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Search Results: 1 - 10 of 471259 matches for " Stephen A. Stohlman "
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Intrathecal Humoral Immunity to Encephalitic RNA Viruses
Timothy W. Phares,Stephen A. Stohlman,Cornelia C. Bergmann
Viruses , 2013, DOI: 10.3390/v5020732
Abstract: The nervous system is the target for acute encephalitic viral infections, as well as a reservoir for persisting viruses. Intrathecal antibody (Ab) synthesis is well documented in humans afflicted by infections associated with neurological complications, as well as the demyelinating disease, multiple sclerosis. This review focuses on the origin, recruitment, maintenance, and biological relevance of Ab-secreting cells (ASC) found in the central nervous system (CNS) following experimental neurotropic RNA virus infections. We will summarize evidence for a highly dynamic, evolving humoral response characterized by temporal alterations in B cell subsets, proliferation, and differentiation. Overall local Ab plays a beneficial role via complement-independent control of virus replication, although cross or self-reactive Ab to CNS antigens may contribute to immune-mediated pathogenesis during some infections. Importantly, protective Ab exert anti-viral activity not only by direct neutralization, but also by binding to cell surface-expressed viral glycoproteins. Ab engagement of viral glycoproteins blocks budding and mediates intracellular signaling leading to restored homeostatic and innate functions. The sustained Ab production by local ASC, as well as chemokines and cytokines associated with ASC recruitment and retention, are highlighted as critical components of immune control.
Enhanced CD8 T-cell anti-viral function and clinical disease in B7-H1-deficient mice requires CD4 T cells during encephalomyelitis
Phares Timothy W,Stohlman Stephen A,Hinton David R,Bergmann Cornelia C
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-269
Abstract: Background Anti-viral CD8 T-cell activity is enhanced and prolonged by CD4 T-cell-mediated help, but negatively regulated by inhibitory B7-H1 interactions. During viral encephalomyelitis, the absence of CD4 T cells decreases CD8 T cell activity and impedes viral control in the central nervous system (CNS). By contrast, the absence of B7-H1 enhances CD8 T-cell function and accelerates viral control, but increases morbidity. However, the relative contribution of CD4 T cells to CD8 function in the CNS, in the absence of B7-H1, remains unclear. Methods Wild-type (WT) and B7-H1 / mice were infected with a gliatropic coronavirus and CD4 T cells depleted to specifically block T helper function in the CNS. Flow cytometry and gene expression analysis of purified T-cell populations from lymph nodes and the CNS was used to directly monitor ex vivo T-cell effector function. The biological affects of altered T-cell responses were evaluated by analysis of viral control and spinal-cord pathology. Results Increased anti-viral activity by CD8 T cells in the CNS of B7-H1 / mice was lost upon depletion of CD4 T cells; however, despite concomitant loss of viral control, the clinical disease was less severe. CD4 depletion in B7-H1 / mice also decreased inducible nitric oxide synthase expression by microglia and macrophages, consistent with decreased microglia/macrophage activation and reduced interferon (IFN)-γ. Enhanced production of IFN-γ, interleukin (IL)-10 and IL-21 mRNA was seen in CD4 T cells from infected B7-H1 / compared with WT mice, suggesting that over-activated CD4 T cells primarily contribute to the increased pathology. Conclusions The local requirement of CD4 T-cell help for CD8 T-cell function is not overcome if B7-H1 inhibitory signals are lost. Moreover, the increased effector activity by CD8 T cells in the CNS of B7-H1 / mice is attributable not only to the absence of B7-H1 upregulation on major histocompatibility complex class I-presenting resident target cells, but also to enhanced local CD4 T-cell function. B7-H1-mediated restraint of CD4 T-cell activity is thus crucial to dampen both CD8 T-cell function and microglia/macrophage activation, thereby providing protection from T-cell-mediated bystander damage.
IFN-γ protects from lethal IL-17 mediated viral encephalomyelitis independent of neutrophils
Carine Savarin, Stephen A Stohlman, David R Hinton, Richard M Ransohoff, Daniel J Cua, Cornelia C Bergmann
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-104
Abstract: Encephalitis induced by a gliatropic murine coronavirus was used as a model to assess the direct contributions of neutrophils, IFN-γ and IL-17 to virus-induced mortality. CNS inflammatory conditions were selectively manipulated by adoptive transfer of virus-primed wild-type (WT) or IFN-γ deficient (GKO) memory CD4+ T cells into infected SCID mice, coupled with antibody-mediated neutrophil depletion and cytokine blockade.Transfer of GKO memory CD4+ T cells into infected SCID mice induced rapid mortality compared to recipients of WT memory CD4+ T cells, despite similar virus control and demyelination. In contrast to recipients of WT CD4+ T cells, extensive neutrophil infiltration and IL-17 expression within the CNS in recipients of GKO CD4+ T cells provided a model to directly assess their contribution(s) to disease. Recipients of WT CD4+ T cells depleted of IFN-γ did not express IL-17 and were spared from mortality despite abundant CNS neutrophil infiltration, indicating that mortality was not mediated by excessive CNS neutrophil accumulation. By contrast, IL-17 depletion rescued recipients of GKO CD4+ T cells from rapid mortality without diminishing neutrophils or reducing GM-CSF, associated with pathogenic Th17 cells in CNS autoimmune models. Furthermore, co-transfer of WT and GKO CD4+ T cells prolonged survival in an IFN-γ dependent manner, although IL-17 transcription was not reduced.These data demonstrate that IL-17 mediates detrimental clinical consequences in an IFN-γ-deprived environment, independent of extensive neutrophil accumulation or GM-CSF upregulation. The results also suggest that IFN-γ overrides the detrimental IL-17 effector responses via a mechanism downstream of transcriptional regulation.
RNase L Mediated Protection from Virus Induced Demyelination
Derek D. C. Ireland,Stephen A. Stohlman,David R. Hinton,Parul Kapil,Robert H. Silverman,Roscoe A. Atkinson,Cornelia C. Bergmann
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000602
Abstract: IFN-α/β plays a critical role in limiting viral spread, restricting viral tropism and protecting mice from neurotropic coronavirus infection. However, the IFN-α/β dependent mechanisms underlying innate anti-viral functions within the CNS are poorly understood. The role of RNase L in viral encephalomyelitis was explored based on its functions in inhibiting translation, inducing apoptosis, and propagating the IFN-α/β pathway through RNA degradation intermediates. Infection of RNase L deficient (RL?/?) mice with a sub-lethal, demyelinating mouse hepatitis virus variant revealed that the majority of mice succumbed to infection by day 12 p.i. However, RNase L deficiency did not affect overall control of infectious virus, or diminish IFN-α/β expression in the CNS. Furthermore, increased morbidity and mortality could not be attributed to altered proinflammatory signals or composition of cells infiltrating the CNS. The unique phenotype of infected RL?/? mice was rather manifested in earlier onset and increased severity of demyelination and axonal damage in brain stem and spinal cord without evidence for enhanced neuronal infection. Increased tissue damage coincided with sustained brain stem infection, foci of microglia infection in grey matter, and increased apoptotic cells. These data demonstrate a novel protective role for RNase L in viral induced CNS encephalomyelitis, which is not reflected in overall viral control or propagation of IFN-α/β mediated signals. Protective function is rather associated with cell type specific and regional restriction of viral replication in grey matter and ameliorated neurodegeneration and demyelination.
IFN-γ Signaling to Astrocytes Protects from Autoimmune Mediated Neurological Disability
Claudia Hindinger, Cornelia C. Bergmann, David R. Hinton, Timothy W. Phares, Gabriel I. Parra, Shabbir Hussain, Carine Savarin, Roscoe D. Atkinson, Stephen A. Stohlman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042088
Abstract: Demyelination and axonal degeneration are determinants of progressive neurological disability in patients with multiple sclerosis (MS). Cells resident within the central nervous system (CNS) are active participants in development, progression and subsequent control of autoimmune disease; however, their individual contributions are not well understood. Astrocytes, the most abundant CNS cell type, are highly sensitive to environmental cues and are implicated in both detrimental and protective outcomes during autoimmune demyelination. Experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice expressing signaling defective dominant-negative interferon gamma (IFN-γ) receptors on astrocytes to determine the influence of inflammation on astrocyte activity. Inhibition of IFN-γ signaling to astrocytes did not influence disease incidence, onset, initial progression of symptoms, blood brain barrier (BBB) integrity or the composition of the acute CNS inflammatory response. Nevertheless, increased demyelination at peak acute disease in the absence of IFN-γ signaling to astrocytes correlated with sustained clinical symptoms. Following peak disease, diminished clinical remission, increased mortality and sustained astrocyte activation within the gray matter demonstrate a critical role of IFN-γ signaling to astrocytes in neuroprotection. Diminished disease remission was associated with escalating demyelination, axonal degeneration and sustained inflammation. The CNS infiltrating leukocyte composition was not altered; however, decreased IL-10 and IL-27 correlated with sustained disease. These data indicate that astrocytes play a critical role in limiting CNS autoimmune disease dependent upon a neuroprotective signaling pathway mediated by engagement of IFN-γ receptors.
Interferon-Induced Ifit2/ISG54 Protects Mice from Lethal VSV Neuropathogenesis
Volker Fensterl,Jaime L. Wetzel,Srividya Ramachandran,Tomoaki Ogino,Stephen A. Stohlman,Cornelia C. Bergmann,Michael S. Diamond,Herbert W. Virgin,Ganes C. Sen
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002712
Abstract: 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.
Culture and Organizational Improvisation in UK Financial Services  [PDF]
Stephen A. Leybourne
Journal of Service Science and Management (JSSM) , 2009, DOI: 10.4236/jssm.2009.24029
Abstract: This paper considers certain aspects of a four-year program of research, and addresses the changing cultural requirements to support the rise of improvisational working practices within the UK financial services sector. Specifically, it reports on some of the outcomes of a study encompassing over 100 hours of interviews, together with a variety of other primary and secondary data. The outcomes of the full study are documented elsewhere, and they identify a number of key factors that contribute to the successful use and control of improvisational working practices. One of these factors is a supportive organizational culture, and this specific area is dealt with in this paper. A particular focus is how the sample of organizations has attempted to identify and create supportive cultural conditions for improvisational work to take place. In order to bring clarity to the outcomes of this study, a matrix of the case study organizations is also offered, which segregates those organizations according to their cultural support for improvisation and apparent improvisation effectiveness. Some comment on the current difficulties in the Financial Services sector has also been included, as it could be argued that improvisation may have contributed to shortcomings in control processes by members of that sector.
Forest Response to the US 1990 Clean Air Act: The Southern Spruce-Fir Ecosystem  [PDF]
Stephen A. Banks
American Journal of Plant Sciences (AJPS) , 2014, DOI: 10.4236/ajps.2014.53050
Abstract:


The history of the Black Mountains in North Carolina and the southern Spruce-Fir ecosystem has been fraught with widespread forest decline since the mid 1960’s. Balsam Woolly Adelgid attacks and acidic deposition were two of the most recognized causes of decline. Uncertainty arose about the future of these forests, and projections were made regarding the endangerment or extinction of the endemic Fraser fir ([Pursh] Poiret). This study analyzed data sets from a permanent plot network in the Black Mountains dating 1985, 2002, and 2012. Indications that the Fraser fir population is stabilizing from a “boom-bust” cycle of population growth and has entered the stem exclusion stage of forest stand development are evident. Fir live stem density increased more than 250% from 1985 to 2002, and then declined 40% by 2012 at the highest elevations in the forest. Overall, fir appeared to be more impacted on western facing slopes than eastern ones. The population of red spruce experienced a steady decrease in live stem counts, but an increase in live basal area through all years, and at all elevation classes (1675 m, 1830 m, and 1980 m), indicating a normal progression through stand development. Red spruce was also most negatively impacted on western facing slopes. Live stem density was significantly higher (P < 0.001) than eastern plots, but live basal area was similar between the two aspects. Atmospheric deposition concentrations of the four main acidic molecules at Mt. Mitchell all peaked in 1998, but decreased by 2012. These reductions, occurring shortly after tightened regulations in the 1990 amendments to the Clean Air Act may have potential implications for increased forest resilience.


Life Cycle Assessment of CCA-Treated Wood Highway Guard Rail Posts in the US with Comparisons to Galvanized Steel Guard Rail Posts  [PDF]
Christopher A. Bolin, Stephen T. Smith
Journal of Transportation Technologies (JTTs) , 2013, DOI: 10.4236/jtts.2013.31007
Abstract:

A cradle-to-grave life cycle assessment is done to identify the environmental impacts of chromated copper arsenate (CCA)-treated timber used for highway guard rail posts, to understand the processes that contribute to the total impacts, and to determine how the impacts compare to the primary alternative product, galvanized steel posts. Guard rail posts are the supporting structures for highway guard rails. Transportation engineers, as well as public and regulatory interests, have increasing need to understand the environmental implications of guard rail post selection, in addition to factors such as costs and service performance. This study uses a life cycle inventory (LCI) to catalogue the input and output data from guard rail post manufacture, service life, and disposition, and a life cycle impact assessment (LCIA) to assess anthropogenic and net greenhouse gas (GHG), acidification, smog, ecotoxicity, and eutrophication potentially resulting from life cycle air emissions. Other indicators of interest also are tracked, such as fossil fuel and water use. Comparisons of guard rail post products are made at a functional unit of one post per year of service. This life cycle assessment (LCA) finds that the manufacture, use, and disposition of CCA-treated wood guard rails offers lower fossil fuel use and lower anthropogenic and net GHG emissions, acidification, smog potential, and ecotoxicity environmental impacts than impact indicator values for galvanized steel posts. Water use and eutrophication impact indicator values for CCA-treated guard rail posts are greater than impact indicator values for galvanized steel guard rail posts.

Life Cycle Assessment of Creosote-Treated Wooden Railroad Crossties in the US with Comparisons to Concrete and Plastic Composite Railroad Crossties  [PDF]
Christopher A. Bolin, Stephen T. Smith
Journal of Transportation Technologies (JTTs) , 2013, DOI: 10.4236/jtts.2013.32015
Abstract:

Creosote-treated wooden railroad crossties have been used for more than a century to support steel rails and to transfer load from the rails to the underlying ballast while keeping the rails at the correct gauge. As transportation engineers look for improved service life and environmental performance in railway systems, alternatives to the creosote-treated wooden crosstie are being considered. This paper compares the cradle-to-grave environmental life cycle assessment (LCA) results of creosote-treated wooden railroad crossties with the primary alternative products: concrete and plastic composite (P/C) crossties. This LCA includes a life cycle inventory (LCI) to catalogue the input and output data from crosstie manufacture, service life, and disposition, and a life cycle impact assessment (LCIA) to evaluate greenhouse gas (GHG) emissions, fossil fuel and water use, and emissions with the potential to cause acidification, smog, ecotoxicity, and eutrophication. Comparisons of the products are made at a functional unit of 1.61 kilometers (1.0 mile) of rail-road track per year. This LCA finds that the manufacture, use, and disposition of creosote-treated wooden railroad crossties offers lower fossil fuel and water use and lesser environmental impacts than competing products manufactured of concrete and P/C.

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