses during BVDV infection and analyze induction of the IFN-γ downstream pathways in fetal lymphoid tissues. Two experiments with in vivo BVDV infections were completed. In Experiment 1, pregnant heifers were infected with ncp BVDV type 2 on day 75 or 175 of gestation or kept naïve to generate PI, TI and control fetuses, respectively. Fetuses were collected by Cesarean section on day 190. In Experiment 2, fetuses were collected on days 82, 89, 97, 192 and 245 following infection of pregnant heifers on day 75 of gestation. The results were consistent with the hypothesis that ncp BVDV infection induces IFN-γ secretion during acute infection in both TI and PI fetuses and that lymphoid tissues such as spleen, liver and thymus, serve both as possible sources of IFN-γ and target organs for its effects. Notably, induction of IFN-γ coincides with a decrease in BVDV RNA concentrations in PI fetal blood and tissues. This is the first report indicating the possible presence of an adaptive immune response in persistent BVDV infections, which may be contributing to the observed reduction of viremia in PI fetuses. Copyright © 2014 Elsevier B.V. All rights reserved.

Hepatitis D virus replication is sensed by MDA5 and induces IFN-β/λ responses in hepatocytes.

PubMed

Zhang, Zhenfeng; Filzmayer, Christina; Ni, Yi; Sültmann, Holger; Mutz, Pascal; Hiet, Marie-Sophie; Vondran, Florian W R; Bartenschlager, Ralf; Urban, Stephan

2018-07-01

Hepatitis B virus (HBV) and D virus (HDV) co-infections cause the most severe form of viral hepatitis. HDV induces an innate immune response, but it is unknown how the host cell senses HDV and if this defense affects HDV replication. We aim to characterize interferon (IFN) activation by HDV, identify the responsible sensor and evaluate the effect of IFN on HDV replication. HDV and HBV susceptible hepatoma cell lines and primary human hepatocytes (PHH) were used for infection studies. Viral markers and cellular gene expression were analyzed at different time points after infection. Pattern recognition receptors (PRRs) required for HDV-mediated IFN activation and the impact on HDV replication were studied using stable knock-down or overexpression of the PRRs. Microarray analysis revealed that HDV but not HBV infection activated a broad range of interferon stimulated genes (ISGs) in HepG2 NTCP cells. HDV strongly activated IFN-β and IFN-λ in cell lines and PHH. HDV induced IFN levels remained unaltered upon RIG-I (DDX58) or TLR3 knock-down, but were almost completely abolished upon MDA5 (IFIH1) depletion. Conversely, overexpression of MDA5 but not RIG-I and TLR3 in HuH7.5 NTCP cells partially restored ISG induction. During long-term infection, IFN levels gradually diminished in both HepG2 NTCP and HepaRG NTCP cell lines. MDA5 depletion had little effect on HDV replication despite dampening HDV-induced IFN response. Moreover, treatment with type I or type III IFNs did not abolish HDV replication. Active replication of HDV induces an IFN-β/λ response, which is predominantly mediated by MDA5. This IFN response and exogenous IFN treatment have only a moderate effect on HDV replication in vitro indicating the adaption of HDV replication to an IFN-activated state. In contrast to hepatitis B virus, infection with hepatitis D virus induces a strong IFN-β/λ response in innate immune competent cell lines. MDA5 is the key sensor for the recognition of hepatitis D virus replicative intermediates. An IFN-activated state did not prevent hepatitis D virus replication in vitro, indicating that hepatitis D virus is resistant to self-induced innate immune responses and therapeutic IFN treatment. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Impact of oral silymarin on virus- and non-virus-specific T-cells responses in chronic hepatitis C infection

PubMed Central

Adeyemo, Oluwasayo; Doi, Hiroyoshi; Reddy, K. Rajender; Kaplan, David E.

2013-01-01

Silymarin displays anti-inflammatory effects on T-lymphocytes in vitro. The immunomodulatory properties of oral silymarin in vivo in humans with chronic hepatitis C have not previously been characterized. We hypothesized that silymarin would suppress T-cell proliferation and pro-inflammatory cytokine production of virus- and non-virus-specific T-cells while increasing anti-inflammatory IL-10 production in vivo. Patients from one site of the SyNCH-HCV double-masked, placebo-controlled study of oral silymarin in prior interferon non-responders with chronic hepatitis C provided blood samples at baseline and treatment week 20. Mononuclear cells were stimulated with recombinant HCV proteins and controls in 3H-thymidine proliferation assays, IFNγ Elispot and IL-10 Elispot. The frequency of CD4+CD25hi and CD4+foxp3+ regulatory T-cells, serum cytokine levels, serum IP-10 and lymphocyte interferon-stimulated gene expression were also quantified at baseline and week 20. Thirty-two patients were recruited (10; placebo, 11; 420mg three times a day, 11; 700mg three times a day). Serum ALT and HCV RNA titers did not change in any group. HCV-specific CD4+ T-cell proliferation and the frequency of IFNγ– and IL-10-producing T-cells were not significantly changed in silymarin-treated subjects. However, C. albicans-induced T-cell IFNγ and phytohemagglutinin-induced T-cell proliferation were suppressed by silymarin therapy. A trend towards augmentation of interferon-induced ISG15 expression was present in the high-dose silymarin group. While no effect on HCV-specific T-cells was identified, these data confirm that high-dose oral silymarin exerts modest non-specific immunomodulatory effects in vivo. The impact of this anti-inflammatory effect on long-term liver health in chronic hepatitis C merits future clinical investigation. PMID:23730838

Efficacy and safety of repaglinide added to sitagliptin in Japanese patients with type 2 diabetes: A randomized 24-week open-label clinical trial.

PubMed

Nishimura, Akihiro; Usui, Shuki; Kumashiro, Naoki; Uchino, Hiroshi; Yamato, Azusa; Yasuda, Daijiro; Nagasawa, Kaoru; Okubo, Minoru; Mori, Yasumichi; Hirose, Takahisa

2016-12-30

Although sitagliptin and repaglinide monotherapies improve postprandial hyperglycemia, the long-term effects and safety of their combination has not been examined. In this randomized 24-week trial of Japanese patients with poor control (HbA1c 7.0-8.5%) by sitagliptin, we divided 40 patients randomly into two equal groups of the repaglinide add-on to sitagliptin (ADD-ON, n=20), or sitagliptin switched to repaglinide (SWITCH, n=20). The meal tolerance test was carried out at weeks 0 and 24. The primary outcomes were changes in HbA1c and area under the curves (AUC) of glucose from the baseline to week 24. The mean change in HbA1c from baseline to week 24 was larger in the ADD-ON (-0.87±0.63%, mean±SD), compared with the SWITCH (0.03±0.65%, p=0.000). Significant improvements were noted in the mean changes in fasting glucose and AUCs of glucose in the ADD-ON vs. SWITCH (p=0.007 and p=0.000). Insulin secretion relative to glucose elevation (ISG; defined as AUC insulin/AUC glucose) increased significantly in the ADD-ON, although the mean change in fasting insulin level was significantly decreased in the ADD-ON (p=0.015 and p=0.026). The AUC of glucagon was significantly lower at 24-week relative to baseline in the ADD-ON, but was not significant in the two groups (p=0.047 and p=0.056, respectively). The combination therapy produced significant reductions in HbA1c, AUC of glucose and fasting glucose compared with switching to repaglinide without weight gain or severe hypoglycemia. The improved glycemic control with this combination therapy may be at least in part due to augmentation of repaglinide-induced insulin secretion by sitagliptin.

JC virus induces altered patterns of cellular gene expression: Interferon-inducible genes as major transcriptional targets

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

Verma, Saguna; Ziegler, Katja; Ananthula, Praveen

2006-02-20

Human polyomavirus JC (JCV) infects 80% of the population worldwide. Primary infection, typically occurring during childhood, is asymptomatic in immunocompetent individuals and results in lifelong latency and persistent infection. However, among the severely immunocompromised, JCV may cause a fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Virus-host interactions influencing persistence and pathogenicity are not well understood, although significant regulation of JCV activity is thought to occur at the level of transcription. Regulation of the JCV early and late promoters during the lytic cycle is a complex event that requires participation of both viral and cellular factors. We have used cDNA microarraymore » technology to analyze global alterations in gene expression in JCV-permissive primary human fetal glial cells (PHFG). Expression of more than 400 cellular genes was altered, including many that influence cell proliferation, cell communication and interferon (IFN)-mediated host defense responses. Genes in the latter category included signal transducer and activator of transcription 1 (STAT1), interferon stimulating gene 56 (ISG56), myxovirus resistance 1 (MxA), 2'5'-oligoadenylate synthetase (OAS), and cig5. The expression of these genes was further confirmed in JCV-infected PHFG cells and the human glioblastoma cell line U87MG to ensure the specificity of JCV in inducing this strong antiviral response. Results obtained by real-time RT-PCR and Western blot analyses supported the microarray data and provide temporal information related to virus-induced changes in the IFN response pathway. Our data indicate that the induction of an antiviral response may be one of the cellular factors regulating/controlling JCV replication in immunocompetent hosts and therefore constraining the development of PML.« less

Pre-hatching embryo-dependent and -independent programming of endometrial function in cattle

PubMed Central

Sponchiado, Mariana; Gomes, Nathália Souza; Fontes, Patrícia Kubo; Martins, Thiago; del Collado, Maite; Pastore, Athos de Assumpção; Pugliesi, Guilherme; Nogueira, Marcelo Fábio Gouveia

2017-01-01

The bovine pre-implantation embryo secretes bioactive molecules from early development stages, but effects on endometrial function are reported to start only after elongation. Here, we interrogated spatially defined regions of the endometrium transcriptome for responses to a day 7 embryo in vivo. We hypothesize that exposure to an embryo changes the abundance of specific transcripts in the cranial region of the pregnant uterine horn. Endometrium was collected from the uterotubal junction (UTJ), anterior (IA), medial (IM) and posterior (IP) regions of the uterine horn ipsilateral to the CL 7 days after estrus from sham-inseminated (Con) or artificially inseminated, confirmed pregnant (Preg) cows. Abundance of 86 transcripts was evaluated by qPCR using a microfluidic platform. Abundance of 12 transcripts was modulated in the Preg endometrium, including classical interferon-stimulated genes (ISG15, MX1, MX2 and OAS1Y), prostaglandin biosynthesis genes (PTGES, HPGD and AKR1C4), water channel (AQP4) and a solute transporter (SLC1A4) and this was in the UTJ and IA mainly. Additionally, for 71 transcripts, abundance varied according to region of the reproductive tract. Regulation included downregulation of genes associated with proliferation (IGF1, IGF2, IGF1R and IGF2R) and extracellular matrix remodeling (MMP14, MMP19 and MMP2) and upregulation of anti-adhesive genes (MUC1) in the cranial regions of uterine horn. Physical proximity to the embryo provides paracrine regulation of endometrial function. Embryo-independent regulation of the endometrial transcriptome may support subsequent stages of embryo development, such as elongation and implantation. We speculate that successful early embryo-dependent and -independent programming fine-tune endometrial functions that are important for maintenance of pregnancy in cattle. PMID:28423001

ERRα negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction

PubMed Central

Tian, Yinyin; Wei, Congwen; Zhu, Yongjie; Li, Feng; Zhang, Pingping; Wang, Penghao; Zhang, Yanhong

2017-01-01

Estrogen-related receptor α (ERRα) is a member of the nuclear receptor superfamily controlling energy homeostasis; however, its precise role in regulating antiviral innate immunity remains to be clarified. Here, we showed that ERRα deficiency conferred resistance to viral infection both in vivo and in vitro. Mechanistically, ERRα inhibited the production of type-I interferon (IFN-I) and the expression of multiple interferon-stimulated genes (ISGs). Furthermore, we found that viral infection induced TBK1-dependent ERRα stabilization, which in turn associated with TBK1 and IRF3 to impede the formation of TBK1-IRF3, IRF3 phosphorylation, IRF3 dimerization, and the DNA binding affinity of IRF3. The effect of ERRα on IFN-I production was independent of its transcriptional activity and PCG-1α. Notably, ERRα chemical inhibitor XCT790 has broad antiviral potency. This work not only identifies ERRα as a critical negative regulator of antiviral signaling, but also provides a potential target for future antiviral therapy. PMID:28591144

5-Hydroxytryptophan, a major product of tryptophan degradation, is essential for optimal replication of human parainfluenza virus.

PubMed

Rabbani, M A G; Barik, Sailen

2017-03-01

Interferon (IFN) exerts its antiviral effect by inducing a large family of cellular genes, named interferon (IFN)-stimulated genes (ISGs). An intriguing member of this family is indoleamine 2,3-dioxygenase (IDO), which catalyzes the first and rate-limiting step of the main branch of tryptophan (Trp) degradation, the kynurenine pathway. We recently showed that IDO strongly inhibits human parainfluenza virus type 3 (PIV3), a significant respiratory pathogen. Here, we show that 5-hydoxytryptophan (5-HTP), the first product of an alternative branch of Trp degradation and a serotonin precursor, is essential to protect virus growth against IDO in cell culture. We also show that the apparent antiviral effect of IDO on PIV3 is not due to the generation of the kynurenine pathway metabolites, but rather due to the depletion of intracellular Trp by IDO, as a result of which this rare amino acid becomes unavailable for the alternative, proviral 5-HTP pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Hepatitis A, B and nAnB: The Viruses and their Prevention

PubMed Central

Minuk, G. Y.

1985-01-01

Three viruses commonly infect the liver: hepatitis A virus (HAV), hepatitis B virus (HBV) and the virus(es) responsible for non A non B hepatitis (nAnB). HAV infection occurs predominantly by the fecal-oral route and thus is more common in areas where living conditions are poor and personal hygiene suboptimal. Immune serum globulin (ISG) prevents this form of hepatitis. HBV infection can be spread by either parenteral (e.g. drug abuse) or non-parenteral (e.g. intimate contact) routes. High risk, susceptible individuals should be vaccinated with the HBV vaccine for longterm protection. Hepatitis B immune globulin (HBIG) remains the treatment of choice after exposure, but its protective effect does not exceed three to four months. The nAnB agent is spread by the same routes as HBV infection. At present there is no convincing evidence that any form of active or passive prophylaxis is beneficial for this form of hepatitis. PMID:21279152

Viperin restricts chikungunya virus replication and pathology

PubMed Central

Teng, Terk-Shin; Foo, Suan-Sin; Simamarta, Diane; Lum, Fok-Moon; Teo, Teck-Hui; Lulla, Aleksei; Yeo, Nicholas K.W.; Koh, Esther G.L.; Chow, Angela; Leo, Yee-Sin; Merits, Andres; Chin, Keh-Chuang; Ng, Lisa F.P.

2012-01-01

Chikungunya virus (CHIKV) is a mosquito-borne arthralgia arbovirus that is reemergent in sub-Saharan Africa and Southeast Asia. CHIKV infection has been shown to be self-limiting, but the molecular mechanisms of the innate immune response that control CHIKV replication remain undefined. Here, longitudinal transcriptional analyses of PBMCs from a cohort of CHIKV-infected patients revealed that type I IFNs controlled CHIKV infection via RSAD2 (which encodes viperin), an enigmatic multifunctional IFN-stimulated gene (ISG). Viperin was highly induced in monocytes, the major target cell of CHIKV in blood. Anti-CHIKV functions of viperin were dependent on its localization in the ER, and the N-terminal amphipathic α-helical domain was crucial for its antiviral activity in controlling CHIKV replication. Furthermore, mice lacking Rsad2 had higher viremia and severe joint inflammation compared with wild-type mice. Our data demonstrate that viperin is a critical antiviral host protein that controls CHIKV infection and provide a preclinical basis for the design of effective control strategies against CHIKV and other reemerging arthrogenic alphaviruses. PMID:23160199

Characterization of common carp (Cyprinus carpio L.) interferon regulatory factor 5 (IRF5) and its expression in response to viral and bacterial challenges.

PubMed

Zhu, Yaoyao; Qi, Chenchen; Shan, Shijuan; Zhang, Fumiao; Li, Hua; An, Liguo; Yang, Guiwen

2016-06-27

Common carp (Cyprinus carpio L.), one of the most economically valuable commercial farming fish species in China, is often infected by a variety of viruses. As the first line of defence against microbial pathogens, the innate immune system plays a crucial role in teleost fish, which are lower vertebrates. Interferon (IFN) regulatory factor 5 (IRF5) is a key molecule in antiviral immunity that regulating the expression of IFN and other pro-inflammatory cytokines. It is necessary to gain more insight into the common carp IFN system and the function of fish IRF5 in the antiviral and antibacterial response. In the present study, we characterized the cDNA and genomic sequence of the IRF5 gene in common carp, and analysed tissue distribution and expression profile of this gene in response to polyinosinic:polycytidylic acid (poly I:C) and lipopolysaccharides (LPS) treatment. The common carp IRF5 (ccIRF5) gene is 5790 bp in length and is composed of 9 exons and 8 introns. The open reading frame (ORF) of ccIRF5 is 1554 bp, and encodes 517 amino acid protein. The putative ccIRF5 protein shares identity (65.4-90.0 %) with other fish IRF5s and contains a DNA binding domain (DBD), a middle region (MR), an IRF-associated domain (IAD), a virus activated domain (VAD) and two nuclear localization signals (NLSs) similar to those found in vertebrate IRF5. Phylogenetic analysis clustered ccIRF5 into the IRF5 subfamily with other vertebrate IRF5 and IRF6 genes. Real-time PCR analysis revealed that ccIRF5 mRNA was expressed in all examined tissues of healthy carps, with high levels observed in the gills and the brain. After poly I:C challenge, expression levels of ccIRF5, tumour-necrosis factor α (ccTNFα) and two IFN stimulated genes [ISGs (ccISG5 and ccPKR)] were up-regulated in seven immune-related tissues (liver, spleen, head kidney, foregut, hindgut, skin and gills). Furthermore, all four genes were up-regulated in vitro upon poly I:C and LPS challenges. Our findings suggest that IRF5 might play an important role in regulating the antiviral and antibacterial response in fish. These results could provide a clue for preventing common carp infection by pathogenic microorganisms present in the aquatic environment.

Cross Talk between Nucleotide Synthesis Pathways with Cellular Immunity in Constraining Hepatitis E Virus Replication

PubMed Central

Wang, Yijin; Wang, Wenshi; Xu, Lei; Zhou, Xinying; Shokrollahi, Ehsan; Felczak, Krzysztof; van der Laan, Luc J. W.; Pankiewicz, Krzysztof W.; Sprengers, Dave; Raat, Nicolaas J. H.; Metselaar, Herold J.; Peppelenbosch, Maikel P.

2016-01-01

Viruses are solely dependent on host cells to propagate; therefore, understanding virus-host interaction is important for antiviral drug development. Since de novo nucleotide biosynthesis is essentially required for both host cell metabolism and viral replication, specific catalytic enzymes of these pathways have been explored as potential antiviral targets. In this study, we investigated the role of different enzymatic cascades of nucleotide biosynthesis in hepatitis E virus (HEV) replication. By profiling various pharmacological inhibitors of nucleotide biosynthesis, we found that targeting the early steps of the purine biosynthesis pathway led to the enhancement of HEV replication, whereas targeting the later step resulted in potent antiviral activity via the depletion of purine nucleotide. Furthermore, the inhibition of the pyrimidine pathway resulted in potent anti-HEV activity. Interestingly, all of these inhibitors with anti-HEV activity concurrently triggered the induction of antiviral interferon-stimulated genes (ISGs). Although ISGs are commonly induced by interferons via the JAK-STAT pathway, their induction by nucleotide synthesis inhibitors is completely independent of this classical mechanism. In conclusion, this study revealed an unconventional novel mechanism of cross talk between nucleotide biosynthesis pathways and cellular antiviral immunity in constraining HEV infection. Targeting particular enzymes in nucleotide biosynthesis represents a viable option for antiviral drug development against HEV. HEV is the most common cause of acute viral hepatitis worldwide and is also associated with chronic hepatitis, especially in immunocompromised patients. Although often an acute and self-limiting infection in the general population, HEV can cause severe morbidity and mortality in certain patients, a problem compounded by the lack of FDA-approved anti-HEV medication available. In this study, we have investigated the role of the nucleotide synthesis pathway in HEV infection and its potential for antiviral drug development. We show that targeting the later but not the early steps of the purine synthesis pathway exerts strong anti-HEV activity. In particular, IMP dehydrogenase (IMPDH) is the most important anti-HEV target of this cascade. Importantly, the clinically used IMPDH inhibitors, including mycophenolic acid and ribavirin, have potent anti-HEV activity. Furthermore, targeting the pyrimidine synthesis pathway also exerts potent antiviral activity against HEV. Interestingly, antiviral effects of nucleotide synthesis pathway inhibitors appear to depend on the medication-induced transcription of antiviral interferon-stimulated genes. Thus, this study reveals an unconventional novel mechanism as to how nucleotide synthesis pathway inhibitors can counteract HEV replication. PMID:26926637

Effects of polyunsaturated fatty acids supplementation on reproductive parameters associated with the performance of suckled beef cows.

PubMed

Fontes, P L P; Henry, D D; Ciriaco, F M; Oosthuizen, N; Cooke, R F; Mercadante, V R G; DiLorenzo, N; Lamb, G C

2018-06-21

To evaluate the effects of a polyunsaturated fatty acids (PUFA) supplement on reproductive parameters of suckled beef cows, two experiments were conducted. In Experiment (Exp.) 1, 60 primiparous cows were randomly assigned to one of two treatments: CTRL - 1.36 kg/day of corn gluten feed (CGF) and MEGR - 1.36 kg/day of CGF and 0.23 kg/day of calcium salts of soybean oil. Supplementation occurred from 30 days before fixed-time artificial insemination (TAI) until 7 days post-TAI. The expression of interferon-stimulated genes (ISG) was measured on days 18 and 21. Pregnancy rates were diagnosed on days 30 and 100. Treatment altered plasma fatty acid profile (P<0.05), however, did not change cow BW (P=0.52) or body condition score (BCS) (P=0.52). Treatment did not alter (P=0.12) pregnancy rates to TAI or final pregnancy rates (P=0.56). Treatments did not impact messenger RNA (mRNA) expression of the ISG OAS1 or MX2 on days 18 (P=0.67; P=0.96, respectively) or 21 (P=0.72; P=0.17, respectively). Length of gestation was greater (P=0.02) for MEGR, however, treatments did not alter calf birth weight (P=0.20). In Exp. two, 66 multiparous cows were assigned to one of two treatments: MEG - 0.65 kg/day of CGF+0.23 kg/day of calcium salts of palm oil and MEGR - 0.65 kg/day of CGF+0.23 kg/day of Ca salts of soybean oil. Cows were supplemented from 30 days prepartum to 30 days postpartum. On day 35 after TAI, pregnancy status, embryo crown-to-rump length (CRL), and plasma concentrations of pregnancy-specific protein-B (PSPB) were evaluated. Treatment altered plasma fatty acid profile (P<0.05). In addition, cows from the MEG treatment had greater BW (P<0.01) and BCS (P<0.01) than those in the MEGR treatment, as well as heavier calves at weaning (P=0.03). Treatment did not affect resumption of estrous cycle (P=0.29). There were no differences in pregnancy rates to TAI (P=0.87) or final pregnancy rates (P=0.29). No differences between treatments were detected on CRL (P=0.24) and plasma concentrations of PSPB (P=0.46). Birth weight (P=0.12) and calving distribution (P=0.52) were not altered. We concluded that PUFA supplementation altered plasma fatty acid profile, however, did not impact the remaining reproductive parameters evaluated.

A moderate increase in ambient temperature modulates the Atlantic cod (Gadus morhua) spleen transcriptome response to intraperitoneal viral mimic injection

PubMed Central

2012-01-01

Background Atlantic cod (Gadus morhua) reared in sea-cages can experience large variations in temperature, and these have been shown to affect their immune function. We used the new 20K Atlantic cod microarray to investigate how a water temperature change which, simulates that seen in Newfoundland during the spring-summer (i.e. from 10°C to 16°C, 1°C increase every 5 days) impacted the cod spleen transcriptome response to the intraperitoneal injection of a viral mimic (polyriboinosinic polyribocytidylic acid, pIC). Results The temperature regime alone did not cause any significant increases in plasma cortisol levels and only minor changes in spleen gene transcription. However, it had a considerable impact on the fish spleen transcriptome response to pIC [290 and 339 significantly differentially expressed genes between 16°C and 10°C at 6 and 24 hours post-injection (HPI), respectively]. Seventeen microarray-identified transcripts were selected for QPCR validation based on immune-relevant functional annotations. Fifteen of these transcripts (i.e. 88%), including DHX58, STAT1, IRF7, ISG15, RSAD2 and IκBα, were shown by QPCR to be significantly induced by pIC. Conclusions The temperature increase appeared to accelerate the spleen immune transcriptome response to pIC. We found 41 and 999 genes differentially expressed between fish injected with PBS vs. pIC at 10°C and sampled at 6HPI and 24HPI, respectively. In contrast, there were 656 and 246 genes differentially expressed between fish injected with PBS vs. pIC at 16°C and sampled at 6HPI and 24HPI, respectively. Our results indicate that the modulation of mRNA expression of genes belonging to the NF-κB and type I interferon signal transduction pathways may play a role in controlling temperature-induced changes in the spleen’s transcript expression response to pIC. Moreover, interferon effector genes such as ISG15 and RSAD2 were differentially expressed between fish injected with pIC at 10°C vs. 16°C at 6HPI. These results substantially increase our understanding of the genes and molecular pathways involved in the negative impacts of elevated ambient temperature on fish health, and may also be valuable to our understanding of how accelerated global climate change could impact cold-water marine finfish species. PMID:22928584

A moderate increase in ambient temperature modulates the Atlantic cod (Gadus morhua) spleen transcriptome response to intraperitoneal viral mimic injection.

PubMed

Hori, Tiago S; Gamperl, A Kurt; Booman, Marije; Nash, Gordon W; Rise, Matthew L

2012-08-28

Atlantic cod (Gadus morhua) reared in sea-cages can experience large variations in temperature, and these have been shown to affect their immune function. We used the new 20K Atlantic cod microarray to investigate how a water temperature change which, simulates that seen in Newfoundland during the spring-summer (i.e. from 10°C to 16°C, 1°C increase every 5 days) impacted the cod spleen transcriptome response to the intraperitoneal injection of a viral mimic (polyriboinosinic polyribocytidylic acid, pIC). The temperature regime alone did not cause any significant increases in plasma cortisol levels and only minor changes in spleen gene transcription. However, it had a considerable impact on the fish spleen transcriptome response to pIC [290 and 339 significantly differentially expressed genes between 16°C and 10°C at 6 and 24 hours post-injection (HPI), respectively]. Seventeen microarray-identified transcripts were selected for QPCR validation based on immune-relevant functional annotations. Fifteen of these transcripts (i.e. 88%), including DHX58, STAT1, IRF7, ISG15, RSAD2 and IκBα, were shown by QPCR to be significantly induced by pIC. The temperature increase appeared to accelerate the spleen immune transcriptome response to pIC. We found 41 and 999 genes differentially expressed between fish injected with PBS vs. pIC at 10°C and sampled at 6HPI and 24HPI, respectively. In contrast, there were 656 and 246 genes differentially expressed between fish injected with PBS vs. pIC at 16°C and sampled at 6HPI and 24HPI, respectively. Our results indicate that the modulation of mRNA expression of genes belonging to the NF-κB and type I interferon signal transduction pathways may play a role in controlling temperature-induced changes in the spleen's transcript expression response to pIC. Moreover, interferon effector genes such as ISG15 and RSAD2 were differentially expressed between fish injected with pIC at 10°C vs. 16°C at 6HPI. These results substantially increase our understanding of the genes and molecular pathways involved in the negative impacts of elevated ambient temperature on fish health, and may also be valuable to our understanding of how accelerated global climate change could impact cold-water marine finfish species.

Plant Line Trial Evaluation of Viable Non-Chromium Passivation Systems for Electrolytin Tinplate, ETP (TRP 9911)

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

John A. Sinsel

2003-06-30

Plant trial evaluations have been completed for two zirconium-based, non-chromium passivation systems previously identified as possible alternatives to cathodic dichromate (CDC) passivation for electrolytic tinplate (ETP). These trials were done on a commercial electrolytic tin plating line at Weirton Steel and extensive evaluations of the materials resulting from these trials have been completed. All this was accomplished as a collaborative effort under the AISI Technology Roadmap Program and was executed by seven North American Tin Mill Products producers [Bethlehem Steel (now acquired by International Steel Group (ISG)), Dofasco Inc., National Steel (now acquired by U.S. Steel), U.S. Steel, USS-Posco, Weirtonmore » Steel, and Wheeling-Pittsburgh Steel] with funding partially from the Department of Energy (DOE) and partially on an equal cost sharing basis among project participants. The initial phases of this project involved optimization of application procedures for the non-chromium systems in the laboratories at Bethlehem Steel and Betz Dearborn followed by extensive testing with various lacquer formulations and food simulants in the laboratories at Valspar and PPG. Work was also completed at Dofasco and Weirton Steel to develop methods to prevent precipitation of insoluble solids as a function of time from the zirconate system. The results of this testing indicated that sulfide staining characteristics for the non-chromium passivation systems could be minimized but not totally eliminated and neither system was found to perform quite as good, in this respect, as the standard CDC system. As for the stability of zirconate treatment, a method was developed to stabilize this system for a sufficient period of time to conduct plant trial evaluations but, working with a major supplier of zirconium orthosulfate, a method for long term stabilization is still under development.« less

Serum MX2 Protein as Candidate Biomarker for Early Pregnancy Diagnosis in Buffalo.

PubMed

Buragohain, L; Kumar, R; Nanda, T; Phulia, S K; Mohanty, A K; Kumar, S; Balhara, S; Ghuman, Sps; Singh, I; Balhara, A K

2016-08-01

Interferon-tau (IFN-τ)-induced molecular markers such as ubiquitin-like modifier (ISG15), 2',5'-oligoadenylate synthetase 1 (OAS1) and myxovirus resistance genes (MX1 and MX2) have generated immense attention towards developing diagnostic tools for early diagnosis of pregnancy in bovine. These molecules are expressed at transcriptional level in peripheral nucleated cells. However, their presence in the serum is still a question mark. This study reports sequential changes in expression of MX2 transcript in whole blood and serum MX2 protein level on days 0, 7, 14, 21, 28 and 35 in pregnant (n = 9) buffalo heifers, and on days 0, 7 and 14 in non-inseminated (n = 8) and inseminated non-pregnant (n = 10) control animals. In non-inseminated and inseminated non-pregnant heifers, the differential expression of MX2 transcript and MX2 protein level remained similar between day 7 and 14 post-oestrus. However, in pregnant heifers, on 14th and 28th day post-insemination MX2 transcript was 16.38 ± 1.57 and 28.16 ± 1.91 times upregulated as compared to day 0. Similarly, serum MX2 protein concentration followed analogous trend as MX2 transcript and increased gradually with the progression of pregnancy. Correlation analysis between expression of MX2 transcript and its serum protein level showed a significant positive correlation in pregnant animals, while it was random in other two groups. Therefore, MX2 surge at transcriptional and serum protein level after day 14-28 of pregnancy in buffalo holds potential for its use in early pregnancy detection. © 2016 Blackwell Verlag GmbH.

Evolution of IFN-λ in tetrapod vertebrates and its functional characterization in green anole lizard (Anolis carolinensis).

PubMed

Chen, Shan Nan; Zhang, Xiao Wen; Li, Li; Ruan, Bai Ye; Huang, Bei; Huang, Wen Shu; Zou, Peng Fei; Fu, Jian Ping; Zhao, Li Juan; Li, Nan; Nie, Pin

2016-08-01

IFN-λ (IFNL), i.e. type III IFN genes were found in a conserved gene locus in tetrapod vertebrates. But, a unique locus containing IFNL was found in avian. In turtle and crocodile, IFNL genes were distributed in these two separate loci. As revealed in phylogenetic trees, IFN-λs in these two different loci and other amniotes were grouped into two different clades. The conservation in gene presence and gene locus was also observed for the receptors of IFN-λ, IFN-λR1 and IL-10RB in tetrapods. It is further revealed that in North American green anole lizard Anolis carolinensis, a single IFNL gene was situated collinearly in the conserved locus as in other tetrapods, together with its receptors IFN-λR1 and IL-10RB also identified in this study. The IFN-λ and its receptors were expressed in all examined organs/tissues, and their expression was stimulated following the injection of polyI:polyC. The ISREs in promoter of IFN-λ in lizard were responsible to IRF3 as demonstrated using luciferase report system, and IFN-λ in lizard functioned through the receptors, IFN-λR1 and IL-10RB, as the up-regulation of ISGs was observed in ligand-receptor transfected, and also in recombinant IFN-λ stimulated, cell lines. Taken together, it is concluded that the mechanisms involved in type III IFN ligand-receptor system, and in its signalling pathway and its down-stream genes may be conserved in green anole lizard, and may even be so in tetrapods from xenopus to human. Copyright © 2016. Published by Elsevier Ltd.

High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II study.

PubMed

Boye, Kjetil; Del Prever, Adalberto Brach; Eriksson, Mikael; Saeter, Gunnar; Tienghi, Amelia; Lindholm, Paula; Fagioli, Franca; Skjeldal, Sigmund; Ferrari, Stefano; Hall, Kirsten Sundby

2014-05-01

Patients with metastatic osteosarcoma at diagnosis or axial primary tumors have a poor prognosis. The aim of the study was to evaluate the feasibility and efficacy of intensified treatment with high-dose chemotherapy (HDCT) and stem cell rescue in this group. From May 1996 to August 2004, 71 patients were included in a Scandinavian-Italian single arm phase II study. Preoperative chemotherapy included methotrexate, doxorubicin, cisplatin and ifosfamide, and postoperative treatment consisted of two cycles of doxorubicin, one cycle of cyclophosphamide and etoposide and two courses of high-dose etoposide and carboplatin with stem cell rescue. Twenty-nine patients (43%) received two courses and 10 patients (15%) received one course of HDCT. HDCT was associated with significant toxicity, but no treatment-related deaths were recorded. Fourteen patients (20%) had disease progression before completion of the study protocol, and only 29/71 patients (41%) received the full planned treatment. Median event-free survival (EFS) was 18 months, and estimated 5-year EFS was 27%. Median overall survival (OS) was 34 months, and estimated 5-year OS was 31%. When patients who did not receive HDCT due to disease progression were excluded, there was no difference in EFS (P = 0.72) or OS (P = 0.49) between patients who did or did not receive HDCT. The administration of high-dose chemotherapy with stem cell rescue was feasible, but associated with significant toxicity. Patient outcome seemed comparable to previous studies using conventional chemotherapy. We conclude that HDCT with carboplatin and etoposide should not be further explored as a treatment strategy in high-risk osteosarcoma. © 2013 Wiley Periodicals, Inc.

Two distinct interferon-γ genes in Tetraodon nigroviridis: Functional analysis during Vibrio parahaemolyticus infection.

PubMed

Peng, Wan; Lu, Dan-Qi; Li, Gao-Fei; Zhang, Xu; Yao, Mi; Zhang, Yong; Lin, Hao-Ran

2016-02-01

Interferon gamma (IFNγ) is a Th1 cytokine that plays a very important role in almost all phases of immune and inflammatory responses. In this study, we explored the functions of IFNγ1 and IFNγ2 of Tetraodon nigroviridis. Treating T. nigroviridis spleen and head kidney cells in vitro with recombinant T. nigroviridis IFNγ1 protein (rTn IFNγ1) or recombinant T. nigroviridis IFNγ2 protein (rTn IFNγ2) enhanced their nitric oxide responses. Both rTn IFNγ1 and rTn IFNγ2 also induced the expression of interferon-stimulated gene 15 (ISG15), a common anti-viral gene, although the expression of the interferon-inducible Mx gene was markedly inhibited by rTn IFNγ1 and was induced by rTn IFNγ2. The in vivo effects of rTn IFNγ1 and rTn IFNγ2 on Vibrio parahaemolyticus (V. parahaemolyticus) infection were assessed by intraperitoneally injecting rTn IFNγ1 or rTn IFNγ2 (100 ng) and V. parahaemolyticus (8 × 10(10)CFU/mL) into T. nigroviridis. A comparison of the group treated only with V. parahaemolyticus and those also treated with rTn IFNγ1 or rTn IFNγ2 showed that neither of these IFNγs protected T. nigroviridis from V. parahaemolyticus infection. However, rTn IFNγ1 more rapidly and robustly promoted inflammatory responses compared with rTn IFNγ2, whereas rTn IFNγ2 was involved in inducing the host to develop a more effective response earlier during the later stage of a V. parahaemolyticus infection. Moreover, microRNA-29b (miR-29b) expression is inversely correlated with IFNγ2 expression in T. nigroviridis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Non-alcoholic Fatty Liver Disease and Metabolic Syndrome-Position Paper of the Indian National Association for the Study of the Liver, Endocrine Society of India, Indian College of Cardiology and Indian Society of Gastroenterology.

PubMed

Duseja, Ajay; Singh, Shivaram P; Saraswat, Vivek A; Acharya, Subrat K; Chawla, Yogesh K; Chowdhury, Subhankar; Dhiman, Radha K; Jayakumar, Rohinivilasam V; Madan, Kaushal; Misra, Sri P; Mishra, Hrudananda; Modi, Sunil K; Muruganathan, Arumugam; Saboo, Banshi; Sahay, Rakesh; Upadhyay, Rajesh

2015-03-01

Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic syndrome. Prevalence of metabolic risk factors including diabetes mellitus, obesity, etc. is rapidly increasing in India putting this population at risk for NAFLD. Patients with NAFLD are at increased risk for liver-related morbidity and mortality and also cardiovascular disease risk and increased incidence of diabetes mellitus on long-term follow-up. Management of patients with NAFLD may require a multi-disciplinary approach involving not only the hepatologists but also the internists, cardiologists, and endocrinologists. This position paper which is a combined effort of the Indian National Association for Study of the Liver (INASL), Endocrine Society of India (ESI), Indian College of Cardiology (ICC) and the Indian Society of Gastroenterology (ISG) defines the spectrum of NAFLD and the association of NAFLD with insulin resistance and metabolic syndrome besides suggesting preferred approaches for the diagnosis and management of patients with NAFLD in the Indian context.

IL-7–dependent STAT1 activation limits homeostatic CD4+ T cell expansion

PubMed Central

Le Saout, Cecile; Luckey, Megan A.; Villarino, Alejandro V.; Smith, Mindy; Hasley, Rebecca B.; Myers, Timothy G.; Imamichi, Hiromi; Park, Jung-Hyun; O’Shea, John J.; Lane, H. Clifford

2017-01-01

IL-7 regulates homeostatic mechanisms that maintain the overall size of the T cell pool throughout life. We show that, under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in an IL-7–dependent STAT1 and STAT5 activation. Consequently, the IL-7–induced transcriptome is altered with enrichment of IFN-stimulated genes (ISGs). Moreover, STAT1 overexpression was associated with reduced survival in CD4+ T cells undergoing lymphopenia-induced proliferation (LIP). We propose a model in which T cells undergoing LIP upregulate STAT1 protein, “switching on” an alternate IL-7–dependent program. This mechanism could be a physiological process to regulate the expansion and size of the CD4+ T cell pool. During HIV infection, the virus could exploit this pathway, leading to the homeostatic dysregulation of the T cell pools observed in these patients. PMID:29202461

Halbach array-based design and simulation of disc coreless permanen-magnet integrated starter generator

NASA Astrophysics Data System (ADS)

Li, Y. B.; Yang, Z. X.; Chen, W.; He, Q. Y.

2017-11-01

The functional performance, such as magnetic flux leakage, power density and efficiency, is related to the structural characteristics and design technique for the disc permanent magnet synchronous generators (PMSGs). Halbach array theory-based magnetic circuit structure is developed, and Maxwell3D simulation analysis approach of PMSG is proposed in this paper for integrated starter generator (ISG). The magnetization direction of adjacent permanent magnet is organized in difference of 45 degrees for focusing air gap side, and improving the performance of the generator. The magnetic field distribution and functional performance in load and/or unload conditions are simulated by Maxwell3D module. The proposed approach is verified by simulation analysis, the air gap flux density is 0.66T, and the phase voltage curve has the characteristics of a preferable sinusoidal wave and the voltage amplitude 335V can meet the design requirements while the disc coreless PMSG is operating at rated speed. And the developed magnetic circuit structure can be used for engineering design of the disc coreless PMSG to the integrated starter generator.

Non-alcoholic Fatty Liver Disease and Metabolic Syndrome—Position Paper of the Indian National Association for the Study of the Liver, Endocrine Society of India, Indian College of Cardiology and Indian Society of Gastroenterology

PubMed Central

Duseja, Ajay; Singh, Shivaram P.; Saraswat, Vivek A.; Acharya, Subrat K.; Chawla, Yogesh K.; Chowdhury, Subhankar; Dhiman, Radha K.; Jayakumar, Rohinivilasam V.; Madan, Kaushal; Misra, Sri P.; Mishra, Hrudananda; Modi, Sunil K.; Muruganathan, Arumugam; Saboo, Banshi; Sahay, Rakesh; Upadhyay, Rajesh

2015-01-01

Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic syndrome. Prevalence of metabolic risk factors including diabetes mellitus, obesity, etc. is rapidly increasing in India putting this population at risk for NAFLD. Patients with NAFLD are at increased risk for liver-related morbidity and mortality and also cardiovascular disease risk and increased incidence of diabetes mellitus on long-term follow-up. Management of patients with NAFLD may require a multi-disciplinary approach involving not only the hepatologists but also the internists, cardiologists, and endocrinologists. This position paper which is a combined effort of the Indian National Association for Study of the Liver (INASL), Endocrine Society of India (ESI), Indian College of Cardiology (ICC) and the Indian Society of Gastroenterology (ISG) defines the spectrum of NAFLD and the association of NAFLD with insulin resistance and metabolic syndrome besides suggesting preferred approaches for the diagnosis and management of patients with NAFLD in the Indian context. PMID:25941433

Development and Implementation of the Midwest Geological Sequestration Consortium CO 2-Technology Transfer Center

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

Greenberg, Sallie E.

2015-06-30

In 2009, the Illinois State Geological Survey (ISGS), in collaboration with the Midwest Geological Sequestration Consortium (MGSC), created a regional technology training center to disseminate carbon capture and sequestration (CCS) technology gained through leadership and participation in regional carbon sequestration projects. This technology training center was titled and branded as the Sequestration Training and Education Program (STEP). Over the last six years STEP has provided local, regional, national, and international education and training opportunities for engineers, geologists, service providers, regulators, executives, K-12 students, K-12 educators, undergraduate students, graduate students, university and community college faculty members, and participants of community programsmore » and functions, community organizations, and others. The goal for STEP educational programs has been on knowledge sharing and capacity building to stimulate economic recovery and development by training personnel for commercial CCS projects. STEP has worked with local, national and international professional organizations and regional experts to leverage existing training opportunities and provide stand-alone training. This report gives detailed information on STEP activities during the grant period (2009-2015).« less

Synthetic Oligodeoxynucleotides (ODN) Containing Suppressive TTAGGG Motifs Inhibit AIM2 Inflammasome Activation

PubMed Central

Kaminski, John J.; Schattgen, Stefan A.; Tzeng, Te-Chen; Bode, Christian; Klinman, Dennis M.; Fitzgerald, Katherine A.

2013-01-01

Synthetic oligodeoxynucleotides comprised of the immunosuppressive motif TTAGGG block TLR9 signaling, prevent STAT1 and STAT4 phosphorylation and attenuate a variety of inflammatory responses in vivo. Here, we demonstrate that such suppressive oligodeoxynucleotides (sup ODN) abrogate activation of cytosolic nucleic acid sensing pathways. Pretreatment of dendritic cells and macrophages with the suppressive ODN-A151 abrogated type I IFN, TNFα and ISG induction in response to cytosolic dsDNA. In addition, A151 abrogated caspase-1-dependent IL-1β and IL-18 maturation in dendritic cells stimulated with dsDNA and murine cytomegalovirus (MCMV). Inhibition was dependent on A151’s phosphorothioate backbone while substitution of the guanosine residues for adenosine negatively affected potency. A151 mediates these effects by binding to AIM2 in a manner that is competitive with immune-stimulatory DNA and as a consequence prevents AIM2 inflammasome complex formation. Collectively, these findings reveal a new route by which suppressive ODNs modulate the immune system and unveil novel applications for suppressive ODNs in the treatment of infectious and autoimmune diseases. PMID:23986531

Murine cytomegalovirus: detection of latent infection by nucleic acid hybridization technique.

PubMed Central

Cheung, K S; Huang, E S; Lang, D J

1980-01-01

The technique of nucleic acid hybridization was used to detect the presence of murine cytomegalovirus (MCMV)-specific deoxyribonucleic acid (DNA) in cell cultures and salivary gland tissues. The presence of approximately 4.5 and 0.2 genome equivalents per cell of MCMV-specific DNA was identified in cultures of salivary (ISG2) and prostate gland (IP) cells, respectively. These cells, derived from animals with experimentally induced latent infections, were negative for virus-specific antigens by immunofluorescence and on electron microscopy revealed no visible evidence of the presence of herpesviruses. A cell line derived from the salivary gland of an uninoculated animal (NSG2) was also found to possess MCMV-specific DNA (0.2 genome equivalents per cell). For this reason, salivary gland tissues from uninoculated animals supplied as "specific pathogen-free" mice by three commercial sources were tested upon arrival for the presence of MCMC-specific DNA. MCMV-specific DNA was detectable in pooled salivary gland extracts from uninoculated animals derived from two commercial sources. All of these animals were seronegative and virus negative by conventional infectivity assays. PMID:6247281

Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes.

PubMed

Verrier, Eloi R; Colpitts, Che C; Bach, Charlotte; Heydmann, Laura; Zona, Laetitia; Xiao, Fei; Thumann, Christine; Crouchet, Emilie; Gaudin, Raphaël; Sureau, Camille; Cosset, François-Loïc; McKeating, Jane A; Pessaux, Patrick; Hoshida, Yujin; Schuster, Catherine; Zeisel, Mirjam B; Baumert, Thomas F

2016-10-25

Chronic hepatitis B, C, and D virus (HBV, HCV, and HDV) infections are the leading causes of liver disease and cancer worldwide. Recently, the solute carrier and sodium taurocholate co-transporter NTCP has been identified as a receptor for HBV and HDV. Here, we uncover NTCP as a host factor regulating HCV infection. Using gain- and loss-of-function studies, we show that NTCP mediates HCV infection of hepatocytes and is relevant for cell-to-cell transmission. NTCP regulates HCV infection by augmenting the bile-acid-mediated repression of interferon-stimulated genes (ISGs), including IFITM3. In conclusion, our results uncover NTCP as a mediator of innate antiviral immune responses in the liver, and they establish a role for NTCP in the infection process of multiple viruses via distinct mechanisms. Collectively, our findings suggest a role for solute carriers in the regulation of innate antiviral responses, and they have potential implications for virus-host interactions and antiviral therapies. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Herpes simplex virus-1 infection causes the secretion of a type I interferon-antagonizing protein and inhibits signaling at or before Jak-1 activation

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

Johnson, Karen E.; Knipe, David M., E-mail: david_knipe@hms.harvard.ed

2010-01-05

Host cells respond to viral infection by the production of type I interferons (IFNs), which induce the expression of antiviral genes. Herpes simplex virus I (HSV-1) encodes many mechanisms that inhibit the type I IFN response, including the ICP27-dependent inhibition of type I IFN signaling. Here we show inhibition of Stat-1 nuclear accumulation in cells that express ICP27. ICP27 expression also induces the secretion of a small, heat-stable type I IFN antagonizing protein that inhibits Stat-1 nuclear accumulation. We show that the inhibition of IFN-induced Stat-1 phosphorylation occurs at or upstream of Jak-1 phosphorylation. Finally, we show that ISG15 expressionmore » is induced after IFNalpha treatment in mock-infected cells, but not cells infected with WT HSV-1 or ICP27{sup -} HSV-1. These data suggest that HSV-1 has evolved multiple mechanisms to inhibit IFN signaling not only in infected cells, but also in neighboring cells, thereby allowing for increased viral replication and spread.« less

Characterization of hMTr1, a Human Cap1 2′-O-Ribose Methyltransferase*

PubMed Central

Bélanger, François; Stepinski, Janusz; Darzynkiewicz, Edward; Pelletier, Jerry

2010-01-01

Cellular eukaryotic mRNAs are capped at their 5′ ends with a 7-methylguanosine nucleotide, a structural feature that has been shown to be important for conferring mRNA stability, stimulating mRNA biogenesis (splicing, poly(A) addition, nucleocytoplasmic transport), and increasing translational efficiency. Whereas yeast mRNAs have no additional modifications to the cap, called cap0, higher eukaryotes are methylated at the 2′-O-ribose of the first or the first and second transcribed nucleotides, called cap1 and cap2, respectively. In the present study, we identify the methyltransferase responsible for cap1 formation in human cells, which we call hMTr1 (also known as FTSJD2 and ISG95). We show in vitro that hMTr1 catalyzes specific methylation of the 2′-O-ribose of the first nucleotide of a capped RNA transcript. Using siRNA-mediated knockdown of hMTr1 in HeLa cells, we demonstrate that hMTr1 is responsible for cap1 formation in vivo. PMID:20713356

Regulation of the nuclear factor (NF)-kappaB pathway by ISGylation.

PubMed

Minakawa, Miki; Sone, Takayuki; Takeuchi, Tomoharu; Yokosawa, Hideyoshi

2008-12-01

Post-translational modification with ISG15 (interferon-stimulated gene 15 kDa) (ISGylation) is mediated by a sequential reaction similar to ubiquitination, and various target proteins for ISGylation have been identified. We previously reported that ISGylation of the E2 ubiquitin-conjugating enzyme Ubc13 suppresses its E2 activity. Ubc13 forms a heterodimer with Uev1A, a ubiquitin-conjugating enzyme variant, and the Ubc13-Uev1A complex catalyzes the assembly of a Lys63-linked polyubiquitin chain, which plays a non-proteolytic role in the nuclear factor (NF)-kappaB pathway. In this study, we examined the effect of ISGylation on tumor necrosis factor receptor-associated factor (TRAF)-6/transforming growth factor beta-activated kinase (TAK)-1-dependent NF-kappaB activation. We found that expression of the ISGylation system suppresses NF-kappaB activation via TRAF6 and TAK1 and that the level of polyubiquitinated TRAF6 is reduced by expression of the ISGylation system. Taken together, the results suggest that the NF-kappaB pathway is negatively regulated by ISGylation.

Innate immune restriction and antagonism of viral RNA lacking 2'-O methylation

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

Hyde, Jennifer L.; Diamond, Michael S., E-mail: diamond@borcim.wustl.edu; Molecular Microbiology, Washington University School of Medicine, St Louis., MO 63110

N-7 and 2′-O methylation of host cell mRNA occurs in the nucleus and results in the generation of cap structures (cap 0, m{sup 7}GpppN; cap 1, m{sup 7}GpppNm) that control gene expression by modulating nuclear export, splicing, turnover, and protein synthesis. Remarkably, RNA cap modification also contributes to mammalian cell host defense as viral RNA lacking 2′-O methylation is sensed and inhibited by IFIT1, an interferon (IFN) stimulated gene (ISG). Accordingly, pathogenic viruses that replicate in the cytoplasm have evolved mechanisms to circumvent IFIT1 restriction and facilitate infection of mammalian cells. These include: (a) generating cap 1 structures on theirmore » RNA through cap-snatching or virally-encoded 2′-O methyltransferases, (b) using cap-independent means of translation, or (c) using RNA secondary structural motifs to antagonize IFIT1 binding. This review will discuss new insights as to how specific modifications at the 5′-end of viral RNA modulate host pathogen recognition responses to promote infection and disease.« less

Mixed matrix hollow fiber membranes for removal of protein-bound toxins from human plasma.

PubMed

Tijink, Marlon S L; Wester, Maarten; Glorieux, Griet; Gerritsen, Karin G F; Sun, Junfen; Swart, Pieter C; Borneman, Zandrie; Wessling, Matthias; Vanholder, Raymond; Joles, Jaap A; Stamatialis, Dimitrios

2013-10-01

In end stage renal disease (ESRD) waste solutes accumulate in body fluid. Removal of protein bound solutes using conventional renal replacement therapies is currently very poor while their accumulation is associated with adverse outcomes in ESRD. Here we investigate the application of a hollow fiber mixed matrix membrane (MMM) for removal of these toxins. The MMM hollow fiber consists of porous macro-void free polymeric inner membrane layer well attached to the activated carbon containing outer MMM layer. The new membranes have permeation properties in the ultrafiltration range. Under static conditions, they adsorb 57% p-cresylsulfate, 82% indoxyl sulfate and 94% of hippuric acid from spiked human plasma in 4 h. Under dynamic conditions, they adsorb on average 2.27 mg PCS/g membrane and 3.58 mg IS/g membrane in 4 h in diffusion experiments and 2.68 mg/g membrane PCS and 12.85 mg/g membrane IS in convection experiments. Based on the dynamic experiments we estimate that our membranes would suffice to remove the daily production of these protein bound solutes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Coping with Aging and Amputation

MedlinePlus

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Reflections: The Value of Patient Support Groups.

PubMed

Hu, Amanda

2017-04-01

A patient support group is defined as "a group of people with common experiences and concerns who provide emotional and moral support for one another." Support groups fulfill many functions: educating patients/family, sharing the illness experience, providing strength to its members, raising public awareness, and fundraising. Some research has shown an improvement in quality of life of patients with head and neck cancer who have participated in support groups. A wide variety of support groups are available for otolaryngology patients, ranging from head and neck oncology to tinnitus and spasmodic dysphonia. Some support groups are face-to-face, while others use social media and the Internet. Surprisingly, engagement in patient support groups is low-about 10%. Some barriers to accessing support groups are awareness, time constraints, and confrontation of negative aspects of the disease. As otolaryngologists, we can help our patients access support groups so that they can benefit from these resources.

Histophilus somni Stimulates Expression of Antiviral Proteins and Inhibits BRSV Replication in Bovine Respiratory Epithelial Cells

PubMed Central

Lin, C.; Agnes, J. T.; Behrens, N.; Tagawa, Y.; Gershwin, L. J.; Corbeil, L. B.

2016-01-01

Our previous studies showed that bovine respiratory syncytial virus (BRSV) followed by Histophilus somni causes more severe bovine respiratory disease and a more permeable alveolar barrier in vitro than either agent alone. However, microarray analysis revealed the treatment of bovine alveolar type 2 (BAT2) epithelial cells with H. somni concentrated culture supernatant (CCS) stimulated up-regulation of four antiviral protein genes as compared with BRSV infection or dual treatment. This suggested that inhibition of viral infection, rather than synergy, may occur if the bacterial infection occurred before the viral infection. Viperin (or radical S-adenosyl methionine domain containing 2—RSAD2) and ISG15 (IFN-stimulated gene 15—ubiquitin-like modifier) were most up-regulated. CCS dose and time course for up-regulation of viperin protein levels were determined in treated bovine turbinate (BT) upper respiratory cells and BAT2 lower respiratory cells by Western blotting. Treatment of BAT2 cells with H. somni culture supernatant before BRSV infection dramatically reduced viral replication as determined by qRT PCR, supporting the hypothesis that the bacterial infection may inhibit viral infection. Studies of the role of the two known H. somni cytotoxins showed that viperin protein expression was induced by endotoxin (lipooligosaccharide) but not by IbpA, which mediates alveolar permeability and H. somni invasion. A naturally occurring IbpA negative asymptomatic carrier strain of H. somni (129Pt) does not cause BAT2 cell retraction or permeability of alveolar cell monolayers, so lacks virulence in vitro. To investigate initial steps of pathogenesis, we showed that strain 129Pt attached to BT cells and induced a strong viperin response in vitro. Thus colonization of the bovine upper respiratory tract with an asymptomatic carrier strain lacking virulence may decrease viral infection and the subsequent enhancement of bacterial respiratory infection in vivo. PMID:26859677

Histophilus somni Stimulates Expression of Antiviral Proteins and Inhibits BRSV Replication in Bovine Respiratory Epithelial Cells.

PubMed

Lin, C; Agnes, J T; Behrens, N; Shao, M; Tagawa, Y; Gershwin, L J; Corbeil, L B

2016-01-01

Our previous studies showed that bovine respiratory syncytial virus (BRSV) followed by Histophilus somni causes more severe bovine respiratory disease and a more permeable alveolar barrier in vitro than either agent alone. However, microarray analysis revealed the treatment of bovine alveolar type 2 (BAT2) epithelial cells with H. somni concentrated culture supernatant (CCS) stimulated up-regulation of four antiviral protein genes as compared with BRSV infection or dual treatment. This suggested that inhibition of viral infection, rather than synergy, may occur if the bacterial infection occurred before the viral infection. Viperin (or radical S-adenosyl methionine domain containing 2--RSAD2) and ISG15 (IFN-stimulated gene 15--ubiquitin-like modifier) were most up-regulated. CCS dose and time course for up-regulation of viperin protein levels were determined in treated bovine turbinate (BT) upper respiratory cells and BAT2 lower respiratory cells by Western blotting. Treatment of BAT2 cells with H. somni culture supernatant before BRSV infection dramatically reduced viral replication as determined by qRT PCR, supporting the hypothesis that the bacterial infection may inhibit viral infection. Studies of the role of the two known H. somni cytotoxins showed that viperin protein expression was induced by endotoxin (lipooligosaccharide) but not by IbpA, which mediates alveolar permeability and H. somni invasion. A naturally occurring IbpA negative asymptomatic carrier strain of H. somni (129Pt) does not cause BAT2 cell retraction or permeability of alveolar cell monolayers, so lacks virulence in vitro. To investigate initial steps of pathogenesis, we showed that strain 129Pt attached to BT cells and induced a strong viperin response in vitro. Thus colonization of the bovine upper respiratory tract with an asymptomatic carrier strain lacking virulence may decrease viral infection and the subsequent enhancement of bacterial respiratory infection in vivo.

Japanese Cancer Survivors' Awareness of and Participation in Support Groups.

PubMed

Hatano, Yutaka; Mitsuki, Sachiko; Hosokawa, Toyoshi; Fukui, Kenji

2018-02-01

Cancer survivors face many challenges, and cancer support groups provide a range of support. Several reports have shown the benefits of support groups. However, it is not clear how Japanese cancer survivors use them. This study aimed to examine cancer survivors' awareness of and reasons for participation or non-participation in cancer support groups. We conducted a cross-sectional questionnaire survey with ambulatory patients with cancer across eight designated cancer hospitals. The questionnaire covered patients' demographics, disease characteristics, participation/non-participation in cancer support groups, and reasons for participation/non-participation. In total, 569 questionnaires were distributed, and responses were received from 275 patients with cancer. Of these, 135 patients were aware of support groups and 23 had participated in a group. Patients who were aware of support groups were more likely to be young, female patients. Many patients learned about support groups from hospital notices. Most support group participants expected to receive information about the disease and treatment (91%). They also wanted to hear about other patients' experiences (73%). The most common reasons for non-participation were "no particular reason" (38%) and "family or friends support me" (27%). About half of participating patients were unaware of support groups. Even among patients who were aware, many did not attend a support group. Developing a better understanding of support group use in cancer survivors may enhance provision of adequate care based on individual needs.

A Host Susceptibility Gene, DR1, Facilitates Influenza A Virus Replication by Suppressing Host Innate Immunity and Enhancing Viral RNA Replication

PubMed Central

Hsu, Shih-Feng; Su, Wen-Chi; Jeng, King-Song

2015-01-01

ABSTRACT Influenza A virus (IAV) depends on cellular factors to complete its replication cycle; thus, investigation of the factors utilized by IAV may facilitate antiviral drug development. To this end, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNA interference (RNAi) screen. Knockdown (KD) of DR1 resulted in reductions of viral RNA and protein production, demonstrating that DR1 acts as a positive host factor in IAV replication. Genome-wide transcriptomic analysis showed that there was a strong induction of interferon-stimulated gene (ISG) expression after prolonged DR1 KD. We found that beta interferon (IFN-β) was induced by DR1 KD, thereby activating the JAK-STAT pathway to turn on ISG expression, which led to a strong inhibition of IAV replication. This result suggests that DR1 in normal cells suppresses IFN induction, probably to prevent undesired cytokine production, but that this suppression may create a milieu that favors IAV replication once cells are infected. Furthermore, biochemical assays of viral RNA replication showed that DR1 KD suppressed viral RNA replication. We also showed that DR1 associated with all three subunits of the viral RNA-dependent RNA polymerase (RdRp) complex, indicating that DR1 may interact with individual components of the viral RdRp complex to enhance viral RNA replication. Thus, DR1 may be considered a novel host susceptibility gene for IAV replication via a dual mechanism, not only suppressing the host defense to indirectly favor IAV replication but also directly facilitating viral RNA replication. IMPORTANCE Investigations of virus-host interactions involved in influenza A virus (IAV) replication are important for understanding viral pathogenesis and host defenses, which may manipulate influenza virus infection or prevent the emergence of drug resistance caused by a high error rate during viral RNA replication. For this purpose, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNAi screen as a positive regulator in IAV replication. In the current studies, we showed that DR1 suppressed the gene expression of a large set of host innate immunity genes, which indirectly facilitated IAV replication in the event of IAV infection. Besides this scenario, DR1 also directly enhanced the viral RdRp activity, likely through associating with individual components of the viral RdRp complex. Thus, DR1 represents a novel host susceptibility gene for IAV replication via multiple functions, not only suppressing the host defense but also enhancing viral RNA replication. DR1 may be a potential target for drug development against influenza virus infection. PMID:25589657

GEOGRAPHIC INFORMATION SYSTEM APPROACH FOR PLAY PORTFOLIOS TO IMPROVE OIL PRODUCTION IN THE ILLINOIS BASIN

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

Beverly Seyler; John Grube

2004-12-10

Oil and gas have been commercially produced in Illinois for over 100 years. Existing commercial production is from more than fifty-two named pay horizons in Paleozoic rocks ranging in age from Middle Ordovician to Pennsylvanian. Over 3.2 billion barrels of oil have been produced. Recent calculations indicate that remaining mobile resources in the Illinois Basin may be on the order of several billion barrels. Thus, large quantities of oil, potentially recoverable using current technology, remain in Illinois oil fields despite a century of development. Many opportunities for increased production may have been missed due to complex development histories, multiple stackedmore » pays, and commingled production which makes thorough exploitation of pays and the application of secondary or improved/enhanced recovery strategies difficult. Access to data, and the techniques required to evaluate and manage large amounts of diverse data are major barriers to increased production of critical reserves in the Illinois Basin. These constraints are being alleviated by the development of a database access system using a Geographic Information System (GIS) approach for evaluation and identification of underdeveloped pays. The Illinois State Geological Survey has developed a methodology that is being used by industry to identify underdeveloped areas (UDAs) in and around petroleum reservoirs in Illinois using a GIS approach. This project utilizes a statewide oil and gas Oracle{reg_sign} database to develop a series of Oil and Gas Base Maps with well location symbols that are color-coded by producing horizon. Producing horizons are displayed as layers and can be selected as separate or combined layers that can be turned on and off. Map views can be customized to serve individual needs and page size maps can be printed. A core analysis database with over 168,000 entries has been compiled and assimilated into the ISGS Enterprise Oracle database. Maps of wells with core data have been generated. Data from over 1,700 Illinois waterflood units and waterflood areas have been entered into an Access{reg_sign} database. The waterflood area data has also been assimilated into the ISGS Oracle database for mapping and dissemination on the ArcIMS website. Formation depths for the Beech Creek Limestone, Ste. Genevieve Limestone and New Albany Shale in all of the oil producing region of Illinois have been calculated and entered into a digital database. Digital contoured structure maps have been constructed, edited and added to the ILoil website as map layers. This technology/methodology addresses the long-standing constraints related to information access and data management in Illinois by significantly simplifying the laborious process that industry presently must use to identify underdeveloped pay zones in Illinois.« less

Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats

PubMed Central

2014-01-01

Background A thorough investigation of the neurobiology of HIV-induced neuronal dysfunction and its evolving phenotype in the setting of viral suppression has been limited by the lack of validated small animal models to probe the effects of concomitant low level expression of multiple HIV-1 products in disease-relevant cells in the CNS. Results We report the results of gene expression profiling of the hippocampus of HIV-1 Tg rats, a rodent model of HIV infection in which multiple HIV-1 proteins are expressed under the control of the viral LTR promoter in disease-relevant cells including microglia and astrocytes. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analysis. Gene expression changes observed are consistent with astrogliosis and microgliosis and include evidence of inflammation and cell proliferation. Among the genes with increased expression in HIV-1 Tg rats was the interferon stimulated gene 15 (ISG-15), which was previously shown to be increased in the cerebrospinal fluid (CSF) of HIV patients and to correlate with neuropsychological impairment and neuropathology, and prostaglandin D2 (PGD2) synthase (Ptgds), which has been associated with immune activation and the induction of astrogliosis and microgliosis. GSEA-based pathway analysis highlighted a broad dysregulation of genes involved in neuronal trophism and neurodegenerative disorders. Among the latter are genesets associated with Huntington’s disease, Parkinson’s disease, mitochondrial, peroxisome function, and synaptic trophism and plasticity, such as IGF, ErbB and netrin signaling and the PI3K signal transduction pathway, a mediator of neural plasticity and of a vast array of trophic signals. Additionally, gene expression analyses also show altered lipid metabolism and peroxisomes dysfunction. Supporting the functional significance of these gene expression alterations, HIV-1 Tg rats showed working memory impairments in spontaneous alternation behavior in the T-Maze, a paradigm sensitive to prefrontal cortex and hippocampal function. Conclusions Altogether, differentially regulated genes and pathway analysis identify specific pathways that can be targeted therapeutically to increase trophic support, e.g. IGF, ErbB and netrin signaling, and reduce neuroinflammation, e.g. PGD2 synthesis, which may be beneficial in the treatment of chronic forms of HIV-associated neurocognitive disorders in the setting of viral suppression. PMID:24980976

An Approach for Validating Actinide and Fission Product Burnup Credit Criticality Safety Analyses--Criticality (keff) Predictions

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

Scaglione, John M; Mueller, Don; Wagner, John C

2011-01-01

One of the most significant remaining challenges associated with expanded implementation of burnup credit in the United States is the validation of depletion and criticality calculations used in the safety evaluation - in particular, the availability and use of applicable measured data to support validation, especially for fission products. Applicants and regulatory reviewers have been constrained by both a scarcity of data and a lack of clear technical basis or approach for use of the data. U.S. Nuclear Regulatory Commission (NRC) staff have noted that the rationale for restricting their Interim Staff Guidance on burnup credit (ISG-8) to actinide-only ismore » based largely on the lack of clear, definitive experiments that can be used to estimate the bias and uncertainty for computational analyses associated with using burnup credit. To address the issue of validation, the NRC initiated a project with the Oak Ridge National Laboratory to (1) develop and establish a technically sound validation approach (both depletion and criticality) for commercial spent nuclear fuel (SNF) criticality safety evaluations based on best-available data and methods and (2) apply the approach for representative SNF storage and transport configurations/conditions to demonstrate its usage and applicability, as well as to provide reference bias results. The purpose of this paper is to describe the criticality (k{sub eff}) validation approach, and resulting observations and recommendations. Validation of the isotopic composition (depletion) calculations is addressed in a companion paper at this conference. For criticality validation, the approach is to utilize (1) available laboratory critical experiment (LCE) data from the International Handbook of Evaluated Criticality Safety Benchmark Experiments and the French Haut Taux de Combustion (HTC) program to support validation of the principal actinides and (2) calculated sensitivities, nuclear data uncertainties, and the limited available fission product LCE data to predict and verify individual biases for relevant minor actinides and fission products. This paper (1) provides a detailed description of the approach and its technical bases, (2) describes the application of the approach for representative pressurized water reactor and boiling water reactor safety analysis models to demonstrate its usage and applicability, (3) provides reference bias results based on the prerelease SCALE 6.1 code package and ENDF/B-VII nuclear cross-section data, and (4) provides recommendations for application of the results and methods to other code and data packages.« less

The impact of an online Facebook support group for people with multiple sclerosis on non-active users.

PubMed

Steadman, Jacqui; Pretorius, Chrisma

2014-01-01

Multiple sclerosis (MS) is a debilitating disease and there is little research on support networks for people with MS (PwMS). More specifically, most studies on online support groups focus on those who actively participate in the group, whereas the majority of those who utilise online support groups do so in a passive way. This study therefore aimed to explore the experiences of non-active users of an online Facebook support group for PwMS. Emphasis was placed on the facilitators and the barriers that were associated with membership to this group. An exploratory qualitative research design was implemented, whereby thematic analysis was utilised to examine the ten semi-structured interviews that were conducted. Several facilitators were acquired through the online support group; namely emotional support (constant source of support, exposure to negative aspects of the disease), informational support (group as a source of knowledge, quality of information) and social companionship (place of belonging). Some barriers were also identified; namely emotional support (emotions lost online, response to messages, exposure to negative aspects of the disease), informational support (information posted on the group, misuse of group) and social companionship (non-active status). These findings demonstrate that the non-active members of the online support group for PwMS have valid reasons for their non-active membership status. More important, the findings suggest that the online Facebook support group provided the group members with an important support network in the form of emotional support, informational support and social companionship, despite their non-active membership status or the barriers that have been identified.

A comparison of lurkers and posters within infertility online support groups.

PubMed

Malik, Sumaira H; Coulson, Neil S

2011-10-01

Current research shows that online support groups can offer people affected by infertility a unique and valuable source of social support. However, to date most research has focused on the experiences of people who post messages to online infertility support groups; in comparison, little is known about how "lurkers" (i.e., those individuals who read messages but do not post messages) use and benefit from online infertility support groups. The purpose of the present study was to compare the use and experience of online infertility support groups between lurkers and posters. A total of 295 participants who were recruited from several online infertility support groups completed an online questionnaire containing questions about their use and experience of online support groups and measures of loneliness, social support, marital satisfaction, and perceived infertility-related stress. Differences between lurkers and posters were analyzed using Mann-Whitney U and χ or Fisher exact tests. Results revealed that compared with posters, lurkers visited the online support groups less often and scored significantly lower in overall satisfaction with the online support group. However, both lurkers and posters reported gaining a range of unique benefits from access to an online support group. Furthermore, there were no significant differences in loneliness, social support, infertility-related stress, and marital satisfaction between lurkers and posters. These findings suggest that reading messages posted to online support groups may be as beneficial as interacting with the group.

The impact of an online Facebook support group for people with multiple sclerosis on non-active users

PubMed Central

Steadman, Jacqui

2014-01-01

Background Multiple sclerosis (MS) is a debilitating disease and there is little research on support networks for people with MS (PwMS). More specifically, most studies on online support groups focus on those who actively participate in the group, whereas the majority of those who utilise online support groups do so in a passive way. Objectives This study therefore aimed to explore the experiences of non-active users of an online Facebook support group for PwMS. Emphasis was placed on the facilitators and the barriers that were associated with membership to this group. Method An exploratory qualitative research design was implemented, whereby thematic analysis was utilised to examine the ten semi-structured interviews that were conducted. Results Several facilitators were acquired through the online support group; namely emotional support (constant source of support, exposure to negative aspects of the disease), informational support (group as a source of knowledge, quality of information) and social companionship (place of belonging). Some barriers were also identified; namely emotional support (emotions lost online, response to messages, exposure to negative aspects of the disease), informational support (information posted on the group, misuse of group) and social companionship (non-active status) Conclusion These findings demonstrate that the non-active members of the online support group for PwMS have valid reasons for their non-active membership status. More important, the findings suggest that the online Facebook support group provided the group members with an important support network in the form of emotional support, informational support and social companionship, despite their non-active membership status or the barriers that have been identified. PMID:28730005

Facilitating social support: member-leader communication in a breast cancer support group.

PubMed

Beck, Stephenson J; Keyton, Joann

2014-01-01

Early detection and treatment have resulted in more women surviving breast cancer; increased survivorship has also increased the need for breast cancer support groups (BCSG). The ostensible goal of such groups is to provide support for the physical and emotional stressors that cancer survivors face, as well as provide information on coping and treatment options. Although scholars have examined the effects of support groups on their group members, the examination of group facilitator messages has been largely neglected. The goal of this study was to extend theory on group leader behavior, specifically investigating how member-leader messages create social support in support groups. The transcribed conversations of weekly meetings of a BCSG were examined using Interaction Process Analysis to discover how the member-leader facilitated the group's enactment and management of social support. Across the meetings, task talk dominated (primarily statements of orientation or information). Furthermore, analysis of interaction sequences between the support group facilitator and other members revealed 2 broad categories of task-oriented facilitation techniques (changing the focus, clarification) and 1 category of socioemotional facilitation techniques (showing support). Support group facilitators need the ability to facilitate both task and relational aspects of social support. Facilitator behaviors were highlighted as being instrumental to the creation of social support. The results from this study indicate that the ability to change the focus of interaction, to provide and require clarification on complex issues, and to show support through relational messages is needed in facilitator training.

Evaluation of an ongoing psychoeducational inflammatory bowel disease support group in an adult outpatient setting.

PubMed

McMaster, Kristin; Aguinaldo, Laika; Parekh, Nimisha K

2012-01-01

Previous studies assessing efficacy of support groups for patients with inflammatory bowel disease showed mixed results in terms of attendance and overall effectiveness. In this study, researchers evaluated the use of an ongoing open psychoeducational support group for adult patients with inflammatory bowel disease in an outpatient tertiary setting. The sample consisted of 18 adults who have attended more than 2 meetings of the support group. Topics addressed in the support group include complementary medicine, diet and nutrition, the psychological impact of inflammatory bowel disease, medication and side effects, and insurance/disability. Participants were asked to complete the Client Satisfaction Questionnaire, Multidimensional Support Scale, 11 general demographic questions, and a brief open-ended qualitative questionnaire developed by the researchers. Results demonstrated that participants reported very high satisfaction with the support group and rated the adequacy of peer support from others with inflammatory bowel disease higher than support from family/friends and professionals. A majority of group members reported joining the group for mutual support and education; this expectation was met through the psychoeducational structure of the group. This study demonstrates the potential for success of an ongoing psychoeducational inflammatory bowel disease support group for adult patients and their caregivers.

Using peer support groups to enhance community integration of veterans in transition.

PubMed

Drebing, Charles E; Reilly, Erin; Henze, Kevin T; Kelly, Megan; Russo, Anthony; Smolinsky, John; Gorman, Jay; Penk, Walter E

2018-05-01

Peer support groups, also known as "self-help groups," provide a unique tool for helping veterans working through the military-to-civilian transition to achieve higher levels of social support and community integration. The number and variety of community-based peer support groups has grown to the point that there are now more visits to these groups each year than to mental health professionals. The focus of these groups on the provision of social support, the number and variety of groups, the lack of cost, and their availability in the community make them a natural transition tool for building community-based social support. A growing literature suggests that these groups are associated with measurable improvements in social support, clinical symptoms, self-efficacy and coping. For clinical populations, the combination of peer support groups and clinical care results in better outcomes than either alone. Given this evidence, we suggest clinical services use active referral strategies to help veterans engage in peer support groups as a means of improving community reintegration and clinical outcomes. Finally, suggestions for identifying appropriate peer support groups and assisting with active referrals are provided. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Reasons for Not Participating in Scleroderma Patient Support Groups: A Cross-Sectional Study.

PubMed

Gumuchian, Stephanie T; Delisle, Vanessa C; Peláez, Sandra; Malcarne, Vanessa L; El-Baalbaki, Ghassan; Kwakkenbos, Linda; Jewett, Lisa R; Carrier, Marie-Eve; Pépin, Mia; Thombs, Brett D

2018-02-01

Peer-led support groups are an important resource for many people with scleroderma (systemic sclerosis; SSc). Little is known, however, about barriers to participation. The objective of this study was to identify reasons why some people with SSc do not participate in SSc support groups. A 21-item survey was used to assess reasons for nonattendance among SSc patients in Canada and the US. Exploratory factor analysis (EFA) was conducted, using the software MPlus 7, to group reasons for nonattendance into themes. A total of 242 people (202 women) with SSc completed the survey. EFA results indicated that a 3-factor model best described the data (χ 2 [150] = 302.7; P < 0.001; Comparative Fit Index = 0.91, Tucker-Lewis Index = 0.88, root mean square error of approximation = 0.07, factor intercorrelations 0.02-0.43). The 3 identified themes, reflecting reasons for not attending SSc support groups were personal reasons (9 items; e.g., already having enough support), practical reasons (7 items; e.g., no local support groups available), and beliefs about support groups (5 items; e.g., support groups are too negative). On average, respondents rated 4.9 items as important or very important reasons for nonattendance. The 2 items most commonly rated as important or very important were 1) already having enough support from family, friends, or others, and 2) not knowing of any SSc support groups offered in my area. SSc organizations may be able to address limitations in accessibility and concerns about SSc support groups by implementing online support groups, better informing patients about support group activities, and training support group facilitators. © 2017, American College of Rheumatology.

Social support, organizational characteristics, psychological well-being, and group appraisal in three self-help group populations.

PubMed

Maton, K I

1988-02-01

This study examined the relationship of three social support and three organizational variables to two well-being and two group appraisal variables among 144 members of Compassionate Friends, Multiple Sclerosis, and Overeaters Anonymous self-help groups. An anonymous questionnaire was the major research instrument. Receiving social support was not significantly related to depression or anxiety but was positively related to perceived group benefits and group satisfaction. Providing social support and friendship were each positively related to one well-being and one group appraisal variable. Bidirectional supporters (i.e., individuals high on both receiving and providing support) reported more favorable well-being and group appraisal than Receivers, Providers, and Low Supporters. At the group level of analysis (n = 15 groups), groups with higher levels of role differentiation, greater order and organization, and in which leaders were perceived as more capable contained members who reported more positive well-being and group appraisal. The implications for future research and professional consultation to self-help groups are discussed.

Support group processes: Perspectives from HIV-infected women in South Africa.

PubMed

Mundell, J P; Visser, M J; Makin, J D; Forsyth, B W; Sikkema, K J

2012-01-01

This study examined the experiences and perceived benefits of support group participation among HIV-infected women in South Africa. From a qualitative analysis of responses, key psychological processes through which support groups are potentially beneficial were identified. These processes included: identification; modeling; acceptance; and empowerment. The participants' consequent life changes were explored in order to associate these processes with the positive outcomes of support group participation. Through understanding the relationship between the psychological processes within a support group setting and the potential benefits, and by targeting these processes in the development and implementation of future support group interventions, a framework is provided for achieving positive outcomes associated with support group participation.

Support group processes: Perspectives from HIV-infected women in South Africa

PubMed Central

Mundell, J.P.; Visser, M.J.; Makin, J.D.; Forsyth, B.W.; Sikkema, K.J.

2012-01-01

This study examined the experiences and perceived benefits of support group participation among HIV-infected women in South Africa. From a qualitative analysis of responses, key psychological processes through which support groups are potentially beneficial were identified. These processes included: identification; modeling; acceptance; and empowerment. The participants’ consequent life changes were explored in order to associate these processes with the positive outcomes of support group participation. Through understanding the relationship between the psychological processes within a support group setting and the potential benefits, and by targeting these processes in the development and implementation of future support group interventions, a framework is provided for achieving positive outcomes associated with support group participation. PMID:22514790

The Task and Relational Dimensions of Online Social Support.

PubMed

Beck, Stephenson J; Paskewitz, Emily A; Anderson, Whitney A; Bourdeaux, Renee; Currie-Mueller, Jenna

2017-03-01

Online support groups are attractive to individuals suffering from various types of mental and physical illness due to their accessibility, convenience, and comfort level. Individuals coping with depression, in particular, may seek social support online to avoid the stigma that accompanies face-to-face support groups. We explored how task and relational messages created social support in online depression support groups using Cutrona and Suhr's social support coding scheme and Bales's Interaction Process Analysis coding scheme. A content analysis revealed emotional support as the most common type of social support within the group, although the majority of messages were task rather than relational. Informational support consisted primarily of task messages, whereas network and esteem support were primarily relational messages. Specific types of task and relational messages were associated with different support types. Results indicate task messages dominated online depression support groups, suggesting the individuals who participate in these groups are interested in solving problems but may also experience emotional support when their uncertainty is reduced via task messages.

Are participants in face-to-face and internet support groups the same? Comparison of demographics and depression levels among women bereaved by stillbirth.

PubMed

Gold, Katherine J; Normandin, Margaret M; Boggs, Martha E

2016-12-01

Support groups can help individuals cope with difficult health situations but have been understudied for women with perinatal bereavement. An early study suggested those using internet support groups had high rates of positive depression screens, raising the question whether these users were more symptomatic than those in similar face-to-face support groups. We therefore conducted two convenience sample surveys of women bereaved by perinatal loss, one looking at use of online support groups and the other in-person support groups. The surveys identified demographics, use of peer support, potential confounders, and current depression symptoms using the Edinburgh Postnatal Depression Scale (EPDS). Four hundred sixteen women from 18 internet groups and 60 women from 13 in-person groups met inclusion criteria. Participants in both groups were predominantly Caucasian, highly educated, and had private insurance. Severe depression symptoms were similar in the two groups despite the different modalities. Women in both face-to-face or internet groups for pregnancy and perinatal loss demonstrated similar scores on depression screens. Women of color, poor, and less-educated women were starkly underrepresented in both types of groups, raising questions about knowledge of support options, barriers to use, preferences for bereavement support, and optimization of groups for a broader population.

Telephone Support During Overseas Deployment for Military Spouses Formerly: Telephone Support During Deployment for OEF/OIF Spouses

DTIC Science & Technology

2016-04-01

distance relationships, and other common problems. The study compared telephone support groups to online education sessions for 161 spouses. In the...Telephone Support groups , a group leader and participants 12 times over six months to focus on education, skills building and support. Education Only...coping. Both groups reported self-efficacy as a driver of benefit. For webinar participants, there was no effect for dosage. For support group

Exploration of Support Behavior in Counseling Groups with Counseling Trainees

ERIC Educational Resources Information Center

Harel, Yoni; Shechtman, Zipora; Cutrona, Carolyn

2012-01-01

The study explores the types of support expressed in counseling groups attended by trainee counselors. Support is a crucial factor in human life in general, and in groups in particular, yet little is known about the type of support presented in counseling groups. Type of support was categorized by means of the Social Support Behavior Code (SSBC;…

The Impact of Demographic Characteristics on Awareness and Usage of Support Groups.

PubMed

Coleman, Linda Jane; Shah, Nehal; Jain, Sanjay

2015-01-01

There are support groups established for one's emotional and/or physical health; as a result, marketing has appeared in regards to the needs, benefits, and hesitations regarding these groups. This study addresses several types of individuals and situations that lend themselves to using support groups. The authors conducted a study designed to examine demographic characteristics as they relate to a person's decision to go to support groups for health conditions. Looking at the demographics of users and the types of support groups, the authors discuss diverse opportunities for support groups and their organizations to promote communication, improve marketing strategies, and create influential users.

Reasons for attending support groups and organizational preferences: the European scleroderma support group members survey.

PubMed

Gumuchian, Stephanie T; Delisle, Vanessa C; Kwakkenbos, Linda; Pépin, Mia; Carrier, Marie-Eve; Malcarne, Vanessa L; Peláez, Sandra; El-Baalbaki, Ghassan; Thombs, Brett D

2017-12-19

The objectives were to identify reasons why patients attend scleroderma support groups and to ascertain preferences for how meetings are best organized. The survey included 30-items on reasons for attending and nine items on organizational preferences. Patients were recruited through European patient organizations. Exploratory factor analysis was used to group reasons for attendance thematically. About 213 scleroderma patients (192 women) completed the survey. A three-factor model best described reasons for attending [χ 2 (348) = 586.1, p < 0.001; Comparative Fit Index = 0.98; Tucker Lewis Index = 0.97; Root Mean Square Error of Approximation = 0.06] with themes that included: (1) obtaining interpersonal and social support, (2) learning about treatment and symptom management strategies, and (3) discussing other aspects of scleroderma. Among organizational preferences, respondents emphasized that meetings should include educational aspects and the opportunity to share information and support. People with scleroderma attend support groups to give and obtain social support and for education about managing their disease and other aspects of living with scleroderma. Support groups should be structured to facilitate both educational and informational aspects and to provide opportunities for sharing and support between members. Implications for rehabilitation Local peer-led support groups are an important support and informational resource for patients living with scleroderma. People with scleroderma attend support groups in order to: (1) obtain interpersonal and social support, (2) learn about disease treatment and symptom management strategies, and (3) discuss other aspects of living with scleroderma outside of symptom management. Most support group members prefer groups with a trained facilitator, that include family members or loved ones in the groups, that include between 11and 20 members, that last between 1 and 2 h, and that meet once every 1-3 months. Rehabilitation professionals can support the formation and management of local support groups or can refer patients to national scleroderma patient organizations for information on support groups that they may be able to access.

Characteristics of the interferon regulatory factor 5 (IRF5) and its expression in response to LCDV and poly I:C challenges in Japanese flounder, Paralichthys olivaceus.

PubMed

Hu, Guo-Bin; Lou, Hui-Min; Dong, Xian-Zhi; Liu, Qiu-Ming; Zhang, Shi-Cui

2012-10-01

Interferon regulatory factor 5 (IRF5) has been identified as a key transcriptional mediator regulating expression of both type I interferons (IFNs) and proinflammatory cytokines. In this study, the cDNA and genomic sequences of IRF5 were isolated from Japanese flounder, Paralichthys olivaceus. The gene of Japanese flounder (Jf)IRF5 is 7326 bp long, contains 9 exons and 8 introns and encodes a putative protein of 472 amino acids. The predicted protein sequence shares 61.1-81.9% identity to fish IRF5 and possesses a DNA-binding domain (DBD), a middle region (MR), an IRF association domain (IAD), a virus activated domain (VAD) and two nuclear localization signals (NLSs) conserved in all known IRF5s. Phylogenetic analysis clustered it into the teleost IRF5 subgroup within vertebrate IRF5 group. JfIRF5 mRNA was constitutively expressed in all tissues examined, with higher levels observed in the gills and head kidney. Gene expression of JfIRF5 was analyzed over a 7-day time course in the gills, head kidney, spleen and muscle of Japanese flounders challenged with lymphocystis disease virus (LCDV) and polyinosinic:polycytidylic acid (poly I:C). The data showed that JfIRF5 expression was slightly up-regulated by LCDV, but its induction time was clearly moved up; in contrast, the induction upon poly I:C challenge started not earlier than day 2 post-injection and was stronger and more persistent with a later peak time in all four organs. The late and long-lasting inductive expression of JfIRF5 following poly I:C challenge suggests that it might be an interferon stimulated gene (ISG), the induction of which is driven by poly I:C-induced type I IFNs. Copyright © 2012 Elsevier Ltd. All rights reserved.

Coping with Loss and Grief through On-Line Support Groups.

ERIC Educational Resources Information Center

Gary, Juneau Mahan; Remolino, Linda

On-line support groups provide an alternative to traditional support groups by linking grieving people who seek support, especially if support is not available in their local community. Furthermore, these groups can reduce the sense of isolation caused by geographical or physical/medical constraints and increase feelings of validations. Although…

Impact of support groups on well-being of older women.

PubMed

Segrist, Kathleen A

2008-01-01

The goal of this study was to determine whether differences in incidence of depression and level of well-being are manifested between older women, aged 60 and older, who attend either (a) a peer-run support group, (b) a staff-run support group, or (c) a comparison group (i.e., who do not attend a support group). Thirty-six women participating in peer-run and staff-run support groups and 9 women receiving nongroup support were administered the Geriatric Depression Scale and the Philadelphia Geriatric Center Morale Scale. Separate analyses of variance were employed on each scale to determine the significance of differences in scores according to facilitator type (i.e., peer-run vs. staff-run vs. comparison group). Analysis of scores on the Geriatric Depression Scale indicated significant differences between women in the peer-run groups and women in the comparison group, but no significant differences between women in the peer-run groups and women in the staff-run groups or between women in the staff-run groups and women in the comparison group. Analysis of scores on the Philadelphia Geriatric Center Morale Scale did not indicate any significant differences between women based on facilitator type. Results of this study have implications for those who run face-to-face support groups for older adults, for those who train peer group facilitators, and for community agencies that desire to initiate a support group system for their clientele.

Stress and nurses' horizontal mobbing: moderating effects of group identity and group support.

PubMed

Topa, Gabriela; Moriano, Juan A

2013-01-01

Horizontal mobbing is a process of systematic and repeated aggression towards a worker by coworkers. Among others, stress has been pointed out as one of the antecedents that favors the onset of horizontal mobbing, whereas group support to the target could act as a buffer. Moreover, the social identity approach emphasizes that group identity is an antecedent of group support. This study explores the interaction of group support and group identity in the explanation of horizontal mobbing in a sample (N = 388) of registered nurses and licensed practical nurses employed at two large hospitals in Madrid and Navarre (Spain). The results show that stress is positively associated to horizontal mobbing, whereas group support and group identity were negative predictors of horizontal mobbing. Furthermore, the combination of low group identity and low group support precipitated HM among nurses. Copyright © 2013 Elsevier Inc. All rights reserved.

Religiosity and Participation in Mutual-Aid Support Groups for Addiction

PubMed Central

Atkins, Randolph G.; Hawdon, James E.

2007-01-01

Mutual-aid support groups play a vital role in substance abuse treatment in the United States. A national survey of mutual-aid support groups for addiction was conducted to identify key differences between participants in recovery groups. Survey data indicate that active involvement in support groups significantly improves one's chances of remaining clean and sober, regardless of the group in which one participates. Respondents whose individual beliefs better matched those of their primary support groups showed greater levels of group participation, resulting in better outcomes as measured by increased number of days clean and sober. Religious respondents were more likely to participate in 12-Step groups and Women for Sobriety. Non-religious respondents were significantly less likely to participate in 12-Step groups. Religiosity had little impact on SMART Recovery participation, but actually decreased participation in SOS. These results have important implications for treatment planning and matching individuals to appropriate support groups. PMID:17889302

PDGF-BB Promotes Type I IFN-Dependent Vascular Alterations and Monocyte Recruitment in a Model of Dermal Fibrosis.

PubMed

Cho, John S; Fang, Terry C; Reynolds, Taylor L; Sofia, Daniel J; Hamann, Stefan; Burkly, Linda C

2016-01-01

Systemic sclerosis (SSc) is a chronic autoimmune disorder that can result in extensive tissue damage in the skin and, in advanced cases, internal organs. Vasculopathy, aberrant immune activation, and tissue fibrosis are three hallmarks of the disease that have been identified, with vasculopathy and aberrant immunity being amongst the earliest events. However, a mechanistic link between these processes has not been established. Here, we have identified a novel role of platelet derived growth factor-BB (PDGF-BB)/PDGFRβ activation in combination with dermal injury induced by bleomycin as a driver of early, aberrant expression of interferon stimulatory genes (ISGs) and inflammatory monocyte infiltration. Activation of PDGFRβ in combination with bleomycin-induced dermal injury resulted in increased dermal thickness, vascular density, monocyte/macrophage infiltration, and exacerbation of tissue injury. Many of these features were dependent on IFNAR-signaling, and an increase in the number of interferon-beta (IFN-β) producing monocytes cells was found in the skin lesions. Taken together, these results identify a novel link between PDGFRβ activation, and Type I IFN-driven vascular maintenance and monocyte/macrophage cell recruitment, and provide a potential explanation linking key features of SSc that were previously thought to be unrelated.

A dual-channel flux-switching permanent magnet motor for hybrid electric vehicles

NASA Astrophysics Data System (ADS)

Hua, Wei; Wu, Zhongze; Cheng, Ming; Wang, Baoan; Zhang, Jianzhong; Zhou, Shigui

2012-04-01

The flux-switching permanent magnet (FSPM) motor is a relatively novel brushless machine having both magnets and concentrated windings in the stator, which exhibits inherently sinusoidal PM flux-linkage, back-EMF waveforms, and high torque capability. However, in the application of hybrid electric vehicles, it is essential to prevent magnets and armature windings moving in radial direction due to the possible vibration during operation, and to ensure fault-tolerant capability. Hence, in this paper based on an original FSPM motor, a dual-channel FSPM (DC-FSPM) motor with modified structure to fix both armature windings and magnets and improved reliability is proposed for a practical 10 kW integral starter/generator (ISG) in hybrid electric vehicles. The influences of different solutions and the end-effect on the static characteristics, are evaluated based on the 2D and 3D finite element analysis, respectively. Finally, both the predicted and experimental results, compared with a prototype DC-FSPM motor and an interior PM motor used in Honda Civic, confirm that the more sinusoidal back-EMF waveform and lower torque ripple can be achieved in the DC-FSPM motor, whereas the torque is smaller under the same coil current.

Insight into Buffalo (Bubalus bubalis) RIG1 and MDA5 Receptors: A Comparative Study on dsRNA Recognition and In-Vitro Antiviral Response

PubMed Central

Singh, Manvender; Brahma, Biswajit; Maharana, Jitendra; Patra, Mahesh Chandra; Kumar, Sushil; Mishra, Purusottam; Saini, Megha; De, Bidhan Chandra; Mahanty, Sourav; Datta, Tirtha Kumar; De, Sachinandan

2014-01-01

RIG1 and MDA5 have emerged as important intracellular innate pattern recognition receptors that recognize viral RNA and mediate cellular signals controlling Type I interferon (IFN-I) response. Buffalo RIG1 and MDA5 genes were investigated to understand the mechanism of receptor induced antiviral response. Sequence analysis revealed that RIG1 and MDA5 maintain a domain arrangement that is common in mammals. Critical binding site residues of the receptors are evolutionary conserved among mammals. Molecular dynamics simulations suggested that RIG1 and MDA5 follow a similar, if not identical, dsRNA binding pattern that has been previously reported in human. Moreover, binding free energy calculation revealed that MDA5 had a greater affinity towards dsRNA compared to RIG1. Constitutive expressions of RLR genes were ubiquitous in different tissues without being specific to immune organs. Poly I:C stimulation induced elevated expressions of IFN-β and IFN-stimulated genes (ISGs) through interferon regulatory factors (IRFs) mediated pathway in buffalo foetal fibroblast cells. The present study provides crucial insights into the structure and function of RIG1 and MDA5 receptors in buffalo. PMID:24587036

The gravity field observations and products at IGFS

NASA Astrophysics Data System (ADS)

Barzaghi, Riccardo; Vergos, George; Bonvalot, Sylvain; Barthelmes, Franz; Reguzzoni, Mirko; Wziontek, Hartmut; Kelly, Kevin

2017-04-01

The International Gravity Field Service (IGFS) is a service of the International Association of Geodesy (IAG) that was established in 2003 at the IAG/IUGG General Assembly in Sapporo (Japan). This service aims at coordinating the actions of the IAG services related to the Earth gravity field, i.e. the Bureau Gravimétrique International (BGI), the International Service for the Geoid (ISG), the International Geodynamics and Earth Tides Service (IGETS), the International Center for Global Earth Models (ICGEM) and the International Digital Elevation Model Service (IDEMS). Also, via its Central Bureau hosted at the Aristotle University of Thessaloniki (Greece), IGFS provides a link to the Global Geodetic Observing System (GGOS) bureaus in order to communicate their requirements and recommendations to the IGFS-Centers. In this work, a presentation is given on the recent activities of the service, namely those related to the contributions to the implementation of: the International Height Reference System/Frame; the Global Geodetic Reference System/Frame; the new Global Absolute Gravity Reference System/Frame. Particularly, the impact that these activities have in improving the estimation of the Earth's gravity field, either at global and local scale, is highlighted also in the framework of GGOS.

Unique nonstructural proteins of Pneumonia Virus of Mice (PVM) promote degradation of interferon (IFN) pathway components and IFN-stimulated gene proteins.

PubMed

Dhar, Jayeeta; Barik, Sailen

2016-12-01

Pneumonia Virus of Mice (PVM) is the only virus that shares the Pneumovirus genus of the Paramyxoviridae family with Respiratory Syncytial Virus (RSV). A deadly mouse pathogen, PVM has the potential to serve as a robust animal model of RSV infection, since human RSV does not fully replicate the human pathology in mice. Like RSV, PVM also encodes two nonstructural proteins that have been implicated to suppress the IFN pathway, but surprisingly, they exhibit no sequence similarity with their RSV equivalents. The molecular mechanism of PVM NS function, therefore, remains unknown. Here, we show that recombinant PVM NS proteins degrade the mouse counterparts of the IFN pathway components. Proteasomal degradation appears to be mediated by ubiquitination promoted by PVM NS proteins. Interestingly, NS proteins of PVM lowered the levels of several ISG (IFN-stimulated gene) proteins as well. These results provide a molecular foundation for the mechanisms by which PVM efficiently subverts the IFN response of the murine cell. They also reveal that in spite of their high sequence dissimilarity, the two pneumoviral NS proteins are functionally and mechanistically similar.

The Child with Recurrent Mycobacterial Disease.

PubMed

Reed, Brian; Dolen, William K

2018-06-23

Many genetic conditions predispose affected individuals to opportunistic infections. A number of immunodeficiency diseases, including genetic defects termed Mendelian susceptibility to mycobacterial disease (MSMD), permit infection from many different strains of mycobacteria that would otherwise not cause disease. These include tuberculous and nontuberculous mycobacteria, and bacille Calmette-Guérin vaccine (BCG). Patients may present with infections from other organisms that depend on macrophage function for containment. Defects in multiple genes in the IL-12 and NFKB signaling pathways can cause the MSMD phenotype, some of which include IL12RB1, IL12B, IKBKG, ISG15, IFNGR1, IFNGR2, CYBB, TYK2, IRF8, and STAT1. Multiple autosomal recessive and dominant, and 2 X-linked recessive gene defects resulting in the MSMD phenotype have been reported, and others await discovery. This review presents the known gene defects and describes clinical findings that result from the mutations. If MSMD is suspected, a careful clinical history and examination and basic immunodeficiency screening tests will narrow the differential diagnosis. A specific diagnosis requires more sophisticated laboratory investigation. Genetic testing permits a definitive diagnosis, permitting genetic counseling. Mild cases respond well to appropriate antibiotic therapy, whereas severe disease may require hematopoietic stem cell transplantation.

The Effect of Social Support on Psychological Flourishing and Distress Among Migrants in Australia.

PubMed

du Plooy, Daniel R; Lyons, Anthony; Kashima, Emiko S

2018-05-04

We examine the access that culturally diverse migrant groups in Australia have to different sources of social support and how this access, or lack thereof, is associated with psychological flourishing and distress. A national online survey was conducted with 1334 migrants in Australia, examining 11 different sources of social support, including family, friends, relationship partner, acquaintances, work colleagues, health professionals, government agencies, community organisations, religious groups, social groups and online groups. We also examined migrants from different cultural groups. All sources of support were significantly associated with mental health, but somewhat differently for the dimensions of distress and flourishing. Flourishing was linked to higher support from all 11 sources, though not for all cultural groups. High psychological distress was linked to lower support only from family, friends, a partner, acquaintances, work colleagues and social groups, and only for some cultural groups. In particular, for distress, there was no link between migrants from Southern Asia and family support, as well as Confucian Asia groups and friend support. Understanding where migrants from different cultural origins draw their support from could help policymakers and support workers improve health and well-being in migrant populations, especially by focusing on sources of support that are linked to lower distress and greater flourishing, as indicated in this study.

Virtually supportive: a feasibility pilot study of an online support group for dementia caregivers in a 3D virtual environment.

PubMed

O'Connor, Mary-Frances; Arizmendi, Brian J; Kaszniak, Alfred W

2014-08-01

Caregiver support groups effectively reduce stress from caring for someone with dementia. These same demands can prevent participation in a group. The present feasibility study investigated a virtual online caregiver support group to bring the support group into the home. While online groups have been shown to be helpful, submissions to a message board (vs. live conversation) can feel impersonal. By using avatars, participants interacted via real-time chat in a virtual environment in an 8-week support group. Data indicated lower levels of perceived stress, depression and loneliness across participants. Importantly, satisfaction reports also indicate that caregivers overcame the barriers to participation, and had a strong sense of the group's presence. This study provides the framework for an accessible and low cost online support group for a dementia caregiver. The study demonstrates the feasibility of interactive group in a virtual environment for engaging members in meaningful interaction. Copyright © 2014 Elsevier Inc. All rights reserved.

Quality of Life in a Vitiligo Support Group.

PubMed

Zabetian, Saba; Jacobson, Gordon; Lim, Henry W; Eide, Melody J; Huggins, Richard H

2017-04-01

BACKGROUND: No study has examined the impact of vitiligo support group membership on vitiligo patient quality of life (QoL).

OBJECTIVE: We sought to examine the QoL impact of vitiligo support groups by comparing QoL and associated patient characteristics between vitiligo patients who are and are not members of a vitiligo support group.

METHODS: Members of a Henry Ford Hospital-sponsored, Southeast Michigan Vitiligo Support Group were compared to non-member vitiligo patients recruited from a previous study cohort.17 Eligible patients were asked to complete the Dermatology Life Quality Index (DLQI) and a study-specific questionnaire designed to collect relevant patient characteristics.

RESULTS: The mean DLQI scores for the support group members and non-members were similar (7.1 ± 5.4 and 6.0 ± 6.5, respectively; P-value 0.2), despite the support group members reporting more severe overall disease and increased disease severity in exposed portions of the body. The African-American: Caucasian ratio and the prevalence of unemployment were both significantly higher among the support group participants. Small sample size may have limited the study's ability to demonstrate the differences between the support group participants and the controls.

CONCLUSIONS: The similar QoL despite an increased prevalence of poorer QoL indicators among the support group participants suggests a protective effect of support group membership.

J Drugs Dermatol. 2017;16(4):344-350.

Effect of mother support groups on nutritional status in children under two years of age in Laisamis village, Kenya.

PubMed

Undlien, Mattias; Viervoll, Håvard-Amund; Rostad, Berit

2016-12-01

In tackling the ongoing malnutrition problem in many parts of Kenya, the government has initialized preventive actions such as mother support groups in order to improve health and nutrition among children. Few studies have evaluated the effectiveness of such intervention. This study aimed at determining how mother support groups affect the nutrition status of children under 2 years of age. 41 children participated. Anthropometric measurements were taken of the children once a month during 12 months. Medical history, nutrition status and socioeconomic factors were collected by interviews with the mothers. The children were divided into two groups depending on their mother's assigned group; mother support group or not. Nutritional status was significantly better among children in the mother support group (P=0.001). There were significantly more children with severe acute malnutrition among the children not in support group (P=0.040). The mean height (P=0.001) and mean weight (P=0.0281) were significantly higher among children in the non-support group. Mother support groups may have a beneficial effect on the nutritional status of children under 2 years of age. Cases of severe acute malnutrition seemed to be less prevalent in children whose mothers attend mother support groups.

Gays and Lesbians Older and Wiser (GLOW): A Support Group for Older Gay People.

ERIC Educational Resources Information Center

Slusher, Morgan P.; And Others

1996-01-01

Describes Gays and Lesbians Older and Wiser (GLOW), a support group sponsored by a geriatric medical clinic in the midwestern United States. Scheduling, professional involvement, and special attention to social support seem critical for the group's success. Concludes that carefully designed support groups can meet some support needs for this older…

Efficacy of Neurofeedback Versus Pharmacological Support in Subjects with ADHD.

PubMed

González-Castro, Paloma; Cueli, Marisol; Rodríguez, Celestino; García, Trinidad; Álvarez, Luis

2016-03-01

Behavioral training in neurofeedback has proven to be an essential complement to generalize the effects of pharmacological support in subjects who have attention deficit with hyperactivity disorder (ADHD). Therefore, this investigation attempts to analyze the efficacy of neurofeedback compared with pharmacological support and the combination of both. Participants were 131 students, classified into four groups: control (did not receive neurofeedback or pharmacological support), neurofeedback group, pharmacological support group, and combined group (neurofeedback + pharmacological support). Participants' executive control and cortical activation were assessed before and after treatment. Results indicate that the combined group obtained more benefits and that the neurofeedback group improved to a greater extent in executive control than the pharmacological support group. It is concluded that this kind of training may be an alternative to stimulate activation in subjects with ADHD.

Psychosocial needs assessment post kidney transplant: Feasibility of a post-transplant specific support group.

PubMed

Brijmohan, Angela; Famure, Olusegun; Sihota, Kiren; Shea, Mary; Marzario, Barbara; Mitchell, Margot

2015-01-01

This project assessed unmet psychosocial needs of kidney transplant recipients and the feasibility of a support group located at an urban Canadian hospital to meet those needs. A survey assessed transplant recipient concerns about psychosocial issues related to transplantation, interest in a support group, desired group composition, facilitation, leadership, barriers and alternative forms of support. Most respondents were more than two years since transplant and were more concerned about medical complications, returning to normalcy, and had a greater desire to talk to other transplant recipients. Forty per cent of respondents indicated they would be interested in a support group. However, 60% indicated that a support group hosted in the hospital setting would be a deterrent to attending, citing time and transportation as the greatest barriers. More research is needed to assess the feasibility of post-kidney transplant support groups closer to recipients' homes and the feasibility of alternative forms of support.

Receiving social support online: implications for health education.

PubMed

White, M; Dorman, S M

2001-12-01

Online support groups are expanding as the general public becomes more comfortable using computer-mediated communication technology. These support groups have certain benefits for users who may not be able to or do not have the desire to attend face-to-face sessions. Online support groups also present challenges when compared to traditional face-to-face group communication. Communication difficulties may arise resulting from lack of visual and aural cues found in traditional face-to-face communication. Online support groups have emerged within health care as a result of the need individuals have to know more about health conditions they are confronting. The proliferation of these online communities may provide an opportunity for health educators to reach target populations with specific messages. This paper reviews the development of health-related online support groups, examines research conducted within these communities, compares their utility with traditional support groups and discusses the implications of these groups for health education.

Group cohesion and social support of the nurses in a special unit and a general unit in Korea.

PubMed

Ko, Yu Kyung

2011-07-01

To identify the degree of group cohesion and social support of nurses in special and general units in hospitals in Korea, and to compare group cohesion and social support between the two groups. The level of commitment nurses have to their organizations has been shown to correlate with work group cohesion and social support. The participants were 1751 nurses who were working in Korean hospitals. Data were collected using a structured questionnaire and were analysed using SAS. The statistical methods included: descriptive statistics, t-test, anova and Pearson's correlation coefficients. Group cohesion of nurses on special wards was significantly higher than for nurses on general wards. No significant difference was found between types of units in terms of social support. The degree of group cohesion was significantly different in terms of the respondents' clinical experience, position, religion, job satisfaction, number of supportive superiors and number of supportive peers. A statistically significant correlation was found between group cohesion scores and degree of social support. Hospital management can accomplish their goals more effectively through knowledge of the level of group cohesion, superior support and peer support for nursing staff in accordance with unit specialty. © 2011 The Author. Journal compilation © 2011 Blackwell Publishing Ltd.

Leukemia Support Groups: How Are They Doing?

PubMed

Moss

1997-10-01

BACKGROUND: Support groups help their participants to cope with the emotional and practical impact of their illnesses. METHODS: The effectiveness of the Leukemia Society of America support groups in enhancing the quality of life for their participants is reviewed. The groundwork, purpose, and structure of such groups, as well as alternate sources of support, are presented. Evaluation and future directions for oncology groupwork are discussed. RESULTS: Support groups complement the therapies provided by clinical practitioners and scientists by addressing the additional needs of cancer patients over the course of illness and survival. CONCLUSIONS: New concepts and methods that address the needs of specific age-groups and incorporate the newly generated data on cancer treatments will further enhance the benefits provided by support groups.

Who helps the leaders? Difficulties experienced by cancer support group leaders.

PubMed

Kirsten, Laura; Butow, Phyllis; Price, Melanie; Hobbs, Kim; Sunquist, Kendra

2006-07-01

Cancer support groups are an important source of support for cancer patients, yet little is known about the challenges and training needs of both professionally trained and untrained leaders. The aim of this study was to discover the difficulties experienced and training desired by cancer support group leaders. Twenty-seven leaders of 34 cancer support groups participated in focus groups or individual interviews. Groups were purposively selected as representative of 173 support groups identified in New South Wales which were for adults with cancer and/or their adult carers and were not therapeutic or education-only groups. Difficulties identified included dealing with people's different communication styles and needs; dealing with recurrence, metastases and death; practical issues, including resources, setting the programme and funding security; maintaining personal balance and preventing burn out; establishing group credibility; dealing with group cycles; and leading groups in rural areas. Leaders also identified benefits and rewards from group leadership such as contributing to others' well-being, self-development and insight into others' lives. Non-professionally trained leaders experienced more difficulties, particularly in dealing with group process and practical issues. Difficulties identified were related both to working with a cancer population specifically and to working with groups in general. While some issues were common to both health professionals and non-health professionals, non-health professionals reported greater supportive needs. Clear guidelines, targeted training and development of better methods of support to reduce the stress and burn out experienced by group leaders are needed.

Families affected by childhood cancer: an analysis of the provision of social support within online support groups.

PubMed

Coulson, N S; Greenwood, N

2012-11-01

With increasing access to the Internet, there are new opportunities available to families to seek information, advice and support about childhood cancer online. A total of 487 messages were retrieved from three childhood cancer online support groups and were analysed using deductive thematic analysis for the presence of support-intended communication using Cutrona and Suhr's social support typology. In addition, the messages were examined for negative experiences or disadvantages. The results revealed the presence of five types of social support: emotional, informational, esteem support and tangible assistance. In addition, some potential limitations of online support were identified, including a lack of responses and difficulties in maintaining relationships outside the online group context. This study suggests that online support groups may offer the potential to support family members of children with cancer. In particular, it may be a useful resource for those seeking emotional and information support. However, there may be limitations associated with the use of online support groups. © 2011 Blackwell Publishing Ltd.

Online support groups for women with breast cancer.

PubMed

McCaughan, Eilis; Parahoo, Kader; Hueter, Irene; Northouse, Laurel; Bradbury, Ian

2017-03-10

Survival rates for women with a diagnosis of breast cancer continue to improve. However, some women may experience physical, psychological and emotional effects post diagnosis, throughout treatment and beyond. Support groups can provide opportunities for people to share their experiences and learn from others. As the number of online support groups increases, more and more women with breast cancer will likely access them. To assess effects of online support groups on the emotional distress, uncertainty, anxiety, depression and quality of life (QoL) of women with breast cancer. We searched for trials in the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 4), MEDLINE, Embase and PsycINFO on 2 May 2016, and we handsearched journals and reference lists. We also searched the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) search portal and clinicaltrials.gov on 2 May 2016. We included randomised controlled trials (RCTs) assessing effects of online support groups on women with a diagnosis of breast cancer and women who have completed breast cancer treatment. We included studies comparing online support groups with a usual care group, and studies comparing two or more types of online support groups (without a usual care group). Two review authors independently extracted data and assessed risk of bias. We presented outcome data using mean differences (MDs) and standardised mean differences (SMDs) along with 95% confidence intervals (CIs), and we used the fixed-effect model when appropriate. We assessed the quality of the body of evidence using the GRADE approach. We included six studies (492 women) that assessed online support groups for women with breast cancer. Online support groups in these six trials lasted from six to 30 weeks. Women participated in these groups between 1.5 and 2.5 hours per week, and investigators conducted all studies in the USA. Participants were predominantly white and well educated and were moderate to high earners. Four studies compared an online support group versus a control group, and the other two compared a 'moderated' versus a 'peer-led' online support group, and a 'standard' versus an 'enhanced' online support group, respectively.None of the included studies measured 'emotional distress' or uncertainty. One study (78 women) for which data for analysis were missing reported no positive effects of online support on 'distress' and 'cancer-specific distress' versus support provided by a control group. Two studies measured anxiety: One study (72 women) found no difference in anxiety at the end of the intervention between the online support group and the control group (MD -0.40, 95% CI -6.42 to 5.62; low-quality evidence), and the second study (184 women) reported a reduction in anxiety levels at the end of the intervention when comparing the 'standard' support group (run by participants without prompting from health professionals) versus an 'enhanced' online support group (in which participants were specifically asked by the researcher to respond to one another's need for support).Five studies (414 women) measured depression. Three studies compared depression in the online support group with depression in the control group. Pooled data from two studies (120 women) showed a small to moderate reduction in depression in the online support group compared with control groups at the end of the intervention (SMD -0.37, 95% CI -0.75 to 0.00; very low-quality evidence). The third study, a pilot study (30 women), provided no data for analysis but reported no difference in depression between participants in support and control groups at the end of the intervention. Of the remaining two studies that measured depression, one study (60 women) provided no extractable data for comparison but reported no difference in depressive symptoms between a 'moderated' and a 'peer-led' support group; the other study (184 women) reported greater reduction in depression in the 'standard' support group than in the 'enhanced' online support group.Three studies measured quality of life. One pilot study (30 women) provided limited data for analysis but reported no change in quality of life at the end of the intervention. Only two studies (140 women) provided data for pooling and showed no positive effects on quality of life at four months post intervention compared with controls (SMD -0.11, 95% CI -0.47 to 0.24; very low-quality evidence). At 12 months post intervention, one study (78 women) reported that the intervention group did not attain better quality of life scores than the control group (MD -10.89, 95% CI -20.41 to -1.37; low-quality evidence).We found no data for subgroup analyses on stage of disease, treatment modality and types and doses of interventions. No studies measured adverse effects. This review did not find the evidence required to show whether participation in online support groups was beneficial for women with breast cancer, because identified trials were small and of low or very low quality. Large, rigorous trials with ethnically and economically diverse participants are needed to provide robust evidence regarding the psychosocial outcomes selected for this review.

Cultural and Global Linkages of Emotional Support through Online Support Groups.

ERIC Educational Resources Information Center

Gary, Juneau Mahan

Computer technology is altering the way people cope with emotional distress. Computers enable people worldwide and from all cultural groups to give and receive emotional support when it may be culturally stigmatizing to seek face-to-face support or when support services are limited or non-existent. Online support groups attract a broad range of…

Facilitation of self-transcendence in a breast cancer support group: II.

PubMed

Coward, Doris Dickerson

2003-01-01

To pilot a second support group intervention study promoting self-transcendence perspectives and activities and to document changes over time in well-being in support group participants compared with nonparticipants. Quasiexperimental, partial randomization, preference trial design. An urban breast cancer resource center established by survivors. 41 women with newly diagnosed breast cancer were recruited, and 39 completed the study. 22 women participated in three intervention support groups; 17 were in a comparison group. The intervention was an eight-week, closed support group based on self-transcendence theory. Data were collected three times during 14 months. Support group intervention, self-transcendence, and emotional and physical well-being. The intervention group had lower scores than the comparison group on self-transcendence and well-being variables at baseline (time [T] 1). Scores were higher for both groups postintervention (T2), with no differences between groups. One year postintervention (T3), intervention group scores again were lower than comparison group scores. Intervention group T3 scores were unchanged from T2. Most potential participants were unwilling to risk being randomized into a nonpreferred group. Activities based on self-transcendence theory were associated with expanded perspectives and activities and an improved sense of well-being in support group participants at the end of the intervention, but not one year later. Findings from the pilot studies informed a study currently in progress. Nurses should maintain awareness of local resources for support and make that information available to women when they are newly diagnosed with breast cancer, during their treatment, and later.

Social and Psychological Determinants of Levels of Engagement with an Online Breast Cancer Support Group: Posters, Lurkers, and Non-Users

PubMed Central

Han, Jeong Yeob; Kim, Jung-Hyun; Yoon, Hye Jin; Shim, Minsun; McTavish, Fiona M.; Gustafson, David H.

2013-01-01

Despite the benefits and growing availability of online cancer support groups, many breast cancer patients still do not actively participate in the support groups. To better understand cancer patients’ online information and support seeking behaviors, this study explores how various social and psychological characteristics predict different levels of engagement with an online breast cancer support group: posters, lurkers, and non-users. The study sample included 231 recently diagnosed breast cancer patients. Data included baseline survey scores of demographic, disease-related, and psychosocial factors and automatically collected discussion group use data over the 4-month intervention. Patterns of engagement with the cancer support group differed according to the patients’ characteristics, suggesting that (1) cancer patients have very different orientations to and engagement with an online support group, and (2) ‘deficits’ in social and psychological resources may not be barriers to participation in a cancer support group, but rather motivators to interact with other patients. Theoretical and practical implications of the findings are discussed. PMID:22085215

Family support group in psychosocial rehabilitation

PubMed Central

Ponnuchamy, L.; Mathew, Baijumon K.; Mathew, Sheeba; Udayakumar, G.S.; Kalyanasundaram, S.; Ramprasad, Dharitri

2005-01-01

Background: Support groups for families of persons with mental illness are emerging as significant components in psychosocial rehabilitation programmes. Aim: To ascertain the expectations of family members who attend family support group meetings and to find out the efficacy of such programmes. Methods: The data were collected from support group members using a semi-structured interview schedule. The study sample (n=20) was drawn from family members who attended the support group meetings regularly for a minimum period of 6 months. Data analysis was done using percentile. Results: Analysis of the data revealed that members attending the support group meetings expected to get more information about the illness, develop skills to cope with problems at home and learn skills to deal with the ill person. An important finding of the study was that the members developed a ‘feeling of togetherness’ as a result of being a member of a group with common aims. Conclusion: Participation in a support group meeting positively affects key variables in the participant's adaptation to mental illness in a relative. PMID:20814460

Effectiveness of comprehensive social support interventions among elderly patients with tuberculosis in communities in China: a community-based trial.

PubMed

Li, Xuhui; Wang, Bin; Tan, Dixin; Li, Mengyu; Zhang, Dandan; Tang, Cong; Cai, Xiaonan; Yan, Yaqiong; Zhang, Sheng; Jin, Bo; Yu, Songlin; Liang, Xunchang; Chu, Qian; Xu, Yihua

2018-05-01

With the increasing of ageing population, tuberculosis in the elderly brings a challenge for the tuberculosis (TB) control in China. Enough social support can promote the treatment adherence and outcome of the elderly patients with TB. Exploring effective interventions to improve the social support of patients is of great significance for TB management and control. A community-based, repeated measurement trial was conducted. Patients with TB >65 years of age were allocated into the intervention or control group. Patients in the intervention group received comprehensive social support interventions, while those in the control group received health education alone. The social support level of patients was measured at baseline and at the first, third and sixth months during the intervention to assess the effectiveness of comprehensive social support interventions. A total of 201 patients were recruited into the study. Compared with the control group, social support for patients in the intervention group increased significantly over time (β group*time =0.61, P<0.01) in the following three dimensions: objective support (β group*time =0.15, P<0.05), subjective support (β group*time =0.32, P<0.05) and support utilisation (β group*time =0.16, P<0.05). The change in the scores in the control group was not statistically significant. The intervention programme in communities, including health education, psychotherapy and family and community support interventions, can improve the social support for elderly patients with TB compared with single health education. ChiCTR-IOR-16009232. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The Effectiveness of Support Groups in Asian Breast Cancer Patients: An Integrative Review.

PubMed

Chou, Fang-Yu; Lee-Lin, Frances; Kuang, Lily Y

2016-01-01

Cancer support group has been studied as an intervention to improve patient psychosocial well-being. The effectiveness of support groups among Asian breast cancer (BC) patients has been unclear and received limited attention to the evidence of its effectiveness. The social-cognitive processing theory underlies the principles of support groups and advocates that a positive, supportive social environment can improve cognitive processing. The purpose of this paper is to present an integrative review of research evidence on the effectiveness of cancer support groups with Asian BC patients. Empirical studies related to support group among Asian and Asian American BC patients published between 1982 and April 2014 are reviewed. There are 15 studies selected (12 from the Asian-Pacific region and 3 from Western countries). The review includes 1 qualitative study, 3 descriptive studies, 1 mixed method design, and 10 experimental or quasi-experimental studies. The support group intervention activities include psycho-educational program such as health education, problem-solving, and stress management. These studies support the effectiveness of support group in alleviating psychological distress and supporting quality of life of Asian BC women. Overall, there is limited research on the use and effectiveness of support groups with Asians cancer patients in Asia and in Western countries. Without accounting for Asian immigrants overseas, the Asian population is expected to grow from 4.3 to 5.3 billion by 2050. As cancer patients become more diverse due to global emigration, more rigorous studies examining the effectiveness of psychosocial intervention among transcultural cancer patients are needed.

Effects of Pre-Structuring Discussion Threads on Group Interaction and Group Performance in Computer-Supported Collaborative Argumentation

ERIC Educational Resources Information Center

Brooks, C. Darren; Jeong, Allan

2006-01-01

This study examined the effects of pre-structuring discussion threads on group performance in computer-supported collaborative argumentation where students labeled their messages as arguments, challenges, supporting evidence, and explanations on a threaded discussion board. In the pre-structured group students were required to post supporting and…

A mixed methods study of peer-to-peer support in a group-based lifestyle intervention for adults with serious mental illness.

PubMed

Aschbrenner, Kelly A; Naslund, John A; Bartels, Stephen J

2016-12-01

There is potential for peer support to enhance healthy lifestyle interventions targeting changes in body weight and fitness for adults with serious mental illness. The purpose of this study was to explore peer-to-peer support among individuals participating in a group lifestyle intervention that included social media to enhance in-person weight management sessions. A mixed methods study design was used to explore participants' perceptions and experiences of support from other group members during a 6-month group lifestyle intervention. Twenty-five individuals with serious mental illness reported their perceptions of the peer group environment and social support during the intervention. Seventeen of these individuals also participated in focus group interviews further exploring their experiences with group members. More than 80% of participants agreed that other group members were trustworthy and dependable, and 92% reported a high level of shared purpose and active participation in the group. Participants described how shared learning and group problem-solving activities fostered friendships and provided essential support for health behavior change. Sharing information, personal successes and challenges, and "being in the same boat" as other group members were key features of peer-to-peer support. Findings from this exploratory study suggest that participants enrolled in a group-based lifestyle intervention for people with serious mental illness experience peer-to-peer support in various ways that promote health behavior change. These findings highlight opportunities to enhance future lifestyle interventions with collaborative learning and social network technologies that foster peer support among participants. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Exploring the impact of training on the experience of Australian support group leaders: current practices and implications for research

PubMed Central

Zordan, Rachel D.; Juraskova, Ilona; Butow, Phyllis N; Jolan, Afsaneh; Kirsten, Laura; Chapman, Julie; Sedgwick, Christine; Charles, Margaret; Sundquist, Kendra

2010-01-01

Abstract Background  Existing literature suggests that the effectiveness of a support group is linked to the qualifications, skills and experience of the group leader. Yet, little research has been conducted into the experiences of trained vs. untrained support group leaders of chronic‐illness support groups. The current study aimed to compare the experience of leaders, trained vs. untrained in group facilitation, in terms of challenges, rewards and psychological wellbeing. Methods  A total of 358 Australian leaders of cancer and multiple sclerosis (MS) support groups, recruited through State Cancer Councils and the MS society (response rate of 66%), completed a mailed survey. Results  Compared with untrained leaders, those with training were significantly younger, leading smaller groups and facilitating more groups, more frequently (all P < 0.05). Trained leaders were more likely to be female, educated beyond high school, paid to facilitate, a recipient of formal supervision and more experienced (in years) (all P < 0.01). Untrained leaders reported more challenges than trained leaders (P < 0.03), particularly struggling with being contacted outside of group meetings (52%) and a lack of leadership training (47%). Regardless of level of training, leaders identified a number of unmet support and training needs. Overwhelmingly, leaders found their facilitation role rewarding and the majority reported a high level of psychological wellbeing. Conclusions  Group facilitator training has the potential to reduce the burden of support group leadership. Developing interventions to assist support group leaders will be particularly beneficial for leaders with minimal or no training group facilitation training. PMID:20550596

Social support and online postpartum depression discussion groups: a content analysis.

PubMed

Evans, Marilyn; Donelle, Lorie; Hume-Loveland, Laurie

2012-06-01

Social support has a positive influence on women's childbearing experience and is shown to be a preventive factor in postpartum depression. This study examined the perceived value and types of social supports that characterize the discussions of women who participate in postpartum depression online discussion groups. A directed content analysis was used to examine 512 messages posted on a postpartum depression online support group over six months. The majority of the women's postings illustrated emotional support followed by informational and instrumental support. Online support groups provide women experiencing postpartum depression a safe place to connect with others and receive information, encouragement and hope. Education strategies are needed to address the many questions regarding PPD medical treatment. Recommending vetted links to PPD online support groups will create opportunities for women to share their experiences and obtain support. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Impact Exerted by Nutritional Risk Screening on Clinical Outcome of Patients with Esophageal Cancer.

PubMed

Wang, Rui; Cai, Hongfei; Li, Yang; Chen, Caiwen; Cui, Youbin

2018-01-01

Preoperative nutritional status of patients is closely associated with their recovery after the surgery. This study aims to ascertain the impact exerted by the nutritional risk screening on clinical outcome of patients with esophageal cancer. 160 patients with esophageal cancer aged over 60, having got therapy at the First Hospital of Jilin University from Jun 2016 to Feb 2017 were evaluated by adopting the NRS2002. 80 cases of patients got active therapy of nutritional support, and the other patients not supported nutritionally were selected as the control group. The comparison was drawn between two groups in serum albumin, serum immunoglobulin, postoperative complications, hospitalization, and hospitalization expenses. For all the patients, in 3 and 7 days after the surgery, the serum albumin in the nutritionally supported group outstripped that in group without nutritional support ( P < 0.05) regardless of the nutritional risk. For the patients in the risk of nutrition, the IgA in the nutritionally supported group outstripped that of group without nutritional support ( P < 0.05) in 3 and 7 days before the surgery, and the serum IgG outstripped that of the group without nutritional support in 1 and 3 days before the surgery ( P < 0.05). In terms of the patients in the risk of nutrition, the average hospitalization of nutritionally supported group was shorter ( P < 0.05), and the average hospitalization expenses were lower compared with those of the group without nutritional support. And for the patients in no risk, the hospitalization expenses of supported group surmounted those of group without nutritional support ( P < 0.05), whereas the average hospitalization took on no statistic difference ( P > 0.05). For the patients in the risk of nutrition, preoperative nutritional support can facilitate the nutritional status and immunization-relative result after surgery, which shall also decrease the average hospitalization and hospitalization cost.

Impact Exerted by Nutritional Risk Screening on Clinical Outcome of Patients with Esophageal Cancer

PubMed Central

Cai, Hongfei; Li, Yang; Chen, Caiwen

2018-01-01

Objective Preoperative nutritional status of patients is closely associated with their recovery after the surgery. This study aims to ascertain the impact exerted by the nutritional risk screening on clinical outcome of patients with esophageal cancer. Methods 160 patients with esophageal cancer aged over 60, having got therapy at the First Hospital of Jilin University from Jun 2016 to Feb 2017 were evaluated by adopting the NRS2002. 80 cases of patients got active therapy of nutritional support, and the other patients not supported nutritionally were selected as the control group. The comparison was drawn between two groups in serum albumin, serum immunoglobulin, postoperative complications, hospitalization, and hospitalization expenses. Results For all the patients, in 3 and 7 days after the surgery, the serum albumin in the nutritionally supported group outstripped that in group without nutritional support (P < 0.05) regardless of the nutritional risk. For the patients in the risk of nutrition, the IgA in the nutritionally supported group outstripped that of group without nutritional support (P < 0.05) in 3 and 7 days before the surgery, and the serum IgG outstripped that of the group without nutritional support in 1 and 3 days before the surgery (P < 0.05). In terms of the patients in the risk of nutrition, the average hospitalization of nutritionally supported group was shorter (P < 0.05), and the average hospitalization expenses were lower compared with those of the group without nutritional support. And for the patients in no risk, the hospitalization expenses of supported group surmounted those of group without nutritional support (P < 0.05), whereas the average hospitalization took on no statistic difference (P > 0.05). Conclusion For the patients in the risk of nutrition, preoperative nutritional support can facilitate the nutritional status and immunization-relative result after surgery, which shall also decrease the average hospitalization and hospitalization cost. PMID:29780831

Making meaning in a burn peer support group: qualitative analysis of attendee interviews.

PubMed

Davis, Trevor; Gorgens, Kim; Shriberg, Janet; Godleski, Matthew; Meyer, Laura

2014-01-01

There is a paucity of literature on the personal experiences of burn support group members, the members' perceived benefits of group participation, and the meaning the survivors make of the support they receive. In order to provide effective psychosocial rehabilitation services and to meet the needs of burn survivors, it is important to understand the influence a support group has on its members as well as the personal experiences of those individuals who attend these groups. The purpose of this study was to explore the experiences of burn survivors in a burn survivor support group. Six self-identified burn survivors were interviewed by using a guided in-depth interview technique to explore their experiences in the support group. Key informant interviews and group observations served to triangulate the findings from the individual interviews. The experiences of the group members coalesced around four main themes: acceptance of self, perspective change, value of community, and reciprocity. The findings demonstrated the overall perceived positive impact the support group had on psychosocial recovery. For these members, the group aided the process of adjustment through the encouragement of adaptive coping strategies and the facilitation of community and relationships. Their experiences mirrored much of the literature on psychological growth from adversity. Burn survivors reported unique opportunities that allowed them to integrate their injury into their identity within an encouraging and safe environment. Using these accounts, the authors generated clinical suggestions that may encourage similar growth in other support group settings.

A single blind randomized control trial on support groups for Chinese persons with mild dementia.

PubMed

Young, Daniel K W; Kwok, Timothy C Y; Ng, Petrus Y N

2014-01-01

Persons with mild dementia experience multiple losses and manifest depressive symptoms. This research study aimed to evaluate the effectiveness of a support group led by a social worker for Chinese persons with mild dementia. Participants were randomly assigned to either a ten-session support group or a control group. Standardized assessment tools were used for data collection at pretreatment and post-treatment periods by a research assistant who was kept blind to the group assignment of the participants. Upon completion of the study, 20 treatment group participants and 16 control group participants completed all assessments. At baseline, the treatment and control groups did not show any significant difference on all demographic variables, as well as on all baseline measures; over one-half (59%) of all the participants reported having depression, as assessed by a Chinese Geriatric Depression Scale score ≥8. After completing the support group, the depressive mood of the treatment group participants reduced from 8.83 (standard deviation =2.48) to 7.35 (standard deviation =2.18), which was significant (Wilcoxon signed-rank test; P=0.017, P<0.05), while the control group's participants did not show any significant change. This present study supports the efficacy and effectiveness of the support group for persons with mild dementia in Chinese society. In particular, this present study shows that a support group can reduce depressive symptoms for participants.

The use of an online support group for neuromuscular disorders: a thematic analysis of message postings.

PubMed

Meade, Oonagh; Buchanan, Heather; Coulson, Neil

2017-06-08

People affected by neuromuscular disorders can experience adverse psychosocial consequences and difficulties accessing information and support. Online support groups provide new opportunities for peer support. The aim of this study was to understand how contributors used the message board function of a newly available neuromuscular disorders online support group. Message postings (n = 1951) from the first five months of the message board of a newly formed online support group for neuromuscular disorders hosted by a charitable organization were analyzed using inductive thematic analysis. Members created a sense of community through disclosing personal information, connecting with people with similar illness experiences or interests, welcoming others and sharing aspirations for the development of a resourceful community. Experiences, emotional reactions and support were shared in relation to: delayed diagnosis; symptom interpretation; illness management and progression; the isolating impact of rare disorders; and the influence of social and political factors on illness experiences. This study provided a novel insight into individuals' experiences of accessing a newly available online support group for rare conditions hosted by a charitable organization. The findings highlight how the online support group provided an important peer support environment for members to connect with others, exchange information and support and engender discussion on political and social issues unique to living with often-rare neuromuscular disorders. Online support groups may therefore provide an important and easily accessible support outlet for people with neuromuscular disorders as well as a platform for empowering members to raise awareness about the impact of living with these conditions. Further research is needed to examine member motivations for using such groups and any effects of participation in greater detail. Implications for rehabilitation Online support groups may provide a unique forum for information sharing and peer support between people affected by often rare, neuromuscular conditions. Rehabilitation professionals may wish to signpost those affected by neuromuscular disorders to such groups. An advantage is that these groups are freely available and can be accessed from anywhere and at any time. Members may be able to learn about the diagnosis and symptom experiences of others, discuss coping strategies, validate illness experiences and discuss social and political issues relating to living with these conditions. Further research is needed before researchers and clinicians can fully understand participants' motivations for, and experiences of, using such groups and any potential psychosocial benefits.

Emergence of Yalom's therapeutic factors in a peer-led, asynchronous, online support group for family caregivers.

PubMed

Diefenbeck, Cynthia A; Klemm, Paula R; Hayes, Evelyn R

2014-01-01

Support groups fill a critical void in the health care system, harnessing the power of shared experiences to provide support to group members. Likewise, family caregivers fill a void in the health care system, providing billions in unpaid care to the chronically ill. Caregiver support groups offer an opportunity for alleviating the psychological burden of caregiving. The power of any group, including a support group, to foster psychological well-being lies in its ability to cultivate Yalom's therapeutic factors. Gaps in the literature remain regarding the ability of non-prototypical groups to promote therapeutic mechanisms of change. The purpose of this study was to determine if and when Yalom's therapeutic group factors emerged in a peer-led support group delivered in an asynchronous, online format. Qualitative content analysis utilizing deductive category application was employed. Participants' responses were coded and frequency counts were conducted. Results revealed that 9 of 11 therapeutic factors emerged over the course of the group, with Group Cohesiveness, Catharsis, Imparting of Information, and Universality occurring most often. Several factors, including Interpersonal Learning, Corrective Recapitulation of the Primary Family Group, Imitative Behavior, and Development of Socializing Techniques were absent or virtually absent, likely due to the peer-led format of the group. Progression of therapeutic factors over the course of the group is presented. Findings demonstrate the presence of a variety of Yalom's therapeutic factors in an asynchronous, peer-led online support group.

Online Support Groups: Nuts and Bolts, Benefits, Limitations and Future Directions. ERIC/CASS Digest.

ERIC Educational Resources Information Center

Gary, Juneau M.; Remolino, Linda

Online support groups provide an alternative vehicle of support for people in distress by linking people who have similar problems. They have the potential to improve the access and delivery of support to a wide range of people, including some who would not seek face-to-face support at all. Online support groups reduce the sense of isolation…

Improving Emotional and Cognitive Outcomes for Domestic Violence Survivors: The Impact of Shelter Stay and Self-Compassion Support Groups.

PubMed

Allen, Ashley Batts; Robertson, Emily; Patin, Gail A

2017-10-01

This study examined the effectiveness of a domestic violence shelter and tested the impact of a self-compassion support group curriculum on outcomes valued by shelters such as autonomy, emotional restoration, and safety. Data were collected from 251 women staying in a domestic violence shelter who had the opportunity to attend a self-compassion support group during their stay. Women completed a pre- and posttest survey assessing self-compassion, empowerment, positive emotion, and perceptions of safety. First, women experienced a positive change ( N = 36) from pretest to posttest across all four outcome variables, suggesting the domestic violence shelter was effective at improving survivors' well-being. Second, participants who attended a self-compassion support group at least once reported more positive posttest scores compared with those who did not attend a group ( N = 79); however, this effect was limited to participants who stayed in shelter a short time. Women who stayed in shelter a longer amount of time experienced more positive posttest scores regardless of group attendance. Although the sample size was limited, analyses directly comparing the traditional shelter support group with the self-compassion support group show that both were equally effective. These findings provide support for shelter effectiveness in terms of improving well-being. They also suggest women who stay in shelter a short period of time may not experience as many shelter benefits unless they attend a support group. Therefore, shelters should consider offering support groups to women very soon after shelter entry. Furthermore, more research is needed to disentangle the benefits of self-compassion interventions over and above a general support group curriculum.

Classification of Support Needs for Elderly Outpatients with Diabetes Who Live Alone.

PubMed

Miyawaki, Yoshiko; Shimizu, Yasuko; Seto, Natsuko

2016-02-01

To investigate the support needs of elderly patients with diabetes and to classify elderly patients with diabetes living alone on the basis of support needs. Support needs were derived from a literature review of relevant journals and interviews of outpatients as well as expert nurses in the field of diabetes to prepare a 45-item questionnaire. Each item was analyzed on a 4-point Likert scale. The study included 634 elderly patients with diabetes who were recruited from 3 hospitals in Japan. Exploratory factor analysis was performed to determine the underlying structure of support needs, followed by hierarchical cluster analysis to clarify the characteristics of patients living alone (n=104) who had common support needs. Exploratory factor analysis suggested a 5-factor solution with 23 items: (1) hope for class and gatherings, (2) hope for personal advice including emergency response, (3) supportlessness and hopelessness, (4) barriers to food preparation, (5) hope of safe medical therapy. The hierarchical cluster analysis of subjects yielded 7 clusters, including a no special-support needs group, a collective support group, a self-care support group, a personal-support focus group, a life-support group, a food-preparation support group and a healthcare-environment support group. The support needs of elderly patients with diabetes who live alone can be divided into 2 categories: life and self-care support. Implementation of these categories in outpatient-management programs in which contact time with patients is limited is important in the overall management of elderly patients with diabetes who are living alone. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

International multi-site survey on the use of online support groups in bipolar disorder.

PubMed

Bauer, Rita; Conell, Jörn; Glenn, Tasha; Alda, Martin; Ardau, Raffaella; Baune, Bernhard T; Berk, Michael; Bersudsky, Yuly; Bilderbeck, Amy; Bocchetta, Alberto; Bossini, Letizia; Castro, Angela M Paredes; Cheung, Eric Y W; Chillotti, Caterina; Choppin, Sabine; Zompo, Maria Del; Dias, Rodrigo; Dodd, Seetal; Duffy, Anne; Etain, Bruno; Fagiolini, Andrea; Hernandez, Miryam Fernández; Garnham, Julie; Geddes, John; Gildebro, Jonas; Gonzalez-Pinto, Ana; Goodwin, Guy M; Grof, Paul; Harima, Hirohiko; Hassel, Stefanie; Henry, Chantal; Hidalgo-Mazzei, Diego; Kapur, Vaisnvy; Kunigiri, Girish; Lafer, Beny; Larsen, Erik R; Lewitzka, Ute; Licht, Rasmus W; Hvenegaard Lund, Anne; Misiak, Blazej; Piotrowski, Patryk; Monteith, Scott; Munoz, Rodrigo; Nakanotani, Takako; Nielsen, René E; O'donovan, Claire; Okamura, Yasushi; Osher, Yamima; Reif, Andreas; Ritter, Philipp; Rybakowski, Janusz K; Sagduyu, Kemal; Sawchuk, Brett; Schwartz, Elon; Scippa, Ângela M; Slaney, Claire; Sulaiman, Ahmad H; Suominen, Kirsi; Suwalska, Aleksandra; Tam, Peter; Tatebayashi, Yoshitaka; Tondo, Leonardo; Vieta, Eduard; Vinberg, Maj; Viswanath, Biju; Volkert, Julia; Zetin, Mark; Whybrow, Peter C; Bauer, Michael

2017-08-01

Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups. To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking. The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data. The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

Racial/ethnic variations in the main and buffering effects of ethnic and nonethnic supports on depressive symptoms among five ethnic immigrant groups in Toronto.

PubMed

Kim, Il-Ho; Noh, Samuel

2016-01-01

This study examined variations in the main and buffering effects of ethnic and nonethnic social support on depressive symptoms associated with discrimination among five immigrant groups in Toronto. Data were taken from the Toronto Study of Settlement and Health, a cross-sectional survey of adult immigrants from five ethnic communities (Vietnamese, Ethiopian, Iranian, Korean, and Irish) in Toronto. A total of 900 surveys were collected through face-to-face interviews conducted between April and September 2001. Significant ethnic variations were observed in the effects of both ethnic and nonethnic social supports on discrimination-related depressive symptoms. Regarding the main effect, ethnic social support was significantly stronger for Iranian, Ethiopian, and Korean immigrants than for Irish immigrants. The benefits of nonethnic support were stronger for Iranian immigrants compared to the effect found in the Irish sample. With respect to stress-buffering or stress-moderating effects of social support, ethnic support was significant in all ethnic groups, except the Vietnamese group. Nonethnic support aggravated the negative impact of discrimination on depressive symptoms in the Irish group, but exerted a stress-buffering effect in the Iranian group. Overall, social supports received from fellow ethnic group members had significant main effects (suppressing depressive symptoms) and stress-buffering effects and were most pronounced in the minority ethnic immigrant groups of Ethiopians, Koreans, and Iranians. The effects were least evident among the Vietnamese and Irish. Evidence for the stress-suppressing and stress-buffering role of cross-ethnic group supports was unclear, and even inverted among Irish immigrants. Empirical evidence from the current study seems to support the sociocultural similarity hypothesis of social support.

Mindfulness-Based Stress Reduction and Group Support Decrease Stress in Adolescents with Cardiac Diagnoses: A Randomized Two-Group Study.

PubMed

Freedenberg, Vicki A; Hinds, Pamela S; Friedmann, Erika

2017-10-01

Adolescents with cardiac diagnoses face unique challenges that can cause psychosocial distress. This study compares a Mindfulness-Based Stress Reduction (MBSR) program to a video online support group for adolescents with cardiac diagnoses. MBSR is a structured psycho-educational program which includes yoga, meditation, cognitive restructuring, and group support. A published feasibility study by our group showed significant reduction in anxiety following this intervention. Participants were randomized to MBSR or video online support group, and completed measures of anxiety, depression, illness-related stress, and coping pre- and post-6-session interventions. Qualitative data were obtained from post-intervention interviews. A total of 46 teens participated (mean 14.8 years; 63% female). Participants had congenital heart disease and/or cardiac device (52%), or postural orthostatic tachycardia syndrome (48%). Illness-related stress significantly decreased in both groups. Greater use of coping skills predicted lower levels of depression in both groups post-study completion. Higher baseline anxiety/depression scores predicted improved anxiety/depression scores in both groups. Each group reported the benefits of social support. The MBSR group further expressed benefits of learning specific techniques, strategies, and skills that they applied in real-life situations to relieve distress. Both the MBSR intervention and video support group were effective in reducing distress in this sample. Qualitative data elucidated the added benefits of using MBSR techniques to manage stress and symptoms. The video group format is useful for teens that cannot meet in person but can benefit from group support. Psychosocial interventions with stress management techniques and/or group support can reduce distress in adolescents with cardiac diagnoses.

Selection criteria and facilitation training for the study of groupware

NASA Technical Reports Server (NTRS)

Robichaux, Barry P.

1993-01-01

Computer support for planning and decision making groups is a growing trend in the 90s. Groupware is a name often applied to group software and has been defined as 'computer-based systems that support groups engaged in a common task (or goal) and that provide an interface to a shared environment'. Unlike most single-user software, groupware assists user groups in their collaboration, coordination, and communication efforts. This paper focuses on groupware to support the meeting process. These systems are often called group decision support systems (GDSS), electronic meeting systems (EMS), or group support systems (GSS). The term 'meeting support groupware' is used here to include any computer-based system to support meetings. In order to understand this technology, one must first understand groups, what they do and the problems they face, and groupware, a wide range of technology to support group work. Guidelines for selecting groups for study as part of an overall research plan are provided in this document. These were taken from the literature and from persons for whom the information in this paper was targeted. Also, guidelines for facilitation training are discussed. Familiarity with known and accepted techniques are the principle duties of the facilitator and any form of training must include practice in using these techniques.

Influence of group cohesion on maternal well-being among participants in a support/education group program for single mothers.

PubMed

Lipman, Ellen L; Waymouth, Marjorie; Gammon, Tara; Carter, Patricia; Secord, Margaret; Leung, Olivia; Mills, Brenda; Hicks, Frances

2007-10-01

Single mothers are at increased risk of psychosocial disadvantage, social isolation and physical and mental health difficulties. The authors present (1) the results of group cohesion assessments completed by mothers participating in a trial of community-based support/education groups, and (2) assessments of the association between group cohesion ratings and intervention outcomes of maternal self-evaluations of well-being (mood, self-esteem, and social support) and parenting. Mothers participating in groups completed the Group Atmosphere Scale, a measure of group cohesion, post-group. Overall, most participants provided strong ratings of group cohesion. Significant associations were found between group cohesion and specific positive outcomes. This suggests a positive association between group cohesion and mood, self-esteem, social support, and parenting, in this trial.

The effects of identification with a support group on the mental health of people with multiple sclerosis.

PubMed

Wakefield, Juliet R H; Bickley, Sarah; Sani, Fabio

2013-05-01

Multiple sclerosis (MS) is associated with various psychological problems, including depression and anxiety. Whilst MS support groups are intended to improve mental health, this goal is not always achieved. Taking a social identity approach, we hypothesise that it is the level of subjective identification with a support group (rather than simply support group membership per se) that positively affects the mental health of people with MS. 152 individuals with MS were recruited via UK MS support groups and completed a questionnaire. This included measures of support group identification, depression, anxiety and satisfaction with life, as well as control variables (education level and age). Analyses revealed that, as hypothesised, support group identification was significantly linked to depression, anxiety and satisfaction with life. Moreover, group identification explained a significant amount of variance in addition to that explained by education and age on each health outcome. Repeating the analysis to compare each of the three main sub-types of MS revealed these effects to be present for individuals with relapsing-remitting (RR) and Primary Progressive (PP) MS, but not for those with secondary progressive (SP) MS. We suggest that identifying highly with an MS support group has important positive outcomes for MS patients' mental health. This has implications for practicing clinicians: people with MS (particularly RRMS and PPMS) should be encouraged to engage with support groups, but more must be done to ensure they subjectively identify with these groups, rather than merely attend them. Copyright © 2013 Elsevier Inc. All rights reserved.

Perceived Benefits and Factors that Influence the Ability to Establish and Maintain Patient Support Groups in Rare Diseases: A Scoping Review.

PubMed

Delisle, Vanessa C; Gumuchian, Stephanie T; Rice, Danielle B; Levis, Alexander W; Kloda, Lorie A; Körner, Annett; Thombs, Brett D

2017-06-01

Support groups are an important resource for many people living with rare diseases. The perceived benefits of participating in support groups for people with rare diseases and factors that may influence the ability to successfully establish and maintain these groups are not well understood. Thus, the objective of this scoping review was to provide a mapping of the available evidence on the (1) benefits or perceived benefits of participating in rare disease support groups and (2) barriers and facilitators of establishing and maintaining these groups. CINAHL and PubMed were searched from January 2000 to August 2015, with no language restrictions. Publications that described the benefits or perceived benefits of participating in rare disease support groups or the barriers and facilitators of establishing and maintaining them were eligible for inclusion. Two investigators independently evaluated titles/abstracts and full-text publications for eligibility, and extracted data from each included publication. Ten publications were included in the scoping review. There was no trial evidence on support group benefits. All ten publications reported on the perceived benefits of participating in rare disease support groups. Three reported on barriers and facilitators of establishing and maintaining them. Overall, seven different perceived benefits of participating in rare disease support groups were identified: (1) meeting and befriending other people with the same rare disease and similar experiences; (2) learning about the disease and related treatments; (3) giving and receiving emotional support; (4) having a place to speak openly about the disease and one's feelings; (5) learning coping skills; (6) feeling empowered and hopeful; and (7) advocating to improve healthcare for other rare disease patients. Several facilitators (e.g., meeting via teleconference) and barriers (e.g., getting patients and/or family members to lead the group) of establishing and maintaining these groups were identified. Rare disease support groups are an important source of emotional and practical support for many patients. There is no trial evidence on the benefits of these groups and limited evidence on the perceived benefits and barriers and facilitators to establishing and maintaining them.

“I think my future will be better than my past”: Examining support group influence on the mental health of HIV-infected Rwandan women

PubMed Central

Walstrom, Paige; Operario, Don; Zlotnick, Caron; Mutimura, Eugene; Benekigeri, Chantal; Cohen, Mardge H.

2017-01-01

Urgent need exists for improved psychological services among HIV-infected women in post-genocide Rwanda. Psychological problems associated with trauma and sexual violence (i.e. depression, PTSD) place women at increased risk for sexual risk behaviour, low health-seeking behaviour, delay of antiretroviral therapy (ART) and reduced ART-adherence. We explored experiences of HIV-infected Rwandan women attending psychosocial support groups and their narratives about how participation affected their mental health and HIV treatment. Focus group discussions examined why participants attended support groups, whether participants perceived support groups as beneficial to their psychological well-being, influenced ART-adherence, and other influences on health behaviours and attitudes. Rwandan women (aged 18-65) were randomly selected from 10 health clinic-facilitated support groups for HIV-infected trauma survivors in Kigali. Results identified positive psychological and physical changes as well as behaviour changes in relationships with men, which participants attributed to support group attendance. Data showed significant improvement in mental health, ART-adherence and HIV-serostatus disclosure resulting from group attendance. Participants acknowledged limitations of support groups with respect to addressing poverty and hunger. Implementing psychosocial support groups may leverage clinical outcomes and rejuvenate the well-being of HIV-infected women with interpersonal trauma and/or PTSD and depressive symptoms, particularly those from post-conflict countries. PMID:22812728

Bridging the gap: support groups do not enhance long-term outcome in chronic back pain.

PubMed

Linton, S J; Hellsing, A L; Larsson, I

1997-09-01

Because back pain patients often relapse within months of treatment, the effects of two types of support groups as a complement to usual medical treatment was investigated on long-term outcome. Regular treatment was compared with an "educational" support group and a professional support group before and 1 year after intervention in a randomized controlled trial. A total of 76 women and 27 men, average age of 50 years and with an accumulated sick leave for musculoskeletal pain of 2-24 weeks during the past year, were randomly assigned to the three groups. Sick leave records were obtained from the National Insurance Authority. A battery of standardized instruments was employed, which featured the Sickness Impact Profile, the Coping Strategies Questionnaire, the Multidimensional Pain Inventory, the Pain and Impairment Relationship Scale, the Pain and Discomfort Scale, the Pain Beliefs and Perceptions Inventory, and the Outcome Evaluation Questionnaire. The Educational Support Group demonstrated greater attendance than did the Professional Support Group. However, long-term outcome was not significantly different between any of the groups for sick leave, coping, function, or experienced pain. Both support groups, relative to the Regular Treatment Group, made greater improvements on the Sickness Impact Profile. This study provides little evidence that support groups, as a complement to regular treatment, enhance long-term outcome for subacute musculoskeletal pain problems. Specific treatment techniques, matched to the patient's needs, stringently taught, and delivered in a more compact form, may be necessary for enhancing outcome.

Application of Early Nutrition Support in Neurosurgical Coma Patients.

PubMed

Ren, Guoqin

2015-12-01

The present study was conducted to investigate the clinical efficacy of early parenteral and enteral nutrition (PN + EN) support in neurosurgical coma patients. Eighty cases of neurosurgical coma patients were randomly divided into intervention group and control group. The intervention group received early PN + EN support, and the control group received only total enteral nutritional (TEN) support. The levels of hemoglobin (HGB), serum albumin (ALB), prealbumin (PA), and retinol-binding protein (RBP) in two groups on days 1, 10, and 20 were observed. The incidences of pneumonia, stress ulcer, abnormal liver function, abdominal distension, and diarrhea between two groups were also compared. Results found that, on day 10, compared with the control group, the levels of HGB, PA, and RBP in the intervention group were significantly increased (P < 0.05). On day 20, ALB in the intervention group significantly increased (P < 0.05), and the incidences of pneumonia, abdominal distension, and diarrhea in the intervention group were significantly lower than those in the control group (P < 0.05). Compared with only TEN support, early PN + EN support can obviously improve the nutritional status of neurosurgical coma patients and reduce the occurrence of complications.

African American Adolescents with Sickle Cell Disease: Support Groups and Psychological Well-Being.

ERIC Educational Resources Information Center

Gardner, Marilyn M.; Telfair, Joseph

1999-01-01

Studied the impact of support groups on the psychological well-being of adolescents with sickle cell disease (SCD). Response of 79 adolescent SCD group members show that psychological well-being was best predicted by fewer physical symptoms and greater satisfaction with the group. Findings suggest the beneficial effects of SCD support groups. (SLD)

"I Feel I Mean Something to Someone:" Solution-Focused Brief Therapy Support Groups for Bullied Schoolchildren

ERIC Educational Resources Information Center

Kvarme, Lisbeth Gravdal; Aabø, Liv Sandnes; Saeteren, Berit

2013-01-01

The aim of this study was to investigate how bullied schoolchildren experience solution-focused brief therapy support groups, and to examine how members of the support group experience their participation in the group. An explorative qualitative design, with individual and focus group interviews, was used. The sample consisted of 19…

Exploring an Online Self-Injury Support Group: Perspectives from Group Members

ERIC Educational Resources Information Center

Haberstroh, Shane; Moyer, Michael

2012-01-01

In this qualitative study, the authors explored an online support group for individuals who self-injure. Twenty members of a private and moderated online group responded to questions about their history of self-injury and experiences with the online self-injury support group. Themes emerged related to the relational and emotional aspects of…

Help seeking in a support group for recipients of implantable cardioverter defibrillators and their support persons.

PubMed

Dickerson, S S; Posluszny, M; Kennedy, M C

2000-01-01

To understand shared meanings of help-seeking experiences in support groups of people with implantable cardioverter defibrillator (ICD) and their support persons. ICD support group at an urban medical center. Fifteen individuals with ICD and 9 support persons. Six related themes and 1 constitutive pattern emerged. Themes included hearing and telling stories, help seeking encouraged by triggers, seeking meaningful information, forming a therapeutic friendship through group camaraderie, gaining assistance from the facilitator, and the sharing of a similar view by support persons. The constitutive pattern is coping with the possibility of death. Health care providers may recommend storytelling as the central mechanism of interactions in support groups that assist in coping with daily anxieties of living with an ICD. Nurses would be appropriate facilitators to guide discussion, to provide technical information, and to promote anticipatory guidance in coping with potential firing events.

Functions of an Adult Sickle Cell Group: Education, Task Orientation, and Support.

ERIC Educational Resources Information Center

Butler, Dennis J.; Beltran, Lou R.

1993-01-01

Reports on development of adult sickle cell support group and provides description of psychosocial factors most prevalent in patients' lives (anxiety about death, disruption of social support network, disability, dependence on pain medication, conflicts with health care providers). Notes that support group enhanced participants' knowledge about…

An Approach for Validating Actinide and Fission Product Burnup Credit Criticality Safety Analyses-Isotopic Composition Predictions

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

Radulescu, Georgeta; Gauld, Ian C; Ilas, Germina

2011-01-01

The expanded use of burnup credit in the United States (U.S.) for storage and transport casks, particularly in the acceptance of credit for fission products, has been constrained by the availability of experimental fission product data to support code validation. The U.S. Nuclear Regulatory Commission (NRC) staff has noted that the rationale for restricting the Interim Staff Guidance on burnup credit for storage and transportation casks (ISG-8) to actinide-only is based largely on the lack of clear, definitive experiments that can be used to estimate the bias and uncertainty for computational analyses associated with using burnup credit. To address themore » issues of burnup credit criticality validation, the NRC initiated a project with the Oak Ridge National Laboratory to (1) develop and establish a technically sound validation approach for commercial spent nuclear fuel (SNF) criticality safety evaluations based on best-available data and methods and (2) apply the approach for representative SNF storage and transport configurations/conditions to demonstrate its usage and applicability, as well as to provide reference bias results. The purpose of this paper is to describe the isotopic composition (depletion) validation approach and resulting observations and recommendations. Validation of the criticality calculations is addressed in a companion paper at this conference. For isotopic composition validation, the approach is to determine burnup-dependent bias and uncertainty in the effective neutron multiplication factor (keff) due to bias and uncertainty in isotopic predictions, via comparisons of isotopic composition predictions (calculated) and measured isotopic compositions from destructive radiochemical assay utilizing as much assay data as is available, and a best-estimate Monte Carlo based method. This paper (1) provides a detailed description of the burnup credit isotopic validation approach and its technical bases, (2) describes the application of the approach for representative pressurized water reactor and boiling water reactor safety analysis models to demonstrate its usage and applicability, (3) provides reference bias and uncertainty results based on a quality-assurance-controlled prerelease version of the Scale 6.1 code package and the ENDF/B-VII nuclear cross section data.« less

Effectiveness of a Unique Support Group for Physicians in a Physician Health Program.

PubMed

Sanchez, Luis T; Candilis, Philip J; Arnstein, Fredrick; Eaton, Judith; Barnes Blood, Diana; Chinman, Gary A; Bresnahan, Linda R

2016-01-01

State Physician Health Programs (PHPs) assess, support, and monitor physicians with mental, behavioral, medical, and substance abuse problems. Since their formation in the 1970s, PHPs have offered support groups following the 12-step model for recovery from substance use disorders (SUDs). However, few programs have developed support groups for physicians without SUDs. This study at the Massachusetts PHP (Physician Health Services Inc.) represents the first effort to survey physician attitudes concerning a unique support group that goes beyond classic addiction models. The group was initiated because of the observation that physicians with problems other than SUDs did not fit easily into the 12-step framework. It was hypothesized that such a group would be effective in helping participants control workplace stress, improve professional and personal relationships, and manage medical and psychiatric difficulties. With a response rate of 43% (85 respondents), the survey identified a strong overall impact of the Physician Health Services Inc. support group, identifying positive effects in all areas of personal and professional life: family and friends, wellness, professional relationships, and career. Respondents identified the role of the facilitator as particularly important, underscoring the facilitator's capacity to welcome participants, manage interactions, set limits, and maintain a supportive emotional tone. The implications for physician health extend from supporting a broader application of this model to using a skilled facilitator to manage groups intended to reduce the stress and burnout of present-day medical practice. The results encourage PHPs, hospitals, medical practices, and physician groups to consider implementing facilitated support groups as an additional tool for maintaining physician health.

The Effects of Intrapartum Supportive Care on Fear of Delivery and Labor Outcomes: A Single-Blind Randomized Controlled Trial.

PubMed

İsbir, Gözde Gökçe; Serçekuş, Pinar

2017-04-01

Supportive care during labor, the primary role of intrapartum nurses and midwives, provides comfort to prepartum women and helps facilitate a positive labor experience. It has been argued that supportive care during labor reduces fear and anxiety as well as the resultant side effects. However, evidence supporting this argument is insufficient. The aim of this study was to assess the effects of intrapartum supportive care on fear of delivery and on the key parameters of the labor process. This study used a single-blind randomized controlled trial approach. Randomized block assignment was used to assign 72 participants to either the intervention group (n = 36) or the control group (n = 36). Three women in the intervention group and six in the control group were later excluded from the study because they received emergency cesarean delivery. The intervention group received continuous supportive care, and the control group received routine hospital care. No significant differences were identified between the two groups at baseline. The intervention group reported less fear of delivery during the active and transient phases of labor, higher perceived support and control during delivery, lower pain scores during the transient phase of labor, and a shorter delivery period than the control group (p < .05). However, no significant difference in the use of oxytocin during delivery between the two groups was reported. The results of this evidence-based study suggest that continuous support during labor has clinically meaningful benefits for women and that all women should receive this support throughout their labor and delivery process.

Participant evaluation of teleconference support for African American women with breast cancer.

PubMed

Heiney, Sue P; Adams, Swann Arp; Wells, Linda M; Johnson, Hiluv; King, Jennifer M

2012-01-01

African American women with breast cancer face obstacles such as transportation and family obligations when attending standard support groups. Teleconference support circumvents barriers such as transportation to participation, but few evaluations have been reported about teleconference support. The purpose of this article was to describe the format of a teleconference group and to provide a descriptive account of the participants' feedback about a teleconference group intervention. A descriptive design was used. Participants completed the Overall Support Group Evaluation tool at the end of the 10th group session. Teleconference group participants' feedback indicated that they perceived they had gained knowledge about breast cancer and coping. The participants expressed that the group helped them to reach out and ask for support and improved family and work relationships. Also, participants rated the group highly for the presence of therapeutic factors. On a scale of 1 to 4, with 4 being the highest, mean scores ranged from 3.97 to 3.56. The participants gave high ratings of satisfaction in terms of knowledge gained, leadership style, and benefits. The participants perceived that the group increased their knowledge about cancer, improved family connections, and increased their ability to deal with their cancer. Using teleconferencing technology to deliver a support group to African American breast cancer patients is a beneficial method to reach a disadvantaged population that may be unable to attend face-to-face groups.

Exploring the barriers to exclusive breastfeeding in black and minority ethnic groups and young mothers in the UK.

PubMed

Ingram, Jenny; Cann, Karen; Peacock, Jennie; Potter, Barbara

2008-07-01

UK health policy for many years has been to increase rates of breastfeeding because of the health benefits conferred on mothers and babies. World Health Organization recommends that babies should be breastfed exclusively for 6 months (without water or other fluids) and the National Institute for Health and Clinical Excellence promotes the provision of peer supporters or breastfeeding support groups to increase breastfeeding rates. This study aimed to explore the barriers to exclusive breastfeeding to 6 months with black and minority ethnic groups and with young mothers, and the strategies for overcoming these barriers, including peer support. Twenty-two mothers from Somali, Afro-Caribbean and South Asian communities or young mothers groups attended five focus groups. Transcripts were analysed using thematic and framework methods. There was enthusiasm for breastfeeding support groups, but with a wider remit to discuss other baby-related issues and provide general social support as well as support for breastfeeding. The Somali and South Asian women preferred the groups to be for their ethnic group, Afro-Caribbean women were keen that they should be open to all cultures and young mothers would like groups for their peers only. Encouraging mothers to breastfeed exclusively to 6 months should be promoted more and emphasized by health professionals when supporting women post-natally, and good support with breastfeeding management should be given to enable mothers to achieve this goal. Breastfeeding support groups may play a part in increasing breastfeeding continuation of breastfeeding, but for the groups studied this was not the greatest influence, with families and older women in the community having more influence in changing practice.

Mutual support groups for long-term recipients of TANF.

PubMed

Anderson-Butcher, Dawn; Khairallah, Angela Oliver; Race-Bigelow, Janis

2004-01-01

This study examined the effect of involvement in mutual support groups on long-term recipients of Temporary Assistance for Needy Families (TANF) and other vulnerable individuals. From qualitative interviews with nine group members, the study identified key themes, benefits, and barriers related to involvement in the groups. Content analysis of the data revealed insights about characteristics of effective self-help and mutual support groups, which social workers and other professionals can use to develop effective support groups in the future. Participants discussed benefits for themselves and their families, such as enhanced parenting and social skills, increased knowledge, and enhanced self-esteem.

Connecting local support: A qualitative study exploring the role of voluntary organisations in long-term condition management.

PubMed

Morris, Rebecca; Kirk, Susan; Kennedy, Anne; Vassilev, Ivaylo; Mathieson, Amy; Jeffries, Mark; Blickem, Christian; Brooks, Helen; Sanders, Caroline; Rogers, Anne

2015-06-01

To examine the role of community groups to support people living with long-term conditions and the organisational factors that influence this role. Thirty-three semi-structured interviews were conducted with voluntary group organisers purposefully sampled in Greater Manchester from a local database of community groups. Interviews explored the organisations role in supporting people living with a long-term condition, their social networks and the origins of the groups. Respondents' construed their role in supporting individual capacity for management either explicitly (e.g. providing exercise) or implicitly (e.g. emotional support). This role was influenced by a combination of group ideology, funding and social networks. Analysis highlights the role of the non-clinical setting, the social support provided within the group, as well as organisational processes that influenced their capacity to support people living with long-term conditions. By examining the organisation of voluntary groups, this study highlights the way in which they may support or constrain access to an extended range of support for people with long-term conditions. This paper has implications for commissioning of services by the health service from the third sector because of the differing ideological perspectives and limited operational capacity. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Group affiliation in self-management: support or threat to identity?

PubMed

Bossy, Dagmara; Knutsen, Ingrid Ruud; Rogers, Anne; Foss, Christina

2017-02-01

Self-management is considered important in chronic illness, and contemporary health policy recommends participation in support groups for individuals with chronic conditions. Although withdrawal from or non-participation in support groups is an important problem, there is limited knowledge about individuals' own motivation for participation in or withdrawal from self-management support groups. To investigate how individuals with type 2 diabetes perceive participation in group-based self-management support. This is a qualitative focus group study using a semi-structured interview guide. Sixteen participants diagnosed with type 2 diabetes were included in the study. Individuals with and without group affiliations were mixed in three focus groups to trigger discussions. In the analysis, reoccurring themes of engagement and discussions between participants were focused within a theoretical frame of institutional logic. The focus groups are seen as social spaces where participants construct identity. Both participation and non-participation in group-based self-management support are associated with dealing with the stigma of having type 2 diabetes. Negotiations contribute to constructing an illness dignity as a response to the logic of moral responsibility for the disease. Contemporary policy contributes to societal understandings of individuals with type 2 diabetes as morally inadequate. Our study shows that group-based self-management support may counteract blame and contribute in negotiations of identity for individuals with type 2 diabetes. This mechanism makes participation in groups beneficial for some but stigma inducing for others. © 2016 The Authors. Health Expectations Published by John Wiley & Sons Ltd.

Effects of Support Groups for Individuals with Early-Stage Dementia and Mild Cognitive Impairment: An Integrative Review.

PubMed

Jao, Ying-Ling; Epps, Fayron; McDermott, Caroline; Rose, Karen M; Specht, Janet K

2017-01-01

Support groups have demonstrated promising outcomes for individuals with mild cognitive impairment (MCI) and early-stage dementia (ESD) in previous literature reviews. However, evidence has not been updated since 2007. The current review aimed to update current evidence on the use and effects of support groups for individuals with MCI and ESD and their care partners. A literature search was conducted in seven databases and 18 eligible research articles were retrieved. Support groups showed positive impacts on participant acceptance of cognitive impairment; performance and satisfaction of meaningful activity; resilience; self-help; and care partner coping self-efficacy, perceived support, and preparation and task effectiveness. Findings also revealed that support groups were well accepted by participants and care partners. Few studies included ethnic diversity, limiting the generalizability of findings. Further large-scale studies are needed to confirm the effects of support groups for individuals with MCI and ESD in all populations. [Res Gerontol Nurs. 2017; 10(1):35-51.]. Copyright 2016, SLACK Incorporated.

A qualitative analysis exploring preferred methods of peer support to encourage adherence to a Mediterranean diet in a Northern European population at high risk of cardiovascular disease.

PubMed

Erwin, Christina M; McEvoy, Claire T; Moore, Sarah E; Prior, Lindsay; Lawton, Julia; Kee, Frank; Cupples, Margaret E; Young, Ian S; Appleton, Katherine; McKinley, Michelle C; Woodside, Jayne V

2018-02-05

Epidemiological and randomised controlled trial evidence demonstrates that adherence to a Mediterranean diet (MD) can reduce cardiovascular disease (CVD) risk. However, methods used to support dietary change have been intensive and expensive. Peer support has been suggested as a possible cost-effective method to encourage adherence to a MD in at risk populations, although development of such a programme has not been explored. The purpose of this study was to use mixed-methods to determine the preferred peer support approach to encourage adherence to a MD. Qualitative (focus groups) and quantitative methods (questionnaire and preference scoring sheet) were used to determine preferred methods of peer support. Sixty-seven high CVD risk participants took part in 12 focus groups (60% female, mean age 64 years) and completed a questionnaire and preference scoring sheet. Focus group data were transcribed and thematically analysed. The mean preference score (1 being most preferred and 5 being least preferred) for group support was 1.5, compared to 3.4 for peer mentorship, 4.0 for telephone peer support and 4.0 for internet peer support. Three key themes were identified from the transcripts: 1. Components of an effective peer support group: discussions around group peer support were predominantly positive. It was suggested that an effective group develops from people who consider themselves similar to each other meeting face-to-face, leading to the development of a group identity that embraces trust and honesty. 2. Catalysing Motivation: participants discussed that a group peer support model could facilitate interpersonal motivations including encouragement, competitiveness and accountability. 3. Stepping Stones of Change: participants conceptualised change as a process, and discussed that, throughout the process, different models of peer support might be more or less useful. A group-based approach was the preferred method of peer support to encourage a population at high risk of CVD to adhere to a MD. This finding should be recognised in the development of interventions to encourage adoption of a MD in a Northern European population.

Effect of nutritional support on terminally ill patients with cancer in a palliative care unit.

PubMed

Amano, Koji; Morita, Tatsuya; Baba, Mika; Kawasaki, Muneyoshi; Nakajima, Shinichiro; Uemura, Minako; Kobayashi, Yuka; Hori, Moeko; Wakayama, Hiroshi

2013-11-01

The role of nutritional support on terminally ill patients with cancer in a palliative care unit has not been clarified. A total of 63 patients were retrospectively investigated; the patients receiving individualized nutritional support (intervention group [n = 22]) were compared to the others (control group [n = 41]). The intervention group received individualized nutritional support. There were no significant differences in the characteristics of patients between the groups. The prevalence of bedsores was significantly lower in the intervention group (14% vs 46%, P = .012). The prevalence of edema and the use of antibiotic therapies tended to be lower in the intervention group than in the control group (36% vs 54%, P = .19; 14% vs 27%, P = .34, respectively). Some terminally ill patients with cancer in a palliative care unit might benefit from nutritional support.

Effect of Autonomy Support on Self-Determined Motivation in Elementary Physical Education.

PubMed

Chang, Yu-Kai; Chen, Senlin; Tu, Kun-Wei; Chi, Li-Kang

2016-09-01

Using the quasi-experimental design, this study examined the effect of autonomy support on self-determined motivation in elementary school physical education (PE) students. One hundred and twenty six participants were assigned to either the autonomy support group (n = 61) or the control group (n = 65) for a six-week intervention period. Perceived teacher autonomy, perceived autonomy in PE, and self-determined motivation in PE were pre- and post-tested using validated questionnaires. Significant increases in perceived teacher autonomy and perceived autonomy in PE were observed in the autonomy support group, but not in the control group. Intrinsic motivation was higher in the autonomy support group than that in the control group. From an experimental perspective, these findings suggest that the autonomy support was successfully manipulated in the PE classes, which in turn increased the students' perceived autonomy and intrinsic motivation.

Interpreting the Need for Initial Support to Perform Tandem Stance Tests of Balance

PubMed Central

Brach, Jennifer S.; Perera, Subashan; Wert, David M.; VanSwearingen, Jessie M.; Studenski, Stephanie A.

2012-01-01

Background Geriatric rehabilitation reimbursement increasingly requires documented deficits on standardized measures. Tandem stance performance can characterize balance, but protocols are not standardized. Objective The purpose of this study was to explore the impact of: (1) initial support to stabilize in position and (2) maximum hold time on tandem stance tests of balance in older adults. Design A cross-sectional secondary analysis of observational cohort data was conducted. Methods One hundred seventeen community-dwelling older adults (71% female, 12% black) were assigned to 1 of 3 groups based on the need for initial support to perform tandem stance: (1) unable even with support, (2) able only with support, and (3) able without support. The able without support group was further stratified on hold time in seconds: (1) <10 (low), (2) 10 to 29, (medium), and (3) 30 (high). Groups were compared on primary outcomes (gait speed, Timed “Up & Go” Test performance, and balance confidence) using analysis of variance. Results Twelve participants were unable to perform tandem stance, 14 performed tandem stance only with support, and 91 performed tandem stance without support. Compared with the able without support group, the able with support group had statistically or clinically worse performance and balance confidence. No significant differences were found between the able with support group and the unable even with support group on these same measures. Extending the hold time to 30 seconds in a protocol without initial support eliminated ceiling effects for 16% of the study sample. Limitations Small comparison groups, use of a secondary analysis, and lack of generalizability of results were limitations of the study. Conclusions Requiring initial support to stabilize in tandem stance appears to reflect meaningful deficits in balance-related mobility measures, so failing to consider support may inflate balance estimates and confound hold time comparisons. Additionally, 10-second maximum hold times limit discrimination of balance in adults with a higher level of function. For community-dwelling older adults, we recommend timing for at least 30 seconds and documenting initial support for consideration when interpreting performance. PMID:22745198

Involvement of zebrafish RIG-I in NF-κB and IFN signaling pathways: insights into functional conservation of RIG-I in antiviral innate immunity.

PubMed

Nie, Li; Zhang, Ying-sheng; Dong, Wei-ren; Xiang, Li-xin; Shao, Jian-zhong

2015-01-01

The retinoic acid-inducible gene I (RIG-I) is a critical sensor for host recognition of RNA virus infection and initiation of antiviral signaling pathways in mammals. However, data on the occurrence and functions of this molecule in lower vertebrates are limited. In this study, we characterized an RIG-I homolog (DrRIG-I) from zebrafish. Structurally, this DrRIG-I shares a number of conserved functional domains/motifs with its mammalian counterparts, namely, caspase activation and recruitment domain, DExD/H box, a helicase domain, and a C-terminal domain. Functionally, stimulation with DrRIG-I CARD in zebrafish embryos significantly activated the NF-κB and IFN signaling pathways, leading to the expression of TNF-α, IL-8 and IFN-induced Mx, ISG15, and viperin. However, knockdown of TRIM25 (a pivotal activator for RIG-I receptors) significantly suppressed the induced activation of IFN signaling. Results suggested the functional conservation of RIG-I receptors in the NF-κB and IFN signaling pathways between teleosts and mammals, providing a perspective into the evolutionary history of RIG-I-mediated antiviral innate immunity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Supporting Unemployed, Middle-Aged Men: A Psychoeducational Group Approach

ERIC Educational Resources Information Center

Murphey, Charlotte M.; Shillingford, M. Ann

2012-01-01

This article presents a comprehensive group counseling approach to support unemployed, middle-aged men. An inclusive group curriculum designed to provide support and address potential mental health issues related to unemployment is introduced. The focus of the group is divided into 6 major areas that research has shown to have a significant impact…

Paths to leisure physical activity among adults with intellectual disabilities: self-efficacy and social support.

PubMed

Peterson, Jana J; Lowe, John B; Peterson, N Andrew; Nothwehr, Faryle K; Janz, Kathleen F; Lobas, Jeffrey G

2008-01-01

This study tested a path model that included perceptions of social support and self-efficacy for leisure physical activity and leisure physical activity participation among adults with intellectual disabilities. A cross-sectional design was used. Data was collected via oral interview. Community-based group, supported-living settings in one Midwestern state. A total of 152 adults with mild to moderate intellectual disabilities, which provided a 39% response rate. Self-efficacy and social support (from family, residential staff and peers with disabilities) for leisure physical activity were assessed using self-reported scales. Leisure physical activity participation was measured with a self-reported checklist of the frequency of leisure physical activity participation. Path analysis was conducted for the entire sample and was repeated for younger and older age groups. The hypothesized model fit the data from each group. Social support and self-efficacy predicted physical activity participation, and self-efficacy served as a mediator between social support and physical activity. Significant sources of social support differed between groups; among younger participants, social support from family predicted physical activity, whereas, for the older group, social support from staff and peers predicted physical activity. Self-efficacy and social support for leisure physical activity are related to leisure physical activity participation among adults with intellectual disabilities who are receiving supported-living services. The results provide information to guide health promotion programs for this group.

Clinical success of implant-supported and tooth-implant-supported double crown-retained dentures.

PubMed

Bernhart, Gunda; Koob, Andreas; Schmitter, Marc; Gabbert, Olaf; Stober, Thomas; Rammelsberg, Peter

2012-08-01

The objective of this retrospective study was to compare biological and technical complications of implant-supported and tooth-implant-supported double crown-retained dentures (DCRDs) with those of tooth-supported DCRDs. Sixty-three DCRDs were monitored. One study group included 16 prostheses with a combination of implants and natural teeth as double crowns (ti group), whereas in the second study group, 19 dentures were retained exclusively on implants (ii group); a third study group with 28 exclusively tooth-supported dentures served as controls (tt group). Tooth loss, implant failure, and technical complications (loss of retention of primary crown, abutment screw loosening, loss of facing, fracture of resin denture teeth and fracture of saddle resin) were analysed. During the observation period of 24 months, no implants or teeth were lost in the ti group and three technical complications were recorded. In the ii group, two implants were lost, two cases of peri-implantitis occurred and four technical complications were observed. In the tt group, two cases of tooth loss and seven technical complications were observed. At the time of the last examination, all prostheses of the ti group and the ii group were functional. Patients of these two study groups reported high satisfaction with both function and aesthetics with no significant difference between the two groups. Treatment with DCRDs showed comparable results in the three study groups. The 2-year results indicate that double crowns can be recommended for implant and combined tooth-implant-retained dentures.

The Family Support Group (FSG) Leaders’ Handbook

DTIC Science & Technology

2000-04-01

family guide. Fort Hood, TX: Author. Granovsky , N. (1998). Family Support Group leader basic handbook (Operation READY). Alexandria, VA: U. S...Readiness and Financial Planning " (22.3 minutes). Granovsky , N. (1998). Family Support Group Leader Basic Handbook (Operation READY). Alexandria

Foot pressure analysis of gait pattern in older Japanese females requiring different personal care support levels.

PubMed

Takayanagi, Naoto; Sudo, Motoki; Fujii, Masahiko; Sakai, Hirokazu; Morimoto, Keiko; Tomisaki, Masumi; Niki, Yoshifumi; Tokimitsu, Ichiro

2018-03-01

[Purpose] This study evaluated gait parameters and foot pressure in two regions of the feet among older females with different personal care support needs to analyze factors that contribute to higher support requirements. [Subjects and Methods] Thirty-two older females were divided into support-need and care-need level groups. Gait parameters (speed, cadence, step length, step width, gait angle, toe angle, double support phase, swing phase, and stance phase) and foot pressure during a 5-m walk were measured and analyzed in the two groups. [Results] The percentage of the double support phase on both feet and the right stance phase were significantly higher in the care-need level group, while that of the right swing phase was significantly lower than that of the support-need level group. Additionally, the phase showing peak pressure on the left rear foot was significantly delayed and the left forefoot pressure in the terminal stance was significantly lower in the care-need level group than in the support-need level group. [Conclusion] These findings show that the temporal duration parameters and foot pressure on a particular side were significantly different between the two groups and suggest that these differences were associated with a higher care level.

Social Support in a Virtual Community: Analysis of a Clinic-Affiliated Online Support Group for Persons Living with HIV/AIDS.

PubMed

Flickinger, Tabor E; DeBolt, Claire; Waldman, Ava Lena; Reynolds, George; Cohn, Wendy F; Beach, Mary Catherine; Ingersoll, Karen; Dillingham, Rebecca

2017-11-01

Social support can improve outcomes for people living with HIV (PLWH) and could be provided through online support groups. The Positive Links smartphone app is a multicomponent intervention that allows users to interact in a clinic-affiliated anonymous online support group. We investigated how social support was exchanged in a group of 55 participants over 8 months, using an adaptation of the Social Support Behavior Code. Participant interviews assessed their experiences and perceptions of the app. Of 840 posts analyzed, 115 (14 %) were coded as eliciting social support and 433 (52 %) as providing social support. Messages providing support were predominantly emotional (41 %), followed by network (27 %), esteem (24 %), informational (18 %), and instrumental (2 %) support. Participants perceived connection and support as key benefits of the app. Technical issues and interpersonal barriers limited some participants in fully using the app. Mobile technology offers a useful tool to reach populations with barriers to in-person support and may improve care for PLWH.

Professional Support of Self-Help Groups: A Support Group Project for Chronic Fatigue Syndrome Patients.

ERIC Educational Resources Information Center

Carlsen, Benedicte

2003-01-01

Study follows a collaborative support group project between a team of health professionals and a Chronic Fatigue Syndrome patients' group. While advantageous for professionals to decide upon the aim of a joint intervention in dialogue with participants, simply asking participants what their aims are does not guarantee actual agreement. Case study…

Logging On: Evaluating an Online Support Group for Parents of Children with Autism Spectrum Disorders

ERIC Educational Resources Information Center

Clifford, Tessen; Minnes, Patricia

2013-01-01

Twenty mothers participated in an online support group for parents of children with autism spectrum disorders. Twenty-five unrelated parents participated in a no-treatment control group. The participants completed online questionnaires prior to and following the 4-month support group, to evaluate changes in mood, anxiety, parenting stress, and…

Community based participatory research of breastfeeding disparities in African American women.

PubMed

Kulka, Tamar Ringel; Jensen, Elizabeth; McLaurin, Sue; Woods, Elizabeth; Kotch, Jonathan; Labbok, Miriam; Bowling, Mike; Dardess, Pamela; Baker, Sharon

2011-08-01

OBJECTIVE: Lack of support for breastfeeding mothers has been consistently identified in the literature as a barrier for breastfeeding across racial and ethnic groups. Using a community-based participatory approach, academic and community-based partners conducted an iterative process to assess barriers, facilitators and potential mediating interventions for breastfeeding in the African-American community in Durham, North Carolina. METHODS: Eight focus groups were conducted with African-American mothers, fathers and grandmothers. Researchers transcribed and coded each focus group and analyzed using Atlas ti. 5.2. Patterns and themes that emerged informed the development of community stakeholder interviews; 41 interviews were conducted with community representatives. These findings informed the development of a support group pilot intervention. The pilot support groups were evaluated for increase in knowledge of attendees. RESULTS: Focus group and community interviews indicate that African Americans may disproportionately experience inadequate support for breastfeeding. This lack of support was reported in the home, the workplace, among peers, and from healthcare providers. The pilot support groups resulted in increased knowledge of breastfeeding among group participants OR=3.6 (95% CI: 2.5, 5.2). CONCLUSIONS: The findings from this research underscore the importance of a multi-level approach to breastfeeding support for African American women to address breastfeeding disparities.

A content analysis of cognitive and affective uses of patient support groups for rare and uncommon vascular diseases: comparisons of may thurner, thoracic outlet, and superior mesenteric artery syndrome.

PubMed

Walker, Kimberly K

2015-01-01

Rare disease patients are the predominant group of patients who are now connecting online to patient support groups, yet research on their uses of support groups has received little attention. This is a content analysis of three vascular diseases of differing degrees of rarity. Wall posts from Facebook patient support groups for May Thurner syndrome, thoracic outlet syndrome, and superior mesenteric artery syndrome were analyzed over a period of two years. Using Uses and Gratifications as the theoretical framework, the study purpose was to assess how variations in health condition and rarity of condition affect online support group user needs. Results indicated common main cognitive and affective uses across conditions, indicating a consistent pattern of needs communicated by all patients. However, there were nuanced differences in subcategories of cognitive and affective uses between the most and least rare disorders, which inform areas for tailored support mechanisms. Additionally, these vascular patients used their respective support groups primarily for cognitive reasons, especially for the rarest conditions, which informs of basic medical informational needs these patients face related to tests, treatment, surgery, and diagnoses.

A Speech-Language Pathologist's Guide to Creating a Support Group for Caregivers of Persons with Dementia

ERIC Educational Resources Information Center

Morrow-Odom, K. Leigh; Robbins, Sarah M.

2012-01-01

The purpose of this article is to provide basic guidelines to successfully establish a support group for caregivers of persons with dementia. Support groups should provide its members with a community of support, as well as coping and management strategies to improve daily function of loved ones. This should improve the care provided, and the…

Effects of a new sports companion on received social support and physical exercise: an intervention study.

PubMed

Rackow, Pamela; Scholz, Urte; Hornung, Rainer

2014-11-01

The role of social support in physical exercise is well documented. However, the majority of studies that investigate the associations between social support and physical exercise target perceived instead of received social support. Moreover, most studies investigate the effects of received social support using a descriptive correlational design. Thus, our study aimed at investigating the effects of received social support by conducting an intervention study. Participants were randomly assigned to an intervention (n = 118) or control group (n = 102). The intervention comprised regularly exercising with a new sports companion for eight weeks. To investigate the time course of physical exercise and received social support, growth curve modelling was employed. Generally, both groups were able to improve their physical exercise. However, the control group tended to decrease again during the final point of measurement. Received social support, however, decreased slightly in the control group, but remained stable in the intervention group. The intervention was suitable to sustain received social support for physical exercise across a two-month interval. Overall, these findings highlight the importance of further investigating social support for physical exercise applying an experimental approach. © 2014 The International Association of Applied Psychology.

Help for breastfeeding mothers. Support groups.

PubMed

1991-09-01

Many people including some health workers and physicians believe bottle feeding is just as good as breast feeding, even though bottle feeding poses some dangers to infants. Further, health workers in hospital often are too busy to counsel new mothers in breast feeding or are simply not trained to do so. Moreover, young women often live in areas away from their family and friends thus not living close to women with whom they are familiar and who could guide them in mastering breast feeding skills. So new mothers who want to breast feed have no support, lack confidence, and/or feel they cannot do so because they work or have other responsibilities. Support groups for new breast feeding mothers can provide them with the needed confidence to breast feed by allowing them to discuss concerns with other new mothers and an experienced leader and to learn the advantages of breast feeding, e.g., a breast fed infant is never constipated. A confident experienced woman in breast feeding is best suited to start a support group in a community. She needs to promote the group by talking to health workers and physicians and advertising at maternity hospitals, women's organizations, and health centers. Once the support group has become successful, several mothers can undergo training to start and lead new support groups. If no national breast feeding promotion organization exists to offer advice on starting a support group, the article provides addresses of international organizations. At support group meetings, mothers learn how to breast feed, how to express and store breast milk, breast feed inconspicuously in public, how their bodies work, and about child growth and development. Support group members from the Philippines, Belize, Trinidad and Tobago, Australia, and singapore share their experiences.

Exploring what motivates and sustains support group engagement amongst young people with allergies: a qualitative study.

PubMed

Jones, Christina J; Sommereux, Lauren A; Smith, Helen E

2018-06-14

Positive self-care behaviours are more likely in young people who engage with allergy support groups, but reasons for this association are not well understood. This study explored how and why young people engage with allergy support groups to identify what activities and resources are beneficial. In-depth, semi-structured interviews were conducted with young people aged 12-21 years who reported engaging with allergy support groups (in person or on-line). Interviews were audiotaped, transcribed verbatim and analysed using thematic content analysis. The 21 participants had a range of allergies; initially most joined support groups on suggestion of their parent/carer although older participants sought groups independently. Feeling included and sharing experiences with people with similar problems/challenges were highly valued. Through membership, young people reported improved self-esteem and confidence in both managing their allergies and lives generally. Information, such as allergy alerts and hard-hitting video campaigns were reported to positively influence adherence to self-care behaviours such as carrying medication which led to sustained engagement. Participants wanted greater availability of allergy support groups, and higher profiles in healthcare and educational settings, as well as through social media. Participants valued the psychological and practical support of networking with others with allergies, and described how membership improved their confidence. This study also provides insight into the ways support groups improve young people's adherence to medical advice and positive self-care behaviours; participants responded well to hard-hitting video campaigns which appeared to emphasise the severity and susceptibility of anaphylaxis. Participants identified the need for more active promotion of support groups amongst young people and their clinicians, as well as making them available in more localities. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Association between suicidal ideation and behavior, and depression, anxiety, and perceived social support in cancer patients.

PubMed

Balcı Şengül, Melike Ceyhan; Kaya, Vildan; Şen, Cenk Ahmet; Kaya, Kemal

2014-02-27

The aim of this study was to determine the relationship between suicidal behavior and associated factors such as depression, anxiety, and perceived social support level in cancer patients. The study group included 102 patients who were under treatment in the oncology department and the control group included 100 individuals with similar sociodemographic features. A sociodemographic information form, Beck depression inventory, Beck anxiety inventory, suicidal behavior inventory, suicidal ideation inventory, and multidimensional inventory of perceived social support were used. The mean Beck depression inventory and Beck anxiety inventory scores in the study group were significantly higher compared to the control group. Thirteen patients in the study group attempted suicide, whereas 3 individuals attempted suicide in the control group. Similarly, the mean suicide behavior and ideation scores in the study group were significantly higher compared to the control group. The mean total multidimensional inventories of perceived social support score, as well as the mean family and friend sub-inventory scores in the control group were significantly higher compared to the study group. This study revealed that depression and anxiety occur frequently in cancer patients. Suicide attempts and ideation are higher in cancer patients compared to the control group. Social support perceived from family and friends is lower in cancer patients. Suicide attempts are correlated with depression, anxiety, low level of perceived social support, and advanced disease stage.

Trainee experiences of intellectual disability psychiatry and an innovative leaderless support group: a qualitative study

PubMed Central

Spackman, Ross; Toogood, Hannah; Kerridge, Jayne; Nash, Jon; Anderson, Elizabeth; Rai, Dheeraj

2017-01-01

Aims and method There is very little research into the challenges of training in intellectual disability psychiatry or into interventions which may address these challenges. Using focus groups, we explored the experiences of intellectual disability psychiatry trainees, and evaluated a leaderless trainee support group developed in Bristol. Results Five distinct themes were identified via framework analysis: that trainees felt unprepared for the difference from previous posts; the need for support; the value of the group; that trainees were concerned about judgement in supervision; that the group structure was valued. Clinical implications Our findings highlight the support needs specific to intellectual disability psychiatry trainees. Leaderless peer support groups may be a valued resource to address such issues, and may be a useful model to be considered by other training schemes. PMID:28811919

Direction to an Internet Support Group Compared With Online Expressive Writing for People With Depression And Anxiety: A Randomized Trial.

PubMed

Dean, Jeremy; Potts, Henry Ww; Barker, Chris

2016-05-17

Depression and anxiety are common, often comorbid, conditions, and Internet support groups for them are well used. However, little rigorous research has been conducted on the outcome of these groups. This study aimed to evaluate the efficacy of an Internet support group in reducing depression and anxiety, and increasing social support and life satisfaction. A randomized trial compared direction to an existing Internet support group for depression and anxiety with an online expressive writing condition. A total of 863 (628 female) United Kingdom, United States, and Canadian volunteers were recruited via the Internet. Online, self-report measures of depression, anxiety, social support, and satisfaction with life were administered at baseline, 3, and 6 months. All four outcomes - depression, anxiety, social support, and satisfaction with life - improved over the 6 months of the study (all P <.001). There was no difference in outcome between the two conditions: participants responded similarly to the expressive writing and the Internet support group. Engagement with the Internet support group was low, it had high 6-month attrition (692/795, 87%) and low adherence, and it received mixed and often negative feedback. The main problems reported were a lack of comfort and connection with others, negative social comparisons, and the potential for receiving bad advice. Expressive writing had lower attrition (194/295, 65%) and participants reported that it was more acceptable. Until further evidence accumulates, directing people with depression and anxiety to Internet support groups cannot be recommended. On the other hand, online expressive writing seems to have potential, and its use for people with depression and anxiety warrants further investigation. Clinicaltrials.gov NCT01149265; https://clinicaltrials.gov/ct2/show/NCT01149265 (Archived by WebCite at http://www.webcitation.org/6hYISlNFT).

Population Support Before and After the Implementation of Smoke-Free Laws in the United States: Trends From 1992–2007

PubMed Central

Nagelhout, Gera E.; Wolfson, Tanya; Zhuang, Yue-Lin; Gamst, Anthony; Willemsen, Marc C.

2015-01-01

Introduction: Several states implemented comprehensive smoke-free laws in workplaces (14 states), restaurants (17 states), and bars (13 states) between 2002 and 2007. We tested the hypothesis that public support for smoke-free laws increases at a higher rate in states that implemented smoke-free laws between 2002 and 2007 (group A) than in states that implemented smoke-free laws after that time or not at all (group B). The period before the implementation (1992–2001) was also considered. Methods: Data was used from the Current Population Survey (CPS) Tobacco Use Supplements (TUS), which is representative for the U.S. adult population. Respondents were asked whether they thought smoking should not be allowed in indoor work areas, restaurants, and bars and cocktail lounges. Differences in trends were analyzed with binomial mixed effects models. Results: Population support for smoke-free restaurants and bars was higher among group A than among group B before 2002. After 2002, support for smoke-free restaurants and bars increased at a higher rate among group A than among group B. Population support for smoke-free workplaces did not differ between group A and B, and the increase in support for smoke-free workplaces also did not differ between these groups. Conclusions: The positive association between the implementation of smoke-free restaurant and bar laws and the rate of increase in support for these laws partly supported the hypothesis. The implementation of the laws may have caused support to increase, but also states that have higher support may have been more likely to implement smoke-free laws. PMID:25143293

A Call for Research: The Need to Better Understand the Impact of Support Groups for Suicide Survivors

PubMed Central

Cerel, Julie; Padgett, Jason H.; Conwell, Yeates; Reed, Gerald A.

2013-01-01

Support groups for suicide survivors (those individuals bereaved following a suicide) are widely used, but little research evidence is available to determine their efficacy. This paper outlines the pressing public health need to conduct research and determine effective ways to identify and meet the needs of suicide survivors, particularly through survivor support groups. After describing the various approaches to survivor support groups, we explain the need for further research, despite the inherent challenges. Finally, we pose several questions for researchers to consider as they work with survivors to develop a research agenda that sheds more light on the experiences of survivors and the help provided by survivor support groups. PMID:19606919

Social support and social strain in inter-episode bipolar disorder

PubMed Central

Eidelman, Polina; Gershon, Anda; Kaplan, Katherine; McGlinchey, Eleanor; Harvey, Allison G

2015-01-01

Objectives This study focused on social support and social strain and their cross-sectional associations with instabilities in sleep and social rhythms in inter-episode bipolar disorder (BD). Methods Thirty-five adults diagnosed with inter-episode BD type I and 38 healthy controls completed measures of perceived social support and social strain. Group differences in support and strain were examined. Within the BD group, instabilities in sleep and social rhythms were assessed with 28 days of daily diary and actigraphy. Correlation and regression analyses were used to examine cross-sectional and prospective associations between social support, social strain, instabilities in sleep and social rhythms, and mood symptoms. Results The BD group reported lower social support and higher social strain than the control group. Additionally, social strain was positively correlated with manic and depressive symptoms in the BD group. Furthermore, there was a cross-sectional association between social support and more stable sleep on actigraphy in the BD group, although social support did not predict future sleep instability. Conclusions These results indicate that inter-episode BD is associated with deficient social support and elevated social strain compared to controls, and that this may be due to persistent inter-episode mood symptoms. Social strain may be particularly important given its association withmanic and depressive symptoms. The results also raise the possibility that sleep instability is related to poor social support in BD. PMID:22862999

Effect of luteal-phase support on endometrial microRNA expression following controlled ovarian stimulation

PubMed Central

2012-01-01

Background Studies suggested that microRNAs influence cellular activities in the uterus including cell differentiation and embryo implantation. In assisted reproduction cycles, luteal phase support, given to improve endometrial characteristics and to facilitate the implantation process, has been a standard practice. The effect of different types of luteal phase support using steroid hormones in relation to endometrial miRNA profiles during the peri-implantation period has not seen described. This study was designed to evaluate the expression of miRNAs during the luteal phase following controlled ovarian stimulation for IVF and the influence of different luteal phase support protocols on miRNA profiles. Methods The study was approved by the Johns Hopkins Hospital Institutional Review Board. Endometrial biopsies were obtained on the day of oocyte retrieval from 9 oocyte donors (group I). An additional endometrial biopsy was obtained 3–5 days later (Group II) after the donors were randomized into three groups. Group IIa had no luteal-phase support, group IIb had luteal support with micronized progesterone (P), and Group IIc had luteal support with progesterone plus 17-beta-estradiol (P + E). Total RNA was isolated and microarray analysis was performed using an Illumina miRNA expression panel. Results A total of 526 miRNAs were identified. Out of those, 216 miRNAs were differentially regulated (p < 0.05) between the comparison groups. As compared to the day of retrieval, 19, 11 and 6 miRNAs were differentially regulated more than 2 fold in the groups of no support, in the P support only, and in the P + E support respectively, 3–5 days after retrieval. During the peri-implantation period (3–5 days after retrieval) the expression of 33 and 6 miRNAs increased, while the expression of 3 and 0 miRNAs decreased, in the P alone and in the P + E group respectively as compared to the no steroid supplementation group. Conclusion Luteal support following COS has a profound influence on miRNA profiles. Up or down regulation of miRNAs after P or P + E support suggest a role(s) of luteal support in the peri-implantation uterus in IVF cycles through the regulation of associated target genes. PMID:22950660

Social support in cyberspace: a content analysis of communication within a Huntington's disease online support group.

PubMed

Coulson, Neil S; Buchanan, Heather; Aubeeluck, Aimee

2007-10-01

Huntington's disease (HD) is an inherited disorder, characterized by a progressive degeneration of the brain. Due to the nature of the symptoms, the genetic element of the disease, and the fact that there is no cure, HD patients and those in their support network often experience considerable stress and anxiety. With an expansion in Internet access, individuals affected by HD have new opportunities for information retrieval and social support. The aim of this study is to examine the provision of social support in messages posted to a HD online support group bulletin board. In total, 1313 messages were content analyzed using a modified version of the social support behavior code developed by [Cutrona CE, Suhr J. Controllability of stressful events and satisfaction with spouse support behaviors. Commun Res 1992;19:154-74]. The analysis indicates that group members most frequently offered informational (56.2%) and emotional support (51.9%) followed by network support (48.4%) with esteem support (21.7%), and tangible assistance (9.8%) least frequently offered. This study suggests that exchanging informational and emotional support represents a key function of this online group. Online support groups provide a unique opportunity for health professionals to learn about the experiences and views of individuals affected by HD and explore where and why gaps may exist between evidence-based medicine and consumer behavior and expectations.

Enhancing group cognitive-behavioral therapy for hoarding disorder with between-session Internet-based clinician support: A feasibility study.

PubMed

Ivanov, Volen Z; Enander, Jesper; Mataix-Cols, David; Serlachius, Eva; Månsson, Kristoffer N T; Andersson, Gerhard; Flygare, Oskar; Tolin, David; Rück, Christian

2018-02-07

Hoarding disorder (HD) is difficult to treat. In an effort to increase efficacy and engagement in cognitive-behavioral therapy (CBT), we developed and evaluated a novel intervention comprising group CBT combined with between-session Internet-based clinician support for people with HD. Twenty participants with HD received group CBT combined with an Internet-support system enabling therapist-participant communication between group sessions. The treatment was associated with a significant reduction on the Saving Inventory-Revised (SI-R) and a large effect size (Cohen's d = 1.57) was found at posttreatment. Treatment gains were maintained at the 3-month follow-up. Group attendance was high and no participants dropped out from treatment prematurely. Between-session motivational support from the therapist was most frequently mentioned as the main strength of the system. The results of this study support adding Internet-based clinician support to group CBT for HD to increase treatment adherence and, potentially, improve the overall efficacy of CBT. © 2018 Wiley Periodicals, Inc.

A Support Group for Home-Quarantined College Students Exposed to SARS: Learning from Practice

ERIC Educational Resources Information Center

Pan, Peter J. D.; Chang, Shih-Hua; Yu, Yen-Yen

2005-01-01

This article is an initial description of a meaningful and valuable clinical experience in interacting with SARS home-quarantined college students in a support group in Taiwan. Information about SARS and home quarantine, the tasks of the Counseling Centers and group work after the SARS outbreak, the support group for home-quarantined members, the…

Support Groups: Make Connections, Get Help

MedlinePlus

... A qualitative exploration of the empowering and disempowering processes of participation within HIV/AIDS-related online support groups. International Journal of Nursing Studies. 2014;51:983. Understanding psychosocial support services: Types of support services. American Cancer Society. https:// ...

Facilitation of self-transcendence in a breast cancer support group.

PubMed

Coward, D D

1998-01-01

To examine the feasibility and patterns of effectiveness of a breast cancer support group intervention specifically designed to facilitate self-transcendence views and perspectives that would enhance emotional and physical well-being. Pre-experimental design pilot intervention study with a quantitative approach to data analysis. Survivor-established breast cancer resource center in Austin, TX. Women with recently diagnosed breast cancer (N = 16) participating in 90-minute support group sessions that met weekly for eight weeks. Theory-driven support group intervention facilitated by an oncology clinical nurse specialist, a psychotherapist, and a breast cancer survivor. Activities planned for individual sessions were based on self-transcendence theory, cancer support group literature, and the facilitators' extensive previous support group experience. Self-transcendence, emotional well-being, physical well-being. Good networking, coordination, and follow-up were essential for participant recruitment and retention throughout the intervention period. Although specific theory-driven activities were planned for group sessions, facilitators maintained flexibility in meeting immediate concerns of the participants. Relationships among participants' scores on study variables indicated an association between self-transcendence and emotional well-being. Scores on self-transcendence and well-being variables at the end of the intervention increased from baseline, but only functional performance status, mood state, and satisfaction with life reached statistical significance. The pilot study was invaluable in providing direction for the conduct of future experimental studies. Provides preliminary support for the use of theory-driven activities for promotion of self-transcendence views and behaviors within a cancer support group setting.

Self-reported differences in empowerment between lurkers and posters in online patient support groups.

PubMed

van Uden-Kraan, Cornelia F; Drossaert, Constance H C; Taal, Erik; Seydel, Erwin R; van de Laar, Mart A F J

2008-06-30

Patients who visit online support groups benefit in various ways. Results of our earlier study indicated that participation in online support groups had a profound effect on the participants' feelings of "being empowered." However, most studies of online patient support groups have focused on the members of these groups who actively contribute by sending postings (posters). Thus far, little is known about the impact for "lurkers" (ie, those who do not actively participate by sending postings). In the present study, we explored if lurkers in online patient support groups profit to the same extent as posters do. We searched the Internet with the search engine Google to identify all Dutch online support groups for patients with breast cancer, fibromyalgia, and arthritis. Invitations to complete an online survey were sent out by the owners of 19 groups. In the online questionnaire, we asked questions about demographic and health characteristics, use of and satisfaction with the online support group, empowering processes, and empowering outcomes. The online questionnaire was completed by 528 individuals, of which 109 (21%) identified themselves as lurkers. Lurkers (mean age 47 years) were slightly older than active participants (mean age 43 years, P = .002), had a shorter disease history (time since diagnosis 3.7 years vs 5.4 years, P = .001), and reported lower mental well-being (SF 12 subscore 37.7 vs 40.5, P = .004). No significant differences were found in other demographic variables. Posters indicated visiting the online support groups significantly more often for social reasons, such as curiosity about how other members were doing, to enjoy themselves, as a part of their daily routine (all P < .001), and because other members expected them to be there (P = .003). Lurkers and posters did not differ in their information-related reasons for visiting the online support group. Lurkers were significantly less satisfied with the online support group compared to posters (P < .001). With regard to empowering processes such as "exchanging information" and "finding recognition," lurkers scored significantly lower than posters. However, lurkers did not differ significantly from posters with regard to most empowering outcomes, such as "being better informed," "feeling more confident in the relationship with their physician," "improved acceptance of the disease," "feeling more confident about the treatment," "enhanced self-esteem," and "increased optimism and control." The exception was "enhanced social well-being," which scored significantly lower for lurkers compared to posters (P < .001). Our study revealed that participation in an online support group had the same profound effect on lurkers' self-reported feelings of being empowered in several areas as it had on posters. Apparently, reading in itself is sufficient to profit from participation in an online patient support group.

Internet support groups for suicide survivors: a new mode for gaining bereavement assistance.

PubMed

Feigelman, William; Gorman, Bernard S; Beal, Karyl Chastain; Jordan, John R

2008-01-01

Taken among parents who sustained the loss of a child to suicide this study explores the participation of parents in Internet support groups, comparing their demographic and loss-related characteristics (N = 104) to other parent survivors participating in face-to-face support groups (N = 297). Contrary to expectations that Internet affiliates would be concentrated in under-served rural areas, we found similar levels of urban, suburban, small city and rural residents in both Internet and face-to-face subsamples. Bivariate and multivariate analyses suggested several important factors contributing to interest in Internet grief support including: 24/7 availability and opportunities to invest more time into this type of support group experience. Compared to their face-to-face group counterparts, Internet affiliates experienced greater suicide stigmatization from their families and other associates. Unable to find ready comfort and support from their personal communities, Internet users-and especially highly depressed survivors-sought and obtained valuable help from the Internet support resource.

Effect of self-efficacy and social support on adherence to antihypertensive drugs.

PubMed

Criswell, Thomas J; Weber, Cynthia A; Xu, Yinghui; Carter, Barry L

2010-05-01

To determine the relationship between poor adherence and self-efficacy or social support after a pharmacist intervention. Post-hoc analysis of data from two randomized controlled trials of physician-pharmacist collaborative interventions (6 and 9 mo, respectively) to improve blood pressure control. Eleven university-affiliated primary care clinics. Five hundred eighty-four patients (aged 21-85 yrs) with uncontrolled primary hypertension; 296 were in the intervention group and 288 were in the control group. Pharmacists provided intensified hypertension management and drug adherence counseling to patients in the intervention group. Social support and self-efficacy questionnaires were administered at baseline and end-of-study visits. Patient adherence was monitored by using the Morisky self-reported adherence questionnaire. Self-reported adherence scores improved significantly in the control group (p=0.0053) but not in the intervention group; however, adherence at baseline in both groups was high. There were small, but significant, improvements in self-efficacy (p<0.04) and social support (p<0.05) scores in the intervention group but not the control group at the end of the study. Social support and, to a lesser extent, self-efficacy improved as a function of duration of study participation (9-mo vs 6-mo intervention), regardless of whether the patient received the intervention. Blood pressure control in both groups improved significantly at the end of the study; however, mean blood pressure was significantly lower in the intervention group (129.7/76.6 mm Hg) compared with the control group (140.8/78.9 mm Hg; p<0.0001 for systolic, p=0.032 for diastolic). Social support and self-efficacy improved significantly in the intervention group at the end of the pharmacist intervention. Drug adherence was correlated with self-efficacy even though drug adherence did not improve significantly in the intervention group. The fact that social support and self-efficacy improved as a function of duration of study participation suggests that participation in a research study may have had a positive influence on these measures. Even though the changes in social support, self-efficacy, and drug adherence were modest, there was significantly better blood pressure control in the intervention group compared with the control group. These findings indicate that changes in drug adherence, self-efficacy, or social support probably played a minor role in the blood pressure outcomes in these studies.