23 research outputs found

    Selective blockade of interferon-α and -β reveals their non-redundant functions in a mouse model of West Nile virus infection

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    Although type I interferons (IFNs) were first described almost 60 years ago, the ability to monitor and modulate the functional activities of the individual IFN subtypes that comprise this family has been hindered by a lack of reagents. The major type I IFNs, IFN-β and the multiple subtypes of IFN-α, are expressed widely and induce their effects on cells by interacting with a shared heterodimeric receptor (IFNAR). In the mouse, the physiologic actions of IFN-α and IFN-β have been defined using polyclonal anti-type I IFN sera, by targeting IFNAR using monoclonal antibodies or knockout mice, or using Ifnb-/- mice. However, the corresponding analysis of IFN-α has been difficult because of its polygenic nature. Herein, we describe two monoclonal antibodies (mAbs) that differentially neutralize murine IFN-β or multiple subtypes of murine IFN-α. Using these mAbs, we distinguish specific contributions of IFN-β versus IFN-α in restricting viral pathogenesis and identify IFN-α as the key mediator of the antiviral response in mice infected with West Nile virus. This study thus suggests the utility of these new reagents in dissecting the antiviral and immunomodulatory roles of IFN-β versus IFN-α in murine models of infection, immunity, and autoimmunity

    Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cε

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    Mice lacking protein kinase Cε (PKCε) are supersensitive to positive allosteric modulators of gamma aminobutyrate type A (GABA(A)) receptors. Since many of these compounds are anxiolytic, we examined whether anxiety-like behavior is altered in these mice. PKCε-null mice showed reduced anxiety-like behavior and reduced levels of the stress hormones corticosterone and adrenocorticotrophic hormone (ACTH). This was associated with increased sensitivity to neurosteroid modulators of GABA(A) receptors. Treatment of PKCε-null mice with the GABA(A) receptor antagonist bicuculline restored corticosterone levels and anxiety-like behavior to wild-type levels. These results suggest that increased GABA(A) receptor sensitivity to neurosteroids contributes to reduced anxiety-like behavior and stress hormone responses in PKCε-null mice. The findings also suggest PKCε as a possible therapeutic target for development of anxiolytics

    Embracing cultural diversity – Leadership perspectives on championing meaningful engagement for residents living with advanced dementia

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    Resource constraints and high staff turnover are perceived as substantial barriers to high quality residential aged care. Achieving relationship-focused, person-centered care (PCC) is an ongoing challenge. This paper reports on an international project that explored how residential care leadership understand meaningful engagement for residents with dementia from culturally and linguistically diverse (CALD) backgrounds. This paper critically appraises the process, and outcomes, of an adapted Delphi method. Participants were the residential care leadership (i.e. staff in supervisory capacity) from four international facilities. Participation in the Delphi process was limited even though surveys were designed to require minimal time for completion. No participants opted for the alternative option of being interviewed. Findings indicate that residential care leadership recognised the importance of meaningful engagement for residents from CALD backgrounds. Limitations of time, resources and policy infrastructure were cited as barriers to achieving PCC. These findings suggest that facility leadership understand the importance of PCC, but identify multiple barriers rather than enablers for delivering PCC. Alternative methods, such as collecting data in interactive sessions allowing real-time discussion should be initiated to more effectively engage residential care leaders for a collaborative approach to explore PCC practices

    Novel Gene Expression Profile of Women with Intrinsic Skin Youthfulness by Whole Transcriptome Sequencing

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    <div><p>While much is known about genes that promote aging, little is known about genes that protect against or prevent aging, particularly in human skin. The main objective of this study was to perform an unbiased, whole transcriptome search for genes that associate with intrinsic skin youthfulness. To accomplish this, healthy women (n = 122) of European descent, ages 18–89 years with Fitzpatrick skin type I/II were examined for facial skin aging parameters and clinical covariates, including smoking and ultraviolet exposure. Skin youthfulness was defined as the top 10% of individuals whose assessed skin aging features were most discrepant with their chronological ages. Skin biopsies from sun-protected inner arm were subjected to 3’-end sequencing for expression quantification, with results verified by quantitative reverse transcriptase-polymerase chain reaction. Unbiased clustering revealed gene expression signatures characteristic of older women with skin youthfulness (n = 12) compared to older women without skin youthfulness (n = 33), after accounting for gene expression changes associated with chronological age alone. Gene set analysis was performed using Genomica open-access software. This study identified a novel set of candidate skin youthfulness genes demonstrating differences between SY and non-SY group, including pleckstrin homology like domain family A member 1 (PHLDA1) (p = 2.4x10<sup>-5</sup>), a follicle stem cell marker, and hyaluronan synthase 2-anti-sense 1 (HAS2-AS1) (p = 0.00105), a non-coding RNA that is part of the hyaluronan synthesis pathway. We show that immunologic gene sets are the most significantly altered in skin youthfulness (with the most significant gene set p = 2.4x10<sup>-5</sup>), suggesting the immune system plays an important role in skin youthfulness, a finding that has not previously been recognized. These results are a valuable resource from which multiple future studies may be undertaken to better understand the mechanisms that promote skin youthfulness in humans.</p></div

    HAS2-AS1 expression is decreased in SY and increases with increasing HAS2 transcript level.

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    <p>(A) Expression difference of HAS2-AS1 between SY group (n = 12) and no-SY (n = 33) group by 3’seq, p = 0.00105. (B) By RT-PCR, expression of HAS2-AS1 was decreased in SY group (n = 10), with trend toward statistical significance, p = 0.09067. (C) Scatterplot of HAS2-AS1 expression in SY individuals (yellow dots) shows this decreased expression of HAS2-AS1 occurs across different chronological ages. (d) In general, there is a positive correlation between HAS2-AS1 and HAS2 levels among all patients (n = 45), correlation coefficient (R) = 0.49, p = 0.00063.</p
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