IκBβ acts to inhibit and activate gene expression during the inflammatory response

The activation of pro-inflammatory gene programs by nuclear factor-κB (NF-κB) is primarily regulated through cytoplasmic sequestration of NF-κB by the inhibitor of κB (IκB) family of proteins1. IκBβ, a major isoform of IκB, can sequester NF-κB in the cytoplasm2, although its biological role remains unclear. Although cells lacking IκBβ have been reported3, 4, in vivo studies have been limited and suggested redundancy between IκBα and IκBβ5. Like IκBα, IκBβ is also inducibly degraded; however, upon stimulation by lipopolysaccharide (LPS), it is degraded slowly and re-synthesized as a hypophosphorylated form that can be detected in the nucleus6, 7, 8, 9, 10, 11. The crystal structure of IκBβ bound to p65 suggested this complex might bind DNA12. In vitro, hypophosphorylated IκBβ can bind DNA with p65 and c-Rel, and the DNA-bound NF-κB:IκBβ complexes are resistant to IκBα, suggesting hypophosphorylated, nuclear IκBβ may prolong the expression of certain genes9, 10, 11. Here we report that in vivo IκBβ serves both to inhibit and facilitate the inflammatory response. IκBβ degradation releases NF-κB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-α (TNF-α). Surprisingly, absence of IκBβ results in a dramatic reduction of TNF-α in response to LPS even though activation of NF-κB is normal. The inhibition of TNF-α messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-IκBβ bound to p65:c-Rel heterodimers at a specific κB site on the TNF-α promoter. Therefore IκBβ acts through p65:c-Rel dimers to maintain prolonged expression of TNF-α. As a result, IκBβ^(−/−) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IκBβ might be a promising new strategy for selectively inhibiting the chronic phase of TNF-α production during the inflammatory response

Augmented reality for speech and language intervention in autism spectrum disorder

Individuals with autism spectrum disorder (ASD) present with a complex profile of individual strengths and atypical behaviors, but generally show a weakness in social communication and attention with a preference for visual stimuli (Bryan & Gast, 2000; Cihak et al., 2016; Rayner, Denholm, & Sigafoos, 2009). New technology may be able to address communication needs and support by building on strengths in a flexible and engaging manner. The purpose of this project is to explore the potential use of augmented reality (AR, (Craig, 2013)) as a tool for speech-language pathologists (SLPs) to use in the therapeutic setting. Research shows several applications of AR to improve language and communication skills in individuals with ASD, including in the areas of emotion identification, vocabulary learning, and developing foundation play skills. Positive outcomes from AR use may include increased motivation, attention, and learning new tasks. Benefits are weighed against the limitations of the use of emerging technology, with recommendations provided for clinicians. A guide is provided to give SLPs step-by-step instructions for creating simple AR-based materials to use in the clinical setting, with suggestions for utilization and application of such materials. AR shows promise as a means to increase engagement for some clients with ASD; a practical guide may make more accessible this tool and provide support for both clinicians and the individuals they treat.Communication Sciences and Disorder

High rates of early treatment discontinuation in hepatitis C-infected US veterans.

BackgroundPatients with chronic hepatitis C (HCV) frequently discontinued dual therapy with pegylated interferon alfa (Peg-IFN) plus ribavirin (RBV) before reaching the recommended duration of 48 or 24 weeks for genotypes (G) 1/4 or 2/3, respectively. We quantified rates of discontinuation despite efficacy (non-LOE) versus lack of efficacy (LOE) versus discontinuation for unknown reasons in a national database of United States veterans.MethodsWe identified a population-based cohort of U.S. veterans with encounters from 2004 through 2009 who had lab-confirmed HCV infection and initiated therapy with Peg-IFN plus RBV in Veterans Health Administration medical centers. Pharmacy data were used to determine therapy duration, defined as the sum of Peg-IFN days supplied. Patients "discontinued" if they failed to receive at least 44 (G1/4) or 20 weeks (G2/3) of therapy. We classified discontinuations as due to non-LOE, LOE, or unknown reasons using a classification rule based on treatment duration and laboratory confirmed response.ResultsOf 321,238 diagnosed HCV patients during the evaluation period, 9.7% initiated therapy and 6.4% met all other inclusion criteria. 54.9% of patients discontinued early; of these, 41.2% discontinued due to non-LOE reasons, 12.5% discontinued for LOE reasons, and 46.3% discontinued for unknown reasons. Among non-LOE discontinuers, most (60.1%) discontinued in the first 4 weeks of therapy, which constitutes 13.6% of all treated patients.ConclusionsWe observed a high proportion of early discontinuations with dual-therapy regimens in a national cohort of HCV-infected veterans. If this trend persists in the triple-therapy era, then efforts must be undertaken to improve adherence

IkappaBbeta acts to inhibit and activate gene expression during the inflammatory response.

The activation of pro-inflammatory gene programs by nuclear factor-kappaB (NF-kappaB) is primarily regulated through cytoplasmic sequestration of NF-kappaB by the inhibitor of kappaB (IkappaB) family of proteins. IkappaBbeta, a major isoform of IkappaB, can sequester NF-kappaB in the cytoplasm, although its biological role remains unclear. Although cells lacking IkappaBbeta have been reported, in vivo studies have been limited and suggested redundancy between IkappaBalpha and IkappaBbeta. Like IkappaBalpha, IkappaBbeta is also inducibly degraded; however, upon stimulation by lipopolysaccharide (LPS), it is degraded slowly and re-synthesized as a hypophosphorylated form that can be detected in the nucleus. The crystal structure of IkappaBbeta bound to p65 suggested this complex might bind DNA. In vitro, hypophosphorylated IkappaBbeta can bind DNA with p65 and c-Rel, and the DNA-bound NF-kappaB:IkappaBbeta complexes are resistant to IkappaBalpha, suggesting hypophosphorylated, nuclear IkappaBbeta may prolong the expression of certain genes. Here we report that in vivo IkappaBbeta serves both to inhibit and facilitate the inflammatory response. IkappaBbeta degradation releases NF-kappaB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-alpha (TNF-alpha). Surprisingly, absence of IkappaBbeta results in a dramatic reduction of TNF-alpha in response to LPS even though activation of NF-kappaB is normal. The inhibition of TNF-alpha messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-IkappaBbeta bound to p65:c-Rel heterodimers at a specific kappaB site on the TNF-alpha promoter. Therefore IkappaBbeta acts through p65:c-Rel dimers to maintain prolonged expression of TNF-alpha. As a result, IkappaBbeta(-/-) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IkappaBbeta might be a promising new strategy for selectively inhibiting the chronic phase of TNF-alpha production during the inflammatory response

The 2006 BFA Graduating Class Department of Visual Arts

Incredible as it may seem to those of us who were here when the Division of Fine Arts opened in the fall of 1988, with this exhibit we are celebrating our 15th graduating class from the BFA Program in Visual Arts. Simple arithmetic suggests that since 1992 literally hundreds of wonderfully trained and educated painters, printmakers, photographers, sculptors and multi-media artists have left the school to pursue their careers across the province, across Canada, and around the world. The significance of the effect these graduates are having on the cultural life of Newfoundland an Labrador cannot be overestimated. The variety and range of talent you see in the work of this year's graduates is a perfect example of the quality of imagination and craft that our students are contributing to the artistic community in this province, and in doing so they enrich all of our lives

Detection of Cytomegalovirus in Whole Blood Using Three Different Real-Time PCR Chemistries

Several different primer-probe chemistries have been produced commercially for real-time PCR detection and quantification of cytomegalovirus, but there are few studies evaluating their relative performance. We assessed three such commercial reagents with respect to analytical and clinical operating characteristics. The samples included 149 clinical whole blood specimens that were de-identified and assayed in parallel with all primer–probe systems. Individual methods used TaqMan, dual fluorescence resonance energy transfer hybridization probes, and labeled primer chemistries. Method comparability was determined both qualitatively, based on pair-wise assessment of concordance, and quantitatively, based on pair-wise linear regression analysis. Analytical sensitivity and the lower end of the linear dynamic range reached 10 target copies per reaction for the TaqMan and labeled primer systems and 100 target copies per reaction for the dual fluorescence resonance energy transfer probe system. Quantitative linearity reached an upper limit of 105 copies per reaction for all methods. No assay cross-reactivity was seen with other common viral pathogens (100% analytical specificity). Pair-wise analysis of qualitative results from clinical samples showed no significant differences in sensitivity between the three sets of reagents, and linear regression analysis indicated that the quantitative values achieved were comparable in all positive specimens. The findings demonstrate that similar analytical and clinical performance characteristics can be demonstrated for quantitative detection of cytomegalovirus in clinical whole blood extracts using a wide variety of real-time PCR chemistries

High rates of early treatment discontinuation in hepatitis C-infected US veterans

BACKGROUND: Patients with chronic hepatitis C (HCV) frequently discontinued dual therapy with pegylated interferon alfa (Peg-IFN) plus ribavirin (RBV) before reaching the recommended duration of 48 or 24 weeks for genotypes (G) 1/4 or 2/3, respectively. We quantified rates of discontinuation despite efficacy (non-LOE) versus lack of efficacy (LOE) versus discontinuation for unknown reasons in a national database of United States veterans. METHODS: We identified a population-based cohort of U.S. veterans with encounters from 2004 through 2009 who had lab-confirmed HCV infection and initiated therapy with Peg-IFN plus RBV in Veterans Health Administration medical centers. Pharmacy data were used to determine therapy duration, defined as the sum of Peg-IFN days supplied. Patients “discontinued” if they failed to receive at least 44 (G1/4) or 20 weeks (G2/3) of therapy. We classified discontinuations as due to non-LOE, LOE, or unknown reasons using a classification rule based on treatment duration and laboratory confirmed response. RESULTS: Of 321,238 diagnosed HCV patients during the evaluation period, 9.7% initiated therapy and 6.4% met all other inclusion criteria. 54.9% of patients discontinued early; of these, 41.2% discontinued due to non-LOE reasons, 12.5% discontinued for LOE reasons, and 46.3% discontinued for unknown reasons. Among non-LOE discontinuers, most (60.1%) discontinued in the first 4 weeks of therapy, which constitutes 13.6% of all treated patients. CONCLUSIONS: We observed a high proportion of early discontinuations with dual-therapy regimens in a national cohort of HCV-infected veterans. If this trend persists in the triple-therapy era, then efforts must be undertaken to improve adherence